United States Patent
`Bar-Shalom et al.
`
`I 19[
`
`[54] USE OF SUCRALFATE TO TREAT
`BALDNESS
`
`[ 76 [
`
`Inventor~: Daniel Bar-Shalom, Rypcvacngcl 213,
`DK-29XO Kokkcdal: Niels Hukh,
`Strandvcjen 122, DK-2900 Hellcrup,
`both or Denmark
`
`121] Appl. No.: 247,478
`
`[221
`
`Filed:
`
`May 23, 1994
`
`lllllllllllllllllllllllllllllllllllllllllllllllllllllllllllllll 111111111111
`5,618,798
`Apr. 8, 1997
`
`US0056l8798A
`1111 Patent Number:
`1451 Date of Patent:
`
`97625
`107209
`.134585
`354595
`46-1 OS75
`1150082
`936916
`1098935
`W08900047
`WOII'J0564.~
`W08905646
`W08907932
`
`111989 European Pal OfT.
`511989 European Pat. OfT.
`91l989 European Pal. OIT.
`2/1990 European Pal. OfT.
`'i/1965
`Japan .
`7/191\1 USSR
`911963 United Kingdom
`111961\ United Kingdom .
`\VIPO
`l/1989
`61198<) WIPO.
`611989 WIPO.
`811 '!89 W1PO.
`
`Related U.S. Application Data
`
`OTIIER PUBLIC/\TIONS
`
`[63] Continuation of Scr. No. 47,078, Apr. 16, 1993, abandoned,
`which is a continuation of Scr. ~o. 613,559, ~ov. 21, 1990.
`ahandoncd.
`
`[ 30]
`
`Foreign Application Priority Data
`
`Apr. 20, 198\i
`
`[ DK I Denmark .................... .
`
`1918
`
`Int. CI.'' ................................................... A61K 3tno
`[51[
`[52] U.S. CI. .................................. 514/53: 514/25: 514/54
`[5X I Field of Search .................................. 514/23, 25. 53,
`514/59
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,912,09.1
`
`311'!\ill Michacli ............................. ..... 51415.1
`
`FOREIGN PATENT DOCUMENTS
`
`911985 European Pat. OfT.
`136100
`161816 1111985 European Pat. OfT
`182756
`5/1986 European Pat. OfT.
`211610
`2/1987 European Pat. OfT.
`107885
`511987 European Pat. OfT.
`23002.3
`711987 European Pat. OfT.
`245855 1111'!87 E uropcan Pat. OfT
`277428
`811988 European Pat. OfT.
`279244
`811988 European Pat. Off
`295092 1211988 European Pat. OIT.
`297455
`111989 European Pat. OfT.
`
`Cassero. Chemical Abstracts. vol. 105 (8) ( 1986) No.
`66249f.
`The Merck l'vlanu~l. 15th ed ( 19H7) pp. 22H 1-2282.
`I OH ( 7 ), No.
`Couchman et al, Chemic~! ;\ hstracts, vol.
`565394.
`Gonz~lez. et al., Conn· s Current Therapy. 599-603 ( 19ll4);
`Latest Approved Method or Treatmenl for the Practicing
`Physician.
`W. Scott Brooks, Jr., American Journal of Gastroenterology
`80:206-209 ( 19H5); Sucralfatc: Nonulccr Uses.
`
`Primary f.'J;amilzcr- Elli Pcselcv
`Allomcy, Jlgem, or Firm- -Ivcr P. Cooper
`
`[57]
`
`ABSTRACT
`
`A method of treating and/or preventing alopecia (baldness,
`deficient hair growth) comprises administering to a patient
`in need thereof a therapeutically or prophylactically ctrcc(cid:173)
`tivc amount or a sulfated mono-, di- or oligosaccharide or a
`derivative, salt or complex thereof. The saccharide is pref(cid:173)
`erably polysulfatcd, such as a polysulrated disaccharide, in
`particular sucrose, or a derivative, complex or salt thereof.
`Especially interesting polysulfated disaccharidcs arc sucrose
`pcntasulfate, sucrose hexasulfate, sucrose heptasulfatc and
`sucrose octasulfatc, e.g. in the form or a potassium or
`sodium salt, or in the form of sucralfate.
`
`IS Claims, l"'o Drawings
`
`1
`
`

`

`1
`t:SE OF SUCRALFATE TO TREAT
`BALDNESS
`
`5,618,798
`
`10
`
`This application is a continuation of application Scr. No.
