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WO2010112221A1 - Compositions pharmaceutiques renfermant de la mémantine - Google Patents

Compositions pharmaceutiques renfermant de la mémantine Download PDF

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Publication number
WO2010112221A1
WO2010112221A1 PCT/EP2010/002077 EP2010002077W WO2010112221A1 WO 2010112221 A1 WO2010112221 A1 WO 2010112221A1 EP 2010002077 W EP2010002077 W EP 2010002077W WO 2010112221 A1 WO2010112221 A1 WO 2010112221A1
Authority
WO
WIPO (PCT)
Prior art keywords
memantine
composition according
composition
tablet
water
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2010/002077
Other languages
English (en)
Inventor
Álvarez Fernández LISARDO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synthon BV
Original Assignee
Synthon BV
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 Synthon BV filed Critical Synthon BV
Publication of WO2010112221A1 publication Critical patent/WO2010112221A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines

Definitions

  • the present invention relates to pharmaceutical compositions that contain memantine, to unit dosage forms made therefrom, and to processes for making the same.
  • Memantine or 3,5-dimethyl-l-adamantan-amine can be represented by the formula
  • Memantine has been known for a long time. A process for making it has been published, for example, by Gerzon K, et. al, J. Med. Chem. 6, 760 (1963) /CA 60:4022f/. The pharmaceutical applicability of memantine has been described in U.S. patents 4,122,193 and 5,061,703.
  • the compound is marketed as a hydrochloride salt.
  • the approved medical products comprise film-coated tablets with immediate release of the drug after oral administration and also a solution for oral administration. While the current commercial products are immediate- release dosage forms, an extended-release dosage form is apparently under development for future commercial release.
  • the following patent publications may relate to this development activity.
  • WO2006/0009769 discloses modified release formulations comprising memantine hydrochloride and a polymeric "carrier" in the form of a coating and/or matrix.
  • the formulations release at least 70-80% memantine in 4 to 24 hours in a "use environment" such as gastric fluid.
  • a 6h and 12h formulation are preferred and exemplified, which release 70-80 % of the memantine in about 6 or 12 hours, respectively.
  • the polymeric carrier when used as a polymeric matrix can be a hydrophilic or hydrophobic polymer.
  • the polymeric carrier is a swellable polymeric matrix containing hydroxypropyl methylcellulose (HPMC).
  • WO2006/ 138227 discloses pharmaceutical beads of memantine having immediate or modified release.
  • the beads may be filled into a capsule or compressed into a tablet.
  • Exemplified modified release beads comprise an inert core, a drug containing layer with binder and glidant, optionally a seal coat layer, a modified release layer, and optionally a topcoat. While some modified or extended release compositions of memantine hydrochloride have been suggested, it would be beneficial to have an alternate modified or extended release composition available. In particular, such compositions should be simple in manufacture, reliable in pharmaceutical action and stable and safe during handling.
  • the present invention relates to a pharmaceutical tablet composition
  • a pharmaceutical tablet composition comprising a non-swelling polymer matrix component having dispersed therein a water-soluble memantine salt, preferably memantine hydrochloride, and a pore-forming agent.
  • the preferred non-swelling polymer matrix component is a polyvinylacetate polymer and the preferred pore- forming agent is polyvinylpyrrolidone.
  • the composition can further contain a filler, particularly a water-insoluble filler, and non-functional excipients.
  • the invention relates to the above composition compressed in a form of a tablet, whereby the tablet is a slow-release tablet.
  • the tablet is compressed by means of direct compression.
  • the tablet of the present invention preferably exhibits the following release rate: less than 80 % of memantine is released at 6 hours and 90-100% is released at 12 hours, when measured by an in vitro dissolution test in USP or Ph.Eur. paddle apparatus at 50 rpm, in 900 ml of simulated gastric fluid at 37 + 5° C.
  • Another aspect of the invention relates to a unit dosage form comprising an effective amount of one or more of the above tablets.
  • a further aspect of the invention relates to a process for making memantine tablets which comprises forming a tablet from the above tablet composition without the aid of a liquid, particularly by a direct compression.
  • the process comprises blending a water-soluble memantine salt with a non-swellable polymer, a pore-forming agent and, optionally, a filler to form a blend; combining the blend with additional excipients; and compressing the precompression blend into tablets.
  • the present invention relates to a suitable, stable and technologically simple pharmaceutical composition for slow, suitably controlled delivery of memantine to a human or animal by an oral administration, particularly after the composition is formulated, by a compression, into a pharmaceutically suitable tablet form.
  • a suitable, stable and technologically simple pharmaceutical composition for slow, suitably controlled delivery of memantine to a human or animal by an oral administration, particularly after the composition is formulated, by a compression, into a pharmaceutically suitable tablet form.
  • the tablet delivers memantine throughout the entire digestive tract. No disintegrant is present in the composition, thus the compressed tablet formed from this composition is a nondisintegratable tablet.
