United States Patent [19J
`Gibson
`
`[11] Patent Number:
`[45] Date of Patent:
`
`5,015,470
`May 14, 1991
`
`[54] COSMETIC COMPOSITION
`
`[76]
`
`Inventor: Walter T. Gibson, 8 Braid Court,
`Wellingborough, Northants NN8
`3PF, England
`
`[21]
`
`Appl. No.: 134,422
`
`[22]
`
`Filed:
`
`Dec. 17, 1987
`
`Foreign Application Priority Data
`[30]
`Dec. 23, 1986 [GB] United Kingdom ................. 8630721
`
`Int. CJ.s ................................................ A61K 7/06
`[51]
`[52] U.S. Cl. .......................................... 424/70; 514/2;
`424/603; 424/660; 424/673; 424/663; 424/709;
`424/711; 435/200
`[58] Field of Search ................. 424/70, 603, 660, 673,
`424/663,709, 711; 514/880, 881; 435/200
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4.139,619 2/1979 Chidsey, III .......................... 424/45
`4,508,707 4/1985 Ayukawa .............................. 424/70
`4,529,587 7/1985 Green .................................... 424/70
`4,761,401 8/1988 Couchman eta!. ................. 514/880
`
`FOREIGN PATENT DOCUMENTS
`
`035919 9/1981 European Pat. Off ..
`129197 12/1984 European Pat. Off. .
`2438534 2/1976 Fed. Rep. of Germany .
`2619100 11/1977 Fed. Rep. of Germany.
`59-186991 10/1984 Japan .
`59-212424 12/1984 Japan .
`61-7209 1/1986 Japan .
`8504577 10/1985 PCT Int'l Appl. .
`
`OTHER PUBLICATIONS
`Effect of Acid Mucopolysaccharides on Hair Growth
`in the Rabbit (Meyer, Kaplan & Steigleder), Proceed-
`
`ings of the Society of Experimental & Biological Sci(cid:173)
`ences, vol. 108, pp. 59-61.
`Advances in Enzymology, Edited by Alton Meister,
`Inerscience Publisher, Div. of John Wiley & Sons (vol.
`36-1972).
`Primary Examiner-Ronald W. Griffin
`Attorney, Agent, or Firm-Melvin H. Kurtz
`
`[57]
`ABSTRACT
`A composition suitable for topical application to mam(cid:173)
`malian skin or hair for inducing, maintaining or increas(cid:173)
`ing hair growth comprises:
`(i) a first chemical inhibitor chosen from proteoglyca(cid:173)
`nase
`inhibitors, glycosaminoglycanase
`inhibitors,
`glycosaminoglycan chain cellular uptake inhibitors
`or mixtures thereof; and
`(ii) a cosmetically acceptable vehicle for the chemical
`inhibitor;
`provided that when the first chemical inhibitor is a
`weak inhibitor, such that a 1 mM aqueous solution of
`the
`inhibitor
`reduces
`proteoglycanase
`act1v1ty,
`glycosaminoglycanase activity or cellular uptake of
`glycosaminoglycan chains, by from 5 to 50%, in accor(cid:173)
`dance with at least one of the assay tests as herein de(cid:173)
`scribed, then there is also present in the composition a
`second chemical inhibitor and/or an activity enhancer.
`When minoxidil is the sole chemical inhibitor, then the
`activity enhancer is a penetration enhancer chosen from
`a limited number of materials, including certain esters
`and cationic polymers.
`The total amount of chemical inhibitor present in the
`composition is sufficient to increase hair growth in the
`rat, when said composition is applied topically thereto,
`by at least 10% more than that obtainable using a con(cid:173)
`trol composition from which the said inhibitors have
`been omitted.
`
`31 Claims, No Drawings
`
`1
`
`

`
`1
`
`COSMETIC COMPOSITION
`
`5,015,470
`
`2
`various types of alopecias. The composition in question
`comprises a pyrimidine carbamate.
`It has also been reported in US patent no. 4 139 619 to
`Chidsey assigned to the Upjohn Company, that a topi-
`5 cal composition comprising minoxidil as the free base or
`acid addition salt thereof, or certain specified related
`iminopyrimidines, is useful in stimulating the conver(cid:173)
`sion of vellus hair to growth as terminal hajr, as well as
`increasing the rate of growth of terminal hair.
