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WO2008155620A1 - Forme posologique contenant une matrice dispersible de granulés à libération entretenue - Google Patents

Forme posologique contenant une matrice dispersible de granulés à libération entretenue Download PDF

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Publication number
WO2008155620A1
WO2008155620A1 PCT/IB2008/001561 IB2008001561W WO2008155620A1 WO 2008155620 A1 WO2008155620 A1 WO 2008155620A1 IB 2008001561 W IB2008001561 W IB 2008001561W WO 2008155620 A1 WO2008155620 A1 WO 2008155620A1
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WO
WIPO (PCT)
Prior art keywords
tablet
active agent
zolpidem
released
release
Prior art date
Application number
PCT/IB2008/001561
Other languages
English (en)
Inventor
Mathias Scheer
Helene Rey
Dirk Kramer
Marc Fischer
Original Assignee
Develco Pharma Schweiz Ag
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 Develco Pharma Schweiz Ag filed Critical Develco Pharma Schweiz Ag
Publication of WO2008155620A1 publication Critical patent/WO2008155620A1/fr

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Classifications

    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—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
    • A61K9/2072—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
    • 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

Definitions

  • This invention relates to sustained release pharmaceutical formulations, methods for making them and methods for using them.
  • Drug delivery systems having zero order release profiles are considered very desirable for use in sustained release pharmaceutical formulations.
  • the amount of drug released is independent of the amount of drug remaining in the delivery system and remains constant over the entire delivery profile.
  • a plot of percent of drug released against time is a straight line for a drug delivery system having a zero order release profile.
  • a variety of drug delivery systems having zero (or substantially zero) order release profiles have been proposed.
  • U.S. Patents Nos.3,995,631 and 3,977,404 disclose osmotic pumps in which osmotic pressure pushes the drug out of an almost microscopic orifice.
  • the zero order profile is achieved due to the constant, small, cross-section of the orifice being the rate determining step in the drug release.
  • U.S. Patents Nos.4,839,177 and 5,422,123 disclose zero order drug delivery systems comprising a drug delivery layer sandwiched between two layers that are impermeable. Only the drug delivery layer is eroded and the cross-section of the eroding layer is constant.
  • U.S. PatentNo. 7,195,778 discloses a drug delivery device comprising a core of drug and excipient that has a cylindrical plug embedded therein, and a drug-impermeable coating that at least partially surrounds the core.
  • the cylindrical plug expands upon absorbing water that permeates the coating, punching a hole in the impermeable coating.
  • Drug dissolution or erosion is designed to be the rate determining step of drug release and is said to be constant because of the constant cross-section of the hole formed in the coating.
  • U.S. Patent No.6,090,411 discloses sustained release tablets that are said to be easily manufactured.
  • the tablets are monolithic and comprise a swellable hydrophilic matrix and a salt adapted to control outward diffusion of the active agent by an inwardly progressing hardening reaction between the salt and the matrix.
  • Each of the examples comprises the use of a carbonate or a bicarbonate as the salt to release the active agent over 6-8 hours or more.
  • 20060062846 Al discloses a monolithic composition including alfuzosin as an active agent in a sustained release matrix comprising lactose monohydrate, hydroxypropylmethylcellulose, polyvinylpyrrolidone and magnesium stearate.
  • the composition is designed to release 13-33% of the alfuzosin within 2 hours, 40-60% of the alfuzosin within 7 hours, and greater than 80% of the alfuzosin within 20 hours of administration.
  • U.S. Patent Application Publication No. 20050042289 Al discloses a sustained release tablet comprising active agent granules blended in a sustained release matrix. This tablet is said to achieve nearly zero order release kinetics.
  • a first aspect of the invention is a tablet comprising a dispersible matrix comprising a plurality of granules each containing an active agent in a sustained release matrix, wherein the tablet is monolithic and adapted to release the active agent over a predetermined time period according to a profile of dissolution when measured in a USP type II dissolution apparatus with a paddle rotation speed of 75 rpm in 0.0 IM hydrochloric acid buffer at 37°C and pH 6.8, said profile including a zero order release phase.
  • a second aspect of the invention is a tablet comprising: (a) a dispersible matrix comprising: (i)a plurality of granules each containing an active agent in a sustained release matrix; and (ii) tablet excipients; and (b) a non-functional film coated on a surface of the dispersible matrix, wherein the tablet is monolithic and adapted to release the active agent over a predetermined time period according to a profile of dissolution when measured in a USP type H dissolution apparatus with a paddle rotation speed of 75 rpm in 0.01M hydrochloric acid buffer at 37°C and pH 6.8, said profile including a zero order release phase beginning when 39% or less active agent has been released and ending when 60% or more active agent has been released.