`081047,078 filed Apr. 16, 1993, now abandoned itself a
`continuation ol' application Scr. No. 07/613,559 filed Nov.
`21, 1990, now abandoned which was the national stage or
`PCT/DK90/00104, filed 1\pr. 19, 1990.
`Alopecia (baldness or deficient hair growth) is a condi-
`tion which leads to more or less disabling or discomforl to
`the individual sullcring thercf'rom. ranging from minor cos(cid:173)
`metic disadvantages to severe psychological consequences.
`Alopecia has a number of etiologies.
`The most common form or alopecia is androgcnetic 1.1
`alopecia, more accurately described as common baldness.
`1\ndrogcnetic alopecia occurs in chimpanzees, orang-out(cid:173)
`angs and other primates as well as in man.
`As is implied hy the name. androgcnctic alopecia is
`induced by androgenic stimulation or hair follicles predis- 20
`posed by thl' interdependent inlluences ol' genetic ractors
`and of ageing. Despite its name. it a!Tect both the male and
`the female.
`The initial stage in the condemned lollicles is probably
`the accumulation of 5a-dihydrotcstostcronc, the tissue-ac-
`live androgen which inhibits the metabolism of such fol(cid:173)
`licles.
`Then: is a marked racial variation in the incidence or
`androgcnctic alopecia. The disease is most frequent and
`severe in Caucasoids.
`The earliest histological change is the appearance of foci
`of degeneration in the lower part or the connective-tissue
`sheath of the l'olliclcs. with peri vascular basophilic change.
`The follicle gradually shrinks. leaving beneath it a strand of
`sclerosed and hyaline connective tissue. llowcvcr, even in 35
`areas or scalp in which almost all lolliclcs arc short and
`small, producing at best only tiny vcllus hairs, there remain
`a few yuicsccnt terminal follicles which can be stimulated
`into growth to give false hopes of a cure.
`1\ndrogcnctic alopecia is a very widespread condition. at
`least in its less severe rorms. Thus, during adolescence,
`unil'orm recession of the frontal hair-line occurs in 96'if, of
`males and about 80% of females.
`As mentioned above. there arc a number of other etiolo(cid:173)
`gic;, of alopecia. such as the administration of chemicals,
`such a~> drugs. As examples or these may be mentioned
`anticoagulants such as large doses of heparin, hcparinoids
`and coumarins, cytostatic agents. triparanol and fluorohu(cid:173)
`tyrophcnonc, excessive consumption of vitamin!\, occupa(cid:173)
`tional exposure to sodium borate. potassium thiocyanate. 50
`large amounts of bismuth. Also. oral contraceptives have
`been suspected or giving rise to the disease, and the same
`applies to propranolol, mctoprolol, levodopa. and ibuprofen.
`Also. alopecia may have nutritional or metabolic origin,
`or it may he caused hy disorders of the central nervous
`system. Furthermore. the significant association ol' the atro(cid:173)
`phic state with alopecia arcata has been stressed rclati vcly
`recently in some populations. Also, an association between
`autoimmunity and alopecia arcata has long been recognized.
`Alopecia including arcata is also often seen in association 60
`with skin disease such as scalp eczema, psoriasis and other
`dermatosis and also in association with systemic disease
`such as LE.
`Today, no completely satisfactory treatment or prophy(cid:173)
`laxis of alopecia exists. Although topical administration of 65
`minoxidil can induce regrowth, it is not considered the
`definitive therapy.
`
`2
`Heparin, heparinoids and related glycosaminoglycans
`have been suggested as c!Tectivc in stimulating hair growth
`(e.g. DE 3543221 A I. GB 936 916. GB l 09K 935. EP 35
`Y 19. EP 182 756, EP 277 428. EP 27Y 244, EP 295 092, EP
`297 455).
`In EP 2Y5 092, it is described that hyaluronic acid
`fragments comprising rrom 7 to 50 monosaccharide units
`terminating either with a glucuronic acid unit and/or a
`N-acetyl glucosamine unit. or an unsaturated derivative of
`one or both or these terminal units arc useful as hair
`stimulating agents when topically applied to the scalp. Such
`compounds can he characterized hy being "naturally" occur(cid:173)
`ring mucopolysaccharide moieties.
`It has now surprisingly been observed that after 3-4
`weeks of two daily applications of an ointment containing
`IOo/r· w/w of sucralfatc, there was appearance or hair in the
`otherwise bald lateral-frontal areas in a 40-ycar-old male
`who had a normal common malc-pallern baldness. At the
`beginning, a "plume" appeared in the area, and arter a few
`days the "plume" began turning into real hairs and X days
`after. there were devens or real hairs which were indistin-
`guishable from other hairs or the scalp, apart from heing
`shorter and all coloured, in contrast to the existing hair.