`In spite of the apparent stimulation of hair growth or
`regrowth reported independently by Bazzano and
`Chidsey, following topical application of minoxidil or
`related compounds, there is general concern that sys(cid:173)
`temic side-effects can result, particularly following topi(cid:173)
`cal application of minoxidil. Thus it is generally recog(cid:173)
`nised in the medical literature that the side effects of
`orally administered minoxidil are very serious, and in(cid:173)
`clude fluid retention, tachycardia, dyspnea, gynecomas(cid:173)
`tia, fatigue, nausea and cardiotoxicity. There is also
`evidence that certain side effects have been experienced
`following topical application of minoxidil.
`In addition to the alleged benefits of employing the
`pyrimidine carbamates of Bazzano or minoxidil of Up(cid:173)
`john, many other hair regrowth studies have been re(cid:173)
`ported in the literature. In particular, the work of
`Meyer eta! (1961) in the Proceedings of the Society of
`Experimental and Biological Medicine, 108, 59-61, is
`worthy of mention. Meyer and his co-workers repeat(cid:173)
`edly injected acid mucopolysaccharides into the skin of
`shaved rabbits and reported observing the initiation of
`the hair growth cycle with stimulation of hair growth
`which in some instances appeared to be thicker than
`usual. They found that heparan sulphate was particu(cid:173)
`larly active, while dermatan sulphate and chondroitin-
`6-sulphate were also active in this respect, but to a lesser
`extent.
`It has also been reported by Frajdenrajch in EP-A-0
`035 919 to include chondroitin sulphate in a hair compo(cid:173)
`sition in order to prevent loss and encourage growth of
`40 the hair.
`Also, Shansho Seigaku in JA-59/186911 describes a
`shampoo containing a mucopolysaccharide such as
`chondroitin sulphate.
`There are also other references, mainly of Japanese
`origin, which claim the use of chondroitin sulphate in
`preparations for topical application to h~man skin, par(cid:173)
`ticularly as hair tonics.
`Kohler in DE OLS 24 38 534 reports that D-glucu(cid:173)
`ronic acid and glucuronic acid y-lactone (also known as
`glucurono-6,3-lactone) can be applied externally to the
`skin, together with vitamin C and water, ethanol or
`aqueous ethanol as a vehicle, as a scalp care agent. In a
`particular experiment, Kohler reports regrowth of hair
`following daily application for six months of a I% solu(cid:173)
`tion of D-glucuronic acid.
`Kohler eta! in DE OLS 26 19 100 also claims the use
`of glucuronic acid or glucuronic acid y-lactone as inhib(cid:173)
`itors in agents for inhibiting the activity of ')'-glucuroni(cid:173)
`dase, particularly in combination with vitamin B12·
`Whereas Kohler et a! are concerned with y-blucuroni(cid:173)
`dase as found in unusually high concentrations in heal-
`ing wounds and cancer tissues, they do state that the
`agents also have a beneficial effect on the loss of hair.
`In experiments to be described later in this specifica(cid:173)
`tion, we have found that both glucuronic acid and
`glucurono-6,3-lactone are weak
`inhibitors of
`')'(cid:173)
`glucuronidase activity and require the presence of a
`sec<;:md inhibitor and/or a special activity enhancer, as
`
`FIELD OF THE INVENTION
`The invention relates to cosmetic and pharmaceutical
`compositions for topical application to mammalian skin
`or hair, containing an enzyme inhibitor which is capable
`of promoting hair growth, especially terminal hair
`growth on the human scalp.
`
`10
`
`BACKGROUND
`The Hair Growth Cycle
`It should be explained that in most mammals, hair
`does not grow continuously, but undergoes a cycle of 15
`activity involving alternate periods of growth and rest.
`The hair growth cycle can be divided into three main
`stages, namely:
`(i) the growth phase known as anagen, during which
`the hair follicle penetrates deep into the dermis with the 20
`cells of the bulb dividing rapidly and differentiating to
`form the hair,
`(ii) the transitional stage known as catagen, which is
`heralded by the cessation of mitosis, and during which
`the follicle regresses upwards through the dermis and 25
`hair growth ceases,
`(iii) the resting stage known as telogen, in which the
`regressed follicle contains a small secondary germ with
`an underlying ball of tightly packed dermal papilla cells. 30
`The initiation of a new anagen phase is revealed by
`rapid proliferation in the germ, expansion of the dermal
`papilla and elaboration of basement membrane compo(cid:173)
`nents. The hair cycle is then repeated many times until,
`as a consequence of the onset of male pattern baldness, 35
`most of the hair follicles spend an increasing proportion
`of their time in the telogen stage, and the hairs produced
`become finer, shorter, and less visible; this is known as
`terminal to vellus transformation.