  • a third aspect of the invention is a tablet comprising: (a) a dispersible matrix comprising: (i)a plurality of granules each containing an active agent in a sustained release matrix; and (ii) tablet excipients; and (b) a non- functional film coated on a surface of the dispersible matrix, wherein the tablet is monolithic and adapted to release 20-35% of the active agent within 30 minutes, 4059% of the active agent within 60 minutes and more than 90% of the active agent within 4 hours of adding the tablet to a 0.01M hydrochloric acid buffer at 37°C and pH 6.8 in a USP type II dissolution apparatus with a paddle rotation speed of 75 rpm.
  • a fourth aspect of the invention is a method for providing a tablet of the invention, said method comprising: (a) providing a granulation composition comprising the active agent and a sustained release agent; (b) granulating the granulation composition to form the granules;
  • Figs. 1, 2, 3 and 4 are graphs of the dissolution profiles of certain preferred embodiments of the invention.
  • the invention was driven by the desire to provide an easily manufactured dosage form capable of achieving a controlled release of active agent over a relatively short duration and complete release of the active agent within about 2-6 hours.
  • the invention was further driven by the desire to provide a system in which the slope of the dissolution profile can be easily adjusted.
  • the inventors were able to fulfill these desires by providing a dispersible matrix tablet.
  • the matrix is dispersible in the sense that it is disintegrated into its granules or particles within 30 minutes after being exposed to aqueous media. Such a property of the matrix and of any optional non-functional film coating shall be referred to hereinafter as "dispersible”.
  • non-functional film coating means that the film coating has no effect or substantially no effect on the dissolution profile.
  • the expression is not intended to exclude from the invention film coatings having functions (e.g., taste masking, etc.) other than dissolution modification.
  • tablette is used herein in its broadest sense to encompass solid dosage forms of various sizes and shapes. Suitable shapes include but are not limited to discs, ovoids, ellipsoids, rhomboids, and the like.
  • the size of the tablet should be large enough to delivery at least one dose of the active agent but not so large as to hinder oral, anal and/or vaginal administration in a human or other animal.
  • the tablet is preferably monolithic.
  • monolithic denotes that the tablet (or other object) is not layered.
  • monolithic is not intended to require that the tablet be formed from a single material or comprise a completely homogeneous mixture, although such embodiments are within the scope of the invention.
  • the tablet comprises a plurality of granules, wherein each of the granules contains an active agent in a sustained release matrix.
  • the granules are compressed together with tablet excipients to provide uncoated embodiments of the tablet.
  • the granules and the tablet excipients together constitute the dispersible matrix of the tablet.
  • the dispersible matrix consists of granules compressed together without any tablet excipients.
  • the granules comprise 10-90% or 25-75% or 40-60% of the total tablet weight, with the balance of the tablet weight being optional excipients and an optional external film coating. (All percentages referenced herein are in weight percent unless otherwise noted.)
  • the active agent can be a drug, a nutritional additive (e.g., vitamin), or a diagnostic substance.
  • the active agent is preferably at least one substance which induces or impedes a biological process in an organism to which it is administered. It is particularly preferred that the active agent be a substance that is ideally administered over a prolonged period of time.
  • Non-limiting examples of suitable active agents include Zolpidem, metoprolol, carvedilol, valsartane, amlodipine, nimodipine, felodipine, methylphenidate, paroxetine, fluoxetine, metformine, simvastatine, fluvastatine, oxycodone, hydromorphone, salts thereof, enantiomers thereof, diastereomers thereof, and racemic mixtures thereof.
  • each tablet of the composition preferably contains from 1 mg to 25 mg, preferably 5 to 15 mg, most preferably about 6.25 mg (i.e., 6.25 mg ⁇ 0.1 mg) or about 12.5 mg (i.e., 12.5 mg ⁇ 0.1 mg) Zolpidem tartrate as the active agent.
  • the sustained release matrix of the granules comprises at least one sustained release agent and at least one granule excipient.
  • the sustained release agent is preferably a hydrophilic polymer that gels or swells upon contact with gastrointestinal fluids, such that passage of the formulation from the stomach (duodenum, jejunum, etc.) is delayed.
  • the sustained release agent provides a matrix from which the active agent cannot readily escape.
  • Suitable sustained release agents are biocompatible. They are slowly soluble and/or slowly gelable and/or swell rapidly or at a different rate in aqueous liquids and then may optionally be broken down.
