CA2434976A1 - Medicament formulation containing a muscarinic agonist - Google Patents
Medicament formulation containing a muscarinic agonist Download PDFInfo
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- CA2434976A1 CA2434976A1 CA002434976A CA2434976A CA2434976A1 CA 2434976 A1 CA2434976 A1 CA 2434976A1 CA 002434976 A CA002434976 A CA 002434976A CA 2434976 A CA2434976 A CA 2434976A CA 2434976 A1 CA2434976 A1 CA 2434976A1
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- Prior art keywords
- core
- tablet according
- film
- acid
- talsaclidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
Abstract
The invention relates to a novel medicament formulation containing the muscarinic agonist talsaclidine and to a method for the production thereof.
Description
' , WO 02/064124 CA 02434976 2003-07-15 PCT/EP01/01374 ,, r 77036pct.208 Medical Formulation containing a Muscarinic Agonist The invention relates to a new pharmaceutical formulation containing the muscarinic agonist talsaclidine and processes for preparing it.
Background to the invention Talsaclidine (Wa12014), being a muscarinic agonist, is a pharmacologically valuable compound. Muscarinic agonists may be of great therapeutic benefit in the treatment of Alzheimer's disease, for example. Talsaclidine 1' has the following chemical structure:
O ~~
H
1' The aim of the present invention is to develop a pharmaceutical formulation for oral administration which releases the active substance talsaclidine relatively rapidly and ~5 completely. A further aim of the present invention is to provide a formulation which is characterised by ease of handling during the preparation process and can therefore be reproducibly manufactured on an industrial scale while maintaining a high quality.
Detailed description of the invention 2o The above objectives can be achieved by the formulation described in detail hereinafter.
The present invention relates to a tablet containing talsaclidine 1', characterised in that it consists of a core containing the active substance talsaclidine and a film 25 coating enclosing this core. The tablet according to the invention may also be termed a film-coated tablet within the scope of the present invention.
The active substance talsaclidine is preferably present in the formulation according to the invention in the form of a physiologically acceptable acid addition salt 1. The 3o term physiologically acceptable acid addition salts according to the invention denotes pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and malefic acid. If desired, mixtures of the above acids may also be used to prepare the 35 salts. According to the invention the preferred salts of talsaclidine are selected from among the hydrochloride, hydrobromide, sulphate, phosphate, fumarate and methanesulphonate. Most preferably, the salts are selected from among the hydrochloride, hydrobromide and fumarate, while talsaclidine fumarate is most important according to the invention. The active substance may optionally be in the form of a hydrate. Preferably, however, according to the invention, the talsaclidine is added in an anhydrous form. The active substance is preferably used in crystalline, unground form or after being ground in a pinned disc mill, but preferably in unground form. More preferably, the active substance is used in unground form with a particle size distribution within the following limits: D,o <_ 20Nm, Dso 10-80Nm, Duo <_ 300pm.
Most preferably, the particle size distribution of the active substance used in the 1o formulation according to the invention is in the following ranges: D,o <_ 5 - 15Nm, Duo 25 - 75 Nm, D9o <_ 275Nm. The numerical values given above for D,o, Dso and Duo in Nm (microns) are the particle size ranges within which a through total of 10 vol.%, 50 vol.-% or 90 vol.% of the measured particles (cumulative volume distribution) is achieved. These values were determined by the laser diffractometry method, in the 95 present instance particularly using a so-called dry dispersion at a 2 bar dispersion pressure and a focal length f = 500 mm, e.g. using a SympatecIRODOS apparatus.
This method is known in the prior art.
Where reference is made to salts of talsaclidine within the scope of the present 20 _invention, this is indicated by the numeral 1. Any explicit reference to the base talsaclidine, on the other hand, is indicated by the use of the numeral 1'.
Based on the total mass of the core of the film-coated tablets according to the invention talsaclidine 1' is present according to the invention in amounts of 0.5 to 25 25 wt.%, preferably 0.7 to 20 wt.%, particularly preferably about 0.9 to 15 wt.%.
Particularly preferably, the proportion of 1' is between 9 and 14 wt.% based on the total mass of the core. If talsaclidine is used for example in the form of the preferred salt _1 talsaclidine fumarate according to the invention in the formulation according to the invention, the proportion of 1 based on the total mass of the core of the film-3o coated tablets according to the invention is between about 0.85 and 43 wt.%, preferably between about 1.2 and 34 wt.%, particularly preferably between about 1.5 and 26 wt.%. Particularly preferably the proportion of 1 in the case of talsaclidine fumarate is between about 15 and 24 wt.% based on the total mass of the core.
s5 The core of the pharmaceutical formulation according to the invention contains, in addition to the active substance, at least one excipient as filler/dry binder.
Within the scope of the present invention modified lactose, particularly spray-dried lactose is of particular importance as the excipient. This excipient has proved particularly advantageous in the formulation according to the invention. A
preferred aspect of the present invention thus relates to a film-coated tablet containing talsaclidine which contains in its core, in addition to the active substance, modified lactose, particularly spray-dried lactose, particularly preferably spray-dried lactose monohydrate as excipient.
