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WO2003086366A1 - Preparation a liberation modifiee amelioree - Google Patents

Preparation a liberation modifiee amelioree Download PDF

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Publication number
WO2003086366A1
WO2003086366A1 PCT/AU2003/000434 AU0300434W WO03086366A1 WO 2003086366 A1 WO2003086366 A1 WO 2003086366A1 AU 0300434 W AU0300434 W AU 0300434W WO 03086366 A1 WO03086366 A1 WO 03086366A1
Authority
WO
WIPO (PCT)
Prior art keywords
active ingredient
modified release
release coating
preparation according
preparation
Prior art date
Application number
PCT/AU2003/000434
Other languages
English (en)
Inventor
David Hayes
Angelo Lepore
Stefan Lukas
Eugene Anthony Quinn
Original Assignee
F H Faulding & Co Limited
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 F H Faulding & Co Limited filed Critical F H Faulding & Co Limited
Priority to CA002480783A priority Critical patent/CA2480783C/fr
Priority to NZ535372A priority patent/NZ535372A/en
Priority to JP2003583387A priority patent/JP2005528388A/ja
Priority to EP03709444A priority patent/EP1513505A4/fr
Priority to AU2003213876A priority patent/AU2003213876B2/en
Publication of WO2003086366A1 publication Critical patent/WO2003086366A1/fr
Priority to NO20044463A priority patent/NO20044463L/no

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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
    • 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
    • A61K31/65—Tetracyclines
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • 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
    • 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
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Definitions