`
`50
`
`PRIOR ART
`Alleged Baldness Cures
`Although there have been many claims in the scien(cid:173)
`tific literature to the promotion or maintenance of hair
`growth by the topical application of hair tonics and the 45
`like, with the possible exception of minoxidil, none has
`been shown to be sufficiently free from disadvantageous
`clinical side effects, whether administered topically,
`orally or systemically, to warrant commercial exploita-
`tion as an ethical pharmaceutical, proprietary medicine,
`or as a cosmetic product. Possibly, the only means
`which has met with partial success for growing hair on
`the bald or balding human head is by transplantation of
`hair to the bald areas. This is, however, an extremely 55
`painful operation and is not always successful. Further(cid:173)
`more, it is immediately apparent to the casual observer
`that the subject has received a hair transplant and it may
`take many months or even years before hair regrowth,
`following this operation, assumes an appearance which 60
`resembles that of the original naturally growing hair.
`Among the many hair regrowth studies that have
`been reported in the literature, there is included the
`work of Bazzano as described in PCT International
`Publication No. WO 85/04577. This publication de- 65
`scribes a composition which is useful for increasing the
`rates of hair growth on mammalian skin, prolonging the
`anagen phase of the hair growth cycle and for treating
`
`2
`
`

`
`5,015,470
`
`"Both /3-glucuronidase and a-glucuronidase are fee(cid:173)
`bly inhibited by glucuronic acid ... "
`
`3
`hereinafter defined, to provide significant hair growth
`or regrowth. The weak inhibition by glucuronic acid in
`this respect has also been confirmed by Levvy and
`Snaith (1972) in "Advances in Enzymology" 36 where,
`at page 156 they state that:
`
`4
`We have now identified chemical inhibitors of key
`enzymes and other cellular events involved respectively
`in the breakdown of proteoglycan or glycosaminogly(cid:173)
`can chains, and in the blocking of cellular uptake of
`5 intact glycosaminoglycan chains.
`It should be explained by "chemical inhibitor" is
`meant a substance that is physiologically suitable and
`safe for topical application to human skin, and which is
`capable of inhibiting proteolytic breakdown of the pro-
`10 teoglycans or inhibiting glycosidase or sulphatase en-
`· zymes involved in the breakdown or modification of
`BACKGROUND OF THE INVENTION
`glycosaminoglycan side chains by direct, enzyme inhi-
`The above review of the most relevant references
`bition or by protecting the substrate so that the enzyme
`concerning the alleged promotion of hair growth fol-
`does not recognise it, or inhibiting cellular events in-
`lowing topical or systemic application of specified mol-
`ecules, has prompted the study in greater detail, of the 15 valved in the recognition and uptake of glycosaminog-
`lycans.
`biological and biochemical mechanisms involved in the
`control of the hair growth cycle. The reported role of
`We have accordingly found that these inhibitors will
`. indeed stimulat~ hair growth as predicted on the basis of
`the dermal papilla which is situated at the base of the
`hair follicle, and the closely related cells of the connec-
`the theory outlined above.
`tive tissue sheath which surrounds the hair follicle are 20
`DEFINITION OF THE INVENTION
`alleged to be of key importance in governing the cyclic
`Accordingly, the invention provides a composition
`behaviour of. hair follicles. This has been shown, for
`·suitable for topical application to mammalian skin or
`example, directly by Oliver R F (1970) J Embryo! Exp
`hair for inducing, maintaining or increasing hair growth
`Morpho!., 23, 219-236, and the changes in the dermal 1
`which comprises:
`papilla during the hair cycle are consistent with these - 5
`(i) a first chemical inhibitor chosen from proteoglyca(cid:173)
`observations. At the end of anagen, there is a sudden
`nase
`inhibitors, glycosaminoglycanase
`inhibitors,
`loss of fibronectin [Couchman J R and Gibson W T,
`glycosamincglycan chain cellular uptake inhibitors or
`(1985) Dev Bioi , 108, 290-298]and metachromatic
`mixtures thereof; and
`(glycosaminoglycan) staining [Montagna Wet al, ( 1952) 30
`(ii) a cosmetically acceptable vehicle for the chemical
`Q J Microsc Sci., 93, 241-245]from the connective tis(cid:173)
`inhibitor;
`sue matrix of the dermal papilla which then undergoes
`provided that when the first chemical inhibitor is a
`condensation.