By spray-dried lactose is meant lactose produced by spray agglomeration when spray-drying a suspension of a-lactose monohydrate crystals in an aqueous lactose solution. The spray-drying process results in a free flowing powder with a granulometry suitable for direct tabletting (for example 80-100% < 250Nm) and an ~o amorphous content of for example 5 - 25%, which is responsible for the high binding power of spray-dried lactose.
According to the invention the weight ratio between the components contained in the core of the film-coated tablet, namely modified lactose, preferably spray-dried ~5 lactose, to active substance 1' is in the range from about 1:1 to about 70:1.
Preferably, the ratio of modified, preferably spray-dried lactose to 1' is in the range from about 1.5:1 to about 35:1, particularly preferably in a range from about 2:1 to about 8:1. Preferably, the proportion by weight of modified, preferably spray-dried lactose based on the total mass of the core of the film-coated tablet according to the 2o invention is in a range from about 20 - 70 wt.%, preferably between about wt. %.
The core of the film-coated tablet according to the invention may also contain, in addition to modified, preferably spray-dried lactose and active substance, other 25 excipients or fillers. According to the invention it is preferable to use those compounds which can act as dry binders. Preferred dry binders according to the invention are selected from among powdered cellulose, microcrystalline cellulose, starch, povidone, cellulose derivatives and mixtures of these compounds.
Preferred binders are powdered cellulose and /or microcrystalline cellulose, particularly so preferably microcrystalline cellulose. If one of the abovementioned binders is added to the formulation according to the invention, the weight ratio of modified, preferably spray-dried lactose to binder is preferably about 5:1 to about 1:4, preferably about 4:1 to about 1:3, particularly preferably about 3:1 to 1:2. It is particularly preferable according to the invention if the weight ratio of spray-dried lactose to binder is in the 35 range from about 2:1 to about 1:1.
The core of the film-coated tablet according to the invention may also contain disintegrants in addition to the ingredients mentioned above. Within the scope of the present invention these disintegrants may optionally also be known as breakdown agents. These are preferably selected according to the invention from among sodium starch glycolate, crospovidone, croscarmellose, sodium-carboxymethylcellulose, dried corn starch and mixtures thereof. Particularly preferably, within the scope of the present invention, sodium starch glycolate, crospovidone and croscarmellose, preferably sodium starch glycolate, are used.
If the abovementioned disintegrants are used, the amount by weight used based on the total mass of the core of the film-coated tablet according to the invention is preferably in a range from about 1 -10 wt.%, particularly preferably about 3 -wt. % .
The core of the film-coated tablet according to the invention may also contain flow regulators as additional ingredients. Flow regulators within the scope of the present invention include, for example, silicon dioxide, talc and magnesium stearate.
According to the invention silicon dioxide is preferably used, particularly preferably in ~5 colloidal, highly dispersed form. If the abovementioned flow regulators are used, the amount by weight thereof based on the total mass of the core of the film-coated tablet according to the invention is preferably in a range from about 0.1 - 5 wt.%, preferably about 0.3 - 2 wt.%, particularly preferably between 0.4 and 1.5 wt.%.
2o The core of the film-coated tablet according to the invention may also contain flow agents, lubricants and mould release agents as further ingredients. These include, for example, within the scope of the present invention, stearic acid, magnesium stearate, sodium stearyl fumarate, glycerol tribehenate and mixtures thereof.
According to the invention, stearic acid and magnesium stearate are preferably used.
25 The amount by weight based on the total mass of the core of the film-coated tablet according to the invention is preferably in a range from about 0.1 - 5 wt.%, preferably about 0.5 - 3 wt.%, particularly preferably about 1 - 2 wt.%.
Particularly good release from the mould in the production of the film-coated tablets according to the invention is achieved when magnesium stearate is used in an amount of at least 30 1.0 wt.%, preferably about 1.5 wt.%.
The film or film coating enveloping the core of the film-coated tablets according to the invention contains as essential ingredient a film forming agent selected from among hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, 35 hydroxymethylcellulose, hydroxyethylcellulose and poly(ethylacrylate) methylmethacrylate, the latter in the form of Eudragit NE 30 D, for example.
Alternatively, Eudragit RL 30 D or Eudragit E 12.5 may be used, for example.
The above ingredients may optionally also be used in the form of mixtures thereof.
Preferred film-forming agents are hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose and hydroxyethylcellulose, of which hydroxypropylmethylcellulose and hydroxypropylcellulose are particularly preferred as film-forming agents according to the invention. The abovementioned film-forming agents may be used on their own or in the form of the mixtures thereof. If only one of the abovementioned film-forming agents is used, hydroxypropylmethylcellulose is of particular importance in this context within the scope of the present invention. The amount by weight of film-forming agents based on the total mass of the film coating of the film-coated tablet according to the invention is preferably in a range from about 20 - 95 wt.%, preferably 30 - 90 wt.%.
