WO2004062552A2 - Composition pharmaceutique contenant un ains et un derive benzimidazole - Google Patents

Composition pharmaceutique contenant un ains et un derive benzimidazole Download PDF

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Publication number
WO2004062552A2
WO2004062552A2 PCT/BE2004/000003 BE2004000003W WO2004062552A2 WO 2004062552 A2 WO2004062552 A2 WO 2004062552A2 BE 2004000003 W BE2004000003 W BE 2004000003W WO 2004062552 A2 WO2004062552 A2 WO 2004062552A2
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WIPO (PCT)
Prior art keywords
composition
pharmaceutically acceptable
derivative
enteric coated
oxicam
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PCT/BE2004/000003
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English (en)
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WO2004062552A3 (fr
Inventor
Francis Vanderbist
Antonio Sereno
Philippe Baudier
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Galephar M/F
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Publication of WO2004062552A2 publication Critical patent/WO2004062552A2/fr
Publication of WO2004062552A3 publication Critical patent/WO2004062552A3/fr

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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K9/5084—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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
    • 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

  • composition containing a NSAID and a benzimidazole derivative
  • Non steroidal anti-inflammatory drugs are among the most commonly prescribed and used drugs worldwide.
  • NSAIDs gastrointestinal side effects
  • their use is commonly limited by an increased risk of gastrointestinal (Gl) side effects, mainly upper gastro-intestinal side effects like peptic ulceration and dyspeptic symptoms.
  • Gl gastrointestinal
  • gastro-intestinal side effects of these drugs with enteric coatings have had limited success.
  • the gastro-intestinal side effects of NSAIDs are in part attributable to their ability to inhibit the biosynthesis of gastroprotective prostaglandins, a significant amount of evidence exists that NSAIDs act locally on the mucosa to induce Gl ulcers and bleeding by a prostaglandin-independent mechanism.
  • NSAIDs may be responsible of iatrogenic gastro-intestinal side effects which may lead to discontinuation of the treatment and in some cases necessitate hospital treatment.
  • the term "NSAIDs-induced gastropathy” has been used to describe those adverse effects, which include haemorrhage, erosions and ulcers in the gastro-duodenal mucosa.
  • the pathogenesis of NSAIDs-induced gastropathy is not fully understood, but both local and systemic effects are thought to contribute. Therefore, the galenical improvements consisting in gastro-resistant formulations have been of little influence on the frequence and severity of gastro-intestinal effects provoked by NSAIDs.
  • cox 2 inhibitors A new generation of NSAIDs has been developed, called “cox 2 inhibitors" because they appear to act more specifically on the cyclooxygenase 2 and hence their administration result in a lower incidence of Gl side effects.
  • cox 2 inhibitors are celecoxib and rofecoxib. But now, after several years of marketing of those drugs, they also appear to have significant Gl side effects (even if their incidence and/ or their severity is lower than with the old generation of NSAIDs ). That means that, at the moment there is no safe and efficient acute or chronic antiinflammatory treatment of inflammation disorders in people with potential Gl sensibility or people subjects to ulcers and / or gastritis.
  • the aim of the present invention is to provide such a treatment
  • the "oxicam" family of NSAIDs is a family of well-known efficient antiinflammatory drugs presenting as all the NSAID a relatively high risk of gastrointestinal side effects.
  • the oxicam family contains, among others, piroxicam, meloxicam and tenoxicam. Administered orally, those molecules are indicated in several musculoskeletal disorders such as ankylosng spondylitis, osteoarthritis and rheumatoid arthritis. They are also prescribed in acute inflammation of soft tissues and in acute gout.
  • the molecules owning to the oxicam family present the advantage to possess a relatively high elimination half-life what allows to administer them once daily. This is an important advantage in terms of posology and compliance of patients
  • Benzimidazole derivatives also called proton pump inhibitors (PPIs) are widely known pharmacological agents used in the treatment of gastric and duodenal ulcers and other pathologies of the gastro-intestinal tract.
  • Proton pump inhibitors have been shown to be able to prevent gastric and duodenal erosions in healthy volunteers during treatment with acetylsalicylic acid.
  • Clinical studies have shown that omeprazole heals gastric and duodenal ulcers as fast and effectively in patients on a continuous NSAID treatment as in non NSAID uses (Walon A, Engl. S. Med, 1989;320,69).
