WO2017084680A1

WO2017084680A1 - Pharmaceutical composition containing a non-steroidal antiinflammatory drug and a proton pump inhibitor

Info

Publication number: WO2017084680A1
Application number: PCT/EP2015/002291
Authority: WO
Inventors: Agni GRYPIOTI; Panagiotis BARMPALEXIS
Original assignee: Pharos Ltd; Rontis Hellas SA
Current assignee: Pharos Ltd; Rontis Hellas SA
Priority date: 2015-11-17
Filing date: 2015-11-17
Publication date: 2017-05-26
Anticipated expiration: 2018-05-17
Also published as: EP3377046A1

Abstract

The present invention relates to a stable pharmaceutical composition comprising a therapeutically effective quantity of a NSAID having a pulsatile release profile, such as Diclofenac or a pharmaceutically acceptable salt, prodrug, or derivative thereof, and a therapeutically effective quantity of a PPI, such as Esomeprazole or a pharmaceutically acceptable salt, prodrug, or derivative thereof, in a multi-unit dosage combination, and a process for the preparation thereof.

Description

PHARMACEUTICAL COMPOSITION CONTAINING A NON-STEROIDAL

ANTIINFLAMMATORY DRUG AND A PROTON PUMP INHIBITOR TECHNICAL FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition for oral administration comprising a therapeutically effective quantity of a non-steroidal anti-inflammatory drug (NSAID), such as Diclofenac or a pharmaceutically acceptable salt, prodrug, or derivative thereof, having a pulsatile release profile, in combination with a therapeutically effective quantity of a proton pump inhibitor (PPI), such as Esomeprazole or a pharmaceutically acceptable salt, prodrug, or derivative thereof in one fixed unit dosage form in order to improve patient compliance and a process for the preparation thereof. BACKGROUND OF THE INVENTION

Diclofenac is a non-steroidal anti-inflammatory drug (NSAID) used for the treatment of mild or moderate pain and inflammation in wide range of conditions, including: (i) arthritic conditions: rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gout; (ii) acute musculoskeletal disorders such as periarthritis (for example frozen shoulder), tendinitis, tenosynovitis, bursitis; and (iii) other painful conditions resulting from trauma, including fracture, low back pain, sprains, strains, dislocations, orthopedic, dental and other minor surgery.

Diclofenac's chemical name is 2-(2,6-dichloranilino) phenylacetic acid and its chemical structure is presented by the following Formula I.

Formula I

Although Diclofenac has highly effective pain relieving properties, it may cause gastroduodenal (GD) ulceration and bleeding and abnormal elevation of liver enzymes, which are undesirable effects, especially when it has to be administered for long period of time.

Based on the pharmacological properties of Diclofenac, it can be used either in short-term treatment of acute musculoskeletal injury, acute shoulder pain, postoperative pain and dysmenorrhea, or in long-term treatments, such as rheumatoid arthritis, osteoarthritis etc., while regarding its posology, Diclofenac is usually administrated orally in adults at 75 to 150 mg daily in two or three divided doses depending on the condition.

Moreover, it is well known that patients with chronic inflammatory diseases, which are mainly treated with NSAIDs such as Diclofenac, exhibit among others circadian rhythms, as disease related symptoms. This, for example, has been studied in patients with rheumatoid arthritis (RA) and revealed that these patients, except the "within the day pain", also experience intense joint pain, stiffness, and functional disability in the early morning hours [see in "Circadian Rhythms in Rheumatoid Arthritis Implications for Pathophysiology and Therapeutic Management"; ARTHRITIS & RHEUMATISM, Vol. 56, No. 2, February 2007, pp 399^108].

In order to eliminate this chrono-therapeutic behavior, a pulsatile formulation has been proposed, that releases an adequate quantity of the active ingredient API initially as immediate release, followed by an extended release treatment. In this approaches, an initial dose of the API is being released from a delayed-release (gastro-protective) formulation (in order to overcome some of diclofenac induced GD adverse-effects) while the rest of the dose is being administrated in an extended-release way. Although gastro-protection of the API may lead to a reduction of the GD adverse-effects, this is not enough, as the NSAID GD ulceration and bleeding are caused from both topical irritation and API systematic exposure [see in "How do NSAIDs cause ulcer disease" Bailliere's Clinical Gastroenterology; Vol. 14, No. 1, pp. 147-159, 2000]. In order to overcome all these issues, a combination of a pulsatile formulation of a NSAID, such as Diclofenac, and a proton pump inhibitor (PPI), has been proposed.

It is well known that proton pump inhibitors are used for the prevention and treatment of gastric acid related diseases including, but not limited to, reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. The proton pump inhibitors may also be used for the treatment of acute gastroduodenal ulceration bleeding and other gastrointestinal disorders, and in particular in patients on NSAID therapy. Esomeprazole is a proton pump inhibitor used for the treatment of gastroesophageal reflux disease, Helicobacter pylori (in combination with appropriate antibacterial therapeutic regimens), and Zollinger Ellison Syndrome. Esomeprazole is also used to patients requiring continued NSAID therapy for the treatment and prevention of gastric and duodenal ulcers. It is a weak base and is concentrated and converted to the active form in the highly acidic environment of the secretory canaliculi of the parietal cell, where it inhibits the enzyme H+K+-ATPase - the acid pump and inhibits both basal and stimulated acid secretion. In patients requiring continued NSAID therapy, either for healing or preventing the formation of gastric and duodenal ulcers and bleeding, the usual dose of Esomeprazole is 20mg once daily. Esomeprazole' s chemical name is (S)-5-Methoxy-2-[[(4-methoxy-3,5-dimethyl-2- pyridinyl)methyl]sulfinyl]-benzimidazole and its chemical structure is presented by the following Formula II.