`weak inhibitor, such that a lmM !J.queous solution of the
`Conversely, expansion and elaboration of new matrix
`inhibitor
`reduces
`proteoglycanase
`activity,
`is associated with the onset of anagen. A direct role of 35 glycosaminoglycanase activity or cellular uptake of
`matrix components in stimulating hair growth was sug-
`glycosaminoglycan chains. by from 5 to 50%, in accor-
`gested by the work of Meyer et al (1961), [supra].
`dance with at least one of the assay tests as herein de-
`It is accordingly apparent that glycosaminoglycan
`scribed, then there is also present in the composition a
`breakdown is an important early change in catagen, and
`second chemical inhibitor and/or an activity enhancer;
`since there is already evidence for a link between the 40 provided also that when minoxidil is the sole chemical
`presence of intact glycosaminoglycans and hair growth,
`inhibitor then the activity enhancer is a penetration
`we have suggested that prevention of proteoglycan and
`enhancer chosen .from:
`glycosaminoglycan breakdown may lead to earlier
`Dioctyl adipate
`onset and/or prolongation of anagen. This would effec-
`Dicapryl adipate
`45 Diisopropyl adipate
`tively retard hair loss and reverse baldness.
`When considering the breakdown of glycosaminog-
`Diisopropyl sebacate
`lycans, it must be remembered that these are complex
`Dibutyl sebacate
`polysaccharides built up from alternating hexosamine
`Diethyl sebacate
`and uronic acid units. Modification of these units by
`Dimethyl sebacate
`N-and/or and/or 0-sulphation, and by N-acetylation so Dioctyl sebacate
`provides further scope for diversity, which necessitates
`Dibutyl suberate
`the concerted, sequential action of a range of enzymes
`Dioctyl azelate
`for complete degradation
`to occur. Furthermore,
`Debenzyl sebacate
`glycosaminoglycans normally exist in the form of a
`Dibutyl phthalate
`proteoglycan, in which glycosaminoglycan chains are 55 Dibutyl azelate
`attached to a protein core. Degradation can therefore
`Ethyl myristate
`occur by the action of proteolytic enzymes ("proteo-
`Dimethyl azelate·
`glycanases") on the protein core, causing release of
`Butyl myristate
`intact glycosaminoglycan chains which are taken up by
`Dibutyl succinate
`cells or removed in the circulation, or by the action of 60 Didecyl phthalate
`endoglycosidases, exoglycosidases and
`sulphatases
`Decyl oleate
`("glycosaminoglycanases")
`which
`cleave
`the
`Ethyl caproate
`glycosaminoglycan molecule at specific sites. It follows
`Ethyl salicylate
`that glycosaminoglycan breakdown may be prevented
`Isopropyl palmitate
`in a number of ways, viz by inhibiting proteoglycanase 65 Ethyl laurate
`activity, by blocking cellular uptake of
`intact
`2-ethyl-hexyl pelargonate
`glycosaminoglycan
`chains, and/or by
`inhibiting
`Isopropyl isostearate
`glycosaminoglycanase activity.
`Butyl laurate
`
`3
`
`

`
`5
`
`Benzyl benzoate
`Butyl benzoate
`Hexyl laurate
`L- Ethyl caprate
`Ethyl caprylate
`Butyl stearate
`Benzyl salicylate
`2-hydroxypropanoic acid
`2-hyroxyoctanoic acid,
`esters of pyroglutamic acid having the structure:
`
`~ 0
`
`N
`I
`H
`
`C-O-R
`II
`0
`
`(I)
`
`where R is C1 to C3o alkyl, or
`
`R'
`I
`-CHCOOR"
`
`and where R' and R" are the same or different and are
`each represented by H or the grouping:
`
`(CHJ)u. (CH20H),, (CH2) •. , (CH3CH2lx.
`(CH=CH)zJ-
`
`(2)
`
`5,015,470
`
`6
`that is. it is a strong inhibitor which is normally capable
`at a concentration of lmM of reducing said activity or
`cellular uptake by more than 50%. For less effective
`inhibitors, ie., weak inhibitors, which are only capable,
`at this concentration, of reducing said activity or cellu(cid:173)
`lar uptake by from 5 to 50%, then it is necessary to
`include in the composition according to the invention a
`second chemical inhibitor and/or an activity enhancer.
`In view of the complexity of the proteoglycan and
`10 glycosaminoglycan chain which can be degraded in
`different ways with a variety of enzymes, it is necessary
`to screen a potential chemical inhibitor in at least one of
`several different assay systems. Suitable assays which
`can be employed for endoglycosidases, exoglycosi-
`1 5 dases, sulphatases, sulphamatases are described
`in
`"Lysosomes-A Laboratory Handbook", Second Edi(cid:173)
`tion (1977) edited by J. T. Dingle. Proteoglycanase
`inhibitors may be conveniently assayed by the method
`described by Nagase & Woessner (1980) in Analyst.