`which was partially greyed.
`This observation is mm,t remarkable in view of the ract
`that sucralfatc or sui fated mono-, di- or oligosaccharides
`have apparently not been suggested as means for treating or
`preventing alopecia. 1\lso, the sulfated mono-, di- or oli(cid:173)
`gosaccharidcs do not belong to any chemical or therapeutic
`~o group of compounds previously used or suggested for the
`treatment or alopecia, such as minoxidil. vitamin A, steroids,
`in particular triamcinolone, pyrimidine carbamate, squaric
`acid, allergens and psoralens in PUYA and naturally occur-
`ring mucopolysaccharidcs.
`Sucralfate and other disaccharide polysulfatc-aluminium
`compounds have been indicated as ciTcctive in alleviating
`the symptoms of anorectal disease when topically applied to
`human skin. and as efTcctivc in promoting the healing of
`wounds (WO 89/00047). and sulfated oligosaccharidcs, par-
`ticularly mono- and disaccharides such as sucrose octasul(cid:173)
`fatc, have been mentioned as wound healing agents (EP 230
`02.1 ). WO 89/05645 and WO 89105646 disclose a broad
`range of pharmacological efl'ecls of sucralfate and sucrose
`octasulrate such as anti-inflammatory. anti-infective, anti-
`,1~ malignant, skin-protective and anti-wrinkle and other effects
`after topical or systemic administration. WO 89/07932 dis(cid:173)
`closes the usc of sucralfatc and sucrose octasulfatc in the
`treatment or gingivitis and parodontosis.
`Based upon the observations made in the present inven(cid:173)
`tion and the inventors' knowledge or sulrated saccharides. it
`is reasonable to contemplate that the hair growth stimulating
`effect will extend not only to sucralfate and the sodium salt
`of sucrose octasulfate, hut also to other related sulfated
`mono-, di- and oligosaccharides, which arc of a type no!
`55 naturally occuning in glycosaminoglycan structures.
`
`2.\
`
`40
`
`SCM MARY OF Tl IE INVENTION
`
`In one aspect, the invention provides a method of treating
`and/or preventing alopecia. the method comprising admin(cid:173)
`istering to a patient in need thereof a therapeutically or
`prophylactically cfrcctive amount of a sulfated mono-. di- or
`oligosaccharide or a derivative. salt or complex thereof.
`In another aspect, the invention relates to the usc of a
`sulfated mono-, di- or oligosaccharide for preparing a com(cid:173)
`pm;ition ror usc in the treatment and/or prevention of alope(cid:173)
`cia.
`
`2
`
`

`

`5,618,798
`
`3
`In a further aspect, the invention relates to the cosmetic
`usc of a sulfated mono-, di- or oligosaccharide for combat(cid:173)
`ing or preventing hair loss and/or preserving the natural
`colour of the hair.
`
`DETAILED DISCLOSURE OF TilE !NVEi\TION
`
`5
`
`IS
`
`50
`
`CH,OR
`
`CH,OR H
`
`·O
`
`)
`
`CH,OR
`
`H OR
`
`OR H
`
`wherein R is H. S03[Al 2 (0H) 5 ], S03 11 or an acyl residue of
`the above-mentioned carboxylic acids, the groups desig(cid:173)
`nated R being the same or difl"ercnt, with the proviso that at
`least one R represents a sulfate group,
`or physiologically acceptable salts or complexes thereof.
`The particular preferred compounds according to the
`invention arc sucralfate and the potassium or sodium salt of
`sucrose octakis(hydrogcn sulfate).
`Sucral fate may also be termed sucrose octakis(hydrogen
`sulfate) aluminium complex. lts CAS number is 54182-58-
`0. The commercial product is a white powder which is
`practically insoluble in water and most organic solvents; it
`is soluble in acids and alkalis. In practice, there may be
`slight variations in the chemical composition, e.g., due to the
`fact that the sulfation may be slightly incomplete so that the
`product may, e.g., contain a certain proportion of molecules
`which arc not octasulfatcd (pcrsulfatcd), but rather less
`
`The sulfated saccharide used in accordance with the
`invention may be a sulfated monosaccharide, for instance
`sulfated xylose, fructose, glucose, ribose, arabinose, galac(cid:173)
`tose, rhamnose, fucose, sorbose, psicosc, tagatose or gulose,
`a sulfated disaccharide such as sulfated sucrose, lactose,
`maltose or cellobiose, or a sulfated oligosaccharide such as
`sulfated maltotriosc, maltertreosc, or a sulfated raf1inose.