  • omeprazole significantly reduces the risk of developing gastric ulcers, duodenal ulcers and also dyspeptic symptoms in patients on continuous NSAID treatment.
  • Physicians have already prescribed, in some cases, a therapy comprising a NSAID and proton pump inhibitor but the different active substances are administered separately. It is well known that patient compliance is a main factor in receiving a good result in medical treatments. Therefore, administration of two or even more different tablets to the patient is not convenient or satisfactory to achieve the most optimal results.
  • the benzimidazole derivative is formulated as enteric compositions since it is well known that this class of drugs are very sensitive to the acidic pH of the stomach.
  • a further advantage of the composition of the invention is that a well predetermined amount of NSAID owning to the oxicam family is administered to the patient with a well predetermined amount of benimidazole derivative.
  • US patent 6,365,184 describes a combination of a proton pump inhibitor with a NSAID under the form of a multiple unit tablet dosage form.
  • the PPI is preferably under the form of compressible enteric coated beads.
  • the present invention provides an oral pharmaceutical dosage form consisting in a capsule containing a non steroidal antiinflammatory drug (NSAID) owning to the family of oxicam derivatives or a salt thereof under the form of coated pellets or alternatively coated tablets, and an enteric coated tablet of a benzimidazole derivative, said pharmaceutical composition being suitable for a once a day administration
  • NSAID non steroidal antiinflammatory drug
  • the present invention provides an oral pharmaceutical dosage form consisting in a pharmaceutically acceptable capsule containing a non steroidal antiinflammatory drug (NSAID) owning to the family of oxicam derivatives or a salt thereof under the form of enteric coated or controlled released composition, advantageously enteric coated or controlled release pellets or alternatively one or more coated or controlled release tablets, and an enteric coated tablet of a benzimidazole derivative, both coatings presenting different release characteristics in order to minimize the possible interaction between both classes of drugs.
  • NSAID non steroidal antiinflammatory drug
  • a pharmaceutical composition combining in a single dosage form a NSAID from the oxicam family or salts thereof and a benzimidazole derivative or salts thereof is a new, advantageous and innovative method of treatment of inflammatory disorders, especially in patients presenting an history of gastro-intestinal pathologies line gastritis, Gl ulcers, etc,...
  • the oxicam compound is thus advantageously selected from the group consisting of pharmaceutically acceptable oxicam derivatives, pharmaceutically acceptable salts of oxicam derivatives and mixtures thereof.
  • Preferred oxicam compounds are meloxicam, piroxicam, tenoxicam, salts thereof, and mixtures thereof.
  • the benzimidazole compound is advantageously selected from the group consisting of pharmaceutically acceptable benzimidazole derivatives, pharmaceutically acceptable salts of benzimidazole derivatives, and mixtures thereof.
  • Preferred benzimidazole compounds are omeprazole, lansoprazole, rabeprazole, pantoprazole, pharmaceutically acceptable salts thereof, and mixtures thereof (omeprazole, pharmaceutically acceptable salts thereof and mixtures thereof being more preferred).
  • Oxicam derivatives are usually poorly water soluble molecules. Piroxicam is a white to slightly yellow crystalline powder. It shows polymorphism. Practically insoluble in water, slightly soluble in dehydrated alcohol. Piroxicam is well absorbed from the gastro-intestinal tract. Piroxicam has a long elimination half-life of approximately 50 hours. Enterohepatic recycling occur. Meloxicam is well absorbed after oral administration and is 99% bound to plasma proteins. Meloxicam has a plasma elimination half-life of about 20 hours. The marketed oral compositions of oxicam available on the market until today are immediate release forms (uncoated)
  • Benzimidazole compounds also called proton pump inhibitors (because their mechanism of action is to inhibit the so-called proton pump) are very effective drugs for the treatment of gastric and duodenal ulcers, gastroesophageal reflux diseases and Helicobacter pylori eradication, including the gastro-duodenal pathologies due to NSAID use.
  • the main benzimidazole derivatives used are omeprazole, lansoprazole, rabeprazole and pantoprazole. All the benzimidazole compounds have the common properties of presenting very poor stability. They are sensitive to heat, moisture and light, and in aqueous solution or suspension, their stability decreases with decreasing pH.