`20 Biochem. 107, 385. Cellular uptake inhibition may be
`assessed by using radioactively labelled glycosaminog(cid:173)
`lycans according to the method described by Eskild W,
`et al., (1986) in Int. J. Biochem. 18, 647.
`Suitable assay methods for each of the relevant en-
`zymes and their inhibition by chemical inhibitors will be
`described and illustrated later in this specification.
`
`25
`
`where
`u is zero or 1
`v is zero, or the integer 1 or 2,
`w is zero, or an integer of from I to 21
`x is zero, or an integer of from I to 4,
`y is zero, or the integer 1 or 2,
`z is zero, or an integer of from 1 to 22, and
`u+v+w+x+y+z is an integer of from 1 to 22;
`provided that when the subgrouping (CH=CH) is
`present, then the total number of carbon atoms in said
`grouping is from 10 to 22; and/or
`a cationic polymer chosen·from:
`Guar Hydroxypropyltrimonium chloride
`Quaternium-19
`Quaternium-23
`Quaternium-40
`Quaternium-57
`Poly(dipropyldiallylammonium chloride)
`Poly(methyl-,8-propaniodiallylammonium chloride)
`Poly(diallylpiperidinium chloride)
`Poly(vinyl pyrinium chloride)
`Quaternised poly (vinyl alcohol) and
`Quaternised poly-(dimethylaminoethylmethacrylate);.
`the total amount of chemical inhibitor present in the
`composition being sufficient to increase hair growth in
`the rat, when said composition is applied topically
`thereto, by at least 10% more than that obtainable using 55
`a control composition from which the said inhibitors
`have been omitted.
`·
`
`40
`
`DISCLOSURE OF THE INVENTION
`The Chemical Inhibitor
`As has already been stated, a "chemical inhibitor" is
`a substance which is not only physiologically suitable
`and safe for topical application to skin, but which is
`capable of inhibiting in some way proteoglycanase ac(cid:173)
`tivity, and/or glycosaminoglycanase activity and/or 65
`cellular uptake of glycosaminoglycan chains.
`It is preferred that the chemical inhibitor is one which
`is significantly effective in at least one of these respects,
`
`The Proteoglycanase Inhibitors
`30 According to one 'embodiment of the invention. the
`composition comprises a direct proteoglycanase inhibi(cid:173)
`tor, that is a substance which will suppress the activity
`of proteinase· enzymes present in or in the region of the
`dermal papilla, and/or the connective tissue sheath of
`35 the hair follicle.
`An example of a direct proteoglycanase inhibitor of
`this type is I, 10-phenanthroline, also identified by Gal(cid:173)
`loway et al, (1983) in Biochem. J. 209, 741-742, as a
`bone proteoglycanas inhibitor.
`·
`Further examples of direct proteoglycanase inhibi-
`tors include various thiol, carboxyalkyl and hydrcxamic
`peptide inhibitors, such as those described by Caputo et
`al., (1987) in Biochemical Pharmacology 36,995-1002 as
`effective inhibitors of the action of a metalloproteinase
`45 on proteoglycan core protein. These inhibitors include:
`Thiols, such as
`AcetyiPhe-LeuSH
`AcetyiSer-LeuSH
`AcetyiTrp-LeuSH
`50 Acety!Phe-Phe-LeuSH
`HSCH2CH(i-Butyi)COPheNH2
`HSCH2CH(i-Butyl)COLeu-PheNH2
`AcetylTrp-IleSH
`AcetylPhe-IleSH
`Carboxylic acids, such as
`HOOCCH(i-Butyl)Leu-Leu-LeuOCH3
`HOOCCH(i-Butyl)Leu-Leu-AlaNH2
`HOOCCH(i-Butyl)Leu-Leu-PheNH2
`HOOCCH(i-Butyl)Leu-Leu-Leu-AlaNH2
`60 Hydroxamic acids, such as
`HONHCOCH2CH(n-Pentyl)COLeu-PheNH2
`HONHCOCH2CH(n-Pentyl)COLeu-AlaNH
`HONHCOCH2CH(i-Butyl)COLeu-PheNH2
`HONHCOCH CH(n-Pentyl)COVal-AlaNH2
`According to a further embodiment of the invention,
`the composition can comprise an indirect proteoglyca(cid:173)
`nase inhibitor, that is a substance which modifies the
`
`4
`
`

`
`5,015,470
`
`8
`
`7
`proteoglycan substrate so that the proteoglycanase does
`not recognise it. An example of an indirect proteoglyca(cid:173)
`nase inhibitor of this type is the class of compounds
`defined as cationic oligomers.