Formula II Esomeprazole is rapidly degraded in acidic media, but it has acceptable stability under alkaline conditions. At pH 6.8, the half-life of the magnesium salt (commonly used for oral administration) is about 19 hours at 25°C and about 8 hours at 37°C. Based on these instability problems, the orally administrated pharmaceutical dosage forms of Esomeprazole are generally formulated either in combination of alkaline agents or as delayed release (gastro-protective) formulations.

Various methods are already known for the industrial preparation of oral dosage forms comprising NSAID or a pharmaceutically acceptable salt, prodrug or derivative thereof and PPI or a pharmaceutically acceptable salt, prodrug or derivative thereof, used for the protection of NSAID GD induced ulcers and/or bleeding, in a fixed unit dosage form due to their useful therapeutical properties and patient compliance reasons. However, the prior art has never attempted to combine a NSAID, such as Diclofenac, with a pulsatile release profile, targeting a special chronopharmacological effect, with a PPI. In addition, previous attempts encountered substantial difficulties in the production of a stable composition due to the fact that Esomeprazole is susceptible to acid degradation and should be protected from contact with the acidic gastric fluid.

EP-B-0 814 839 discloses a multiple unit tableted dosage form comprising an acid susceptible proton pump inhibitor (such as S-omeprazole magnesium) in form of individually enteric coating layered pellets compressed together with at least one immediate release NSAID and optionally pharmaceutically acceptable excipients, wherein the enteric coating layer covering the individual pellets comprises a plasticizer and has mechanical properties such that the tableting of the pellets together with the NSAID comprising granules and optionally pharmaceutically acceptable excipients does not significantly affect the acid resistance of the individually enteric coating layered pellets. Further, the tableted dosage form comprises two separate layers, one layer comprising PPI in the form of enteric coating layered pellets compressed with tablet excipients into a layer, and the other layer gives an extended release of NSAID.

WO-A-02/22108 discloses a multi-layer tablet comprising an extended release inner core of a NSAID, such as aspirin or naproxen, that is seal-coated, an immediate release coating of a PPI and an externally, enteric coating. Although each of the above patents represents an attempt to overcome the stability problems associated with pharmaceutical compositions comprising PPI and NSAID, and the adverse effects of NSAID induced GD ulcers and/or bleeding, with the use of a PPI in a combination therapy, there still exists a need for improving the stability and adverse effects of such pharmaceutical compositions in a less complicated production approach.

SUMMARY OF THE INVENTION

It is, therefore, an object of the present invention to provide a pharmaceutical composition for oral administration comprising Diclofenac or a pharmaceutically acceptable salt, prodrug, or derivative thereof, and Esomeprazole or a pharmaceutically acceptable salt, prodrug, or derivative thereof, with enhanced stability which overcomes the deficiencies of the prior art. Still, it is another object of the present invention to provide a pharmaceutical composition for oral administration comprising Diclofenac or a pharmaceutically acceptable salt, prodrug, or derivative thereof, and Esomeprazole or a pharmaceutically acceptable salt, prodrug, or derivative thereof, with improved physicochemical characteristics, better dose and patience compliance.

Moreover, it is another object of the present invention to provide a suitable process for the preparation of a stable pharmaceutical composition for oral administration comprising a therapeutically effective quantity of diclofenac or a pharmaceutically acceptable salt, prodrug, or derivative thereof, and Esomeprazole or a pharmaceutically acceptable salt, prodrug, or derivative thereof, which is cost effective and reproducible.

In accordance with the above objects of the present invention, a pharmaceutical composition for oral administration is provided comprising a therapeutically effective quantity of diclofenac or a pharmaceutically acceptable salt, prodrug, or derivative thereof, and Esomeprazole or a pharmaceutically acceptable salt, prodrug, or derivative thereof, wherein said diclofenac or pharmaceutically acceptable salt, prodrug, or derivative thereof has a pulsatile release profile and the weight ratio of Diclofenac to Esomeprazole is from about 1 : 0.2 to 1 : 0.6 in order to improve the stability of the composition and provide better dose and patience compliance.

Still, according to another embodiment of the present invention, the pharmaceutical composition for oral administration comprises Diclofenac having a pulsatile release profile, where one portion of Diclofenac is in form of extended release beads/spheres and another portion in form of delayed release - enteric coated beads/spheres, and Esomeprazole in form of delayed release - enteric coated beads/spheres.

According to another embodiment, the present invention provides a process for the preparation of a stable pharmaceutical composition for oral administration comprising a therapeutically effective quantity of Diclofenac or a pharmaceutically acceptable salt, prodrug, or derivative thereof, and Esomeprazole or a pharmaceutically acceptable salt, prodrug, or derivative thereof, wherein said diclofenac or pharmaceutically acceptable salt, prodrug, or derivative thereof has a pulsatile release profile and the weight ratio of Diclofenac to Esomeprazole is from about 1 :0.2 to about 1:0.6 in order to improve the stability of the composition and provide better dose and patience compliance, which process comprises preparation of one portion of diclofenac in extended release form and another portion of Diclofenac in delayed release - enteric coated form, and preparation of Esomeprazole in delayed release - enteric coated form, and optionally all said forms are filled into a capsule.

