US20050058706A1 - Delayed release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol - Google Patents
Delayed release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol Download PDFInfo
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- US20050058706A1 US20050058706A1 US10/831,368 US83136804A US2005058706A1 US 20050058706 A1 US20050058706 A1 US 20050058706A1 US 83136804 A US83136804 A US 83136804A US 2005058706 A1 US2005058706 A1 US 2005058706A1
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
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- 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
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- 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
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the present invention relates to a slow-release pharmaceutical formulation, containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof in a matrix.
- 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol is known from European patent no. EP 693,475 as an analgesic pharmaceutical composition and can be administered orally.
- Conventional formulations for oral administration of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol lead to rapid release of the active ingredient in the gastrointestinal tract, so its analgesic action begins rapidly. At the same time, a rapid reduction in the action is observed.
- retard formulations are generally known for a large number of different active ingredients.
- Conventional forms of retardation include coating retardation and matrix retardation.
- the nucleus of a pharmaceutical composition containing an active ingredient is provided with a coating which consists of one or more hydrophilic and/or hydrophobic polymers and slows down release of the active ingredient.
- the active ingredient is contained in a matrix which is formed from one or more excipients and controls release of the active ingredient.
- Published German patent application no. DE 33 09 516 accordingly discloses a process for producing matrix formulations with hydroxypropylmethyl cellulose (HPMC) as excipient and slow release, in part, of the active ingredient, the excipient making up not more than one third of the weight of the formulation and consisting of at least one hydroxypropylmethyl cellulose having a methoxy content of 16 to 24% by weight, a hydroxypropyl content of 4 to 32% by weight and a numerically averaged molecular weight of at least 50,000.
- HPMC hydroxypropylmethyl cellulose
- the formulations disclosed in DE 33 09 516 A1 contain HPMCs having viscosities (in a 2% by weight aqueous solution at 20° C.) between 15 and 30,000 cPs (15 to 30,000 mPa ⁇ s). Release behavior which is independent of the pH of the dissolution medium is not disclosed in DE 33 09 516 A1.
- a slow-release pharmaceutical formulation containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof in a matrix with slow release of active ingredient, in which the matrix contains 1 to 80% by weight, preferably 5 to 80% by weight, of one or more hydrophilic or hydrophobic polymers as pharmaceutically acceptable matrix forming agents and has the following release rate in vitro, measured by the Ph. Eur. Paddle Method at 75 rpm in a buffer (to Ph. Eur.) at a pH of 6.8 at 37° C. and detected using a UV spectrometer:
- the formulation according to the invention not only ensures long-lasting therapeutic efficacy over a relatively long period (at least 12 hours) due to the slow release of the active ingredient, but at the same time allows the active ingredient to start flowing rapidly in the plasma when the pharmaceutical composition is first administered, leading to a rapid onset of pain relief in the patient. Therefore, the pain suffered by a patient can rapidly be alleviated when the formulation according to the invention is administered without the analgesic action quickly fading again.
- the formulation according to the invention therefore combines properties of a formulation with immediate release of active ingredient—rapid pain relief due to adequately high concentration of active ingredient just after administration of the pharmaceutical composition—with properties of a formulation having slow release—long-lasting analgesic action due to maintenance of an adequately high level of active ingredient over a prolonged time.
- analgesic in the formulation according to the invention, the patient can effectively combat his pain acutely and, at the same time, treat it effectively over a prolonged period without further measures and merely by regular administration at 12 (or 24) hourly intervals.
- the active ingredient of the formulation according to the invention is contained in a slow release matrix. It is also conceivable, however, that the active ingredient be contained in a matrix with conventional release behavior and the slow release be achieved by a retarding coating.
- the slow release behavior is achieved by an osmotically driven release system.
- the matrix contains 1 to 80% by weight of one or more hydrophilic or hydrophobic polymers as pharmaceutically acceptable matrix forming agents, for example rubbers, cellulose ethers, cellulose esters, acrylic resins, materials derived from proteins, fats, waxes, fatty alcohols or fatty acid esters.
- hydrophilic polymers it is preferable for the matrix to comprise 5 to 80% by weight matrix forming agents.
