Pastes containing flatting agents and/or texture additives, containing

The invention relates to preparations of flatting and texturing agents for incorporation in coating compounds, more particularly in low-emission, high-solids coating compounds, and to the coating compounds containing the flatting and texturing agent preparations. The coating compounds are used preferably in vehicle and vehicle part lacquering.
For certain applications in vehicle and industrial lacquering it is necessary to prepare lacquers which result in surfaces with reduced gloss and/or textured surfaces. For example, lacquered commercial vehicle bodies should have matt surfaces and plastics parts, e.g., external trim parts on vehicles such as bumpers should receive dull and/or textured surfaces. In order to obtain the matt and/or textured surfaces, flatting agents or texture additives are added to the coating compounds. When the applied lacquer film dries, the flatting agent particles produce a microrough surface texture. As a result, the incident light is reflected in a diffuse manner and gives the observer the impression of a matt surface. The flatting agent particles must be distributed homogeneously in the dry lacquer film. The flatting agents and/or texture additives may be incorporated as material in powder or paste form. Conventional flatting agent pastes generally contain, apart from the flatting agents, binders, solvents and optionally additives.
Examples of binders which may be used in flatting agent pastes include alkyd, aldehyde, acrylic, polyester resins and/or cellulose esters.
EP-A-700 408 describes a matt paste suitable for the production of textured coatings on plastics surfaces, which paste is incorporated in coating compounds based on hydroxy-functional binders and polyisocyanate crosslinking agents. The matt paste contains hydroxy-functional polyesters, hydroxy-functional polyacrylates and optionally cellulose esters as binder. Texturing agents are added in powder form to the coating compound.
Often, with the above-mentioned binders which may be used in flatting agent pastes, the surfaces obtained after application of the lacquer are still too glossy, i.e. the flatting effect is still insufficient.
If the coating compounds which are to result in matt/textured surfaces are prepared by means of a mixed lacquer system of the kind used directly in situ on the user""s premises, for example, in vehicle refinishing usually to provide a plurality of different hues, such a mixed lacquer system generally contains so-called additional mixed lacquers as well as the coloured mixed lacquers, for example, those for obtaining desired textures or degrees of gloss. The components of such a mixed lacquer system may be present as finished lacquers or semi-finished products.
For ecological reasons, low-emission, high-solids lacquers are also increasingly being used in mixed lacquer systems. Adequate flowability is a prerequisite for problem-free handling and good meterability of the mixed lacquers. It is difficult to achieve good flowability with the above-mentioned additional mixed lacquers containing flatting agents and/or texture additives and in high-solids lacquers because in order to obtain predetermined texture effects or degrees of gloss and due to the high solids content required of the lacquers to be processed, the additional mixed lacquers must contain such large proportions of texturing and/or flatting agents that the products are pasty and no longer free-flowing, making acceptable processing impossible. This disadvantage is not solved by the matt pastes described in EP-A-700 408 either.
Moreover, the preparations containing flatting and/or texturing agents generally have the problem that partially dried particles of said preparations or of the coating agents containing them fall from the edge of the can of the lacquer container in question back into the lacquer and may thus lead to pinholing. It is not possible to screen these particles from the lacquer prior to application since the texturing agent would then be removed too. Lacquers containing flatting agents often do not result in a uniform spray pattern. Unsightly patches form, particularly on fairly large surfaces to be lacquered.
The object of the invention was, therefore, to provide flatting agent and/or texturing agent preparations, more particularly for low-emission, high-solids coating agents in paste form which, whilst giving a very good flatting effect and texture, have good flowability and guarantee problem-free meterability. The preparations in paste form should be easy to process. Partially dried particles of said preparations or of the coating agents containing them should be substantially crumb-free and should remain adhering to the can edge of the lacquer containers in question in order to prevent pinholing and consequent lacquer defects. Moreover, the preparations in paste form should be stable in storage and exhibit no settling even after prolonged storage. The lacquers containing the pastes should result in a uniform spray pattern, particularly on relatively large surfaces.
The object is achieved by preparations of flatting agents and/or texture additives in paste form, hereinafter known as flatting agent pastes, containing
A) 5 to 30 wt. %, preferably 7 to 25 wt. % of one or more thixotropic (meth)acrylic copolymers and/or of one or more thixotropic polyesters,
B) 15 to 45 wt. %, preferably 20 to 35 wt. % of one or more flatting and/or texturing agents,
C) 30 to 65 wt. %, preferably 35 to 55 wt. % of one or more organic solvents and optionally wetting and dispersing agents, rheology modifiers, catalysts and optionally further additives and auxiliaries, wherein the proportions of components A), B) and C) add up to 100 wt. % and the weight ratio of thixotropic (meth)acrylic copolymer and/or thixotropic polyester: flatting and/or texturing agents is 1:6 to 1:0.8.
Surprisingly, it was found that the object according to the invention may be achieved by using thixotropic (meth)acrylic copolymers and/or thixotropic polyesters in the flatting agent paste. It could not have been expected that the thixotropic resins used which, in their form of application, are generally present as compact substances, may be filled with the required amounts of flatting and/or texturing agents and result in free-flowing pastes.
Thixotropic (meth)acrylic copolymers and/or thixotropic polyesters (component A) are contained as binders in the flatting agent paste according to the invention. The term thixotropic resins means, for example, resins modified by adding thixotropic agents which exhibit a decrease in viscosity under shear stress and after the shear stress regain their original viscosity in the resting state, albeit with a time lag. The thixotropic behaviour of the resins may be achieved by various methods, which will be discussed in more detail below.
The thixotropic resins to be used according to the invention are those based on (meth)acrylic copolymers and/or polyesters, preferably those based on hydroxy-functional (meth)acrylic copolymers and/or hydroxy-functional polyesters.
(Meth)acrylic copolymers which may be used in component A preferably have a hydroxyl value from 25 to 200, particularly preferably from 40 to 150 and an acid value from 0 to 50. The (meth)acrylic copolymers have a number-average molecular weight (Mn) from 1500 to 30,000 g/mole, preferably from 2000 to 15,000 g/mole.
The preparation of the (meth)acrylic resins may be carried out by polymerisation according to conventional methods, e.g., bulk, solution or suspension polymerisation. The various polymerisation processes are known to the skilled person. The solution polymerisation process is preferred for the preparation of (meth)acrylic resins. The solvent is generally charged to the reaction vessel, heated to boiling point and the monomer/initiator mixture fed in continuously over a certain period. Polymerisation may be carried out preferably at temperatures from 100xc2x0 C. to 160xc2x0 C.
Suitable initiators are per- and azo compounds. An amount from 0.2 to 8 wt. % of initiators, based on the initial weight of monomers, is used in preference.
Examples of suitable organic solvents which may be used advantageously in solution polymerisation include: alcohols, glycol ethers such as ethylene glycol dimethyl ether, propylene glycol dimethyl ether; glycol ether esters such as ethyl glycol acetate, butyl glycol acetate, 3-methoxy-n-butyl acetate, butyl diglycol acetate, methoxy propyl acetate, esters such as butyl acetate, isobutyl acetate, amyl acetate; ketones such as methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, isophorone, aromatic hydrocarbons (e.g. with a boiling range from 136xc2x0 C. to 180xc2x0 C.) and aliphatic hydrocarbons.
Chain transfer agents such as, e.g., mercaptans, thioglycolates, cumene, dimeric alpha-methylstyrene may be used to control the molecular weight.
The (meth)acrylic copolymers to be used are preferably copolymers with vinyl aromatic monomers, such as, e.g., styrene or derivatives thereof, particularly preferably with styrene. The copolymers preferably have a styrene content of at least 30 wt. %.
Hydroxyl groups present in preference are introduced into the (meth)acrylic resin using monomers containing hydroxyl groups. Moreover, further ethylenically unsaturated monomers of the kind known to the skilled person for free-radical polymerisation are suitable as monomers capable of free-radical polymerisation. These may be unsaturated monomers with functional groups, e.g., carboxyl groups or glycidyl groups, and conventional unsaturated monomers without further functional groups.
