A golf ball comprising a core and a cover disposed concentrically about the core, wherein at least one of the core or the cover is formed of a polymer comprising thermally reversible covalent bonds. Additionally, a composition for sporting equipment formed of a polymer comprising thermally reversible covalent bonds.

The present invention relates to golf balls and, in particular, to self-healing polymeric compositions useful in golf ball covers, cores, and intermediate layers to improve the durability of the golf ball during the impact.
The majority of golf balls commercially available today can be grouped into two general classes: solid and wound. Solid golf balls include one-piece, two-piece, and multi-layer golf balls. One-piece golf balls are inexpensive and easy to construct, but have limited playing characteristics and their use is usually confined to the driving range. Two-piece balls are generally constructed with a polybutadiene solid core and a cover and are typically the most popular with recreational golfers because they are very durable and provide good distance. These balls are also relatively inexpensive and easy to manufacture, but are regarded by top players as having limited playing characteristics. Multi-layer golf balls are comprised of a solid core and a cover, either of which may be formed of one or more layers. These balls are regarded as having an extended range of playing characteristics, but are more expensive and difficult to manufacture than are one- and two-piece golf balls.
Wound golf balls, which typically include a fluid-filled center surrounded by tensioned elastomeric material and a cover, are preferred by many players due to their spin and xe2x80x9cfeelxe2x80x9d characteristics but are more difficult and expensive to manufacture than are most solid golf balls. Manufacturers are constantly striving, therefore, to produce a solid ball that retains the beneficial characteristics of a solid ball while concurrently exhibiting the beneficial characteristics of a wound ball.
Golf ball playing characteristics, such as compression, velocity, xe2x80x9cfeel,xe2x80x9d and, therefore, spin, can be adjusted and optimized by manufacturers to suit players having a wide variety of playing abilities. For example, manufacturers can alter any or all of these properties by changing the materials (i.e., polymer compositions) and/or the physical construction of each or all of the various golf ball components (i.e., centers, cores, intermediate layers, and covers). Finding the right combination of core and layer materials and the ideal ball construction to produce a golf ball suited for a predetermined set of performance criteria is a challenging task.
The present invention is related to golf ball materials comprising at least one polymer and at least one healing agent to improve impact durability. Polymers are macromolecules built up by the linking together of large number of smaller molecules called monomers. Upon repetitive impact, the golf balls formed of many types of polymers tend to develop micro-cracks. One aspect of this invention is a way to make a polymeric golf ball component that is xe2x80x9crepairablexe2x80x9d through heating and cooling of the polymer backbone. No catalyst, monomers, or special surface treatments are required. The repaired plastic is believed to regain much of the strength of undamaged polymeric material. There is, therefore, a need for development of suitable healing agents that can be utilized to impart improved durability to golf ball cores, covers, and intermediate layers.
The present invention is directed to a golf ball including a core and a cover disposed concentrically about the core, wherein at least one of the core or the cover is formed of a polymer including thermally reversible covalent bonds. At least about 20%, preferably at least about 30%, of the thermally reversible covalent bonds disconnect upon heating and re-connect upon cooling. Ideally, the reversible bonds disconnect at a temperature less than about 150xc2x0 C., more preferably less than about 120xc2x0 C., most preferably less than about 100xc2x0 C.
The thermally reversible polymer typically include at least one furan diene unit and at least one amine comprising maleimide dienophiles. The furan diene units have the formula:
where R1, R2, and R3 are hydrogen, alkyl, or aryl groups; and the amine comprising maleimide dienophiles has the formula:
where R4, and R5 are hydrogen, alkyl, or aryl groups. Preferably, the polymer includes at least 4 furan diene units and at least 3 maleimide dienophiles.
The ball can be of any construction, but preferably the core comprises a center and an outer core layer. In one construction, the center includes a solid center, a hollow center, a gel, or a fluid. Alternatively, the cover comprises an inner cover layer and an outer cover layer, either one of which has a thickness of between about 0.03 inches and about 0.125 inches, Additionally, at least one of the core or cover may be foamed, includes a density-modifying filler, or both.
The present invention is also directed to a composition for sporting equipment formed of a polymer comprising thermally reversible covalent bonds. At least about 20%, preferably at least about 30%, of the thermally reversible covalent bonds disconnect upon heating and re-connect upon cooling. Ideally, the reversible bonds disconnect at a temperature of less than about 150xc2x0 C., more preferably less than about 120xc2x0 C., and most preferably less than about 100xc2x0 C. The thermally reversible polymer typically include at least one furan diene unit and at least one amine including maleimide dienophiles. The furan diene units have the formula:
where R1, R2, and R3 are hydrogen, alkyl, or aryl groups; and the amine includes maleimide dienophiles has the formula:
where R4, and R5 are hydrogen, alkyl, or aryl groups.
The golf balls of the present invention may comprise any of a variety of constructions. For example, the core of the golf ball may comprise a solid core surrounded by a cover layer. The core may be a single layer or may comprise a plurality of layers, such as a center and an outer core layer. In such a construction, the innermost portion of the core, the center, may be solid or a liquid filled sphere surrounded with an outer core layer. As with the core, the cover layer may also comprise a plurality of layers. For example, the cover may be formed of an inner and an outer cover layer. Additionally, the core, solid or otherwise, may also be surrounded by a wound layer of elastomeric material, generally tensioned. Any of these components may comprise the self-healing polymers of the present invention.
The polymeric compositions may include at least one of a base material and a microencapsulated healing agent. For the base material, the bulk of the golf ball material can be a thermoplastic, such as SURLYN(copyright), or a thermoset, such as polyurethane, polyurethane-urea, polyurea-urethane, polyurea, or crosslinked polybutadiene. Microencapsulated healing agents are the xe2x80x9cgluexe2x80x9d that fixes the micro-cracks formed in the composite material. This healing agent is typically a fluid such as dicyclopentadiene (xe2x80x9cDCPDxe2x80x9d). DCPD is preferably encapsulated in tiny spheres or capsules that are spread throughout the polymeric material. Preferably, there are about 100 to about 200 capsules per cubic inch. Preferably, the spheres are about 300 xcexcm or less in diameter.
In order to polymerize, the healing agent must come into contact with a catalyst. A preferred catalyst, called Grubbs catalyst, is used for this self-healing material. It is important that the catalyst and healing agent remain separated until they are needed to seal a crack. When a micro-crack forms in the base material, it will spread through the material. By doing so, this crack will rupture the microcapsules and release the healing agent. This healing agent will flow down through the crack and will inevitably come into contact with the Grubbs"" catalyst, which initiates the polymerization process. This process will eventually bond the crack closed.
In a preferred embodiment, the self-healing polymer blend has a flexural modulus of from about 2,000 to about 200,000 psi contains microcapsules filled with dicyclopentadiene, dicyclohexa (or penta or octa) diene, (a liquid tricyclic diolefin), and a polymerization catalyst dispersed throughout the cover (in one embodiment) would be a ruthenium carbene complex, known as a xe2x80x9cGrubbs catalyst.xe2x80x9d One source of the Grubbs catalyst is from Strem Chemicals, 7 Mulliken Way, Newburyport, Mass. The Grubbs ruthenium-based catalyst is very efficient at initiating various reactions including olefin metathesis with high functional group tolerance. Unfortunately, we would quickly deplete the world of its supply of ruthenium if we were to use it for all its applications. Looking at related elements that have a higher natural abundance leads to iron, osmium, rhodium, iridium, palladium and platinum. It is believed that iron should have similar electronic behavior, which could lead to a successful iron based olefin metathesis catalyst. In addition, it is believed that the use of living (uninterrupted chain ends) polymerization catalysts is preferred, allowing multiple healing opportunities. The catalyst is commercially available from Advanced Polymer Technologies, Inc. and Hitachi Chemical.
Other suitable self-healing polymeric materials include polymeric networks consisting of a backbone that is linked through thermally reversible covalent bonds. At temperatures less than either the melting point or glass transition temperature of the polymer, preferably less than about 150xc2x0 C., more preferably less than about 120xc2x0 C., most preferably less than about 100xc2x0 C., preferably at least about 20%, more preferably at least about 30% of the linkages disconnect, then re-connect upon cooling. The process is fully reversible and can be used to restore the fractured part of the polymer multiple times without the use of additional components, such as catalysts, monomers, or special surface treatment. The polymer preferably consists of a compound containing furan diene units, more preferably greater than two units, most preferably greater than four units. Additionally, the compound preferably contains an amine having maleimide dienophiles, more preferably greater than two dienophiles, most preferably greater than three dienophiles. Examples of such compounds include:
where R1, R2, R3, R4, and R5 are hydrogen, alkyl, or aryl groups and x and y are greater than or equal to 2. Mechanical properties of the preferred compounds, which are reaction products of the diene and the dienophile, compared to epoxy resins and unsaturated polyesters, are presented in Table I below.
Self-healing polymer layers may be produced in golf balls in accordance with the present invention by various techniques which are known in the art, such as by injection molding or compression molding a layer of self-healing polymer material about a previously formed center or core, cover, or intermediate layer. Cores comprising a self-healing polymer composition may also be formed directly by injection molding or compression molding. When the layer or core is injection molded, a physical or chemical blowing or foaming agent may be included to produce a foamed layer, if desired. Blowing or foaming agents useful in forming foamed polymer blends may be readily selected by one of ordinary skill in the art. In some cases, due to the very thin nature of the golf ball layer (less than 0.05 inches), it is not practical to form the outer cover layers of the ball of the present invention using conventional injection or compression molding techniques ordinarily employed in the golf ball art for applying cover materials. These conventional ball molding processes are not capable of easily applying such thin outer cover layers over a solid spherical surface.