- the present invention also relates to a pharmaceutical formulation which contains 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof in a matrix with slow release of active ingredient, in which the matrix contains 1 to 80% by weight, in particular 5 to 80 by weight, of one or more hydrophilic or hydrophobic polymers as pharmaceutically acceptable matrix forming agents and which comprise cellulose ethers and/or cellulose esters having a viscosity (determined using a Pharm. Eu. capillary viscosimeter) of 3,000 to 150,000 mPa ⁇ s in a 2% by weight aqueous solution at 20° C. as pharmaceutically acceptable matrix forming agents.
- These compositions have the above-mentioned release profile according to the invention.
- Preferred pharmaceutically acceptable matrix forming agents include cellulose ethers and/or cellulose esters having a viscosity between 10,000, in particular 50,000 mPa ⁇ s, and 150,000 mPa ⁇ s in a 2% by weight aqueous solution at 20° C.
- Particularly suitable pharmaceutically acceptable matrix forming agents may be selected from the group consisting of hydroxypropylmethyl celluloses (HPMC), hydroxyethyl celluloses, hydroxypropyl celluloses (HPC), methyl celluloses, ethyl celluloses and carboxymethyl celluloses and are selected, in particular, from the group consisting of HPMCs, hydroxyethyl celluloses and HPCs.
- HPMCs having a viscosity of approx. 100,000 mPa ⁇ s, measured in a 2% by weight aqueous solution at 20° C. are most preferred.
- the active ingredient 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, exists as such, i.e. as a free base, but also in the form of pharmaceutically acceptable salts, for example as a hydrochloride.
- a free base Preparation of the free base is known from published European patent application no. EP 693,475. Where EP 693,475 does not also disclose the preparation of pharmaceutically acceptable salts such as hydrochloride, these may be obtained from the free base by processes generally known in the art.
- 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol has two asymmetric centers, so the compound can exist in the form of four different stereoisomers.
- 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol can exist as a mixture of all four diastereomers in any ratio, but also as a mixture of two or three of the four stereoisomers or in pure stereoisomer form.
- Preferred stereoisomers include (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol and ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, which, in the formulation according to the invention, can exist as a mixture, in particular as a 1:1 mixture (racemate) or particularly preferably in pure isomer form.
- active ingredient denotes 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol as a mixture of various stereoisomers thereof or as one pure stereoisomer thereof as a free base or in the form of a pharmaceutically acceptable salt respectively.
- the slow release active ingredient content is preferably between 0.5 and 85% by weight and the content of pharmaceutically acceptable matrix forming agents between 8 and 40% by weight.
- Particularly preferred pharmaceutical compositions have a slow release active ingredient content between 3 and 70% by weight, in particular between 8 and 66% by weight, and a content of pharmaceutically acceptable matrix forming agents between 10 and 35% by weight, in particular between 10 and 30% by weight.
- the active ingredient content lies at the lower limit, i.e. between 0.5 and 25% by weight (based on the total weight).
- active ingredient content lies between 16 and 66% by weight.
- Further components of the matrix of the formulation according to the invention may optionally include digestible long-chain (i.e. with 8 to 50 carbon atoms, preferably 12 to 50 carbon atoms) unsubstituted or substituted hydrocarbons such as fatty alcohols, fatty acid glyceryl esters, mineral and vegetable oils as well as waxes. Hydrocarbons having a melting point between 25° and 90° C. are preferred. Fatty alcohols are particularly preferred and lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol and cetylstearyl alcohol are more particularly preferred. Their content in the matrix may be 0 to 60% by weight. The matrix can alternatively or additionally contain polyethylene glycols in a content of 0 to 60% by weight.
- the pharmaceutical formulations according to the invention can also contain, as further components, pharmaceutically acceptable auxiliaries such as fillers, for example lactose, microcrystalline cellulose (MCC) or calcium hydrogen phosphate as well as glidants, lubricants and flow regulators such as talcum, magnesium stearate, stearic acid and/or highly dispersed silicon dioxide, of which the total content in the tablet may be between 0 and 80% by weight, preferably between 5 and 65% by weight.
- pharmaceutically acceptable auxiliaries such as fillers, for example lactose, microcrystalline cellulose (MCC) or calcium hydrogen phosphate as well as glidants, lubricants and flow regulators such as talcum, magnesium stearate, stearic acid and/or highly dispersed silicon dioxide, of which the total content in the tablet may be between 0 and 80% by weight, preferably between 5 and 65% by weight.
