CA2245810A1 - Urogenital and intestinal compositions - Google Patents
Urogenital and intestinal compositions Download PDFInfo
- Publication number
- CA2245810A1 CA2245810A1 CA002245810A CA2245810A CA2245810A1 CA 2245810 A1 CA2245810 A1 CA 2245810A1 CA 002245810 A CA002245810 A CA 002245810A CA 2245810 A CA2245810 A CA 2245810A CA 2245810 A1 CA2245810 A1 CA 2245810A1
- Authority
- CA
- Canada
- Prior art keywords
- acid
- species
- group
- mixtures
- lactobacillus
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/13—Coniferophyta (gymnosperms)
- A61K36/14—Cupressaceae (Cypress family), e.g. juniper or cypress
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/02—Algae
- A61K36/05—Chlorophycota or chlorophyta (green algae), e.g. Chlorella
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/45—Ericaceae or Vacciniaceae (Heath or Blueberry family), e.g. blueberry, cranberry or bilberry
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- A—HUMAN NECESSITIES
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- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/896—Liliaceae (Lily family), e.g. daylily, plantain lily, Hyacinth or narcissus
- A61K36/8962—Allium, e.g. garden onion, leek, garlic or chives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Reproductive Health (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
This application relates to compositions useful in preventing and/or treating urogenital and intestinal disorders, comprising an effective amount of at least one plant species of the Ericaceae family or its extract and a culture of at least one species of microencapsulated bacteria selected from the group consisting of lactobacillus, bifidobacterium and mixtures thereof.
Description
I
UROGEN~TAL AND INTLSTINAL COMPOSITIONS
TECHNICAL FIELD
This application relates to compositions useful in preventing and/or treating urogenital and ;~le~ disorders.
BACKGROUND OF THE INVENTION
1~ Complex, microscopic ecosystems pervade the urogenital and intestin~l tracts of warm blooded ~nim~lc. Trillions of microo~ , comprising hundreds of species,occupy the urogenital and intçstin~l tracts of m~mm~lc, infl~enc:in~ and ,~ .g digestive and urologic functions. MicroorD~ c occupying these regions range frompotentially pathogenic strains, such as Esche.ricl~ia coli, enterococci, c~n~ gardnerella, 15 klebsie 11~ and clostridia, to the relatively nonpathogenic, such as lactobacillus and bifidobacterium. Deviations from this delicate flora balance have been etiologically linked to a number of urogenital and/or gastrointestin~l tract disorders; such imh~l~nces usually r~sulting in the proliferation and predo.,.h~allce of pathogenic species~ Establishing and/or preserving such a delicate flora balance is;, therefore, eSsçnti~l to ~ g optimal 20 health.
One way of establishing or 1..~ ;"i,~ the body's flora is by ~riminictering to~cii~lc ~he use of lactobacillus to treat urogenital and intestin~l disorders has been proposed, for in~t~ncP, in C~n~ n Patent 1,298,556, issued April 4, 1992, to Bruce et al., PCT Application Serial Number WO 93/09793, published May 27, 1993, to Reid et al. and U.S. Patent 5,176,911, issued Januarv 5, 1995, to Tosi et al. Researchers hypothesize that tolo~c.illl~s provide host protection via adherence to intestin~l or vaginal epithelial cells.
N~lw;l~ tling such proposals, several factors have been identified, casting doubt on the use of lactobacillus as single agent therapy for urogenital and/or gastroint.ostin~l infection. 1) Variation exists among strains of lactobacillus concerning the degree to which individual strains of lactobacillus can adhere to epithelial surfaces. Reid, G. et al., ,.,.;nO~ion of strains of Lactobacillus for properties that may inflllençe bacterial illlel~el~ce in the urinary tract. J. Urol., 138:330-335;}987. This variation may also extend to individual microorg~i-;s...s. 2) Pathogenic microo- ~ are most reliably ~Yr.lll~7ed where lactobacillus colonies are established prior to pathogenic invasion.
35 E~awthorn, L.A. et al., Exclusion of uropatho~en adhesion to polyrner surfaces by Lactobacillus acidophilus~ Jour. Biomed. Mat. Res., 24;39-46; 1990; a nonexistent CA 0224~810 1997-08-10 W O 97129762 PCTrUS97/01662 situation, however, barring in vitro design. 3) Viability issues exist regarding orally ingested live bacterial cultures. Clinical research reveals that not all live bacteria survive the digestive fluids of the stomach and upper intestin~l tract. Those which do survive may emerge too weak or too few in number to effectively colonize the lower intestine.
5 Moreover, recognizing the need for sound clinical studies in the area, some researchers express further concern as to the efficacy of certain lactobacillus species. Therefore, despite the disclosures relating to lactob~ s products, there still remains a need for improved urogenital and gastrointestin~l tract compositions incorporating lactobacil1us.
The present inventors have found that compositions incorporating plants or 10 extracts of the Ericaceae family with microencapsulated Lactobacillus andlor Bifidobacterium provide improved compositions for treating and/or preventing urogenital and gastrointestin~l disorders by modifying the interaction of pathogens with cellular tissue. Recent studies also suggest the value of Ericaceae extracts in treating urinary tract infections. -Researchers have observed that various species of vaccin~ (e.g. cranberry ~5 and blueberry) contain a polymeric compound which inhibits the adhesion of common urinary pathogens (e.g., E. coli) to infection sites within the urinary tract. Ofek I et al., Anti-Escherichia coli Adhesin Activity of Cranberry and Blueberry Juices. N Engl ~ Med 1991;324;1599. Su~ ingly, the compositions ofthe present invention provide improved environments more conducive to the colonization of lactic acid bacteria. Accordingly, it is 20 an object of the present invention to provide compositions for dietary supplPrnent~tion Another obiect of the present invention ;s to provide improved compositions comp~ ing a viable colony of microencapsulated lactobacillus and/or bifidobacteria.
A further object of the present invention is to provide compositions effective in preventing andlor treating urogenital and intestin~l disorders.
UROGEN~TAL AND INTLSTINAL COMPOSITIONS
TECHNICAL FIELD
This application relates to compositions useful in preventing and/or treating urogenital and ;~le~ disorders.
BACKGROUND OF THE INVENTION
1~ Complex, microscopic ecosystems pervade the urogenital and intestin~l tracts of warm blooded ~nim~lc. Trillions of microo~ , comprising hundreds of species,occupy the urogenital and intçstin~l tracts of m~mm~lc, infl~enc:in~ and ,~ .g digestive and urologic functions. MicroorD~ c occupying these regions range frompotentially pathogenic strains, such as Esche.ricl~ia coli, enterococci, c~n~ gardnerella, 15 klebsie 11~ and clostridia, to the relatively nonpathogenic, such as lactobacillus and bifidobacterium. Deviations from this delicate flora balance have been etiologically linked to a number of urogenital and/or gastrointestin~l tract disorders; such imh~l~nces usually r~sulting in the proliferation and predo.,.h~allce of pathogenic species~ Establishing and/or preserving such a delicate flora balance is;, therefore, eSsçnti~l to ~ g optimal 20 health.
One way of establishing or 1..~ ;"i,~ the body's flora is by ~riminictering to~cii~lc ~he use of lactobacillus to treat urogenital and intestin~l disorders has been proposed, for in~t~ncP, in C~n~ n Patent 1,298,556, issued April 4, 1992, to Bruce et al., PCT Application Serial Number WO 93/09793, published May 27, 1993, to Reid et al. and U.S. Patent 5,176,911, issued Januarv 5, 1995, to Tosi et al. Researchers hypothesize that tolo~c.illl~s provide host protection via adherence to intestin~l or vaginal epithelial cells.
N~lw;l~ tling such proposals, several factors have been identified, casting doubt on the use of lactobacillus as single agent therapy for urogenital and/or gastroint.ostin~l infection. 1) Variation exists among strains of lactobacillus concerning the degree to which individual strains of lactobacillus can adhere to epithelial surfaces. Reid, G. et al., ,.,.;nO~ion of strains of Lactobacillus for properties that may inflllençe bacterial illlel~el~ce in the urinary tract. J. Urol., 138:330-335;}987. This variation may also extend to individual microorg~i-;s...s. 2) Pathogenic microo- ~ are most reliably ~Yr.lll~7ed where lactobacillus colonies are established prior to pathogenic invasion.
35 E~awthorn, L.A. et al., Exclusion of uropatho~en adhesion to polyrner surfaces by Lactobacillus acidophilus~ Jour. Biomed. Mat. Res., 24;39-46; 1990; a nonexistent CA 0224~810 1997-08-10 W O 97129762 PCTrUS97/01662 situation, however, barring in vitro design. 3) Viability issues exist regarding orally ingested live bacterial cultures. Clinical research reveals that not all live bacteria survive the digestive fluids of the stomach and upper intestin~l tract. Those which do survive may emerge too weak or too few in number to effectively colonize the lower intestine.
5 Moreover, recognizing the need for sound clinical studies in the area, some researchers express further concern as to the efficacy of certain lactobacillus species. Therefore, despite the disclosures relating to lactob~ s products, there still remains a need for improved urogenital and gastrointestin~l tract compositions incorporating lactobacil1us.
The present inventors have found that compositions incorporating plants or 10 extracts of the Ericaceae family with microencapsulated Lactobacillus andlor Bifidobacterium provide improved compositions for treating and/or preventing urogenital and gastrointestin~l disorders by modifying the interaction of pathogens with cellular tissue. Recent studies also suggest the value of Ericaceae extracts in treating urinary tract infections. -Researchers have observed that various species of vaccin~ (e.g. cranberry ~5 and blueberry) contain a polymeric compound which inhibits the adhesion of common urinary pathogens (e.g., E. coli) to infection sites within the urinary tract. Ofek I et al., Anti-Escherichia coli Adhesin Activity of Cranberry and Blueberry Juices. N Engl ~ Med 1991;324;1599. Su~ ingly, the compositions ofthe present invention provide improved environments more conducive to the colonization of lactic acid bacteria. Accordingly, it is 20 an object of the present invention to provide compositions for dietary supplPrnent~tion Another obiect of the present invention ;s to provide improved compositions comp~ ing a viable colony of microencapsulated lactobacillus and/or bifidobacteria.
