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WO2006026829A1 - Composition en pate stable d'un agent enterique actif labile acide, enrobe, et son utilisation - Google Patents

Composition en pate stable d'un agent enterique actif labile acide, enrobe, et son utilisation Download PDF

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Publication number
WO2006026829A1
WO2006026829A1 PCT/AU2005/001375 AU2005001375W WO2006026829A1 WO 2006026829 A1 WO2006026829 A1 WO 2006026829A1 AU 2005001375 W AU2005001375 W AU 2005001375W WO 2006026829 A1 WO2006026829 A1 WO 2006026829A1
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WO
WIPO (PCT)
Prior art keywords
composition according
composition
acid labile
omeprazole
paste
Prior art date
Application number
PCT/AU2005/001375
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English (en)
Inventor
William Harold Bamford
James Steven Rowe
Original Assignee
Metelli Pty Ltd
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
Priority claimed from AU2004905152A external-priority patent/AU2004905152A0/en
Application filed by Metelli Pty Ltd filed Critical Metelli Pty Ltd
Publication of WO2006026829A1 publication Critical patent/WO2006026829A1/fr

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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
    • A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—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 having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention is concerned with an oral formulation containing an acid labile active component, suitable for administration to mammals. More specifically the compositions of the present invention incorporate a proton pump inhibitor comprised on or within enteric-coated pellets and formulated into a non-aqueous stable, ready-to-use, paste suitable for delivery to horses and other animals.
  • Acid labile pharmaceutically active agents intended for oral use are usually protected from acid degradation by an enteric coating applied to the dosage form.
  • Such formulations may take the form of tablets, caplets, pellets and the like. However, in these forms they are not suitable for oral administration to animals.
  • PPIs proton pump inhibitors
  • PPIs proton pump inhibitors
  • PPIs have been used extensively in the treatment of gastric acid related diseases in humans and animals. PPIs are regulators of gastric acid secretion, inhibiting the activity of H + K + -ATPaSe, which is an enzyme involved in the last step of hydrogen ion production in the acid producing parietal cells of the stomach.
  • PPIs prevent acid secretion regardless of stimuli.
  • the principle strategy of ulcer therapy with PPIs is to administer treatment that will inhibit gastric acid secretion to maintain gastric acidity above pH 4, thereby rendering the gastric fluid non-aggressive to the squamous mucosal epithelium.
  • gastric ulcers in horses have been shown to spontaneously heal and not recur.
  • Gastric ulcers are particularly common in horses, especially high performance horses such as racehorses, for which it has been estimated that as many as 80-90% suffer from gastric ulcers.
  • PPIs are well known molecules whose preparation, chemistry and pharmaceutical properties are well understood.
  • a principal chemical property of PPIs is their high acid lability, ie. PPIs are unstable in acidic solutions, and are hydrolysed to inactive compounds on contact with an acidic environment, such as in the stomach. The consequence of this acute acid lability is that manufacturers of compositions containing PPIs have gone to great lengths to protect PPIs from acidic degradation in the stomach.
  • Oral formulations of PPIs have been enterically coated to try and protect them from acid degradation in the stomach and enable absorption from the duodenum.
  • WO 94/25070 discloses oral compositions containing a protein pump inhibitor in the form of enterically coated dry pellets mixed with a dried gelling agent.
  • This mixture may then be made into a paste-like gel prior to administration.
  • this composition is enteric coated, thus protecting the acid labile proton pump inhibitor, the carrier used is an aqueous carrier and hence the formulation is inherently unstable for any period of time and must be kept in dry form until required to be mixed and administered.
  • the moist gel is not stable during long term storage at room temperature and hence it cannot be manufactured and sold as a ready-to-use formulation. This makes the formulation inconvenient to use.
  • WO 96/31213 discloses pharmaceutical compositions for oral administration which comprises one or more PPI such as omeprazole, a hydrophobic oily liquid vehicle, a basifying agent, and a thickening agent.
  • the basifying agent such as an amine base or potassium sorbate is used to provide a non-acidic environment for the acid-labile protein pump inhibitors.
  • the thickening agents used in the composition are insoluble or impractically insoluble in water, and in combination with the protein pump inhibitor and hydrophobic liquid vehicle forms a paste.