Further preferred embodiments of the present invention are defined in dependent claims 2 to 7 and 9 to 12.

Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows SEM photos of pellets and cross-section thereof according to composition 1 (Al and A2) and Composition 2 (Bl and B2) of the present invention. Fig. 2 shows SEM photos of enteric-coated pellets and cross-section thereof according to Composition 1 (CI and C2) and Composition 2 (Dl and D2) of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

For the purposes of the present invention, the term "pharmaceutically acceptable salt" refers to a salt that is not toxic at the specific therapeutic dosage and a salt that does not independently possess significant pharmacological activity.

The present invention is directed towards pharmaceutical compositions comprising a combination of therapeutically effective amount of a NSAID and a proton pump inhibitor wherein the PPI is capable of protecting the patients from NSAID GD induced ulcers and bleeding. In preferred embodiment, a pharmaceutical composition is unit dosage form suitable for oral administration to a patient.

The term "unit dosage form" as used herein refers to a single entity for drug administration. For example, a single capsule combining both a PPI and a NSAID would be a unit dosage form.

A "therapeutically effective amount" of NSAIDs comprises but is not limited to an amount effective to reduce or eliminate pain or inflammation, which is safe and well tolerated in patients with acceptable adverse effect profiles. A "therapeutically effective amount" of PPI comprises but is not limited to an amount capable of raising the pH of the GI tract of patients.

The amount of NSAID, which is therapeutically effective, may be different in the present invention than otherwise found in practice due to the pulsatile release characteristics of the present formulation.

PPI and NSAID will include all common forms of these compounds and, in particular, their pharmaceutically acceptable salt(s) or enantiomer(s) or polymorph(s) thereof.

Although the pharmaceutical composition may be in various dosage forms, the preferred solid dosage form is multi-unit dosage form in capsules.

As already mentioned the combination of NSAID and PPI, in particular Esomeprazole in a fixed composition encounters stability issues and said tendency gets stronger when they are formulated and mixed with excipients or other active substances.

It has been surprisingly found that the object of the present invention is achieved by employing a therapeutically effective quantity of Diclofenac or a pharmaceutically acceptable salt, prodrug, or derivative thereof, and Esomeprazole or a pharmaceutically acceptable salt, prodrug, or derivative thereof, wherein said diclofenac has a pulsatile release profile and the weight ratio between diclofenac and Esomeprazole is from about 1: 0.2 to 1: 0.6 in order to improve the stability of the composition and provide better dose and patience compliance.

Further, it has been found that the stability of the pharmaceutical composition in multi-unit particulate system form containing diclofenac having pulsatile release characteristics and esomeprazole can be significantly improved when part of the diclofenac or a pharmaceutically acceptable salt, prodrug, or derivative thereof is administrated as delayed release - enteric coated pellets, while the remaining part is administrated as extended release formulation. Moreover, according to the present invention, it has been found by administering an initial dose of Diclofenac released from a delayed-release (gastro-protective) formulation, it is achieved to overcome some of Diclofenac's induced GD adverse-effects, while the remaining dose is being administrated in an extended-release way. Although this gastro-protection of diclofenac may lead to a reduction of the GD adverse-effects, this is not enough, as diclofenac gastroduodenal ulceration and bleeding are caused from both topical irritation and active ingredient systematic exposure. In order to overcome this GD adverse-effects of diclofenac, a fixed-combination of a Diclofenac pulsatile formulation, and a PPI is being proposed.

The present invention is further directed to a dosage form comprising a therapeutically effective amount of diclofenac having pulsatile release characteristics and an amount of a PPI effective to substantially inhibit GD side effects of the NSAID, wherein said PPI is coated with a material suitable to prevent contact of said PPI with acidic gastric juice (e.g. an enteric coating).

PPIs are known to be highly acid labile, and therefore it is preferred that the PPI contained in the dosage form of the present invention be protected from contact with acidic gastric juice.

The esomeprazole included in the dosage form of the invention is protected from contact with acidic gastric juice, so that it may reach the gastrointestinal tract, where the pH is near neutral, without exposure to gastric fluid.

It is well known, that PPIs are susceptible to degradation and/or transformation in acidic and neutral media.

The degradation of PPIs is catalyzed by acidic compounds and is stabilized in mixtures with alkaline compounds. The stability of this class of compounds is also affected by moisture, heat, aqueous or non-aqueous solvents and to some degree by light. Thus, with regards to the stability properties of the PPIs, it is preferred that in an oral solid dosage form said PPIs to be protected from contact with the acidic gastric juice.

Accordingly, in order to obtain a pharmaceutical dosage form of esomeprazole, wherein esomeprazole is prevented from contact with acidic gastric juice, the multi-unit form of the active ingredient must be enteric coated. However, ordinary enteric coatings are made of acidic compounds. If esomeprazole is covered with such a conventional enteric coating, it will be rapidly decomposed by direct or indirect contact with the coating material, resulting in badly discolored preparations and reduced esomeprazole content during storage.

According to another embodiment of the present invention, in order to enhance the long-term storage stability of esomeprazole, a subcoat comprising pharmaceutical excipients, which are soluble or rapidly disintegrating in water or polymeric, water soluble, film-forming compounds, is being used. This inner subcoat, separates the esomeprazole core from an outer enteric coating layer.