`According to this embodiment of the·invention, there
`is provided a composition which comprises one or more
`oligomeric molecules containing one or more cationic
`groups which will bind to negatively charged anionic
`proteoglycan molecules and protect them from enzymic 10
`attack. Preferred cationic oligomers may be chosen
`from those which are rich in arginine and/or lysine,
`containing up to 20, preferably 5 to 10 amino acids in
`sequences similar to or the same as those found in natu- 15
`rally occurring basic proteins such as prolamines and
`his tones.
`Specific examples of cationic oligomers are:
`Arg-Arg-Arg,
`Cys-Arg-Arg-Arg-Lys-Arg-Arg,
`Pro-Arg-Arg-Arg-Arg, and
`Arg-Pro-Val-Arg-Arg-Arg-Arg-Arg-Pro-Val.
`
`20
`
`where
`AI and A6 are -H,
`
`OR
`OR'
`I
`I
`-CH 3. -c=o or -:C=O
`
`B is OR" or a lactone linkage to position I or 6, or
`-NHCOCH3
`and where R is -H or Cz to Cs alkyl,
`R' is the remainder of the molecule joined through
`another C atom at positions 2 to 5 to form a lac(cid:173)
`tone,
`R" is-H or Cz (ie acetyl) to C4 acyl of either config(cid:173)
`uration with respect to the backbone of this mole(cid:173)
`cule.
`Preferred examples of aldonolactones which inhibit
`the exoglycosidases. as specified, are as follows:
`
`The Glycosaminoglycanase Inhibitors
`
`25
`
`According to a further embodiment of the invention,
`the composition comprises a glycosaminoglycanase
`inhibitor chosen from endoglycosidase inhibitors, exo(cid:173)
`glycosidase inhibitors, sulphatase inhibitors, sulphama- 30
`tase inhibitors and mixtures thereof.
`Examples of these enzyme inhibitors, together with
`the relevant enzymes whose activity they inhibit, can be
`classified as follows:
`
`L-Galactono-1.4-lactone
`
`L-Arubino-1.5-lactone
`35 D-Fucono-1.5-lactone
`D-Glucaro-1.4-lactone
`
`Enzyme(s) Inhibited
`
`D-Glucurono-6.3-lactone
`Galactaric acid lactone
`
`Enzyme(s) tnhthl!cd
`
`{3-I.!.J.Iactosida'lc
`{3- :\-acetyl he\O~i.l.m inuJa..,e
`,6-galactostdase
`,8-':!alacto~ida~e
`,6-glucuronidase
`a-L-iduronidase
`,6-elucuronidase
`J3-glucuronida~e
`a-L-iduronidase
`,6-:\-acetylhexosaminidase
`,6-~-acets·Jhe\osaminidase
`,6-glucuronidase
`a-L-iduronidase
`a-L-iduronidase
`
`Chemical Cbss
`
`(a) Anions
`(as soluble metal or
`ammonium salts)
`
`sulphate
`
`sulphite
`
`pyrophosphate
`
`nuoride
`
`borate
`
`idurono-sulphate
`sulphatase
`sulphatases A and B:
`heparin sulphamatase
`"i-acetylglucosamine-6-
`wlphate sulphatase
`
`sulphatase A;
`
`heparin sulphamatase
`
`sulphatase A;
`c hond roi t i n-6-s u I p ha tase;
`heparin sulphamatase
`
`sulphatase A;
`
`heparin sulphamatase
`
`- heparin sulphamatase
`
`sulphatase B;
`
`(
`
`(
`
`(
`
`(
`
`40 2-Acetamido-2-deoxygluconolactone
`2-Acetamido-2-deoxygalactonolactone
`D-Glucaro-1.4:6.3-dilactone
`
`L-Idaro-1.4-lactone
`
`45
`
`50
`
`Preferred examples of esterified forms of aldonolac(cid:173)
`tones which give a more sustained inhibitory effect are:
`
`2.3.5-Tri-0-acetyl-D-gl ucaro-1.