A further object of the present invention is to provide compositions effective in preventing andlor treating urogenital and intestin~l disorders.
2~ 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 methods for preventing and/or treating urogenital and intestin~l disorders.
These and other objects will become readily a,oparel,l from the disclosure whichfollows.
SUMMARY OF THE INVENTION
The present invention relates to compositions for the l.eaLI,,e.lL or prevention of urog~nit~l and tntestin~l disorders, comprising:
a.) an ~nfi lh~sive amount of at least one plant species of the Ericaceae family or its extract; and W O 97/29762 PCT~US97tO1662 b.) a viable culture of at least one species of microencapsulated bacteria selected from the group eonsisting of lactobacillus, bifidobacterium and mixtures thereof.
The present invention also relates to the above compositions filrther comprising a S growth factor for fz.cilitz~ting the growth of lactic acid bacteria.
The phrase "urogenital and intestin~l compositions," as used herein, means a product which in the ordinaly course of usage may be retained in the oral cavity, swallowed or applied topically to provide urogenital and/or intPstinZll activity.
The phrase "~nti~-lhesive amount," as used herein, means an amount effective to 1 û reduce the number of pathogenic microorg~micmc on the epithelial and/or mucosal lining of the urogenital and/or intestjnz I ~ract.
The term "urogenital," as used herein, means that system of organs concerned with the production and excretion of urine and reproduction.
The terrn "intectinz I " as used herein, means of or relating to the intestin~c The term "nonpathogenic," as used herein, means s~ a~Lially lacking the ability to cause disease or abnormality in healthy m2mms~1c The term "healthy," as used herein, means free of underlying disease and/or immunosuppression.
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.
DETAILED DESCRIPTION OF THE INVENTION
The e~.cç~ as well as optional components of the compositions of the present invention are described in the following paragraphs.
ESSENTIAL COMPONENTS
Plants or extracts of the Family Ericaceae The Ericaceae (heath) fannily, consisting of about 110 genera and 4,000 species, is by far the most i."~o- I~IIL family of the Ericales order, enComraccing a wide variety of fruit producing shrubbery and evergreen plants. Genera falling under Ericaceae family include V~crinil~m, Arctostaphylos, ~Ja~-lt~-~ria, and Gaylnsc~ci~ The Arctostaphylos genus inr~ 1e.s such species as the checkerberry and bearl,clly (Uva ursi). Other edible fruits 3 0 such as the creeping snowberry or moxie plum fall under the genus Gaultheria.
kieberries are a well known species of the genus Gayll~cs~ei~ The Vacrinium genus, best known for its fruits, contain some of the most cornrnon of berries, inrlut1ing the blueberry (e.g., V. australe), cranberry ~e.g., Y. macrocarpon) and bilberry (e.g., Y.
myrt~llus). The term "berry ~ies)," as used herein, means berries, drupes, plums and the lilce.
W O 97/29762 PCTrUS97/01662 E. coli adherence results primarily from ar1hesin.c on the raised hair like fimbriae (or pili) of the microol~ani~lll. These ~tlhe~inc are (lçcign~ted MS (mannose-sensitive) and MR (mannose-resistent). Like most firuit, Ericacease fruit species contain fructose, an inhibitor of MS ~h~cin~. However, it has been recently suggested that the plants or extracts of Ericaceae species further contain an llnic~elltified, non-dialyzable polymeric compound which inhibits the MR adhesins associated with pyelonephritogenic strains of E
Cofi. The llni~ntified polymeric compound, as studied in Vaccinium species, was found to inhibit the adhesion of 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 Cranberry and Blueberry Juices. N Engl J Med 1991;324;1599. It has also been reported that the ingestion of large quantities of cranberry.~uice increased the hippuric acid content of urine by several grams a day. This increase in hippuric acid excretion was accompanied 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 1~ considerably decreased as the urine pH was raised. Papas, N.P., et al., Cranberry Juice In the Treatment of Urinary Tract Infections. Southwestern Medicine, 47:No. I (Jan. 1966).
That the Ericaceae species of the present invention are effective against other pathogenic bacteria ~e.g., Pseudomonas aeruginosa) is disclosed in U.S. Patent 5,474,774, issued December 12, 1995, to Walker et al., herein incorporated by reference in its entirety; no 20 effect was observed with respect to adhesion of lactobacillus strains to cells. Without being lim-ted by theory, it is believed that the pathogenic inhibition caused by the Ericaceae plants or extracts results in decreased pathogenic interaction, providing a more favorable, less antagonistic em,i,~,-"l-G--l for lactobacillus to initially adhere and m~int~in adherence. The phrase "anti-adhesive activity," as used herein, means an amount effective 25 to inhibit the adhesion of pathogenic microoly,~ni~ to the epithelial and/or mucosal lining ofthe urogenital and/or intçstin~l tract.
Plants or extracts useful in the compositions of the present invention come from a wide range of Ericaceae genera incltl~in~, but not limited to, V~ccinillm Arctostaphylos, ~lllt~eria, and Gayl~ c~ c~.l~,d species ;nclude, V. ausfrale~ V. corymbosum, V.30 occidenfale, V. ovatum, V. myrffllus, V. parvifolium, V. uliginosum, V. macrocarpon, V.
o~ycoccus, ~ erythrocarpum, V. vitis-idaea Y. ausfrale~ V. macrocarpon. V~cr.inium species most I)lefc-lcd for use in the present invention include V. ausfrale~ Y.macrocarpon, and V. myrtillus. Mixtures of Ericaceae plants and/or extracts may also be used.
CA 022458l0 l997-08-lO
W O 97/29762 PCTrUS97/01662 The plants or extracts of the present invention are preferably concentrated, having a ratio of at least about 4 pounds of plant concentrate or extracts per pound of concentrate, more preferably from about 4 pounds of plant concentrates or extracts per pound of ~ concentrate to about ~0 pounds of plant concentrate or extracts per pound of concentrate.
The Ericaceae extracts are preferably present at a level of at least lOmg, more preferably from about IOOmg to about 18g, most pler~i~bly from about 250mg to about 4g per unit dose. The amount of extract contained in each dose of product can be adjusted for the dosage form. For example, 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 capsules might range 10 to about 4g. Plef~,led levels of the Ericaceae plants or extracts provide urinary and/or intestin~l tract fluid concenllalions of the above mentioned unid~ntified, non-dialyzable polymeric compound of from about 12 to about 25 micrograms per m~ ter Also, the plants or extracts of the present invention pl erc:. ~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 15 selected to provide the desired level of a~nti-adhesin activity and can be modified as desired. Cranberries and cranberry extracts are useful in the tre~tme-lt and/or prophylaxis of urinary tract infections and are also useful as vaginal deodorants.
Species of Lactobacillus or Bifidobacterium Another ~Sspnti~l component of the present invention is a viable colony of 20 microencapsulated Lactobacillus or Bifidobacterium. Bacteria of the Lactobacillus genus are characterized as rod-shaped, gram-positive and non-spore-forrning bacteria. Of the family Lactob~cill~e~e~ Lactobacillus inhabit the urogenital and gastrointestin~l tracts of animals and h~ n~ and are important members of lactic acid producing group of bacteria.
Various species of Lactobacillus are used c;ommercially in the production of sour milks, 25 cheeses and yogurt. Lactobacilli also sha.re an important role in the m~n~lf~ct~lre of fermented vegetables (e.g., pickles and sauerkraut), beverages ~e.g., beer, wine and juices), sourdough breads, and some s~lls~çs.
T ~ctob~rillus species suitable for use in the present invention are those which 1.) readily adhere to the epi~ l cells of either the urogenital or ~a~ oi~-~estin~l tracts of 30 ~Uhl~ ; 2.) produce hydrogen peroxide; 3.) ~.ol--ole low pH; and produce bacteriocins.
By "bacteriocins," as used herein, mea,ns p~ e;..~ceious, bacteriocidal substances syr~t~e~i~P~d by b..cLe,ia, which usually ha~e a narrow spectrum of activity, inhibiting strains of the same or closely related species. Bacteriocins appear to be capable of ~1i5p~ ~ or supplesslng the growth of other bacteria, and as such may provide an35 advantage to microorg~ni~m~ in -fellllell~ g the female genital tract ecosystem. Pl~r~llcd W O 97/29762 PCTrUS97/01662 species of Lactobacillus include L. aci~ophilus, L. cate~ta~orme, L. brel~is, L. bulgaricus, L. Iac~is, L. reu~erii, L. gasseri, L. helveticus, ~. casei, L. plantar1~m, L. delbru~chi, L.
t*ermop*ilis, L. Jensenii, L Crispatl~S, L. rogosae and r. fermerltum Species ofLactobacillus most prefe--ed for use in the compositions of the present invention include L acidophilus, L. casei, L. crispatl~s, L. fermentum, and L. plantarum. Preferably7 the Lactobacillus species of the present invention are hydrogen peroxide producing such as ~.
ac~dophilus, L. catenaJrorme, L. casei, L. crispatus, L. delbrueckii, L. jensenii, L rogosae.
r.. fermentum, L. gasseri and L. plantarum are also plerelled for use herein in view of their adhesive properties.
Also inhabiting the urogenital and gastrointestin~l tracts of m~mm~lc 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 important regulators of the urogenital and inte5tin~1 flora of m~rnm~lc Species suitable for use in the 1~ present compositions in~lnd.q, but are not limited to, B. longllm B. breve Lactobacillus B~f d~s and L~ctobacillus bif dus s2(bsp pennsylvanicus. Preferred for use in the present compositions is B. Bif dum, most p-ere-led B. Bif dt~m subsp. Pennsylvanicus.
Mixtures of the Lactobacillus and/or Bifidobacterium species may also be used.
Any of the above species may be obtained either commercially or through laboratory 20 cultures.