Further compositions may also be added to the self-healing polymer components of the invention, such as, for example, coloring agents, reaction enhancers, crosslinking agents, blowing agents, dyes, lubricants, fillers (including density modifying fillers), excipients, process aids and other compounds commonly added to polymeric materials and/or golf ball compositions.
The composition of any golf ball component that does not contain the self-healing polymer composition disclosed herein can be any such composition known to those of ordinary skill in the art. Such compositions may be readily selected by those of ordinary skill in the art, for example, from one of the many U.S. Patents assigned to Acushnet Company. The resultant golf balls typically have a coefficient of restitution of greater than about 0.7, preferably greater than about 0.75, and more preferably greater than about 0.78. The golf balls also typically have a compression of at least about 40, preferably from about 50 to 120, and more preferably from about 60 to 100. As used herein, the term xe2x80x9ccompressionxe2x80x9d means as measured by an ATTI Compression Gauge. These gauges are well known to those of ordinary skill in the art and are commercially available from Atti Engineering Corp. of Union City, N.J.
Accordingly, it has been found by the present invention that the use of a castable, reactive material which is applied in a fluid form makes it possible to obtain very thin outer cover layers on golf balls. Specifically, it has been found that castable, reactive liquids which react to form a thermoset material provide desirable very thin outer cover layers.
The castable, reactive liquid employed to form the thermoset material can be applied over the inner core using a variety of application techniques such as spraying, dipping, spin coating or flow coating methods which are well known in the art. An example of a suitable coating technique is that which is disclosed in U.S. Pat. No. 5,733,428, filed May 2, 1995, the disclosure of which is hereby incorporated by reference in its entirety in the present application.
In a further embodiment, self-healing polymer blends may be formed by blending ceramic or glass microspheres with the self-healing polymer either during or before the molding process. Polymeric, ceramic, metal, and glass microspheres, foaming agents are useful in the invention, and may be solid or hollow and filled or unfilled. Microspheres up to about 1000 micrometers in diameter are useful in the polymer compositions of the invention. The present invention also includes the layer compositions that can be foamed by utilizing a well-known process in the art including the micro-cellular process.
For compression molded layers, half-shells made by injection molding a self-healing polymer composition in a conventional half-shell mold are used. The half-shells are placed about a previously formed center or core, cover, or mantle layer, and the assembly is introduced into a compression molding machine, and compression molded at about 250xc2x0 F. to 400xc2x0 F. The molded balls are then cooled while still in the mold, and finally removed when the layer is hard enough to be handled without deforming. Additional core, intermediate, and cover layers are then molded onto the previously molded layers, as needed, until a complete ball is formed. After the final cover layer of the ball has been molded, the ball undergoes various conventional finishing operations such as buffing, painting and stamping, all of which are well known in the art.
Blending of the self-healing polymer compositions and the optional additional polymers is accomplished in a conventional manner using conventional equipment. For example, a conventional injection molding machine may be used either to make preformed half-shells for compression molding or for molding flowable polymer compositions using a retractable-pin mold.
Conventional ionomers useful in this invention may include SURLYN(copyright), ESCOR(copyright), IOTEK(copyright), and IMAC(copyright) copolymers. Such ionomers are obtained by providing thermolabile ionic crosslinking to polymers of monoolefin with at least one member selected from the group consisting of unsaturated mono- or di-carboxylic acids having 3 to 12 carbon atoms and esters thereof (the polymer contains 1 to 50% by weight of the unsaturated mono- or di-carboxylic acid and/or ester thereof). More particularly, such acid-containing ethylene copolymer ionomer component includes E/X/Y copolymers where E is ethylene, X is a softening comonomer such as acrylate or methacrylate present in 0-50 (preferably 0-25, most preferably 0-20), weight percent of the polymer, and Y is acrylic or methacrylic acid present in 5-35 (preferably 10-35, more preferably at least about 16-35, most preferably at least about 16-20) weight percent of the polymer, wherein the acid moiety is neutralized 1-100% (preferably at least 40%, most preferably at least about 60%) to form an ionomer by a cation such as lithium, sodium, potassium, magnesium, calcium, barium, lead, tin, zinc or aluminum, or a combination of such cations. Neutralization approaching and reaching 100% may be accomplished using a fatty acid or its salt. Specific acid-containing ethylene copolymers include ethylene/acrylic acid, ethylene/methacrylic acid, ethylene/acrylic acid/n-butyl acrylate, ethylene/methacrylic acid/n-butyl acrylate, ethylene/methacrylic acid/iso-butyl acrylate, ethylene/acrylic acid/iso-butyl acrylate, ethylene/methacrylic acid/n-butyl methacrylate, ethylene/acrylic acid/methyl methacrylate, ethylene/acrylic acid/methyl acrylate, ethylene/methacrylic acid/methyl acrylate, ethylene/methacrylic acid/methyl methacrylate, and ethylene/acrylic acid/n-butyl methacrylate. Preferred acid-containing ethylene copolymers include ethylene/methacrylic acid, ethylene/acrylic acid, ethylene/methacrylic acid/n-butyl acrylate, ethylene/acrylic acid/n-butyl acrylate, ethylene/methacrylic acid/methyl acrylate and ethylene/acrylic acid/methyl acrylate copolymers. The most preferred acid-containing ethylene copolymers are ethylene/methacrylic acid, ethylene/acrylic acid, ethylene/(meth)acrylic acid/n-butyl acrylate, ethylene/(meth)acrylic acid/ethyl acrylate, and ethylene/(meth)acrylic acid/methyl acrylate copolymers.
The manner in which the ionomers are made is well known in the art as described in, e.g., U.S. Pat. No. 3,262,272, which is incorporated herein in its entirety by reference.
As mentioned above, other suitable materials for forming the cover and/or intermediate layers, i.e., for use in combination with self healing polymers, include ionomers, polyurethanes, epoxy resins, polystyrenes, olefin based epoxy or anhydride copolymers, amine containing polymers, highly neutralized polymers as disclosed in WO 01/29129, acrylics, polyethylenes, polycarbonates, polyamides, polyesters, silicone polymers, silicone elastomers, and silicone resins. For example, the cover and/or intermediate layer may be formed from a blend of microencapsulated healing agents and catalyst and conventionally produced thermoplastic or thermoset urethanes/polyurethanes, urethane ionomers and urethane epoxies, polyurea, epoxy copolymers, anionic ionomers as disclosed in U.S. Pat. No. 6,221,960, single-site catalyzed polymers and blends thereof.
Among the suitable thermoplastic polyurethanes are block copolymers of copolyurethanes which typically contain blocks of a polyurethane oligomer (material with the higher softening point) alternating with lower softening point blocks of either a polyether oligomer, for a block copoly(ether-urethane), a polyester oligomer for a block copoly(ester-urethane) or a polybutadiene or hydrogenated polybutadiene oligomer for a block copoly(butadiene-urethane). The polyether oligomer is typically a polyether macroglycol, such as polytetramethylene ether glycol. The polybutadiene oligomer is a dihydroxy terminated polybutadiene oligomer, which may optionally be partially or fully hydrogenated. The polyurethane block typically consists of 4,4xe2x80x2-diphenylmethane diisocyanate, toluene diisocyanate (any combination of the 2,4- and 2,6-isomers) or para-phenylene diisocyanate, all chain extended with an aliphatic diol, typically 1,4-butanediol. Examples of suitable commercially available thermoplastic polyurethanes include the ESTANE(copyright) series from the B. F. Goodrich Company, which includes ESTANE(copyright) 58133, 58134, 58144 and 58311; the PELLETHANE(copyright) series from Dow Chemical, which includes PELLETHANE(copyright) 2102-90A and 2103-70A; ELASTOLLAN(copyright) from BASF; DESMOPAN(copyright) and TEXIN(copyright) from Bayer; and Q-THANE(copyright) from Morton International.
As noted above, self healing polymer candidates can also be blended with an epoxy resin. Examples of suitable commercially available epoxy resins include but are not limited to EPON(copyright) resins available from Shell and NOVALAC resins from Dow.
Suitable polyethylenes for blending as self healing polymers to form the cover and/or intermediate layer include homo and copolymers of ethylene containing functional groups such as maleic anhydride, carboxylic acid and hydroxyl groups. For example, these functional groups are introduced either by chemical grafting as in the case of grafting maleic anhydride such as that sold commercially under the tradename FUSABOND(copyright) by DuPont (Canada), or by copolymerizing the ethylene monomer with an unsaturated carboxylic acid comonomer such as a methacrylic acid sold commercially under the tradename NUCREL(copyright) by DuPont.
Catalysts such as manganese acetate, antimony oxide and titanium alkoxides are commonly used producing polyester polymers. Examples of suitable commercially available polyesters include materials sold under the tradenames EASTPAK(copyright) PET polyester and EASTAR(copyright) PETG from Eastman Chemicals, DACRON(copyright) and TERLENE(copyright) from DuPont.
Examples of other specific polymers or families of polymers which may be used in conjunction with self healing polymers in golf ball cover and/or intermediate layer compositions include: poly (ethylethylene), poly(heptylethylene), poly(hexyldecylethylene), poly(isopentylethylene), poly(1,1-dimethyltrimethylene), poly(1,1,2-trimethyltrimethylene), aliphatic polyketones (such as ethylene-carbon monoxide-propylene sold commercially under the tradename CARILON by Shell), poly(butyl acrylate), poly(2-ethylbutyl acrylate), poly(heptyl acrylate), poly(2-methylbutyl acrylate), poly(3-methylbutyl acrylate), poly(octadecyl methacrylate), poly(butoxyethylene), poly(methoxyethylene), poly(pentyloxyethylene), poly(l, 1-dichloroethylene), poly(cyclopentylacetoxyethylene), poly(4-dodecylstyrene), poly(4-tetradecylstyrene), poly(oxyethylethylene), poly(oxytetramethylene), poly(silanes), poly(silazanes), poly(furan tetracarboxylic acid diimides), and poly(vinylidene fluoride), as well as the classes of polymers to which they belong.