Furthermore, except the long term stability problems arising in esomeprazole finished dosage form, it is well known that there are several manufacturing processes during production of esomeprazole products, which lead to instability/degradation problems. The most common issue is related with the exposure of the API to aqueous or non-aqueous carriers. In order to overcome this problem, most of the prior art documents suggest esomeprazole formulations using techniques which require limited exposure/contact of the PPI with these solvents, such as of mini-tablets or extrusion/spheronization pellets. In the present invention, in order to overcome this "in-process" degradation of esomeprazole during the production of the finished dosage form, a suspension of the API along with suitable pharmaceutical excipients is spayed on non-pareil seeds, such as sugar, MicroCrystaline Cellulose (MCC) and isomalt spheres or is spray granulated along with suitable excipients.

The Diclofenac extended release and delayed release -enteric coated granules or multi-dosage units, and the Esomeprazole delayed release - enteric coated multi-dosage units according to the present invention may be prepared by several ways, such as: a) process of drug-layering of the active ingredient on non-pareil seeds, such as spheres made of sugar, MCC, isomalt etc.; b) preparation of drug containing pellets by extrusion/speronization; c) preparation of mini-tablets; d) spray drying and spray congealing process; e) cryopelletization process; f) melt spheronization process; g) spherical agglomeration (powder layering) process; and h) preparation of granules/blends with conventional wet granulation, dry granulation etc.

For the preparation of Diclofenac drug-layering units, the process is as follows: the API is initially dispersed/dissolved in a suitable aqueous or non-aqueous liquid along with suitable pharmaceutical excipients, such as viscosity increasing agents, surfactants, binders etc. and/or mixture thereof, and subsequently sprayed on non-pareil seeds, such as sugar, MCC, isomalt spheres etc. A portion of the drug loaded Diclofenac spheres is coated with suitable enteric coating agents, such as cellulose acetate phthalate, hypromellose acetate succinate, hypromellose phthalate, polymethacrylates, polyvinyl acetate phthalate and/or mixtures thereof. The remaining portion of the drug loaded Diclofenac spheres are coated with a suitable extended release agents, such as, polymethacrylates, HPMC, HEC, HPC, SCMC, PEO, xantham gum, sodium alginate, stearic acid, PVA/PVP, EC, waxes, lauryl, cetyl and cetostearyl alcohol, carbopol, carrageenan, chitosan, polycarbophil, agar and/or mixtures thereof. Optionally, all drug-layered Diclofenac pellets may be over-coated with suitable pharmaceutical excipients. For the preparation of Esomeprazole drug-layering units, the process is as follows: the API is initially dispersed/dissolved in a suitable aqueous or non-aqueous liquid along with suitable pharmaceutical excipients, such as viscosity increasing agents, surfactants, binders etc. and/or mixture thereof, and subsequently sprayed on non-pareil seeds, such as sugar, mcc, isomalt spheres etc. The drug loaded Esomeprazole pellets are sub-coated with suitable protective agents such as HPMC, HPC, HEC, PVA, PVP and/or mixture thereof. The above prepare pellets are coated with suitable enteric coating agents, such as cellulose acetate phthalate, hypromellose acetate succinate, hypromellose phthalate, polymethacrylates, polyvinyl acetate phthalate and/or mixture thereof. Optionally, the prepared Esomeprazole delayed release - enteric coated pellets are over-coated with suitable pharmaceutical excipients.

The Diclofenac / Esomeprazole fixed combination product may be in the form of hard or soft gelatin/hpmc capsules filled with pellets, or spheres or minitablets or granules/powder blends, tablets, sachets etc.

In a preferred embodiment the enteric-coated pellets of Esomeprazole of the multi-dosage units according to the present invention, can be mixed with the extended release diclofenac pellets and the enteric-coated Diclofenac pellets and filled into hard gelatin capsules. The pharmaceutical compositions of the present invention may also contain one or more additional formulation ingredients selected from a wide variety of excipients.

The pharmaceutically acceptable excipients used in the composition of the present invention shall be compatible with the NSAID and PPL

According to the desired properties of the composition, any number of ingredients may be selected, alone or in combination, based upon their known uses in preparation of solid oral dosage form compositions.

Such ingredients include, but are not limited to, fillers or diluents, binders, compression aids, disintegrants, surfactants, wetting agents, complexing agents, gelling agents, retarding agents, glidants, lubricants, flavours, water scavengers, colorants, sweetener, coating agents and preservatives.

The composition of the present invention may include further additives (alone or in a combination) such as absorbents, acids, adjuvants, anticaking agents, antitacking agents, antifoamers, anticoagulants, antimicrobials, antiseptics, chelating agents, sequestrants, dyes, pigments, softeners, crystal growth regulators, denaturants, desiccants, dehydrating agents, dispersants, solubilizers, emollients, emulsifiers, flavor masking agents, humectants, moisturizers, bufferants, pH control agents, plasticizers, stabilizers, suspending agents, thickening agents, opacifiers, coloring agents, preservatives, antigellants, rheology control agents, tonicifiers etc.