The Lactobacillus andlor Bifidobacterium species are present as core and/or coating con-ponents at levels of at least about 103 cells per unit dose7 pl~re-ably at levels of ~om about 104 to about 1012 cells per unit dose and most preferably at levels of from about 106 to about IOlQ cells per unit dose. The phrase "unit dose," as used herein, 25 means physically discrete units suitable as unitary dosages for ~tlminictration to m~mm~lc, each such unit co..~ g a predetermined quantity of an active ingredient calculated to produce the desired Lll~ pcutic effect in association with pharrnaceutically acceptable carriers. The level is sçlectecl to provide the desired level of urogenital and gastrointestin~l activity ~nd can be modified as desired. Lactobacillus may loose 4-6 fold of its viability at 30 room ttn~pc-~lure and during m~mlf~r,tllring, so depending on the m~n-lf~ctllring conditions, an excess of Lactobacillus is added to IllAinlAi.~ an adequate number of viable org~nicmC per final unit dose form. Alternatively, a patient can be a-lnninict~red the equivalent of these conc~ ions of org~ni~m.c where the values are expressed by some other measurement such as, for example, total protein concentration.
CA 022458l0 l997-08-l0 WO 97/29762 PCTnUS97/01662 The Lactobacillus and/or Bifidobacterium species of the present invention must also be microencapsulated. Viable I,actobacillus and/or Bifidobacterium bacteria that have been Iyophilized after the removal of the growth media can be used for encapsulation. The bacteria can be obtained from commercial sources, or can be obtained from laboratory S strains. Suitable media include MRS, Thayer-Martin media, Trypticase Soy, Brain-Heart Infusion Broth, or any other enriched rnedia suitable for the cultivation of these or~ni~m.c as no particular med;a is critical to the success of this suppository. The only important factors are the viability and quantity of the micro-o,~lis-"s that are always determined by standard clinical laboratory dilution methotis, such as plating the quantified dilution of bacteria on to blood agar plates or other enriched media, incubating at 37~C for 24-48 hours in a 5-10% carbon dioxide atmosphere, and then perforrning a colony count. The removal ofthe nutrient media is done by centrifugation at 14,000 x g at 0~-4~C., and then was~ing with sterile, balanced salts and 5% glucose solution at least three times after the initial centrifugation. The bacteria are then. "snap frozen" with liquid nitrogen and then 1~ lyophilized under high vacuum. The bact.eria are then microencapsuled according to conventional micro~nc~rsul~tion technolo~y. Suitable methods of encapsulation are disclosed in U.S. Patent 5.466.463. issued November 14, 1995, to Ford and U.S. Patent .407.609. issued April 18, 1995, to Tice, both of which are herein incorporated by le~cl~ce in their entirety.
OPTION~L CO~DPO~nENTS
Lactobacillus Growth Factor Also useful to the compositions of the present invention is a growth factor for f~cilit~ting the growth of lactic acid bacteria. The phrase "a growth factor for f~r.ilit~tin~
the growth of lactic acid bacteria," as used herein is meant a nutrient source or media 25 which supplies a necessary source of food and/or energy for f~çilit~ting the growth of lactic acid producing bacteria. The growth factor is preferably selective for establishing and ..~ g the growth of lactic acid bacteria, preferably Lactobacillus and/or Bifi~obacterium, without f~ it~tin~ extreme growth of pathogenic bacteria The various nutritional requi.t;nle"Ls essential for bactelial and/or colony growth are normally met 30 when the growth factor contain fermentable carbohydrate, peptone, meat and yeast extract. Suppiç~ l;ons with tomato juice, m~n~nç~, acetate and oleic acid esters, especially Tween 80, are stim~ tory or even eS.~enti~l for most species and are, therefore, in~ .lded in most M~S mefli-lm Lactic acid bacteria adapted to very particular substrates rnay require special growth factors.
CA 0224~810 1997-08-10 W O 97/29762 PCT~US97/01662 Examples of suitable growth factors include, but are not limited to, yeast extracts;
gangliosides; salicin; mono-, di- and polysaccharide sugars such as glycogen, glucose, fructose, rhamnose, lactulose, methyl-a-D-mannoside, p-nitrophenol-a-D-mannoside, maltose, maltodextrin, dextrin, dextran, levan, sialic acid and acetylglucosamine as well as 5 oligosaccharides such as, but not limited to, fructooligosaccharides, galactooligosaccharides and soybean oligos~cch~rides. Fiber or fermentable substrates such as psyllium may be used in the present compositions as may gums such as guar gum and x~nthum gum. Similarly, proteinacious materials such as, peptone, keratin; vegetable;
soy and unsaturated fatty acids such as lauric acid and teichoic acids such as lipoteichoic 10 acid and esters such as glycerophosphates or ~-glycerophosphates are also useful as growth factors. The growth factor is preferably selective for establishing and m~int~ining the growth of lactic acid bacteria, most preferably Lactobacillus and/or Bifidobacterium species. Growth factors preferable for use in the compositions of the present invention include lactose, lactulose, rhamnose, oligosaccharides and glycogen. Mixtures of these 15 nutrients may also be used.
More preferably the growth factor of the present invention is an oligosaccharidesuch as, but not limited to, galactooligosaccharides, soybean oligosaccharides and fructooligosaccharides. Oligosaccharides possess bioadhesive properties which help fix the location of these growth factors for easier access by lactic acid bacteria. Most 20 p, ~l, ed for use herein are fructooligos~cch~rides. Lactic acid bacteria, such as l,actobacillus and Bifidobacterium, partially utilize fructooligosaccharides as an energy source ~y converting it, via rw.,lenlalion, to lactic acid or a mixture of lactic acid, acetic acid, and CO2. The lactic acid and other fatty acids produced by this carbohydrate fermentation contribute to the ~n~int~n~nce of low pH which is an important control 25 mPr.h~nicm for preventing colonization of pathogens.
Ch~mic~lly~ oligofructose is the oligosaccharide fraction of inulin. It is composed of the GFn and Fn type [G = glucose; F = fructose; n = number of frutose moieties linked by ,~ (2,1) linkages in a ratio of about 2:1, with n = 2-6, and an average degree of pol~meli~Lion of 4. Inulin is p~t;paled by hot water extraction of chicory roots and is 30 composed of molecllles of the GFn type, n ranging as high as 60 with an average degree of polymerization 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 olis~os~cr.h~rides 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.
CA 0224~810 1997-08-lO
W O 97/29762 PCT~US97/01662 Fructooligos~cçh~rides most preferred 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 displace 5 pathogenic microorganisms from epithelial surfaces. The increase in the number of Lactobacillus and/or Bifidobacterium species con,peLiLively exclude the pathogens causing them to be displaced and excreted; the resLlt is an overall reduction of host pathogens.
Moreover, as vaginal infections are generally believed to result from pathogenic migrating from the rectum to the vagina, the number of pathogens invading the vagina are also 10 reduced as the number of migratory pathogens decreases.
Growth factors are preferably incorporated into the compositions of the present invention at from about 5% to about 75%, more preferably from about 20% to about70%, and most pl~;re-~bly from about 30% to about 65% per unit dose.
Coating Material The compositions of the present invention may further comprise a coating material.
Coating materials useful to the compositions of the present invention may be water soluble as well as water insoluble. The coating material of the present invention is preferably dried to a water activity (Aw) of less than about 0.6, more preferably less than about 0.45, most preferably less than about 0.3. The term "wa.ter activity," as used herein, is well known in 20 the art as the measure of the ratio of the equilibrium vapor pressure of water above a substance such as food ~solid or liquid) to the vapor pressure of pure water, both taken at the same tel~ L-Ire. A more detailed description of water activity is found in U.K.
Patent 2,014,429.
Water soluble co~tin~S useful to the compositions of the present invention may 25 include sugar or organic coatings. Sugar cozltin~.~ useful to the present compositions may be syrupy materials co..~ ;n~ monos~cch~rides or polymers of two or more saccharide units. Organic coaLii)gs are also useful to the compositions of the present invention.
Useful organic polymers or copolymers used include those having a plurality of carboxylic ac;d and ester groups. Such groups are largely responsible for physical or chem;e~l 30 il~lela-;Lions with an active ingredient for effective taste m~c~ing properties. The p~c;re~led polymers or copolymers contain either a vinyl and acrylic acid and/or ester groups or carboxylic acid and/or ester groups. The specific polymers/copolymers are readily ascci.~a;lled by one of c,l-lh~a-y skill in the art. Generally, polymers/copolymers that are pharm~ce~ltic~lly acceptable in terrns of safei:y and toxicity may be used. It is pl~rell~d 35 that such polymers/copolymers be soluble in a solvent or a mixture of solvents. Such CA 0224~810 1997-08-10 W O 97J29762 PCT~US97/0166 polymers/copolymers include polymeric or resinous substances such as: co-polymers of acrylic and substituted acrylic acids; cellulose esters; vinyl and substituted vinyl esters;
polysulfonic acids, their esters and amides. Specific examples include naturally occurring materials such as shellac and zein and synthetic and semi-synthetic materials such as ethyl S cellulose, cellulose ?Icet~tes, cellulose acetate phthallates, ethyl vinyl ~cet~tçs and/or phth~l~tes, polyvinyl ~cet~tes and/or phth~l~te~, ethyl and/or methyl methacrylic acids, esters and co-polymers, hydroxy alkyl cellulose ~cet~tes and/or phth~l~tPc Such compounds include commercially available materials sold under trade names such as Eudragit S (trademark of Rohm Pharma) and Phthalavin (trademark of Colorcon). The 10 coating material of the present invention is preferably a polymeric mixture of meth~crylic acid and meth~crylate Mixtures of sugar and organic coating may also be used.
One particular embodiment of the present invention comprises a core cont~ining at least one species o~the Ericaceae family and a coating material cont~ining a viable culture of at least one species of the above described microencapsulated bacteria. Alternatively, 15 the micropnç~rs~ ted Lactobacillus can reside in the core coated with a coating material co~ g the Ericaceae species. The latter may find use in providing an acidic environment for the Lactobacillus to survive and grow. Additional coating layers may also be added.
Additionally, Protein-like coating components may be included. Useful for 20 improvement of gastrointestin~l disorders, such components may contain branched amino acid-modified proteins. Whey powders, for example, are treated with papain in the presence of the amino acids ethyl L-leucine (16.1 parts), ethyl L-isoleucine (7.4 parts), ethyl ~-valine (10.2 parts), cysteine hydrochloride (1.5 parts), and sodium carbonate (26 parts) in water at 40~C for 20 minlltes to m~n~-~ct--~e coated powders co~ 10%
25 free arnino acids and 43% branched arnino acids. The branched amino acid-modified powders can be mixed with fats, dextrins, salts, vitamins, and the like to make tablets.