  • the present invention relates to improvements in modified release preparations, such as modified release pharmaceutical preparations.
  • Modified release preparations are those that provide an in vivo release profile (a 'modified release') of an active ingredient, such as a pharmaceutically active ingredient, that is different from the in vivo release profile of the active ingredient without the modification (an 'immediate release').
  • the modified release may be such as a delayed, extended, pulsed or sustained release.
  • the modification of the release may be desired for a number of reasons, such as for minimising the side effects of the drug or for decreasing the frequency of dosing to improve patient compliance.
  • a preparation's shelf life is linked to two aspects; firstly, the stability of the ingredients themselves, namely the maintenance of their chemical, microbiological, therapeutic and toxicological properties over time; and secondly, the maintenance over time of the originally intended rate of drug release from the dosage form.
  • the present invention is directed towards this second aspect of stability.
  • All pharmaceutical preparations must have an appropriate shelf life, being the time for which it can be guaranteed that the preparation has the same properties that it had at the time it was manufactured. These properties may be such as impurity content, drug degradants or rate of drug release.
  • this shelf life is usually at least 18 months.
  • some delayed release preparations that have been formulated with an enteric coating so as to release only small amounts of active (10% or less) after 20 minutes might release up to 80% of active by 20 minutes after the preparation has been stored. This increase in rate of release can detract from the utility and effectiveness of the product.
  • the present invention provides a modified release preparation having one or more coated core elements, each core element including an active ingredient and having a modified release coating, wherein a stabilising coat is provided between each core element and its modified release coating so that, upon in vitro dissolution testing, the amount of active ingredient released at any time on a post-storage dissolution profile is within 40 percentage points of the amount of active ingredient released at any time on a pre-storage dissolution profile.
  • the amount of active ingredient released at the majority of time points on the post-storage dissolution profile is within 30 percentage points of the amount of active ingredient released at the same time on the pre-storage dissolution profile, although more preferably it will be within 20 percentage points and more preferably within 10 percentage points.
  • reference to 'percentage points' is reference to a cumulative amount of active ingredient released.
  • the in vitro dissolution testing may be carried out on preparations subjected to a standardised storage test based on the accelerated conditions of storage referred to in the United States' Food & Drug Administration (FDA) guidelines.
  • FDA Food & Drug Administration
  • the guidelines define accelerated conditions as the storage of a pharmaceutical product (namely, in its container and package) at 75% relative humidity (RH) and 40°C for 6 months.
  • RH relative humidity
  • suitable accelerated conditions for such pharmaceutical products would be storage at 60% RH and 30°C for 12 months.
  • the in vitro dissolution testing should also of course be conducted so as to provide a dissolution profile, being a plot of percentage of active ingredient released in a prescribed aqueous media as a function of time.
  • a dissolution profile may be measured utilising the standard USP XXIV 2000 - Apparatus 1 (baskets).
  • Modified release preparations in accordance with the present invention will typically be such as to provide a delayed release of the active ingredient, with reference to the active ingredient's dissolution profile.
  • the modified release is such as to provide a delayed release (generally referred to as a 'delayed release preparation')
  • the preparation aims to slow the release of the active ingredient in the stomach to minimise the side effects of the active ingredient that may be caused by release in the stomach.
  • side effects include nausea and gastrointestinal irritation.
  • the active ingredient is able to start working as soon as possible after ingestion without side effects caused by active ingredient being released in the stomach;
  • the stomach contents of healthy individuals who have eaten average meals usually have a residence time of 30 minutes to an hour and are at a pH in the stomach usually in the range of 1 to 3.
  • the stomach contents then move to the intestines where the pH usually ranges from 4 to 7, where a rapid release of the active ingredient is desired to allow rapid and complete absorption of the active ingredient.
  • an ideal delayed release profile has minimal active ingredient released in the low pH of the stomach for approximately 20 minutes, and then when put in an aqueous solution with a pH of at least 4, 100% of the active ingredient is released within 60 minutes.
  • a realistic profile would be for less than 10% of the active ingredient to be released in a pH of about 1.2 after 20 minutes and at least 90% of the active ingredient released after 60 minutes in a pH of at least 5 in in vitro tests.
  • no more than 20% of the active ingredient is released in a pH of about 1.2 by 20 minutes and at least 80% of the active ingredient in a pH of at least 5 by 60 minutes.
  • a release profile may be determined at pH 1.2 using a 0.6N hydrochloric acid solution, and at pH 5.5 using a 0.05M phosphate buffer.
  • Such a release profile is preferred for some pharmaceutical active ingredients such as antibiotics, or for any active ingredient that can cause nausea or gastrointestinal irritation but that has a narrow absorption window high in the intestinal tract.
  • active ingredients such as antibiotics