Pharmaceutically acceptable fillers or diluents may be selected from starch, microcrystalline cellulose, microcrystalline silicified cellulose, powdered cellulose, dicalcium phosphate, lactose anhydrous, lactose monohydrate, lactose dihydrate, lactose trihydrate, calcium carbonate, magnesium carbonate, calcium phosphate tribasic, calcium phosphate, dibasic sorbitol, mannitol, sucrose, dextrine, kaolin, magnesium oxide, calcium sulfate, xylitol, isomalt, glucose, fructose, maltose, acids like citric acid, tartaric acid, dextrates, dextrose, fructose, lactitol, pregelatinized starch, talc, xylitol, maltose, isomalt, maltodextrin, maltitol fumaric acid, co-polymers such as those from vinyl pyrrolidone and vinyl acetate or those of polyethylene glycol, and mixtures thereof. Preferred diluents are lactose monohydrate and microcrystalline cellulose.

Binders may be selected from acacia, alginic acid, carbomer, carboxymethylcellulose calcium, carbomethylcellulose sodium, microcrystalline cellulose, powdered cellulose, ethyl cellulose, gelatin liquid glucose, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, maltodextrin, methylcellulose, polydextrose, polyethylene oxide, povidone, sodium alginate, starch paste, pregelatinized starch, sucrose, tragacanth, low- substituted hydroxypropyl cellulose, glucose, sorbitol.

Disintegrants may be selected from alginic acid, carbon dioxide, carboxymethylcellulose calcium, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, croscarmelose sodium, crospovidone, sodium docusate, gaur gum, hydroxypropyl cellulose, methylcellulose, polacrilin potassium , poloxamer, povidone, sodium alginate, sodium glycine carbonate, sodium laulyl sulfate, sodium starch glycolate, starch, pregelatinized starch, low- substituted hydroxypropyl cellulose and the like.

Pharmaceutically acceptable lubricants may be selected from magnesium stearate, calcium stearate, stearic acid, stearic acid, glyceryl behenate, magnesium lauryl sulphate, talc, polyethylene glycol, hexanedioic acid, hygrogenated vegetable oil sodium stearyl fumarate and glycerine fumarate. Glidants may be selected from calcium silicate, powdered cellulose, starch, talc, colloidal silicon dioxide and the like.

Suitable sweeteners may be selected from sugars such as sucrose, lactose and glucose; cyclamate and salts thereof; saccharin and salts thereof; aspartame and the like.

Flavouring agents may be selected from natural or synthetic flavours such as strawberry flavour, wild cherry flavour, green apple flavour, spearmint flavor, peppermint flavor and the like.

Enteric coated agents may be selected from cellulose acetate phthalate, hypromellose acetate succinate, hypromellose phthalate, polymethacrylates, polyvinyl acetate phthalate and the like. Extended release agent may be selected from ethyl-cellulose, cellulose acetate, vinyl acetate/vinyl chloride copolymers, acrylate/methacrylate copolymers, polyethylene oxide, hydroxypropyl methylcellulose, carrageenan, alginic acid and salts thereof, hydroxyethyl cellulose, hydroxypropyl cellulose, karaya gum, acacia gum, tragacanth gum, locust bean gum, guar gum, sodium carboxymethyl cellulose, methyl cellulose, beeswax, carnauba wax, cetyl alcohol, hydrogenated vegetable oils, stearyl alcohol and the like.

According to the present invention the formulations with said diclofenac/esomeprazole dosage form improve patient compliance through an easily followed dosing regimen.

The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention.

EXAMPLES

Example 1 : Preparation of Diclofenac drug loaded pellets

Pellets of the compositions of Example 1 according to the present invention were prepared according to the following manufacturing process:

In Composition 1 and Composition 2 the active ingredient (Diclofenac sodium) is completely dissolved in a solution of hydroxypropylmethyl cellulose (HPMC) with EtOH and H₂0. Then, the formed solution of the active ingredient is sprayed on either microcrystalline cellulose MCC (Composition 1) or sugar spheres (Composition 2) using a fluid bed coater. The drug- layered pellets are dried and further used to prepare the enteric and extended release pellets. In Composition 3, the active ingredient is suspended in an aqueous solution of hydroxypropylmethyl cellulose (HPMC) and Tween™ 80 (Polysorbate 80) and sprayed on sugar spheres using a fluid bed coater. The drug-layered pellets are dried and are further used to prepare the enteric and extended release pellets.

The produced pellets were filled in hard gelatin capsules and tested for assay, related substances, content uniformity, disintegration, water content and dissolution proving that they are meeting the specifications.

In order to check the drug-layer consistency and efficacy of the fluid bed coating process, SEM analysis was performed on pure diclofenac drug-loaded pellets and their cross-sections (see Fig.

1).

Results of the SEM micro-images revealed a smooth and homogeneous slightly porous external surface with high degree of homogeneity though the entire coating layer. The thickness of the coating layer was measured between 100 and 130 μπι, in all tested batches, indicating a stable and efficient fluid bed coating procedure.

Example 2: Preparation of Diclofenac enteric coated pellets Drug-loaded pellets prepared by the above described methods were enteric coated with poly(methacrylic acid, ethyl acrylate) at a ratio of 1 :1 at a weight gain of 10% to 13% w/w using a fluid bed coater.

The produced enteric-coated pellets were filled in hard gelatin capsules and tested for assay, related substances, content uniformity, and water content proving that they are meeting the specifications.

The dissolution rate results of the compositions of Example 2 are given in Table 1.