  • benzimidazole must be protected from gastric fluids since it is rapidly chemically degraded at acidic pH.
  • Different oral compositions of benzimidazole compounds have been patented including our previous patent (WO 02/32425) describing a stable oral formulation containing a benzimidazole derivative.
  • the main challenge(s) when combining two or more molecules in the same pharmaceutical form is (i) to guarantee the chemico-physical compatibility between the different active ingredients and/or between the active ingredients and the excipients used; and (ii) to insure the therapeutical compatibility between active ingredients regarding their pharmacokinetic and/or pharmaceutical properties in order that the posology of the combined composition allows to obtain safe and efficient plasma levels of both pharmacological agents.
  • the metabolism of PPI is mainly due to cytochromes P450 2C19 system while the oxicams are mainly metabolized by P450 2C9 system. There are consequently no significant direct pharmacokinetic interactions described between those 2 family of drugs. But another kind of interaction may occur between two drugs, which can result in significant alteration of the bioavailability of the drugs. This interaction results from the physico- chemical properties of drugs. Oxicam derivatives present the properties of possessing a pH dependent solubility profile with a lower solubility at low pH than at higher pH.
  • the oxicams are available on the market in immediate release uncoated forms (tablets or capsules) and benzimidazoles derivatives are available in enteric coated forms
  • the oxicam de ⁇ vative will be released in first position in stomach and the beginning of intestine while the benzimidazole derivative will be released only after the passage of the pylori (i.e. after the stomach) because of the presence of the enteric coating.
  • oxicam composition is released first, so releasing the alkaline excipients contained in the oxicam composition which present a pH between 6 to 9, may locally attack the enteric coating of the benzimidazole derivative, so provoking holes in the coating and then releasing the benzimidazole in the stomach where it is unstable and degrades very rapidly. This will result in a loss of bioavailability of oxicam derivative due to an early release and degradation of the benzimidazole derivative in the stomach.
  • oxicams which are acidic molecule may also possibly provoke a direct degradation of benzimidazole compound by direct chemical contact in the gastro-intestinal tract.
  • the present invention provides a solution to avoid this potential interaction between meloxicam and benzimidazole derivatives.
  • the invention consists in avoiding, at the same time or at the same site, important release of both drugs.
  • a possible aspect of this invention is to provide an oxicam composition form which is coated with an enteric release coating having a dissolution pH of at least 0.5 pH unit, advantageously comprised between 0.5 and 5 pH unit preferably comprised between 0.5 and 3 pH unit (such as about 0.5, about 1 , about 1.5, advantageously about 0.5 to about 1 ), superior to the enteric coating of the benzimidazole derivative, in order that when taken simultaneously, the oxicam derivative will be released after the benzimidazole derivative (due to its higher pH soluble coating), so avoiding possible interactions between meloxicam or alkaline excipients contained in the meloxicam composition and the benzimidazole derivatives.
  • the dissolution pH of enteric coating formulations of benzimidazole derivatives is usually 5 to 5.5
  • the dissolution pH of the meloxicam formulation is from 5.5 to 8, preferably between 6 to 7.
  • Suitable enteric polymer for obtaining release at those pH are for example, but not limited to, acrylic derivatives such as EUDRAGIT ® L30D-55 (pH 5.5), EUDRAGIT ® L100 (pH 6), EUDRAGIT ® S100 (pH 7-8) or mixtures thereof.
  • the tablet containing the benzimidazole derivative or salt thereof is advantageously provided with at least two coating layers, preferably two different coating layers, such as a precoating and an outer enteric coating.
  • the tablet containing the benzimidazole derivative or salt thereof is preferably free of oxicam derivative.
  • the composition of the invention is adapted (for example the control release coating or the enteric coating is adapted) so that the benzimidazole derivative starts to be released before the release of oxicam derivative.
  • the peak of release of benzimidaole derivative is reached before the peak of release of oxicam derivative, preferably before reaching a level of release of oxicam derivative corresponding to less than 50% of the peak of release of oxicam.
  • the composition of the invntion is adapted (for example the control release coating or the enteric coating is adapted) so that the release peak of oxicam derivative is retarded with respect to the release peak of benzimidazole derivative.
  • the time between the two peaks is comprised for example between 5 minutes and 6 hours, advantageously between 15 minutes and 3 hours, for example 20 minutes, 30 minutes, 45 minutes, 1 hour, 90 minutes, 120 minutes.