Other eA~mi)t-- of a tablet coating materials are zeolites and clays to make tablets more p~l~t~le Zeolites have found use as bacterial feed coatings for domestic animals.
For example, in ehe domestic animal business, ti~mlllin fumarate is dissolved in methanol, 30 supported on mordenite-type zeolite or starch, dried and further premixed with the supports to produce s~lst~ined-release, coated granules. Still other examples of tablet cQ~tinge include co-",.l~ - carbohydrate and inclusion complexes.
The sugar and/or organic co~ting.~ of the present invention may be applied by conventional means inclnding .,.ec~ ical methods such as pan coating, air suspension 35 techni~ues, multiorifice centrifugal techniques and spray drying techniques as well as CA 0224~810 1997-08-10 .
physicochemical methods such as coacervation-phase separation. Coating procedures are more fully discussed in Remington's Pharmz~ceutic~l Sciences (Alfonso Gennarol, editor), 1666-1675 (1990), herein incorporated by reference.
Bufferin~ A~ents The compositions of the present invention may also contain a buffering agent~ For oral compositions, buffering to an acidic pH to enhance 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 ~IIAi~ ill;llg a urogenital pH of about 3.0 to a~out 5.5. Any mild pharm~ce~tically acceptable acid, other than those found in the Ericaceae species disclosed herein, can be used. Suitable acids include bonc acid, or organic acids such as 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 colllbhlalion with their respective sodium or other pharrn~ceutically acceptable salt ~to the extent necess~ry 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, preferably from about 3.7 to about 4.7, and plerel~bly using lactic acid with sodium lactate or a collll~ lion lactic acid/sodium lactate and benzoic acid or lactic acid/sodium lactate and proprionic acid.
Additional Plant Extracts Additional therapeutic and/or medicinal plants or extracts may also be incorporated into the compositions of the present invention. Such plants or extracts include echin~c~
allium, bucha, juniper gincerlg 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 invention. Such additives inchldç; but are not limited to, proteins and carbohydrates other than those ,.~nLiol-ed herein as growth factors, vitamins, minerals, amino acids such as glycine, phytochemicals and mixtures thereof. These additives may, alternatively, be first incorporated into the Lactobacillus andlor Bifidobacterium of the present invention.
Pha~ ce~ltical Actives The compositions of the present invention may also be used in combination with pharrn~ce~ltic~l actives. The pharm~ce~ltical active is ,c~t;felably selected from at least one of an ~n~lg~ic agent and/or a ga~LIui~ l agent. When incorporating pharm~ce~ltic~l actives, appropliale measures should be taken to avoid contact with the microor~ni~m~ of CA 0224~810 1997-08-10 W O 97/29762 PCTrUS97/01662 lZ
the present invention. Such measures may include, but are not limited to, modifying the microencapsulation process as suggested by U.S. Patent 5,466,463 to Ford.
Examples of analgesics ,~l efe~ ~ ~d for use in the present invention include ~cet~minophen, acetyl salicylic acid, indomethacin and optically active isomers or 5 r~cem~tee of ibuprofen, naproxen, flurbiprofen, carprofen, tiaprofenic acid, cicloprofen, ketoprofen, ketorolac, etodolac, indometh~cin elllin~C7 fenoprofen, diclofenac, piroxicam, benzydomine, nabumetone, their pharrn~centically acceptable salts and mixtures thereof.
Examples of gastrointçstin~l agents preferred for use in the present invention 10 include anticholinergics including atropine, clirlin;~ln and dicyclomine; antacids including aluminum hydroxide, bismuth subsalicylate, bismuth subcillate~ simethicone, calcium carbonate and magaldrate; ~2-receptor antagonists including cimetidine, famotidine, ni7~ti-1ine and ranitidine; laxatives including: docusate, phenolphthalein and c~e~nthrol;
gastroprotect~nts inclu-~ing sucralfate and sucralfate humid gel; gastrokinetic agents 15 inc~ ing metoclopramide and cisapride; proton pump inhibitors incl~ing omeprazole and antidiarrheals inclll~ing f~iphenoxylate, kaolin pectin, attapulgite and loperamide.
Carrier Materials The carriers into which the compositions of the present invention may be incorporated are many and varied and depend largely upon the end use of the 20 compositions. These carriers are pharrn~celltically acceptable and include orally acceptable as well as topical compositions. They may be completely inert or contain or may be other active ingredients, yet the carriers must be co~ alible with the herein disclosed compositions. The term "colllpalible,'' as used herein, means that the carrier components are capable of being commin~le(l with the components of the present 25 invention, and with each other, in a manner such that there is no interaction which would subst~nti~lly reduce the activity or viability of the compositions under ordinary use situa-tions. Carrier materials must, of course, be of s~lfficiently high purity and sufficiently low toxicity to render them suitable for arl~inietration to the human being treated. Preferably the compo ,iLions of the present invention comprise from about 0.01% to about 99.99% of 30 one or more carrier materials.
Carriers suitable for topical ~minictration of the present compositions include suppositories, vaginal tablets or capsules, ovules, creams, solutions for lavages, emulsions, foams, gels, ~ c-~tc~ oils and ointmente, douches.
Creams, gels and other base formulations may be used in topical ~f~ Lion of 35 the present compositions to, for example, male or female ~nit~ (incl-l~ling the vulva , CA 0224~810 1997-08-10 W O 97/29762 PCTrUS97/~1662 and vagina~ and are prepared according to conventional 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, S acrylamides. meth~crylamides, derivatives of cellulose and carboxyvinylpolymers Ovules, suppositories, vaginal capsules 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 polyethylene glycols and optionally also emulsifiers and surfactants.
The vaginal capsules are gelatinous 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 thickening agents. The tablets, shaped suitably for vaginal use, contain as main excipients lactose, starch, polyvinylpyrrolidone, cellulose derivatives, mAgnecium stearate, glycol. The effervescent tablets contain chemical 1~ components (i.e. sodium bicarbonate with citric acid or tartaric acid), which are nec~ss~ry to develop carbon dioxide in order to produce effervescence.
The compositions of the present in~vention may also be incorporated into and topically applied by woven or nonwoven fabric materials such as tissues, wipes, rell~illine n~pkin.~, panty liners, l,llnpolls, diapers, incontinent care products and the like. Preferred 20 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 incorporated by reference.
Oral dosage forms are also usefu1 as carriers for the present invention. These dosage forms contain compatible solid or liquid filler diluents or encaps~llAting substances 25 which are suitable for oral ~ 1. ation to a human or lower animal.
Liquid dosage forms for oral ~rimini~tl-ation may comprise dissolving or suspending the compositions of the present invention in a potable liquid, such as sterile or purified water. Alternatively, liquid or dry oral ~ Lion forrns can comprise an enterically coated capsule co..~ p the dosage forms. Suitable forms include emulsions, 30 suspensions, solutions, syrups, and elixirs co..lAil~ inert diluents commonly used in the art, such as purified water, sugars, polysaccharides, silicate gels, gelatin, or an alcohol.
These inert tlih~nts do not actively participate in the therapeutic effect of the present invention. However, such liquid forms may require special care where free water is present with the Lactobacillus to prevent fel ll,c;~llalion or degradation of the Lactobacillus.
35 Besides the inert diluents, such colllposiLions; can also contain wetting agents, emulsifying -CA 0224~810 1997-08-10 W O 97/29762 PCTrUS97/0166i agents, suspending agents, as well as additional therapeutic actives. For a more detaile description of liquid and liquid-like dosage forms, see Remington's Pharmaceutical Sciences, 17th ed., M[ack Publishing Company, Easton, Pa. (1990), pages lS19-1544, herein incorporated by reference.
Tablets can be col,lplessed, molded, triturated, enteric-coated, sugar-coated, film-coated or multiple colllpl essed, cont~inin~ suitable binders, lubricants, rliluents, rli~inte~rating agents, and flow-inducing agents.
Also useful are soft or hard gelatin ç~ps-l~çs Preferably, the gelatin shell is essentially Ll~llsl)alt;lll so as to enhance the aesthetic qualities of the capsule. Soft and hard gelatin shells generally comprise gelatin, a plasticizer and water The starting gelatin material generally used in the m~mif~l~t~re of these capsules is obtained by the partial hydrolysis of collagenous material. Gelatin suitable for capsule m~nuf~ctllre iscommercially available from the Sigma Chemical Company, St. Louis, Mo.. One or more plasticizers is incorporated to produce a gelatin shell. Useful plasticizers of the present invention include glycerin, sorbitan, sorbitol, or similar low molecular weight polyols, and mixtures thereof.
Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," Modern Pharrn~ce~ltics, Vol. 7, (Banker andRhodes, editors), 359-427 (1979), incorporated by reference herein. Techniques and compositions for making tablets (COlll~l t;ssed and molded), capsules (hard and soft gelatin), troches and pills are described in Remington's Pharm~ceutical Sciences (Arthur Osol, editor), 1553-1593 (1980) and U.S. Patent 4,935,243, to ~orkan et al., issued ~une 1~, 1990; these two references being incorporated herein by reference in their entirety.
Specific examples of pharm~cel1ti~11y acceptable carriers and excipients that may be used to forrnulate oral dosage forms, are described in U.S. Patent 3,903,297, Robert, issued September 2, 1975, inco",ol~ed by reference 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 Iyophilization f~ tAtes ~icintegration of the composition by forming the dried composition into an open matrix network. In most cases, this results in rapid perrmeation by the aqueous media, promoting timely delivery of the product.
Suitable metho-~s of freeze drying are well known in the art and eollllllonly employed.
Any suitable conventional method of freeze-drying may be l~tili7e(l A preferable method of rree~ing 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 CA 0224~Xl0 1997-08-10 Wo 97/29762 PCT/US97/01662 production are taught by U.S. Patent 4,642,903, Febru~ry 17, 1987, to Davies, U.S.