- the release rate of an active ingredient from an administrable form frequently depends on the pH of the release medium. This can vary in a pH range from less than 1 to about 8 as the pharmaceutical composition passes through the gastrointestinal tract. These variations also can vary from one person to another. One and the same person can also have a different pH/time profile during passage through the gastrointestinal tract from one administration to another. Thus, if the release rate of the active ingredient from the pharmaceutical composition is dependent on the pH, this can lead to different release rates in vivo and therefore different biocompatibility.
- the release profiles of the active ingredient (either in the form of the base or of a pharmaceutically acceptable salt thereof) from a pharmaceutical formulation according to the invention are independent of the pH which can occur physiologically during passage through the gastrointestinal tract.
- the release profiles with an ambient pH of 1.2, 4.0 and 6.8 are identical to one another and also in comparison to the release during a pH/time profile from pH 1.2 via pH 2.3 and pH 6.8 to pH 7.2.
- the quantity of matrix forming agent and the quantity of optional components can each vary over a relatively large range without affecting the therapeutic efficacy of at least 12 hours or with twice daily administration (providing that the above-mentioned limits on the quantity of active ingredient, matrix forming agent and further optional components are adhered to). Efficacy over at least 12 hours is assured, for example, with an active ingredient content of approx. 32.25% by weight (based on the weight of the total composition) in a composition of approx. 12.9% by weight HPMC having a viscosity of 100,000 mPa ⁇ s as matrix forming agent and a content of approx.
- compositions according to the invention with a higher or lower active ingredient content within the specified limits.
- compositions according to the invention which have a t max value in the in vivo plasma concentration/time graph of between 2 and 10 hours, in particular between 3.5 and 6 hours and more particularly preferably between 4 and 5.5 hours after oral administration of the composition, i.e. compositions which yield peak plasma levels during said periods, are also preferred.
- the formulation according to the invention contains 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol as such and/or as a pharmaceutically acceptable salt in an amount typically of 2.5 to 800 mg, in particular 5 to 400 mg, more particularly preferably 10 to 250 mg (weight of the active ingredient 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol as hydrochloride) per dose unit.
- the release behavior of the formulation according to the invention is not affected by the exact amount of the active ingredient provided that the above-mentioned limits are adhered to.
- (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol and ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol it is preferred if the stronger (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol exists in an amount of 2.5 to 80 mg, in particular 5 to 40 mg and more particularly preferably in an amount of 10 to 25 mg active ingredient (based on the hydrochloride) in the formulations according to the invention, while the ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol preferably is present in an amount of 25 to 800 mg, in particular 50 to 400 mg and more particularly preferably in an amount of 100 to 250 mg active
- the term “pharmaceutically acceptable salt” of the active ingredient refers to a salt of the active ingredient which is physiologically acceptable for pharmaceutical use, in particular when administered to mammals and/or humans.
- Pharmaceutically acceptable salts of this type may be formed, for example, with inorganic or organic acids.
- the pharmaceutical formulations according to the invention can exist both as a simple tablet and as a coated tablet, for example as a film tablet or dragee.
- the tablets are typically round and biconvex, but oblong tablet shapes which allow the tablet to be divided are also possible.
- Granules, spheroids, pellets or microcapsules which are poured into sachets or capsules or may be compressed to disintegrating tablets are also possible within the scope of the invention.
- One or more coating layers may be used for the coated tablets.
- Suitable coating materials include known hydroxypropylmethyl celluloses having a low viscosity of approx. 1 to 100 mPa ⁇ s and a low molecular weight of ⁇ 10,000 (for example Pharmacoat 606 with a viscosity of 6 mPa ⁇ s in a 2% by weight aqueous solution at 20° C.), which only slightly influence the release profile of the pharmaceutical compositions according to the invention.
- Diffusion coatings known to persons skilled in the art and based, for example, on swellable but water-insoluble poly(meth)acrylates lead to modulation of the slow release of the active ingredients from pharmaceutical formulations according to the invention.
- the tablet core which contains the active ingredient releases the active ingredient slowly and has an active ingredient content preferably between 0.5 and 85% by weight, particularly preferably between 3 and 70% by weight and more particularly preferably between 8 and 66% by weight.
- the tablet core can be sheathed with additional active ingredient which is released as an initial dose without retardation by various processes known to persons skilled in the art, for example dragee production, spraying from solutions or suspensions or by application of powder, but without this being absolutely essential for the desired slow release with a simultaneous rapid initial flow of the active ingredient for rapid pain relief on first administration of the pharmaceutical formulation according to the invention.