  • the present invention relates to pharmaceutical compositions of memantine that do not comprise a swellable polymeric matrix.
  • Matrices made from a swellable polymer, particularly the HPMC matrices show an initial burst of drug release rate owing to the time required for the formation of an efficient gel layer. To obtain a zero-order release, the matrix must be prepared by combining HPMC with other polymers which reduce this effect. It is therefore desirable to provide a pharmaceutical dosage form providing a controlled release of memantine without using a composition formed from a swellable polymer. By avoiding the use of a swellable polymer, problems with the initial burst of the release rate may be solved.
  • the memantine is formulated into the compositions of the present invention in a form of a water-soluble memantine salt.
  • a "water-soluble memantine salt” is any acid addition salt of memantine, exhibiting a solubility in water at 25°C higher than 25 mg/ml.
  • Suitable salts of the compound include, but are not limited to, acid addition salts made with hydrochloric, hydrobromic, acetic, propionic, glycolic, lactic, malonic, succinic, maleic, fumaric, maleic, tartaric, citric, benzoic, mandelic, methanesulfonic, ethanesulfonic, benzenesulfonic, p- toluene sulfonic acid.
  • the preferred salt is memantine hydrochloride, but the invention is not limited thereto. Memantine salts are commercially available or may be made by contacting memantine with a corresponding acid by methods known per se.
  • the memantine salt is formulated into the composition of the present invention in a solid state, whereby such solid state may represent a crystalline state in any suitable crystal form, or an amorphous form.
  • the memantine salt is generally used in the form of a powder; i.e. fine particles.
  • the particles can have a variety of particle size distributions but preferably at least 90% of the particles are 150 microns or less in particle size.
  • the relative amount of the memantine salt present in the composition is advantageously of between 1 and 40 % of the tablet composition. As used herein all percentages refer to weight percent based on the entire weight of the tablet composition.
  • the composition of the present invention further contains a matrix-forming component/excipient, which is a water-insoluble non-swellable polymer.
  • a "non- swellable" polymer is one that does not absorb a significant amount of water (i.e., it absorbs less than about 10 weight percent water).
  • the polymer component is not readily degraded in the body or, if the polymer is biodegradable, the rate at which it degrades is slower than the rate at which the therapeutic agent elutes.
  • such polymer component is sufficiently compressible to permit tablet formation, especially via direct compression, and has sufficient binding properties to bind memantine component in the formed matrix.
  • the composition of the present invention may contain from 20 to 80 % of the non-swellable polymer.
  • the advantageous matrix-forming non-swellable polymer in compositions of the present invention is a pharmaceutically acceptable polyvinylacetate (PVA) polymer.
  • PVA polyvinylacetate
  • Such polymer has suitably good tabletting and binding properties for direct compression.
  • Some other non-swellable polymers e.g. polyacrylate polymers or polymetacrylate polymers, may be used.
  • the third component is a pore-forming agent.
  • This pore-forming agent is a solid material that dissolves in the body environment, thereby forming pores in the matrix.
  • the size of the pores can, to some extent, be controlled by the size of the solid particulate material being used.
  • the particulate material can range from less than about 1 micrometer in diameter to about 1000 micrometers, preferably about 1 micrometer to about 100 micrometers, more preferably about 5 micrometers to about 50 micrometers. For uniformity of pores, the particulate material can be screened through successively finer mesh sieves to produce a desired range of particle sizes.
  • the particulate material may include inorganic and organic particulate material, including, for example, polyvinylpyrrolidone, sodium chloride, sucrose, glucose, sorbitol, sodium citrate, dextran, poly(ethylene glycol), mannitol, or combinations thereof.
  • the pore forming material is polyvinylpyrrolidone (PVP).
  • composition of the present invention may contain from 5 to 25 % of the pore-forming material.
  • a commercially available ready-to-use mixture of polyvinylacetate and polyvinylpyrrolidone, sold under brand name of Kollidon SR ® may be used for making the controlled release compositions comprising water-soluble memantine salts.
  • This mixture comprises both the matrix-forming component (PVA) and the pore- forming component (PVP) in a single excipient.
  • the Kollidon SR is a spray-dried non-hygroscopic powder of medium particle size of about 100 micrometers.
  • the ratio of PVA and PVP is fixed in Kollidon SR at approx. 80% to approx. 20%, and it further comprises minimal amounts of sodium lauryl sulphate and silica.
  • the excellent flowability and compressibility of Kollidon SR ® makes this excipient particularly suitable for the manufacture of sustained release matrix tablets obtained by direct compression.
  • the composition of the present invention may further contain a water- insoluble inert filler.
  • a filler in the tablet composition is generally advantageous.
  • the role of the filler is mostly practical, e.g., to assure the desired concentration of the active and the necessary amount of the composition in making tablets.