`which is an oligosaccharide comprising a sulfated sucrose
`moiety together with a galactose moiety, or a sulfated
`mcluitosc. which is a sulfated sucrose moiety together with
`a glucose moiety. In the present context, the term "an
`is a saccharide consisting of 3-20
`oligosaccharide"
`in accordance with the generally 2o
`monosaccharide units
`accepted terminology.
`The sulfated mono-, di- or oligosaccharide is preferably a
`polysulfatcd or persulfatcd saccharide, which means that
`two or more, possibly all, sulfur-containing moieties arc
`present as substituents on hydroxy groups of the carbohy-
`dratc moiety.
`In some cases. the sulfated mono-, di- or oligosaccharide
`may he complexed with or form a salt with a metal, e.g. an
`alkali or alkaline earth metal such as ;>;a, K, Ca, Mg or Ba,
`or AI, Zn. Cu, Zr, TL Bi, Mn or Os, or with an organic base
`(e.g. an amino acid). The currently preferred salts arc
`potassium and sodium salts. and the preferred complex is the
`aluminium complex. Furthermore, the mono-, di- or oli(cid:173)
`gosaccharide may be in the form of a suitable derivative, e.g.
`a mono-, di- or polyester of aliphatic carboxylic acids such 35
`as formic, acetic, propionic, butanoic. myristic or stearic
`acid.
`Preferably, the composition of the invention contains a
`pcrsul fated disaccharide, for example sucrose octasulfatc.
`The preferred sulfated disaccharide can be represented by
`the following formula:
`
`2:'i
`
`30
`
`4
`sulfated such as hcptasulfated. Such minor variations in the
`commercial product arc well known and arc rcllccted in the
`fact that e.g., the aluminium content in commercial products
`may range from 17 to 21% and sulfur from 9.5 to 12.5%. In
`the present context, the term "sucralfatc" also comprises
`such generally accepted minor variations.
`Sucralfate may, for instance, be prepared as disclosed in
`U.S. Pat. No. 3,432,489 by reacting a 1-10% w/w aqueous
`solution of sucrose oetasulfatc or an alkali metal or alkaline
`10 earth metal salt thereof with a l-1 0% w/w aqueous solution
`containing aluminium ions, preferably AlCl(OHi~ at room
`temperature and a pH of 4-4.5. The sucrose octasulfatc may
`be prepared by reacting sucrose with CIS0311, ll:>S0 1 or
`H)S0.1-C,H 5 N.
`The sulfated saccharides may otherwise he prepared, for
`example, as disclosed in EP 230023.
`The sulfated sucrose is preferably selected from the group
`consisting of sucrose pentasulfate, sucrose hcxasulfatc,
`sucrose heptasulfate and sucrose octasulfate.
`The administration form in which the sulfated saccharide
`is administered will normally be a form suitable for topical
`application to the aflcctcd area. However, also administra(cid:173)
`tion into the skin or administration under the skin, e.g. by
`injection (by needle or dermajct) or other methods. arc
`contemplated.
`Although there may be cases where the sulfated saccha(cid:173)
`ride may he administered as such, it will typically be
`compounded with one or more pharmaceutically acceptable
`carriers or excipient~> to present it in a form which is suitable
`for topical application or for injection or other form of
`introduction into or under the skin. In other words, it will be
`in the form of a liquid, semi-solid or solid topical or sy:.temic
`preparation such as an ointment, lotion, gel, cream, emul(cid:173)
`sion, solution, suspension. microcmulsion, liposomcs or as a
`roll-hall applicator, sponge applicator or a spray device; a
`shampoo, hair tonic, hair conditioner, soap, balm, spray,
`paste, powder, sponge, strip, plaster, pad, dressing. or a
`comb or brush impregnated with or carrying the sulfated
`saccharide in such a manner that it is released when the
`40 comb or brush is used at the afl"cctcd area.
`The above-mentioned compositions arc also suitable for
`cosmetic purposes where the compositions arc applied to the
`hair or the skin areas normally covered with hair in order to
`prevent hair loss and/or to preserve the natural colour of the
`45 hair. Preferred compositions for cosmetic usc arc e.g. gels,
`emulsions, suspensions, liposomes, shampoos, hair tonics,
`hair conditioners, soaps, balms or sponges.