- Multilayered and shell-type tablets represent further embodiments, in which 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof is released slowly in one or more layers of the multilayer tablet with an active ingredient content preferably between 0.5 and 85% by weight, particularly preferably between 3 and 70% by weight, and more particularly preferably between 8 and 66% by weight, or in the core of the shell-type tablet with an active ingredient content preferably between 0.5 and 85% by weight, particularly preferably between 3 and 70% by weight, and more particularly preferably between 8 and 66% by weight by a pharmaceutically acceptable matrix forming agent, and the release of the active ingredient takes place without retardation in one or more layers of the multilayer tablet or the outer shell layer of the shell-type tablets.
- Multilayer and shell-type tablets can contain one or more coatings which are free from active ingredients.
- the active ingredient can be contained in a conventional matrix of microcrystalline cellulose and optionally further pharmaceutical auxiliaries such as binders, fillers, glidants, lubricants and flow regulators, which are covered or coated with a material controlling the slow release of the active ingredient in an aqueous medium.
- suitable coating agents include, for example, water-insoluble waxes and polymers such as polymethacrylates (Eudragit or the like) or water-insoluble celluloses, in particular ethyl cellulose.
- the coating material can optionally also contain water-soluble polymers such as polyvinyl pyrrolidone, water-soluble celluloses such as hydroxypropylmethyl cellulose or hydroxypropyl cellulose, other water-soluble agents such as Polysorbate 80 or hydrophilic pore-forming agents such as polyethylene glycol, lactose or mannitol.
- water-soluble polymers such as polyvinyl pyrrolidone, water-soluble celluloses such as hydroxypropylmethyl cellulose or hydroxypropyl cellulose, other water-soluble agents such as Polysorbate 80 or hydrophilic pore-forming agents such as polyethylene glycol, lactose or mannitol.
- an osmotically driven release system can also be used to achieve a slow release.
- a release system of this type preferably an oral system
- at least one, preferably all, surface(s) of the release system preferably those which are in contact or which may come into contact with the release medium, are semi-permeable, preferably provided with a semi-permeable coating, so the surfaces are permeable to the release medium but substantially, and preferably completely, impermeable to the active ingredient, whereby the surface and/or optionally the coating comprises at least one opening for releasing the active ingredient.
- the active ingredient 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof, preferably (+)-(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof and/or ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof or a mixture thereof can, but does not have to, be present in a matrix.
- This is preferably taken to mean a system in tablet form with a delivery opening, an osmotic pharmaceutical composition core, a semi-permeable membrane and a polymeric part which exerts pressure.
- a useful example of such a system is the OROS® system from ALZA Corporation, USA, details of which are available on the Alza Corporation internet site and/or in product literature of Alza Corporation. These include in particular the OROS® Push-PullTM system, the OROS® Delayed Push-PullTM system, the OROS® Multi-Layer Push-PullTM system, the OROS® Push-Stick System and in certain cases the L-OROSTM.
- Embodiments and examples of the actual production of osmotically driven release systems can be found in U.S. Pat. Nos. 4,765,989; 4,783,337 and 4,612,008, the complete disclosures of which are incorporated herein by reference.
- compositions according to the invention may be produced, for example, by the following general processes: weighed amounts of the components of the composition (active ingredient, matrix forming agent and optional components) successively introduced and then screened on a conventional screening machine, for example a Quadro Comil U10 screening machine using, for example, a conventional screen size of approx. 0.813 mm.
- a conventional screening machine for example a Quadro Comil U10 screening machine using, for example, a conventional screen size of approx. 0.813 mm.
- the screened material is then mixed in a container mixer, for example a Bohle container mixer.
- Typical mixer operating conditions are: duration approx. 15 min ⁇ 45 seconds at a speed of 20 ⁇ 1 rpm.
- the resulting powder mixture is subsequently compressed to a tablet on a tablet press, for example a Korsch EKO tablet press with a round die curved in the form of a dragee having a diameter of 10 mm.
- a tablet press for example a Korsch EKO tablet press with a round die curved in the form of a dragee having a diameter of 10 mm.
- the powder mixture can be compacted and the compacts subsequently screened (Comill 3 mm friction macerating sieve and subsequent 1.2 mm round hole screen), the resulting granules then being compressed in the above-described manner with addition of lubricant (for example magnesium stearate) for example on an EKO tablet press with 10 mm round dies.