  • any active ingredient that can cause nausea or gastrointestinal irritation but that has a narrow absorption window high in the intestinal tract For example, bisphosphonates are known to cause gastrointestinal ulceration at higher doses, opioid analgesics are known to cause nausea, and very basic active ingredients can be neutralised by the acidic conditions of the stomach, precipitate and not be absorbed. Additionally, other reactions may take place causing the activity of the active ingredient to be lost.
  • the dissolution profile for a modified release preparation in accordance with the present invention is significantly less affected after being subjected to storage. This gives rise to a high degree of confidence, when determining an expiration date for a pharmaceutical product made from the preparation, that the desired release profile will still be maintained through to the expiration date. It also permits an extended expiration date to be set.
  • the amount of active ingredient released at various times might be as follows (in vitro dissolution testing conducted pre-storage in a pH 1.2 solution):
  • a preparation in accordance with the present invention would desirably release amounts of active ingredient in the following ranges (namely, within 40 percentage points) after exposure to accelerated conditions of storage (in vitro dissolution testing conducted post-storage in a pH 1.2 solution):
  • the amounts of active ingredient released after exposure to accelerated conditions of storage would desirably be in the following ranges (namely within 20 (but preferably 10) percentage points for times up to and including about 20 minutes, and within 30 (but again preferably 10) percentage points thereafter):
  • a modified release preparation in accordance with the present invention should thus satisfy the various national regulatory and approval requirements in relation to shelf life and stability.
  • the preferred dosage forms for the modified release preparations of the present invention will be formulated from a plurality of cores.
  • Each core will preferably be one of the coated core elements mentioned above, being a core element containing an active ingredient and having a modified release coating, there being a stabilising coat between the core element and the modified release coating.
  • a plurality of such coated core elements may be provided in a capsule.
  • a plurality of such coated core elements (or a plurality of suitably agglomerated coated core elements) may be compressed, along with suitable normal tablet excipients, and provided as a tablet. It is also possible for the dosage form to be a single coated core element, large enough itself to be referred to as a tablet.
  • the optimal formulation of the tablet involves balancing the need for content uniformity (namely, making sure the same number of coated core elements is present in each tablet and therefore the same amount of active ingredient is present in each tablet) and the amount of excipients required to protect the friable coating of the modified release coated core elements.
  • the percentage of coated core elements in each tablet is ideally in the range of 20 to 40% (more preferably 25 to 35%, but most preferably about 30%) by weight of the total dosage weight.
  • the active ingredient is present in the form of core elements with a modified release coating.
  • the tablet may also contain other ingredients such as flavours, colours etc.
  • the coated core elements may be present in an amount of 5 to 50% w/w, based on the total tablet weight. Below a level of about 5% w/w coated core elements in the tablet formulation there may be potency problems or the tablet may be too large to swallow. Above a level of about 50% w/w coated core elements in the tablet formulation the tablet may contain too many coated core elements and insufficient binder and the core coating may be compromised or the coated core elements may stick together under the compression forces required to form the tablets.
  • lactose, microcrystalline cellulose and/or starch are used as fillers in the tablet.
  • the total amount of lactose, microcrystalline cellulose plus starch present in the tablet can range between 50 to 95% w/w, based on the total weight of the tablet.
  • a suitable disintegrant for use in a tablet of the present invention is crospovidone, and this may be present in a range of 0 to 15% w/w, based on the total weight of the tablet.
  • a suitable lubricant for use in a tablet of the invention is magnesium stearate and the lubricant may be present in a range of between 0.1 to 1.0% w/w, based on the total weight of the tablet.
  • the core elements provide the active ingredient.
  • the active ingredient may be embodied within and through the core element, and may be combined with or without the normal excipients, additives and fillers. Alternatively, the active ingredient may itself be coated onto, for example, an inert bead to provide the core element.
  • the core elements each have a diameter in the range of 50 microns to 2000 microns. If a single core element is to be used the size of the core element will preferably range from 5mm to 20mm.
  • the core elements may be formed by any suitable method.
  • the core elements may be formed by spheronisation onto seed core, extrusion, marumerisation, or rotogranulation.
  • the core elements will be formed by extrusion.
  • the core elements may contain any suitable or required additives, such as excipients, fillers or other ingredients.
  • the composition of the core element is carefully determined to further enhance the likelihood of the post-storage dissolution profile being acceptably similar to the dissolution profile pre-storage.
  • the core element is formed by extrusion using an extruding solution.
  • the material to be extruded to form the core element preferably contains the active ingredient, a binder, a wicking agent and a lubricant.
  • the binder is microcrystalline cellulose, however powdered cellulose or any of the co-processed microcrystalline celluloses that contain additives such as silica, may be used.
  • the amount of binder used ranges between 8 to 45% by weight, based on the total weight of the core element.