The invention is further directed to a golf ball cover and/or intermediate layer composition comprising a blend of self healing polymers in conjunction with non-ionomeric thermoplastic polymers. For example, such non-ionomeric thermoplastic polymers may include: block copolymer of poly(ether-ester) copolymers, such as HYTREL(copyright) available from DuPont, partially or fully hydrogenated styrene-butadiene-styrene block copolymers, such as the KRATON D(copyright) grades available from Shell Chemical, styrene-(ethylene-propylene)-styrene or styrene-(ethylene-butylene)-styrene block copolymers, such as the KRATON G(copyright) series from Shell Chemical, Septon HG-252 from Kurary, either of the KRATON(copyright)-type copolymers with maleic anhydride or sulfonic graft or hydroxyl functionality, such as the KRATON FD(copyright) or KRATON FG(copyright) series available from Shell Chemical, olefinic copolymers, such as the ethylene-methyl acrylate or ethylene-butyl acrylate series available from Quantum Chemical, ethylene-octene copolymers made with metallocene catalysts, such as the AFFINITY(copyright) or ENGAGE(copyright) series available from Dow, ethylene-alpha olefin copolymers and terpolymers made from metallocene catalysts, such as the EXACT(copyright) series available from Exxon, block copolymer of poly(urethane-ester) or block copolymer of poly(urethane-ether) or block copolymer of poly(urethane-caprolactone), polyethylene glycol, such as CARBOWAX(copyright) available from Union Carbide, polycaprolactone, polycaprolactam, polyesters, such as EKTAR(copyright) available from Eastman, ethylene-propylene-(diene monomer) terpolymers and their sulfonated or carboxylated derivatives, and SANTOPRENE(copyright) from Monsanto. The invention is further directed to a golf ball cover and intermediate layer comprising poly(trimethylene terephthalate).
Other examples of non-ionomeric thermoplastic elastomer polymers can be selected from the group consisting of a block copolymer of copoly(ester-ester), a block copolymer of copoly(ester-ether), a block copolymer of copoly(urethane-ester), a block copolymer of copoly(urethane-ether), a block polystyrene thermoplastic elastomer comprising an unsaturated rubber, a block polystyrene thermoplastic elastomer comprising a functionalized substantially saturated rubber, a thermoplastic and elastomer blend comprising polypropylene and ethylene-propylene-diene monomer terpolymer or ethylene-propylene copolymer rubber where the rubber is dynamically vulcanized, poly(ethylene terephthalate), poly(butylene terephthalate), poly(vinyl alcohol), poly(vinyl acetate), poly(silane), poly(vinylidene fluoride), acrylonitrile-butadiene-styrene copolymer, olefinic polymers, their copolymers, including functional comonomers, and mixtures thereof.
One-piece golf balls comprising self-healing polymers, either alone or as a blend with other polymers, two-piece golf balls comprising a cover surrounding a core and wound golf balls, in which a liquid, semi-solid, or solid core is surrounded by an elastic synthetic material are all within the scope of the invention. Any type of golf ball core can be used in the golf balls of the invention. However, preferred cores include some amount of cis-polybutadiene.
The polymer blends of this invention can be prepared with or without the addition of a compatibilizer and with varying molecular architecture of blend components, such as varying molecular weight, tacticity, degrees of blockiness, etc., as is well known to those knowledgeable in the art of blending polymers.
Blending of the polymers is accomplished in a conventional manner using conventional equipment. Good results may be obtained by mixing the polymers or resins in a solid, pelletized form and then placing the mix into a hopper which is used to feed the heated barrel of an injection molding machine. Further mixing is accomplished by a screw in the heated barrel. The injection molding machine is used either to make preformed half-shells for compression molding about a core or for molding flowable cover stock about a core using a retractable-pin mold. Such machines are conventional.
Additionally, conventional components, known to those skilled in the art, which can be added to the cover compositions of the invention include white pigments, optical brighteners, processing aids and UV stabilizers such as TINUVIN(copyright) 213 and TINUVIN(copyright) 328. Also, light stabilizers such as, for example, TINUVIN(copyright) 770 and TINUVIN(copyright) 765, may also be used. TINUVIN(copyright) products are available from Ciba-Geigy. Dyes, as well as fluorescent pigments may also be used in the golf ball covers produced with polymers formed according to the invention. Such additional ingredients may be used in any amounts that will achieve their desired purpose. However conventional amounts range of from about 0.05% to about 1.5%, or more preferably, from about 0.5% to about 1.0%.
Other conventional ingredients, e.g., fillers are well known to the person of ordinary skill in the art and may be included in cover and intermediate layer blends of the invention in amounts effective to achieve their known purpose.
An optional filler component may be chosen to impart additional density to blends of the previously described components. The selection of such filler(s) is dependent upon the type of golf ball desired (i.e., one-piece, two-piece multilayer or wound), as will be more fully detailed below. Generally, the filler will be inorganic, having a density greater than about 2 g/cc, preferably greater than 4 g/cc, and will be present in amounts between 5 and 65 weight percent based on the total weight of the polymer components. Examples of useful fillers include metals, such as tungsten and titanium; metal alloys, such as brass and bronze; metal oxides, such as zinc oxide and calcium oxide; metal salts, such as barium sulfate, lead silicate and tungsten carbide; and other well known corresponding salts and oxides thereof.
Self-healing polymers may be incorporated into conventional core compositions to form cores for two-piece balls or centers of wound balls. Conventional core compositions comprise polybutadiene as the elastomer and, in parts by weight based on 100 parts polybutadiene (pph), 20-50 pph of a metal salt acrylate derivative such as zinc diacrylate, zinc dimethacrylate, or zinc monomethacrylate, preferably zinc diacrylate. The core compositions of this invention may be foamed or unfoamed.
The compositions of the invention may also include fillers, added to the elastomeric composition to adjust the density and/or specific gravity of the core. Fillers useful in the golf ball core according to the invention include, for example, zinc oxide, calcium oxide, barium sulfate, and regrind (which is recycled core molding matrix ground to 20 mesh particle size). The amount and type of filler utilized is governed by the amount and weight of other ingredients in the composition, since a maximum golf ball weight of 1.620 ounces has been established by the USGA. Appropriate fillers, including reactive fillers, known by those skilled in the art, generally have a specific gravity in the range of from about 2.0 to 5.6.
Antioxidants may also be included in the elastomer cores produced according to the invention. Antioxidants are compounds which prevent the breakdown of the elastomer. Antioxidants useful in the invention include, but are not limited to, quinoline type antioxidants, amine type antioxidants, and phenolic type antioxidants.
Other ingredients such as accelerators, e.g., tetra methylthiuram, processing aids, processing oils, plasticizers, dyes and pigments, as well as other additives well known to the skilled artisan may also be used in the invention in amounts sufficient to achieve the purpose for which they are typically used.
The core compositions of the invention may be produced by forming a mixture comprising, for example, polybutadiene, zinc diacrylate. In preparing the core compositions, when a set of predetermined conditions is met, i.e., time and temperature of mixing, the free radical initiator is added in an amount dependent upon the amounts and relative ratios of the starting components, all of which would be well understood by one of ordinary skill in the art. In particular, as the components are mixed, the resultant shear causes the temperature of the mixture to rise. Peroxide(s) free radical initiator(s) and optionally a trans-converting agent such as organic or inorganic sulfides are blended into the mixture for crosslinking purposes in the molding process.
After completion of the mixing, the golf ball core composition is milled and hand prepped or extruded into pieces (xe2x80x9cprepsxe2x80x9d) suitable for molding. The milled preps are then compression molded into cores at an elevated temperature. These cores can then be used to make finished golf balls by surrounding the cores with an intermediate layer and/or cover materials.
Layers including a composition of self healing polymers may be produced in golf balls in accordance with the invention by injection molding or compression molding a layer of the self healing polymer composition about a previously formed center or core, cover, or intermediate layer. Cores comprising a self-healing composition may also be formed directly by injection molding or compression molding. When the layer or core is injection molded, a physical or chemical blowing or foaming agent may be included to produce a foamed layer. Blowing or foaming agents useful in forming foamed compositions include, but are not limited to organic blowing agents, such as azobisformamide; azobisisobutyronitrile; diazoaminobenzene; N, N-dimethyl-N, N-dinitroso terephthalamide; N,N-dinitrosopentamethylene-tetramine; benzenesulfonyl-hydrazide; benzene-1,3-disulfonyl hydrazide; diphenylsulfon-3-3, disulfonyl hydrazide; 4,4xe2x80x2-oxybis benzene sulfonyl hydrazide; p-toluene sulfonyl semicarbizide; barium azodicarboxylate; butylamine nitrile; nitroureas; trihydrazino triazine; phenyl-methyl-uranthan; p-sulfonhydrazide; peroxides; and inorganic blowing agents such as ammonium bicarbonate and sodium bicarbonate. A gas, such as air, nitrogen, carbon dioxide, etc., can also be injected into the blend during the injection molding process.
In a further embodiment, compositions may be formed by blending microspheres with the self healing polymer composition either during or before the molding process. Polymeric, ceramic, metal, and glass microspheres are useful in the invention, and may be solid or hollow and filled or unfilled. Microspheres up to about 1000 xcexcm in diameter are useful in the self-healing polymer compositions of the invention.