Table 1: Dissolution rate of enteric coated Diclofenac drug layered compositions

For the dissolution analysis, USP apparatus II (rotating paddle method) Agilent VK 708DS was used. Initially, the capsules were placed in 300mL 0.1N HC1 (37°C ± 0.5 °C) and stirred at lOOrpm for 120min. Then, 700mL of phosphate buffer was added (final stage pH was 6.8) and the pellets were stirred at 50rpm (37°C ± 0.5 °C) for another 60min. Sink conditions were maintained throughout the test. In the acidic stage of 0.1 N HC1 an aliquot of 4 mL of samples was collected at 120 min; while for pH 6.8 stage, 4 mL of samples were collected at 5, 10, 15, 20, 30, 45 and 60 min, respectively, using an automatic sampler. Diclofenac content is assayed by a validated HPLC method.

Results from dissolution experiments showed that the enteric coating was adequate in order to reduce the exposure of Diclofenac in the gastric fluids, while the dissolution analysis of the Diclofenac in the pH 6.8 revealed immediate release profiles especially in the case of composition 2 and 3 where more than 80% of diclofenac was dissolved in less than 30 min.

In order to check the enteric coating layer's consistency and efficacy of the fluid bed coating process SEM analysis was performed on enteric-coated pellets and their cross-sections (see Figure 2).

The results of the SEM micro-images revealed a smooth and homogeneous slightly porous external surface with high degree of homogeneity through the entire enteric coating layer. The thickness of the enteric coating layer was measured between 30 and 35 μπι, in all tested batches indicating a stable and efficient fluid bed enteric coating procedure.

Example 3: Preparation of Diclofenac extended release coated pellets

The extended release pellets of Example 3 according to the present invention were prepared by spray coating the extended release excipients (Eudragit RS and RL) along with the antitacking agent (Talc) and plasticizer (Triethyl citrate) on drug-loaded pellets. The pellets were dried and cured for 24h in a tray oven at 40°C. The produced pellets were filled in hard gelatin capsules and tested for assay, related substances, content uniformity and water content proving that they are meeting the specifications.

For dissolution analysis, USP apparatus II (rotating paddle method) Agilent VK 708DS was used. Initially, the capsules were placed in 300 mL 0.1N HC1 (37°C ± 0.5 °C) and stirred at lOOrpm for 120 min. Then, 700 mL of phosphate buffer was added (final stage pH was 6.8) and the pellets were stirred at 50rpm (37°C ± 0.5 °C) for another 600 min. An aliquot of 4 mL of samples was collected at 30, 60, 120, 300 and 600 using an automatic sampler. Diclofenac content is assayed by a validated HPLC method.

The dissolution rate results of compositions of Example 3 are given below in Table 2.

The results of dissolution tests showed extended release profiles in all compositions. Especially, in Composition 5 and Composition 6 diclofenac dissolved in 300 min was 38.3% and 67.6 %, respectively. Table 2: Dissolution rate of enteric coated Diclofenac drug layered Trials

Example 4: Preparation of Diclofenac pulsatile release pellets In order to prepare the pulsatile release Diclofenac pellets, the enteric coated pellets of composition 3 enteric coated from example 2 comprising 25mg of Diclofenac sodium and the extended release coated pellets of composition 6 from example 3 comprising 75mg of diclofenac were mixed and filled into hard gelatin capsules.

The produced capsules were tested for assay, related substances, content uniformity, and water content proving that they are meeting the specifications.

The dissolution rate results of Example 4 are given below in Table 3.

Table 3: Dissolution rate of pulsatile release Diclofenac drug layered compositions

Tested

t (min) % API dissolved

Condition

0.1N HC1 120 0.6

5 20.1

10 30.2

15 37.0

pH 6.8 20 42.4

30 52.1

45 58.2

60 62.8

120 75.5

300 92.3

600 98.4 For the dissolution analysis, USP apparatus II (rotating paddle method) Agilent VK 708DS was used. Initially, the capsules were placed in 300mL 0.1N HC1 (37°C ± 0.5 °C) and stirred at lOOrpm for 120min. Then, 700mL of phosphate buffer was added (final stage pH was 6.8) and the pellets were stirred at 50rpm (37°C ± 0.5 °C) for another 60min. Sink conditions were maintained throughout the test. In the acidic stage of 0.1N HC1 an aliquot of 4 mL of samples was collected at 120 min; while for pH 6.8 stage, 4 mL of samples were collected at 5, 10, 15, 20, 30, 45, 60, 120, 300 and 600 min, respectively, using an automatic sampler. Diclofenac content is assayed by a validated HPLC method.

Results from dissolution tests showed good gastro-protective behaviour with only 0.6% released in the simulated gastric conditions (0.1N HC1). Then, a pulsatile release profile is observed. Initially, the 25% of diclofenac is being released within the first 10 min of exposure, while an extended release is observed in the remaining release profile with approximately 75% of diclofenac being dissolved in 120 min.

The hard gelatin capsules in example 4 were exposed to normal (25°C±2°C/60%±5% RH), intermediate (30°C±2°C/65%±5% RH) and accelerated (40°C±2°C/75%±5% RH) stability studies according to the current ICH guidelines. The results have shown a good stability of the product and compatibility between the active ingredients and the excipients proposed by the present invention.

The excellent results regarding the pulsatile release, the physicochemical characteristics, the excellent stability of the product as well as the simple and economic manufacturing process indicate the advantages of the present invention relative to the prior art used methods.