~o The film coating may contain, as further ingredients, emulsifiers and plasticisers such as, for example, polyethyleneglycol, glycerol and propyleneglycol, optionally in the form of the mixtures thereof. Preferably, polyethyleneglycols are used as plasticisers.
Without restricting the subject matter of the invention thereto, polyethyleneglycol 400 ~s and polyethyleneglycol 6000 are examples of particularly preferred polyethyleneglycols. The amount of plasticiser by weight based on the total mass of the film coating of the film-coated tablet according to the invention is preferably in a range from about 1 - 30 wt.%, preferably 3 - 25 wt.%, particularly preferably wt. %.
The film coating of the film-coated tablet according to the invention may also contain coloured pigments and pigmenting excipients. Iron oxide, titanium dioxide, talc and mixtures thereof may be mentioned by way of example.
The following procedure may be used, for example, to prepare the film-coated tablet according to the invention.
In a suitable free-fall mixer the excipient spray-dried lactose is mixed with the active substance _1. The active substance premix obtained therefrom is then mixed in a suitable screening machine. This reduces the proportion of coarser particles of active 3o substance which may possibly go into the manufacturing process. Depending on the particle size of the compound 1 used, the preparation of this premix with the subsequent screening process may also be avoided.
In another step of the process, more excipient is added to this active substance premix. As well as spray-dried lactose one or more other excipients may also be added. Moreover, during this step of the process, other ingredients of the formulation such as disintegrants and flow regulators may optionally also be added. After the mixing process has finished the mixture obtained is screened again. This intermediate screening is the essential step for obtaining a uniformity of the contents of the mixture in conformity with the Pharmacopoeia. The flow agent, lubricant and mould release agent are then added to this screened active substance mixture.
The mixture of active substance and excipient thus obtained is then compressed in a suitable tablet press to form the film-coated tablet cores according to the invention.
The compressing force should be kept within a range from 5 - 15 kN, preferably 12 kN, for example, in the case of tablet cores which contain 36 mg of talsaclidine 1'.
Higher compressing forces may lead to tablets with a delayed release of active substance. Lower compressing forces may lead to tablets which are mechanically unstable.
The tablet cores may take various forms, of which round biplanar or biconvex and oval or oblong shapes are preferred.
In order to prepare the film coating suspension the essential and optional ingredients ~5 of the film coating are taken up in a suitable solvent. According to the invention water is preferably used as the solvent. When water is used as solvent, the ingredients of the film coating are partly in dispersed form.
After the coating suspension is finished the tablet cores obtained previously are 2o coated with the desired film in a suitable coating apparatus analogously to coating methods known in the art.
Background to the invention Talsaclidine (Wa12014), being a muscarinic agonist, is a pharmacologically valuable compound. Muscarinic agonists may be of great therapeutic benefit in the treatment of Alzheimer's disease, for example. Talsaclidine 1' has the following chemical structure:
O ~~
H
1' The aim of the present invention is to develop a pharmaceutical formulation for oral administration which releases the active substance talsaclidine relatively rapidly and ~5 completely. A further aim of the present invention is to provide a formulation which is characterised by ease of handling during the preparation process and can therefore be reproducibly manufactured on an industrial scale while maintaining a high quality.
Detailed description of the invention 2o The above objectives can be achieved by the formulation described in detail hereinafter.
The present invention relates to a tablet containing talsaclidine 1', characterised in that it consists of a core containing the active substance talsaclidine and a film 25 coating enclosing this core. The tablet according to the invention may also be termed a film-coated tablet within the scope of the present invention.
The active substance talsaclidine is preferably present in the formulation according to the invention in the form of a physiologically acceptable acid addition salt 1. The 3o term physiologically acceptable acid addition salts according to the invention denotes pharmaceutically acceptable salts selected from among the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and malefic acid. If desired, mixtures of the above acids may also be used to prepare the 35 salts. According to the invention the preferred salts of talsaclidine are selected from among the hydrochloride, hydrobromide, sulphate, phosphate, fumarate and methanesulphonate. Most preferably, the salts are selected from among the hydrochloride, hydrobromide and fumarate, while talsaclidine fumarate is most important according to the invention. The active substance may optionally be in the form of a hydrate. Preferably, however, according to the invention, the talsaclidine is added in an anhydrous form. The active substance is preferably used in crystalline, unground form or after being ground in a pinned disc mill, but preferably in unground form. More preferably, the active substance is used in unground form with a particle size distribution within the following limits: D,o <_ 20Nm, Dso 10-80Nm, Duo <_ 300pm.
Most preferably, the particle size distribution of the active substance used in the 1o formulation according to the invention is in the following ranges: D,o <_ 5 - 15Nm, Duo 25 - 75 Nm, D9o <_ 275Nm. The numerical values given above for D,o, Dso and Duo in Nm (microns) are the particle size ranges within which a through total of 10 vol.%, 50 vol.-% or 90 vol.% of the measured particles (cumulative volume distribution) is achieved. These values were determined by the laser diffractometry method, in the 95 present instance particularly using a so-called dry dispersion at a 2 bar dispersion pressure and a focal length f = 500 mm, e.g. using a SympatecIRODOS apparatus.