  • the oxicam derivative composition, pellets, beads or tablets
  • the oxicam derivative may be coated with a controlled release coating in order to release the drug slowly all along the gastro-intestinal tract. In this manner, high concentrations of the oxicam derivative are never in contact with high concentration of the benzimidazole derivative.
  • the controlled release of the oxicam derivative can be obtained by using well-known polymers films like acrylic (polyacrylate dispersions,%) or cellullosic (ethylcellulose,...) sustained release polymer.
  • the oxicam derivative can also have the form of a controlled release matrix.
  • the capsule used in the composition of the invention is advantageously a hard gelatin capsule, an hypromellose capsule, a starch capsule or any other pharmaceutically acceptable capsule.
  • the oxicam derivative is present in said capsule for example as enteric coated pellets or alternatively as controlled release pellets and/or as an one or more enteric coated tablets or alternatively as on or more controlled release tablets, said oxicam derivative containing pellets or tablets being preferably free of benzimidazole derivative.
  • the weight ratio between the pharmaceutically acceptable oxicam derivative or salt thereof and the pharmaceutically acceptable benzimidazole derivative is between 0.2 (w/w) and 5 (w/w), most preferably between 0.5 and 2.
  • the composition of the invention comprises advantageously only two different pharmaceutically active agents, namely one pharmaceutically acceptable oxicam derivative and one pharmaceutically acceptable benzimidasole derivative.
  • the pellets of the oxicam derivative or salt thereof have advantageously a diameter comprised between 0.2 and 3 mm, preferably between 0.5 and 2 mm, and most preferably between 0.7 and 1.6 mm
  • the pellets containing the oxicam derivative or salt thereof are preferably manufactured by the process of extrusion - spheronisation
  • the enteric coated tablets containing the benzimidazole derivative or salt thereof is advantageously manufactured by direct compression, coated with a pre-coating and subsequently coated with an enteric coating
  • the enteric coated tablets containing the benzimidazole de ⁇ vative or salt thereof contains preferably at least one pharmaceutically acceptable lipophilic antioxidant, advantageously selected from the group consisting of ascorbyl palmitate, butylhydroxyanisole, butyl
  • the oxicam derivative is selected from the group consisting of meloxicam, pharmaceutically acceptable salts thereof, and mixtures thereof, while the benzimidazole de ⁇ vative is selected from the group consisting of omeprazole, pharmaceutically acceptable salts thereof, and mixtures thereof.
  • the oxicam derivative is selected from the group consisting of piroxicam, pharmaceutically acceptable salts thereof, and mixtures thereof, while the benzimidazole derivative is selected from the group consisting of omeprazole, pharmaceutically acceptable salts thereof, and mixtures thereof.
  • the amount of the benzimidazole (determined as base for salts thereof) per capsule is advantageously between 5 and 80 mg, preferably between 5 and 40 mg
  • the amount of the oxicam derivative per capsule is between 5 and 40 mg, preferably between 5 and 25 mg.
  • the composition is preferably suitable for a once a day administration to patients in need in such a treatment.
  • the invention relates also to a manufacturing process suitable to obtain a composition of the invention.
  • a manufacturing process suitable to obtain a composition of the invention.
  • an enteric coated tablet containing at least one pharmaceutically acceptable benzimidazole derivative or salt thereof and
  • an enteric or controlled release composition containing a nonsteroidal antiinflammatory drug from the family of oxicams or pharmaceutically acceptable salt thereof, both coatings presenting different release characteristics in order to minimize the possible interaction between both classes of drugs
  • said pharmaceutical composition being suitable for a once a day administration
  • the tablet (a) and the composition (b) being filled together in a capsule.
  • the tablet (a) and the composition (b) can be administered or released separately, but simultaneously orally absorbed.
  • the invention relates also to an oral pharmaceutical composition or kit comprising (a) a first enteric coated tablet containing at least one pharmaceutically acceptable benzimidazole derivative or salt thereof and (b) a second enteric coated composition containing a nonsteroidal antiinflammatory drug from the family of oxicams and pharmaceutically acceptable salts thereof, the coating dissolution of the first enteric coated tablet (a) being at least 0.5 pH unit, advantageously between 0.5 pH unit and 3 pH unit (such as about 0.5 pH unit, 1 pH unit and 1.5 pH unit) lower than the coating dissolution of the second enteric coated composition (b), and the first enteric coated tablet (a) and the second enteric coated tablet (b) being in a form for being administered or released separately
  • the invention further relates to the use of a composition of the invention for a once a day administration to patients in need in such a treatment.
  • a composition of the invention for a once a day administration to patients in need in such a treatment.
  • Different examples of formulations corresponding to the present invention are given hereinbelow together with examples of manufacturing process to obtain the composition of the invention.
  • meloxicam sodium 200 g of microcrystalline cellulose (Avicel pH 101 , FMC), 25 g of sucroester (Crodesta, Gattefosse, France) and 10 g of Povidone (Plasdone K25, BASF, Germany) are introduced in a planetary mixer.
  • the powders are mixed together for 10 minutes at speed 1.
  • 200 g of demineralized water are then added, under mixing, to the powder blend in order to obtain granulates presenting adequate plastic properties.
  • the granulates obtained are extruded through a 1.2 mm sieve of the extruder (Fuji-paudal, Japan).
  • the extrudates obtained are then spheronized at 800 and 1000 rpm for 60 seconds in order to obtain pellets.
  • the pellets obtained are dried in an oven at 60°C for 16 hours.
  • the dried pellets are sieved between 0.7 and 1.4 mm.
  • the enteric coating solution is obtained by dispersing 40 g hypromellose phthalate (HP55 ® , Shin-etsu) which has a dissolution pH of 5.5, 24 g of talc, 10 g of glycerol triacetate in a mixture alcohol 96 % - water 85/15 (w/w).
  • the enteric coating is applied on the uncoated pellets with the following parameters :
  • Omeprazole 100 g of Omeprazole, 10 g of ascorbyl palmitate, 765 g of lactose monohydrate, 250 g of cellulose microcrystalline, 85 g of crospovidone and 10 g of magnesium stearate, are blended together for 10 minutes at speed in a planetary mixer.
  • the powder is then compressed directly to obtain tablets using round biconvex stamps of 6.5 mm of diameter.
  • the tablets obtained are then coated with a precoating solution in order to avoid direct contact between the benzimidazole derivative and the enteric polymer, which could result in a degradation of omeprazole.
  • the tablets will then be coated using (i) a pre-coating layer or insulating coating destined to avoid contact between omeprazole and the enteric coating polymer and (ii) an enteric coating layer
  • the precoating solution is obtained by dissolving 15 g of povidone in absolute alcohol (100 g ethanol anhydrous).
  • the coating process is preferably performed on a pan-coating machine (GS Pellegrini or Accela- Cota) but can alternatively be performed on fluidized bed apparatuses
  • Glatt (Aeromatic or Glatt).
  • the enteric coating layer is then applied on the precoated tablets using a
  • the enteric coating solution is obtained by dispersing 40 g hypromellose phthalate (HP50 ® , Shin-etsu) which has a dissolution pH of 5.0, 24 g of talc, 10 g of glycerol triacetate and 10 g of red iron oxide in a mixture alcohol 96 % - water 85/15 (w/w).
  • the final pharmaceutical form of the present invention is a
  • capsules were filled with one enteric coated tablet
  • the disintegration test is designed to control the enteric resistance of the tablet coating over time. It is performed according to the monograph "Gastro-resistant tablet” of the 4 th edition of the European Pharmacopoeia. No signs of either disintegration (apart from fragments of coating) or cracks that would allow the escape of the contents after 2 hours in HCI 0.1 M medium.
  • Example 2 combination in a hard gelatin capsule of piroxicam pellets / lansoprazole coated tablets
  • piroxicam pellets were similar as this described in example 1 for meloxicam.
  • the pellets of piroxicam were not enteric coated but controlled release coated.
  • the controlled release coating used was a polyacrylate dispersion at 30% (EUDRAGIT NE30D ® ) together with other excipients : talc, polysorbate 80, hypromellose, magnesium stearate. 12 % (w/w) of coating was applied on
  • the precoating and the enteric coating applied on lansoprazole tablets have the same compostion as the coatings described in example 1 for omeprazole enteric coated tablets.