Example 5: Stability evaluation of Esomeprazole suspension for drug layering As mentioned above it is well known that PPIs are susceptible to degradation and/or transformation in acidic and neutral media. However, apart from the long-term stability problems arising in esomeprazole finished dosage form, it is also well known, that several manufacturing processes during the production of esomeprazole products lead to instability/degradation problems. The most common issue is related to the exposure of esomeprazole compound to aqueous or non-aqueous carriers. In order to overcome this problem most of the prior art documents comprise esomeprazole formulations using techniques which require limited exposure/contact of the PPI with these solvents, such as of mini-tablets or extrusion/spheronization pellets. According to the present invention, it has been surprisingly found that this "in-process" degradation of esomeprazole during the production of the finished dosage form is prevented by employing a suspension of esomeprazole along with suitable pharmaceutical excipients that is spayed on non-pareil seeds, such as sugar, MCC and isomalt spheres.

The stability of esomeprazole in several suitable coating carriers was evaluated as shown below in Table 4. Table 4: Stability evaluation of Esomeprazole in suitable coating carriers.

The results indicated that esomeprazole is not stable in all cases where the API is dissolved in the suitable carrier. This instability problem was unexpectedly observed also in the case of pH 10 alkaline buffer, where the API was unstable.

On the other hand, when esomeprazole was suspended in an aqueous solution of HPMC E5LV and Tween™ 80, a stable suspension was observed for at least 1920 min, which is adequate time for esomeprazole drug-layering.

Example 6: Preparation of Esomeprazole enteric-coated pellets

Pellets of the composition of Example 6 according to the present invention were prepared according to the following manufacturing process:

Esomeprazole API was dispersed in aqueous solution of HPMC ELV and Tween™ 80 and sprayed on sugar spheres 30/35 using a fluid bed coater. The drug-layered pellets were dried and further coated in the fluid bed coater with Opadry™ 03 K clear, used as sub-coating for the protection of esomeprazole. The sub-coated pellets were enteric-coated with acryl-eze II.

The produced pellets were filled in hard gelatin capsules and tested for assay, related substances, content uniformity, disintegration, water content and dissolution proving that they are meeting the specifications. The hard gelatin capsules of example 6 of the present invention were exposed to normal (25°C±2°C/60%±5% RH), intermediate (30°C±2°C/65%±5% RH) and accelerated (40°C±2°C/75%±5% RH) stability studies according to the current ICH guidelines. The results have shown a good stability of the product and compatibility between the active ingredients and the excipients proposed by the present invention.

The excellent results regarding the delayed release, the physicochemical characteristics, the excellent stability of the product as well as the simple and economic manufacturing process indicate the advantages of the present invention relative to the prior art used methods.

Example 7: Preparation of Diclofenac pulsatile release pellets and Esomeprazole enteric coated pellets

Pellets of the compositions of Example 7 according to the present invention were prepared according to the following manufacturing process:

Diclofenac API is suspended in an aqueous solution of HPMC and Tween™ 80 and sprayed on sugar spheres using a fluid bed coater. The drug-layered pellets are dried and divided into two portions. One portion comprising 25mg of diclofenac API in the finished dosage form is enteric coated with acryl-eze II, while the remaining portion comprising 75mg of diclofenac API is coated with Eudragit RS and RL using Talc as anti-tacking agent and Triethyl Citrate as plasticizer.

Esomeprazole API is suspended in aqueous solution of HPMC and Tween™ 80 and sprayed on sugar spheres using a fluid bed coater. The drug-layered pellets are dried and sub-coated with Opadry™ 03K. The sub-coated pellets are then enteric coated with acryl-eze II.

The fixed combination finished dosage form comprises enteric-coated pellets of Esomeprazole mixed with extended release Diclofenac pellets and enteric-coated Diclofenac pellets and filled into hard gelatin capsules.

The hard gelatin capsules were tested for assay, related substances, content uniformity, disintegration, water content and dissolution proving that they are meeting the specifications. The hard gelatin capsules of example 7 of the present invention were exposed to normal (25°C±2°C/60%±5% RH), intermediate (30°C±2°C/65%±5% RH) and accelerated (40°C±2°C/75%±5% RH) stability studies according to the current ICH guidelines. The results have shown a good stability of the product and compatibility between the active ingredients and the excipients proposed by the present invention.

The excellent results regarding the release profile, the physicochemical characteristics, the excellent stability of the product as well as the simple and economic manufacturing process indicate the advantages of the present invention relative to the prior art used methods.

The compositions of the present invention are ideal for oral delivery systems, since they are homogeneous and thermodynamically stable. The results show a good stability of the product and compatibility between the drug substance and the excipients proposed by the present invention. The excellent results regarding the physicochemical characteristics, the excellent stability of the product as well as the simple and economic manufacturing process indicate the advantages of the present invention relative to the commonly used methods and excipients.

The improved solid pharmaceutical composition of the present invention is characterized by physicochemical properties suitable for the present formulation having adequate release rate of the active ingredients and storage stability. In all previous prior art attempts to overcome the GD side effects of NSAID by combining NSAID with PPI in a stable composition, none of them is attempting to achieve a special chronopharmacological profile of diclofenac such as pulsatile release profile in a fixed combination with PPI, such as esomeprazole. While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the spirit and scope thereof, as defined in the appended claims.