This method is known in the prior art.
Where reference is made to salts of talsaclidine within the scope of the present 20 _invention, this is indicated by the numeral 1. Any explicit reference to the base talsaclidine, on the other hand, is indicated by the use of the numeral 1'.
Based on the total mass of the core of the film-coated tablets according to the invention talsaclidine 1' is present according to the invention in amounts of 0.5 to 25 25 wt.%, preferably 0.7 to 20 wt.%, particularly preferably about 0.9 to 15 wt.%.
Particularly preferably, the proportion of 1' is between 9 and 14 wt.% based on the total mass of the core. If talsaclidine is used for example in the form of the preferred salt _1 talsaclidine fumarate according to the invention in the formulation according to the invention, the proportion of 1 based on the total mass of the core of the film-3o coated tablets according to the invention is between about 0.85 and 43 wt.%, preferably between about 1.2 and 34 wt.%, particularly preferably between about 1.5 and 26 wt.%. Particularly preferably the proportion of 1 in the case of talsaclidine fumarate is between about 15 and 24 wt.% based on the total mass of the core.
s5 The core of the pharmaceutical formulation according to the invention contains, in addition to the active substance, at least one excipient as filler/dry binder.
Within the scope of the present invention modified lactose, particularly spray-dried lactose is of particular importance as the excipient. This excipient has proved particularly advantageous in the formulation according to the invention. A
preferred aspect of the present invention thus relates to a film-coated tablet containing talsaclidine which contains in its core, in addition to the active substance, modified lactose, particularly spray-dried lactose, particularly preferably spray-dried lactose monohydrate as excipient.
By spray-dried lactose is meant lactose produced by spray agglomeration when spray-drying a suspension of a-lactose monohydrate crystals in an aqueous lactose solution. The spray-drying process results in a free flowing powder with a granulometry suitable for direct tabletting (for example 80-100% < 250Nm) and an ~o amorphous content of for example 5 - 25%, which is responsible for the high binding power of spray-dried lactose.
According to the invention the weight ratio between the components contained in the core of the film-coated tablet, namely modified lactose, preferably spray-dried ~5 lactose, to active substance 1' is in the range from about 1:1 to about 70:1.
Preferably, the ratio of modified, preferably spray-dried lactose to 1' is in the range from about 1.5:1 to about 35:1, particularly preferably in a range from about 2:1 to about 8:1. Preferably, the proportion by weight of modified, preferably spray-dried lactose based on the total mass of the core of the film-coated tablet according to the 2o invention is in a range from about 20 - 70 wt.%, preferably between about wt. %.
The core of the film-coated tablet according to the invention may also contain, in addition to modified, preferably spray-dried lactose and active substance, other 25 excipients or fillers. According to the invention it is preferable to use those compounds which can act as dry binders. Preferred dry binders according to the invention are selected from among powdered cellulose, microcrystalline cellulose, starch, povidone, cellulose derivatives and mixtures of these compounds.
Preferred binders are powdered cellulose and /or microcrystalline cellulose, particularly so preferably microcrystalline cellulose. If one of the abovementioned binders is added to the formulation according to the invention, the weight ratio of modified, preferably spray-dried lactose to binder is preferably about 5:1 to about 1:4, preferably about 4:1 to about 1:3, particularly preferably about 3:1 to 1:2. It is particularly preferable according to the invention if the weight ratio of spray-dried lactose to binder is in the 35 range from about 2:1 to about 1:1.
The core of the film-coated tablet according to the invention may also contain disintegrants in addition to the ingredients mentioned above. Within the scope of the present invention these disintegrants may optionally also be known as breakdown agents. These are preferably selected according to the invention from among sodium starch glycolate, crospovidone, croscarmellose, sodium-carboxymethylcellulose, dried corn starch and mixtures thereof. Particularly preferably, within the scope of the present invention, sodium starch glycolate, crospovidone and croscarmellose, preferably sodium starch glycolate, are used.
If the abovementioned disintegrants are used, the amount by weight used based on the total mass of the core of the film-coated tablet according to the invention is preferably in a range from about 1 -10 wt.%, particularly preferably about 3 -wt. % .
The core of the film-coated tablet according to the invention may also contain flow regulators as additional ingredients. Flow regulators within the scope of the present invention include, for example, silicon dioxide, talc and magnesium stearate.
According to the invention silicon dioxide is preferably used, particularly preferably in ~5 colloidal, highly dispersed form. If the abovementioned flow regulators are used, the amount by weight thereof based on the total mass of the core of the film-coated tablet according to the invention is preferably in a range from about 0.1 - 5 wt.%, preferably about 0.3 - 2 wt.%, particularly preferably between 0.4 and 1.5 wt.%.