Patent 4,946,6847 August 7, 1990, to Blank et al., U.S. Patents 4,305,50~ and 4,371,516, issued December 15, 1981 and February 1, 1983 respectively, to Gregory et al., and U.S.
- Patent 5,188,825, February 23,1993, to Iles et al.; which are all incorporated herein by S reference.
Similarly, the compositions of the present invention may be vacuum dried.
Vacuum drying involves at least the partial drying of compositions at temperatures above compositions' collapse temperature. Freeze drying, on the other hand, involves the drying of compositions at temperatures below the compositions; collapse temperature. Any 10 suitable method of vacuum drying may be used. Suitable vacuum drying processes are described in U.S. Patent 5,298,261, to Pebley et al., issued March 29, 1994, herein incorporated by I efe, e.,ce.
One other form of tableting technology that may be applicable to the present invention is a liquid/liquid extract developed by Janssen Pharrnaceutica Inc. and is 15 identified by the trade name QuicksolvTM. This technology is fully described in U.S.
Patent 5,215,756 herein incorporated by reference.
Other optional ingredients well known to the pharmacist's art may also be ir~luded in amounts generally known for these ingredients, for example, natural or artificial sweeteners, flavoring agents, colorants, perfilming agents, buffering agents and the like to 20 provide a palatable and pleasant looking final product, antioxidants, for example, butylated hydroxy anisole or butylated hydroxy toluene, and preservatives, for example, methyl or propyl p~,~e,n, potassium sorbate, or sodiurn benzoate, to prolong and çnh~nce shelf life.
A l)lere~,ed optional component is also c~ffeine Those of ordinary skill in the art ~,-ill quickly reaiize other suitable ingredients, 25 rlilu~nts and dosage forms, or will be able to ascertain such, using routine c~ .h~nt~tion Further, the ~ . alion of the various compositions can be carried out using standard techniques common to those of ordinary slcill in the art.
Exarnples The following examples further describe and demonstrate embodimente within the 30 scope of the present invention. These e~xamples are strictly given for illustration purposes and are not to be construed as limitations of the present invention, as many variations are possible without dep&- ling from the spirit and scope of the invention as set forth herein.
Example I
The T ~ctob~c~ e and/or Bifidobacterium species cultures can be freeze dried (or35 purchased freeze dried). To provide freeze dried cultures, an inoculum of Lactobacillus CA 0224~810 1997-08-10 W O 97/29762 PCT~US97/01662 and/or Bifidobacterium is grown in a sterile nutrient media ~e.g. Trypticase Soy agar broth). The media is removed by centrifugation. The bacteria isolates are washed using a sterile b~l~nced salt and 5% glucose solution. The bacteria are then "snap frozen" with liquid nitrogen and vacuum freeze dried. The freeze dried product is then checked for 5 bacterial plate count and then diluted so that the plate count per unit dose composition is from about 103 to about 1012.
Example II
The freshly obtained, washed and Iyophilized bacteria obtained as described above are suspended in 10 ml of 5% glucose saline solution in such volume so as to obtain a 10 heavy suspension of bacteria which contains between one to 101~ organisms per ml, at 0-4~C. All of these procedures are performed in the 0-4~C temperature range unlessotherwise noted, in order to "~ viability of the lactobacilli bacteria which at room temperature lose viability. The suspension of bacteria is rapidly, but gently, stirred while 0.2-0.4 ml of sodium alginate solution (1.5% weight by volume) is added. The above 15 rnixture is then transferred into a 4 liter round bottom flask by using a nitrogen stream through a ~he~thec~ 14 gauge needle. The 4 liter round bottom flask was previously washed with a 5% albumin solution, and thereafter heated for at least 10 hours at 6~~C, and the needle and the tubing used in the process have also been treated this way.
Thereafter the above mixture is forced through a 30 gauge multi-beveled needle 20 under pressure using a large syringe and nitrogen stream. Very small droplets are generated at the end of the needle which are dried by the nitrogen and air stream around the 30 gauge needle, and the droplets are collected in an aqueous solution of 1.3-2%
calcium chloride where they gel. Thereafter, they are washed at least three times with 0.08-0.13% 2-(N-cyclohexyl-amino) ethanesulfonic acid (CHES) solution and 1.0-1.5%
25 calcium chloride solution.
The gelled droplets or little spheres are further washed with at least a five fold excess of the 0.1% CHES 1.1% calcium chloride, and norrnal saline solution. The rçslllt~nt spheres are then "snap frozen" in liquid nitrogen and then Iyophilized. After these steps, the encapsulated org~nicm~ can be used in the forrnulations of the present 30 invention.
Example III
A tablet forrn of the present invention is made by combining the following components using conventional mixing and tableting technology.
Ingredient % Weight Concentrated Cranberry Extract 37 300%
W O 97/29762 PCTrUSg7/01662 Lactobacillusl 29.900%
~, K2932 (5% ethanol soln)2 13.4.00%
Avicel (pH 101)3 13.400%
~, Explotab4 1.8%
Talc 3.600%
~ne~il-m stearate 0.6û0%
1 Microencapsulated ~.actobnr~ 2~ Caseii l~ar. rhamnosus (108 cfu/g).
2 Polyv~ py~ ollidone 3 TM for microcrystalline cellulose, a highl)~ purified particulate form of cellulose 10 4 Abrandofsodiumstarchglycolate The cranberry extract is gr~n~ ted with half the Avicel and the K2932 in ethanol.
The granl~l~tin~n is then passed through a I2 mesh screen and dried at 120~F. The dried granulation mixture is passed through a 20 mesh screen. To the sieved granulation is added the lactobacill--~, re~inin~ Avicel, Explotab and talc and mixed until uniform.
15 ~gn~cillm stearate is then added to the uniforrn mixture with mixing. The resultant granulation mixture is then con,pressed using conventional tableting processes.
Example IV
A oral capsule form of the present invention is made by combining the following components using conventional mixing techr~ology.
Ingredient % Weight Conce"Ll~led Cl~l.l,~.ly Extract 29.900%
Bifidobacteriuml 15.000%
fructooligosaccharide2 29.900%
Avicel3 22.400%
Ac Di Sol4 2.800%
Microencapsulated Lactobacillus bif dus subsp pennsylvanicus ( 108 cfu/g).
2 Available as NutraFlora FOS from Golden Technologies Company, Inc.
3 TM for microcrystalline cellulose, a highly purified particulate form of cellulose.
4 A brand of a cross-linked form of sodium carboxymethylcellulose.
Combine and mix the cranberry extract, fructooligosaccharide, Lactobacillus culture, Avicel and Act Di Sol in a V-blender until uniro~ . Unit dose amounts of the res~lt~nt mixture is then placed into suitably sized hard gelatin capsules.
Example V
A topical gel form of the present invention is made by colllbilfing the following 35 components using conventional mixing technolog,v.
CA 0224~810 1997-08-lO
W O 97/29762 PCTrUS97/01662 Ingredient % Weight Concentrated (~ranberry Extract 0.50%
Lactobacillus 1 2.50%
fructooligosaccharide2 6.00%
Polyacrylamide and C 13-14 Isoparaffin and Laureth-73 4.00%
PPG-14 Butylether 8.00%
Water, Purified q.s.
Microencapsulated Lactobacillus Caseii var. rhamnost~s (108 cfu/g).
10 2 Available as NutraFlora FOS from Golden Technologies Company, Inc.
3 Available as Sepigel from Seppic Corporation.
Water is added to a suitable size container. While mixing at a moderate speed (300 rpm), the Polyacrylamide and C13 14 Isoparaffln 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 15 covered. Using a r.i~htnin' Mixer with a 3 blade paddle prop, the cranberry extract and fructooligos~cch~ride are added to the PPG-14 Butyl ether and mixed at a low speed (100 rpm) until the el ~nbe- l y extract and fructooligosaccharide are dissolved. Thelactobacillus culture is added to the water phase and mixed at low speed (100 rpm) until a uniform solution results. The PPG-14 Butyl ether is slowly added to the water phase to 20 form a gel. The reslllting gel is mixed at moderate speed until uniform.
An even further object of the present invention is to provide methods for preventing and/or treating urogenital and intestin~l disorders.
These and other objects will become readily a,oparel,l from the disclosure whichfollows.
SUMMARY OF THE INVENTION
The present invention relates to compositions for the l.eaLI,,e.lL or prevention of urog~nit~l and tntestin~l disorders, comprising:
a.) an ~nfi lh~sive amount of at least one plant species of the Ericaceae family or its extract; and W O 97/29762 PCT~US97tO1662 b.) a viable culture of at least one species of microencapsulated bacteria selected from the group eonsisting of lactobacillus, bifidobacterium and mixtures thereof.
The present invention also relates to the above compositions filrther comprising a S growth factor for fz.cilitz~ting the growth of lactic acid bacteria.
The phrase "urogenital and intestin~l compositions," as used herein, means a product which in the ordinaly course of usage may be retained in the oral cavity, swallowed or applied topically to provide urogenital and/or intPstinZll activity.
The phrase "~nti~-lhesive amount," as used herein, means an amount effective to 1 û reduce the number of pathogenic microorg~micmc on the epithelial and/or mucosal lining of the urogenital and/or intestjnz I ~ract.
The term "urogenital," as used herein, means that system of organs concerned with the production and excretion of urine and reproduction.
The terrn "intectinz I " as used herein, means of or relating to the intestin~c The term "nonpathogenic," as used herein, means s~ a~Lially lacking the ability to cause disease or abnormality in healthy m2mms~1c The term "healthy," as used herein, means free of underlying disease and/or immunosuppression.
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.
DETAILED DESCRIPTION OF THE INVENTION
The e~.cç~ as well as optional components of the compositions of the present invention are described in the following paragraphs.