  • a wicking agent allows water to be transported throughout the core element and aids in the release of all of the active ingredient present in the core element.
  • the wicking agent is selected from lactose, microcrystalline cellulose, starch or sorbitol. Most preferably the wicking agent is lactose.
  • the wicking agent is present in an amount of from 0 to 45% by weight, based on the total weight of the core element.
  • the core element may also include a lubricant, and a number of suitable lubricants will be known to the person skilled in the art.
  • the lubricant is selected from sodium lauryl sulphate or magnesium stearate.
  • the lubricant is present in an amount ranging from 0 to 10% by weight, based on the total weight of the core element.
  • the active ingredient may be present in the core element in any suitable amount, and for instance may be provided in an amount from 5 to 95% by weight, preferably from 20 to 80% by weight, based on the total weight of the core element.
  • the active ingredient may be any suitable and desirable pharmaceutical, medicament or chemical.
  • the active ingredient may be acid salts of doxycycline, tetracycline, oxytetracycline, minocycline, chlortetracycline, or demeclocycline. Any active ingredient that causes nausea or irritation, but also has a narrow absorption window high in the intestines will benefit from the application of this invention.
  • the stabilising coat is a physical barrier between the active ingredient and the modified release coating.
  • the stabilising coat may also be referred to as a seal coat or an intermediary layer.
  • the purpose of the stabilising coat is to keep the active ingredient and the modified release coating separated. In this respect, it is believed that the stabilising coat slows migration of moisture or solvent between the modified release coating and the active ingredient. Whilst the stabilising coat will preferably keep the active ingredient separated from the modified release coating during storage, the stabilising coat will ideally not interfere significantly with the rate of release of the active ingredient, and therefore should be at least semi-permeable in aqueous media and may even be soluble. Indeed, the stabilising coat is intended to keep migration of core materials to a minimum such that their interaction with coating materials is reduced or prevented, whilst still allowing for release of core materials in an aqueous environment.
  • the stabilising coat may be any suitable material which makes an inert barrier between the core element, or the active ingredient containing layer, and the modified release coating, and may be water soluble, water swellable or water permeable polymeric or monomeric materials.
  • suitable materials include, but are not limited to, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyethylene glycol or methacrylate based polymers (e.g. Eudragit® RS or Eudragit® RL).
  • the stabilising coat includes a water-soluble polymer that does not interfere with the release of the active ingredient, and talc or another agent that performs the same function as talc.
  • the water soluble polymer and talc may be present in the range of between 9 parts polymer to 1 part talc, through to 1 part polymer to 9 parts talc.
  • the modified release coating may also be any suitable coating material, or combination of coating materials, that will provide the desired modified release profile.
  • coatings such as enteric coatings, semi-enteric coatings, delayed release coatings or pulsed release coatings may be desired.
  • a coating will be suitable if it provides an appropriate lag in active ingredient release prior to the rapid release at a rate essentially equivalent to immediate release of the active ingredient.
  • materials such as hydroxypropylmethyl cellulose phthalate of varying grades (and also as an aqueous dispersion), methacrylate based polymers (e.g. Eudragit® L100-55 and Eudragit® L30D) and hydroxypropylmethyl cellulose acetate succinate are all suitable. It is also possible to use a mixture of enteric polymers to produce the modified release coating. It is also possible to use a mixture of enteric polymer with a water permeable, water swellable or water-soluble material.
  • Suitable water-soluble or water permeable materials include but are not limited to hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyethylene glycol or mixtures thereof.
  • the modified release coating may contain between 40 to 90% w/w enteric polymer, and between 10 to 60% w/w water-soluble or water permeable material, based on the total weight of the modified release coating.
  • the modified release coating may also contain 0 to 30% w/w of a plasticiser, based on the total weight of the modified release coating.
  • the polymer coat weight of the modified release coating (as a percentage of the total core) will vary depending on the delay desired and the polymer used, but generally will be between and 5 %w/w and 30%w/w.
  • polymer coat weight it is meant the polymer and plasticiser in the coating layer, and does not include additives such as talc.
  • the stabilising coat and the modified release coating may be applied to a core element to form a coated core element in any suitable manner, such as by fluidised bed coating, including wurster coating, and rotacoating. In a preferred form, both coats will be applied by wurster coating.
  • Drying the core using any one of a number of drying techniques known in the art, such as oven drying or drying in a fluidised bed apparatus, may further improve stability.
  • Figure 1 illustrates the rate of active ingredient release of the cores from Example 1 , immediately after production and after various lengths of storage;
  • Figure 2 illustrates the rate of active ingredient release of tablets containing the cores from Example 1 , immediately after production and after various lengths of storage;
  • Figure 3 illustrates the rate of active ingredient release of dried cores from Example 1 , immediately after production and after various lengths of storage;
