CA2739611C - Pharmaceutical containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol and providing delayed release of the active ingredient - Google Patents
Pharmaceutical containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol and providing delayed release of the active ingredient Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
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- 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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- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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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
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- 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]
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Abstract
The invention relates to a pharmaceutical formulation which is characterised by delayed release of the active ingredient. Said formulation contains 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or one of its pharmaceutically acceptable salts in a matrix with delayed release of the active ingredient. Said matrix contains between 1 and 80 wt.% of at least one hydrophilic or hydrophobic polymer as a pharmaceutically acceptable matrix forming agent and exhibits, in vitro, the following dissolution speed: between 3 and 35 wt.% (in relation to 100 wt.% of active ingredient) of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol is released after half an hour, between 5 and 50 wt.% of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol is released after one hour, between 10 and 75 wt.% of 3-(3-dimethylamino-1-ethyl- 2- methyl-propyl)phenol is released after two hours, between 15 and 82 wt.% of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol is released after three hours, between 30 and 97 wt.% of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol is released after six hours, more than 50 wt.% of 3-(3-dimethylamino-1-ethyl-2- methyl- propyl)phenol is released after twelve hours, more than 70 wt.% of 3-(3- dimethylamino- 1-ethyl-2-methyl-propyl)phenol is released after eighteen hours, and more than 80 wt.% of 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol is released after twenty- four hours. The slow release of the active ingredient is achieved by means of a slow release matrix, by means of a normal matrix with a coating which retards the release of the active ingredient or by means of an osmotically driven release system.
Description
Pharmaceutical containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol and providing delayed release of the active ingredient This is a divisional application of Canadian Patent Application No. 2,464,578, filed October 22, 2002.
The 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.
The subject matter of this divisional application is directed to a slow-release pharmaceutical composition wherein the slow-release is achieved by means of a normal matrix with a coating which retards the release of active ingredient or by means of an osmotically driven release system.
The subject matter of the parent application has been restricted to a slow-release pharmaceutical composition wherein the slow-release is achieved by means of a slow-release matrix. However, it should be understood that the expression "the invention" and the like, when used herein, encompasses the subject matter of both the parent and this divisional application.
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol is known from EP 0 693 475 B1 as an analgesic pharmaceutical composition and can be administered orally.
Conventional formulations for the oral administration of 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol lead to fast 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.
Therefore, the treatment of pronounced chronic pain with 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol formerly necessitated the administration of the pharmaceutical composition at relatively short intervals, for example four to eight times daily to ensure an adequately high concentration of active ingredient in the patient's blood plasma. However, the need for frequent dosing easily leads to errors in administration and to undesirable variations in concentration in the plasma which are detrimental to patient compliance and the therapeutic benefit, particularly when treating chronically painful conditions. A form for la pharmaceutical administration with slow release (retard formulation) for oral administration of the active ingredient, 3-(3-dimethylamino- 1 -ethyl-2-methyl-propyl)phenol, is therefore desirable.
In the prior art, retard formulations are generally known for a large number of different active ingredients. Conventional forms of retardation include coating retardation and matrix retardation.
In the case of coating retardation, of the type described, for example, in DE
36 25 458 Al, 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.
In the case of matrix retardation, the active ingredient is contained in a matrix which is formed from one or more excipients and controls release of the active ingredient.
DE 33 09 516 Al, for example, 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. The formulations disclosed in DE 33 09 516 Al contain HPMCs having viscosities (in a 2% by weight aqueous solution at 20 C) between and 30,000 cPs (15 to 30,000 inPa.$). Release behaviour which is independent of the pH of the dissolution medium is not disclosed in DE 33 09 516 Al.
An object of the present invention is accordingly to prepare a 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol-containing pharmaceutical formulation with slow release of active ingredient.
This object is achieved by a slow-release pharmaceutical formulation, containing 3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof in a matrix with slow release of active ingredient, wherein 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 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.
The subject matter of this divisional application is directed to a slow-release pharmaceutical composition wherein the slow-release is achieved by means of a normal matrix with a coating which retards the release of active ingredient or by means of an osmotically driven release system.
The subject matter of the parent application has been restricted to a slow-release pharmaceutical composition wherein the slow-release is achieved by means of a slow-release matrix. However, it should be understood that the expression "the invention" and the like, when used herein, encompasses the subject matter of both the parent and this divisional application.
3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol is known from EP 0 693 475 B1 as an analgesic pharmaceutical composition and can be administered orally.
Conventional formulations for the oral administration of 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol lead to fast 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.
Therefore, the treatment of pronounced chronic pain with 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol formerly necessitated the administration of the pharmaceutical composition at relatively short intervals, for example four to eight times daily to ensure an adequately high concentration of active ingredient in the patient's blood plasma. However, the need for frequent dosing easily leads to errors in administration and to undesirable variations in concentration in the plasma which are detrimental to patient compliance and the therapeutic benefit, particularly when treating chronically painful conditions. A form for la pharmaceutical administration with slow release (retard formulation) for oral administration of the active ingredient, 3-(3-dimethylamino- 1 -ethyl-2-methyl-propyl)phenol, is therefore desirable.
In the prior art, retard formulations are generally known for a large number of different active ingredients. Conventional forms of retardation include coating retardation and matrix retardation.
In the case of coating retardation, of the type described, for example, in DE
36 25 458 Al, 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.
In the case of matrix retardation, the active ingredient is contained in a matrix which is formed from one or more excipients and controls release of the active ingredient.
DE 33 09 516 Al, for example, 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. The formulations disclosed in DE 33 09 516 Al contain HPMCs having viscosities (in a 2% by weight aqueous solution at 20 C) between and 30,000 cPs (15 to 30,000 inPa.$). Release behaviour which is independent of the pH of the dissolution medium is not disclosed in DE 33 09 516 Al.
An object of the present invention is accordingly to prepare a 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol-containing pharmaceutical formulation with slow release of active ingredient.
This object is achieved by a slow-release pharmaceutical formulation, containing 3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof in a matrix with slow release of active ingredient, wherein 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:
3 to 35% by weight (based on 100 by weight active ingredient) 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 0.5 hours, to 50% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 1 hour, to 75% by weight 3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol released after 2 hours, 5 15 to 82% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 3 hours, 30 to 97% by weight 3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol released after 6 hours, more than 50% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 10 12 hours, more than 70% by weight 3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol released after 18 hours, more than 80% by weight 3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol released after 24 hours.