  • Preferred polymers for use as sustained release agents include hydroxymethylcellulose, hydroxyethyl-cellulose, hydroxypropylmethylcellulose having a molecular weight of from 1000 to 4,000,000, hydroxypropylcellulose having a molecular weight of from 2000 to 2,000,000, carboxyvinyl polymers, chitosans, mannans, galactomannans, xanthans, carrageenans, amylose, alginic acid, its salts and its derivatives, pectins, acrylates, methacrylates, acrylic/methacrylic copolymers, polyanhydrides, polyamino acids, poly(methyl vinyl ether/maleic anhydride) polymers, polyvinyl alcohols, glucans, scleroglucans, polyethylene oxides, carboxymethylcellulose and its derivatives, ethylcellulose, methylcellulose and, in general, hydrophilic cellulose derivatives.
  • HPMC is the most preferred sustained release agent, as it is pharmaceutically acceptable and non-ionic, such that no interactions between the polymer and other constituents are to be expected.
  • HPMC provides a hydrophilic matrix in which the active agent is preferably distributed homogeneously (or uniformly), and is released over a sustained period of time.
  • the various HPMC quality grades commercially available differ in their molecular weight. The molecular weight of the polymer used and its concentration in the tablet are of particular importance for the release of the drug substance. Adjustment of these parameters to achieve desired results is possible with routine experimentation using the present disclosure as a guide.
  • the content of sustained release agent can range from 5 to 95% relative to the total weight of the granules, but is preferably from' 25 to 75% and more preferably about 40 to 60%.
  • the granules also contain at least one pharmacologically inert ingredient, referred to as a granule excipient.
  • Excipients can be broadly classified according to their intended function, although many excipients have more than one function. It should be noted that the expressions "granule excipient” and “tablet excipient” are not necessarily intended to convey any information about the function of an excipient so characterized.
  • a granule excipient is an excipient that is present in the granule.
  • a tablet excipient is any excipient that is present in the tablet other than in the granules. All, none or some of the granule excipients can be identical to the tablet excipients.
  • Suitable granule excipients include but are not limited to binders, flow enhancers, lubricants, fillers, stabilizers, and other pharmaceutically acceptable additives. Soluble granule excipients usually increase the release rate of embodied active ingredients, whereas the release rate is reduced by insoluble granule excipients.
  • the total amount of excipients in the granules can range from 5 to 95% relative to the total weight of the granules, but is preferably from 25 to 75% and more preferably about 40-60%.
  • Preferred binders include povidone (e.g., Plasdone K 29-32), hydroxypropylmethylcellulose (eg., Methocel K5), starch, etc. Required quantities of binders can be determined by persons skilled in the art using the present disclosure as a guide.
  • Preferred flow enhancers and lubricants include silicas (e.g., anhydrous colloidal silica), talc, magnesium stearate, sodium stearyl fumarate, etc. Required quantities can be determined by persons skilled in the art using the present disclosure as a guide.
  • Preferred fillers include cellulose (e.g., macrocrystalline cellulose, such as AVICEL PH 200), lactose monohydrate, sorbitol, mannitol, maize starch, starch, pregelatinized maize starch, calcium phosphate etc.
  • Required quantities can be determined by persons skilled in the art using the present disclosure as a guide.
  • Preferred stabilizers include pharmaceutically acceptable organic acids, such as maleic, tartaric, malic, fumaric, lactic, citric, adipic or succinic acid and their acid salts where these exist, in the form of racemates or isomers, where these exist. According to the invention, acids particularly preferred are tartaric, fumaric, citric, and succinic and their acid salts. Preferred stabilizers also include antioxidants such as Vitamin E, BHT, etc. It can also contain alkalizing agents for stabilization such as sodium triphosphate and calcium carbonate, are also suitable for use in the invention. [00351 The granules are combined with tablet excipients, tableted to form tablets, and optionally coated with a film as discussed in further detail below.
  • the tablet excipients can be the same as or different from the granule excipients.
  • the tablet excipients form the dispersible matrix in which the sustained release granules are contained, and thus, the tablet excipients should be selected and combined so as to achieve immediate dispersion of the granules.
  • the tablet excipients include at least a disintegrant, a flow enhancer and a lubricant.
  • Preferred disintegrants include but are not limited to microcrystalline cellulose, povidone XL, croscarmellose sodium, sodium starch glycolate, etc.
  • the slope of the release profile can be adjusted.
  • Preferred lubricants include but are not limited to magnesium stearate, sodium stearyl fumarate, hydrogenated castor oil, etc.
  • Preferred flow enhancers can be selected from the same list of flow enhancers discussed above with respect to granule excipients.
  • the invention further comprises a method for providing the tablets.
  • the method comprises providing the sustained release granules, combining the granules with excipients and compressing them to form uncoated tablets, and optionally coating the uncoated tablets to form a coated tablet in accordance with the invention.