  • the final pharmaceutical form of the present invention is a pharmaceutically acceptable capsule (hard gelatin capsule, Hypromellose capsule, starch capsule, polyethyleneglycol ).
  • size 0 hard gelatin capsules were filled with one enteric coated tablet containing 30 mg of lansoprazole and 20 mg of controlled release pellets of piroxicam.
  • Example 3 combination in a HPMC capsule of meloxicam enteric tablets / omeprazole enteric coated tablets
  • Table 3 enteric coated tablets of meloxicam
  • the enteric coated omeprazole tablets were the same as described in example 1 (with a dissolution pH of 5.0).
  • One enteric coated tablet of meloxicam and one enteric coated tablet of omeprazole were then filled in a HPMC capsule to obtain the final pharmaceutical composition.
  • enteric coated meloxicam pellets are filled in a capsule and the enteric coated tablet of benzimidazole de ⁇ vative remains as a tablet and both drugs are administered separately but simalteneously, without significant interaction.

Abstract

La présente invention concerne une forme posologique orale associant en une seule prise, des cachets et/ou comprimés à pelliculage gastro-résistant ou à libération contrôlée, et un comprimé gastro-résistant d'un dérivé benzimidazole, les deux pelliculages présentant des caractéristiques de libération différentes.
PCT/BE2004/000003 2003-01-09 2004-01-09 Composition pharmaceutique contenant un ains et un derive benzimidazole WO2004062552A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BE0300004 2003-01-09
BEPCT/BE03/00004 2003-01-09

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WO2004062552A2 true WO2004062552A2 (fr) 2004-07-29
WO2004062552A3 WO2004062552A3 (fr) 2004-10-14

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1655026A1 (fr) * 2004-10-04 2006-05-10 Espinosa Abdala, Leopoldo Composition pharmaceutique solide comprénant diacerein et meloxicame
WO2007064274A1 (fr) * 2005-11-30 2007-06-07 Astrazeneca Ab Forme de dosage pharmaceutique pour la voie orale comprenant comme ingrédients actifs un inhibiteur de la pompe à protons ainsi que de l'acide acétylsalicylique
WO2007078874A2 (fr) * 2005-12-30 2007-07-12 Cogentus Pharmaceuticals, Inc. Formulations pharmaceutiques à usage oral contenant des médicaments anti-inflammatoires non stéroïdiens et des inhibiteurs d'acides
WO2008018825A1 (fr) * 2006-08-10 2008-02-14 Astrazeneca Ab Capsules orales d'alcool polyvinylique comprenant des inhibiteurs de la pompe à protons
WO2008095263A1 (fr) * 2007-02-09 2008-08-14 Alphapharm Pty Ltd Forme pharmaceutique contenant deux ou davantage de principes actifs pharmaceutiques sous des formes physiques différentes
WO2008151415A1 (fr) * 2007-06-11 2008-12-18 Nathan Bryson Combinaison destinée au traitement du diabète sucré
EP2015731A2 (fr) * 2006-04-28 2009-01-21 Wockhardt Limited Compositions pharmaceutiques contenant un médicament anti-inflammatoire non stéroïdien, un médicament antipyrétique et analgésique et un inhibiteur de la pompe à protons
US8206741B2 (en) 2001-06-01 2012-06-26 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
CN104208039A (zh) * 2014-08-26 2014-12-17 杭州新诺华医药有限公司 一种萘普生埃索美拉唑镁肠溶制剂及制备方法
WO2016155786A1 (fr) * 2015-03-31 2016-10-06 Laboratorios Bagó S.A. Granules gastro-résistants contenant un inhibiteur de la pompe à protons
US9801824B2 (en) 2008-09-09 2017-10-31 Pozen Inc. Method for delivering a pharmaceutical composition to patient in need thereof
US9987231B2 (en) 2011-12-28 2018-06-05 Pozen Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid

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US8206741B2 (en) 2001-06-01 2012-06-26 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