The invention is further directed to a method of making a golf ball. The method comprises, in one embodiment, the steps of forming a golf ball core by conventional means and subsequently forming a cover around the core by either compression molding preformed half-shells of cover stock material comprising a self-healing polymer composition about the core or by injection molding cover stock material comprising the self-healing polymer composition about the core.
The present invention relates to golf balls of any size. While USGA specifications limit the size of a competition golf ball to more than 1.68 inches in diameter, golf balls of any size can be used for leisure golf play. The preferred diameter of the golf balls is from about 1.68 inches to about 1.8 inches. The more preferred diameter is from about 1.68 inches to about 1.76 inches. A diameter of from about 1.68 inches to about 1.74 inches is most preferred. The cover of the golf balls typically has a thickness of at least about 0.03 inches, preferably 0.03 to 0.125 inches, and more preferably from about 0.05 to 0.1 inches. The golf balls also typically have at least about 60 percent dimple coverage, preferably at least about 70 percent dimple coverage, of the surface area.

Self healing polymers in sports equipment


A computing device for state transitions of recursive state machines and a computer-implemented method for the definition, design and deployment of domain recursive state machines for computing devices of that type; such devices are intended for the simulation of large systems involving human and automated components, particularly the type generally called “Enterprise Applications”; such devices are also applicable to a much wider range of fields, such as cognitive modelling or robotics. The commonality between the computing device and the computer-implemented method is the Subject Predicate Object Protocol (SPOP) which is used to capture instructions by the computer-implemented method for the definition, design and deployment of recursive state machines and also is the protocol used by the computing device for state transitions of recursive state machines to communicate inbound and outbound events based on the captured instructions.

Any reference to publications or acts cited in this specification is not an admission that the disclosures constitute common general knowledge in Australia or elsewhere.
Enterprise Software History
In the early days of computing, software was not thought of as an independent category of activity or product. In fact, the word software itself only acquired widespread usage in the 1960's. Up to the middle of the 1960s, there were programs, delivered to the buyer with the computing machinery (hardware) by the manufacturer. The more adventurous users slowly undertook to write their own programs in FORTRAN, Algol or, later COBOL. The first companies dedicated to developing software were founded in 1955 (Computer Usage Company) and 1959 (Computer Services Corporation), and the plan was to offer programming services.
Typically, the early applications of computers were military or scientific (mainly in fields of interest to the military or government, e.g., census, weather forecasting or mechanical translation). The first business-oriented languages were introduced in the late 1950's (FLOW-MATIC, COMTRAN, FACT, then COBOL)
The introduction of symbolic, compilable languages was the first step of abstraction in the separation of software (yet to be openly so named) from the underlying machinery. This step gave rise to two development trends leading to an independent software industry.
The first trend was motivated by the commercial imperatives of fledgling software companies. Bespoke program writing in large contracts for public or private organisations represented a narrow, constricted market, by comparison with the large field of business. There was strong incentive to develop "pre-written" products which would be usable on any machine of a certain type, or, more ambitious still, on a variety of hardware platforms (compilable, "high-level" languages made this conceivable).
Given IBM's domination of the hardware market, it is not surprising that many of the more successful software companies were founded by ex-IBM engineers.
The initial strategy was to identify a part of business activity which was similar if not identical across the range of businesses, and to reduce it to automation. Not surprisingly, the first successes were in the domain of business accounting.
The approach was extended to all repeatable aspects of business. By the early 1970s, the concept of Enterprise Resource Planning (ERP) was taking root, promoted in particular by SAP. ERP software is typically made up of modules for each business function; adopting modules from the same vendor almost guarantees perfect integration. However, not all of one company's modules are necessarily the "best of breed"; some vendors may specialise in particular areas (e.g., supply chain, or customer relationship) and produce superior products in their particular specialty. This in turn raises the issue of integrating offerings from different vendors.
At this point, the attractiveness of "packaged software" brought to the fore a new issue in business automation strategy: the "make or buy" decision. Wholly integrated solutions were typically expensive, while combining individual best-of-breed modules or developing in-house raised architecture, design and cost issues.
Software vendors responded to this new challenge in two ways. On the one hand, some vendors kept the concept of a unified business solution, but specialised to particular industry "verticals", such as banking or telecommunications. This approach enabled them to address the idiosyncratic needs of a given industry in a more precise way. Other vendors developed middleware products targeting the integration problem (transaction monitors, messaging platforms, business hubs). Middleware is positioned between system software, which addresses issues of machinery (hardware drivers and operating systems) and application software, which addresses issues of business needs.
The whole domain of Enterprise Application Integration (EAI) has proved to be a major step in the evolution of business software. Initially, EAI approaches were individual and ad hoc. Progressively, a body of wisdom and best practices emerged, and vendors followed by offering tools and products to implement those. As a result, there is a new balance in the enterprise software industry: while adopting integrated solutions from a single vendor still offers some advantages, the availability of integration resources makes best-of-breed approaches less risky.
The second trend concerns the engineering of software.
The term software engineering appeared almost simultaneously with the word software itself. Programmers, inspired by existing branches of engineering, were investigating how the engineering stance might apply to their work.
This concern with engineering was exacerbated by the software crisis in the 1960s. The lack of an established discipline for software construction has disastrous effects on software project costs and on the quality of results. The profession of software engineer was acknowledged as a result of two NATO conferences in the late 1960s.
The objective of software engineering is to apply a systematic, disciplined, quantifiable approach to the design, development, operation, and maintenance of software. This trend is independent of subject matter. The notion of reuse had flourished much earlier. As early software was free, it was shared without restraint. Some groups (e.g., IBMSHARE) offered catalogues of reusable components. But there were no principles to guide reuse.
The first successful, systematic form of reuse was based on the concept of libraries. A library offers a collection of implementation of common functions or algorithms, which can be invoked from any client program. The programmer remained responsible for designing and implementing the overarching logic flow of the program. Libraries were very successful in boosting the efficiency of programming, beginning with FORTRAN mathematic and scientific libraries.
Another approach inverted the problem: how to address a family of software tasks which share an overall logic flow, but in which small individual parts need to be customised. This gave rise to frameworks. In a typical framework, the core software can run "out of the box" and provide a useful function. This is made possible by the fact that all possible variable options have been given a "default" value. However, for each such point on the software, a mechanism is available to override the default and introduce newly defined behaviour. An interesting form of framework architecture is the "plug-in," introduced in Apache and systematised in Eclipse.
The concept of framework has been generalised to more complex arrangements, while maintaining the original characteristic of customisation points. In each case, the effect is to facilitate software development by allowing designers and programmers to devote their time to meeting requirements, rather than dealing with the details of providing a working system. Software frameworks include support programs, application programming interface (API) and tool sets that bring together all the different components to enable development of a solution. This approach is particularly suited to business software development, once the fundamental features of a given business problem are understood.
Another development in software engineering relates to the relationship between algorithms and data. According to Niklaus Wirth's formula "Algorithms+Data Structures=Programs". There is therefore a necessary coupling between some algorithms and some data structures. Identifying and investigating the nature of such couplings led to the formulation of Abstract Data Types (ADT). An ADT is a packaging of a Data type typically complex) with the functions (algorithms) which can operate on it. Expressing a software design in terms of ADT eliminates the need to manage the coupling separately, supports the factoring of the software into self-contained units which are more amenable to reuse, and supports the principle of information hiding, in that data structures are only accessible to functions which must operate on them, which protects against integrity violations and increases the potential for software quality.
The natural progression from ADT led to Objects. While ADTs are defined individually, it quickly appears that they in fact form "families" of similar types in which one is derived from another by specialisation—or conversely several can be grouped together by abstraction. Several forms of inheritance have been defined and codified in various languages. "Object-oriented programming" has known an overwhelming success, among other reasons because it is appealing to ordinary human cognition. In particular, objects defined in software engineering have often been interpreted as reflections of objects in the "real world", partly because much of object orientation arose from simulation.
On the other hand, objects tend to partition a domain of interest and fail to capture features common to different domains. Thus arose another perspective, around the concept of Aspects. Tooling has been developed to incorporate Aspect-oriented elements of code in Object-oriented software, thus taking advantage of both kinds of factoring.
All the above inventions amounted to various ways of raising the level of abstraction in the representation of what the software is meant to accomplish. In effect, the larger, more complex units identified in these efforts (library routines, framework structures, ADTs, Objects, Aspects) consisted in clustering the low-level commands to the hardware (instructions) into aggregates associated with a concept more amenable to human cognition.
The next step in this progression was the concept of a software engine, that is, a construct which had a defined, parameterised behaviour, such that the parameters could be declared in an appropriate notation ("high-level language", "4GL", etc.). In this group of innovations can be found interpreters, virtual machines, rules engines, process engines, reasoning engines, etc.
Of special importance to Enterprise applications are process engines which mechanise the execution of a (business) process. The desired behaviour of the process is declared using an appropriate language, e.g., BPMN (Business Process modeling notation). Changes in the process can now be implemented without having to write new code explicitly (with some process engines the high-level notation must be translated by a tool similar to a compiler; others are interpretive, and execute the notation directly)
Similarly, rules engine can execute rules, declared in a rule notation (e.g., Rule Speak), either interpretively or after compilation. This approach to software blurs the distinction between modelling and execution, and leads to the concept of an executable model.
If the granularity of the units identified and enacted by engines is such that they map to well-understood business concepts, the resulting software architecture is that known as Service-oriented.