  • Water insoluble pharmaceutically acceptable fillers are well known in the art.
  • a suitable filler is microcrystalline cellulose as it also aids in achieving good content uniformity of the tablet blends.
  • Other suitable fillers include methyl cellulose and/or starch.
  • the composition may also contain some non-functional excipients, such a colourants, glidants, lubricants, as known in the art of making pharmaceutical tablet compositions. In general, their amounts are very low and do not affect the release rate.
  • the composition of the present invention can be in the form of a powder blend or, more preferably as a tablet.
  • the tablets of the present invention can be made by any known tabletting technique including wet granulation, direct compression, etc. Processes in which a liquid is absent, i.e., the tablets are formed by a dry process, are commercially more attractive due to ease of manufacture. It is an advantage of the compositions of the present invention that they may be formulated into tablets by such dry process.
  • the advantageous tabletting process is a direct compression process, which is a simple process comprising preparing the blend by careful mixing of the components and compressing the blend, including a lubricant and/or glidant, to form a tablet in a tablet press by a suitable compression force.
  • the compression force used in the tabletting process may, in certain extent, modify the overall release rate.
  • a suitable compression force is from 10 to 20 kN.
  • the overall mass of the tablet is generally from 50 to lOOOmg.
  • the amount of the memantine drug (calculated as the free base) in a tablet is preferably from 1 to 100 mg,
  • the tablets Preferably, contain 7 mg, 10 mg, 20 mg, 28 mg, 40 mg, or 80 mg active ingredient.
  • Enteric coating of the tablets is, in essence, not necessary.
  • a tablet may be film-coated to improve its appearance and/or handling, using conventional film-coating materials and techniques. Such a film-coat does not substantially affect the release rate.
  • the weight of such a cosmetic coating, if present, is not included in the overall or total mass of the tablet for purposes of calculating the above-mentioned component percentages.
  • the controlled release of memantine can be manipulated to a desired release profile.
  • the tablet typically has an in vitro dissolution profile such that less than 80 % of memantine is released at 6 hours and 90-100% is released at 12 hours, when measured by an in vitro dissolution test in USP or Ph.Eur. paddle apparatus at 50 rpm at 37 + 5° C, in 900 ml of simulated gastric fluid (typically without enzymes as is common in the art).
  • the tablets should provide the same release profile also when tested in a dissolution medium of pH 4.5 (simulated gastric fluid of a fasten state) and pH 6.8 (simulated intestinal fluid). This would indicate none or minimal influence of pH of various places of the intestinal tract.
  • the composition of the present invention does not assure the proper slow release rate of memantine in a body environment by a diffusion from a formed viscous gel, as common at swellable compositions, but by a slow diffusion after permeation of water through the eroded pores in the tablet matrix, whereby the erosion/diffusion rate may be modulated by the choice of mutual amounts of the matrix-forming nonswellable polymer and the pore-forming agent, as well as by the nature of the polymer.
  • the diffusion rate, and thus also the release rate of the memantine drug is generally pH-independent, which is an advantage as the release of memantine is not affected by the actual place of release (stomach vs. intestines) and/or by the physiological state of the patient (fasten or fed at the administration).
  • the release rate is also not dependent on the ionic strength of the body fluid.
  • the tablet composition of the present invention is not swellable, it does not substantially increase its volume in the stomach. Accordingly, the compressed tablet of this composition may be more easily transported into the intestines and continue in slow releasing the memantine after many hours.
  • the tablets provided from the composition of the present invention are conventionally packed into suitable dosage forms, such as blisters or bottles. They may be used, in an effective amount, which represents an administration of one or more tablets, in treatment of all memantine-treatable diseases such as Alzheimer's disease or a dementia of Alzheimer type.
  • Memantine hydrochloride was mixed with colloidal silica anhydrous and with microcrystalline cellulose.
  • the blend was sieved over a 0.7 mm sieve and mixed with the Kollidon excipient at 72 rpm for 30 minutes.
  • Magnesium stearate were sieved over 0.71 mm sieve and added to the blend.
  • the whole blend was mixed for another 5 minutes at 72 rpm.
  • the blend was compressed into round tablets of a 300 mg weight, in a eccentric press machine with a compression force of 10 kN.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention porte sur une composition de comprimé pharmaceutique renfermant un composant de matrice polymère non gonflant possédant, dispersé en lui, un sel de mémantine soluble dans l'eau, de préférence du chlorhydrate de mémantine et un agent formant des pores, sur un procédé de production de cette composition et sur l'utilisation d'un polymère polyvinylacétate en combinaison avec un polymère polyvinylpyrrolidone dans la production d'une composition à libération contrôlée renfermant un sel de mémantine soluble dans l'eau.
PCT/EP2010/002077 2009-04-03 2010-03-29 Compositions pharmaceutiques renfermant de la mémantine Ceased WO2010112221A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16646509P 2009-04-03 2009-04-03
US61/166,465 2009-04-03