ESSENTIAL COMPONENTS
Plants or extracts of the Family Ericaceae The Ericaceae (heath) fannily, consisting of about 110 genera and 4,000 species, is by far the most i."~o- I~IIL family of the Ericales order, enComraccing a wide variety of fruit producing shrubbery and evergreen plants. Genera falling under Ericaceae family include V~crinil~m, Arctostaphylos, ~Ja~-lt~-~ria, and Gaylnsc~ci~ The Arctostaphylos genus inr~ 1e.s such species as the checkerberry and bearl,clly (Uva ursi). Other edible fruits 3 0 such as the creeping snowberry or moxie plum fall under the genus Gaultheria.
kieberries are a well known species of the genus Gayll~cs~ei~ The Vacrinium genus, best known for its fruits, contain some of the most cornrnon of berries, inrlut1ing the blueberry (e.g., V. australe), cranberry ~e.g., Y. macrocarpon) and bilberry (e.g., Y.
myrt~llus). The term "berry ~ies)," as used herein, means berries, drupes, plums and the lilce.
W O 97/29762 PCTrUS97/01662 E. coli adherence results primarily from ar1hesin.c on the raised hair like fimbriae (or pili) of the microol~ani~lll. These ~tlhe~inc are (lçcign~ted MS (mannose-sensitive) and MR (mannose-resistent). Like most firuit, Ericacease fruit species contain fructose, an inhibitor of MS ~h~cin~. However, it has been recently suggested that the plants or extracts of Ericaceae species further contain an llnic~elltified, non-dialyzable polymeric compound which inhibits the MR adhesins associated with pyelonephritogenic strains of E
Cofi. The llni~ntified polymeric compound, as studied in Vaccinium species, was found to inhibit the adhesion of 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 Cranberry and Blueberry Juices. N Engl J Med 1991;324;1599. It has also been reported that the ingestion of large quantities of cranberry.~uice increased the hippuric acid content of urine by several grams a day. This increase in hippuric acid excretion was accompanied 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 1~ considerably decreased as the urine pH was raised. Papas, N.P., et al., Cranberry Juice In the Treatment of Urinary Tract Infections. Southwestern Medicine, 47:No. I (Jan. 1966).
That the Ericaceae species of the present invention are effective against other pathogenic bacteria ~e.g., Pseudomonas aeruginosa) is disclosed in U.S. Patent 5,474,774, issued December 12, 1995, to Walker et al., herein incorporated by reference in its entirety; no 20 effect was observed with respect to adhesion of lactobacillus strains to cells. Without being lim-ted by theory, it is believed that the pathogenic inhibition caused by the Ericaceae plants or extracts results in decreased pathogenic interaction, providing a more favorable, less antagonistic em,i,~,-"l-G--l for lactobacillus to initially adhere and m~int~in adherence. The phrase "anti-adhesive activity," as used herein, means an amount effective 25 to inhibit the adhesion of pathogenic microoly,~ni~ to the epithelial and/or mucosal lining ofthe urogenital and/or intçstin~l tract.
Plants or extracts useful in the compositions of the present invention come from a wide range of Ericaceae genera incltl~in~, but not limited to, V~ccinillm Arctostaphylos, ~lllt~eria, and Gayl~ c~ c~.l~,d species ;nclude, V. ausfrale~ V. corymbosum, V.30 occidenfale, V. ovatum, V. myrffllus, V. parvifolium, V. uliginosum, V. macrocarpon, V.
o~ycoccus, ~ erythrocarpum, V. vitis-idaea Y. ausfrale~ V. macrocarpon. V~cr.inium species most I)lefc-lcd for use in the present invention include V. ausfrale~ Y.macrocarpon, and V. myrtillus. Mixtures of Ericaceae plants and/or extracts may also be used.
CA 022458l0 l997-08-lO
W O 97/29762 PCTrUS97/01662 The plants or extracts of the present invention are preferably concentrated, having a ratio of at least about 4 pounds of plant concentrate or extracts per pound of concentrate, more preferably from about 4 pounds of plant concentrates or extracts per pound of ~ concentrate to about ~0 pounds of plant concentrate or extracts per pound of concentrate.
The Ericaceae extracts are preferably present at a level of at least lOmg, more preferably from about IOOmg to about 18g, most pler~i~bly from about 250mg to about 4g per unit dose. The amount of extract contained in each dose of product can be adjusted for the dosage form. For example, 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 capsules might range 10 to about 4g. Plef~,led levels of the Ericaceae plants or extracts provide urinary and/or intestin~l tract fluid concenllalions of the above mentioned unid~ntified, non-dialyzable polymeric compound of from about 12 to about 25 micrograms per m~ ter Also, the plants or extracts of the present invention pl erc:. ~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 15 selected to provide the desired level of a~nti-adhesin activity and can be modified as desired. Cranberries and cranberry extracts are useful in the tre~tme-lt and/or prophylaxis of urinary tract infections and are also useful as vaginal deodorants.
Species of Lactobacillus or Bifidobacterium Another ~Sspnti~l component of the present invention is a viable colony of 20 microencapsulated Lactobacillus or Bifidobacterium. Bacteria of the Lactobacillus genus are characterized as rod-shaped, gram-positive and non-spore-forrning bacteria. Of the family Lactob~cill~e~e~ Lactobacillus inhabit the urogenital and gastrointestin~l tracts of animals and h~ n~ and are important members of lactic acid producing group of bacteria.
Various species of Lactobacillus are used c;ommercially in the production of sour milks, 25 cheeses and yogurt. Lactobacilli also sha.re an important role in the m~n~lf~ct~lre of fermented vegetables (e.g., pickles and sauerkraut), beverages ~e.g., beer, wine and juices), sourdough breads, and some s~lls~çs.
T ~ctob~rillus species suitable for use in the present invention are those which 1.) readily adhere to the epi~ l cells of either the urogenital or ~a~ oi~-~estin~l tracts of 30 ~Uhl~ ; 2.) produce hydrogen peroxide; 3.) ~.ol--ole low pH; and produce bacteriocins.
By "bacteriocins," as used herein, mea,ns p~ e;..~ceious, bacteriocidal substances syr~t~e~i~P~d by b..cLe,ia, which usually ha~e a narrow spectrum of activity, inhibiting strains of the same or closely related species. Bacteriocins appear to be capable of ~1i5p~ ~ or supplesslng the growth of other bacteria, and as such may provide an35 advantage to microorg~ni~m~ in -fellllell~ g the female genital tract ecosystem. Pl~r~llcd W O 97/29762 PCTrUS97/01662 species of Lactobacillus include L. aci~ophilus, L. cate~ta~orme, L. brel~is, L. bulgaricus, L. Iac~is, L. reu~erii, L. gasseri, L. helveticus, ~. casei, L. plantar1~m, L. delbru~chi, L.
t*ermop*ilis, L. Jensenii, L Crispatl~S, L. rogosae and r. fermerltum Species ofLactobacillus most prefe--ed for use in the compositions of the present invention include L acidophilus, L. casei, L. crispatl~s, L. fermentum, and L. plantarum. Preferably7 the Lactobacillus species of the present invention are hydrogen peroxide producing such as ~.
ac~dophilus, L. catenaJrorme, L. casei, L. crispatus, L. delbrueckii, L. jensenii, L rogosae.
r.. fermentum, L. gasseri and L. plantarum are also plerelled for use herein in view of their adhesive properties.
Also inhabiting the urogenital and gastrointestin~l tracts of m~mm~lc 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 important regulators of the urogenital and inte5tin~1 flora of m~rnm~lc Species suitable for use in the 1~ present compositions in~lnd.q, but are not limited to, B. longllm B. breve Lactobacillus B~f d~s and L~ctobacillus bif dus s2(bsp pennsylvanicus. Preferred for use in the present compositions is B. Bif dum, most p-ere-led B. Bif dt~m subsp. Pennsylvanicus.
Mixtures of the Lactobacillus and/or Bifidobacterium species may also be used.
Any of the above species may be obtained either commercially or through laboratory 20 cultures.
The Lactobacillus andlor Bifidobacterium species are present as core and/or coating con-ponents at levels of at least about 103 cells per unit dose7 pl~re-ably at levels of ~om about 104 to about 1012 cells per unit dose and most preferably at levels of from about 106 to about IOlQ cells per unit dose. The phrase "unit dose," as used herein, 25 means physically discrete units suitable as unitary dosages for ~tlminictration to m~mm~lc, each such unit co..~ g a predetermined quantity of an active ingredient calculated to produce the desired Lll~ pcutic effect in association with pharrnaceutically acceptable carriers. The level is sçlectecl to provide the desired level of urogenital and gastrointestin~l activity ~nd can be modified as desired. Lactobacillus may loose 4-6 fold of its viability at 30 room ttn~pc-~lure and during m~mlf~r,tllring, so depending on the m~n-lf~ctllring conditions, an excess of Lactobacillus is added to IllAinlAi.~ an adequate number of viable org~nicmC per final unit dose form. Alternatively, a patient can be a-lnninict~red the equivalent of these conc~ ions of org~ni~m.c where the values are expressed by some other measurement such as, for example, total protein concentration.
CA 022458l0 l997-08-l0 WO 97/29762 PCTnUS97/01662 The Lactobacillus and/or Bifidobacterium species of the present invention must also be microencapsulated. Viable I,actobacillus and/or Bifidobacterium bacteria that have been Iyophilized after the removal of the growth media can be used for encapsulation. The bacteria can be obtained from commercial sources, or can be obtained from laboratory S strains. Suitable media include MRS, Thayer-Martin media, Trypticase Soy, Brain-Heart Infusion Broth, or any other enriched rnedia suitable for the cultivation of these or~ni~m.c as no particular med;a is critical to the success of this suppository. The only important factors are the viability and quantity of the micro-o,~lis-"s that are always determined by standard clinical laboratory dilution methotis, such as plating the quantified dilution of bacteria on to blood agar plates or other enriched media, incubating at 37~C for 24-48 hours in a 5-10% carbon dioxide atmosphere, and then perforrning a colony count. The removal ofthe nutrient media is done by centrifugation at 14,000 x g at 0~-4~C., and then was~ing with sterile, balanced salts and 5% glucose solution at least three times after the initial centrifugation. The bacteria are then. "snap frozen" with liquid nitrogen and then 1~ lyophilized under high vacuum. The bact.eria are then microencapsuled according to conventional micro~nc~rsul~tion technolo~y. Suitable methods of encapsulation are disclosed in U.S. Patent 5.466.463. issued November 14, 1995, to Ford and U.S. Patent .407.609. issued April 18, 1995, to Tice, both of which are herein incorporated by le~cl~ce in their entirety.
OPTION~L CO~DPO~nENTS
Lactobacillus Growth Factor Also useful to the compositions of the present invention is a growth factor for f~cilit~ting the growth of lactic acid bacteria. The phrase "a growth factor for f~r.ilit~tin~
the growth of lactic acid bacteria," as used herein is meant a nutrient source or media 25 which supplies a necessary source of food and/or energy for f~çilit~ting the growth of lactic acid producing bacteria. The growth factor is preferably selective for establishing and ..~ g the growth of lactic acid bacteria, preferably Lactobacillus and/or Bifi~obacterium, without f~ it~tin~ extreme growth of pathogenic bacteria The various nutritional requi.t;nle"Ls essential for bactelial and/or colony growth are normally met 30 when the growth factor contain fermentable carbohydrate, peptone, meat and yeast extract. Suppiç~ l;ons with tomato juice, m~n~nç~, acetate and oleic acid esters, especially Tween 80, are stim~ tory or even eS.~enti~l for most species and are, therefore, in~ .lded in most M~S mefli-lm Lactic acid bacteria adapted to very particular substrates rnay require special growth factors.
CA 0224~810 1997-08-10 W O 97/29762 PCT~US97/01662 Examples of suitable growth factors include, but are not limited to, yeast extracts;
gangliosides; salicin; mono-, di- and polysaccharide sugars such as glycogen, glucose, fructose, rhamnose, lactulose, methyl-a-D-mannoside, p-nitrophenol-a-D-mannoside, maltose, maltodextrin, dextrin, dextran, levan, sialic acid and acetylglucosamine as well as 5 oligosaccharides such as, but not limited to, fructooligosaccharides, galactooligosaccharides and soybean oligos~cch~rides. Fiber or fermentable substrates such as psyllium may be used in the present compositions as may gums such as guar gum and x~nthum gum. Similarly, proteinacious materials such as, peptone, keratin; vegetable;
soy and unsaturated fatty acids such as lauric acid and teichoic acids such as lipoteichoic 10 acid and esters such as glycerophosphates or ~-glycerophosphates are also useful as growth factors. The growth factor is preferably selective for establishing and m~int~ining the growth of lactic acid bacteria, most preferably Lactobacillus and/or Bifidobacterium species. Growth factors preferable for use in the compositions of the present invention include lactose, lactulose, rhamnose, oligosaccharides and glycogen. Mixtures of these 15 nutrients may also be used.
More preferably the growth factor of the present invention is an oligosaccharidesuch as, but not limited to, galactooligosaccharides, soybean oligosaccharides and fructooligosaccharides. Oligosaccharides possess bioadhesive properties which help fix the location of these growth factors for easier access by lactic acid bacteria. Most 20 p, ~l, ed for use herein are fructooligos~cch~rides. Lactic acid bacteria, such as l,actobacillus and Bifidobacterium, partially utilize fructooligosaccharides as an energy source ~y converting it, via rw.,lenlalion, to lactic acid or a mixture of lactic acid, acetic acid, and CO2. The lactic acid and other fatty acids produced by this carbohydrate fermentation contribute to the ~n~int~n~nce of low pH which is an important control 25 mPr.h~nicm for preventing colonization of pathogens.
Ch~mic~lly~ oligofructose is the oligosaccharide fraction of inulin. It is composed of the GFn and Fn type [G = glucose; F = fructose; n = number of frutose moieties linked by ,~ (2,1) linkages in a ratio of about 2:1, with n = 2-6, and an average degree of pol~meli~Lion of 4. Inulin is p~t;paled by hot water extraction of chicory roots and is 30 composed of molecllles of the GFn type, n ranging as high as 60 with an average degree of polymerization 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 olis~os~cr.h~rides 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.
CA 0224~810 1997-08-lO
W O 97/29762 PCT~US97/01662 Fructooligos~cçh~rides most preferred 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 displace 5 pathogenic microorganisms from epithelial surfaces. The increase in the number of Lactobacillus and/or Bifidobacterium species con,peLiLively exclude the pathogens causing them to be displaced and excreted; the resLlt is an overall reduction of host pathogens.
Moreover, as vaginal infections are generally believed to result from pathogenic migrating from the rectum to the vagina, the number of pathogens invading the vagina are also 10 reduced as the number of migratory pathogens decreases.
Growth factors are preferably incorporated into the compositions of the present invention at from about 5% to about 75%, more preferably from about 20% to about70%, and most pl~;re-~bly from about 30% to about 65% per unit dose.
Coating Material The compositions of the present invention may further comprise a coating material.
Coating materials useful to the compositions of the present invention may be water soluble as well as water insoluble. The coating material of the present invention is preferably dried to a water activity (Aw) of less than about 0.6, more preferably less than about 0.45, most preferably less than about 0.3. The term "wa.ter activity," as used herein, is well known in 20 the art as the measure of the ratio of the equilibrium vapor pressure of water above a substance such as food ~solid or liquid) to the vapor pressure of pure water, both taken at the same tel~ L-Ire. A more detailed description of water activity is found in U.K.
Patent 2,014,429.
Water soluble co~tin~S useful to the compositions of the present invention may 25 include sugar or organic coatings. Sugar cozltin~.~ useful to the present compositions may be syrupy materials co..~ ;n~ monos~cch~rides or polymers of two or more saccharide units. Organic coaLii)gs are also useful to the compositions of the present invention.
Useful organic polymers or copolymers used include those having a plurality of carboxylic ac;d and ester groups. Such groups are largely responsible for physical or chem;e~l 30 il~lela-;Lions with an active ingredient for effective taste m~c~ing properties. The p~c;re~led polymers or copolymers contain either a vinyl and acrylic acid and/or ester groups or carboxylic acid and/or ester groups. The specific polymers/copolymers are readily ascci.~a;lled by one of c,l-lh~a-y skill in the art. Generally, polymers/copolymers that are pharm~ce~ltic~lly acceptable in terrns of safei:y and toxicity may be used. It is pl~rell~d 35 that such polymers/copolymers be soluble in a solvent or a mixture of solvents. Such CA 0224~810 1997-08-10 W O 97J29762 PCT~US97/0166 polymers/copolymers include polymeric or resinous substances such as: co-polymers of acrylic and substituted acrylic acids; cellulose esters; vinyl and substituted vinyl esters;
polysulfonic acids, their esters and amides. Specific examples include naturally occurring materials such as shellac and zein and synthetic and semi-synthetic materials such as ethyl S cellulose, cellulose ?Icet~tes, cellulose acetate phthallates, ethyl vinyl ~cet~tçs and/or phth~l~tes, polyvinyl ~cet~tes and/or phth~l~te~, ethyl and/or methyl methacrylic acids, esters and co-polymers, hydroxy alkyl cellulose ~cet~tes and/or phth~l~tPc Such compounds include commercially available materials sold under trade names such as Eudragit S (trademark of Rohm Pharma) and Phthalavin (trademark of Colorcon). The 10 coating material of the present invention is preferably a polymeric mixture of meth~crylic acid and meth~crylate Mixtures of sugar and organic coating may also be used.
One particular embodiment of the present invention comprises a core cont~ining at least one species o~the Ericaceae family and a coating material cont~ining a viable culture of at least one species of the above described microencapsulated bacteria. Alternatively, 15 the micropnç~rs~ ted Lactobacillus can reside in the core coated with a coating material co~ g the Ericaceae species. The latter may find use in providing an acidic environment for the Lactobacillus to survive and grow. Additional coating layers may also be added.
Additionally, Protein-like coating components may be included. Useful for 20 improvement of gastrointestin~l disorders, such components may contain branched amino acid-modified proteins. Whey powders, for example, are treated with papain in the presence of the amino acids ethyl L-leucine (16.1 parts), ethyl L-isoleucine (7.4 parts), ethyl ~-valine (10.2 parts), cysteine hydrochloride (1.5 parts), and sodium carbonate (26 parts) in water at 40~C for 20 minlltes to m~n~-~ct--~e coated powders co~ 10%
25 free arnino acids and 43% branched arnino acids. The branched amino acid-modified powders can be mixed with fats, dextrins, salts, vitamins, and the like to make tablets.
Other eA~mi)t-- of a tablet coating materials are zeolites and clays to make tablets more p~l~t~le Zeolites have found use as bacterial feed coatings for domestic animals.
For example, in ehe domestic animal business, ti~mlllin fumarate is dissolved in methanol, 30 supported on mordenite-type zeolite or starch, dried and further premixed with the supports to produce s~lst~ined-release, coated granules. Still other examples of tablet cQ~tinge include co-",.l~ - carbohydrate and inclusion complexes.
The sugar and/or organic co~ting.~ of the present invention may be applied by conventional means inclnding .,.ec~ ical methods such as pan coating, air suspension 35 techni~ues, multiorifice centrifugal techniques and spray drying techniques as well as CA 0224~810 1997-08-10 .
physicochemical methods such as coacervation-phase separation. Coating procedures are more fully discussed in Remington's Pharmz~ceutic~l Sciences (Alfonso Gennarol, editor), 1666-1675 (1990), herein incorporated by reference.
Bufferin~ A~ents The compositions of the present invention may also contain a buffering agent~ For oral compositions, buffering to an acidic pH to enhance 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 ~IIAi~ ill;llg a urogenital pH of about 3.0 to a~out 5.5. Any mild pharm~ce~tically acceptable acid, other than those found in the Ericaceae species disclosed herein, can be used. Suitable acids include bonc acid, or organic acids such as 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 colllbhlalion with their respective sodium or other pharrn~ceutically acceptable salt ~to the extent necess~ry 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, preferably from about 3.7 to about 4.7, and plerel~bly using lactic acid with sodium lactate or a collll~ lion lactic acid/sodium lactate and benzoic acid or lactic acid/sodium lactate and proprionic acid.
Additional Plant Extracts Additional therapeutic and/or medicinal plants or extracts may also be incorporated into the compositions of the present invention. Such plants or extracts include echin~c~
allium, bucha, juniper gincerlg 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 invention. Such additives inchldç; but are not limited to, proteins and carbohydrates other than those ,.~nLiol-ed herein as growth factors, vitamins, minerals, amino acids such as glycine, phytochemicals and mixtures thereof. These additives may, alternatively, be first incorporated into the Lactobacillus andlor Bifidobacterium of the present invention.