Many commercial packages are architected as combinations of engine and framework: like frameworks, they provide for specific locations where the user can insert code additions to override defaults (software extensions). Like engines, they offer a rich set of parameters which can be declared by the user (configuration). However, this flexibility has strict limits: if the user introduces customisations, i.e., modifications which do not fit the prescribed extensions or configurations, the vendor offers no guarantee as to compatibility with future versions. Also, because extensions and customisations are specific to a given package, the associated concepts are not portable across packages, and cannot support an enterprise-wide approach.
Service Oriented Architecture (SOA) is an approach to address the resulting challenge. While an Enterprise's IT resources must serve the changing needs of the business, they must also be free to evolve in the best and most efficient way possible with technology trends. The concept of service supports the decoupling of Business dynamics (associated with the first trend), from Technology dynamics (associated with the second trend).
The dynamics of the business and of the information systems that support it are quite different. Business is driven internally by the enterprise mission and its strategy; and externally by the nature of the markets and by statutory obligations. Information systems are driven internally by the automation strategy (if any); and externally by technology trends and available vendors.
SOA is the first architectural approach which gives "first-class" status to the business view of services. While ITIL and other accepted norms of Information Technology refer to services, and may provide guidance on their management, there was no accurate definition of a service as such. SOA declares a service to be a unit of technology deployment which provides a definite business function. In simple terms, like a word in a language, a service within SOA has a "form"—its technical implementation and deployment—and a "meaning"—the function it provides to the business endeavour.
The analogy with language goes further. If services are like words in a language, there must be a way to combine them into meaningful "sentences" (read: service invocations must be combinable to form business-valuable scenarios). The "syntax" of a service language is called orchestration, and draws on the concepts of process engine and process notation.
The SOA approach has a major implication for IT professionals: a service's meaning is defined in the context of business operations. This means that any SOA effort presupposes a precise definition of the structure and behaviour of the business endeavour. IT Architects have long realised that they cannot devise sensible solutions without first having defined the business problem. However, in the past this definition was done piecemeal, addressed a limited scope, and took the form of a collection of requirements often lacking any sort of internal structure. SOA requires that services should be defined in a properly articulated business context, and brings to the fore the need for a Business Architecture as an essential part of the architecture of the enterprise.
With SOA, the level of abstraction has finally been raised all the way to "business value". In principle, services defined by their business value can be reused as long as the business meanings remain stable. Introduction of a new line of business might reuse some services and specify a few new ones. Innovations in technology might warrant the design of a new implementation; new deployment techniques (e.g., cloud deployment) may warrant changes in physical detail. All this can be accomplished economically and flexibly provided that the Business architecture exists to provide the base context.
The present invention is positioned at the convergence of the two trends discussed above. It supports defining a Business Architecture in terms of the activity types targeted in the first (commercial) trend, thereby leveraging the experience acquired in domain specification. It supports a fine, recursive decomposition of these domains into granular services (a necessity of structure, as will be shown in the following section on complex systems). Finally it supports the articulation of the business "meaning" of the services with a variety of implementation and deployment "forms", leveraging the engineering resources discussed in the second trend, which make it possible to anchor the conceptual business model in practical realisation.
The challenge of IT Architecture arises from the fact that Business Information Systems are complex systems, which embody several kinds of regularities at once. Any notation designed to document one kind of regularity (e.g., process) may be incompatible with notations for other kinds. A major contribution of the present invention is the devising of a meta-grammar which makes it possible to define grammars suitable for each regularity and yet to connect them as compatible formal devices. The detail of this development is the topic of the next section.
Complex Systems
The present invention arises as a response to the challenge of engineering, or simply modelling, complex systems, and addresses four characteristic issues of such systems.                Fitness for purpose: Such systems exist—or are intended to exist—within a context of intents and motivations which provide the criteria for their validity and adequacy.        Degree of Definition: The quality and precision of specification vary widely among the domains of knowledge implied by the various components.        Structural Diversity: The structure and dynamics of the components are diverse, and cannot be simply related to each other.        Interoperability: Because of this internal diversity, explicit protocols must be specified to ensure joint operation of the components.

Computing device for state transitions of recursive state machines and a computer-implemented method for the definition, design and deployment of domain recursive state machines for computing devices of that type


Methods for treating hair loss using a composition including a compound having the following structure

The present invention relates to methods for treating hair loss in mammals, including arresting and/or reversing hair loss and promoting hair growth.
Hair loss is a common problem which occurs, for example, through natural processes or is often chemically promoted through the use of certain therapeutic drugs designed to alleviate conditions such as cancer. Often such hair loss is accompanied by lack of hair regrowth which causes partial or full baldness.
As is well-known in the art, hair growth occurs by a cycle of activity which involves alternating periods of growth and rest. This cycle is often divided into three main stages which are known as anagen, catagen, and telogen. Anagen is the growth phase of the cycle and may be characterized by penetration of the hair follicle deep into the dermis with rapid proliferation of cells which are differentiating to form hair. The next phase is catagen, which is a transitional stage marked by the cessation of cell division, and during which the hair follicle regresses through the dermis and hair growth is ceased. The next phase, telogen, is often characterized as the resting stage during which the regressed follicle contains a germ with tightly packed dermal papilla cells. At telogen, the initiation of a new anagen phase is caused by rapid cell proliferation in the germ, expansion of the dermal papilla, and elaboration of basement membrane components. Wherein hair growth ceases, most of the hair follicles reside in telogen and anagen is not engaged, thus causing the onset of full or partial baldness.
There have been many attempts in the literature to invoke the regrowth of hair by, for example, the promotion or prolongation of anagen. Currently, there are two drugs approved by the United States Food and Drug Administration for the treatment of male pattern baldness: topical minoxidil (marketed as Rogaine(copyright) by Pharmacia and Upjohn), and oral finasteride (marketed as Propecia(copyright) by Merck and Co., Inc.). For several reasons, however, including safety concerns and or lack of efficacy, the search for efficacious hair growth inducers is ongoing.
Interestingly, it is known that the thyroid hormone known as thyroxine (xe2x80x9cT4xe2x80x9d) converts to thyronine (xe2x80x9cT3xe2x80x9d) in human skin by deiodinase I, a selenoprotein. Selenium deficiency causes a decrease in T3 levels due to a decrease in deiodinase I activity; this reduction in T3 levels is strongly associated with hair loss. Consistent with this observation, hair growth is a reported side effect of administration of T4. See, e.g., Berman, xe2x80x9cPeripheral Effects of L-Thyroxine on Hair Growth and Coloration in Cattlexe2x80x9d, Journal of Endocrinology, Vol. 20, pp. 282-292 (1960); and Gunaratnam, xe2x80x9cThe Effects of Thyroxine on Hair Growth in the Dogxe2x80x9d, J. Small Anim. Pract., Vol. 27, pp. 17-29 (1986). Furthermore, T3 and T4 have been the subject of several patent publications relating to treatment of hair loss. See, e.g., Fischer et al., DE 1,617,477, published Jan. 8, 1970; Mortimer, GB 2,138,286, published Oct. 24, 1984; and Lindenbaum, WO 96/25943, assigned to Life Medical Sciences, Inc., published Aug. 29, 1996.
Unfortunately, however, administration of T3 and/or T4 to treat hair loss is not practicable because these thyroid hormones are also known to induce significant cardiotoxicity. See, e.g., Walker et al., U.S. Pat. No. 5,284,971, assigned to Syntex, issued Feb. 8, 1994 and Emmett et al., U.S. Pat. No. 5,061,798, assigned to Smith Kline and French Laboratories, issued Oct. 29, 1991. Surprisingly, however, the present inventors have discovered compounds which promote hair growth without inducing cardiotoxicity. Consistent with this discovery, but without intending to be limited by theory, the present inventors have surprisingly discovered that the compounds useful in the present invention interact strongly with hair-selective thyroid hormone receptors but interact less strongly, or not at all, with heart-selective hormone receptors. These unique properties are, of course, not shared with T3 and/or T4. Accordingly, the compounds described for use in the methods and compositions herein are cardiac-sparing compounds useful for treating hair loss, including arresting and/or reversing hair loss and promoting hair growth.
The present invention relates to methods for treating hair loss comprising administering a cardiac-sparing compound which has been found by the present inventors to be particularly useful for treating hair loss in mammals, including arresting and/or reversing hair loss and promoting hair growth. The compounds utilized in the present method have the structure:
and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein R1, R3, R5, R31, and R41, are defined herein.
The present invention relates to methods of using compounds and compositions which are particularly useful for treating hair loss in mammals, including arresting and/or reversing hair loss and promoting hair growth.
In addition to discovering that the present compounds are useful for treating hair loss, the present inventors have also surprisingly discovered that the preferred compounds are cardiac-sparing. The preferred compounds useful in the method of the present invention are therefore, as defined herein below, cardiac-sparing.
Publications and patents are referred to throughout this disclosure. All references cited herein are hereby incorporated by reference.
All percentages, ratios, and proportions used herein are by weight unless otherwise specified.
In the description of the invention various embodiments and/or individual features are disclosed. As will be apparent to the ordinarily skilled practitioner all combinations of such embodiments and features are possible and can result in preferred executions of the invention.
As used herein, wherein any variable, moiety, group, or the like occurs more than one time in any variable or structure, its definition at each occurrence is independent of its definition at every other occurrence.
The following is a list of definitions for terms used herein:
As used herein xe2x80x9csaltxe2x80x9d is a cationic salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art. Preferred cationic salts include the alkali metal salts (such as, for example, sodium and potassium), alkaline earth metal salts (such as, for example, magnesium and calcium), and organic salts. Preferred anionic salts include the halides (such as, for example, chloride salts). Such acceptable salts must, when administered, be appropriate for mammalian use.
As used herein, xe2x80x9calkoxyxe2x80x9d is an oxygen radical having an alkyl substituent. Examples of alkoxy radicals include xe2x80x94O-methyl and xe2x80x94O-ethyl.