- Granulation can also be carried out by wet granulation using aqueous or organic solvents. Aqueous solvents with or without a suitable binder are preferred.
- the production process can readily be adapted to the respective requirements and the desired form of administration by procedures well known to persons skilled in
- the production of pharmaceutical formulations according to the invention is characterized by high repeatability of the release properties of the resulting compositions containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof.
- the release profile of pharmaceutical compositions according to the invention has proven to be stable for a storage time of at least one year under conventional storage conditions according to ICH Q1AR Stability Testing Guidelines.
- a batch of 1,000 matrix tablets was produced as described below having with the following composition per tablet: ( ⁇ )-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol 100 mg hydrochloride Hydroxypropylmethyl cellulose (Metolose 90 80 mg SH 100,000 from Shinetsu, 100,000 mPa ⁇ s Microcrystalline cellulose (Avicel PH 102 from FMC) 123 mg Highly dispersed silicon dioxide 4 mg Magnesium stearate 3 mg Total amount 310 mg
- 3,000 matrix tablets were produced having the following composition per tablet: ( ⁇ )-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol 200 mg hydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 80 mg from Shinetsu, 100,000 mPa ⁇ s Microcrystalline cellulose (Avicel PH 102 from FMC) 23 mg Highly dispersed silicon dioxide 4 mg Magnesium stearate 3 mg Total amount 310 mg
- the in vitro release was determined as in Example 1. Total amount of active ingredient Time (min) released [%] 0 0 30 19 60 30 120 46 180 58 240 68 360 84 480 93 720 99
- the in vitro release was determined as in Example 1. In addition, the release was determined under otherwise identical conditions at stirring speeds of 50 and 100 rpm. Total amount of Total amount of Total amount of active ingredient active ingredient active ingredient Time released [%] released [%] released [%] (min) at 50 rpm at 75 rpm at 100 rpm 0 0 0 0 30 20 20 21 60 35 33 35 120 54 51 53 180 67 63 66 240 76 73 76 360 89 87 89 480 97 95 97 600 100 100 100 100 100 100
- the in vitro release was determined as in Example 1.
- Total amount of active ingredient Time (min) released [%] 0 0 30 16 60 26 120 39 180 49 240 57 360 71 480 81 600 87 720 92
- the in vitro release was determined as an Example 1.
- the in vitro release was determined as in Example 1. Total amount of active ingredient Time (min) released [%] 0 0 30 17 60 27 120 40 180 51 240 59 360 72 480 82 600 89 720 93
- the in vitro release was determined as in Example 1. Total amount of active ingredient Time (min) released [%] 0 0 30 18 60 31 120 49 180 61 240 70 360 82 480 90 600 94 720 96
- the cooled granules were screened through a 1 mm screen. After blending with magnesium stearate and talcum, the granules were pressed on a EK0 eccentric press (Korsch) to 6 ⁇ 15 mm size oblong tablets with a breaking notch.
- Example 2 The in vitro release was determined as in Example 1. Total amount of active ingredient Time (min) released [%] 0 0 30 28 60 39 120 56 180 68 240 80 360 97 390 99
- Example 1 The in vitro release was determined as in Example 1. Total amount of active ingredient Time (min) released [%] 0 0 30 15 60 24 120 36 180 44 240 51 360 61 480 69 600 75 720 79
- Matrix tablets with the following composition per tablet ( ⁇ )-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol 100 mg hydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from 80 mg Shinetsu, 100,000 mPa ⁇ s Microcrystalline cellulose (Avicel PH 102 from FMC) 63 mg Highly dispersed silicon dioxide 4 mg Magnesium stearate 3 mg Total amount 250 mg were produced by a process similar to that described in Example 1 in a batch size of 100 tablets.
- the in vitro release was determined under the following conditions:
- Pellets were produced as described below having the following composition: ( ⁇ )-(1R,2R)3-(3-dimethylamino-1-ethyl-2-methyl-propyl) 100 mg phenol hydrochloride Low-substituted hydroxypropyl cellulose (L-HPC LH 31 from 75 mg Shinetsu) Aquacoat (aqueous ethyl cellulose dispersion from FMC) 20 mg (calculated as dry substance) Microcrystalline cellulose (Avicel PH 101 from FMC) 75 mg Dibutyl sebacate (DBS) 4 mg Tween 80 0.4 mg Total amount 274.4 mg The active ingredient, Avicel and L-HPC were mixed for 10 minutes in a planetary mixer (Kenwood K Mixer) and then granulated with water.