`It may be interesting in certain cases to combine the
`sulfated saccharide with other forms of therapy, in particular
`therapies known to either produce hair growth hy them(cid:173)
`selves such as vitamin A, minoxidil, squaric acid, allergens,
`irritants. corticosteroids, or agents which attack or modify
`the mechanism responsible for the alopecia, such as in the
`case of fungal infection, an ointment containing sucralfatc
`55 and an antifungal agent such as kctoconazole, miconazolc,
`clotrimazolc, antiviral agents, such as acyclovir, antiinflam(cid:173)
`matory agents, antibacterial agents, etc. Also, it may advan(cid:173)
`tageous to combine the sulfated saccharide with other phar(cid:173)
`maceutical products known to have beneficial cll"ccts on the
`60 skin, such as vitamins, including vitamins B, vitamin E,
`lactic acid, astringents, emollients, or other agents, such as
`hyaluronic acid or other glycosaminoglycans, dcrmatan sul(cid:173)
`fate. chondroitin sulfate, keratan sulfate, hcparan or hcparan
`sulfate. Normally, the sulfate saccharide will be the prc-
`65 dominant active component of the preparation.
`Furthermore, advantages may he achieved by incorporat(cid:173)
`ing pharmaceutically acceptable amounts of penetration
`
`3
`
`

`

`5,618,798
`
`Ill
`
`!5
`
`5
`enhancers in the formulatiom, such as salicylic acid and
`other keratolytics, amino acids, thioglycollates, dimethyl(cid:173)
`sulfoxide, and hydrating agents, such as glycerol.
`Plasters. sponges, strips, pads or other dressings may he
`prepared hy impregnating a dressing material such as cotton 5
`wool or gauze or a polymeric substance with a solution or
`suspension or the sulfated saccharide followed hy drying.
`Alternatively, a paste, lotion. cream or gel containing the
`sulfated saccharide may he spread over the dressing mate(cid:173)
`rial.
`Alternatively, the sulfated mono-, di- or oligosaccharide
`may in certain cases he injected or otherwise introduced into
`or under the skin or scalp.
`Por topical application, the preparation may he formu(cid:173)
`lated in accordance with conventional pharmaceutical prac(cid:173)
`tice with pharmaceutical excipienls conventionally used for
`topical applications. The nature of the vehicle employed in
`the preparation of any particular composition will depend on
`the method intended for administration of that composition.
`Vehicles other than water that can he used in compositions
`can include solids or liquids such as emollients, solvcms.
`humectant,, thickeners and powders. Examples of each of
`these types of vehicles, which can he used singly or a;,
`mixtures of one or more vehicles. arc as follows:
`Emollients. such as stearyl alcohol, glyccryl monoricino(cid:173)
`leatc, glyceryl monostearate, propane-! ,2-diol, butane-1.3-
`diol, cetyl alcohol, isopropyl isostearatc, stearic acid, isobu-
`tyl palmitate, isocctyl stearate, oleyl alcohol, isopropyl
`laurate, hexyllaurate, dccyl oleate, octadecan-2-ol, isocetyl
`alcohol, cetyl palmitate, dimcthylpolysiloxane, di-n-hutyl
`schacatc, isopropyl myristate, isopropyl palmitate, isopropyl
`stearate, hutyl stearate, polyethylene glycol, tricthylenc gly(cid:173)
`col, lanolin, castor oil, acetylatcd lanolin alcohols. petro(cid:173)
`leum, mineral oil, butyl myristate, isostcaric acid, palmitic
`acid, isopropyl linolcatc, lauryl lactate, myristyl lactate,
`dccyl oleate, myristyl myristatc;
`sol vents, such as water, methylene chloride, isopropanol,
`castor oiL ethylene glycol monocthyl ether, diethylene gly(cid:173)
`col monobutyl ether, diethylene glycol monocthyl ether,
`dimethyl sulfoxide, tetrahydrofuran. vegetable and animal
`oils, glycerol, ethanol, propanol, propylene glycol, and other
`glycols or alcohols, fixed oils;
`humectants. such as glycerin, sorbitol, sodium 2-pyrroli(cid:173)
`donc-5-carhoxylate, soluble collagen. dibutyl phthalate.