According to one aspect of the invention of the parent application, there is provided a slow-release pharmaceutical composition comprising 3-(3-dimethylamino-1 -ethy1-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof in a matrix with slow release of active ingredient, wherein the matrix comprises 1 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:
3 to 35% by weight (based on 100 by weight active ingredient) 3-(3-dimethylamino-1 -ethy1-2-methyl-propyl)phenol released after 0.5 hours, 3a to 50% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 1 hour, to 75% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 2 hours, 5 15 to 82% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 3 hours, 30 to 97% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 6 hours, more than 50% by weight 3-(3-dimethylamino- 1 -ethyl-2-methyl-propyl)phenol released after 10 12 hours, more than 70% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 18 hours, more than 80% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 24 hours.
According to another aspect of the invention of the parent application, there is provided a slow-release pharmaceutical composition comprising 3-(3-dimethylamino- 1 -ethy1-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof in a matrix with slow release of active ingredient, wherein the matrix comprises 1 to 80% by weight of one or more hydrophilic or hydrophobic polymers as pharmaceutically acceptable matrix forming agents and, as pharmaceutically acceptable matrix forming agents, comprises cellulose ethers and/or cellulose esters having a viscosity of 3,000 to 150,000 mPa.s in a 2%
by weight aqueous solution at 20 C.
According to yet another aspect of the invention of the parent application, there is provided a tablet for the twice daily oral administration of 3-(3-dimethylamino-1 -ethyl-2-methyl-propyl)phenol comprising a pharmaceutical composition as described herein.
3b According to one aspect of the invention of the present divisional application, there is provided a slow-release pharmaceutical composition comprising 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof as active ingredient in a matrix coated with a material controlling the slow release of the active ingredient in an aqueous medium, the coating material comprising a water-insoluble wax, a polymethacrylate or a water-insoluble cellulose, wherein the active ingredient 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 spectometer:
3 to 35% by weight (based on 100% by weight active ingredient) 3-(3-dimethylamino-1-1 0 ethyl-2-methyl-propyl)phenol released after 0.5 hours, 5 to 50% by weight 3-(3-dimethylamino-1 -ethy1-2-methyl-propyl)phenol released after 1 hour, to 75% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 2 hours, 15 to 82% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 3 hours, 30 to 97% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 6 hours, more than 50% by weight 3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol released after 12 hours, more than 70% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 18 hours, and more than 80% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 24 hours.
3c According to another aspect of the invention of the present divisional application, there is provided a slow-release pharmaceutical composition comprising 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof as active ingredient in an oral osmotically driven release system, wherein surfaces of the oral osmotically driven release system that are in contact or that are contactable with a release medium are provided with a semipermeable-coating, so that the surfaces are permeable to the release medium but substantially impermeable to the active ingredient, wherein one or both of the surface and the coating comprise at least one opening for releasing the active ingredient, wherein the active ingredient 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 spectometer:
3 to 35% by weight (based on 100% by weight active ingredient) 3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol released after 0.5 hours, 5 to 50% by weight 3-(3-dimethylamino- 1 -ethy1-2-methyl-propyl)phenol released after 1 hour, 10 to 75% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 2 hours, 15 to 82% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 3 hours, 30 to 97% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 6 hours, more than 50% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 12 hours, more than 70% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 18 hours, and 3d more than 80% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 24 hours.
Throughout this specification, the composition described is sometimes referred to as a "formulation".
It has surprisingly been found that the formulation according to the invention releases the active ingredient, 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol, slowly when administered orally and is therefore suitable for administration at intervals of at least 12 hours. The formulation according to the invention therefore allows pain therapy, during which the analgesic, 3-(3-dimethylamino-1-ethy1-2-methyl-1 0 propyl)phenol, only has to be administered once daily, for example at 24 hour intervals, or twice daily, preferably at 12 hourly intervals, in order to ensure an adequate concentration of the active ingredient in the plasma. A corresponding duration of efficacy and the maintenance of an adequate level in the blood plasma are demonstrated by simulation studies and experimental investigations.
It is particularly surprising that the formulation according to the invention not only ensures long-lasting therapeutic efficacy over a relatively long period (at least 12 hours) owing to the slow release, 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 owing to an adequately high level of active ingredient over a prolonged time. By taking the 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 is contained in a matrix with conventional release behaviour and the slow release is achieved by a retarding coating.
In a further possibility the slow release behaviour is achieved by an osmotically driven release system.
If the formulation according to the invention contains a slow release matrix, 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. When using hydrophilic polymers as matrix forming agents, 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-ethy1-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof in a matrix with slow release of active ingredient, wherein 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 is characterised in that as pharmaceutically acceptable matrix forming agents, comprises cellulose ethers and/or cellulose esters having a viscosity of 3,000 to 150,000 mPas in a 2% by weight aqueous solution at 20 C. (The viscosity is determined using a Pharm. Eu. capillary viscosimeter). The 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 mPas, and 150,000 mPas in a 2% by weight aqueous solution at 20 C.
Particularly suitable pharmaceutically acceptable matrix forming agents selected from the group comprising hydroxypropylmethyl celluloses (HPMC), hydroxyethyl celluloses, hydroxypropyl celluloses (HPC), methyl celluloses, ethyl celluloses and carboxymethyl celluloses and are selected, in particular, from the group comprising = HPMCs, hydroxyethyl celluloses and HPCs. HPMCs having a viscOsity of approx.
100,000 mPas, measured in a 2% by weight aqueous solution at 20 C are most preferred.
The active ingredient, 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol, exists as such, i.e. as a free base, but also in the form of a pharmaceutically acceptable salt, for example as hydrochloride. Preparation of the free base is known from EP 0 475 Al. Where EP 0 693 475 Al 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 from the prior art.
3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol has two centres of asymmetry, so the compound can exist in the form of four different stereoisomers. In the formulation according to the invention 3-(3-dimethylamino-1-ethy1-2-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-l-ethy1-2-methyl-propyl)phenol and (-)-(1R,2R)-3-(3-dimethylamino-l-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.
For the purposes of the present invention, therefore, the term "active ingredient"
denotes 3-(3-dimethylamino-l-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.
In the pharmaceutical compositions according to the invention, 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. If the =
enantiomer-pure (+)-(1S,2S)-3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol (or a mixture of the (+) and (-) enantiomers with a large excess of the (+) enantiomer) is used as active ingredient, it is particularly preferred if the active ingredient content lies at the lower limit, i.e. between 0.5 and 25% by weight (based on the total weight). If the enantiomer-pure (-)-(1R,2R)-3-(3-dimethylamino-l-ethyl-' 2-methyl-propyl)phenol (or a mixture of the (+) and (-) enantiomers with a large excess of the (-) enantiomer) is used as active ingredient, it is particularly preferred if the active ingredient content lies between 16 and 66% by weight.
Further components of the matrix of the formulation according to the invention may optionally be 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 being 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 is 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 sliding agents, 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 is between 0 and 80% by weight, preferably between 5 and 65%
by weight.