Claims

-1-

CLAIMS 1. A pharmaceutical composition for oral administration comprising a therapeutically effective quantity of Diclofenac or a pharmaceutically acceptable salt, prodrug, or derivative thereof, and a therapeutically effective quantity of Esomeprazole or a pharmaceutically acceptable salt, prodrug, or derivative thereof, wherein said diclofenac or pharmaceutically acceptable salt, prodrug, or derivative thereof has a pulsatile release profile and the weight ratio of Diclofenac to Esomeprazole is from about 1: 0.2 to about 1: 0.6 in order to improve the stability of the composition and provide better dose and patience compliance.

2. The pharmaceutical composition according to claim 1, wherein said composition comprises Diclofenac or a pharmaceutically acceptable salt, prodrug, or derivative thereof in a pulsatile release profile comprising one portion of Diclofenac in extended release form and another portion of Diclofenac in delayed release - enteric coated form.

3. The pharmaceutical composition according to claim 2, wherein said composition comprises Esomeprazole or a pharmaceutically acceptable salt, prodrug, or derivative thereof, wherein Esomeprazole is in delayed release - enteric coated form.

4. The pharmaceutical composition according to claim 1, wherein said composition comprises a therapeutically effective quantity of lOOmg or 75mg Diclofenac or a pharmaceutically acceptable salt, prodrug, or derivative thereof, and 20mg or 40mg Esomeprazole or a pharmaceutically acceptable salt, prodrug, or derivative thereof.

5. The pharmaceutical composition according to claim 2 or 3, wherein said Diclofenac extended release form, Diclofenac delayed release - enteric coated form and Esomeprazole delayed release -enteric coated form are in form of pellets, beads, spheres, mini-tablets, tablets, granules, powder blends or mixtures thereof.

6. The pharmaceutical composition according to claim 5, wherein said composition is in form of hard or soft capsules filled with Diclofenac extended release form, Diclofenac delayed release - enteric coated form and Esomeprazole delayed release -enteric coated form being in form of pellets, beads, spheres, mini-tablets, tablets, granules, powder blends or mixtures thereof.

7. The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition further comprises pharmaceutically acceptable excipients selected from a group comprising of absorbents, acids, adjuvants, anticaking agents, glidants, antitacking agents, antifoamers, anticoagulants, antimicrobials, antiseptics, diluents, binders, chelating agents, sequestrants, coating agents, colorants, dyes, pigments, complexing agents, softeners, crystal growth regulators, denaturants, desiccants, dehydrating agents, dispersants, solubilizers, emollients, emulsifiers, fillers, flavor masking agents, gelling agents, humectants, lubricants, moisturizers, bufferants, pH control agents, plasticizers, retarding agents, stabilizers, suspending agents, sweeteners, disintegrants, thickening agents, surfactants, opaciflers, coloring agents, preservatives, antigellants, rheology control agents, tonicifiers and their combinations thereof. -2-

8. A process for the preparation of a stable pharmaceutical composition for oral administration comprising a therapeutically effective quantity of Diclofenac or a pharmaceutically acceptable salt, prodrug, or derivative thereof, and a therapeutically effective quantity of Esomeprazole or a pharmaceutically acceptable salt, prodrug, or derivative thereof, wherein said diclofenac or pharmaceutically acceptable salt, prodrug, or derivative thereof has a pulsatile release profile and the weight ratio of Diclofenac to Esomeprazole is from about 1 :0.2 to about 1 :0.6 in order to improve the stability of the composition and provide better dose and patience compliance, which process comprises preparation of one portion of diclofenac in extended release form and another portion of Diclofenac in delayed release - enteric coated form, and preparation of Esomeprazole in delayed release - enteric coated form, and optionally all said forms are filled into a capsule.

9. The process according to claim 8, wherein Diclofenac is dispersed/dissolved in a suitable aqueous or non-aqueous liquid along with at least one pharmaceutically acceptable excipient such as viscosity increasing agents, surfactants, binders, and subsequently, sprayed on non-pareil seeds, such as sugar, MCC, or isomalt spheres, wherein a portion of the drug loaded Diclofenac seeds is coated with at least one pharmaceutically acceptable enteric coating agent, and the remaining portion of the drug loaded Diclofenac seeds are coated with at least one pharmaceutically acceptable extended release agent.

10. The process according to claim 8, wherein Esomeprazole is dispersed/dissolved in a suitable aqueous or non-aqueous liquid along with at least one pharmaceutically acceptable excipient, such as viscosity increasing agents, surfactants, binders, and subsequently, sprayed on non-pareil seeds, such as sugar, MCC, or isomalt spheres, wherein the drug loaded Esomeprazole seeds are sub-coated with at least one pharmaceutically acceptable protective agent, and the above prepared seeds are coated with at least one pharmaceutically acceptable enteric coating agent.

11. The process according to any preceding claim, wherein said delayed release -enteric coated seeds of Esomeprazole are mixed with the extended release and delayed release- enteric coated

Diclofenac seeds and filled into hard gelatin capsules.

12. The process according to any preceding claim, wherein said at least one enteric coating agent is selected from cellulose acetate phthalate, hypromellose acetate succinate, hypromellose phthalate, polymethacrylates, polyvinyl acetate phthalate and/or mixtures thereof and said at least one extended release agent is selected from polymethacrylates, HPMC, HEC, HPC, SCMC, PEO, xantham gum, sodium alginate, stearic acid, PVA/PVP, EC, waxes, lauryl, cetyl and cetostearyl alcohol, carbopol, carrageenan, chitosan, polycarbophil, agar,and/or mixtures thereof, and said at least one protective agent is selected from HPMC, HPC, HEC, PVA, PVP and/or mixtures thereof.