`gelatin;
`powders, such as chalk. talc, kaolin, starch and derivative;,
`thereoL gums, colloidal silicon dioxide, sodium polyacry(cid:173)
`latc, chemically modified magnesium aluminium silicate,
`hydrated aluminium silicate, carboxyvinyl polymer, sodium
`carboxymethyl cellulose, ethylene glycol monostearatc;
`gelling or swelling agents, such as pectin, gelatin and
`derivatives thereof, cellulose derivatives such as methyl
`cellulose. carboxymethyl cellulose or oxidised cellulose,
`guar gum. acacia gum, karaya gum, tragacanth gum, ben(cid:173)
`tonite, agar, carhomer, bladdcrwraek. ccratonia. dextran and 55
`derivatives thereof, ghatti gum. hectorite, ispaghula husk.
`xanthan gum;
`polymers, such as polylactic acid or polyglycolic acid
`polymers or copolymers thereof'. parallin. polyethylene,
`polyethylene oxide, polyethylene glycol, polypropylene gly-
`col, polyvinylpyrrolidone;
`surfactants. such as non-ionic surfactants, e.g. glycol and
`glycerol esters, macrogol ethers and esters, sugar ethers aml
`esters, such as sorbitan esters, ionic surfactants, such as
`amine soaps, metallic soaps, sulfated fatty alcohols, alkyl 65
`ether sulfates, sulfated oils, and ampholytic surfactants and
`lecitins;
`
`6
`bulTcring agents. such as sodium, potassium. aluminium,
`magnesium or calcium salts (such as the chloride. carbonate,
`hicarhonale, citrate, gluconatc, lactate, acetate, gluceptatc or
`tartrate).
`The preparation of the invention may also contain other
`additives such as stabilizing agents, preservatives, etc.
`Furthermore, it may he advantageous to provide modi tied
`release preparations in which the sulfated saccharide is
`incorporated into a polymer matrix, or nanoparticles, or
`liposomes or micelles, or adsorbed on ion exchange resins,
`or carried hy a polymer.
`The pharmacologically active clement in sucralfate is
`prohahly the non-aluminium complcxed sodium and/or
`potassium salt of sucrose octakis(hydrogcn sulfate). Since
`such a salt is soluble in water, it would seem that a small
`particle size would he an important factor when preparing
`formulations of the sparingly soluble sucralfatc. One way of
`achieving a small sucralfatc particle size is hy mcam of
`milling, grinding or disintegrating apparatu~, e.g. a three roll
`20 mill, where the sucralfatc powder is ground. preferably
`together with a suitable liquid vehicle having a viscosity
`adapted to cfTcctively suspend the resulting fine particles,
`and prcl'crably a relatively low vapour pressure so that no
`excessive evaporation with resulting agglomeration of the
`flne particles will occur. such as a polyalcohol, for example
`glycerin or polyethylene glycol, normally having a molecu(cid:173)
`lar weight in the range of 200-6000, such as PEG 400. The
`resulting preparation will normally contain up to 60-709(, hy
`weight of sucralfate particles with a fairly uniform particle
`size of ahoul 5-l 0 J.lm or less (for 959(; hy weight of the
`sucralfatc), the particles heing substantially evenly sus(cid:173)
`pended in the vehicle. Such a paste can then he further
`suspended in any suitable pharmaceutical preparation using
`well known pharmaceutical methods. Another starting point
`for a small particle size sucralfatc formulation is sucrall'ate
`"filter cake", which is an intermediary product ohtaincd
`from the synthesis of sucralfatc. The "tiller cake" comprises
`sucralfate with a content of water of ahout 50% hy weight,
`and with a particle size of ahout 5-l 0 J.lm or less. This
`40 material can he mixed with, for instance, a water-miscible
`liyuid which has a relatively low vapour pressure. such as
`glycerin, in order to prevent the water from evaporating. and
`the sucralfatc particles will retain their small size. Another
`important factor to take into consideration when preparing
`formulations of sucralfatc and other sui fated saccharides is
`the strong negative charge of salts of sucrose octakis(hy(cid:173)
`drogcn sulfate), and probably of most sulfated saccharides.
`The pharmacological e!Tcct of sucralfatc, salts of sucrose
`octakis(hydrogen sulfate) and other sulfated saccharides
`so prohahly depends on this negatively charged entity, and the
`pharmacological cJTcct of the drug may he reduced hy the
`presence of positively charged mono- and divalent ions in
`the vehicle. The person skilled in the art will he ahlc to take
`this into consideration, using guidelines from the relevant
`literature, e.g., Martindale, The Extra Pharmacopoeia, The
`Pharmaceutical Press, London, or other pharmaceutical text-
`hooks.