  • the nature of the formulations has the disadvantage that the basifying agents would appear to be only partially protective and, therefore, relatively high levels of PPIs need to be used in the final composition, such as 4mg/kg bodyweight to try and allow for significant losses during passage through the stomach.
  • WO 00/50038 describes oral formulations which comprise omeprazole, two to four basifying agents, a thickening agent and hydrophobic oily liquid vehicle.
  • the basifying agents according to the application are amine bases such as monoethanolamine, diethanolamine, triethanolamine, or salts of carboxylic acid such as sodium acetate, sodium citrate, potassium sorbate, sodium stearate.
  • the total basifying agent is 2% maximum and all are highly water soluble.
  • This application appears to be an improvement on WO 96/31213 employing a multiplicity of basifying agents in an attempt to counteract omeprazole inactivation in the acidic environment in the stomach.
  • the basifying agents in the compositions may not fully protect the omeprazole from inactivation in the watery acidic environment of the stomach and appears to be primarily present as a formulation stabiliser to improve formulation shelf life.
  • the presence of omeprazole together with basifying agents which are water soluble have the potential to increase the hydrophilic nature of the omeprazole making it more likely to be partitioned out of the protective oily phase into the acidic aqueous environment of the stomach.
  • enterically coated formulations are also sensitive to moisture uptake which affects product storage and stability.
  • the paste formulations as described herein are stable, ready-to-use paste formulations which can include any acid labile active agent, and is suitable for use with acid labile proton pump inhibitors, within a plurality of enteric coated pellets, suitable for administering to animals such as horses, cattle, pigs and other domestic animals and pets and to human subjects who cannot easily swallow solid dosage forms.
  • the paste formulations of the present invention are stable during long term storage at room temperature as well as being able to protect the active agent from acid environments in which the formulation may find itself.
  • Another advantage of the present formulations is enhanced bioavailability of acid labile active agents such as PPIs. This enables administration of smaller amounts of active agents to achieve comparable therapeutic effects.
  • the present invention provides a stable composition of an acid labile active agent comprising, a. an inert particulate matrix, b. an acid labile active agent, c. enteric coating and d. a non-aqueous carrier in the form of a ready-to-use orally administrable paste.
  • the preferred active agent is a proton pump inhibitor (PPI) such as for example Omeprazole. It will be understood however that other, or more than one, PPI can be used in the formulation.
  • PPI proton pump inhibitor
  • PPIs examples include lansoprazole, pantoprazole, leminoprazole and related compounds.
  • the inert particulate matrix is chosen from the group comprising sugar spheres or any other inert matrix such as spheres comprising lactose, mannitol or non- pariel seeds.
  • the enteric coating can consist of cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, shellac, methacrylic acid copolymer or any other enteric coat which will be readily known to those skilled in the art.
  • the enteric coating may be separated from the acid labile agent-coated matrix (the core) by a sub-coating layer which forms a protective barrier between the enteric coating and the acid labile agent.
  • the sub-coating layer may be comprised of any water soluble or dispersible agent or agents as long as it is capable of protecting the core from the enteric coating, should that be required.
  • Other water soluble and/or dispersible sub-coats may consist of polyvinyl pyrrolidone, methylcellulose, hydroxymethylcellulose, polyethylene glycol, polyvinyl alcohol and the like. Other suitable sub-coats would be known to those skilled in the art.
  • the preferred non-aqueous carrier is liquid paraffin but other similar carriers, for example, saturated and unsaturated vegetable oils, mineral oils, synthetic and natural triglycerides and the like. In essence any non-aqueous carrier may be used which is acceptable from a toxicology viewpoint.
  • Suitable vehicles include fats and oils such as paraffin oil, sesame oil, peanut oil and other pharmaceutical oils.
  • Various esters of oils which are suitable for oral use are also within the scope of the invention such as ethyl oleate and various di and triglycerides which are esters of fatty acids and glycerol, for example glyceryl stearate, ethyl oleate and the like.
  • Hydroxylic solvents such as glycerol, propylene glycol and polyethylene glycol (PEG) are also suitable for use in the formulations of the present invention as are the higher alcohols and fats provided they exist in the liquid form. Any non-aqueous liquid material which is non-toxic when administered orally and will not damage the enteric coat of the beads can be used.