As used herein, xe2x80x9calkylxe2x80x9d is a saturated, straight or branched chain monovalent hydrocarbon radical. Unless otherwise specified, alkyls have from 1 to about 4 carbon atoms (C1-C4). Preferred alklyls include, for example, methyl, ethyl, propyl, iso-propyl, tert-butyl, n-butyl, sec-butyl, and iso-butyl.
As used herein, xe2x80x9cbiohydrolyzable amidesxe2x80x9d are amides of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
As used herein, xe2x80x9cbiohydrolyzable estersxe2x80x9d are esters of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
As used herein, xe2x80x9cbiohydrolyzable imidesxe2x80x9d are imides of the compounds used in the present invention which do not interfere with the activity of the compound, or that are readily converted in vivo by a mammalian subject to yield an active compound.
As used herein, xe2x80x9ccarbocyclic ringxe2x80x9d, xe2x80x9ccarbocyclexe2x80x9d, or the like is a hydrocarbon ring radical. Carbocyclic rings are monocyclic or are fused, bridged, or spiro polycyclic rings. Unless otherwise specified, monocyclic rings contain from 3 to about 9 atoms, preferably from about 4 to about 7 atoms, and most preferably 5 or 6 atoms. Polycyclic rings contain from about 7 to about 17 atoms, preferably from about 7 to about 14 atoms, and most preferably 9 or 10 atoms. Carbocyclic rings (carbocycles) may be substituted or unsubstituted.
As used herein, xe2x80x9ccycloalkylxe2x80x9d is a saturated carbocyclic ring radical having from four to six carbon atoms, such as cyclopentyl and cyclohexyl. Optionally, the cycloalkyl may be substituted with one or more alkyl groups.
As used herein, xe2x80x9chaloalkylxe2x80x9d is an alkyl moiety substituted at one or more positions with a halogen radical.
As used herein, xe2x80x9chalocycloalkylxe2x80x9d an cycloalkyl moiety substituted at one or more positions with a halogen radical.
As used herein xe2x80x9chalogenxe2x80x9d refers to chlorine, bromine, iodine, and fluorine, preferably chlorine, bromine, and iodine, more preferably chlorine and iodine, and most preferably iodine.
As used herein, xe2x80x9cpharmaceutically acceptablexe2x80x9d means suitable for use in a human or other mammal.
As used herein, xe2x80x9csafe and effective amount of a compoundxe2x80x9d (or composition, or the like) means an amount that is effective to exhibit biological activity, preferably wherein the biological activity is arresting and/or reversing hair loss or promoting hair growth, at the site(s) of activity in a mammalian subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio when used in the manner of this invention.
The present invention relates to methods of treating hair loss comprising administering a composition comprising a compound having the structure:
and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof, wherein:
(a) R1 is xe2x80x94(CH2)n(CHNR7R8)mC(O)R9;
(b) n is an integer from 1 to 3;
(c) m is an integer from 0 to 1;
(d) R3 and R5 are each, independently, selected from the group consisting of chlorine, bromine, iodine, and xe2x80x94CH3;
(e) R7 and R8 are each, independently, selected from the group consisting of hydrogen and C1-C4 alkyl;
(f) R9 is selected from the group consisting of hydroxy, C1-C4 alkoxy, and xe2x80x94NR7R8;
(g) R31 is selected from the group consisting of hydrogen, chlorine, bromine, iodine, C1-C4 alkyl, C4-C6 cycloalkyl, C1-C4 haloalkyl, C4-C6 halocycloalkyl, and xe2x80x94CH(R10)Ar;
(h) Ar is selected from the group consisting of 5-hydroxypyrid-2-yl6-hydroxypyrid-3-yl, 6-hydroxypyridazin-3-yl, 6-methoxypyridazin-3-yl N-oxide, and 6-hydroxypyridazin-3-yl N-oxide;
(i) R10 is selected from the group consisting of hydrogen and C1-C4 alkyl; and
(j) R41 is selected from the group consisting of hydroxy and C1-C4 alkoxy.
The compounds useful in the method herein are further described in Walker et al., U.S. Pat. No. 5,284,971, assigned to Syntex, Inc., issued Feb. 8, 1994. However, for convenience, the compounds are more fully described herein below:
The R1 Moiety
The R1 moiety is xe2x80x94(CH2)n(CHNRxe2x80x94R8)mC(O)R9.
The integer n is from 1 to 3. Preferably, n is 1 or 2. The integer m is either 0 or 1.
R7 and R8 are each, independently, selected from hydrogen and C1-C4 alkyl. Preferably, R7 and R8 are each hydrogen.
R9 is selected from hydroxy, C1-C4 alkyl, and xe2x80x94NR7R8. As stated above, R7 and R8 are preferably each hydrogen.
Preferably, R1 is an alkanoic or 2-aminoalkanoic acid radical derived from acetic acid, propionic acid, or 2-aminopropionic acid, or the methyl or ethyl ester thereof. As used herein, the term xe2x80x9calkanoic acid radicalxe2x80x9d refers to a monovalent carboxylic acid radical formed by removal of a hydrogen from the xcfx89-carbon of an acid having from two to four carbon atoms, e.g., acetyl (xe2x80x94CH2COOH), propionyl (xe2x80x94CH2CH2COOH), and butyryl (xe2x80x94CH2CH2CH2COOH). As used herein, xe2x80x9caminoalkanoic acid radicalxe2x80x9d refers to a monovalent alkanoic acid radical having an amino or mono- or dialkylamino substituent on the xcex1-carbon, e.g., 2-aminopropionyl (xe2x80x94CH2CH(NH2)COOH).
The R3 and R5 Moieties
R3 and R5 are; each, independently, selected from chlorine, bromine, iodine, and xe2x80x94CH3 (a methyl radical). Preferably, R3 and R5 are each, independently, selected from iodine and bromine. Most preferably R3 and R5 are either both bromine or both iodine.
The R31 Moiety
R31 is selected from hydrogen, chlorine, bromine, iodine, C1-C4 alkyl, C4-C6 cycloalkyl, C1-C4 haloalkyl, C4-C6 halocycloalkyl, and xe2x80x94CH(R10)Ar.
Ar is selected from 5-hydroxypyrid-2-yl, 6-hydroxypyrid-3-yl, 6-hydroxypyridazin-3-yl, 6-methoxypyridazin-3-yl N-oxide, and 6-hydroxypyridazin-3-yl N-oxide. Preferably Ar is selected from 6-hydroxypyrid-3-yl, 6-hydroxypyridazin-3-yl, 6-methoxypyridazin-3-yl N-oxide, and 6-hydroxypyridazin-3-yl N-oxide.
R10 is selected from hydrogen and C1-C4 alkyl.
Preferably, R31 is selected from iodine, iso-propyl, cyclopentyl, cyclohexyl, and xe2x80x94CH(R10)Ar.
The R41 Moiety
R41 is selected from hydroxy and C1-C4 alkoxy, preferably hydroxy. A preferred alkoxy for R41 is methoxy.
Preferred compounds useful in the methods and compositions of the present invention are:
(a) 3,5-dibromo4-(4-hydroxy-3-iodophenylsulfonyl)phenylacetic acid;
(b) 3,5-dibromo4-(3-iodo-4-methoxyphenylsulfonyl)phenylacetic acid;
(c) 3,5-dibromo4-(4-hydroxy-3-(6-methoxypyridazin-3-ylmethyl)phenylsulfonyl)phenylacetic acid;
(d) 3,5-dibromo4-(3-cyclohexyl4-hydroxyhenylsulfonyl)phenylacetic acid;
(e) 3,5-dibromo4-(3-cyclohexyl4-methoxyphenylsulfonyl)phenylacetic acid;
(f) 3,5-dibromo4-(3-cyclopentyl4-hydroxyphenylsulfonyl)phenylacetic acid;
(g) 3-(3,5-dibromo-4-(4-hydroxy-3-iso-propylphenylsulfonyl)phenyl)propionic acid;
(h) 2-amino-3-(3,5-dibromo4-(4-hydroxy-3-iso-propylphenylsulfonyl)phenyl)propionic acid;
(i) 3,5-dibromo4-(4-hydroxy-(6-hydroxypyridazin-3-ylmethyl)phenylsulfonyl)phenylacetic acid;
(j) 3,5-dibromo4-(4-hydroxy-3-iso-propylphenylsulfonyl)phenylacetic acid; and
(k) 3,5-dibromo4-(3-iso-propyl)4-methoxyphenylsulfonyl)phenylacetic acid.
Of these, the most preferred compounds for use in the present invention are 3,5-dibromo4-(3-cyclohexyl4-hydroxyphenylsulfonyl)phenylacetic acid and 3,5-dibromo4-(3-cyclohexyl4-methoxyphenylsulfonyl)phenylacetic acid.
The present invention relates to methods of treating hair loss by administering a compound having a structure as described herein. Preferably, the compound utilized in the present invention will be cardiac-sparing. Compounds (test compounds) may be tested for their ability to induce anagen and their lack of cardiotoxicity (cardiac-sparing) using the following methods. Alternatively, other methods well-known in the art may be used (but with the term xe2x80x9ccardiac-sparingxe2x80x9d being defined according to the method disclosed herein below).