`4-lactone
`2.5-Di-0-acetyl-D-glucaro- I .4:
`6.3-dilactone
`
`;'3-gl ucuronidase
`a-L-iduronidase
`,6-glucuronidase
`a-L-iduronidase
`
`55
`
`(c) Monosaccharides and esterified monosaccharides
`having the structure:
`
`chloride
`
`(
`
`chondroitin-6-sulphatase
`--~g-Ju_c_on_a_te _________________ ._s_u~Jp~h-a_ta_se __ B ____________ 60
`
`Of the above anion inhibitors of sulphatase A or B,
`particularly preferred examples are sulphate and gluco(cid:173)
`nate, especially in the form of magnesium sulphate and 65
`zinc gluconate respectively.
`(b) Aldonolactones and esterified aldonolactones
`having the structure:
`
`ctHo
`I,
`H-C--A
`I.
`H-C-'-OR
`I
`H-c•-oR
`1.
`H-C'-OR
`I
`CH2R'
`
`where
`
`5
`
`

`
`5,015,470
`
`10
`An example of this class of inhibitors is given by
`hexuronic acid and esters thereof which may be repre(cid:173)
`sented by the generic structure:
`
`9
`A is -OR or -NHCOCH3
`R is -H, -S03M, C2 (ie acetyl) to C4 acyl
`R' is -H or -OR
`M is -H or a metal cation.
`Functional groups can be in either configuration with 5
`respect to the backbone of the above molecule.'
`Preferred examples of monosaccharides and esters
`thereof which inhibit exoglycosidases or a sulphatase, as
`specified, are as follows:
`
`10
`
`Monosaccharide/esters
`
`N-Acetylglucosamine
`
`N-Acetylgalactosamine
`
`Enzymes(s) inhibited
`a-N-acetylglucosaminidase
`13-galactosidase
`13-N-acetylhexosaminidase
`13-galactosidase
`13-N-acetylhexosaminidase
`13-N-acetylhexosaminidase
`D-Galactosamine
`Sulphatase 'B'
`D-Giucosamine-3-sulphate
`a-N-acetylglucosaminidase
`N-Acetylmannosamine
`_____ :...._ __________ ..;....;;.._______
`
`(
`
`(
`
`(d) Piperidines having the structure:
`
`A ADA
`
`A
`
`A
`
`N
`I
`R
`
`where
`LA is -H, -OR' or
`
`0
`II
`-C-OR'
`
`15 where R is-H, -S0 3M, C2 (ie acetyl) to C4 acyl; R' is
`-H or C2 to Cg alkyl.
`Functional groups can be in either configuration with
`respect to the backbone of the above molecule.
`Preferred inhibitors belonging to this class are glucu-
`20 ronic acid, iduronic acid alld esters thereof.
`The total amount of chemical inhibitor present in the
`
`25
`
`composition according to the invention is sufficient to
`increase hair growth in the rat, the model selected for
`this test, when said composition is applied topically
`thereto, by at least 10% more than that obtainable using
`a control composition from which the said inhibitors
`have been omitted.
`Preferably, the amount of chemical inhibitor should
`be sufficient to increase hair growth in the rat by at least
`30 20%, more preferably by at least 30o/c, most preferably
`by at J~ast 40% and ideally by at least 50%.
`The sufficient amount will depend on the effective(cid:173)
`ness of a chemical inhibitor, some being more effective
`than others, but in general. an amount of from 0.0001 to
`35 99%, preferably from 0.1 to 20'7c by weight of the com(cid:173)
`position will provide an adequate dose to the skin after
`topical application.
`
`45
`
`40
`
`R is-H, C2 to Cs alkyl or diamino-pyrimidine N-oxide
`Compositions containing minoxidil
`R' is -H or C2 (ie acetyl) to C4 acyl;
`Minoxidil is a weak inhibitor of ,8-glucuronidase ac(cid:173)
`substituent groups A can be identical or can be repre(cid:173)
`tivity and accordingly, \vhen minoxidil is present in the
`sented by 2 or 3 of the groups defined above on the
`composition, then there is also present a second chemi(cid:173)
`same ring structures. They can also be in either configu(cid:173)
`cal inhibitor and/or an activity enhancer.
`ration with respect to the plane of the ring.
`Particularly preferred mixtures of minoxidil and a
`Preferred examples of piperidines which inhibit exo(cid:173)
`second chemical inhibitor include the following:
`glycosidases, as specified, are as follows:
`Minoxidil and Zinc gluconate
`Minoxidil which inhibits the enzyme ,8-glucuronidase
`Minoxidil and Magnesium sulphate
`and
`Minoxidil and D-glucaro-1,4-lactone
`2(S)-Carboxy-3(R),4(R),5(S)-trihydroxypiperidine
`50 Minoxidil and I, I 0-phenanthroline
`which Inhibit the enzymes ,8-glucuronidase and
`Minoxidil and D-glucosamine-3-sulphate
`a-L-iduronidase.