  • the present invention provides a method of treating a disorder or a disease in an animal comprising orally administering the composition according to the first aspect.
  • the disorder or disease to be treated is a gastrointestinal disorder and even more preferably it is gastric and/or duodenal ulcer and associated disorders.
  • the preferred animal is a horse but it will be understood that any animal requiring similar treatment can be treated with the compositions of the present invention.
  • Treatment Phase - Drug Group Mean lesion score in each location before and after two weeks' treatment with omeprazole 1.Omg/kg BW Q.D. There was a significant decrease (p ⁇ 0.05) in severity and surface area of lesions in all three locations after two-weeks' treatment. The "After" scores in the FU for both variables were zero in all horses.
  • Figure 2. Mean lesion score in each location before and after two weeks' treatment with sham paste (placebo).
  • FIG. 3 Maintenance Phase. Mean lesion score in each location before and after two weeks' maintenance treatment with omeprazole at 0.5mg/kg BW Q.D. The "Before” and “After” scores for all Drug treated horses were zero in every location. After two weeks' Maintenance Placebo, lesions recurred with a severity and area equal to that at the beginning of the first phase of the trial. Description of the Preferred Embodiment
  • the present invention provides a stable, ready-to-use oral paste formulation, particularly of proton pump inhibitors such as 2-[(2-pyridyl)methylsulphinyl] benzimidazole or a derivitive thereof (hereninafter also referred to collectively as "benzimidazole compounds" which are useful as antiulcer agents.
  • proton pump inhibitors such as 2-[(2-pyridyl)methylsulphinyl] benzimidazole or a derivitive thereof
  • benzimidazole compounds which are useful as antiulcer agents.
  • examples of which are omeprazole, lansoprazole, pantoprazole, leminoprazole and related compounds
  • the combination of excipients and carriers, including the final paste formulation is suitable for use with any acid labile active agent intended for oral administration or otherwise exposed to an acid environment.
  • compositions comprising one or more proton pump inhibitors and an inert particular matrix which is enteric coated following the application of the active agent, and finally formulated into a stable, ready- to-use paste with a non aqueous carrier.
  • the paste formulation can be advantageously used for oral administration of PPIs and other acid labile active agents to domestic animals and human patients for the treatment of various conditions and diseases in which the active agent is likely to come into contact with an acid environment.
  • PPIs are well known molecules whose preparation, chemistry and pharmaceutical properties are well understood.
  • the PPIs used in the present invention merely as an example of acid labile active agents, are compounds of the general formula I:
  • R 2 is:
  • R 1 and R 3 are independently selected from hydrogen, lower alkyl, lower alkoxy and halogen
  • R 2 is selected from hydrogen, lower alkyl, lower alkoxy, lower alkoxy-lower alkoxy, lower fluoralkoxy and
  • R 4 and R 5 are independently selected from lower alkyl, A is
  • R 6 and R 7 are independently selected from hydrogen, lower alkyl, lower alkoxy, lower fluoroalkoxy, lower fluoroalkyl, halogen,
  • R is lower alkyl or lower alkoxy.
  • Examples of proton pump inhibitors according to Formula I are:
  • the preferred proton pump inhibitor is Omeprazole.
  • This and other proton pump inhibitors are known compounds, as are methods for their preparation.
  • the non-aqueous carrier and, optionally, colouring, sweetener and/or preservative are combined, mixed, heated gently and homogenised to a base paste of uniform consistency.
  • the enteric-coated PPI pellets are then added to the base paste and mixed until uniformly dispersed.
  • Methods for preparing pharmaceutical and veterinary formulations are well know and can be sourced from standard manuals such as for example The Theory and Practice of Industrial Pharmacy, Lachman L., et al. Lea & Febiger, Philadelphia 3 rd Edition, incorporated herein by reference.
  • the present composition may include additional ingredients commonly used in the formulation of human and veterinary medicines.
  • flavoring agents such as caramel, carrot, apple, vanillin and sausage flavours
  • coloring agents such as iron oxide, zinc oxide, titanium dioxide, aluminium lakes
  • sweeteners such as sugar, sodium saccharin
  • preservatives such as parabens
  • antioxidants such as BHT, BHA and viscosity regulating agents
  • white wax or synthetic waxes such as glyceryl tribehenate, glyceryl trimyristate, hydrogenated coco-glycerides
  • suitable carriers and excipients will be know to those skilled in the art from standard manuals such as for example Bentley's Textbook of Pharmaceutics Ed. EA Rawlings Ballilliere Tindall, London 8 th Edition, incorporated herein by reference.