  • Figure 4 illustrates the comparative active ingredient release at 20 minutes of tablets containing cores with and without a stabilising coat from Comparative Example 1 , immediately after production and after various lengths of storage.
  • Examples 1 and 2 exemplify a first preferred embodiment of a preparation in accordance with the invention, with Example 1 directed to core elements and Example 2 directed to tablets formed from those core elements, there being supporting data illustrating the improved stability for those preparations;
  • Example 3 exemplifies the core elements of Example 1 after having been subjected to a drying step, and also provides supporting data illustrating improved stability;
  • Example 4 exemplifies a second preferred embodiment of a preparation in accordance with the invention, being directed to tablets formed from core elements, which preparation is also expected to provide improved stability;
  • Comparative Example 1 exemplifies a third preferred embodiment of a preparation in accordance with the invention, and provides comparative data for the stability of tablets containing coated core elements having a stabilising coat relative to those that do not contain a stabilising coat.
  • the core element is formed in a wet granulation process using a saturated solution of sodium chloride and in a high shear mixer.
  • the mixture is then extruded using a screen size of between 0.4 and 1.5 mm.
  • the extrudate is then marumerised to produce rounded core elements.
  • the core elements are dried in a fluidised bed or an oven.
  • a stabilising coat is applied to the core elements using a fluidised bed coating process.
  • the stabilising coat consists of hydroxypropylmethyl cellulose and talc in a 2:1 mixture.
  • the aim polymer coat weight (the weight of the polymer only, not including the talc) is between 3 and 5% of the total weight of the core element and the stabilising coat.
  • the polymer coat weight will vary due to a number of factors, such as the efficiency of the coating process, the batch of raw materials etc.
  • the modified release coating is applied to the stabilising coated core elements using a fluidised bed coating process to form coated core elements.
  • the aim polymer coat weight is 15% of the total weight of the coated core element.
  • the following table shows the raw data for Figure 1 from which it can be seen that, after storage for 6 months at accelerated conditions, the change in the amount of active ingredient released at most time points is less than 10 percentage points, and at all time points is less than 20 percentage points. It can also be seen that during the more critical early time period of up to 20 minutes, the change in the amount of active ingredient released is within the lower range.
  • the coated core elements prepared in Example 1 were formulated into tablets.
  • the ingredients were combined in a tumble blender and then tabletted using a rotary tablet press.
  • Example 3 The coated core elements of Example 1 were additionally dried in an oven at 50°C for 5 days before storage, and in vitro dissolution provided the pre-storage and post-storage dissolution profiles shown in Figure 3.
  • the core elements are formed using a wet granulation technique with the solution being a saturated solution of sodium chloride.
  • the core elements are extruded to be between 0.4 and 1.5mm in diameter. They then are marumerised and dried to provide a core element of formulation:
  • the core elements are dried they are coated, using a fluidised bed, with the stabilising coat as below. Once the stabilising coat is dry, the coated core element is then coated with the modified release coat, as below, again using a fluidised bed process. The complete coated core elements are then tabletted with tabletting excipients as described below.
  • the coated core elements were formed according to the method described in Example 4 with the exception of the extruding solution being water.
  • the coated core elements had the following formulation.
  • the coated core elements were then tabletted as in Example 2 to provide tablets with the following formulation.
  • the tablets were stored in a controlled environment at a temperature of 40°C and 75% relative humidity for 12 weeks and the in vitro dissolution properties of the two tablet formulations were measured.
  • the following table shows the comparative raw data for the graph in Figure 4 showing the percent released at 20 minutes of tablets containing coated core elements with and without a stabilising coat.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention se rapporte à une préparation à libération modifiée comportant un ou plusieurs éléments noyaux enrobés. Chaque élément noyau contient un principe actif et possède un enrobage à libération modifiée. Un enrobage de stabilisation est prévu entre chaque élément noyau et son enrobage à libération modifiée, pour que, lors d'un test de dissolution in vitro, la quantité de principe actif libérée à n'importe quel moment sur une courbe de dissolution après stockage est inférieure ou égale à 40 points de pourcentage de la quantité de principe actif libérée à n'importe quel moment sur une courbe de dissolution avant stockage. Cette invention concerne également un procédé permettant d'administrer un principe actif qui, lors de son administration sous une forme à libération immédiate, provoque normalement des nausées et des irritations gastriques, ce procédé consistant à administrer une telle préparation à libération modifiée faisant l'objet de cette invention.
PCT/AU2003/000434 2002-04-12 2003-04-11 Preparation a liberation modifiee amelioree WO2003086366A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CA002480783A CA2480783C (fr) 2002-04-12 2003-04-11 Preparation a liberation modifiee amelioree
NZ535372A NZ535372A (en) 2002-04-12 2003-04-11 An improved modified release preparation
JP2003583387A JP2005528388A (ja) 2002-04-12 2003-04-11 改善された制御放出調製物
EP03709444A EP1513505A4 (fr) 2002-04-12 2003-04-11 Preparation a liberation modifiee amelioree
AU2003213876A AU2003213876B2 (en) 2002-04-12 2003-04-11 An improved modified release preparation
NO20044463A NO20044463L (no) 2002-04-12 2004-10-20 Forbedret modifisert-frigjoringspreparat

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPS1676A AUPS167602A0 (en) 2002-04-12 2002-04-12 An improved modified release preparation
AUPS1676 2002-04-12

Publications (1)

Publication Number Publication Date
WO2003086366A1 true WO2003086366A1 (fr) 2003-10-23

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PCT/AU2003/000434 WO2003086366A1 (fr) 2002-04-12 2003-04-11 Preparation a liberation modifiee amelioree

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EP (1) EP1513505A4 (fr)
JP (1) JP2005528388A (fr)
AU (1) AUPS167602A0 (fr)
CA (1) CA2480783C (fr)
NO (1) NO20044463L (fr)
NZ (1) NZ535372A (fr)
WO (1) WO2003086366A1 (fr)

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WO2012059338A1 (fr) * 2010-10-21 2012-05-10 Galderma S.A. Comprimé à libération prolongée et son procédé de préparation
CN102579408A (zh) * 2012-03-19 2012-07-18 河南中帅医药科技发展有限公司 盐酸多西环素双释放制剂及其制备方法
US9119793B1 (en) 2011-06-28 2015-09-01 Medicis Pharmaceutical Corporation Gastroretentive dosage forms for doxycycline
US9238029B2 (en) 2004-06-16 2016-01-19 Takeda Pharmaceuticals U.S.A., Inc. Multiple PPI dosage form
US9241910B2 (en) 2008-03-11 2016-01-26 Takeda Pharmaceutical Company Limited Orally-disintegrating solid preparation
US10201517B2 (en) 2010-10-21 2019-02-12 Galderma Laboratories, L.P. Brimonidine gel compositions and methods of use
US10842802B2 (en) 2013-03-15 2020-11-24 Medicis Pharmaceutical Corporation Controlled release pharmaceutical dosage forms

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WO1999003453A1 (fr) * 1997-07-14 1999-01-28 Lek, Tovarna Farmacevtskih In Kemic^¿Nih Izdelkov , D.D. Nouvelle formulation pharmaceutique avec liberation controlee de substances actives

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WO1994002140A1 (fr) * 1992-07-17 1994-02-03 Astra Aktiebolag Composition pharmaceutique contenant un agent antiulcereux
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US9238029B2 (en) 2004-06-16 2016-01-19 Takeda Pharmaceuticals U.S.A., Inc. Multiple PPI dosage form
US9889152B2 (en) 2004-06-16 2018-02-13 Takeda Pharmaceuticals U.S.A., Inc. Multiple PPI dosage form
US9241910B2 (en) 2008-03-11 2016-01-26 Takeda Pharmaceutical Company Limited Orally-disintegrating solid preparation
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US10201517B2 (en) 2010-10-21 2019-02-12 Galderma Laboratories, L.P. Brimonidine gel compositions and methods of use
US9119793B1 (en) 2011-06-28 2015-09-01 Medicis Pharmaceutical Corporation Gastroretentive dosage forms for doxycycline
CN102579408A (zh) * 2012-03-19 2012-07-18 河南中帅医药科技发展有限公司 盐酸多西环素双释放制剂及其制备方法
CN102579408B (zh) * 2012-03-19 2013-06-05 河南中帅医药科技发展有限公司 盐酸多西环素双释放制剂及其制备方法
US10842802B2 (en) 2013-03-15 2020-11-24 Medicis Pharmaceutical Corporation Controlled release pharmaceutical dosage forms

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JP2005528388A (ja) 2005-09-22
EP1513505A1 (fr) 2005-03-16
CA2480783C (fr) 2010-01-19
NO20044463L (no) 2004-11-11
NZ535372A (en) 2008-03-28
AUPS167602A0 (en) 2002-05-16
CA2480783A1 (fr) 2003-10-23
EP1513505A4 (fr) 2011-02-16

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