2o The core of the film-coated tablet according to the invention may also contain flow agents, lubricants and mould release agents as further ingredients. These include, for example, within the scope of the present invention, stearic acid, magnesium stearate, sodium stearyl fumarate, glycerol tribehenate and mixtures thereof.
According to the invention, stearic acid and magnesium stearate are preferably used.
25 The amount by weight based on the total mass of the core of the film-coated tablet according to the invention is preferably in a range from about 0.1 - 5 wt.%, preferably about 0.5 - 3 wt.%, particularly preferably about 1 - 2 wt.%.
Particularly good release from the mould in the production of the film-coated tablets according to the invention is achieved when magnesium stearate is used in an amount of at least 30 1.0 wt.%, preferably about 1.5 wt.%.
The film or film coating enveloping the core of the film-coated tablets according to the invention contains as essential ingredient a film forming agent selected from among hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, 35 hydroxymethylcellulose, hydroxyethylcellulose and poly(ethylacrylate) methylmethacrylate, the latter in the form of Eudragit NE 30 D, for example.
Alternatively, Eudragit RL 30 D or Eudragit E 12.5 may be used, for example.
The above ingredients may optionally also be used in the form of mixtures thereof.
Preferred film-forming agents are hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxymethylcellulose and hydroxyethylcellulose, of which hydroxypropylmethylcellulose and hydroxypropylcellulose are particularly preferred as film-forming agents according to the invention. The abovementioned film-forming agents may be used on their own or in the form of the mixtures thereof. If only one of the abovementioned film-forming agents is used, hydroxypropylmethylcellulose is of particular importance in this context within the scope of the present invention. The amount by weight of film-forming agents based on the total mass of the film coating of the film-coated tablet according to the invention is preferably in a range from about 20 - 95 wt.%, preferably 30 - 90 wt.%.
~o The film coating may contain, as further ingredients, emulsifiers and plasticisers such as, for example, polyethyleneglycol, glycerol and propyleneglycol, optionally in the form of the mixtures thereof. Preferably, polyethyleneglycols are used as plasticisers.
Without restricting the subject matter of the invention thereto, polyethyleneglycol 400 ~s and polyethyleneglycol 6000 are examples of particularly preferred polyethyleneglycols. The amount of plasticiser by weight based on the total mass of the film coating of the film-coated tablet according to the invention is preferably in a range from about 1 - 30 wt.%, preferably 3 - 25 wt.%, particularly preferably wt. %.
The film coating of the film-coated tablet according to the invention may also contain coloured pigments and pigmenting excipients. Iron oxide, titanium dioxide, talc and mixtures thereof may be mentioned by way of example.
The following procedure may be used, for example, to prepare the film-coated tablet according to the invention.
In a suitable free-fall mixer the excipient spray-dried lactose is mixed with the active substance _1. The active substance premix obtained therefrom is then mixed in a suitable screening machine. This reduces the proportion of coarser particles of active 3o substance which may possibly go into the manufacturing process. Depending on the particle size of the compound 1 used, the preparation of this premix with the subsequent screening process may also be avoided.
In another step of the process, more excipient is added to this active substance premix. As well as spray-dried lactose one or more other excipients may also be added. Moreover, during this step of the process, other ingredients of the formulation such as disintegrants and flow regulators may optionally also be added. After the mixing process has finished the mixture obtained is screened again. This intermediate screening is the essential step for obtaining a uniformity of the contents of the mixture in conformity with the Pharmacopoeia. The flow agent, lubricant and mould release agent are then added to this screened active substance mixture.
The mixture of active substance and excipient thus obtained is then compressed in a suitable tablet press to form the film-coated tablet cores according to the invention.
The compressing force should be kept within a range from 5 - 15 kN, preferably 12 kN, for example, in the case of tablet cores which contain 36 mg of talsaclidine 1'.
Higher compressing forces may lead to tablets with a delayed release of active substance. Lower compressing forces may lead to tablets which are mechanically unstable.
The tablet cores may take various forms, of which round biplanar or biconvex and oval or oblong shapes are preferred.
In order to prepare the film coating suspension the essential and optional ingredients ~5 of the film coating are taken up in a suitable solvent. According to the invention water is preferably used as the solvent. When water is used as solvent, the ingredients of the film coating are partly in dispersed form.
After the coating suspension is finished the tablet cores obtained previously are 2o coated with the desired film in a suitable coating apparatus analogously to coating methods known in the art.
The Examples that follow serve to illustrate some formulations according to the invention. They are intended solely as possible methods given by way of example, without restricting the invention to their content.