- L-HPC LH 31 from 75 mg Shinetsu
- Aquacoat aqueous ethyl cellulose dispersion from FMC
- Microcrystalline cellulose Avicel PH 101 from FMC
- DBS Di
- the moist granules were extruded in a Nica extruder with a 0.8 ⁇ 0.8 mm matrix and then rounded for 10 min in the Nica spheronizer at 500 rpm (1 kg loading). The pellets were dried overnight in a drying oven at 50° C. and then classified into screen fractions.
- Pellets measuring 0.6 to 1.0 mm were coated in the WSG (smooth GPCG1 with a Wurster insert) at incoming air temperatures of 60° C. (product temperature 40° C.) with an aqueous dispersion of Aquacoat and DBS (20%, calculated on Aquacoat solids content), so they had an increase in weight of 9.8% (based on the original weight).
- the dispersion was produced in accordance with the manufacturer's instructions (FMC), the DBS together with the Tween 80 being homogenized in a proportion of the water and then being added to the dilute Aquacoat dispersion.
- the final dispersion had a solids content of 20% by weight and was stirred for at least 3 hours.
- the coated pellets were dried in the WSG and tempered in the drying oven (2 hours at 60° C.). The release was tested as in Example 1, but by the basket method at 100 rpm. Total amount of active ingredient Time (min) released [%] 0 0 30 5 60 15 120 28 180 43 240 56 360 73 480 82 600 87 720 90 Clinical Trial
- Capsule 100 mg capsules with immediate release of the active ingredient and 100 mg of active ingredient
- Capsule 25 mg capsules with immediate release of the active ingredient and 25 mg of active ingredient
- Tablet 100 mg tablet according to Example 1 (100 mg of active ingredient)
- Tablet 200 mg tablet according to Example 2 (200 mg of active ingredient)
- the capsules were white-opaque hard gelatine capsules of size 0 EL with a filling of 360 mg, which were made up as follows:
- Capsule 100 mg 100 mg ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol hydrochloride, 152 mg microcrystalline cellulose, 8 mg Aerosil, 20 mg magnesium stearate and 80 mg Primojel (sodium carboxymethyl starch type A from Avebe);
- Capsule 25 mg 25 mg ( ⁇ )-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol hydrochloride, 227 mg microcrystalline cellulose, 8 mg Aerosil, 20 mg magnesium stearate and 80 mg Primojel (sodium carboxymethyl starch type A from Avebe))
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/242,800 US20120034304A1 (en) | 2001-10-24 | 2011-09-23 | Prolonged Release Pharmaceutical Composition Containing 3-(3-Dimethylamino-1-Ethyl-2-Methyl-Propyl)Phenol |
US13/868,635 US20130237608A1 (en) | 2001-10-24 | 2013-04-23 | Prolonged Release Pharmaceutical Composition Containing 3-(3-Dimethylamino-1-Ethyl-2-Methyl-Propyl)Phenol |
US15/018,529 US20160151309A1 (en) | 2001-10-24 | 2016-02-08 | Prolonged release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol |
US15/377,628 US20170087103A1 (en) | 2001-10-24 | 2016-12-13 | Prolonged release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol |
US15/943,175 US20180221308A1 (en) | 2001-10-24 | 2018-04-02 | Prolonged release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol |
US16/600,974 US11007156B2 (en) | 2001-10-24 | 2019-10-14 | Prolonged release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10152469A DE10152469A1 (de) | 2001-10-24 | 2001-10-24 | 3-(3-Dimethylamino-1-ethyl-2-methyl-propyl)phenol enthaltendes Arzneimittel mit verzögerter Wirkstofffreisetzung |
DE10152469.2 | 2001-10-24 | ||
DE10248309.4 | 2002-10-16 | ||
DE2002148309 DE10248309A1 (de) | 2002-10-16 | 2002-10-16 | 3-(3- Dimethylamino-1-ethyl-2-methyl-propyl) phenol enthaltendes Arzeimittel mit verzögerter Wirkstofffreisetzung |