Cardiotoxicity Assay:
The cardiotoxicity assay measures the potential of a test compound to adversely affect the cardiovascular system. As thyroid hormone (T3) damages the cardiovascular system, the heart enlarges. See, e.g., Gomberg-Maitland et al., xe2x80x9cThyroid hormone and Cardiovascular Diseasexe2x80x9d, American Heart Journal, Vol. 135(2), pp. 187-196 (1998); Klein and Ojamaa, xe2x80x9cThyroid Hormone and the Cardiovascular Systemxe2x80x9d, Current Opinion in Endocrinology and Diabetes, Vol. 4, pp.341-346 (1997); and Klemperer et al., xe2x80x9cThyroid Hormone Therapy and Cardiovascular Diseasexe2x80x9d, Progress in Cardiovascular Diseases, Vol. 37 (4), pp. 329-336 (1996). This increases the weight of the heart relative to whole body weight. The cardiotoxicity assay herein below is used to test compounds for potentially adverse cardiac effects by measuring their effect on the heart-to-body weight ratio.
Two groups each of six male Sprague Dawley rats (Harlan Sprague Dawley, Inc., Indianapolis, Ind.) (each weighing from approximately 220 grams to 235 grams) are utilized. The first group is a vehicle control group and the second group is a test compound group. The length of the assay is 30 days, with treatment of vehicle or test compound in vehicle daily for 28 of those days as described below.
Prior to initiation of the assay, each rat is allowed to acclimate to standard environmental conditions for 5 days. Each rat receives food (standard rat chow diet) and water ad libitum 5 days prior to initiation of the assay as well as to termination of the study.
The vehicle is 91:9 (v:v) propylene glycol:ethanol. The test compound is prepared at a concentration of 500 xcexcg/mL in the vehicle.
Each rat is weighed on day 1 of the assay. Dosage calculations are then performed: each rat will be administered daily a dosing solution of vehicle or test compound in vehicle (depending on whether the rat is in the vehicle control group or the test compound group, respectively) at 500 xcexcL of dosing solution per kg of rat. For rats in the test compound group, this corresponds to a dose of 250 xcexcg of test compound per kg of rat.
Day 2 is the first day of treatment with dosing solution for both groups. Body weights are taken for each rat on days 3, 5, 8, 10, 12, 15, 17, 19, 22, 24, 26, and 29 prior to dosing for that day; for each rat, the dosing solutions are recalculated and administered accordingly upon change in body weight.
Treatment occurs once daily in the morning on days 2 through 29, inclusive, for each rat in each group. For each treatment, the dosing solution is administered subcutaneously between the shoulders of the rat such that the injection sites are rotated in this area.
On day 30 in the morning, the rats of each group are euthanized with CO2 from dry ice. Each rat is immediately weighed for total body weight.
The hearts of each rat are then excised as follows. An incision is made to expose the abdominal cavity. The rib cage is carefully cut at the sternum with small scissors, such that the heart and lungs are exposed. With small scissors and forceps, the vessels connected to the heart are cut away from the heart. These vessels include the caudal vena cava, left cranial vena cava (pulmonary trunk), right cranial vena cava, thoracic aorta, right subclavian artery, internal thoracic artery and vein, and any other small attachments. The heart is then immediately taken out intact, including the left and right auricles and left and right ventricles. Immediately thereafter, any excess tissue is trimmed away, the heart is lightly blotted on a paper towel until no more blood is visibly left behind on the paper towel, and the heart is weighed.
The heart weight is divided by the body weight after euthanization for each rat to give the heart/body ratio. The heart/body ratios for each rat in the vehicle control group are added together and divided by 6 (i.e., the total number of rats in the group) to give RV (ratio for vehicle control group). Similarly, the heart/body ratios for each rat in the test compound group are added together and divided by 6 to give RT (ratio for test compound group).
The index C is then calculated by dividing RT by RV. As defined herein, where C is less than 1.3, the test compound is cardiac-sparing. Preferably, C is less than 1.2, more preferably less than 1.15, and most preferably less than 1.1. In accordance with this method, T3 and T4 are not cardiac-sparing.
Telogen Conversion Assay:
The Telogen Conversion Assay measures the potential of a test compound to convert mice in the resting stage of the hair growth cycle (xe2x80x9ctelogenxe2x80x9d), to the growth stage of the hair growth cycle (xe2x80x9canagenxe2x80x9d).
Without intending to be limited by theory, there are three principal phases of the hair growth cycle: anagen, catagen, and telogen. It is believed that there is a longer telogen period in C3H mice (Harlan Sprague Dawley, Inc., Indianapolis, Ind.) from approximately 40 days of age until about 75 days of age, when hair growth is synchronized. It is believed that after 75 days of age, hair growth is no longer synchronized. Wherein about 40 day-old mice with dark fur (brown or black) are used in hair growth experiments, melanogenesis occurs along with hair (fur) growth wherein the topical application of hair growth inducers are evaluated. The Telogen Conversion Assay herein below is used to screen compounds for potential hair growth by measuring melanogenesis.
Three groups of 44 day-old C3H mice are utilized: a vehicle control group, a positive control group, and a test compound group, wherein the test compound group is administered a compound used in the method of the present invention. The length of the assay is at least 19 days with 15 treatment days (wherein the treatment days occur Mondays through Fridays). Day 1 is the first day of treatment. Most studies will end on Day 19, but a few may be carried out to Day 24 if the melanogenesis response looks positive, but occurs slowly. A typical study design is shown in Table 1 below. Typical dosage concentrations are set forth in Table 1, however the skilled artisan will readily understand that such concentrations may be modified.
The mice are treated topically Monday through Friday on their lower back (base of tail to the lower rib). A pipettor and tip are used to deliver 400 xcexcL to each mouse""s back. The 400 xcexcL application is applied slowly while moving hair on the mouse to allow the application to reach the skin.
While each treatment is being applied to the mouse topically, a visual grade of from 0 to 4 will be given to the skin color in the application area of each animal. As a mouse converts from telogen to anagen, its skin color will become more bluish-black. As indicated in Table 2, the grades 0 to 4 represent the following visual observations as the skin progresses from white to bluish-black. Following this method, cyclosporin A typically receives a grade of 4 by day 19.
The compounds used in the methods of the present invention are prepared according to procedures which are well-known to those ordinarily skilled in the art. The starting materials used in preparing the compounds are known, made by known methods, or are commercially available as a starting material.
It is recognized that the ordinarily skilled artisan in the art of organic chemistry can readily carry out standard manipulations of organic compounds without further direction. Examples of such manipulations are discussed in standard texts such as J. March, Advanced Organic Chemistry, John Wiley and Sons (1992).
The ordinarily skilled artisan will readily appreciate that certain reactions are best carried out when other functionalities are masked or protected in the compound, thus increasing the yield of the reaction and/or avoiding any undesirable side reactions. Often, the artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many such manipulations can be found in, for example, T. Greene, Protecting Groups in Organic Synthesis, John Wiley and Sons (1981).
The compounds of the present invention may have one or more chiral centers. As a result, one may selectively prepare one optical isomer, including diastereomers and enantiomers, over another, for example by chiral starting materials, catalysts or solvents, or may prepare both stereoisomers or both optical isomers, including diastereomers and enantiomers at once (a racemic mixture). Since the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, may be separated using known methods, such as through the use of, for example, chiral salts and chiral chromatography.
In addition, it is recognized that one optical isomer, including a diastereomer and enantiomer, or a stereoisomer, may have favorable properties over the other. Thus, when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.
The syntheses of the compounds useful in the present invention are described in the art. Accordingly, the ordinarily skilled artisan will be able to prepare the compounds described herein. For further guidance, the syntheses of the present compounds are described in Walker et al., U.S. Pat. No. 5,284,971, assigned to Syntex, Inc., issued Feb. 8, 1994.
The methods of the present invention are performed by administering to a mammal (preferably a human) a compound having a structure as described herein and, preferably, a pharmaceutically-acceptable or cosmetically-acceptable carrier.
The compounds herein may be used for the treatment of such conditions as treating hair loss in mammals, including arresting and/or reversing hair loss and promoting hair growth. Such conditions may manifest themselves in, for example, alopecia, including male pattern baldness and female pattern baldness.
Preferably the compounds of the present invention are, as defined herein, cardiac-sparing.
Preferably, in the methods of the present invention, the compounds are formulated into pharmaceutical or cosmetic compositions for use in treatment or prophylaxis of conditions such as the foregoing. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington""s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa. (1990).
Typically, from about 5 mg to about 3000 mg, more preferably from about 5 mg to about 1000 mg, more preferably from about 10 mg to about 100 mg, of a compound having a structure as described herein is administered per day for systemic administration. It is understood that these dosage ranges are by way of example only, and that daily administration can be adjusted depending on various factors. The specific dosage of the compound to be administered, as well as the duration of treatment, and whether the treatment is topical or systemic are interdependent. The dosage and treatment regimen will also depend upon such factors as the specific compound used, the treatment indication, the efficacy of the compound, the personal attributes of the subject (such as, for example, weight, age, sex, and medical condition of the subject), compliance with the treatment regimen, and the presence and severity of any side effects of the treatment.
According to the present invention, the subject compounds are co-administered with a pharmaceutically-acceptable or cosmetically-acceptable carrier (herein collectively described as xe2x80x9ccarrierxe2x80x9d). The term xe2x80x9ccarrierxe2x80x9d, as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to a mammal. The term xe2x80x9ccompatiblexe2x80x9d, as used herein, means that the components, of the composition are capable of being commingled with a compound of the present invention, and with each other, in a manner such that there is no interaction which would substantially reduce the efficacy of the composition under ordinary use situations. Carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the animal, preferably mammal (most preferably human), being treated. The carrier can itself be inert or it can possess pharmaceutical and/or cosmetic benefits of its own.
The compositions of this invention may be in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal, ocular or parenteral administration. Of these, topical and/or oral administration are especially preferred with topical being most preferred. Depending upon the particular route of administration desired, a variety of carriers well-known in the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances. Optional pharmaceutically-active or cosmetically-active materials may be included which do not substantially interfere with the activity of the compound of the present invention. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker and Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).