Example 1:
Core talsaclidine fumarate: 61.287 mg lactose monohydrate (spray-dried): 99.363 mg 1o microcrystalline cellulose: 90.450 mg sodium starch glycolate: 13.500 mg highly dispersed silicon dioxide: 1.350 mg magnesium stearate: 4.050 mg Total (core): 270.00 mg Film coating hydroxypropylmethylcellulose: 3.500 mg polyethyleneglycol 400 0.350 mg titanium dioxide: 1.750 mg 2o talc: 1.358 mg iron oxide (yellow): 0.042 mg Total (coating): 7.000 mg Total (film-coated tablet): 277.000 mg Example 2:
Core so talsaclidine fumarate: 5.11 mg lactose monohydrate (spray-dried): 209.09 mg microcrystalline cellulose: 102.00 mg sodium starch glycolate: 17.00 mg highly dispersed silicon dioxide: 3.40 mg a5 stearic acid' 3.40 mg Total (core): 340.00 mg Film coating hydroxypropylmethylcellulose: 1.1416 mg polyethyleneglycol 6000 1.4269 mg titanium dioxide: 1.5696 mg talc: 4.5662 mg methacrylic acid copolymer Eudrac~it: 1.2843 mg Total (coating): 10.000 mg Total (film-coated tablet): 350.000 mg Example 3:
Core ~5 talsaclidine fumarate: 10.21 mg lactose monohydrate (spray-dried): 203.99 mg microcrystalline cellulose: 102.00 mg sodium starch glycolate: 17.00 mg highly dispersed silicon dioxide: 3.40 mg 2o stearic acid: 3.40 mg Total (core): 340.00 mg Film coating: analogously to Example 2 25 Total (film-coated tablet): 350.000 mg Example 4:
30 Core talsaclidine fumarate: 20.43 mg lactose monohydrate (spray-dried): 193.77 mg microcrystalline cellulose: 102.00 mg sodium starch glycolate: 17.00 mg 35 highly dispersed silicon dioxide:3.40 mg stearic acid' 3.40 mg Total (core): 340.00 mg Film coatincl: analogously to Example 2 Total (film-coated tablet): 350.000 mg Example 5:
Core talsaclidine fumarate: 40.86 mg 90 lactose monohydrate (spray-dried):173.34 mg microcrystalline cellulose: 102.00 mg sodium starch glycolate: 17.00 mg highly dispersed silicon dioxide: 3.40 mg stearic acid: 3.40 mg 95 Total (core): 340.00 mg film coating: analogously to Example 2 Total (film-coated tablet): 350.000 mg Example 6:
Core talsaclidine fumarate: 51.07 mg lactose monohydrate (spray-dried): 163.13 mg microcrystalline cellulose: 102.00 mg sodium starch glycolate: 17.00 mg highly dispersed silicon dioxide: 3.40 mg so stearic acid' 3.40 mq Total (core): 340.00 mg film coating: analogously to Example 2 Total (film-coated tablet): 350.000 mg Example 7:
core talsaclidine fumarate: 61.29 mg 5 lactose monohydrate (spray-dried):152.91 mg microcrystalline cellulose: 102.00 mg sodium starch glycolate: 17.00 mg highly dispersed silicon dioxide: 3.40 mg stearic acid: 3.40 mg 9o Total (core): 340.00 mg film coating: analogously to Example 2 Total (film-coated tablet): 350.000 mg Example 8:
Core 2o talsaclidine fumarate: 81.72 mg lactose monohydrate (spray-dried): 132.48 mg microcrystalline cellulose: 102.00 mg sodium starch glycolate: 17.00 mg highly dispersed silicon dioxide: 3.40 mg 25 stearic acid: 3.40 mg Total (core): 340.00 mg Film coating: analogously to Example 2 so Total (film-coated tablet): 350.000 mg Example 9:
Core talsaclidine fumarate: 40.86 mg lactose monohydrate (spray-dried):66.24 mg microcrystalline cellulose: 60.30 mg sodium starch glycolate: 9.00 mg highly dispersed silicon dioxide: 0.90 mg stearic acid: 2.70 mA
~o Total (core): 180.00 mg Film coating: analogously to Example 1 Total (film-coated tablet): 185.000 mg
Example 1:
Core talsaclidine fumarate: 61.287 mg lactose monohydrate (spray-dried): 99.363 mg 1o microcrystalline cellulose: 90.450 mg sodium starch glycolate: 13.500 mg highly dispersed silicon dioxide: 1.350 mg magnesium stearate: 4.050 mg Total (core): 270.00 mg Film coating hydroxypropylmethylcellulose: 3.500 mg polyethyleneglycol 400 0.350 mg titanium dioxide: 1.750 mg 2o talc: 1.358 mg iron oxide (yellow): 0.042 mg Total (coating): 7.000 mg Total (film-coated tablet): 277.000 mg Example 2:
Core so talsaclidine fumarate: 5.11 mg lactose monohydrate (spray-dried): 209.09 mg microcrystalline cellulose: 102.00 mg sodium starch glycolate: 17.00 mg highly dispersed silicon dioxide: 3.40 mg a5 stearic acid' 3.40 mg Total (core): 340.00 mg Film coating hydroxypropylmethylcellulose: 1.1416 mg polyethyleneglycol 6000 1.4269 mg titanium dioxide: 1.5696 mg talc: 4.5662 mg methacrylic acid copolymer Eudrac~it: 1.2843 mg Total (coating): 10.000 mg Total (film-coated tablet): 350.000 mg Example 3:
Core ~5 talsaclidine fumarate: 10.21 mg lactose monohydrate (spray-dried): 203.99 mg microcrystalline cellulose: 102.00 mg sodium starch glycolate: 17.00 mg highly dispersed silicon dioxide: 3.40 mg 2o stearic acid: 3.40 mg Total (core): 340.00 mg Film coating: analogously to Example 2 25 Total (film-coated tablet): 350.000 mg Example 4:
30 Core talsaclidine fumarate: 20.43 mg lactose monohydrate (spray-dried): 193.77 mg microcrystalline cellulose: 102.00 mg sodium starch glycolate: 17.00 mg 35 highly dispersed silicon dioxide:3.40 mg stearic acid' 3.40 mg Total (core): 340.00 mg Film coatincl: analogously to Example 2 Total (film-coated tablet): 350.000 mg Example 5:
Core talsaclidine fumarate: 40.86 mg 90 lactose monohydrate (spray-dried):173.34 mg microcrystalline cellulose: 102.00 mg sodium starch glycolate: 17.00 mg highly dispersed silicon dioxide: 3.40 mg stearic acid: 3.40 mg 95 Total (core): 340.00 mg film coating: analogously to Example 2 Total (film-coated tablet): 350.000 mg Example 6:
Core talsaclidine fumarate: 51.07 mg lactose monohydrate (spray-dried): 163.13 mg microcrystalline cellulose: 102.00 mg sodium starch glycolate: 17.00 mg highly dispersed silicon dioxide: 3.40 mg so stearic acid' 3.40 mq Total (core): 340.00 mg film coating: analogously to Example 2 Total (film-coated tablet): 350.000 mg Example 7:
core talsaclidine fumarate: 61.29 mg 5 lactose monohydrate (spray-dried):152.91 mg microcrystalline cellulose: 102.00 mg sodium starch glycolate: 17.00 mg highly dispersed silicon dioxide: 3.40 mg stearic acid: 3.40 mg 9o Total (core): 340.00 mg film coating: analogously to Example 2 Total (film-coated tablet): 350.000 mg Example 8:
Core 2o talsaclidine fumarate: 81.72 mg lactose monohydrate (spray-dried): 132.48 mg microcrystalline cellulose: 102.00 mg sodium starch glycolate: 17.00 mg highly dispersed silicon dioxide: 3.40 mg 25 stearic acid: 3.40 mg Total (core): 340.00 mg Film coating: analogously to Example 2 so Total (film-coated tablet): 350.000 mg Example 9:
Core talsaclidine fumarate: 40.86 mg lactose monohydrate (spray-dried):66.24 mg microcrystalline cellulose: 60.30 mg sodium starch glycolate: 9.00 mg highly dispersed silicon dioxide: 0.90 mg stearic acid: 2.70 mA
~o Total (core): 180.00 mg Film coating: analogously to Example 1 Total (film-coated tablet): 185.000 mg
Claims (17)
1) Tablet containing talsaclidine 1', characterised in that it consists of a core containing the active substance talsaclidine and a film coating enveloping this core.
2) Tablet according to claim 1, characterised in that the core further contains the excipient modified lactose, preferably spray-dried lactose.
3) Tablet according to claim 1 or 2, characterised in that talsaclidine is present in the form of an acid addition salt 1 which is selected from the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.
4) Tablet according to one of claims 1, 2 or 3, characterised in that the core contains talsaclidine 1' in an amount of 0.5 to 25 wt.%, preferably 0.7 to 20 wt. %.
5) Tablet according to one of claims 2 to 4, characterised in that the weight ratio between the components contained in the core of the film-coated tablet, namely modified lactose to active substance 1', is in a range from about 1:1 to about 70:1, preferably between about 1.5:1 and about 35:1.
6) Tablet according to one of claims 2 to 5, characterised in that the core further contains a dry binder.
7) Tablet according to claim 6, characterised in that in the core the weight ratio of modified lactose to dry binder is in the range from about 5:1 to about 1:4, preferably about 4:1 to about 1:3.
8) Tablet according to one of claims 2 to 7, characterised in that the core further contains a disintegrant.
9) Tablet according to claim 8, characterised in that the amount by weight of the disintegrant based on the total mass of the core in a range from about 1 - 10 wt. %.
10) ~Tablet according to one of claims 2 to 9, characterised in that the core further contains a flow regulator.
11) ~Tablet according to claim 10, characterised in that the amount by weight of the flow regulator based on the total mass of the core is in a range from about 0.1 -wt.%.
12) ~Tablet according to one of claims 2 to 11, characterised in that the core further contains flow agents, lubricants and mould release agents.
13) ~Tablet according to claim 12, characterised in that the amount by weight of the flow agents, lubricants and mould release agents based on the total mass of the core is in a range from about 0.1 - 5 wt.%.