US9707181B2 (en) 2001-06-01 2017-07-18 Pozen Inc. Pharmaceutical compositions for the coordinated delivery of NSAIDs
EP1655026A1 (fr) * 2004-10-04 2006-05-10 Espinosa Abdala, Leopoldo Composition pharmaceutique solide comprénant diacerein et meloxicame
WO2007064274A1 (fr) * 2005-11-30 2007-06-07 Astrazeneca Ab Forme de dosage pharmaceutique pour la voie orale comprenant comme ingrédients actifs un inhibiteur de la pompe à protons ainsi que de l'acide acétylsalicylique
WO2007078874A2 (fr) * 2005-12-30 2007-07-12 Cogentus Pharmaceuticals, Inc. Formulations pharmaceutiques à usage oral contenant des médicaments anti-inflammatoires non stéroïdiens et des inhibiteurs d'acides
WO2007078874A3 (fr) * 2005-12-30 2008-03-06 Cogentus Pharmaceuticals Inc Formulations pharmaceutiques à usage oral contenant des médicaments anti-inflammatoires non stéroïdiens et des inhibiteurs d'acides
EP2614818A1 (fr) * 2006-04-28 2013-07-17 Wockhardt Limited Compositions pharmaceutiques contenant un médicament anti-inflammatoire non stéroïdien, un médicament antipyrétique et analgésique et un inhibiteur de la pompe à protons
EP2015731A2 (fr) * 2006-04-28 2009-01-21 Wockhardt Limited Compositions pharmaceutiques contenant un médicament anti-inflammatoire non stéroïdien, un médicament antipyrétique et analgésique et un inhibiteur de la pompe à protons
EP2015731A4 (fr) * 2006-04-28 2010-05-12 Wockhardt Ltd Compositions pharmaceutiques contenant un médicament anti-inflammatoire non stéroïdien, un médicament antipyrétique et analgésique et un inhibiteur de la pompe à protons
WO2008018825A1 (fr) * 2006-08-10 2008-02-14 Astrazeneca Ab Capsules orales d'alcool polyvinylique comprenant des inhibiteurs de la pompe à protons
EP2120878A4 (fr) * 2007-02-09 2013-05-08 Alphapharm Pty Ltd Forme pharmaceutique contenant deux ou davantage de principes actifs pharmaceutiques sous des formes physiques différentes
WO2008095263A1 (fr) * 2007-02-09 2008-08-14 Alphapharm Pty Ltd Forme pharmaceutique contenant deux ou davantage de principes actifs pharmaceutiques sous des formes physiques différentes
EP2120878A1 (fr) * 2007-02-09 2009-11-25 Alphapharm PTY LTD Forme pharmaceutique contenant deux ou davantage de principes actifs pharmaceutiques sous des formes physiques différentes
AU2008213744B2 (en) * 2007-02-09 2013-12-05 Alphapharm Pty Ltd A dosage form containing two or more active pharmaceutical ingredients in different physical forms
JP2010518028A (ja) * 2007-02-09 2010-05-27 アルファファーム ピーティーワイ リミテッド 異なる物理的形態の２種以上の有効医薬成分を含有する投薬形態
CN101674811B (zh) * 2007-02-09 2015-08-19 阿尔法制药有限公司 含有两种或更多种不同物理形态的活性药物成分的剂型
WO2008151415A1 (fr) * 2007-06-11 2008-12-18 Nathan Bryson Combinaison destinée au traitement du diabète sucré
US9801824B2 (en) 2008-09-09 2017-10-31 Pozen Inc. Method for delivering a pharmaceutical composition to patient in need thereof
US9987231B2 (en) 2011-12-28 2018-06-05 Pozen Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid
US10603283B2 (en) 2011-12-28 2020-03-31 Genus Lifesciences, Inc. Compositions and methods for delivery of omeprazole plus acetylsalicylic acid
CN104208039A (zh) * 2014-08-26 2014-12-17 杭州新诺华医药有限公司 一种萘普生埃索美拉唑镁肠溶制剂及制备方法
WO2016155786A1 (fr) * 2015-03-31 2016-10-06 Laboratorios Bagó S.A. Granules gastro-résistants contenant un inhibiteur de la pompe à protons
RU2679652C1 (ru) * 2015-03-31 2019-02-12 Лабораториос Баго С. А. Способ получения гранул с энтеросолюбильным покрытием, содержащих ингибитор протонного насоса, и фармацевтических композиций, состоящих из множества частиц и содержащих эти гранулы
US10786458B2 (en) 2015-03-31 2020-09-29 Laboratorios Bago S.A. Procedure for preparing enteric-coated pellets containing a proton pump inhibitor and multi-particle pharmaceutical compositions containing them

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