The release rate of an active ingredient from an administrable form is often dependent 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 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. 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.
However, the release profiles of the active ingredient (in the form of the base or a pharmaceutically acceptable salt thereof) from a pharmaceutical formulation according to the invention are surprisingly dependent on 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 comparative to the release during a pH/time profile of pH 1.2 over pH 2.3 and pH
6.8 to pH 7.2.
It has been found that it is immaterial for achieving the slow release of active ingredient from the formulation according to the invention which preferably exists in tablet form, whether a water-soluble filler, for example lactose, an insoluble filler which does not swell in an aqueous medium, for example calcium hydrogen phosphate, or an insoluble filler which swells in an aqueous medium, for example microcrystalline cellulose, is used as filler with otherwise unchanged values and unchanged composition of the tablet, based on the active ingredient, the matrix forming agent and the optional components. All these pharmaceutical compositions exhibit mutually corresponding release behaviour.
It is also surprising that, in the compositions according to the invention with a given amount of active ingredient, 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 h or with twice daily administration (providing that the above-mentioned limits to the quantity of active ingredient, matrix forming agent and further optional components are adhered to). Efficacy over at least 12 h is ensured, 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, for example MCC as filler of approx. 52.6% by weight and also in a composition of approx. 25.8% by weight of the same HPMC and approx. 39.7% by weight MCC (or lactose monohydrate) with otherwise identical amounts of sliding agent, lubricant and flow regulators. The same applies to compositions according to the invention with a higher or lower active ingredient content within the specified limits.
According to one aspect of the invention of the parent application, there is provided a slow-release pharmaceutical composition comprising 3-(3-dimethylamino-1 -ethy1-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof in a matrix with slow release of active ingredient, wherein the matrix comprises 1 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:
3 to 35% by weight (based on 100 by weight active ingredient) 3-(3-dimethylamino-1 -ethy1-2-methyl-propyl)phenol released after 0.5 hours, 3a to 50% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 1 hour, to 75% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 2 hours, 5 15 to 82% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 3 hours, 30 to 97% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 6 hours, more than 50% by weight 3-(3-dimethylamino- 1 -ethyl-2-methyl-propyl)phenol released after 10 12 hours, more than 70% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 18 hours, more than 80% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 24 hours.
According to another aspect of the invention of the parent application, there is provided a slow-release pharmaceutical composition comprising 3-(3-dimethylamino- 1 -ethy1-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof in a matrix with slow release of active ingredient, wherein the matrix comprises 1 to 80% by weight of one or more hydrophilic or hydrophobic polymers as pharmaceutically acceptable matrix forming agents and, as pharmaceutically acceptable matrix forming agents, comprises cellulose ethers and/or cellulose esters having a viscosity of 3,000 to 150,000 mPa.s in a 2%
by weight aqueous solution at 20 C.
According to yet another aspect of the invention of the parent application, there is provided a tablet for the twice daily oral administration of 3-(3-dimethylamino-1 -ethyl-2-methyl-propyl)phenol comprising a pharmaceutical composition as described herein.
3b According to one aspect of the invention of the present divisional application, there is provided a slow-release pharmaceutical composition comprising 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof as active ingredient in a matrix coated with a material controlling the slow release of the active ingredient in an aqueous medium, the coating material comprising a water-insoluble wax, a polymethacrylate or a water-insoluble cellulose, wherein the active ingredient 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 spectometer:
3 to 35% by weight (based on 100% by weight active ingredient) 3-(3-dimethylamino-1-1 0 ethyl-2-methyl-propyl)phenol released after 0.5 hours, 5 to 50% by weight 3-(3-dimethylamino-1 -ethy1-2-methyl-propyl)phenol released after 1 hour, to 75% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 2 hours, 15 to 82% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 3 hours, 30 to 97% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 6 hours, more than 50% by weight 3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol released after 12 hours, more than 70% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 18 hours, and more than 80% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 24 hours.
3c According to another aspect of the invention of the present divisional application, there is provided a slow-release pharmaceutical composition comprising 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof as active ingredient in an oral osmotically driven release system, wherein surfaces of the oral osmotically driven release system that are in contact or that are contactable with a release medium are provided with a semipermeable-coating, so that the surfaces are permeable to the release medium but substantially impermeable to the active ingredient, wherein one or both of the surface and the coating comprise at least one opening for releasing the active ingredient, wherein the active ingredient 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 spectometer:
3 to 35% by weight (based on 100% by weight active ingredient) 3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol released after 0.5 hours, 5 to 50% by weight 3-(3-dimethylamino- 1 -ethy1-2-methyl-propyl)phenol released after 1 hour, 10 to 75% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 2 hours, 15 to 82% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 3 hours, 30 to 97% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 6 hours, more than 50% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 12 hours, more than 70% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 18 hours, and 3d more than 80% by weight 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol released after 24 hours.
Throughout this specification, the composition described is sometimes referred to as a "formulation".
It has surprisingly been found that the formulation according to the invention releases the active ingredient, 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol, slowly when administered orally and is therefore suitable for administration at intervals of at least 12 hours. The formulation according to the invention therefore allows pain therapy, during which the analgesic, 3-(3-dimethylamino-1-ethy1-2-methyl-1 0 propyl)phenol, only has to be administered once daily, for example at 24 hour intervals, or twice daily, preferably at 12 hourly intervals, in order to ensure an adequate concentration of the active ingredient in the plasma. A corresponding duration of efficacy and the maintenance of an adequate level in the blood plasma are demonstrated by simulation studies and experimental investigations.
It is particularly surprising that the formulation according to the invention not only ensures long-lasting therapeutic efficacy over a relatively long period (at least 12 hours) owing to the slow release, 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 owing to an adequately high level of active ingredient over a prolonged time. By taking the 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 is contained in a matrix with conventional release behaviour and the slow release is achieved by a retarding coating.
In a further possibility the slow release behaviour is achieved by an osmotically driven release system.
If the formulation according to the invention contains a slow release matrix, 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. When using hydrophilic polymers as matrix forming agents, 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-ethy1-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof in a matrix with slow release of active ingredient, wherein 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 is characterised in that as pharmaceutically acceptable matrix forming agents, comprises cellulose ethers and/or cellulose esters having a viscosity of 3,000 to 150,000 mPas in a 2% by weight aqueous solution at 20 C. (The viscosity is determined using a Pharm. Eu. capillary viscosimeter). The 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 mPas, and 150,000 mPas in a 2% by weight aqueous solution at 20 C.