Publications (1)

Publication Number Publication Date
WO2010112221A1 true WO2010112221A1 (fr) 2010-10-07

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PCT/EP2010/002077 Ceased WO2010112221A1 (fr) 2009-04-03 2010-03-29 Compositions pharmaceutiques renfermant de la mémantine

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109833309A (zh) * 2019-02-25 2019-06-04 山东省药学科学院 美金刚缓释微片胶囊及其制备方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4122193A (en) 1972-04-20 1978-10-24 Merz & Co. Drugs or medicines for influencing the central nervous system
US5061703A (en) 1989-04-14 1991-10-29 Merz + Co. Gmbh & Co. Adamantane derivatives in the prevention and treatment of cerebral ischemia
WO2006009769A1 (fr) 2004-06-17 2006-01-26 Forest Laboratories, Inc. Formulation de liberation modifiee de memantine
US20060062851A1 (en) * 2002-12-23 2006-03-23 Vergez Juan A Delivery device containing venlafaxine and memantine and methods of use thereof
WO2006138227A1 (fr) 2005-06-16 2006-12-28 Forest Laboratories, Inc. Formulation de gouttes de memantine a liberation modifiee et immediate
WO2008005534A2 (fr) * 2006-07-06 2008-01-10 Forest Laboratories, Inc. Formulations à dissolution orale de mémantine
WO2008005036A1 (fr) * 2006-07-05 2008-01-10 Teva Pharmaceutical Industries Ltd. Composition pharmaceutique de mémantine

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4122193A (en) 1972-04-20 1978-10-24 Merz & Co. Drugs or medicines for influencing the central nervous system
US5061703A (en) 1989-04-14 1991-10-29 Merz + Co. Gmbh & Co. Adamantane derivatives in the prevention and treatment of cerebral ischemia
US20060062851A1 (en) * 2002-12-23 2006-03-23 Vergez Juan A Delivery device containing venlafaxine and memantine and methods of use thereof
WO2006009769A1 (fr) 2004-06-17 2006-01-26 Forest Laboratories, Inc. Formulation de liberation modifiee de memantine
WO2006138227A1 (fr) 2005-06-16 2006-12-28 Forest Laboratories, Inc. Formulation de gouttes de memantine a liberation modifiee et immediate
WO2008005036A1 (fr) * 2006-07-05 2008-01-10 Teva Pharmaceutical Industries Ltd. Composition pharmaceutique de mémantine
WO2008005534A2 (fr) * 2006-07-06 2008-01-10 Forest Laboratories, Inc. Formulations à dissolution orale de mémantine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GERZON K, J. MED. CHEM., vol. 6, 1963, pages 760

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109833309A (zh) * 2019-02-25 2019-06-04 山东省药学科学院 美金刚缓释微片胶囊及其制备方法

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