  • the amount of the proton pump inhibitor can vary from 0.5 to 20% w/w in the final composition, preferably from about 2 to 8% w/w.
  • the non-aqueous carrier comprises approximately 50 to 90% of the final composition; preferably, it is about 60 to 85% w/w depending on the amount of other excipients in the paste.
  • the amount of enterically-coated particulate matrix (pellets) used in the formulation is preferably 50 to 200 g/mL final paste formulation. The incorporation of acid labile drug substance in this formulation results in an orally palatable and pharmaceutically stable, ready-to-use paste with enhanced stability and bioavailability characteristics.
  • the composition of the present invention are useful in the treatment of peptic ulcer and associated conditions in animals or humans.
  • it can be used for any treatment involving an acid labile drug to be delivered orally for systemic activity in animals.
  • the composition can also be used for the delivery of the acid labile drugs in humans with difficulty of swallowing solid dosage forms such as enteric coated tablets and capsules.
  • the composition may be administered directly into the back of the mouth of an animal, such as a horse, in need of anti-ulcer therapy.
  • a paste dosing syringe is used to facilitate drug administration. The consistency of this paste is such that it cannot easily drip out or be expelled once it is deposited on the dorsal part of the animal's tongue.
  • compositions to be administered may vary according to the particular animal species to be treated, the specific active ingredient in the composition, the severity of the disease, the physical condition of the afflicted animal, and other factors.
  • a physician or veterinarian skilled in the art will be able to determine the proper dosage for the specific host under treatment. In general, a dose range of from about 0.5 to 1.0 mg/kg BW may be used. Of course, higher doses may be used if desired.
  • Example 1 Batch Formula For Omeprazole Pellets 30%
  • omeprazole enteric-coated 30% involves the micronization of the omeprazole, layering on an inert particulate matrix of sugar spheres, sub-coating the layered matrix and finally applying an enteric-coating and drying to form PPI enteric coated pellets.
  • enteric coated pellets comprising other acid labile active agents and in particular other proton pump inhibitors such as dose of Formula I described above or, more specifically, lansoprazole, pantoprazole, leminoprazole and the like. Less acid labile active agents may not require the sub-coating layer.
  • Step 1 Into the batch vessel combine the Parrafin liquid light BP 5 Zinc oxide BP,
  • Step 2 Heat with mixing to 65-70 degrees Celsius. Homogenise to disperse the zinc oxide. In small increments, add Aerosil 200 slowly while homogenising. Homogenise thoroughly between additions ensuring all solids are dispersed. Continue mixing until the paste is smooth and of uniform consistency.
  • Step 3 Add Vanillin to the bulk. Mix until of uniform consistency.
  • Step 4. Add PPI enteric-coated pellets and mix until uniformly dispersed.
  • Step 5. Quality Check for appearance, colour, viscocity, specific gravity and external determination of active to Certificate of analysis.
  • the final ready-to-use paste formulation can be conveniently packaged into Dial-a-Dose® syringes or any other suitable packaging or container, depending on the intended use and storage criteria.
  • omeprazole paste was administered orally to the Drug Group 1OmL once-a-day (1.0mg/kg BW Q.D.). Sham paste blinded to the investigators was administered to the Placebo Group. After the two-week treatment phase lesions were again scored using endoscopy. Horses in the Drag Group were then divided further into two groups: a Maintenance Drag Group and a Maintenance Placebo Group. Omeprazole paste was administered to the Maintenance Drug Group orally 5mL once-a-day (0.5mg/kg BW Q.D.). Sham paste blinded to the investigators was administered to the Placebo Group. After two weeks lesions were again scored. Scoring gastric lesions
  • Gastroendoscopy was performed on horses at time zero, two-week and four- week time points. All horses were starved between the night feed and endoscopy on the afternoon of the following day. Prior to examination, each horse was sedated with detomidine HCl (12 ⁇ g/kg IV) and a 3 -metre fibreoptic gastroscope was used to visualize the GC, LC and FU in the stomach. Lesions were graded using the following scales.
  • the surface area of lesions was graded on a scale of 0 to 4 as follows:
  • variable of interest was the change in the score for severity and for surface area for each horse before and after the two-week treatment phase and then after the two-week maintenance phase.
  • the MANOVA revealed no significant differences between groups at the start of treatment and a significant (P ⁇ 0.05) group effect after the two-week treatment phase.
  • Table 2 Stability data (Container type - 30ml Dial-a-Dose® syringe calibrated in ImI increments and numbered at 5ml intervals)