`In this connection it should be mentioned that while the
`incorporation of sucralfate or other water-insoluble or spar(cid:173)
`ingly water-soluble sulfated saccharides is best performed as
`described herein taking into consideration the physical and
`chemical properties of the sulfated saccharide. in particular
`the particle size considerations mentioned below, the incor(cid:173)
`poration of water-soluble sulfated saccharides, such as
`sodium and potassium salts of sucrose oktakis (hydrogen
`sulfate) in preparations discussed herein will normally be
`extremely simple and will ordinarily consist in the addition
`
`25
`
`.10
`
`.1:1
`
`45
`
`60
`
`4
`
`

`

`5,618,798
`
`111
`
`7
`of the sulfated saccharide to the preparation or to constitu(cid:173)
`ents thereof in either dry or dissolved form.
`The sulfated saccharide will normally he used in a prepa(cid:173)
`ration in an amount of 0.001-99%, typically about 0.1-75%,
`such as about 0.2-30%·, preferably about 0.5-20%. such as
`about 2-20%, e.g., 3-15%, by weight of the total prepara(cid:173)
`tion. Por therapeutic and/or prophylactic usc. the sulfated
`saccharide may also be used in a preparation in an amount
`of about 0 00 i -99'1< w/w. typically about 0.01-50% w/w,
`such as about 0.05-30% w/w, preferably about 0.1--20%
`w/w such as about 0.5-15% w/w.
`Th~ concentration of the sulfated saccharide to he used in
`each particular case will of course depend upon the type of
`preparation and the intended usc, but also on the solub!llly
`characteristics of the sulfated saccharide and. for spanngly
`soluble and substantially insoluble sulfated saccharides. on 15
`the particle size thereoi·: the smaller the particle size, the
`faster will be the dissolution of even spanngly soluble or
`even substantially insoluble sulfated saccharides or com(cid:173)
`plexes thereof. ]~soluble or sparingly soluble salts or com(cid:173)
`plexes of sulfated saccharides arc preferably used m the 20
`form of a fine powder. lor example having a part1clc S!J:e of
`200 flm or less. such as 100 flm or less. Examples of very
`small particle size>. which may be des1rahle for ccrta~n
`purposes arc e.g. 50 )lm or less, such as 20 f.!m or less, m
`certain cases 10 f.!m or less, such as 5 f.!m or less.
`A topical preparation containing the sulfated saccharide is
`normally administered between l and 10 l!mes a .d.ay,
`depending on the formulation, the severity of the cond1lwn
`to be treated. the age of the patient, and other factors. Based
`upon experience with other substances used in the treatment 30
`of alopecia. in particular minoxidil, it is expected that the
`efTect will depend on continuing application of the prepa(cid:173)
`ration. for several months, or even years. In view of the fact
`that sucralfatc is remarkably free of side effects, there should
`he no adverse long term consequences of such a treatment.
`The invention is further illustrated by the following 35
`non-limiting examples.
`
`25
`
`EXAMPLE 1
`
`Preparation or Sodium and Potassium Sucrose
`Octasulfate
`
`8
`wet filter cake was dried in vacuo at 50° C. The substance
`was reprccipitatcd twice as mentioned above.
`Yield: 137 g (about 53%) of potassium sucrose octasul(cid:173)
`fate.
`Ill. Sodium sucrose octasulfatc
`One portion of sucrose octasulfatc solution prepared as
`described in I above was adjusted with 10% w/w aqueous
`sodium hvdroxidc to pl-1=9 with stirring at room tempera(cid:173)
`ture. The~ solution was evaporated at 50'' C. in vacuo to
`remove pyridine and water. When 250 ml were distilled, 5HO
`ml of ethylene glycol were added and the evaporatwn was
`continued until 10 mm vacuum. 100 ml of ethanol were
`added to the solution. The solution was filtered. and pH was
`adjusted to 9.5. 350 ml of ethanol were slowly added with
`vigorous stirring at 30°-35° C., and the substance w!ll then
`precipitate. After the addition was ended, the m1xture was
`cooled to I oo C., and the solid substance was filtered and
`washed with 50 ml of 1: I ethanol/ethylene glycol and 200
`ml of methanol. The wet filter cake was dried in vacuo at 500
`C. The crude product was dis sol vcd in 520 ml or ethylene
`glycol and heated to 40° C., and 100 ml of' ethanol were
`added. The solution was filtered and pi I was adjusted to 9.5.