Examples of olefinically unsaturated monomers having hydroxyl groups include hydroxyalkyl esters or hydroxyaryl esters of unsaturated carboxylic acids. Hydroxyalkyl esters of acrylic acid or methacrylic acid with aliphatic diols having 2 to 20 carbon atoms are preferred. Examples of such hydroxyalkyl esters with a primary hydroxyl group are hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate, hydroxybutyl (meth)acrylate, hydroxyamyl (meth)acrylate, neopentyl glycol monoacrylate, hydroxyhexyl (meth)acrylate, hydroxyoctyl (meth)acrylate. Examples of hydroxyalkyl esters with a secondary hydroxyl group are 2-hydroxypropyl (meth)acrylate, 2-hydroxybutyl (meth)acrylate, 3-hydroxybutyl (meth)acrylate. The corresponding esters of other unsaturated carboxylic acids such as, e.g., crotonic acid or isocrotonic acid may also, however, be used.
A further group of OH-functional monomers are hydroxyalkyl amides of unsaturated carboxylic acids such as, e.g., acrylic acid, methacrylic acid and fumaric acid. Examples hereof are N-hydroxyethyl methacrylic acid amide, N-(2-hydroxypropyl)-methacrylamide or N-hydroxyalkyl flimaric acid mono- or diamide. Reaction products of one mole of hydroxyallryl (meth)acrylate and 2 moles of epsilon caprolactone and adducts of (meth)acrylic acid and glycidyl esters of saturated alpha,alpha-dialkyl alkane monocarboxylic acids, for example, glycidyl esters of versatic acid, are also highly suitable.
Other unsaturated compounds containing hydroxyl groups are allyl alcohol, monovinyl ethers of polyalcohols, particularly of diols such as, e.g., the monovinyl ether of ethylene glycol or of butane diol, allyl ethers or esters containing hydroxyl groups such as 2,3-dihydroxypropyl monoallyl ether, trimethylolpropane monoallyl ether or 2,3-dihydroxypropanoic acid allyl ester and glycerol mono(meth)acrylate.
Hydroxyalkyl (meth)acrylates are particularly suitable, such as in particular hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate and hydroxybutyl (meth)acrylate.
Examples of suitable unsaturated monomers without further functional groups include esters of unsaturated monocarboxylic acids with aliphatic monohydric, branched or unbranched and cyclic alcohols having 1 to 20 carbon atoms. These are preferably esters of acrylic or methacrylic acid. Examples of esters with aliphatic alcohols are methyl acrylate, ethyl acrylate, isopropyl acrylate, tert.-butyl acrylate, n-butyl acrylate, isobutyl acrylate, 2-ethylhexyl acrylate, 2-ethylhexyl acrylate, lauryl acrylate, stearyl acrylate and the corresponding methacrylates. Examples of esters with cyclic alcohols are cyclohexyl (meth)acrylate, trimethyl cyclohexyl (meth)acrylate, 4-tert. butylcyclohexyl (meth)acrylate and isobomyl (meth)acrylate.
Further unsaturated monomers are, for example, vinyl esters such as vinyl acetate. Ethylenically polyunsaturated monomers may also, however, be used. These are monomers having at least two double bonds capable of free-radical polymerisation. Examples hereof are divinyl benzene, butane 1,4-diol diacrylate, hexane 1,6-diol diacrylate, neopentyl glycol dimethacrylate, glycerol dimethacrylate.
Preferred monomer components for the preparation of the (meth)acrylic copolymers are alkyl esters and hydroxyalkyl esters of (meth)acrylic acid and styrene as well as optionally other alpha-, beta-unsaturated monomers and/or optionally (meth)acrylic acid. Examples of alkyl esters are those having 1 to 7 carbon atoms in the alkyl radical, e.g., methyl (meth)acrylate, ethyl (meth)acrylate, butyl (meth)acrylate, pentyl (meth)acrylate and cyclohexyl (meth)acrylate. Examples of hydroxyalkyl esters are hydroxyethyl (meth)acrylate, hydroxypropyl (meth)acrylate, butane 1,4-diol monoacrylate, hexane 1,6-diol monomethacrylate and reaction products of hydroxyalkyl (meth)acrylates with epsilon caprolactone.
Polyesters which may be used in component A preferably have a hydroxyl value from 25 to 200, particularly preferably from 40 to 150 and an acid value from 0 to 50. The polyesters preferably have a number-average molecular weight (Mn) from 1000 to 6000, preferably from 1000 to 3000. The polyesters are polycondensation products of polyvalent polycarboxylic acids or anhydrides thereof and polyhydric polyols, optionally with the use of monocarboxylic acids. In order to obtain appropriate OH values, the polyesters are prepared preferably with an excess of alcohol. If the polyesters are to contain carboxyl groups, these may be obtained by incomplete esterification or by using monomers containing carboxyl groups.
Examples of suitable polycarboxylic acids are aromatic, cycloaliphatic and aliphatic such as, e.g., ortho-phthalic anhydride, isophthalic acid, tetrahexahydrophthalic acid, 1,4-cyclohexane dicarboxylic acid, 4-methylhexahydrophthalic acid, succinic acid (anhydride), adipic acid, sebacic acid and dimeric fatty acid.
Examples of suitable alcohol components include glycols such as ethylene glycol, polyethylene glycols, butane diols, neopentyl glycol, cyclohexane dimethanol, trimethyl pentane diol and higher alcohols, such as, e.g., trimethylol ethane and pentaerythritol.
Optionally, natural and synthetic monocarboxylic acids may also be used in addition, e.g., benzoic acid, lauric acid, fatty acids of naturally occurring oils.
The (meth)acrylic resins and/or polyester resins may be rendered thixotropic in the conventional manner. The various possibilities are well known in the art and are known to the skilled person. For example, conventional thixotropic agents may be used. It is assumed that thixotropy in the resin is developed substantially by way of H-bridge formation.
For example, so-called SCA agents (SCA=Sag Control Agent) may be used to obtain thixotropic behaviour. These substances are generally low molecular weight, semi-crystalline organic compounds based on urea. Such compounds are generally prepared from monoamines and/or polyamines and/or polymeric substances having at least one amino group, and from mono- and/or polyisocyanates and/or polymeric substances having at least one isocyanate group. A large number of these SCA agents and the processes for the preparation thereof are described in the literature.
Polyurethanes, polyurethane ureas and/or polyamides may also be used to obtain thixotropic behaviour. Thixotropic behaviour is obtained preferably with polyurethanes or polyurethane ureas. The polyurethanes and polyurethane ureas are, for exanple, reaction products of isocyanate compounds, e.g., diisocyanates and/or polyisocyanates, and hydroxy-functional components, e.g., hydroxy-functional (meth)acrylates and/or polyesters and/or low molecular weight hydroxy-functional compounds and/or mono- and/or polyamines. Optionally, the reaction products may also have ether groups. Starting substances used in preference are compounds having aromatic structures.
In the thixotropic (meth)acrylic and/or polyester resins, the proportions of (meth)acrylic and/or polyester to the proportions of thixotropic agents, e.g., the polyurethane proportions, are for example in the weight ratio from 95:5 to 50:50, preferably 90:10 to 55:45. The thixotropic (meth)acrylic and/or polyester resins preferably have a nitrogen content from, for example, 10 to 150 mmole/100 g of solid resin, preferably from 20 to 100 mmole/100 g of solid resin. The thixotropic resins may be prepared, for example, by preparing the individual constituents separately and then mixing them or combining them in a suitable manner. The thixotropic resins may also be prepared, for example, by preparing the thixotropic agents in the presence of the (meth)acrylic and/or polyester resins.