Some examples of substances which can serve as carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate;. vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate: coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.
The choice of a carrier to be used in conjunction with the subject compound is typically determined by the way the compound is to be administered.
In particular, carriers for systemic administration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the carrier, in compositions for parenteral administration, comprises at least about 90% by weight of the total composition.
Various oral dosage forms can be used, including Such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of a compound used in the present invention. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
The carriers suitable for the preparation of unit dosage forms for oral administration are well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FDandC dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules (including time release and sustained release formulations) typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be readily made by a person skilled in the art.
Orally administered compositions also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups, and the like. The carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.
Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.
Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
The compounds of the present invention may also be topically administered. The carrier of the topical composition preferably aids penetration of the present compounds into the skin to reach the environment of the hair follicle. Topical compositions of the present invention may be in any form including, for example, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like.
Topical compositions containing the active compound can be admnixed with a variety of carrier materials well known in the art, such as, for example, water, alcohols, aloe vera gel, allantoin, glycerine, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, and the like.
Other materials suitable for use in topical carriers include, for example, emollients, solvents, humectants, thickeners and powders. Examples of each of these types of materials, which can be used singly or as mixtures of one or more materials, are as follows:
Emollients, such as stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, iso-propyl isostearate, stearic acid, iso-butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl paimitate, dimethylpolysiloxane, di-n-butyl sebacate, iso-propyl myristate, iso-propyl palmitate, iso-propyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, and myristyl myristate; propellants, such as propane, butane, iso-butane, dimethyl ether, carbon dioxide, and nitrous oxide; solvents, such as ethyl alcohol, methylene chloride, iso-propanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene; glycol monoethyl ether, dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran; humectants, such as. glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, and gelatin; and powders, such as chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically modified magnesium aluminium silicate, organically modified montmorillonite clay, hydrated aluminium silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, and ethylene glycol monostearate.
The compounds used in the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines. A preferred formulation for topical delivery of the present compounds utilizes liposomes such as described in Dowton et al., xe2x80x9cInfluence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporin A: I. An in vitro Study Using Hairless Mouse Skinxe2x80x9d, S.T.P. Pharma Sciences, Vol. 3, pp. 404-407 (1993); Wallach and Philippot, xe2x80x9cNew Type of Lipid Vesicle: Novasomet(copyright)xe2x80x9d, Liposome Technology, Vol. 1, pp. 141-156 (1993); Wallach, U.S. Pat. No. 4,911,928, assigned to Micro-Pak, Inc., issued Mar. 27, 1990; and Weiner et al., U.S. Pat. No. 5,834,014, assigned to The University of Michigan and Micro-Pak, Inc., issued Nov. 10, 1998 (with respect to Weiner et al., with a compound as described herein administered in lieu of, or in addition to, minoxidil).
The compounds of the present invention may also be administered by iontophoresis. See, e.g., internet site www.unipr.it/arpa/dipfarm/erasmus/erasm14.html; Banga et al., xe2x80x9cHydrogel-based lontotherapeutic Delivery Devices for Transdermal Delivery of Peptide/Protein Drugsxe2x80x9d, Pharm. Res., Vol. 10 (5) pp. 697-702 (1993); Ferry, xe2x80x9cTheoretical Model of Iontophoresis Utilized in Transdermal Drug Deliveryxe2x80x9d, Pharmaceutical Acta Helvetiae, Vol 70, pp. 279-287 (1995); Gangarosa et al., xe2x80x9cModern Iontophoresis for Local Drug Deliveryxe2x80x9d, Int. J. Pharm, Vol. 123, pp. 159-171 (1995); Green et al., xe2x80x9cIontophoretic Delivery of a Series of Tripeptides Across the Skin in vitroxe2x80x9d, Pharm. Res., Vol 8, pp. 1121-1127 (1991); Jadoul et al., xe2x80x9cQuantification and Localization of Fentanyl and TRH Delivered by Iontophoresis in the Skinxe2x80x9d, Int. J Pharm., Vol. 120, pp. 221-8 (1995); O""Brien et al., xe2x80x9cAn Updated Review of its Antiviral Activity, Pharmacokinetic Properties and Therapeutic Efficacyxe2x80x9d, Drugs, Vol. 37, pp. 233-309 (1989); Parry et al., xe2x80x9cAcyclovir Biovailability in Human Skinxe2x80x9d, J. Invest. Dermatol., Vol. 98 (6), pp. 856-63 (1992); Santi et al., xe2x80x9cDrug Reservoir Composition and Transport of Salmon Calcitonin in Transdermal Iontophoresisxe2x80x9d, Pharm. Res., Vol 14 (1), pp. 63-66 (1997); Santi et al., xe2x80x9cReverse Iontophoresisxe2x80x94Parameters Determining Electroosmotic Flow: I. pH and Ionic Strengthxe2x80x9d, J. Control. Release, Vol. 3.8, pp. 159-165 (1996); Santi et al., xe2x80x9cReverse Iontophoresisxe2x80x94Parameters Determining Electroosmotic Flow: II. Electrode Chamber Formulationxe2x80x9d, J. Control. Release, Vol. 42, pp. 29-36 (1996); Rao et al. xe2x80x9cReverse Iontophoresis: Noninvasive Glucose Monitoring in vivo in Humansxe2x80x9d, Pharm. Res., Vol. 12 (12), pp. 1869-1873 (1995); Thysman et al., xe2x80x9cHuman Calcitonin Delivery in Rats by Iontophoresisxe2x80x9d, J. Pharm. Pharmacol., Vol. 46, pp. 725-730 (1994); and Volpato et al., xe2x80x9cIontophoresis Enhances the Transport of Acyclovir through Nude Mouse Skin by Electrorepulsion and Electroosmosisxe2x80x9d, Pharm. Res., Vol. 12 (11), pp. 1623-1627 (1995).
The compositions used in the present invention may also optionally comprise an activity enhancer. The activity enhancer can be chosen from a wide variety of molecules which can function in different ways to enhance hair growth effects of a compound of the present invention. Particular classes of activity enhancers include other hair growth stimulants and penetration enhancers.
Non-limiting examples of other hair growth stimulants which may be used in the compositions herein, including both systemic and topical compositions, include, for example, benzalkonium chloride, benzethonium chloride, phenol, estradiol, diphenhydramine hydrochloride, chlorpheniramine maleate; chlorophyllin derivatives, cholesterol, salicylic acid, cysteine, methionine, red pepper tincture, benzyl nicotinate, D,L-menthol, peppermint oil, calcium pantothenate, panthenol, castor oil, hinokitiol, prednisolone, resorcinol, monosaccharides and esterified monosaccharides, chemical activators of protein kinase C enzymes, glycosaminoglycan chain cellular uptake inhibitors, inhibitors of glycosidase activity, glycosaminoglycanase inhibitors, esters of pyroglutamic acid, hexosaccharic acids or acylated hexosaccharic acids, aryl-substituted ethylenes, N-acylated amino acids, and, of course, minoxidil or finasteride. The most preferred activity enhancers are minoxidil and finasteride, most preferably minoxidil.
Non-limiting examples of penetration enhancers which may be used in the compositions herein include, for example, 2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-diol, POE(2) ethyl ether, di(2-hydroxypropyl) ether, pentan-2,4-diol, acetone, POE(2) methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-1-ol, 1,4dioxane, tetrahydrofuran, butan-1,4-diol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropyl adipate; di-isopropyl sebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate, dibutyl suberate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethyl myristate, dimethyl azelate, butyl myristate, dibutyl succinate, didecyl phthalate, decyl oleate, ethyl caproate, ethyl salicylate, iso-propyl palmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, iso-propyl isostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl salicylate, 2-hydroxypropanoic acid, 2-hyroxyoctanoic, acid, dimethyl sulphoxide, N,N-dimethyl acetamide, N,N-dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine oxides, sugar esters, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide, and, 1 -dodecylazacyloheptan-2-one.
In all of the foregoing, of course, the compounds used in the present methods can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication.
The present invention further relates to kits comprising a compound and/or composition herein and information and/or instructions by words, pictures, and/or the like, that use of the kit will provide treatment for hair loss in mammals (particularly humans) including, for example, arresting and/or reversing hair loss and or promoting hair growth. In addition or in the alternative, the kit may comprise a compound and/or composition herein and information and/or instructions regarding methods of application of the compound and/or composition, preferably with the benefit of treating hair loss in mammals.

Method of treating hair loss using sulfonyl thyromimetic compounds

Abstract: and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof are provided. R1 is xe2x80x94(CH2)n(CHNR7R8)mC(O)R9, wherein n is an integer from 1 to 3, and m is an integer from 0 to 1. R3 and R5each, independently, is chlorine, bromine, iodine and xe2x80x94CH3. R7 and R8 each, independently, is hydrogen or C1 to C4 alkyl. R9 is hydroxy, C1 to C4 alkoxy and xe2x80x94NR7R8. R31 is a hydrogen, chlorine, bromine, iodine, C1 to C4 alkyl, C4 to C6 cycloalklyl, C1 to C4 haloalkyl, C4 to C6 halocycloalkyl, or CH(R10)Ar. Ar is 5-hydroxypyrid-2-yl, 6-hydroxypyrid-3-yl, 6-hydroxypyridazin-3-yl, 6-methioxypyridazin-3-yl N-oxide or 6-hydroxypyridazin-3-yl N-oxide. R10 is hydrogen or C1 to C4 alkyl. R41 is hydroxy or C1 to C4 alkoxy.

The University of Texas Southwestern Medical Center