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
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Abstract

L'invention concerne des formulations orales, en pâte, stables, prêtes à l'emploi, non aqueuses, contenant un composant actif labile acide, tel qu'un inhibiteur de la pompe à protons, approprié pour l'administration à des mammifères.
PCT/AU2005/001375 2004-09-09 2005-09-09 Composition en pate stable d'un agent enterique actif labile acide, enrobe, et son utilisation WO2006026829A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AU2004905152A AU2004905152A0 (en) 2004-09-09 Enteric coated paste compositions and uses thereof
AU2004905152 2004-09-09

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WO2006026829A1 true WO2006026829A1 (fr) 2006-03-16

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010018593A3 (fr) * 2008-07-03 2010-04-15 Torrent Pharmaceuticals Ltd. Composition de comprimé de benzimidazole à unités multiples résistante à l'acide gastrique
WO2014167342A1 (fr) * 2013-04-12 2014-10-16 Special Products Limited Suspension huileuse longue durée contenant des billes d'oméprazole à enrobage entérique
JP2015172032A (ja) * 2014-02-20 2015-10-01 ライオン株式会社 経口製剤及びその製造方法
WO2017185123A1 (fr) * 2016-04-29 2017-11-02 Alan Thompson Composition vétérinaire
US10076494B2 (en) 2016-06-16 2018-09-18 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions
US11077055B2 (en) 2015-04-29 2021-08-03 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions

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WO2004014345A1 (fr) * 2002-08-02 2004-02-19 Ratiopharm Gmbh Preparation pharmaceutique contenant un compose de benzimidazole melange a de la cellulose microcristalline et procede pour sa preparation

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US6274173B1 (en) * 1995-07-05 2001-08-14 Byk Gulden Lomberg Chemische Fabrik Gmbh Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole
US6316481B1 (en) * 1999-02-23 2001-11-13 Merck & Co. Inc. Pharmaceutical composition containing proton pump inhibitors
WO2004004682A2 (fr) * 2002-07-02 2004-01-15 Laboratorios S.A.L.V.A.T., S.A. Formulation pharmaceutique orale de microgranules en suspension, stable a long terme
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ANDREWS M A ET AL: "Effective Gastric Acid Suppression After Oral Administration of Enteric-Coated Omeprazole Granules.", DIG DIS SCI., vol. 42, no. 4, April 1997 (1997-04-01), pages 715 - 719 *
GOLD B D.: "Review article: epidemiology and management of gastro-oesophangeal reflux in children.", ALIMENT PHARMACOL THER., vol. 19, no. 1, 2004, pages 22 - 27 *
HAVEN M L ET AL: "Comparison of the antisecretory effects of omeprazole when administered intravenously, as acid-stable granules and as an oral paste in horses.", EQUINE VET J., vol. 29, 1999, pages 54 - 58 *
VATISTAS N J ET AL: "Acceptability of a paste formulation and efficacy of high dose omeprazole in healing gastric ulcers in horses maintained in race training.", EQUINE VET J SUPPL., vol. 29, 1999, pages 71 - 76 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010018593A3 (fr) * 2008-07-03 2010-04-15 Torrent Pharmaceuticals Ltd. Composition de comprimé de benzimidazole à unités multiples résistante à l'acide gastrique
WO2014167342A1 (fr) * 2013-04-12 2014-10-16 Special Products Limited Suspension huileuse longue durée contenant des billes d'oméprazole à enrobage entérique
GB2517232A (en) * 2013-04-12 2015-02-18 Special Products Ltd Formulation
GB2517232B (en) * 2013-04-12 2018-02-21 Veriton Pharma Ltd Formulation
JP2015172032A (ja) * 2014-02-20 2015-10-01 ライオン株式会社 経口製剤及びその製造方法
US11077055B2 (en) 2015-04-29 2021-08-03 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions
US11986554B2 (en) 2015-04-29 2024-05-21 Dexcel Pharma Technologies Ltd. Orally disintegrating compositions
WO2017185123A1 (fr) * 2016-04-29 2017-11-02 Alan Thompson Composition vétérinaire
US10076494B2 (en) 2016-06-16 2018-09-18 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions
US10835488B2 (en) 2016-06-16 2020-11-17 Dexcel Pharma Technologies Ltd. Stable orally disintegrating pharmaceutical compositions

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