The thixotropic (meth)acrylic and/or polyester resins are generally present in the solvent form with various solids proportions. Examples of suitable solvents include those of the kind already mentioned for the preparation of the (meth)acrylic copolymers. Examples of solvents are alcohols, esters such as ethyl acetate, isopropyl go acetate, n-propyl acetate, isobutyl acetate and 2-ethylhexyl acetate, aromatic hydrocarbons such as toluene, o-, m-, p-xylene, ethylbenzene, Solvesso 100 (mixture of aromatic hydrocarbons with a boiling range from 153xc2x0 C. to 180xc2x0 C.), aliphatic hydrocarbons.
The resins may be in solvent form, for example, with a solids content from 40 to 85 wt. %.
Thixotropic (meth)acrylic and/or polyester resins which may be used are known to the skilled person and also available as commercial products. Thixotropic (meth)acrylic resins are available, for example, under the name Jagotex(copyright) F216 THIX, Jagotex(copyright) F219 THIX, Jagotex SCA-Y, Halwemer F 2200 or Setalux C-91389 VX-45. Thixotropic polyester resins are available, for example, under the name of Jxc3xa4gapol PE 300 THIX.
(Meth)acrylic copolymers which have been rendered thixotropic with polyurethanes and/or polyureas and/or polyurethane ureas may be used particularly advantageously.
Apart from the thixotropic (meth)acrylic and/or polyester resins, the flatting agent paste according to the invention also contains one or more flatting and/or texturing agents (component B). The flatting agents may be of an inorganic or organic nature. Examples of inorganic flatting agents are amorphous or pyrogenic silica, silica gels and layered silicates, e.g., hydrated magnesium silicate (talc). The inorganic flatting agents may be untreated, or surface-treated with organic compounds, e.g., with suitable wax types or with inorganic compounds. Examples of organic flatting agents are Al, Zn, Ca or Mg stearate, waxy compounds such as, e.g., micronised polypropylene waxes, and urea-formaldehyde condensates. Flatting agents are available as commercial products (e.g. under the name Syloid(copyright)) and are known to the skilled person. They are supplied in various particle sizes. The chosen particle size of the flatting agents may be adjusted closely to the dry film thickness in the usual manner in order to guarantee the desired compromise between good flatting effect and surface smoothness. Coarse flatting agents exhibit a greater flatting effect for the same pore volume, but also produce a rougher film surface. The average particle size may be, for example, 2 to 16 xcexcm.
Examples of suitable texturing agents include ground plastics such as, e.g., ground polyamide or ground polypropylene. Corresponding products are available, e.g., under the trade names Propyltex, Vestosint and Orgasol. Moreover, ground sand or ground glass may be used as texturing agents. The particle size of the texturing agents is preferably in the range from 30 to 200 xcexcm.
During the preparation of the flatting agent pastes it has proved advantageous to use, as flatting agent, 65 to 90 wt. %, based on the total amount of flatting and/or texturing agents, of platelet-like fillers with a flatting effect. Examples of platelet-like fillers with a flatting effect are hydrated magnesium silicate (talc) and platelet-like intergrown minerals such as platelet-like intergrowths of mica, chlorite and quartz. The flatting agent paste according to the invention contains one or more organic solvents (component C). These may be conventional solvents which may be used for a lacquer formulation.
More particularly, these may be glycol ethers such as ethylene glycol dimethylether, propylene glycol dimethyl ether; glycol ether esters such as ethyl glycol acetate, butyl glycol acetate, 3-methoxy-n-butyl acetate, butyl diglycol acetate, methoxypropyl acetate; esters such as butyl acetate, isobutyl acetate, amyl acetate; ketones such as methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, isophorone and aromatic or aliphatic hydrocarbons.
The flatting agent paste according to the invention may also contain wetting and dispersing agents, rheology modifiers, catalysts and optionally further additives and auxiliaries.
Examples of suitable wetting and dispersing agents include those based on polyester polyacrylic acid and/or polyacrylate. Examples of suitable rheology modifiers include those based on pyrogenic silica, based on layered silicates, hydrogenated castor oils and polymeric urea or urea-urethane compounds. These products are also well known to the skilled person and available commercially, for example, the various Disperbyk and Byk types from Byk-Chemie, or the various Efka types from Efka. The wetting and dispersing agents and rheology modifiers are used preferably in amounts from 0.3 to 8 wt. % based on the total amount of flatting agent paste.
Catalysts optionally present in the flatting agent paste may serve, for example, to catalyse the crosslinking reaction taking place in the finished coating compound, in so far as crosslinkable binders are used. In the case of isocyanate-crosslinking binder systems containing hydroxyl groups, examples of suitable catalysts include organic tin compounds or tertiary amines.
The additives optionally used are conventional lacquer additives such as, for example, anti-settling agents, levelling agents, plasticisers and light stabilisers.
The flatting agent paste is prepared in the conventional manner by mixing and dispersing the individual components.
The flatting agent pastes according to the invention obtained in this way are very free-flowing and meterable and may be incorporated without difficulty in, e.g., high-solids coating compounds. Partially dried residues of flatting agent pastes or of the lacquers containing them remain adhering to the lacquer containers in question (no crumbling). The fact that the flatting agent pastes may be used as additional mixed lacquers in a high-solids mixed lacquer system due to the good flow and processing properties is a particular advantage.
The invention also relates, therefore, to coating compounds which contain the flatting agent pastes according to the invention, and to the use of the flatting agent pastes in pigmented and unpigmented coating compounds, particularly the use in pigmented top coats. The coating compounds are the clear lacquers or pigmented top coats known to the skilled person which are usually used in vehicle lacquering and refinishing. They may be one-pack, two-pack or multi-component lacquers.
The coating compounds contain a) one or more film-forming binders, b) optionally one or more crosslinking agents, c) a flatting agent paste as described above, and optionally one or more organic solvents, pigments, fillers, conventional lacquer additives and auxiliaries.
Film-forming binders used may be physically drying or chemically crosslinking binders. These are all the types of binders known to the skilled person, of the kind usually used in solvent-based clear lacquers and pigmented top coats in the field of vehicle lacquering, particularly vehicle refinishing. Examples of physically drying binders include polyacrylic, polyurethane and polyester resins, which may also optionally be modified. The resins may be used on their own or in combination. The chemically crosslinking binders are preferably binder systems based on hydroxyl group-containing binders and polyisocyanate crosslinking agents.
Optionally, reactive thinners may also be contained in the binder systems.
Preferred coating compounds thus contain
a) one or more hydroxyl group-containing polyaddition, polymerisation and/or polycondensation resins,
b) one or more polyisocyanates as crosslinking agents,
c) a flatting agent paste, as described above
and optionally one or more organic solvents, pigments, fillers, conventional lacquer additives and auxiliaries.
The components a) and b) are used preferably in an amount such that the ratio of hydroxyl groups of component a) to the isocyanate groups of component b) is 1:3 to 3:1. If the thixotropic resins used are hydroxy-functional resins, said resins must also be taken into account when calculating the OH/NCO ratios.
Examples of hydroxyl group-containing binder components a) which may be used include polyurethanes, polyesters and polyacrylates, alone or in combination. The resins generally have a hydroxyl value from 20 to 250 mg KOH/g and may optionally be modified. Polyacrylic resins with hydroxyl values from 80 to 200 mg KOH/g and acid values from 0 to 40 mg KOH/g are used in particular preference as hydroxyl group-containing binder component a). The polyacrylic resins have a preferred number-average molecular weight Mn from 1000 to 20,000, particularly preferably from 1000 to 10,000.
The polyacrylates which may be used in preference are prepared by free-radical polymerisation of olefinically unsaturated monomers, preferably by solution polymerisation.
The hydroxyl groups are introduced into the polyacrylic resin using hydroxyl group-containing monomers. Moreover, practically all the olefinically unsaturated monomers of the kind commonly used for free-radical polymerisation are suitable as monomers capable of free-radical polymerisation. They may be unsaturated monomers with functional groups, e.g., carboxyl groups or glycidyl groups, and conventional unsaturated monomers without further functional groups. Reference is made to the above description of the (meth)acrylic resins present in the flatting agent paste for the description of suitable monomer groups and for the preparation of the polyacrylates.