`350 ml of ethanol were slowly added with vigorous stirring
`at 30°-35° C. and the substance will then precipitate. After
`the addition was ended. the mixture was cooled to 1 oo C. and
`the solid substance was filtered. It was washed with 50 ml
`of 1: 1 ethanol/ethylene glycol and 200 ml of ethanol. The
`wet filter cake was dried in vacuo at 50° C. The substance
`was rcprccipitatcd once as above and then dried for 2 hours
`at room temperature in 500 ml or ethanol. The substance was
`filtered. washed with 200 ml of ethanol and dried at 50° C.
`in vacuo.
`Yield: 146 g (about 63%) of sodium sucrose octasulfate.
`
`EXAMPLE 2
`
`A cream consisting of the following ingredients is pre(cid:173)
`pared (all percentages arc by weight):
`
`40 2:1 suspension of ~ucralfJlc* in polyethylene
`glycol 400 ( 10% 5ucralfatc in the flnal
`product)
`Lanolin
`Vegetable oil (cvcmng primrose oil)
`Pol yeth y lcnc gt yeo I 400 monostcaratc
`Water
`
`15.09'c
`
`10 OS•c
`20.0(,1[,
`I ()()S•a
`
`100 o,.,
`
`[O
`
`I. Sucrose octasulfate
`254.7 g (1.6 mol) or sulfur trioxide pyridine were slurried
`in 1300 ml or water-free pyridine. With stirring, 68.5 g (0.2 40
`mol) of sucrose were added. The reaction mixture was
`heated to 65" C. and kept at this temperature for 240
`minutes. As the reaction proceeded, the substance was
`separated as a thick flowing oil. When the reaction was
`terminated. the agitator was stopped, the pyridine phase was
`decanted. and the oily phase was dissolved in 600 ml ol
`ion-exchanged water.
`11. Potassium sucrose octasulfate
`One portion of sucrose octasulfatc solution prepared as
`described in I above was adjusted with I Oo/c.- w/w aqueous 55
`potassium hydroxide to pH=9 with stirrin~ at .room tem(cid:173)
`perature. The solution was evaporated at 50 C m. vacuo to
`remove pyridine and water until 880 g were left. 1 he warm
`solution was filtered, adjusted to pH=9.5, and the substance
`was precipitated with slow cooling to SO C. The substance
`was filtered and washed with 300 ml of l: 1 ion-exchanged
`water/methanol and 300 ml of methanol. The wet filler cake
`was dried in vacuo at 50° C The crude product was
`dissolved at 40" C in 700 ml of ion-exchanged water. The
`liquid was filtered and adjusted to pH=9.5, and the su?stancc
`was precipitated with slow cooling to 5° C. The prectpllatcd 65
`substance was filtered and washed w1th 300 m! ol 1:1
`ion-exchanged water/methanol and 300 ml or methanol. The
`
`50
`
`60
`
`*Sucralfatc provided hy Guilini Chemic. W. Germany.
`
`The vegetable oil. lanoline and polyethylene glycol 400
`monostearatc were melted and thoroughly mixed with the
`warmed water to form an ointment. The sucralfatc suspen(cid:173)
`sion was incorporated into the ointment.
`
`EXAMPLE 3
`
`A lotion is prepared from the following ingredients (all
`percentages arc by weight):
`
`2:1 suspension of sucralfatc* in polyethylene
`glycol 400 110% sucmlfatc in the tina!
`product)
`Glycerol
`Ethanol
`Water
`
`100%
`50.09(,
`IOO.Oo/c
`
`to
`
`*Sucralfatc provided by Guilini Chemic, W. Germany.
`
`The ingredients were mixed together in the order stated to
`obtain a lotion.
`
`5
`
`

`

`5,618,798
`
`9
`EXAMPLE 4
`
`10
`EXAMPLE 10
`
`A hair tonic is prepared from the following ingredients
`I all percentages arc hy weight):
`
`A shampoo is prepared from the following ingredients (all
`percentages arc by weight):
`
`Sodium ~unos~ sulfate(cid:173)
`Ethanol
`\VaLcr
`
`J.O%
`25.09~
`100.0');,
`
`Ill
`
`Sodium sucrose sulfate wa~ dissolved in water and ctha-
`nol was then added to the solution.
`
`10
`
`EXAMPLE 5
`
`A hair tonic is prepared as deserihcd in Example 4 from 15
`the following ingredients (all percentages arc by weight):
`
`Sodium suLTOse sulfalc
`Ethanol
`\\later
`
`1.59(,
`~o.osc
`1110.0');,
`
`to
`
`20
`
`EXAMPLE 6
`
`A lotion is prepared from the following ingredients (all 25
`percentages arc by weight):
`
`Sodium ::.m:ro: