Note: Descriptions are shown in the official language in which they were submitted.
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UROGENITAL ANU INTESTINAL DISORDER COMPOSITIONS COMPRISING A SUBSTANCE DERIVED
FROM PLANT SPECIES OF THE ERICACEAE FAMILY AND A LACTIC ACID BACTERIA GROWTH
FhCTOR
llEC~DNIC~L FrELD
This application relates to compositions useful in preventing and/or treating
urogenital and intestin~l disorders.
BACKGROUND OF THE ~NVENTION
Compl~x, rnicroscopic ecosystems pervade the urogenital and intestin~l tracts ofwarm blooded ~nimAIc Trillions of microor~Ani~mc7 co~ lising hundreds of species,
occupy the urogenital and intestin~l tracts of ~ , inflll~ncing and m~int~ining
digestive and urologic functions. Microo~ -c occupying these regions range from
potentially pathogenic strains, such as Escherichia coli, enterococci, c~n~ , gardnerella,
15 klebsiella and clostridia, to the relatively nonpathogenic, such as lactobacillus and
bifidobacterium. Deviations from this delicate floral balance have been etiologically linked
to a I~UIII~el of urogenital and/or ~a~l-u;~ l tract disorders; such imhAl~n~ps usually
resulting in the proliferation and predo...;n~ e of pathogenic species. Establishing and/or
preserving such a dPlic~te floral balance is, therefore, e~sentiAl to mAinl~in;~g optimal
20 health.
One way of establishing or ll-A;-I~ the body's flora is by promoting the growth
of lactic acid bacteria (e.g., lactobacillus or bifidobacterium). The use of growth factors to
treat urogenital and int~stin~l disorders has been proposed, for inct~ncP, in CanA~ n
Patent 1,298,556, issued April 4, 1992 and to Bruce et al., PCT Application Serial
2~ Number WO 93/09?93, published May 27, 1993, to Reid et al. Ideally, such growth
factors sele,~Li~ provide lactic acid bacteria with nutrients and an en~..o~ ec~nti~l
for ~ontin~ growth. Despite such selectivity, however, alternative nutrient sources
remain available for pathogenic bacteria. Furth~,....ole, growth substrates fail to provide
direct activity against ol~nding microorp~n~ Therefore, nolwi~ l;..g such
30 p~ ,osals, there still remains a need for improved urogenital and ~,a~Llu;-~l~Stin~l tract
co...l~o~;~ ;onc co..l~ g lactic acid bacteria growth factors.
The present inventors have found that compositions incorporating plants or
e~l.a~Ls of the Ericaceae family with Lactobacillus and/or Bifidobacterium provide
improved compositions for treating and/or pl~ c.llillg urogenital and ga,l..,;..~e~ Al
35 ~}i~..l.,,~ by modifying the interaction of pathogens with cellular tissue. Recent studies
also st~ 5t the value of such extracts in L~ .ling urinary tract i.~rP~il;onc. Researchers
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have observed that various species of V~cçini--m (e.g. cranberry and blueberry) contain a
high molecular weight compound that inhibits the adhesion of common urinary pathogens
~e.g., F~. co~i) to in~fection sites within the urinary tract. Ofek I et al., Anti-Escherichia coli
Adhesin Activity of Cranberry and Blueberr,v Juices~ N Engl J Med 1991;324;1~;99.
Surprisingly, the compositions of the present invention provide improved environments
more conducive to the colonization of lactic acid bacteria.
Accordingly, it is an obJect of the present invention is to promote a healthy
envho.u..~.-L for the growth of lactic acid bacteria in the urogenital and gastrointçstin~l
traets.
Another object of the present invention is to provide improved compositions
comprising a growth factor for lactic acid bacteria.
A further object of the present invention is to provide compositions for dietary
suppl~m~nt~tiQn~
A still further object of the present invention is to provide topical compositions for
vaginal use.
An even further object of the present invention is to provide compositions and
methods effective in preventing and/or treating urogenital and intçstin~l disorders.
These and other objects wil! bccon.c readily appd-~,nl from the disclosure whichfollows.
SUMM~RY OF THE INVENI'ION
The present invention relates to compositions for the l.~ or prevention of
urogenital and intestin~l disorders, con.p-i~i..g.
a.) at 1east one plant species of the Ericaceae family or its extract; and
b.) an effective amount of a growth factor for f~..;l;~,.l;.,g the growth of lactic
~5 acid bacteria selected from the group con~i~tin~ of glycogen, rh~mnose7
gangliosides, salicin7 oli~osac~ . ;des, ~ tosç, lactulose, methyl-oc-D-
mannoside, p-nitrophenol-a-D-mannoside, maltose, dextrin, dextran, levan,
sialic acid, acetylgl~cos~ ~, yeast extracts, peptone, keratin, vegetable,
soy, lauric acid, glyceropho:,ph~ s and ml~lul~_s thereof.
The phrase "urogenital and i.. l~sl;.-~l compositions," as used herein, means a
product which in the ordinary course of usage may be relaillc~ in the oral cavity,
swallowed or applied topically to provide urogenital and/or intçstin~l activity.The term '~urog~snit~ as used herein, means that system of organs conce~ I-ed with
the prodllction and excretion of urine and reprod~lction
The term "intestin~l," as used herein, means of or relating to the intestines
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All percentages and ratios used herein are by weight unless otherwise specified.Also, all measurements referred to herein are made at 25~C unless otherwise specified.
PETAILEP DESCRIPTION OF THE INVENTION
The f-cct~nti~l as well as optional components of the compositions of the present
5 invention are described in the following paragraphs.
ESSENTIAL COMPONENTS
Plant or Extract of the Family Ericaceae
The Ericaceae (heath) family, consisting of about 110 genera and 4,000 species, is
by far the most important family of the Ericales order, encomp~csing a wide variety of fruit
10 producing shrubbery and e~,e-g-t;en plants. Genera falling under Ericaceae family include
V~cini-lm, Arctostaphylos, G~lltheria, and Gayll-sc~ The Arctostaphylos genus
in~llld~s such species as the checkerberry and be&.l,e..y (Uva ursi). Other edible fruits
such as the w ~,ping snowberry or moxie plum fall under the genus ~'J~ theria,
Huckleberries are a well known species of the genus Gayl~cs~ci~ The Vac-~ini-lm genus,
15 best known for its fruits, contain some of the most common of berries, in~hl~1ing the
blueberry (e.g., Y. aus~rale), ~ nb~,.,y (e.g., V. macrocarpon) and bilberry (e.g., Y.
myrffllus). The term "berry (ies)," as used herein, means berries, drupes, plums and the
like.
E. coli adherence results primarily from ~dh~cin.c on the raised hair like fimbriae (or
20 pili) of the microo.~,~-~h~"n. These iq~he~inC are desis~n~ted MS (mannose-sensitive) and
MR (mannose-.~s;,l&..l). Like most fruit, Eric~ce~ce fruit species contain fructose, an
inhibitor of MS ~lh~cin~ However, it has been recently s~l~gested that the plants or
extracts of Ericaceae species further contain an unid~ntifie(l, non-dialyzable polymeric
compound which inhibits the MR ~hesin~ associated with pyelonephritogenic strains of E.
25 Co~. The llnitl~ntified polymeric compound, as studied in Vncçinil~m species, was found
to inhibit both urinary and fecal isolates of E. Coli, the urinary isolates being inhibited to a
greater extent. Ofek, I. et al., Anti-Escherichia coli Adhesin Activity of Cl~nbe"y and
B~ueberry Juices. N Engl J Med 1991;324;1599. It has also been reported that theingl~sfi~n of large ~ A~ ;es of ~ nb_.l y juice il~ cased the hippuric acid content of urine
30 by several grams a day. This hlcl-,ase in hippuric acid excretion was acco.~ ;ed by small
decreases in urine pH. In vivo tests have established that hippuric acid was bacteriostatic
at pH 5.0 for common pathogens of the urinary tract, but this action was considerably
dc_rcased as the urine pH was raised. Papas, N.P., et al., Cldnl)e..y Juice In the
T~e~t~ of Urinary Tract Infections. Southwestern Me~licine~ 47:No. I (Jan. 1966).
35 'rhat the Fricace~e species of the present invention are effective against other pathogenic
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bacteria (e.g., Pseudomonas aeruginosa~ is disclosed in U.S. Patent 5,474,774, herein
incorporated by reference in its entirety; no effect was observed with respect to adhesion
of lactobacillus strains to cells. Without being limited by theory, it is believed that the
pathogenic inhibition caused by the Ericaceae plants or extracts results in decreased
5 pathogenic interaction, providing a more favorable, less antagonistic environment for
lactobacillus to initially adhere and ~ adherence. The phrase "anti-adhesive
activity," as used herein, means an amount effective to inhibit the adhesion of pathogenic
microorg~ to the epithelial and/or mucosal lining of the urogenital and/or intestin
tract.
Plants or extracts useful in the compositions of the present invention come from a
wide range of genera within the Ericaceae family in~ din5~, but not limited to, V~ccinillm~
Arctostaphylos, (7Al-ltheria, and Gayll-~s~c~ crc:l~cd species inCl~d~ V. a2~strale, V.
corymbos~m, ~. occidentale, V. ovatum, V. myrtill~s, V. parvifofium, ~ uliginosum, V.
macrocarpon, V. oxycoccus, V. e~yt*roca~m, V. vitis-idaea. ~. australe, V.
15 macroca7pon. VAGCini~lm species most pl~,rcllcd for use in the present invention include
V. a~s~rafe, V. macrocarpon, and V. myrtillus. Mixtures of Ericaceae plants and/or
extracts may also be used.
The plants or extracts of the present invention are preferably concellLI~Led, having a
ratio of at least about 4 pounds of plant conce"L.ate or extracts per pound of concentrate,
20 more p,c~.~bly from about 4 pounds of plant conce.,L-~Les or extracts per pound of
CQ~ te to about 50 pounds of plant concentrate or extracts per pound of col-re.~ te.
'rhe Ericaceae extracts are p.t~tl~bly present at a level of at least lOmg, more preferably
from about lOOmg to about 18g, most preferably from about 250mg to about 4g per unit
dose. The Amollnt of extract contained in each dose of product can be adjusted for the
25 dosage form. lFor . -A."ple, the amount of extract in powdered form used in a drink mix
can range up to 18g per dose while the amount used in swallowable cArsl~l~s might range
to about 4g. lF'~ ,d levels of the Ericaceae plants or extracts provide urinary and/or
;..le:,l.,-AI tract fluid conc~ lions of the above mentioned l~n~en~ified non-dialyzable
polymeric compound of from about 12 to about 25 micrograms per millilit~r Also, the
30 plants or extracts of the present invention l)fc~l~bly retain greater than 2. 5% of their total
acid content and greater than about 0.1% of their benzoic acid content. The level is
s.olected to provide the desired level of anti-adhesin activity and can be modified as
desired. G~ull/e.lies and .ilanbe.,y extracts are usefill in the ~ C~I and/or prophyiaxis
of urinary tract infections and are also useful as vaginal deodorants.
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S
Growth Factor for Lactic acid Bacteria
The compositions of the present invention also incorporate a growth factor for
lactic acid bacteria. The phrase "a growth factor for f~cilit~ting the growth of lactic acid
bacteria," as used herein, means a nutrient source or media which supplies a necessAry
source of food and/or energy for f~cilit~ting the growth of lactic acid producing bacteria.
The growth factor is preferably selective for establishing and ...~ Ai";"~ the growth of
lactic acid bacteria, pl c;rel ~bly Lactobacillus and/or Bifidobacterium species, without
fis~eilits-tin~ extreme growth of pathogenic bacteria. The various nutritional requirements
~Pnti:ll for bacterial and/or colony growth are normally met when the growth factor
10 contains ft;llllelllable carbohydrate, peptone, meat or yeast extract. Suppl~ tAIions with
tomato juice, m~n~nese, acetate and oleic acid esters, especially Tween 80, are
stim~ tory or even çc~çnti~l for most species and are, the,erc,le, inrl~lded in most MRS
medjllm Lactic acid bacteria adapted to very particular substrates may require special
growth factors.
Growth factors suitable for use in the present invention are s~1ecter~ from the group
con~ ~t;..g of glycogen; D-m~nnose; msnnitol, çsc~linç; lactose; saccharose; tr~h~losP; D-
raffinose; ~ntibiose; gluconate; rh~mnose; g~nglio~i~P$~ salicin; oli~os~crh~rides,
ctose; l~r~-losP; methyl~-D-mannoside; p-nitrophenol~-D-mannoside; m~ltose;
dextrin; maltodextrin; dextran; levan; sialic acid; acetyl~ cos~mine; yeast extracts;
20 proteinacious materials such as, peptone, keratin; vegetable; soy and unsaturated fatty
acids such as lauric acid and teichoic acids such as li~,ot~içl-rJic acid and esters such as
lycefophG~h~Pc or ,B-glycerophosphates. Fiber or fe""~ al)le substrates such as
psyllium may be used in the present co-,-posilions as may gums such as guar gum and
~;.."t.~-~ gum. When used vaginally monos~cç~ ides such as fructose and glucose as well
25 as whey proteins may also be incorporated. The growth factor is plt;rel~bly selected from
the group con~ ng of rh~mnose, oligos~c~h~rides and glucogen.
More p~ere.~bly the growth factor of the present invention is an oligosaccharidesuch as, but not limited to, galactooligosacch&, ides, soybean oligosaccharides and
fructoo5;~ns~c.~ ides. In addition to being a carbohydrate source, oligos~c~h~rides also
30 possess bio~lhPsive p,~,pe,lies which help f~x the location of these growth factors for
easier ac~;ess by lactic acid bacteria. Most ~r~,f~ d for use herein are
tooligl-sac~ ides. Lactic acid bacteria, such as T ~ctob~ci~ and Bifidobacterium,
partially utiiize ~uctooligosaccharides as an energy source by converting it, via
r ,....c ~ ;on, to lactic acid or a mixture of lactic acid, acetic acid, and C02. The lactic
35 acid and other fatty acids produced by this carbohydrate r~ A~;on contribute to the
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m:~int~n~nce of low pH which is an important control mechanism for preventing
co~onization of pathogens.
Ch~mic~lly~ oligofructose is the oligosaccharide fraction of inulin. It is composed
of the G~n and Fn type [G = glucose; F = fructose; n = number of frets moieties linked by
,B ~2,1) linkages in a ratio of about 2:1, with n = 2-6, and an average degree of
polymerization of 4. Inulin is prepared by hot water extraction of chicory roots and is
composed of molecl-lPs of the GFn type, n ranging as high as 60 with an average degree of
pol~,-"c-i~-lion of 10. Fructooligosaccharides suitable for use herein may or may not have
non-fructosyl units in place of fructosyl end units. The same is true for other
oligosaccharides with respect to their osyl end units. Non-fructosyl units may include, but
are not limited to, polyalcohols such as xylitol, m~nnitol, and sorbitol.
Fructooii.~os~cch~rides most p-c~c--cd for use in the present compositions are inulin or
oligofructose. Mixtures of these nutrients may also be used.
Without being limited by theory, it is believed that, upon ingestion, growth factors
increase the number of Lactobacillus and/or Bifidobacterium species available to ~icpl~re
pathogenic microor~niem.C from epithelial surfaces. The ir!crease lll the number of
Lactobacillus and/or Btfi~ob~ctçrium species co~p~ ely exclude the pathogens causing
them to be displaced and excreted; the result is an overall reduction of host pslthogf~nc
Moreover, as vaginal infections are generally believed to result from patnogenic migrating
from the rectum to the vagina, the number of pathogens invading the vagina are also
~c~luced as the number of migratory p~thog~nc dec~cascs.
Growth factors are p,crc-~ly incorporated into tlhe compositions of the present
invention at from about 5% to about 75%, more p~cre.~ly from about 20% to about
70%, and most prercr~bly from about 30% to about 65% per unit dose.
OPTIONAL CO~ONENTS
Species of Lactobacillus or Bifidobacterium
An optional co"-po,le"l of the present invention is a viable colony of Lactobacillus
or Bifidobacterium. Bacteria of the Lactobacillus genus are characterized as rod-shaped,
gram-positive and non-spore-rc" "ung bacteria. Of the farnily Lactob~ ce~
Lactobacillus inhabit the urog~nit~l and ga~l,o;~ tracts of animals and humans and
are i,~ ,la-,~ mf~mh~rs of lactic acid producing group of bacteria. Various species of
Lactobacillus are used con~ ially in the production of sour milks, cheeses and yogurt.
ob~ li also share an i,l,pO,l~,.l role in the m~n~lf~ctl-re offermented vegetables (e.g.,
pickles and sauerkraut), beverages (e.g., beer, wine and juices), sourdough breads, and
sorne r
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Lactobacillus species suitable for use in the present invention are those which 1.)
readily adhere to the epithelial cells of either the urogenital or gastrointestin~i tracts of
m51mm~1~; 2.) produce hydrogen peroxide; 3.~ promote low pH; and produce bacteriocins.
By "bacteriocins," as used herein, means proteinaceious, bacteriocidal substances
5 syntheci7ecl by bacteria, which usually have a narrow spectrum of activity, inhibiting
strains of the same or closely related species Bacteriocins appear to be capable of
~liepl~ring or su~ essing the growth of other bacteria, and as such may provide an
advantage to microor~nieme in rc~ g the female genital tract ecosystem. PlercllGd
species of Lactobacillus include L. acidophilus, L. johnsonii, L. catenaforme, L. brevis, L.
10 br~gc~ricus, L. Iactis, L. reuterii, L. gasseri, J. helveticus, L. casei, L. plantarum, L.
~elbrueckJi, L. thermophilis, L. jensenii, L crispa~us, L. rogosae and L. fermentum.
Species of T.~f.tobacilllls most pler~,.cd for use in the compositions of the present
invention include L. acidophilus, L. casei, L. crispatus, L. fermentum, and L. plantarum.
Preferably, the Lactobacillus species of the present invention are hydrogen peroxide
1~ producing such asL. acidophilus, L. catenaforme, L. casei, L. crispatus, L. delbrueckii, L.
Jensenii, L rogosae. L. fermentum, L. gasseri and L. p~antarum are also plere.,cd for use
herein in view of their adhesive 1~1 Up~il lies.
Also inhabiting the urogenital and ~aslloi..lestin~l tracts of ,..~."",~1~ and useful to
the compositions of the present invention are species of the genus Bifidobacterium (family
Actinomycet~ce~e). Bifidobacterium species are non-acid-fast, nonmotile gram negative
rods. Lactic and acetic acid producing Bifidobacteria are also considered i.~ ollall~
regulators of the urogenital and intestin~l flora of "~."".s~le Species suitable for use in the
present compositions inrlud~, but are not limited to, B. Iongum, B. breve, I,actobacillus
Bif dus and ~actobacillus bif dus subsp pennsylvanicus. r~ ercl l ~d for use in the present
compositions is B. Bif dum, most p-crc-lcd B. Bif dum subsp. Pennsylvanicus.
Mixtures of the T ~rtob~cilllls and/or Bifi-lob~ct~rium species may also be used.
Any of the above species may be obtained either com-nercially or through laboratory
cultures.
The T ~r-tobaci~ s and/or Bifidobacterium species are present at levels of at least
about 103 cells per unit dose, plcrwably at levels of from about 104 to about 1012 cells
per ul~it dose and most prcrel~bly at levels of from about 106 to about 101~ cells per unit
dose. The phrsse "unit dose," as used herein, means physically discrete units s ~it~ble as
unitary dos~es for ~ alion to .--~------~lc, each such unit co.~l~;..;.-g a predelc..,l.ned
quantity of an sctive ingredient c~lc~ ted to produce the desired Llle~ ic effect in
35 Pecor;stit~n with pharn~PceutiC~lly ~ccept~hle carriers. The level is srlected to provide the
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desired level of urogenital and gastrointestin~l activity and can be modified as desired.
Lactobacillus may loose 4-6 fold of its viability at room temperature and duringnl~mlfActllring~ so depending on the m~nllf~ctllring conditions, an excess of Lactobacillus
is added to ...~;..1~;.. an adequate number of viable org~nicmC per final unit dose forrn.
5 Alternatively, a patient can be a(lministered the equivalent of these concentrations of
or~nScme where the values are eA,~)Iessed by some other measurement such as, forexample, total protein concentration.
Buffering Agents
The compositions of the present invention may also contain a buffering agent. For
10 oral compositions, buffering to an acidic pH to enh~nce flavor may be done. For products
used in the vaginal area, buffering agents suitable for use in the compositions of the
present invention are those capable of ~ ing a urogenital pH of 3.0 to 5.5. Any
mild pha...-Ace~ltir~lly acceptable acid, other than those found in the ~ricaceae species
disciosed herein, can be used. Suitable acids include boric acid, or organic acids such as
15 quinnic acid, proprionic acid, malic acid, pyruvic acid, hippuric acid, tartaric acid, sorbic
acid, benzoic acid, lactic acid, ascorbic acid, citric acid, or acetic acid, in co...binalion with
their ~c~,e_Li~e sodium or other pharm~ceutic~lly acc~ ablc salt (to the extent neceSs".y
to achieve the desired pH). When buffered, the compositions of the present invention are
preferably buffered to a pH range of from about 3.5 to about 5.0, plt;re.al~ly from about
20 3.7 to about 4.7, and preferably using lactic acid ~,vith sodium lactate or a col,.b,.,aLioll
3actic acid~sodium lactate and benzoic acid or lactic acid/sodium lactate and proprionic
acid.
Additional Plant Extracts
A~ditional Ill~àp~.ltic and/or medicinal plants or extracts may also be incol~)olaLcd
25 into the composition~ of the present invention. Such plants or extracts include e~hin~ce~
alliurn, bucha, juniper ~inC.ong, allicin, chlorella, algin and the like. Mixtures of these
additional plants or extracts may also be used.
Nutritional Additives
Nutritional additives may also be incorporated into the compositions of the present
30 invention. Such additives inclucle, but are not limited to, proteins and carbohydrates other
than those mentionecl herein 2S growth factors, vitarnins such as nicotinic acid, pallLOlh~,.Lic
acid, and riboflavin; minerals such as ...A~ se, phytoc~ ; amino acids such as
serine, ~ ..;..ç, rnethionine, glycine, cysteine, leucine, i~o~c!lcine~ llueolulle7 valine.
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Phar~n~ce~1tical Actives
-. The compositions of the present invention may also be used in con~ alion with
phatm~reutic~l actives. The pharrn~ce-ltical active is preferably selected from at least one
of an an~lgesic agent and/or a ga .~- u;-~lestin~l agent.
FY~ P1~75 of ~n~lgecics plt;f~-~t;d for use in the present invention include
~cet~minophen, acetyl saiicylic acid, indomP,th~cin and optically active isomers or
r~cem~tes of ibuprofen, naproxen, flurbiprofen, carprofen, tiaprofenic acid, cicloprofen,
keloploren, ketoroiac, etodolac, indometh~c.in slllin~c, fenoprofen, diclofenac,piroxicam, benzydomine, nabumetone, their pharm~ceutically acceptable salts and rnixtures
thereof.
~..~,lcs of gastrointestin~l agents p-el~,.ed for use in the present invention
include anticholinergics in~ ing al-opille, clillinil~m and dicyclomine; ~nt~ri~s in~ in~
~IIlmin~lm hydroxide, bismuth subsalicylate, bismuth subcitrate, cimethicone7 calcium
carbonate and m~g~lrlrate; H2-receptor antagonists incl~rling cimeti~line, famotidine,
ni~ticline and r~niti~ine; laxatives incl~ing docusate, phenolphthalein and c~c~nthrol;
ga.,LI.~plotect~nts inr,lu~lin5~ sucralfate and sucralfate humid gel; gastrokinetic agents
inr.llt-ling metoclopramide and cisapride; proton pump inhibitors inrlu-ling omeprazole and
antidiarrheals i13rl~ltling diphello~ylate, kaolin pectin, attapulgite and loperamide.
Carrier Material~
The carriers into which the compositions of the present invention may be
i,,col~ol~led are many and varied and depend largely upon the end use of the
compositions. These carriers include orally acceptable as well as topical compositions.
They may be co-"plclely inert or contain or may be other active ingredients, yet the
carriers must be co~ Jali~lc with the herein disclosed compocitiQnc The term
25 "co~ ,le," as used herein, means that the carrier components are capable of being
co... ~g3fd with the components of the present invention, and with each other, in a
manner such that there is no interaction which would sub.st~nti~11y reduce the activity of
the compositions under Ol~indl~ use situations. Carrier materials must, of course, be o
s-tfl~r.i~ntly high purity and sufficiently low toxicity to render them suitable for
30 ~ rninictratjon to the human being treated. Prefe.~llly the compositions of the present
inY~,n~ion comprise from about 0.01% to about 99.99% of one or more carrier materials.
r ,;~,, suitable for topical ~ ion of the present compositions include
suppositories, vaginal tablets or capsules, ovules, creams, solutions for lavages, emulsions,
foams, soaps, gels, t;..;...~ s, oils and o;..~
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Crearns and gels, other base forrnulations may be used in topical ~flmini~tration of
the present compositions to, for example, the genital region and are p- ~,"a, ~d according to i'
conve.,liollal methods for semi-solid compositions using excipients like vaseline, paraffin,
vaseline oil, vegetable oils, animal oils, solid and liquid synthetic glycerides, waxes, lanolin,
lanolin alcohols, sorbitan esters, fatty alcohols, liquid/solid polyethylene glycols, propylene
glycols, polyethylene, starch, acryl~mides, mPth~rylamides, derivatives of cellulose and
carboxyvinyipolymers.
Ovules, suppositories, vaginal c~psule~ or tablets and effervescent tablets may also
be useful in topical application of the prevention. Ovules are similar to suppositories,
ovoidal shaped and the excipients mainly used are semi-synthetic glycerides and
po~yethylene glycols and optionally also em-~lcifif-rs and surf~ct~ntc
The vaginal capsules are ~f~l~tinol-c envelopes or sachets within which is
subdivided the suspension which is generally anhydrous and contains liquid paraffin,
vaseline, vegetable oils and semi-synthetic oils and thic~ening agents. The tablets, shaped
suitably for vaginal use, contain as main excipients lactose, starch, polyvinylpyrrolidone,
cellulose derivatives, m~nçsillm stearate, glycol. The effervescent tablets contain chf-mif ~1
components (i.e. sodium bicarbonate with citric acid or tartaric acid), which are nf-cf~ss~ry
to develop carbon dioxide in order to produce effervescçnf,e.
The compositions of the present invention may also be inco,l30,~ted into and
topicaliy applied by woven or nonwoven fabric materials such as tissues, wipes, fem,.u,,e
n~p~inS, panty liners, ~a,--pons, diapers, incontinent care products and the like. Plt:rellt;d
for use herein are nonwoven fabrics. Nonwoven fabrics suitable for incorporating the
present compositions are described in U.S. Patent 4,891,227 to Thaman et al., herein
incolpo-ated by ~crerence.
Oral dosage forrns are also useful as carriers for the present invention. These
dosage forms contain cf r..l~nl;ble solid or liquid filler f~ entc or f~nc~pslll~ting sukst~nf~ f-c
which are suitable for oral s-l...;..;~l~lion to a human or lower animal.
Liquid dosage forms for oral ~f~ on may co.n~.,ise dissolving or suspendingthe colllpo~iliolls of the present invention in a potable liquid, such as sterile or distilled
30 water. Alternatively, liquid or dry oral ~lminictration forms can conll,.ise an enterically
coated capsule c~ g the dosage forms. Suitable forms include emulsions,
= ons, solutions, syrups, and elixirs col ~ g inert diluents coll"llonly used in the
art, such as purified water, sugars, polysaccharides, silicate gels, gelatin, or an alcohol.
These inert ~ ntc do not actively participate in the Ll,e,~ tic effect of the present
35 inv~ ioll. R~d~s the inert ~ uP!ntc, such compositions can also contain wetting agents,
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emulsifying agents, suspending agents, as well as additional therapeutic actives. For a
more ~letAilç~l description of liquid and liquid-like dosage forms, see Remington's
Pharmaceutical Sciences. 17th ed., Mack Publishing Company, Easton, Pa. (199~), pages
1519-1~44, herein incorporated by reference
Tablets can be co~ ressed, molded, triturated or multiple compressed, con~ining
suitable binders, lubricants"~ çnts, disinteg. dling agents, and flow-inducing agents.
Tablets may be enteric-, film- or sugar-coated Protein-like coating components may
also be inçl~lded Useful for improvement of ga~,l-oi-~lestini~l disorders, such components
may contain branched amino acid-modified proteins. Whey powders, ~or example, are
1 Q treated with papain in the presence of the amino acids ethyl L-leucine (16.1 parts), ethyl L-
isoleucine ~7.4 parts), ethyl L-valine (10.2 parts), cysteine hydrochloride (1.~ parts), and
sodium carbonate (26 parts) in water at 40~C for 20 minlltes to m~nl-f~ct--re coated
powders col-~Aio;~g 10% free amino acids and 43% branched amino acids. The branched
amino acid-mo-lifi~d powders can be mixed with fats, dextrins, salts, vitamins, and the like
to make tablets.
Other examples of a tablet coating materials are zeolites and clays to make tablets
more palatable. Zeolites have found use as bacterial feed co~tings for domestic ~nim~
For P~mple, in the domestic animal b--eine~, timPIine fumarate is dissolved in ,,.~ oi,
supported on mordenite-type zeolite or starch, dried and further premixed with the
supports to produce s~t~inec~-release, coated granules. Still other examples of tablet
coatings include complex carbohydrate and inclusion complexes.
Also useful are soft or hard gelatin c~rS~Ies P,~re.dbly, the gelatin shell is
essçnti~lly lldns~drelll so as to enh~nce the aesthetic qualities of the capsule. Soft and
hard gelatin shells generally colllp-ise gelatin, a pl~tiri7pr and water. The starting gelatin
material generally used in the m~nllf~r,t~lre of these c~rs~le~ is obtained by the partial
hydrolysis of coll~:çno~s material. Gelatin suitable for capsule m~n~f~ctl~re isco.n.~ .,;ally available from the Sigma Chemical Company, St. Louis, Mo. One or more
. is ~nco~ed t.~ ~ro~luce ~ gdati~ shell. Urse~! pl~ i7~ ~ the ~resent
,e.lL;on include glycerin, so-bilan, sorbitol, or similar low molecular weight polyols, and
3{~ mixtures thereof.
l~e~ln;~lues and compositions for making solid oral dosage forms are described in
Marshall, "Solid Oral Dosage Forms," Modern Pharm~çe~tics. Vol. 7. (Banker and
Rhodes7 editors), 359~27 (1979~, inc~ ,o-~led by r~rt;.~,nce herein. Techniques and
COIll~O'-'l;Ol-~ for making tablets (co---~ ,scd and molded), ç~ps--les (hard and so~
35 gelatin), troches and pills are described in Rc ~ on's Pharm~çMltical Sciences (Arthur
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Osol, editor), 1553-1593 (1980) and U.S. Patent 4,935,243, to Borkan et al., issued June
19, 1990; these two references being incorporated herein by reference in their entirety.
Specific examples of pharm~cel-tic~lly acceptable carriers and excipients that may be used
to formulate oral dosage forms, are described in U.S. Patent 3,903,297, Robert, issued
September 2,1975, incorporated by r~lc:ilce herein.
Alternatively, the compositions of the present invention may be achieved by
incorporating the compositions of the present invention into freeze-dried or Iyophilized
tablets. Freeze-drying or lyophil,~lion f~rilit~tes Aicinte~ration of the composition by
forming the dried composition into an open matrix network. In most cases, this results in
rapid permeation by the aqueous media, promoting timely delivery of the product.Suitable metho~s of freeze drying are well known in the art and comrnonly employed.
Any suitable con~ Lional method of freeze-drying may be l.lti~ ~d A prt:r~.~ble method
of fi ee~;-lg and drying is to fast freeze the composition and then dry the composition to a
final moisture content of about 2% to about 5% Suitable methods of freeze-drying and
production are taught by U.S. Patent 4.642.903~ February 17, 1987, to Davies, U.S.
Patent 4.946~684~ August 7,1990, to Blank et al., U.S Patents 4.305~502 and 4.371~516
issued Decemhçr 15,1981 and February 1, 1983 respectively, to Gregory et al., and U.S.
Patent 5~1~8~825~ February 23,1993, to Iles et al.; which are all incorporated herein by
I ~r~ ce.
Similarly, the compositions of the present invention may be vacuum dried.
Vacuum drying involves at least the partial drying of compositions at tel~lpelaLLIres above
compositions' collapse teln,vc.~ re. Freeze drying, on the other hand, involves the drying
of compositions at te~ L~res below the composition's collapse temperature. Any
suitable method of vacuum drying may be used. Suitable vacuum drying processes are
described in U.S. Patent 5298~261~ to Pebley et al., issued March 29, 1994, herein
incorporated by reference.
One other form of tabl " teçhnolQgy that may be applicable to the present
invention is a liquid/liquid extract developed by Janssen Pharm~ce~tic~ Inc. and is
ntified by the trade name QuicksolvTM. This technology is fully described in U.S. Patent
5~215~756, herein h~col~ora~ed by le~,~.lce.
Other optional ingredients well known to the pharrnacist's art may also be inclllded
in amounts generally known for these ingredients, for ~,A~nlple, natural or artificial
sweeteners, fiavoring agents, colorants, perfuming agents, buffering agents and the like to
provideap-' ~leand~l~~~ lookingfinalproduct,~ntioxi~nte~for-~...pl~ butylated
35 hydroxy anisole or butylated hydroxy to!--çne, and preservatives, for example, methyl or
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propyl paraben, potassium sorbate, or sodium benzoate, to prolong and .onh~nce shelf life.
A p-erel,ed optional component is also caffeine.
Those of ordinary skill in the art will quickly realize other suitable ingredients,
iiln~ntS and dosage forms, or will be able to ascertain such, using routine experim~nt~tion.
5 Further, the a~lminictration of the various compositions can be carried out using standard
techni~ ec common to those of ordinary skill in the art.
Examples
The following examples further describe and demon~ te embodiments within the
scope of the present invention. These examples are strictly given for illustration purposes
10 and are not to be construed as limitations of the present invention, as many variations are
possible without departing from the spirit and scope of the invention as set forth herein.
Example I
A tablet form of the present invention is made by co~ ung the following
components using conventional mixing and tableting technology.
In~redient % Wei~ht
Concentrated Cranberry Extract 17.600%
fructooligosaccharide1 56.340%
Ethylcellulose, l00 cps (5% ethanol soln)9.900%
Starch 1 1.230%
Talc 4.230%
Stearic Acid 0.700%
Available as NutraFlora FOS from Golden Technologies Company, Inc.
The ~ nbe.~y extract and fructooligosaccharide are gr~n~ ted with 5%
ethylc~ ose in ethanol. The granulation is then passed through a 12 mesh screen and
dried at 120~F. To the dried granulation is added stearic acid. The granulation mixhlre is
passed through a 20 mesh screen. To the sieved gr~n-~i~tinn is added the starch and talc
and mixing until uniform. The res~-lt~nt granulation mixture is then co"")ressed using
conventional tableting processes.
Example II
A capsule form of the present invention is made by colnbil~ing the following
co.... ..,yvnellls using conventional mixing technology.
Ingredient ~~Q Weight
Conce--l-~l~d Cranber~y Extract 35.000%
fructooligosaccharide 1 3 5 .000%
Avicel2 26.300%
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Ac Di Sol3 3 700%
Available as NutraFlora FOS from Golden Technologies Company, Inc.
2 TM for microcrystalline cellulose, a highly purified particulate form of cellulose.
3 A brand of a cross-linked form of sodium carbox~nnethylcellulose.
Combine and mix the 1ldnbelly extract, fructooligosaccharide, Avicel and Ac Di
Sol in a V-blender until uniform. Unit dose amounts of the resultant mixture is then
placed into suitably sized hard gelatin c~psllles
Example III
A topical gel forrn of the present invention is made by combining the following
components using conventional mixing technology.
Ingredient % Weight
Concentrated Cranberry Extract 0.50%
fructooligo~cch~ride1 6.00%
Polyacrylamide and Cl3-14
Isopd~rr" and Laureth-72 4.00%
PPG-14 Butylether 8.00%
Water, Purified q.s.
Available as NutraFlora FOS from Golden Technologies Company, Inc.
2 Available as Sepigel from Seppic Corporation.
Water is added to a suitable size co.. Lainer. While mixing at a moderate speed (300
rpm), the Po1yacrylamide and Cl3 14 Isopa.drrlil and Laureth-7 is added to the water to
form a water phase. Separately, the PPG-14 Butyl ether is placed in a container and
covered. Using a T.ightnin' Mixer with a 3 blade paddle prop, the cld~ ly extract and
~uctooli~ cch~ride are added to the PPG-14 Butyl ether and mixed at a low speed (100
25 rpm) until the cranberry extract and fructooligosaccharide are dissolved. The PPG-14
Butyl ether .~lu.e is slowly added to the water phase to form a gel. The resl-lting gel is
mixed at moderate speed until uniform.
Furthermore, the above described compositions may also contain a growth factor
such as glycogen, rh~mnos~ oligosaccharides, l~r~t-llQs~ methyl-a-D-m~nnos;~l~, p-
30 lul.o~)henol~c-D-m~nnosid~, maltose, dextrin, levan, acetylglucosamine, amino acids,
pn~le;l.acious materials such as, peptone, keratin, vegetable, soy, glycerophosyhaLes and
mi~Lules thereof. Those skilled in the art will quickly realize other suitable ingredients,
diluents and dosage forms (or readily ascertain such using routine eXperim~nt~tiQn) which
may filrther be inco- ~Jo. ~ted into the above compositions without dc,-d- ling from the scope
35 and spirit ofthe present invention.
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While the invention has been described in terms of its l~lef~..t;d embo~im~
- those skilled in the art will recognize that the invention can also be practiced by
5 ~minietering the herein described components separately and still remain within the scope
and spirit of the present invention