Particularly suitable pharmaceutically acceptable matrix forming agents selected from the group comprising hydroxypropylmethyl celluloses (HPMC), hydroxyethyl celluloses, hydroxypropyl celluloses (HPC), methyl celluloses, ethyl celluloses and carboxymethyl celluloses and are selected, in particular, from the group comprising = HPMCs, hydroxyethyl celluloses and HPCs. HPMCs having a viscOsity of approx.
100,000 mPas, measured in a 2% by weight aqueous solution at 20 C are most preferred.
The active ingredient, 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol, exists as such, i.e. as a free base, but also in the form of a pharmaceutically acceptable salt, for example as hydrochloride. Preparation of the free base is known from EP 0 475 Al. Where EP 0 693 475 Al 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 from the prior art.
3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol has two centres of asymmetry, so the compound can exist in the form of four different stereoisomers. In the formulation according to the invention 3-(3-dimethylamino-1-ethy1-2-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-l-ethy1-2-methyl-propyl)phenol and (-)-(1R,2R)-3-(3-dimethylamino-l-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.
For the purposes of the present invention, therefore, the term "active ingredient"
denotes 3-(3-dimethylamino-l-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.
In the pharmaceutical compositions according to the invention, 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. If the =
enantiomer-pure (+)-(1S,2S)-3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol (or a mixture of the (+) and (-) enantiomers with a large excess of the (+) enantiomer) is used as active ingredient, it is particularly preferred if the active ingredient content lies at the lower limit, i.e. between 0.5 and 25% by weight (based on the total weight). If the enantiomer-pure (-)-(1R,2R)-3-(3-dimethylamino-l-ethyl-' 2-methyl-propyl)phenol (or a mixture of the (+) and (-) enantiomers with a large excess of the (-) enantiomer) is used as active ingredient, it is particularly preferred if the active ingredient content lies between 16 and 66% by weight.
Further components of the matrix of the formulation according to the invention may optionally be 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 being 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 is 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 sliding agents, 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 is between 0 and 80% by weight, preferably between 5 and 65%
by weight.
The release rate of an active ingredient from an administrable form is often dependent 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 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. 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.
However, the release profiles of the active ingredient (in the form of the base or a pharmaceutically acceptable salt thereof) from a pharmaceutical formulation according to the invention are surprisingly dependent on 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 comparative to the release during a pH/time profile of pH 1.2 over pH 2.3 and pH
6.8 to pH 7.2.
It has been found that it is immaterial for achieving the slow release of active ingredient from the formulation according to the invention which preferably exists in tablet form, whether a water-soluble filler, for example lactose, an insoluble filler which does not swell in an aqueous medium, for example calcium hydrogen phosphate, or an insoluble filler which swells in an aqueous medium, for example microcrystalline cellulose, is used as filler with otherwise unchanged values and unchanged composition of the tablet, based on the active ingredient, the matrix forming agent and the optional components. All these pharmaceutical compositions exhibit mutually corresponding release behaviour.
It is also surprising that, in the compositions according to the invention with a given amount of active ingredient, 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 h or with twice daily administration (providing that the above-mentioned limits to the quantity of active ingredient, matrix forming agent and further optional components are adhered to). Efficacy over at least 12 h is ensured, 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, for example MCC as filler of approx. 52.6% by weight and also in a composition of approx. 25.8% by weight of the same HPMC and approx. 39.7% by weight MCC (or lactose monohydrate) with otherwise identical amounts of sliding agent, lubricant and flow regulators. The same applies to compositions according to the invention with a higher or lower active ingredient content within the specified limits.
It has also extremely surprisingly been found that, when the pharmaceutical formulations according to the invention with slow release of the active ingredient are administered to human volunteers, biocompatibility which is the same as in formulations with immediate release of active ingredients is unexpectedly achieved despite the high first-pass effect for the active ingredient..
Compositions according to the invention of which the tma, value in the in vivo plasma concentration/time graph is between 2 and 10 h, in particular between 3.5 and 6 h and more particularly preferably between 4 and 5.5 h after oral administration of the composition, i.e. of which the peak plasma level occurs in said periods, are also preferred.
The formulation according to the invention contains the active ingredient, 3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol as such and/or as a pharmaceutically acceptable salt in an amount conventionally 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 behaviour of the formulation according to the invention not being affected by the exact amount of the active ingredient providing the above-mentioned limits are adhered to. Owing to the different active strength of the two particularly preferred enantiomers (+)-(1S,2S)-3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol and (-)-(1R,2R)-3-(3-dimethylamino- 1 -ethyl-2-methyl-propyl)phenol, it is preferred if the stronger (+)-(1S,25)-3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol exists in an arnount 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 exists 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 ingredient (based on the hydrochloride) in the formulations according to the invention, more specifically on condition that the above-mentioned limits are adhered to.
In the scope of this invention, pharmaceutically acceptable salts of the active 5 ingredient are salts of the active ingredient which are 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.
Compositions according to the invention of which the tma, value in the in vivo plasma concentration/time graph is between 2 and 10 h, in particular between 3.5 and 6 h and more particularly preferably between 4 and 5.5 h after oral administration of the composition, i.e. of which the peak plasma level occurs in said periods, are also preferred.
The formulation according to the invention contains the active ingredient, 3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol as such and/or as a pharmaceutically acceptable salt in an amount conventionally 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 behaviour of the formulation according to the invention not being affected by the exact amount of the active ingredient providing the above-mentioned limits are adhered to. Owing to the different active strength of the two particularly preferred enantiomers (+)-(1S,2S)-3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol and (-)-(1R,2R)-3-(3-dimethylamino- 1 -ethyl-2-methyl-propyl)phenol, it is preferred if the stronger (+)-(1S,25)-3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol exists in an arnount 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 exists 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 ingredient (based on the hydrochloride) in the formulations according to the invention, more specifically on condition that the above-mentioned limits are adhered to.
In the scope of this invention, pharmaceutically acceptable salts of the active 5 ingredient are salts of the active ingredient which are 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.
10 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 conventionally 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.
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 rnPa-s and a low molecular weight of < 10,000 (for example Pharrnacoat 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 a person 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, can be sheathed with additional active ingredient which is released as an initial dose without retardation by various processes known to a - person 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-l-ethy1-2-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.
Instead of a slow release matrix in the slow release pharmaceutical formulation, it is also possible to use a normal release matrix with a coating which retards release of the active ingredient. For example, the active ingredient can be contained in a conventional matrix of microcrystalline cellulose and optionally further pharmaceutical auxiliaries such as binders, fillers, sliding agents, 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.
The tablets are conventionally 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.
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 rnPa-s and a low molecular weight of < 10,000 (for example Pharrnacoat 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 a person 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, can be sheathed with additional active ingredient which is released as an initial dose without retardation by various processes known to a - person 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-l-ethy1-2-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.
Instead of a slow release matrix in the slow release pharmaceutical formulation, it is also possible to use a normal release matrix with a coating which retards release of the active ingredient. For example, the active ingredient can be contained in a conventional matrix of microcrystalline cellulose and optionally further pharmaceutical auxiliaries such as binders, fillers, sliding agents, 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.
In addition or by way of supplement to the possibilities of a slow release matrix in the pharmaceutical formulation with slow release or a normal release matrix with a coating which retards the release of the active ingredient, an osmotically driven release system can also be used to achieve a slow release. With a, preferably oral, release system of this type, at least one, preferably all, surface(s) of the release system, preferably that/those which is/are, or may come into contact with the release medium, are semi-permeable, preferably provided with a semi-permeable coating, so the surface(s) is/are permeable to the release medium but substantially, preferably completely, impermeable to the active ingredient, the surface(s) and/or optionally the coating comprising at least one opening to release the active ingredient.
The active ingredient 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof, preferably (+)-(15,2S)-3-(3-dimethylarnino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof and/or (-)-(1R,2R)-3-(3-dimethylamino-l-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 pharamaceutical composition core, a semi-permeable membrane and a polymeric part which exerts pressure. A good and preferred example of a system of this type is the OROS system from ALZA
Corporation, USA, of which the Internet site or other items of product information contain(s) details on the OROS system. In particular, these are also the OROS
Push-PullTM system, the OROS Delayed Push-PullTm system, the OROS Multi-Layer PushPullTM system, the OROS Push-Stick System and in certain cases the LOROSTM. Embodiments and examples of the actual production of osmotically driven release systems can be found in US patents US 4,765,989, US 4,783,337 and US 4, 612, 008.
The compositions according to the invention may be produced, for example, by the following general processes: the components of the composition (active ingredient, =
matrix forming agent and optional components) are weighed in in succession and then screened on a conventional screening machine. The Quadro Comil U10 screening machine, for example, can be used here, a conventional screen size being approx. 0.813 mm. The screened material is then mixed in a container mixer, for example in a Bohle container mixer; typical operating conditions are: duration approx. 15 min 45 s at a speed of 20 1 rpm. The powder mixture obtained is subsequently compressed to a tablet on a tablet press. A Korsch EKO tablet press, for example, with a round die curved in the form of a dragee with a diameter of 10 mm can be used for this purpose. Alternatively, 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 resultant 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 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 in the prior art.
The production of pharmaceutical formulations according to the invention is characterised by high repeatability of the release properties of the compositions obtained, which contain 3-(3-dimethylamino-1-ethy1-2-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.
With once or twice daily administration of a pharmaceutical formulation according to the invention by the patient, good therapeutic efficacy is reliably achieved in the case of continuously strong pain.
=
The active ingredient 3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof, preferably (+)-(15,2S)-3-(3-dimethylarnino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof and/or (-)-(1R,2R)-3-(3-dimethylamino-l-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 pharamaceutical composition core, a semi-permeable membrane and a polymeric part which exerts pressure. A good and preferred example of a system of this type is the OROS system from ALZA
Corporation, USA, of which the Internet site or other items of product information contain(s) details on the OROS system. In particular, these are also the OROS
Push-PullTM system, the OROS Delayed Push-PullTm system, the OROS Multi-Layer PushPullTM system, the OROS Push-Stick System and in certain cases the LOROSTM. Embodiments and examples of the actual production of osmotically driven release systems can be found in US patents US 4,765,989, US 4,783,337 and US 4, 612, 008.
The compositions according to the invention may be produced, for example, by the following general processes: the components of the composition (active ingredient, =
matrix forming agent and optional components) are weighed in in succession and then screened on a conventional screening machine. The Quadro Comil U10 screening machine, for example, can be used here, a conventional screen size being approx. 0.813 mm. The screened material is then mixed in a container mixer, for example in a Bohle container mixer; typical operating conditions are: duration approx. 15 min 45 s at a speed of 20 1 rpm. The powder mixture obtained is subsequently compressed to a tablet on a tablet press. A Korsch EKO tablet press, for example, with a round die curved in the form of a dragee with a diameter of 10 mm can be used for this purpose. Alternatively, 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 resultant 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 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 in the prior art.
The production of pharmaceutical formulations according to the invention is characterised by high repeatability of the release properties of the compositions obtained, which contain 3-(3-dimethylamino-1-ethy1-2-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.
With once or twice daily administration of a pharmaceutical formulation according to the invention by the patient, good therapeutic efficacy is reliably achieved in the case of continuously strong pain.
=
Examples The examples serve to illustrate the present invention and preferred embodiments, but should not restrict its scope of protection.
Example 1 Matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-di methylami no-1 -ethyl-2-methyl-prop yl)phenol hydrochloride 100 mg Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from Shinetsu, 80 mg 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 were produced in the following manner in a batch size of 1,000 tablets:
all components were weighed in and screened on a Quadro Comil U10 screening machine using a screen size of 0.813 mm, mixed in a container mixer (Bohle LM
40) for 15 min 15 s at a speed of 20 1 rpm and pressed on a Korsch EKO
eccentric press to tablets curved in the manner of dragees with a diameter of 10 mm, a radius of curvature of 8 mm and an average tablet weight of 310 mg.
The in vitro release was determined by the Ph. Eur. Paddle Method at 75 rpm in ml pH 6.8 buffer according to Ph. Eur. at 37 C and with detection using a UV
spectrometer, and is reproduced in the following table.
. Time (min) Total amount of active ingredient released [%]
180 5= 0 240 5= 9 720 9= 3 Example 2 3,000 matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol hydrochloride 200 mg Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from Shinetsu, 80 mg 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 =
were produced by a process similar to that described in Example 1.
The in vitro release was determined as in Example 1.
Time (min) Total amount of active ingredient released [%]
Example 3 Matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol hydrochloride 100 mg Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from Shinetsu, 40 mg -100,000 mPa.s Microcrystalline cellulose (Avicel PH 102 from FMC) 163 mg Highly dispersed silicon dioxide 4 mg Magnesium stearate 3 mg Total amount 310 mg were produced by a process similar to that described in Example 1 in a batch size of 3,000 tablets.
The in vitro release was determined as an Example 1; in addition, the release was determined under otherwise identical conditions at a stirring speed of 50 rpm and 100 rpm.
Time (min) Total amount of active Total amount of active Total amount of active ingredient released PY0] ingredient released ingredient released [%1 at 50 rpm [%] at 100 rpm at 75 rpm ¨240 76 73 76 Example 4 Matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol 100 mg hydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from 80 mg Shinetsu, 100,000 mPa-s Lactose monohydrate 230 (Megglel 123 mg Highly dispersed silicon dioxide 4 mg Magnesium stearate 3 mg .Total amount 310 mg =
were produced by a process similar to that described in Example 1 in a batch size of 200 tablets.
The in vitro release was determined as in Example 1.
Time (min) Total amount of active ingredient released [%]
Example 5 Matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol 100 mg hydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from 40 mg Shinetsu, 100,000 mPa.s Cellactose 80 (Meggle) 163 mg Highly dispersed silicon dioxide 4 ma Magnesium stearate 3 ma Total amount 310 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 as an Example I.
Time (min) Total amount of active ingredient released [%]
Example 6 Matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-dimethylamino- 1-ethy1-2-methyl-propyl)phenol 100 mg hydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from 80 mg Shinetsu, 100,000 mPa.s Ludipress (BASF) 123 mg Highly dispersed silicon dioxide 4 mg Magnesium stearate 3 mg Total amount 310 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 as in Example 1.
Time (min) Total amount of active ingredient released [%]
Example 7 Matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol hydrochloride 50 mg Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from Shinetsu, 40 mg 100,000 mPa-s Microcrystalline cellulose (Avicel PH 102 from FMC) 163 mg Lactose 200 (Meggle) 50 mg Highly dispersed silicon dioxide 4 mg Magnesium stearate 3 mg Total amount 310 mg were produced by a process similar to that described in Example 1 in a batch size of 200 tablets.
10 The in vitro release was determined as in Example 1.
Time (min) Total amount of active ingredient released r/01 Example 8 Matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol 100 hydrochloride mg Cellactose (Meggle) 72.5 mg TM 12.5 Hydroxyethyl cellulose (Natrosol 250 HX from Herkules) mg Cutina HR (Henkel) . mg =
Talcum 3 mg Magnesium stearate 2 mg Total amount 320 mg were produced as follows in a batch size of 200 tablets:
the active ingredient, Cellactose, Natrosol and Cutina were mixed then heated to TPA
80 C in a drying oven and granulated in a Kenwood Chef kitchen mixer. The cooled granules were screened through a 1 mm screen. After blending with magnesium stearate and talcum, the granules were pressed on a EKO eccentric press (Korsch) to 6 x 15 mm size oblong tablets with a breaking notch.
The in vitro release was determined as in Example 1.
=
Time (min) Total amount of active ingredient released ro]
180 68 =
Example 9 Matrix tablets with the following composition per tablet (+)-(IS,2S)3-(3-dimethylarnino-l-ethyl-2-methyl-propyl)phenol 10 mg hydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from 80 mg Shinetsu, 100,000 mPa.s Microcrystalline cellulose (Avicel PH 102 from FMC) 213 mg Lactose 200 (Meggle) 50 mg Highly dispersed silicon dioxide 4 mg Magnesium stearate 3 mg Total amount 310 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 as in Example 1.
Time (min) Total amount of active ingredient released [%]
Example 10 Matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-dimethylamino-l-ethy1-2-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:
(A) application of the Ph. Eur. Paddle Method at 75 rpm in 900 ml pH 7.2 buffer to USP 22 at 37 C and with detection using a UV spectrometer;
(B) application of the Ph. Eur. Paddle Method at 75 rpm, a pH of 1.2 being 5 adjusted from 0 to 30 min, a pH of 2.3 from 30 to 120 min, a pH of 6.5 from 120 to 180 min and a pH of 7.2 for the remaining test period. The table shows the results for both experimental conditions:
Time (min) Total amount of active Total amount of active ingredient released [%) ingredient released [Vol under condition (A) under condition (B) 10 The experiment shows that the release behaviour of the formulations according to the invention is independent of the pH of the release medium.
Example 11 15 Pellets having the following composition (-)-(1R,2R)3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol 100 mg hydrochloride Low-substituted hydroxypropyl cellulose (L-HPC LH 31 from Shinetsu) 75 mg =
Aquacoat (aqueous ethyl cellulose dispersion from FMC) (calculated as 20 mg 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 were produced in the following manner:
The active ingredient, Avicel and L-HPC were mixed for 10 minutes in a planetary mixer (Kenwood K Mixer) and then granulated with water. The moist granules were extruded in a Nica extruder with a 0.8 x 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 (yields about 95%) 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 homogenised 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 h. The coated pellets were dried in the WSG And tempered in the drying oven (2 h at 60 C). The release was tested as in Example 1, but by the basket method at 100 rpm.
Time (min) Total amount of active ingredient released (%]
Clinical trial In a monocentric, open, randomised individual dose four-way crossover trial, various forms of administration of (-)-(1R,2R)-3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol hydrochloride (active ingredient) were administered to sixteen healthy male white subjects aged from 18 to 45 years, to determine pharmacokinetic data. Data was determined experimentally by HPLC analysis.
The following were administered:
"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, mg magnesium stearate and 80 mg Primojel (sodium carboxymethyl starch type A
from Avebe);
"Capsule 25 mg": 25 mg (-)-(1R,2R)-3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol hydrochloride, 227 mg microcrystalline cellulose, 8 mg Aerosil, mg magnesium stearate and 80 mg Primojel (sodium carboxymethyl starch type A
from Avebe)) The essential pharmacokinetic data are shown in the following table and the characteristic of the experimentally determined average serum concentration in Fig.
1.
Parameter "Capsule 25 "Capsule 100 "Tablet 100 "Tablet me, me, [ng=h/m1]
C[ng/m1] 14 4 64 19 23 5 51 13 trnax [h] 1.2 0.4 1.5 0.9 4.6 1.3 4.8 1.1 MRT* [h] 5.8 0.7 5.9 0.9 10.7 1.5 10.3 1.1 HVD** 35 1.2 3.6 1.1 12.4 2.8 11.9 2.3 *MRT = "Mean Residence Time"
**}{VD = "Half Value Duration"
On the one hand, a comparison of "Capsule 100 mg" and "Tablet 100 mg"
immediately shows that the formulations according to the invention excellently fulfil the task of providing a pharmaceutical formulation containing a 3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol with slow release of active ingredient. On the other hand, when "Tablet 100 mg" is compared with "Tablet mg" there is also very advantageous dose proportionality in the release behaviour.
However, this also shows that the two compositions according to the invention, "Tablet 100 mg" and "Tablet 200 mg" release the active ingredient in a discernible amount but more slowly at the beginning than the two formulations with immediate release; with the two retarded formulations, however, the plasma level is higher than 1.0 ng/ml after only one hour and still sufficiently high after 16 h to ensure an analgesic action. Simulation studies for "Tablet 100 mg" also showed that, with repeated administration of the pharmaceutical composition at 12 hourly intervals, serum levels are achieved which do not fall below 20 ng/ml, so good analgesic efficacy is ensured by twice daily administration. This represents great progress for 5 the treatment, in particular of chronic painful conditions, and allows a significant improvement in patient compliance.
Example 1 Matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-di methylami no-1 -ethyl-2-methyl-prop yl)phenol hydrochloride 100 mg Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from Shinetsu, 80 mg 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 were produced in the following manner in a batch size of 1,000 tablets:
all components were weighed in and screened on a Quadro Comil U10 screening machine using a screen size of 0.813 mm, mixed in a container mixer (Bohle LM
40) for 15 min 15 s at a speed of 20 1 rpm and pressed on a Korsch EKO
eccentric press to tablets curved in the manner of dragees with a diameter of 10 mm, a radius of curvature of 8 mm and an average tablet weight of 310 mg.
The in vitro release was determined by the Ph. Eur. Paddle Method at 75 rpm in ml pH 6.8 buffer according to Ph. Eur. at 37 C and with detection using a UV
spectrometer, and is reproduced in the following table.
. Time (min) Total amount of active ingredient released [%]
180 5= 0 240 5= 9 720 9= 3 Example 2 3,000 matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol hydrochloride 200 mg Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from Shinetsu, 80 mg 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 =
were produced by a process similar to that described in Example 1.
The in vitro release was determined as in Example 1.
Time (min) Total amount of active ingredient released [%]
Example 3 Matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol hydrochloride 100 mg Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from Shinetsu, 40 mg -100,000 mPa.s Microcrystalline cellulose (Avicel PH 102 from FMC) 163 mg Highly dispersed silicon dioxide 4 mg Magnesium stearate 3 mg Total amount 310 mg were produced by a process similar to that described in Example 1 in a batch size of 3,000 tablets.
The in vitro release was determined as an Example 1; in addition, the release was determined under otherwise identical conditions at a stirring speed of 50 rpm and 100 rpm.
Time (min) Total amount of active Total amount of active Total amount of active ingredient released PY0] ingredient released ingredient released [%1 at 50 rpm [%] at 100 rpm at 75 rpm ¨240 76 73 76 Example 4 Matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol 100 mg hydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from 80 mg Shinetsu, 100,000 mPa-s Lactose monohydrate 230 (Megglel 123 mg Highly dispersed silicon dioxide 4 mg Magnesium stearate 3 mg .Total amount 310 mg =
were produced by a process similar to that described in Example 1 in a batch size of 200 tablets.
The in vitro release was determined as in Example 1.
Time (min) Total amount of active ingredient released [%]
Example 5 Matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-dimethylamino-l-ethyl-2-methyl-propyl)phenol 100 mg hydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from 40 mg Shinetsu, 100,000 mPa.s Cellactose 80 (Meggle) 163 mg Highly dispersed silicon dioxide 4 ma Magnesium stearate 3 ma Total amount 310 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 as an Example I.
Time (min) Total amount of active ingredient released [%]
Example 6 Matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-dimethylamino- 1-ethy1-2-methyl-propyl)phenol 100 mg hydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from 80 mg Shinetsu, 100,000 mPa.s Ludipress (BASF) 123 mg Highly dispersed silicon dioxide 4 mg Magnesium stearate 3 mg Total amount 310 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 as in Example 1.
Time (min) Total amount of active ingredient released [%]
Example 7 Matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol hydrochloride 50 mg Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from Shinetsu, 40 mg 100,000 mPa-s Microcrystalline cellulose (Avicel PH 102 from FMC) 163 mg Lactose 200 (Meggle) 50 mg Highly dispersed silicon dioxide 4 mg Magnesium stearate 3 mg Total amount 310 mg were produced by a process similar to that described in Example 1 in a batch size of 200 tablets.
10 The in vitro release was determined as in Example 1.
Time (min) Total amount of active ingredient released r/01 Example 8 Matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-dimethylamino-1-ethy1-2-methyl-propyl)phenol 100 hydrochloride mg Cellactose (Meggle) 72.5 mg TM 12.5 Hydroxyethyl cellulose (Natrosol 250 HX from Herkules) mg Cutina HR (Henkel) . mg =
Talcum 3 mg Magnesium stearate 2 mg Total amount 320 mg were produced as follows in a batch size of 200 tablets:
the active ingredient, Cellactose, Natrosol and Cutina were mixed then heated to TPA
80 C in a drying oven and granulated in a Kenwood Chef kitchen mixer. The cooled granules were screened through a 1 mm screen. After blending with magnesium stearate and talcum, the granules were pressed on a EKO eccentric press (Korsch) to 6 x 15 mm size oblong tablets with a breaking notch.
The in vitro release was determined as in Example 1.
=
Time (min) Total amount of active ingredient released ro]
180 68 =
Example 9 Matrix tablets with the following composition per tablet (+)-(IS,2S)3-(3-dimethylarnino-l-ethyl-2-methyl-propyl)phenol 10 mg hydrochloride Hydroxypropylmethyl cellulose (Metolose 90 SH 100,000 from 80 mg Shinetsu, 100,000 mPa.s Microcrystalline cellulose (Avicel PH 102 from FMC) 213 mg Lactose 200 (Meggle) 50 mg Highly dispersed silicon dioxide 4 mg Magnesium stearate 3 mg Total amount 310 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 as in Example 1.
Time (min) Total amount of active ingredient released [%]
Example 10 Matrix tablets with the following composition per tablet (-)-(1R,2R)3-(3-dimethylamino-l-ethy1-2-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:
(A) application of the Ph. Eur. Paddle Method at 75 rpm in 900 ml pH 7.2 buffer to USP 22 at 37 C and with detection using a UV spectrometer;
(B) application of the Ph. Eur. Paddle Method at 75 rpm, a pH of 1.2 being 5 adjusted from 0 to 30 min, a pH of 2.3 from 30 to 120 min, a pH of 6.5 from 120 to 180 min and a pH of 7.2 for the remaining test period. The table shows the results for both experimental conditions:
Time (min) Total amount of active Total amount of active ingredient released [%) ingredient released [Vol under condition (A) under condition (B) 10 The experiment shows that the release behaviour of the formulations according to the invention is independent of the pH of the release medium.
Example 11 15 Pellets having the following composition (-)-(1R,2R)3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol 100 mg hydrochloride Low-substituted hydroxypropyl cellulose (L-HPC LH 31 from Shinetsu) 75 mg =
Aquacoat (aqueous ethyl cellulose dispersion from FMC) (calculated as 20 mg 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 were produced in the following manner:
The active ingredient, Avicel and L-HPC were mixed for 10 minutes in a planetary mixer (Kenwood K Mixer) and then granulated with water. The moist granules were extruded in a Nica extruder with a 0.8 x 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 (yields about 95%) 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 homogenised 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 h. The coated pellets were dried in the WSG And tempered in the drying oven (2 h at 60 C). The release was tested as in Example 1, but by the basket method at 100 rpm.
Time (min) Total amount of active ingredient released (%]
Clinical trial In a monocentric, open, randomised individual dose four-way crossover trial, various forms of administration of (-)-(1R,2R)-3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol hydrochloride (active ingredient) were administered to sixteen healthy male white subjects aged from 18 to 45 years, to determine pharmacokinetic data. Data was determined experimentally by HPLC analysis.
The following were administered:
"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, mg magnesium stearate and 80 mg Primojel (sodium carboxymethyl starch type A
from Avebe);
"Capsule 25 mg": 25 mg (-)-(1R,2R)-3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol hydrochloride, 227 mg microcrystalline cellulose, 8 mg Aerosil, mg magnesium stearate and 80 mg Primojel (sodium carboxymethyl starch type A
from Avebe)) The essential pharmacokinetic data are shown in the following table and the characteristic of the experimentally determined average serum concentration in Fig.
1.
Parameter "Capsule 25 "Capsule 100 "Tablet 100 "Tablet me, me, [ng=h/m1]
C[ng/m1] 14 4 64 19 23 5 51 13 trnax [h] 1.2 0.4 1.5 0.9 4.6 1.3 4.8 1.1 MRT* [h] 5.8 0.7 5.9 0.9 10.7 1.5 10.3 1.1 HVD** 35 1.2 3.6 1.1 12.4 2.8 11.9 2.3 *MRT = "Mean Residence Time"
**}{VD = "Half Value Duration"
On the one hand, a comparison of "Capsule 100 mg" and "Tablet 100 mg"
immediately shows that the formulations according to the invention excellently fulfil the task of providing a pharmaceutical formulation containing a 3-(3-dimethylamino-l-ethy1-2-methyl-propyl)phenol with slow release of active ingredient. On the other hand, when "Tablet 100 mg" is compared with "Tablet mg" there is also very advantageous dose proportionality in the release behaviour.
However, this also shows that the two compositions according to the invention, "Tablet 100 mg" and "Tablet 200 mg" release the active ingredient in a discernible amount but more slowly at the beginning than the two formulations with immediate release; with the two retarded formulations, however, the plasma level is higher than 1.0 ng/ml after only one hour and still sufficiently high after 16 h to ensure an analgesic action. Simulation studies for "Tablet 100 mg" also showed that, with repeated administration of the pharmaceutical composition at 12 hourly intervals, serum levels are achieved which do not fall below 20 ng/ml, so good analgesic efficacy is ensured by twice daily administration. This represents great progress for 5 the treatment, in particular of chronic painful conditions, and allows a significant improvement in patient compliance.
Claims (2)
1. A
slow-release pharmaceutical composition comprising 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof as active ingredient in a matrix coated with a material controlling the slow release of the active ingredient in an aqueous medium, the coating material comprising a water-insoluble wax, a polymethacrylate or a water-insoluble cellulose, wherein the active ingredient 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
spectometer:
3 to 35% by weight (based on 100% by weight active ingredient) 3-(3-dimethylamino-1 -ethyl-2-methyl-propyl)phenol released after 0.5 hours, to 50% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 1 hour, to 75% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 2 hours, to 82% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 3 hours, 30 to 97% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 6 hours, more than 50% by weight 3-(3-dimethylamino-1 -ethyl-2-methyl-propyl)phenol released after 12 hours, more than 70% by weight 3-(3-dimethylamino- 1 -ethyl-2-methyl-propyl)phenol released after 18 hours, and more than 80% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 24 hours.
slow-release pharmaceutical composition comprising 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol or a pharmaceutically acceptable salt thereof as active ingredient in a matrix coated with a material controlling the slow release of the active ingredient in an aqueous medium, the coating material comprising a water-insoluble wax, a polymethacrylate or a water-insoluble cellulose, wherein the active ingredient 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
spectometer:
3 to 35% by weight (based on 100% by weight active ingredient) 3-(3-dimethylamino-1 -ethyl-2-methyl-propyl)phenol released after 0.5 hours, to 50% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 1 hour, to 75% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 2 hours, to 82% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 3 hours, 30 to 97% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 6 hours, more than 50% by weight 3-(3-dimethylamino-1 -ethyl-2-methyl-propyl)phenol released after 12 hours, more than 70% by weight 3-(3-dimethylamino- 1 -ethyl-2-methyl-propyl)phenol released after 18 hours, and more than 80% by weight 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol released after 24 hours.
2. The slow-release pharmaceutical composition according to claim 1, wherein the coating material further comprises a water-soluble polymer or a hydophilic pore-forming agent.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10152469A DE10152469A1 (en) | 2001-10-24 | 2001-10-24 | Delayed release analgesic formulations, comprising 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol in hydrophilic or hydrophobic polymer matrix |
| DE10152469.2 | 2001-10-24 | ||
| CA2464578A CA2464578C (en) | 2001-10-24 | 2002-10-22 | Pharmaceutical containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol and providing delayed release of the active ingredient |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2464578A Division CA2464578C (en) | 2001-10-24 | 2002-10-22 | Pharmaceutical containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol and providing delayed release of the active ingredient |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2739611A1 CA2739611A1 (en) | 2003-05-01 |
| CA2739611C true CA2739611C (en) | 2013-12-10 |
Family
ID=7703560
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2739611A Expired - Lifetime CA2739611C (en) | 2001-10-24 | 2002-10-22 | Pharmaceutical containing 3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol and providing delayed release of the active ingredient |
Country Status (4)
| Country | Link |
|---|---|
| AR (1) | AR104921A2 (en) |
| CA (1) | CA2739611C (en) |
| DE (1) | DE10152469A1 (en) |
| RU (1) | RU2325905C2 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI2352494T1 (en) * | 2008-10-30 | 2019-12-31 | Gruenenthal Gmbh | Novel and potent tapentadol dosage forms |
| EP4121013A1 (en) | 2020-03-16 | 2023-01-25 | Grünenthal GmbH | Scored tablet |
-
2001
- 2001-10-24 DE DE10152469A patent/DE10152469A1/en not_active Withdrawn
-
2002
- 2002-10-22 RU RU2004116066/15A patent/RU2325905C2/en active
- 2002-10-22 CA CA2739611A patent/CA2739611C/en not_active Expired - Lifetime
-
2016
- 2016-06-07 AR ARP160101684A patent/AR104921A2/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AR104921A2 (en) | 2017-08-23 |
| DE10152469A1 (en) | 2003-06-26 |
| RU2325905C2 (en) | 2008-06-10 |
| RU2004116066A (en) | 2005-05-10 |
| CA2739611A1 (en) | 2003-05-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20221024 |