14) ~Tablet according to one of claims 1 to 13, characterised in that the film enveloping the core of the film-coated tablets according to the invention contains, as an essential ingredient, a film-forming agent which is selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, poly(ethylacrylate) methylmethacrylate, for example in the form of Eudragit NE 30 D, Eudragit RL
30 D, Eudragit E 12.5 and mixtures of these film-forming agents.
30 D, Eudragit E 12.5 and mixtures of these film-forming agents.
15) ~Tablet according to claim 14, characterised in that the amount by weight of film-forming agents based on the total mass of the film coating of the film-coated tablet according to the invention is in a range from about 20 - 95 wt.%.
16) ~Tablet according to one of claims 14 or 15, characterised in that the film coating contains as a further ingredient emulsifiers and plasticisers.
17) ~Tablet according to claim 16, characterised in that the amount by weight of plasticiser based on the total mass of the film coating is in a range from about 1 -30 wt. %.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10106971A DE10106971A1 (en) | 2001-02-15 | 2001-02-15 | Drug formulation containing a muscarinic agonist |
| DE10106971.5 | 2001-02-15 | ||
| PCT/EP2002/001374 WO2002064124A2 (en) | 2001-02-15 | 2002-02-09 | Medicament formulation containing a muscarinic agonist |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2434976A1 true CA2434976A1 (en) | 2002-08-22 |
Family
ID=7674095
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002434976A Abandoned CA2434976A1 (en) | 2001-02-15 | 2002-02-09 | Medicament formulation containing a muscarinic agonist |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP1361871A2 (en) |
| JP (1) | JP2004518710A (en) |
| AR (1) | AR033862A1 (en) |
| AU (1) | AU2002247705A1 (en) |
| CA (1) | CA2434976A1 (en) |
| DE (1) | DE10106971A1 (en) |
| MX (1) | MXPA03007272A (en) |
| UY (1) | UY27170A1 (en) |
| WO (1) | WO2002064124A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9402907B2 (en) | 2011-08-10 | 2016-08-02 | Daiichi Sankyo Company, Limited | Pharmaceutical composition containing diamine derivative |
| US9918975B2 (en) | 2010-03-19 | 2018-03-20 | Daiichi Sankyo Company, Limited | Method for improving dissolution of anticoagulant agent |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BRPI0809205B8 (en) * | 2007-03-29 | 2021-05-25 | Daiichi Sankyo Co Ltd | pharmaceutical composition |
| WO2010033045A1 (en) * | 2008-09-16 | 2010-03-25 | Igor Anatolievich Pomytkin | Compositions and methods for prevention or treatment of beta amyloid deposition |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE8817121U1 (en) * | 1988-11-22 | 1993-02-04 | Boehringer Ingelheim Kg, 6507 Ingelheim, De | |
| WO1998030243A1 (en) * | 1997-01-08 | 1998-07-16 | Warner-Lambert Company | Acetylcholinesterase inhibitors in combination with muscarinic agonists for the treatment of alzheimer's disease |
| WO1998046225A1 (en) * | 1997-04-11 | 1998-10-22 | Eli Lilly And Company | Method for treating schizophrenia |
| WO1998046601A1 (en) * | 1997-04-11 | 1998-10-22 | Eli Lilly And Company | Composition for treating pain |
| DE19851126A1 (en) * | 1998-11-06 | 2000-05-11 | Boehringer Ingelheim Pharma | Use of talsaclidine for treating schizophrenia |
-
2001
- 2001-02-15 DE DE10106971A patent/DE10106971A1/en not_active Withdrawn
-
2002
- 2002-02-09 EP EP02716755A patent/EP1361871A2/en not_active Withdrawn
- 2002-02-09 AU AU2002247705A patent/AU2002247705A1/en not_active Abandoned
- 2002-02-09 CA CA002434976A patent/CA2434976A1/en not_active Abandoned
- 2002-02-09 JP JP2002563919A patent/JP2004518710A/en active Pending
- 2002-02-09 MX MXPA03007272A patent/MXPA03007272A/en unknown
- 2002-02-09 WO PCT/EP2002/001374 patent/WO2002064124A2/en not_active Application Discontinuation
- 2002-02-13 UY UY27170A patent/UY27170A1/en not_active Application Discontinuation
- 2002-02-15 AR ARP020100515A patent/AR033862A1/en not_active Withdrawn
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9918975B2 (en) | 2010-03-19 | 2018-03-20 | Daiichi Sankyo Company, Limited | Method for improving dissolution of anticoagulant agent |
| US9402907B2 (en) | 2011-08-10 | 2016-08-02 | Daiichi Sankyo Company, Limited | Pharmaceutical composition containing diamine derivative |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2004518710A (en) | 2004-06-24 |
| UY27170A1 (en) | 2002-09-30 |
| EP1361871A2 (en) | 2003-11-19 |
| DE10106971A1 (en) | 2002-08-29 |
| WO2002064124A3 (en) | 2002-12-05 |
| AR033862A1 (en) | 2004-01-07 |
| MXPA03007272A (en) | 2003-12-04 |
| WO2002064124A2 (en) | 2002-08-22 |
| AU2002247705A1 (en) | 2002-08-28 |
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