The individual monomers are used in amounts such that desired hydroxyl and acid values are obtained.
The poly(meth)acrylates which may be used in preference as binder component a) may be used on their own or in combination. They may also be present in mixture with further hydroxy-functional components, e.g., hydroxy-functional polyesters and/or polyurethanes, and with hydroxyl- and/or amino group-containing reactive thinners. Examples of the polyisocyanates (component b) which may be used as crosslinking agents include any organic polyisocyanates with aliphatically, cycloaliphatically, araliphatically and/or aromatically bound free isocyanate groups. The polyisocyanates are liquid at room temperature or liquefied by the addition of organic solvents. The polyisocyanates generally have a viscosity from 1 to 6000 mPas at 23xc2x0 C., preferably over 5 and under 3000 mPas.
The polyisocyanates are preferably polyisocyanates or polyisocyanate mixtures having exclusively aliphatically and/or cycloaliphatically bound isocyanate groups with an average NCO functionality from 1.5 to 5, preferably 2 to 4.
For example, the so-called xe2x80x9clacquer polyisocyanatesxe2x80x9d based on hexamethylene diisocyanate, 1-isocyanato-3,3,5-trimethyl-5-isocyanatomethyl cyclohexane (IPDI) and/or bis(isocyanatocyclohexyl)methane and the inherently known derivatives of said diisocyanates having biuret, allophonate, urethane and/or isocyanurate groups are particularly suitable.
1,1,6,6-Tetramethylhexamethylene diisocyanate, 1,5-dibutylpentamethyl diisocyanate, p- or m-tetramethylxylylene diisocyanate are also suitable. Further examples of suitable polyisocyanates are 1,4-cyclohexane-, 1,2-cyclohexane diisocyanate, tetramethylene-, pentamethylene diisocyanate.
The diisocyanates may be reacted in the conventional manner to higher-functionality compounds, for example, by trimerisation or by reaction with water or polyols, such as, e.g., trimethylol propane or glycerol.
The flatting agent paste according to the invention is contained in the coating compounds as component c). The proportion of flatting agent paste in the coating compound may vary relatively widely. For example, 5 to 60 wt. %, preferably 20 to 55 wt. % of flatting agent paste may be contained in the total coating compound. The amount to be used depends, for example, on the binder system or lacquer system in question, and on the gloss to be obtained and/or the texture effect to be obtained.
One or more organic solvents, pigments, fillers and/or conventional lacquer additives may be contained in the coating compounds.
The solvents may originate from the preparation of the binders or may be added separately. These are conventional lacquer solvents known to the skilled person. Examples of suitable solvents are glycol ethers such as ethylene glycol dimethyl ether, propylene glycol dimethyl ether; glycol ether esters such as ethyl glycol acetate, butyl glycol acetate, 3-methoxy-n-butyl acetate, butyl diglycol acetate, methoxypropyl acetate; esters such as butyl acetate, isobutyl acetate, amyl acetate; ketones such as methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, isophorone, aromatic hydrocarbons (e.g., with a boiling range from 136xc2x0 C.-180xc2x0 C.) and aliphatic hydrocarbons.
Conventional inorganic and/or organic coloured pigments and/or fillers and transparent pigments may be contained in the coating agents. Examples of inorganic or organic coloured pigments or fillers are titanium dioxide, micronised titanium dioxide, iron oxide pigments, carbon black, micronised mica, azo pigments, phthalocyanine pigments, quinacridone or pyyrolopyrrole pigments, silica, barium sulfate, aluminium and magnesium silicate.
Special-effect pigments may also be contained in the coating compounds. Examples of special-effect pigments are: metallic pigments, e.g. of aluminium, copper or other metals; interference pigments such as, e.g., metal oxide-coated metallic pigments, e.g., titanium dioxide-coated or mixed oxide-coated aluminium, coated mica, such as, e.g., titanium dioxide-coated mica and graphite special-effect pigments.
Moreover, the coating compounds may contain lacquer additives, for example, rheology modifiers such as fine-particle silica, layered silicates or polymeric urea compounds. Anti-settling agents, levelling agents, light stabilisers, anti-foaming agents such as, for example, silicone-containing compounds, wetting agents and adhesion-promoting substances may also be used.
The additives and auxiliaries are used in conventional amounts known to the skilled person.
The preferred coating compounds are two-pack systems. The components a) and b) which react together must therefore be stored separately. They are mixed together only shortly before application, optionally with pigments, fillers and additives. If necessary, solvents may be used to adjust the spray viscosity.
The flatting agent pastes according to the invention may be added in various ways to the coating compounds. If the lacquer to be produced is to be prepared from the base upwards, the flatting agent paste may be added as a component during the preparation of the hydroxy-functional component, generally as a base component. If the lacquer to be produced is prepared by means of a mixed lacquer or modular system, the flatting agent pastes may, as an additional mixed lacquer, be a constituent of the mixed lacquer or modular system and are processed to the finished lacquer according to a predetermined mixing formula with other colour-imparting and/or special-effect imparting mixed lacquers or modular components.
In view of the good flow and processing properties of the flatting agent pastes which remain guaranteed even with high proportions of flatting and/or texturing agents, the flatting agent pastes according to the invention may be used particularly advantageously in a high-solids mixed lacquer system as an additional mixed lacquer. Naturally, the flatting agent pastes may also be used in mixed lacquer systems with a lower solids content and generally for the preparation of medium-solids or low-solids lacquers.
The flatting agent pastes according to the invention can be metered easily. Even after prolonged storage, no settling of the texturing and/or flatting agents is apparent in the pastes.
The coating compounds containing the flatting agent pastes are particularly suitable for the preparation of pigmented or transparent top coats of an air-drying or forced-drying multilayer coating. They may also, however, be cured at relatively high temperatures from, e.g., 80xc2x0 C. to 140xc2x0 C. The coating compounds containing the flatting agent pastes result in a uniform spray pattern even on relatively large surfaces. No unsightly patches are formed.
The flatting agent pastes and the coating compounds containing them may be used in vehicle and industrial lacquering, particular vehicle refinishing. They may be used for coating metal substrates, but also for coating plastics substrates. The fact that no additional elasticising agents are required in the lacquer for plastics because the flatting agent pastes simultaneously exert an elasticising effect is also an advantage in the coating of plastics parts.
The coating compounds containing the flatting agent pastes are applied by well known methods, preferably by spraying. A transparent clear lacquer layer may, for example, be applied to conventional or aqueous base lacquers, whereupon both layers are cured together, e.g., for 15 to 45 minutes at, e.g., 40xc2x0 C. to 80xc2x0 C. A pigmented top coat layer may be applied to conventional 1-pack or 2-pack surfacer layers and cured in a similar manner.
Depending on the gloss required, coatings with matt or dull surfaces may be obtained with the coating compounds containing the flatting agent pastes according to the invention. If texturing agents are added, the desired texturing effect is well developed.

Pastes containing matting and structuring agents and coating agents containing said pastes

Abstract: A) 5 to 30 wt. % of one or more thixotropic (meth)acrylic copolymers and/or one or more thixotropic polyesters

Abstract: B) 15 to 45 wt. % of one or more flatting and/or texturing agents,

Abstract: C) 30 to 65 wt. % of one or more organic solvents


An implantable prosthetic valve assembly includes a radially expandable frame including an inflow portion and a second portion. The inflow portion is configured, in an expanded state, to bear against a native cardiac annulus in a manner so as to resist migration. The second portion extends from the inflow zone in an outflow direction, and is configured, in an expanded state, not to bear against the native cardiac annulus and an ascending aorta. The valve assembly also includes a prosthetic valve coupled to the frame substantially within the second portion.

1. Field
The present invention relates to an assembly for placing a prosthetic valve in a lumen of the body, especially a heart valve, and in particular an aortic valve.
2. Background Art
Documents WO 91/17720, WO 98/29057 and EP 1 057 460 each describe an assembly, including the prosthetic valve to be implanted; a radially expandable framework, called a stent, which is able, in the expanded state, to bear against the wall of the body duct to be fitted with the valve, this bearing making it possible to immobilize this stent with respect to this wall; and means for fixing the valve to the stent. The placement of the stent permits mounting of the valve in the body duct, eliminating the need for an external access route and, thus, a direct surgical intervention.
However, major drawbacks of this technique are that it entails a risk of the valve being damaged by the balloon used to expand the stent, and it limits the force of expansion that can be imparted to the stent. This limitation has repercussions on the anchoring of the stent, making a displacement of said assembly possible. This limitation also has repercussions on the leaktightness of the stent in the area of the valvular ring which is particularly affected when calcified zones give the valvular ring an irregular form and/or a certain rigidity.
Another drawback of the prior art technique is that of directly joining the commissures of the valvules to the stent. The result of this is that an expansion of the stent, and thus of the valve, different than that intended may cause poor coaptation of the valvules and, consequently, defective functioning of the valve. The stent therefore has to undergo a predetermined expansion, which prevents or complicates adaptation of this stent to the anatomical variations.
In the case of implantation of an aortic valve, the prior art technique also has drawbacks in that it necessitates very exact positioning of the stent in the aorta so that the valve is located opposite the natural valvular ring, and it entails a risk of blocking the apertures of the coronary arteries that open out at the coronary ostia.

This patent is subject to a terminal disclaimer.


A motorcycle accommodates an enlarged rear tire by interposing an intermediate shaft between the transmission output gear and the rear wheel drive gear. The intermediate shaft includes a power input gear disposed in the same vertical plane as the transmission output gear, and a first drive belt couples the two together. The intermediate shaft also includes a power output gear disposed in the same vertical plane as the rear wheel drive gear, and a second drive belt couples the two together. The first vertical plane lies closer to the central longitudinal axis of the support frame than does the second vertical plane, allowing the center of mass of the engine and transmission to be maintained substantially along the central longitudinal axis. When incorporated into a soft-tail type motorcycle frame, the intermediate shaft is coincident with the pivot axis of the soft-tail suspension.

1. Field of the Invention
The present invention relates generally to motorcycles, and more particularly, to a motorcycle having an intermediate shaft between the transmission power take-off and the rear wheel.
2. Description of the Relevant Art
Motorcycles have been used for transportation for many years and are still popular today. A particular segment of the motorcycle market consists of high-performance motorcycles having relatively large and powerful engines. Perhaps the most well-known manufacturer of such high performance motorcycles is the Harley Davidson Company of Milwaukee, Wis. Prior art motorcycles typically include a motor and a transmission. The motor crankshaft is coupled to the input of the transmission by a chain or belt drive. The output, or power take-off, of the transmission is then coupled by a second chain or belt drive directly to a sprocket on the rear wheel of the motorcycle.
Motorcycles with wider rear tires, like those installed on cars, have become very popular. However, a rear wheel using a wide tire necessarily displaces the drive gear or sprocket laterally apart from the centerline of the motorcycle frame. In turn, the drive belt or chain that extends between the transmission power take-off and the rear wheel must also be displaced off to the side, away from the centerline of the motorcycle frame, to pass around the wider tire. Manufacturers have been dealing with this problem by shifting the motor and transmission further away from the centerline of the frame, thereby keeping the power take-off of the transmission and the sprocket of the rear wheel in approximately the same plane. However, this practice shifts the center of mass of the motorcycle away from the centerline of the motorcycle frame, and tends to make the bike unbalanced and harder to control.
Accordingly, it is an object of the present invention to provide a motorcycle which accommodates wide rear tires without the need to shift the center of mass of the motorcycle away from the centerline of the motorcycle frame.
It is another object of the present invention to provide such a motorcycle which effectively eliminates the need to laterally displace the motor or transmission in order to accommodate a wide rear tire.
It is a further object of the present invention to provide such a motorcycle which accommodates a wide rear tire without impairing the handling or balance of the motorcycle.
A still further object of the present invention is to allow a motorcycle to incorporate a wide rear tire whether the motorcycle includes a so-called soft tail rear suspension or a rigid tail.
These and other objects of the present invention will become more apparent to those skilled in the art as the description of the present invention proceeds.
Briefly described, and in accordance with the preferred embodiment thereof, the present invention relates to a motorcycle having a transmission system that accommodates an enlarged rear tire through the use of an intermediate shaft, or xe2x80x9cjack shaftxe2x80x9d. The motorcycle includes a conventional support frame for supporting a rider, an engine and a transmission mounted to such frame, and a rear wheel rotatably coupled to the rear end of the support frame. The rear wheel includes a conventional drive gear or sprocket for applying torque to the rear wheel; this rear wheel drive gear extends within a first vertical plane that is laterally spaced apart from the longitudinal axis of the support frame by a first offset distance. The engine mounted generates a turning force to propel the motorcycle, and the transmission is coupled to the engine for selectively coupling the turning force generated by the engine to a transmission output gear or power take-off.
In the present invention, the transmission output gear extends substantially within a second vertical plane spaced apart from the longitudinal axis of the support frame by a second offset distance, but wherein the second offset distance is significantly smaller than the first offset distance. In other words, the power take-off gear of the transmission is significantly closer to the central longitudinal axis of the support frame than is the rear wheel drive gear. To account for the lateral spacing difference between the power take-off gear and the rear wheel drive gear, an intermediate shaft is rotatably secured to the support frame as by a bearing assembly, the intermediate shaft including a power input gear extending substantially within the same vertical plane as the power take-off gear. The intermediate shaft also includes a power output gear that rotates together with the power input gear, but the power output gear extends substantially within the same vertical plane as does the rear drive gear. A first drive belt is engaged with, and extends between, the transmission output gear and the power input gear of the intermediate shaft. A second drive belt is engaged with, and extends between, the power output gear of the intermediate shaft and the rear wheel drive gear.
In one embodiment of the present invention, the first and second drive belts are first and second chains, respectively. In this embodiment, the transmission output gear and power input gear are sprockets that engage the first chain; the power output gear and rear wheel drive gear are also sprockets, and each engages the second chain. Alternatively, the first and second drive belts an be in the form of flexible belts each having a toothed inner surface; in this embodiment, the transmission output gear and power input gear are toothed drive belt pulleys that engage the first toothed drive belt, and the power output gear and rear wheel drive gear are also toothed drive belt pulleys that engage the second toothed drive belt.
The intermediate shaft allows the first and second drive belts to extend within spaced vertical planes, hence allowing the transmission output gear and the rear wheel drive gear to extend within such laterally spaced planes. Accordingly, there is no need to displace the center of mass of either the engine or the transmission away from the longitudinal axis of the support frame, thereby improving the handling and balance of the motorcycle.
As mentioned above, the present invention may be used with both motorcycles having oft-tail suspensions, as well as those having rigid rear suspensions. In motorcycle frames having a soft-tail suspension, the support frame includes a tail frame portion for supporting the rear wheel, wherein the tail frame portion rotatably supports the rear wheel, and is itself pivotally secured to the support frame about a tail pivot axis. The present invention may advantageously be incorporated within such a soft-tail suspension motorcycle by rotatably securing the intermediate shaft to the support frame about a rotational axis that is coincident with the tail pivot axis.

Motorcycle having jack shaft to accommodate wide rear tire


Paroxetine salt compositions having improved stability are formed by controlling the pH to 6.5 or less. The compositions can be made with the aide of water without significant coloration problems. The paroxetine salts include paroxetine hydrochloride salts but preferably use paroxetine sulfonate salts such as paroxetine methane sulfonate.

1. Field of the Invention
The present invention relates to a paroxetine compositions, especially pharmaceutical formulations and dosage forms, and to processes of manufacturing the same.
2. Description of the Related Arts
U.S. Pat. No. 4,007,196 describes certain compounds that possess anti-depressant activity. One specific compound mentioned in this patent is known as paroxetine and is represented by the following formula:
Paroxetine has been approved for treating, inter alia, depression in humans and is being marketed around the world under such brand names as Paxil(copyright) (SmithKline Beecham) and Seroxat. Dosage forms thus far include immediate release tablets, extended release tablets, capsules and suspensions. The active substance in all commercial forms thus far has been paroxetine hydrochloride and specifically with regard to tablets and other solid forms the active has been paroxetine hydrochloride hemihydrate as disclosed in U.S. Pat. No. 4,721,723 and EP 223403.
WO 95/16448 reports that all commercial paroxetine hydrochloride hemihydrate tablets were, at least up until that time, made using a wet granulation process. Further, the commercial tablets exhibited a color change; i.e., these tablets often developed a pink hue that is highly undesirable. This was apparently masked in the commercial product by a colored outer coat layer. The point of the PCT publication is that the pink hue formation can be avoided by carrying out tableting in the absence of water, i.e. by conventional dry granulation and direct compression. The PCT publication does not mention what the coloring compound(s) are or their route of formation. But, subsequent documents reveal that the coloration problem involves the formation of a coloring impurity identified below as the compound of formula A.
Since the publication of WO95/16448, it appears that the brand name paroxetine hydrochloride hemihydrate product in Europe, at least, was changed to a dosage form made by a dry granulation technique in accordance with the teachings in the PCT publication.
It would be advantageous to find a paroxetine composition that does not suffer from coloration or that is less prone to coloration regardless of how the composition is made. Further, it would be desirable to make a paroxetine composition with the aid of water, such as by wet granulation, that nonetheless was not prone to the above-mentioned coloration problems.
In particular, the application of an aqueous granulation process for industrial scale production is desirable in that such a process provides uniform distribution of the active substance within the bulk granulate composition so that the dose uniformity of tablets or capsules is more easily assured. This is especially true in the case of unit dosage forms containing a low dose of a potent active agent. Here, paroxetine is normally used in 20 to 40 mg per tablet and thus its uniformity in large scale production could be of concern. Water is a very suitable solvent for the granulation process because it is non-toxic and non-flammable. Thus, it would be desirable to find a way to use an aqueous granulation process for the industrial scale production of paroxetine final forms that would also avoid or limit the occurrence of the color forming impurities.
U.S. Pat. No. 5,874,447 describes paroxetine sulfonate salts, including paroxetine methane sulfonate also known as paroxetine mesylate. These sulfonate salts have advantageous properties in comparison to the known salts, including the hydrochloride salts. For example, the sulfonate salts have high water solubility and good thermal stability, making them useful in forming a commercial paroxetine dosage form. The U.S. Pat. No. 5,874,447 patent discloses that tablets can be made by any known method including a dry technique (direct compression, dry granulation) or a wet technique (wet granulation). However, no discussion appears in the U.S. Pat. No. 5,874,447 patent regarding the paroxetine hydrochloride coloring problem.
Now, it has surprisingly been discovered that solid paroxetine compositions including granulates and dosage forms made therefrom, can be made more stable against coloration, even if made with the aid of water such as by an aqueous granulation process, by controlling the pH of the composition to 6.5 or less. Further, it appears that paroxetine sulfonate salts are less prone to coloration problems than paroxetine hydrochloride salts, even if made with the assistance of water. Studies by the present inventors reveal that the impurity A is a dimer formed from the paroxetine free base in an aqueous alkaline environment. Oxygen is also apparently needed to allow the dimer reaction to proceed. Given the discovery that coloring impurity A is formed in the presence of water, it is understandable in hindsight how carrying out a dry process as suggested in WO95/16448 would help to minimize and/or avoid coloration; i.e. the required aqueous medium for forming the dimeric impurity is missing thereby inhibiting its formation. Having elucidated the source of the coloring problem, the present invention provides a novel solution thereto by keeping the pH of the composition to 6.5 or less. Alternatively, the present invention unexpectedly solves the coloring problem by switching the paroxetine salt from hydrochloride to sulfonate and thereby allowing the use of water in the preparation of paroxetine granules without incurring any substantial coloration.
Thus, in a first aspect of the invention, there is provided a solid paroxetine composition comprising a paroxetine salt and an excipient wherein said composition has a pH of 6.5 or less, as is hereinafter defined. The paroxetine salt is preferably a paroxetine sulfonate salt such as paroxetine methane sulfonate or a paroxetine hydrochloride salt. The excipients generally include a binder or diluent such as calcium phosphate or microcrystalline cellulose as well as a disintegrant and lubricant. The composition can be an intermediate form or a final dosage form such as a tablet or capsule. In one embodiment, a tablet is made that does not need a taste masking coating to avoid the usual bitter taste associated with paroxetine compositions.
A second aspect of the present invention relates to paroxetine solid dosage forms comprising a paroxetine sulfonate salt as a pharmaceutically active agent and having been made with the aid of water. The solid dosage form can be a tablet, pellet or capsule form, etc., and contains a pharmaceutically effective amount of paroxetine sulfonate, e.g. for treating depression, obsessive-compulsive disorder, or panic attack, etc. Preferably the excipients are selected so that the composition has a pH of 6.5 or less. Further, the composition is normally dried to a sufficient extent that the total content of added water remaining is 2.0 wt % or less, preferably 1.3 wt % or less, and more preferably 1.0 wt % or less. Generally, the composition does not contain any decolorization agent as an excipient. Even though an aqueous process is used, the dosage form of the present invention exhibits no, or substantially no, formation of a pink or other colored hue.
A third aspect of the invention provides for a granulate formed by mixing water, paroxetine sulfonate salt, and at least one excipient and drying the resulting mixture. Typically the water and paroxetine sulfonate salt are provided together as an aqueous solution and added to the powdered or dry excipient(s), although this is not required. In some embodiments, the excipient(s) may be pre-blended and granulated such as by a dry granulation technique before being contacted with a concentrated aqueous paroxetine sulfonate salt solution. The mixture is dried to form a granulate to which additional excipients may be added, if desired. The granulate can be formed into other conventional dosage forms such as tablets, capsules, sachets, pellets, etc. The composition is preferably selected as described above for the dosage forms, namely with a pH of 6.5 or less and with an added water content of 2.0 wt % or less.
A fourth aspect of the invention provides a process for making pharmaceutical compositions which comprises mixing paroxetine sulfonate and at least one excipient with the aid of water. In one convenient embodiment, an aqueous solution containing at least 10 wt % of a paroxetine sulfonate salt is added to at least one solid excipient and dried to form a granulate. Preferably, the aqueous solution is a highly concentrated aqueous solution of paroxetine sulfonate salt having a concentration of not less than 30 wt %. This process can be used advantageously to form the granulates described above which can be subsequently processed into the above-described dosage forms. Alternatively, water can be added to a powder bed of paroxetine sulfonate and one or more excipients and the mixture dried to form granules.
A preferred paroxetine sulfonate salt for use in all aspects of the present invention is paroxetine methanesulfonate, also called paroxetine mesylate. Paroxetine mesylate is compatible with many common pharmaceutical excipients useful in aqueous granulation procedures, which makes the process reliable on an industrial scale.
The present invention relates to solid paroxetine compositions that resist the formation of a color hue and to processes for making the same with the aid of water. As used herein, the expression xe2x80x9cmade with the aid of waterxe2x80x9d means that water is added during some aspect of the formation process of the composition but is substantially or completely removed in the final composition. The water can be added to excipients, to the paroxetine salt especially paroxetine sulfonate salts, or to both. The solid compositions of the invention include solid dosage forms such as tablets, capsules, sachets, etc., and intermediate forms such as granules or pellets.
Paroxetine salts used in the present invention are pharmaceutically acceptable salts, i.e., acid addition salts. Preferred salts include paroxetine hydrochloride salts and paroxetine sulfonate salts. The paroxetine hydrochloride salt can be of any form including the paroxetine hydrochloride hemihydrate form and paroxetine hydrochloride anhydrate forms. The paroxetine sulfonate salts used in the present invention can be any salt of paroxetine where the an anion contains a sulfonate group; i.e. the moiety xe2x80x94S(O2)OH. Preferred sulfonate salts include those having the following structural formula:
wherein R represents a C1-C10 substituted or unsubstituted alkyl group or a substituted or unsubstituted aromatic group wherein the substituents are selected from the group consisting of C1-C10 alkyl, halogen, nitro, hydroxy, alkoxy, and combinations thereof. Preferred paroxetine sulfonate salts include those having a solubility in water of at least 100 mg/1 ml of water. Particularly preferred sulfonate salts include methanesulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate salt forms.
An xe2x80x9cexcipientxe2x80x9d as used herein means any pharmaceutically acceptable inactive component of the composition. As is well known in the art, excipients include diluents, binders, lubricants, disintegrants, colorants, preservatives, pH-adjusters etc. The excipients are selected based on the desired physical aspects of the final form: e.g., obtaining a tablet with desired hardness and friability, being rapidly dispersible and easily swallowed, etc. The desired release rate of the active substance from the composition after its ingestion also plays a role in the choice of excipients.
Suitable excipients for use in this invention include:
a diluent such as calcium hydrogen phosphate, lactose, mannitol etc.
a binder such as microcrystalline cellulose or a modified cellulose, povidone etc.
a disintegrant such as sodium starch glycollate, crosspovidone
a lubricant such as magnesium stearate, sodium stearyl fumarate
a colorant, taste masking agent etc.
It is particularly advantageous that the composition of the invention is not specifically required to use anhydrous excipients or hydrophobic excipients, although such excipients may be used. Similarly, the present invention does not have to strictly control the water content in the excipients prior to their use or incorporation. In a preferred embodiment, no decolorization agent is required to be present in the composition of the invention, although such may be present if desired. xe2x80x9cDecolorization agentxe2x80x9d as used herein means an agent which is being added to a composition with the aim to protect the active substance against reactions that form colored products, such as an antioxidant (e.g. ascorbic acid etc.), free radical scavenger (e.g. tocopherol etc.) etc.
It has now been discovered that the undesired impurity A is preferentially formed in an aqueous alkaline environment from the paroxetine free base. Accordingly, it can be advantageous to employ multiple strategies to reduce or prevent coloration. These strategies include limiting the amount of added water remaining in the composition, controlling the pH of the composition to be sufficiently acidic, limiting the presence of oxygen during formation and/or storage, and reducing the level of paroxetine free base impurity in the active. Indeed, using one or more of these strategies can control the coloring problem encountered with other paroxetine salt forms including paroxetine hydrochloride salt forms, whether made from a dry or wet process. For example controlling the pH to 6.5 or less, controlling (reducing) the level of free base impurity, and/or quickly removing 98% or more of the water used in granulating should allow for the formation of a color stable paroxetine hydrochloride pharmaceutical composition. Additionally, for reasons that are not entirely clear, paroxetine sulfonate salts can provide superior color stability in comparison to paroxetine hydrochloride salts.
The compositions of the present invention, including granulates and final dosage forms, preferably have a pH of 6.5 or less, more preferably a pH of 6.0 or less, including about 5.5 or less. Typically, the pH of the dosage form or a granulate is within the range of 4.5 to 6.5, more typically from 5.0 to 6.0. The pH is determined by forming a slurry of the solid composition with water and measuring the pH of the slurry, as is understood by workers skilled in the art regarding the pH of a solid composition. The concentration of the composition in the slurry is 20 wt %. The pH is measured by any standard technique. The pH can be adjusted by the proper selection of excipients.
In this respect, a proper grade of calcium phosphate (anhydrous or hydrated) having a pH around 5.5 is preferred to be used as a suitable filler. Commercially available/pharmaceutically acceptable calcium phosphates are generally alkaline; i.e. pH greater than 7 when measured as described above in a 20% slurry. For instance, DI-TAB, a commercially available dibasic calcium phosphate dihydrate, is reported as having a pH of about 7.4. Nonetheless some forms and grades of calcium phosphate are acidic or neutral pH. This lower pH can be due to the species of calcium phosphate as well as the treatment during processing of the material, such as in removing impurities/washing. For example, dibasic calcium phosphate anhydrate is generally considered to have a pH of about 7.3 whereas A-Tab(trademark) (Rhodia), also a dibasic calcium phosphate anhydrate, has a pH of about 5.1. Further examples of commercially available non-alkaline calcium phosphates include DiCAFOS P (Budenheim) having a pH of about 7 and Fujicalin SG (Fuji) having a pH from 6.1-7.2. By using a non-alkaline calcium phosphate as an excipient, a pharmaceutical composition meeting the desired pH can be attained. Alternatively, a blend of calcium phosphates, even one using acidic and alkaline calcium phosphates, can be used to achieve the desired acidic pH of the composition. The pH can also be assisted by selection of any other excipients in the composition. For instance, another example of a useful acidic excipient is the disintegrant Explotab((trademark)) of Penwest, which is a cross-linked, low substituted sodium starch glycollate.
Especially advantageous compositions of the invention comprise paroxetine sulfonate salt in the absence of a hydrosoluble or hydrophilic diluent such as lactose or microcrystalline cellulose. Unlike the suggestions in CH 690 024, wherein such a hydrosoluble/hydrophillic diluent is taught for use with paroxetine mesylate, it has been discovered that surprisingly the use of only a calcium phosphate diluent, such as calcium hydrogen phosphate anhydrate, exhibits an additional advantageous feature for industrial application; namely that it efficiently masks or prevents the bitter taste of paroxetine. Thus, after the paroxetine salt, especially paroxetine mesylate, and diluent composition is mixed with a disintergant and a lubricant and compressed into tablets, the tablets may be administered to a human patient without need of a taste-masking coating or a similar tool for taste masking. To the contrary, the presence of a hydrosoluble or hydrophilic diluent rather pronounces the bitter taste of paroxetine so that such tablet is unpleasant to be swallowed unless film-coated. Pharmaceutical compositions comprising paroxetine methane sulfonate and calcium hydrogen phosphate, optionally containing conventional lubricants and/or disintegrants, form a particular aspect of our invention. Of course, these particular compositions can be made by a dry process (dry mixing followed by direct compression) as well as by any of the wet processes known or described herein, and still provide the unexpected taste masking result.
In general, the compositions of the present invention preferably have a remaining added water content of 2.0 wt % or less, preferably 1.3 wt % or less, more preferably 1.2 wt % or less, still more preferably 1.0 wt % or less, and most preferably 0.8 wt % or less. The xe2x80x9cremaining added waterxe2x80x9d content refers to the remaining water that was added in the aid of mixing and does not include water that was present in the excipients such as bound water in microcrystalline cellulose. If the composition was made by a dry process, then the remaining added water content is 0.0%. Generally, each formulation has a threshold amount of remaining added water content below which the dimeric impurity A is formed either very little or not at all. Above this threshold amount, the impurity A is formed abundantly. The occurrence of the impurity is thus not usually a linear function of water content. By controlling the added water content in the final granulate, a color stable product can be attained, even if made by a conventional wet granulation process. The same is true for the final product solid dosage form.
Granules made according to the present invention can be used directly but usually are processed into any of a variety of dosage forms as mentioned above. Typically, the granules, optionally with additional excipients, are compressed into tablets. The paroxetine tablets may be coated by a suitable film-coating, e.g., similar to the coating used in the commercially available tablets of paroxetine hydrochloride hemihydrate. Suitable techniques of coating include aqueous coating, non-aqueous coating or a melt coating process. Coating mixtures are commercially available. Coating for extended or delayed release of the active substance is also applicable to the composition of our invention. Coating mixtures may contain suitable colorants.
The paroxetine-containing granulate may also be used for preparation of capsulized unit dosage forms. The dry granulate may be optionally screened and/or pelletized by methods known per se to obtain particulate material of uniform size and shape. The granules or pellets are then filed into suitable capsules made from e.g. gelatine, hydroxypropylmethyl cellulose or starch. Capsules having low moisture content are preferred. Coating of the produced granulate is normally not necessary.
Paroxetine-containing granulate may also be filled into sachets containing the required unit dose of paroxetine. Such sachets are administered by dispersing or dissolving the content thereof in a suitable liquid, e.g. in water, and drinking. The compositions may contain suitable taste-masking excipients, flavors or sweeteners.
Another suitable final form comprising granulates according to the present invention are effervescent tablets, granulates or powders. They are formed by mixing the granulate with a suitable effervescent system by methods known per se.
The compositions of the present invention can be made by any conventional process including dry process such as dry blending, dry granulation, and direct compression as well as by wet processes such as wet granulation. In some embodiments, especially for paroxetine sulfonate salts, it is preferable to use water in the aide of mixing. For example, a granulate is formed by combining a paroxetine sulfonate salt and at least one excipient and mixing them in the presence of added water, followed by drying to remove substantially all of the added water. The resulting population of granules, or the xe2x80x9cgranulate,xe2x80x9d is dried to have a an average content of remaining xe2x80x9cadded waterxe2x80x9d of 2.0 wt % or less, preferably 1.3 wt % or less, more preferably 1.0 wt % or less and even 0.8 wt % or less, based on the total weight of the granulate.
Typically the water is added in one of two ways, although the invention is not limited thereto. In a first method, water is added to paroxetine sulfonate and an excipient. The amount of water added is normally between 5 and 25 wt %, more typically between 10 and 20 wt %, based on the total weight of the resulting wet mixture. More water can be added, i.e., 30 wt %, 40 wt % or even 50 wt %, but some difficulties may be encountered concerning possible modifications of the excipient (for instance microcrystalline cellulose may change crystal form) and additional energy will be needed to remove the higher amounts of added water. The paroxetine sulfonate salt and the excipient are normally in powder form and pre-mixed or blended to form a powder bed prior to the addition of water. Alternatively, the excipient can be in granulate form and admixed with the paroxetine sulfonate powder. The excipient is generally one or more diluents such as calcium phosphate, microcrystalline cellulose, or both.
The wet mixture is stirred, usually under vigorous conditions, to form a homogeneous mixture. The added water is removed from the wetted mixture normally as rapidly as possible. The added water can be removed by heating as well as by passing a nitrogen gas stream over (or through) the mixture, or a combination thereof. The use of a nitrogen gas stream is also advantageous in that the presence of oxygen is reduced or avoided. The drying of the added water can occur after, during or simultaneously with the mixing/stirring step. To reduce the chance of color formation, the average residence time of the added water in contact with the paroxetine sulfonate and excipient(s) during the mixing and drying steps is generally less than 3 hours, more typically less than 2 hours, more typically less than 1.5 hours, frequently less than or equal to 1 hour and is normally in the range of 30 to 90 minutes, more preferably 30 to 60 minutes, depending upon the apparatus volumes, etc. Upon completion of the stirring and drying steps, a paroxetine sulfonate-containing granulate is obtained having a low added water content as described above.
For preparation of a final mixture for compressing into a tablet core (pre-compression mixture), the above paroxetine sulfonate-containing granulate is optionally mixed with additional diluent(s), a disintegrant and/or a lubricant such as magnesium stearate, in a suitable mixer, e.g. in a free-fall mixer. The pre-compression mixture is finally compressed into tablets by a suitable tableting press under ordinary conditions. The other excipients for mixing with the granulate should also be chosen, in terms of kind and grade, such that the final pre-compressing mixture exhibits a pH value of 6.5 or less as described above.
A second method for forming the granulate involves combining the added water with the paroxetine sulfonate to form an aqueous solution of paroxetine sulfonate. This aqueous solution is then added to at least one excipient. As in the first method, the excipient can be in powder or granulate form. The aqueous solution is generally a concentrated solution having at least 10 wt % paroxetine sulfonate, preferably at least 30 wt %, and more preferably at least 40 wt % paroxetine sulfonate. By using a concentrated solution, less water is needed, thereby saving energy in the drying step and allowing for faster drying times. These highly concentrated solutions are possible because of the advantageous water solubility of paroxetine sulfonate in comparison to other paroxetine salts such as paroxetine hydrochloride. The stirring and drying steps as well as the work up of the granulate into a pre-compression composition are carried out as described above.
A preferred formulation made by this process comprises adding the concentrated paroxetine sulfonate aqueous solution to either calcium hydrogen phosphate or microcrystalline cellulose followed by stirring and drying to form a paroxetine-containing granulate. To the formed granulate is then mixed the other one of the calcium hydrogen phosphate or microcrystalline cellulose which was not used to form the granulate along with sodium starch glycolate (a disintegrant) and magnesium stearate. The resulting mixed composition is ready for compression into tablets. An example of this composition contains 7.24 wt % paroxetine sulfonate (as the equivalent free base), 57.76 wt % of CaHPO4, 30.0 wt % microcrystalline cellulose (Avicel PH 101), 4.0 wt % sodium starch glycolate, and 1 wt % magnesium stearate.
In the aqueous granulation procedure for preparation of tablets or capsules of paroxetine mesylate, microcrystalline cellulose and various forms and grades of calcium phosphate, typically calcium hydrogen phosphate, are the preferred solid diluents. However, the composition of this invention and the process for its preparation is not limited thereto. Alternate diluents include mono- and di saccharide sugars such as lactose, mannitol, lactitol, xylitol or combinations thereof.
Alternatively, a dry process can also be carried out wherein the paroxetine salt is dry blended with an excipient, typically a calcium phosphate or microcrystalline cellulose, or both and optionally with a disintegrant. After blending, the mixture is compressed into a tablet.
For both wet and dry processes, it is sometimes advantageous to provide multiple mixing steps to facilitate high quality, homogenous mixing. For example, a portion of the binder(s) and/or disintegrant(s) are mixed with the paroxetine salt, optionally with the aide of water as described above. To this mixture the remainder of the binder(s) and/or disintegrant(s) are mixed. To this resulting mixture the remaining excipients such as a lubricant(s) are mixed. Such partial mixing can use more steps or fewer steps and can split intermediate mixtures into portions to facilitate apparatus volumes. Additionally, excipients can be pre-treated by techniques known in the art as desired, including wet granulation and dry granulation treatments. The binders or fillers such as calcium phosphate anhydrate can be pretreated with water and dried ( less than 0.5% water) before being combined with the paroxetine salt or solution.
The composition of the present invention can be used to treat or prevent the following disorders: depression, obsessive compulsive disorder, alcoholism, anxiety, panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome, adolescent depression, trichotillomania, dysthymia, substance abuse etc. Most suitably, the composition of the invention is applied for treatment of depression, obsessive compulsive disorder and panic disorder.
The treatment or prevention of any one or more of the above disorders is performed by administering orally the composition comprising an effective and/or prophylactic amount of the paroxetine sulfonate to a patient in need thereof. The patient can be a mammal including a human, a dog, a horse, or a monkey.
The composition of this invention is advantageously presented as a unit dose composition, preferably in a form of a tablet or a capsule, comprising paroxetine sulfonate equivalent to from 1 to 200 mg of paroxetine free base, more usually from 5 to 100 mg, for example from 10 to 50 mg. Typical tablet doses are 10, 20, 30, and 40 mg. Such a composition is normally taken by a human patient from 1 to 6 times daily, but more usually once or twice daily, with the total amount of paroxetine sulfonate administered being generally between 5 to 400 mg of paroxetine. A suitable daily dose is from 0.05 to 6 mg/kg, more preferably 0.14 to 0.86 mg/kg.

Paroxetine compositions and processes for making the same