`Minoxidil and L-idaro-1 ,4-Jactone
`(e) examples of substances which inhibit the activity
`Minoxidil and L-galactono-1 ,4-Jactone
`of the endoglycosidase hyaluronate endoglycosidamini(cid:173)
`Minoxidil and 2-acetarpido-2-deoxygluconolactone
`dase are:
`55 Minoxidil and D-glucaro-1,4:6,3-dilactone
`Phosphorylated hesperidin
`Minoxidil and 2,3,5-tri-0-acetyl-D-glucaro-1 ,4-lactone
`sodium aurothiomalate
`Minoxidil and N~acetylglucosamine
`substituted thiosemicarbazone indoles, and
`Minoxidil and N-acetylmannosamine
`mixtures thereof.
`Minoxidi1 and phosphorylated hesperidin
`The glycosaminoglycan chain cellular uptake inhibitors 60 Minoxidil and glucuronic acid
`When minoxidil is the sole chemical inhibitor present
`According to a further embodiment of the invention,
`in the composition according to the invention, then a
`the composition comprises an inhibitor of cellular up(cid:173)
`special condition on its use in accordance with the in(cid:173)
`take of glycosaminoglycan chains which prevents rec(cid:173)
`vention prevails in that the activity enhancer which
`ognition and binding events at the cell surface·by com(cid:173)
`65 must accompany minoxidil, preferably in an amount
`peting with glycosaminoglyca~ chains, or by modifica(cid:173)
`sufficient to enhance significantly the hair growth activ(cid:173)
`tion of the chains so that they are no longer recognised
`ity of minoxidil, in the composition, is chosen from a
`by the cell.
`·
`limited selection of materials, referred to in detail later
`
`6
`
`

`
`11
`in this specification, namely certain penetration enhanc(cid:173)
`ers and certain cationic polymers.
`
`5,015,470
`
`12
`The amount of vehicle in the composition, including
`water if present, should preferably be sufficient to carry
`at least a portion of a selected chemical inhibitor to the
`skin in an amount which is sufficient effectively to en(cid:173)
`hance hair growth. The amount of the vehicle can com(cid:173)
`prise the balance of the composition, particularly where
`little or no other ingredients are present in the composi(cid:173)
`tion. Accordingly, ·the vehicle or vehicles can comprise
`from 1 to 99.99%, preferably from 50 to 99.5% and
`ideally from 90 to 99% by weight of the composition.
`
`The composition according to the invention can also
`optionally comprise an activity enhancer, especially
`when the chemical inhibitor is a weak inhibitor.
`The activity enhancer can be chosen from a \Vide
`variety of molecules which can function in different
`ways to enhance the hair growth effects of the chemical
`inhibitor. Particular classes of activity enhancers in(cid:173)
`dude other hair growth stimulants, penetration enhanc(cid:173)
`ers and cationic polymers, whose presence can further
`improve the delivery of the chemical inhibitor through
`the stratum corneum to its site of action in the immedi(cid:173)
`ate environment of the hair follicle.
`Some activity enhancers can also function as vehicles
`for the chemical inhibitor.
`
`The Vehicle
`The composition according to the invention also 5
`comprises a solid, semi-solid or liquid cosmetically and(cid:173)
`/or physiologically acceptable vehicle, to enable the
`inhibitor to be conveyed to the skin at an appropriate
`dilution. The nature of the vehicle will depend upon the
`method chosen for topical administration of the compo- 10
`sition. The vehicle can itself be inert or it can possess
`physiological or pharmaceutical benefits of its own.
`The selection of a vehicle for this purpose presents a
`wide range of possibilities depending on the required
`product form of the composition. Suitable vehicles can !5
`be classified as described hereinafter.
`It should be explained that vehicles are substances
`which can act as diluents, dispersants, or solvents for
`the chemical inhibitors which therefore ensure that they
`can be applied to and distributed evenly over the hair 20
`and/or scalp at an appropriate concentration. The vehi(cid:173)
`cle is preferably one which can aid penetration of the
`inhibitors into the skin to reach the immediate environ(cid:173)
`ment of the hair follicle. Compositions according to this
`invention can include water as a vehicle. and/or at least
`one cosmetically acceptable vehicle other than water.
`Vehicles other than water that can be used in compo(cid:173)
`sitions according to the invention can include solids or
`liquids such as emollients, solvents, humectants, thick- 30
`eners and powders. Examples of each of these types of
`vehicles, which can be used singly or as mixtures of one
`or