PCT/EP2002/011809 WO2003035053A1 (de) | 2001-10-24 | 2002-10-22 | 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol enthaltendes arzneimittel mit verzögerter wirkstofffreisetzung |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2002/011809 Continuation WO2003035053A1 (de) | 2001-10-24 | 2002-10-22 | 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol enthaltendes arzneimittel mit verzögerter wirkstofffreisetzung |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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US13/242,800 Continuation US20120034304A1 (en) | 2001-10-24 | 2011-09-23 | Prolonged Release Pharmaceutical Composition Containing 3-(3-Dimethylamino-1-Ethyl-2-Methyl-Propyl)Phenol |
Publications (1)
Publication Number | Publication Date |
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US20050058706A1 true US20050058706A1 (en) | 2005-03-17 |
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Application Number | Title | Priority Date | Filing Date |
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US10/831,368 Abandoned US20050058706A1 (en) | 2001-10-24 | 2004-04-26 | Delayed release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol |
US13/242,800 Abandoned US20120034304A1 (en) | 2001-10-24 | 2011-09-23 | Prolonged Release Pharmaceutical Composition Containing 3-(3-Dimethylamino-1-Ethyl-2-Methyl-Propyl)Phenol |
US13/868,635 Abandoned US20130237608A1 (en) | 2001-10-24 | 2013-04-23 | Prolonged Release Pharmaceutical Composition Containing 3-(3-Dimethylamino-1-Ethyl-2-Methyl-Propyl)Phenol |
US15/018,529 Abandoned US20160151309A1 (en) | 2001-10-24 | 2016-02-08 | Prolonged release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol |
US15/377,628 Abandoned US20170087103A1 (en) | 2001-10-24 | 2016-12-13 | Prolonged release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol |
US15/943,175 Abandoned US20180221308A1 (en) | 2001-10-24 | 2018-04-02 | Prolonged release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol |
US16/600,974 Expired - Lifetime US11007156B2 (en) | 2001-10-24 | 2019-10-14 | Prolonged release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol |
Family Applications After (6)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/242,800 Abandoned US20120034304A1 (en) | 2001-10-24 | 2011-09-23 | Prolonged Release Pharmaceutical Composition Containing 3-(3-Dimethylamino-1-Ethyl-2-Methyl-Propyl)Phenol |
US13/868,635 Abandoned US20130237608A1 (en) | 2001-10-24 | 2013-04-23 | Prolonged Release Pharmaceutical Composition Containing 3-(3-Dimethylamino-1-Ethyl-2-Methyl-Propyl)Phenol |
US15/018,529 Abandoned US20160151309A1 (en) | 2001-10-24 | 2016-02-08 | Prolonged release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol |
US15/377,628 Abandoned US20170087103A1 (en) | 2001-10-24 | 2016-12-13 | Prolonged release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol |
US15/943,175 Abandoned US20180221308A1 (en) | 2001-10-24 | 2018-04-02 | Prolonged release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol |
US16/600,974 Expired - Lifetime US11007156B2 (en) | 2001-10-24 | 2019-10-14 | Prolonged release pharmaceutical composition containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol |
Country Status (29)
Country | Link |
---|---|
US (7) | US20050058706A1 (no) |
EP (1) | EP1439829B1 (no) |
JP (2) | JP4758064B2 (no) |
KR (1) | KR100958045B1 (no) |
CN (1) | CN100402021C (no) |
AR (1) | AR036943A1 (no) |
AT (1) | ATE303802T1 (no) |
AU (1) | AU2002349001C1 (no) |
BR (1) | BRPI0213653B8 (no) |
CA (1) | CA2464578C (no) |
CO (1) | CO5570662A2 (no) |
CY (1) | CY2012022I2 (no) |
DE (1) | DE50204198D1 (no) |
DK (1) | DK1439829T3 (no) |
EC (1) | ECSP045102A (no) |
ES (1) | ES2248622T3 (no) |
HK (1) | HK1068539A1 (no) |
HU (1) | HU230161B1 (no) |
IL (2) | IL161587A0 (no) |
MX (1) | MXPA04003742A (no) |
MY (1) | MY127797A (no) |
NO (2) | NO331896B1 (no) |
NZ (1) | NZ532999A (no) |
PE (1) | PE20030527A1 (no) |
PL (1) | PL216535B1 (no) |
PT (1) | PT1439829E (no) |
SI (1) | SI1439829T1 (no) |
WO (2) | WO2003035054A1 (no) |
ZA (1) | ZA200403928B (no) |
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- 2002-10-22 AU AU2002349001A patent/AU2002349001C1/en active Active
- 2002-10-22 NZ NZ532999A patent/NZ532999A/en not_active IP Right Cessation
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