EP3377046A1 - Composition pharmaceutique contenant un médicament anti-inflammatoire non stéroïdien et un inhibiteur de pompe à protons - Google Patents

Composition pharmaceutique contenant un médicament anti-inflammatoire non stéroïdien et un inhibiteur de pompe à protons

Info

Publication number
EP3377046A1
EP3377046A1 EP15816659.5A EP15816659A EP3377046A1 EP 3377046 A1 EP3377046 A1 EP 3377046A1 EP 15816659 A EP15816659 A EP 15816659A EP 3377046 A1 EP3377046 A1 EP 3377046A1
Authority
EP
European Patent Office
Prior art keywords
diclofenac
esomeprazole
pharmaceutically acceptable
agents
prodrug
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP15816659.5A
Other languages
German (de)
English (en)
Inventor
Agni GRYPIOTI
Panagiotis BARMPALEXIS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharos Ltd
Rontis Hellas SA
Original Assignee
Pharos Ltd
Rontis Hellas SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharos Ltd, Rontis Hellas SA filed Critical Pharos Ltd
Publication of EP3377046A1 publication Critical patent/EP3377046A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose

Definitions

  • 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.
  • NSAID non-steroidal anti-inflammatory drug
  • PPI proton pump inhibitor
  • 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.
  • NSAID non-steroidal anti-inflammatory drug
  • Diclofenac's chemical name is 2-(2,6-dichloranilino) phenylacetic acid and its chemical structure is presented by the following Formula I.
  • Diclofenac 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.
  • GD gastroduodenal
  • Diclofenac 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.
  • a pulsatile formulation that releases an adequate quantity of the active ingredient API initially as immediate release, followed by an extended release treatment.
  • 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.
  • 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].
  • a combination of a pulsatile formulation of a NSAID such as Diclofenac, and a proton pump inhibitor (PPI) has been proposed.
  • PPI proton pump inhibitor
  • 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.
  • Esomeprazole 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.
  • 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.
  • Esomeprazole is rapidly degraded in acidic media, but it has acceptable stability under alkaline conditions.
  • 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.
  • the orally administrated pharmaceutical dosage forms of Esomeprazole are generally formulated either in combination of alkaline agents or as delayed release (gastro-protective) formulations.
  • 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.
  • 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.
  • a NSAID such as aspirin or naproxen
  • 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.
  • 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.
  • a 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 1 : 0.6 in order to improve the stability of the composition and provide better dose and patience compliance.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a pharmaceutical composition is unit dosage form suitable for oral administration to a patient.
  • unit dosage form refers to a single entity for drug administration.
  • 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.
  • the pharmaceutical composition may be in various dosage forms
  • the preferred solid dosage form is multi-unit dosage form in capsules.
  • 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.
  • 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.
  • 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).
  • 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.
  • PPIs are susceptible to degradation and/or transformation in acidic and neutral media.
  • PPIs 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.
  • the multi-unit form of the active ingredient 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • non-pareil seeds such as spheres made of sugar, MCC, isomalt etc.
  • 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.
  • 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.
  • 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.
  • all drug-layered Diclofenac pellets may be over-coated with suitable pharmaceutical ex
  • 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.
  • suitable pharmaceutical excipients such as viscosity increasing agents, surfactants, binders etc. and/or mixture thereof
  • non-pareil seeds such as sugar, mcc, isomalt spheres etc.
  • 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.
  • suitable enteric coating agents such as cellulose acetate phthalate, hypromellose acetate succinate, hypromellose phthalate, polymethacrylates, polyvinyl acetate phthalate and/or mixture thereof.
  • suitable enteric coating agents such as cellulose acetate phthalate, hypromellose acetate succinate, hypromellose phthalate, polymethacrylates, polyvinyl acetate phthalate and/or mixture thereof.
  • 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.
  • 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.
  • composition of the present invention shall be compatible with the NSAID and PPL
  • 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.
  • 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.
  • additives such as absorbents, acids, adjuvants, anticaking agents, antitacking agents, antifoamers, anticoagulants, antimicrobials, antiseptics, chelating agents, sequestrant
  • compositions 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
  • 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.
  • the formulations with said diclofenac/esomeprazole dosage form improve patient compliance through an easily followed dosing regimen.
  • composition 1 and Composition 2 the active ingredient (Diclofenac sodium) is completely dissolved in a solution of hydroxypropylmethyl cellulose (HPMC) with EtOH and H 2 0. 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.
  • Composition 3 the active ingredient is suspended in an aqueous solution of hydroxypropylmethyl cellulose (HPMC) and TweenTM 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.
  • 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 ⁇ , 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 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 ⁇ , in all tested batches indicating a stable and efficient fluid bed enteric coating procedure.
  • 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.
  • Example 4 Preparation of Diclofenac pulsatile release 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.
  • 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.
  • Example 5 Stability evaluation of Esomeprazole suspension for drug layering
  • PPIs are susceptible to degradation and/or transformation in acidic and neutral media.
  • 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.
  • 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.
  • Esomeprazole API was dispersed in aqueous solution of HPMC ELV and TweenTM 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 OpadryTM 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.
  • Example 7 Preparation of Diclofenac pulsatile release pellets and Esomeprazole enteric coated pellets
  • Diclofenac API is suspended in an aqueous solution of HPMC and TweenTM 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 TweenTM 80 and sprayed on sugar spheres using a fluid bed coater.
  • the drug-layered pellets are dried and sub-coated with OpadryTM 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.
  • 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.
  • a special chronopharmacological profile of diclofenac such as pulsatile release profile in a fixed combination with PPI, such as esomeprazole.

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Abstract

La présente invention concerne une composition pharmaceutique stable comprenant une quantité thérapeutiquement efficace d'un AINS ayant un profil de libération pulsatile, tel que le diclofénac ou un sel pharmaceutiquement acceptable, un promédicament, ou un dérivé de celui-ci, et une quantité thérapeutiquement efficace d'un IPP, tel que l'ésoméprazole ou un sel pharmaceutiquement acceptable, un promédicament, ou un dérivé de celui-ci, dans une combinaison de dose multi-unités, et un procédé de préparation de celle-ci.
EP15816659.5A 2015-11-17 2015-11-17 Composition pharmaceutique contenant un médicament anti-inflammatoire non stéroïdien et un inhibiteur de pompe à protons Withdrawn EP3377046A1 (fr)

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US6544556B1 (en) * 2000-09-11 2003-04-08 Andrx Corporation Pharmaceutical formulations containing a non-steroidal antiinflammatory drug and a proton pump inhibitor
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