  • the granules are provided by granulating a composition comprising the active agent and a sustained release agent.
  • the granulation composition can further comprise at least one granule excipient and/or at least one solvent.
  • the granulation composition can be granulated using any suitable methods known in the art.
  • a binder is preferably included in the granulation composition to improve the granulation process.
  • a suitable binder include povidone, hydroxypropyl cellulose
  • HPC hydroxyethyl cellulose, hydroxypropyl methylcellulose, maltodextrin, povidone, pregelatinized starch, zein, starch, and the like.
  • water and/or other solvents can be added to aid the granulation process.
  • the amount of solvent added depends on, e.g., the selection of a granulation process, and is readily determinable by those of skill in the art.
  • the solvent may be added at any suitable time point during the granulation process.
  • a binder may be mixed with a solvent to form a binder solution, and then the binder solution can be sprayed onto the remaining quantity of the granulation composition.
  • the binder can be blended with the active agent and then be sprayed with solvent.
  • Any suitable granulation method can be used to produce the granules. For example, either wet granulation or dry granulation methods can be used.
  • Dry granulation refers to the granulation of a formulation without the use of heat and solvent.
  • the blended granulation composition is compacted into a slug or a sheet and then comminuted into compacted granules. Dry granulation technique is particularly useful when the active agent is sensitive to heat or solvent.
  • wet granulation can be used. In wet granulation, solvents and binders are typically added to a formulation to provide larger aggregates of granules. The temperature during granulation can be set at any suitable point, generally not exceeding the melting point of any components of the granulation composition.
  • the granulation composition is granulated at a temperature of about 35-65°C for about 20-90 minutes.
  • the granules are optionally air dried for a suitable duration (e.g., one or more hours).
  • the granules are formed by high shear mixer granulation or more preferably, fluidized bed granulation.
  • a binder solution is sprayed from, e.g., a spray gun positioned at any suitable manner (e.g., top or bottom). The spray position and the rate of spray may depend on the nature of the active agent and the binder used, and are readily determinable by those skilled in the art.
  • the granules are screened and/or milled, dried and then screened and/or milled to the desired particle size. Milling can be performed using any commercially available apparatuses (e.g., Comil equipped with a 0.0787 inch screen).
  • the mesh size for the screen can be selected depending on the size of the granules desired. Preferably, the mesh size can range from 0.0331 inch screen (mesh 20) to 0.0098 inch screen (mesh 60).
  • the milling process aids in providing relatively uniform granules.
  • the mean size of the granules can range from about 50 ⁇ m to about 3 mm, or about 100 ⁇ m to about 2 mm, or about 300 ⁇ m to about 1 mm.
  • the bulk density or the tap density of the active agent granules ranges from about 0.1 g/ml to about 1.5 g/ml, or about 0.2 to about 0.8 g/ml, or about 0.3 g/ml to about 0.6 g/ml. Bulk density is measured based on USP method (see US Pharmacopoeia, edition XXTV, pages 1913-1914, testing method 616).
  • the granules are combined with at least one tablet excipient and compressed to form an uncoated tablet comprising a plurality of granules.
  • This tablet shaping can be done by any suitable means, with or without compressive force.
  • compression of the formulation after the granulation step can be accomplished using any tablet press, provided that the tablet composition is adequately lubricated.
  • the level of lubricant in the formulation is typically in the range of 0.5-2.0%, with magnesium stearate being the most preferred lubricant.
  • Many alternative means to effectuate this step are available, and the invention is not limited by the use of any particular apparatus.
  • the diameter and shape of the tablet depends on the molds, dies, and punches selected for the shaping or compression of the granulation composition. Tablets can be discoid, oval, oblong, round, cylindrical, triangular, and the like. The tablets maybe scored to facilitate breaking. The top or lower surface can be embossed or debossed with a symbol or letters. [0051]
  • the compression force can be selected based on the type/model of press, what physical properties are desired for the tablets (e.g., desired, hardness, friability, etc.), the desired tablet appearance and size, and the like. The compression force applied is such that the compressed tablets have a suitable hardness and strength to be packaged, shipped and handled by the user.
  • a higher compression force can be applied to the tablet to increase the tablet hardness.
  • the compression force is preferably selected so that it does not hinder the disintegration of the tablet or lead to undesired results (e.g., cracking, capping or breaking).
  • the compression force applied is such that the compressed tablet has a resistance against crushing force of 20 - 250 N.
  • the uncoated tablet will have a weight of about 10 mg to about 2000 mg, or about 50 mg to about 500 mg, or 114 ⁇ 10 mg to about 228 ⁇ 20 mg.
  • the uncoated tablet is optionally coated with a non-functional external film. The external film is preferably immediately dissolved.
  • Polymers suitable for use in the external film include but are not limited to HPMC, polyvinylacetate, povidone, carageenan, hydroxypropylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, methylcellulose, ethylcellulose, cellulose acetate, sodium carboxymethylcellulose, polymers and copolymers of acrylic acid and methacrylic acid and esters thereof, polyethylene glycols and polyethylene oxides.
  • the external film can also include excipients, such as colorants, flavorants, taste-masking agents, light protection agents, lubricants, etc.
  • the present invention provides a method for generating a predetermined sustained release profile of an active agent.
  • the release profile can be in vitro or in vivo.
  • the most preferred release profile achieved by tablets of the invention is zero order.
  • the expression "zero order" as used herein refers to at least a portion of a release profile in which a plot of active ingredient release against time is sufficiently linear such that release rate for each test point within a given time interval does not deviate by more than 30% from the mean release rate within that interval.
  • Table 1 and Fig. 1 of Example 1 below demonstrate an embodiment wherein the zero order portion of the release profile does not deviate by more than 30% from the mean release rate.
  • a zero order release profile is one in which the active agent release rate is constant or near-constant for a given time interval.
  • release profiles other than zero order are also within the scope of the invention, as are release profiles having different phases with different release kinetics.
  • the zero order release phase begins when 39% or less active agent has been released and ends when 60% or more active agent has been released.
  • the zero order release profile begins when 30% or less active agent has been released and ends when 80% or more active agent has been released. More preferably, the zero order release phase begins within 30 minutes of adding the tablet to the dissolution media.
  • the release characteristics of the tablets can also be characterized as a function of time with or without reference to the kinetics of active agent release.
  • less than 40% or less than 30% of the active agent is released within 30 minutes of adding the tablet to the dissolution media.
  • less than 30% of the active agent is released within 30 minutes of adding the tablet to the dissolution media and more than 90% of the active agent is released within 4 hours of adding the tablet to the dissolution media.
  • 20-35% of the active agent is released at 30 minutes, 40-59% of the active agent is released at 60 minutes and more than 90% of the active agent is released at 4 hours.
  • Tablets in accordance with the invention were prepared from the ingredients listed in Tables 1 and 2. [0062] Table 1. Dispersible Film Coated Tablet Formulation
  • Step 1 Zolpidem tartrate, Hypromellose 5cP, microcrystalline cellulose (Avicel PH 101), Silica colloidal (Aerosil 200) and Plasdone K 29 - 32 were spray granulated in a fluidized bed with a granulation liquid consisting of tartaric acid, Plasdone K29 - 32 and water.
  • Step 2 The fluid bed granules of step 1 were screened through sieve # 20.
  • Step 3 The granules of step 2 were mixed with colloidal silica and microcrystalline cellulose (Avicel PH 200).
  • Step 4 The granules of step 3 were lubricated with magnesium stearate.
  • Step 5 The final blend of step 4 was compressed into tablets with the properties listed in Table 3. [0070] Table 3. Tablet Properties
  • Step 6 The tablets were coated with a non-functional coating.
  • Preferred embodiments of the tablets also exhibited dose proportionality (see Example 1). Unlike certain sustained release tablets in the prior art, dose proportional tablets of the invention can be divided into smaller doses, which contain an amount of active agent proportional to the size of the fragment relative to the whole.

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Abstract

L'invention porte sur un comprimé qui a une matrice dispersible de granulés, contenant chacun un agent actif dans une matrice à libération entretenue, le comprimé étant monolithique et apte à libérer l'agent actif sur une période de temps prédéterminée selon un profil de dissolution comprenant une phase de libération d'ordre zéro. Le comprimé peut en outre contenir des excipients de comprimés et/ou un revêtement de film non fonctionnel. L'invention concerne également un procédé de fourniture d'un comprimé de l'invention.
PCT/IB2008/001561 2007-06-20 2008-06-11 Forme posologique contenant une matrice dispersible de granulés à libération entretenue WO2008155620A1 (fr)

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US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form

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WO2011020032A2 (fr) * 2009-08-13 2011-02-17 Kudco Ireland, Ltd. Forme pharmaceutique
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CN102641303B (zh) * 2011-02-18 2015-07-08 上海张江中药现代制剂技术工程研究中心 一种防止中药干法制粒过程中物料黏结滚轮现象的方法
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US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
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