Pha~ ce~ltical Actives The compositions of the present invention may also be used in combination with pharrn~ce~ltic~l actives. The pharm~ce~ltical active is ,c~t;felably selected from at least one of an ~n~lg~ic agent and/or a ga~LIui~ l agent. When incorporating pharm~ce~ltic~l actives, appropliale measures should be taken to avoid contact with the microor~ni~m~ of CA 0224~810 1997-08-10 W O 97/29762 PCTrUS97/01662 lZ
the present invention. Such measures may include, but are not limited to, modifying the microencapsulation process as suggested by U.S. Patent 5,466,463 to Ford.
Examples of analgesics ,~l efe~ ~ ~d for use in the present invention include ~cet~minophen, acetyl salicylic acid, indomethacin and optically active isomers or 5 r~cem~tee of ibuprofen, naproxen, flurbiprofen, carprofen, tiaprofenic acid, cicloprofen, ketoprofen, ketorolac, etodolac, indometh~cin elllin~C7 fenoprofen, diclofenac, piroxicam, benzydomine, nabumetone, their pharrn~centically acceptable salts and mixtures thereof.
Examples of gastrointçstin~l agents preferred for use in the present invention 10 include anticholinergics including atropine, clirlin;~ln and dicyclomine; antacids including aluminum hydroxide, bismuth subsalicylate, bismuth subcillate~ simethicone, calcium carbonate and magaldrate; ~2-receptor antagonists including cimetidine, famotidine, ni7~ti-1ine and ranitidine; laxatives including: docusate, phenolphthalein and c~e~nthrol;
gastroprotect~nts inclu-~ing sucralfate and sucralfate humid gel; gastrokinetic agents 15 inc~ ing metoclopramide and cisapride; proton pump inhibitors incl~ing omeprazole and antidiarrheals inclll~ing f~iphenoxylate, kaolin pectin, attapulgite and loperamide.
Carrier Materials The carriers into which the compositions of the present invention may be incorporated are many and varied and depend largely upon the end use of the 20 compositions. These carriers are pharrn~celltically acceptable and include orally acceptable as well as topical compositions. They may be completely inert or contain or may be other active ingredients, yet the carriers must be co~ alible with the herein disclosed compositions. The term "colllpalible,'' as used herein, means that the carrier components are capable of being commin~le(l with the components of the present 25 invention, and with each other, in a manner such that there is no interaction which would subst~nti~lly reduce the activity or viability of the compositions under ordinary use situa-tions. Carrier materials must, of course, be of s~lfficiently high purity and sufficiently low toxicity to render them suitable for arl~inietration to the human being treated. Preferably the compo ,iLions of the present invention comprise from about 0.01% to about 99.99% of 30 one or more carrier materials.
Carriers suitable for topical ~minictration of the present compositions include suppositories, vaginal tablets or capsules, ovules, creams, solutions for lavages, emulsions, foams, gels, ~ c-~tc~ oils and ointmente, douches.
Creams, gels and other base formulations may be used in topical ~f~ Lion of 35 the present compositions to, for example, male or female ~nit~ (incl-l~ling the vulva , CA 0224~810 1997-08-10 W O 97/29762 PCTrUS97/~1662 and vagina~ and are prepared according to conventional 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, S acrylamides. meth~crylamides, derivatives of cellulose and carboxyvinylpolymers Ovules, suppositories, vaginal capsules 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 polyethylene glycols and optionally also emulsifiers and surfactants.
The vaginal capsules are gelatinous 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 thickening agents. The tablets, shaped suitably for vaginal use, contain as main excipients lactose, starch, polyvinylpyrrolidone, cellulose derivatives, mAgnecium stearate, glycol. The effervescent tablets contain chemical 1~ components (i.e. sodium bicarbonate with citric acid or tartaric acid), which are nec~ss~ry to develop carbon dioxide in order to produce effervescence.
The compositions of the present in~vention may also be incorporated into and topically applied by woven or nonwoven fabric materials such as tissues, wipes, rell~illine n~pkin.~, panty liners, l,llnpolls, diapers, incontinent care products and the like. Preferred 20 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 incorporated by reference.
Oral dosage forms are also usefu1 as carriers for the present invention. These dosage forms contain compatible solid or liquid filler diluents or encaps~llAting substances 25 which are suitable for oral ~ 1. ation to a human or lower animal.
Liquid dosage forms for oral ~rimini~tl-ation may comprise dissolving or suspending the compositions of the present invention in a potable liquid, such as sterile or purified water. Alternatively, liquid or dry oral ~ Lion forrns can comprise an enterically coated capsule co..~ p the dosage forms. Suitable forms include emulsions, 30 suspensions, solutions, syrups, and elixirs co..lAil~ inert diluents commonly used in the art, such as purified water, sugars, polysaccharides, silicate gels, gelatin, or an alcohol.
These inert tlih~nts do not actively participate in the therapeutic effect of the present invention. However, such liquid forms may require special care where free water is present with the Lactobacillus to prevent fel ll,c;~llalion or degradation of the Lactobacillus.
35 Besides the inert diluents, such colllposiLions; can also contain wetting agents, emulsifying -CA 0224~810 1997-08-10 W O 97/29762 PCTrUS97/0166i agents, suspending agents, as well as additional therapeutic actives. For a more detaile description of liquid and liquid-like dosage forms, see Remington's Pharmaceutical Sciences, 17th ed., M[ack Publishing Company, Easton, Pa. (1990), pages lS19-1544, herein incorporated by reference.
Tablets can be col,lplessed, molded, triturated, enteric-coated, sugar-coated, film-coated or multiple colllpl essed, cont~inin~ suitable binders, lubricants, rliluents, rli~inte~rating agents, and flow-inducing agents.
Also useful are soft or hard gelatin ç~ps-l~çs Preferably, the gelatin shell is essentially Ll~llsl)alt;lll so as to enhance the aesthetic qualities of the capsule. Soft and hard gelatin shells generally comprise gelatin, a plasticizer and water The starting gelatin material generally used in the m~mif~l~t~re of these capsules is obtained by the partial hydrolysis of collagenous material. Gelatin suitable for capsule m~nuf~ctllre iscommercially available from the Sigma Chemical Company, St. Louis, Mo.. One or more plasticizers is incorporated to produce a gelatin shell. Useful plasticizers of the present invention include glycerin, sorbitan, sorbitol, or similar low molecular weight polyols, and mixtures thereof.
Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," Modern Pharrn~ce~ltics, Vol. 7, (Banker andRhodes, editors), 359-427 (1979), incorporated by reference herein. Techniques and compositions for making tablets (COlll~l t;ssed and molded), capsules (hard and soft gelatin), troches and pills are described in Remington's Pharm~ceutical Sciences (Arthur Osol, editor), 1553-1593 (1980) and U.S. Patent 4,935,243, to ~orkan et al., issued ~une 1~, 1990; these two references being incorporated herein by reference in their entirety.
Specific examples of pharm~cel1ti~11y acceptable carriers and excipients that may be used to forrnulate oral dosage forms, are described in U.S. Patent 3,903,297, Robert, issued September 2, 1975, inco",ol~ed by reference 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 Iyophilization f~ tAtes ~icintegration of the composition by forming the dried composition into an open matrix network. In most cases, this results in rapid perrmeation by the aqueous media, promoting timely delivery of the product.
Suitable metho-~s of freeze drying are well known in the art and eollllllonly employed.
Any suitable conventional method of freeze-drying may be l~tili7e(l A preferable method of rree~ing 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 CA 0224~Xl0 1997-08-10 Wo 97/29762 PCT/US97/01662 production are taught by U.S. Patent 4,642,903, Febru~ry 17, 1987, to Davies, U.S.
Patent 4,946,6847 August 7, 1990, to Blank et al., U.S. Patents 4,305,50~ and 4,371,516, issued December 15, 1981 and February 1, 1983 respectively, to Gregory et al., and U.S.
- Patent 5,188,825, February 23,1993, to Iles et al.; which are all incorporated herein by S reference.
Similarly, the compositions of the present invention may be vacuum dried.
Vacuum drying involves at least the partial drying of compositions at temperatures above compositions' collapse temperature. Freeze drying, on the other hand, involves the drying of compositions at temperatures below the compositions; collapse temperature. Any 10 suitable method of vacuum drying may be used. Suitable vacuum drying processes are described in U.S. Patent 5,298,261, to Pebley et al., issued March 29, 1994, herein incorporated by I efe, e.,ce.
One other form of tableting technology that may be applicable to the present invention is a liquid/liquid extract developed by Janssen Pharrnaceutica Inc. and is 15 identified by the trade name QuicksolvTM. This technology is fully described in U.S.
Patent 5,215,756 herein incorporated by reference.
Other optional ingredients well known to the pharmacist's art may also be ir~luded in amounts generally known for these ingredients, for example, natural or artificial sweeteners, flavoring agents, colorants, perfilming agents, buffering agents and the like to 20 provide a palatable and pleasant looking final product, antioxidants, for example, butylated hydroxy anisole or butylated hydroxy toluene, and preservatives, for example, methyl or propyl p~,~e,n, potassium sorbate, or sodiurn benzoate, to prolong and çnh~nce shelf life.
A l)lere~,ed optional component is also c~ffeine Those of ordinary skill in the art ~,-ill quickly reaiize other suitable ingredients, 25 rlilu~nts and dosage forms, or will be able to ascertain such, using routine c~ .h~nt~tion Further, the ~ . alion of the various compositions can be carried out using standard techniques common to those of ordinary slcill in the art.
Exarnples The following examples further describe and demonstrate embodimente within the 30 scope of the present invention. These e~xamples are strictly given for illustration purposes and are not to be construed as limitations of the present invention, as many variations are possible without dep&- ling from the spirit and scope of the invention as set forth herein.
Example I
The T ~ctob~c~ e and/or Bifidobacterium species cultures can be freeze dried (or35 purchased freeze dried). To provide freeze dried cultures, an inoculum of Lactobacillus CA 0224~810 1997-08-10 W O 97/29762 PCT~US97/01662 and/or Bifidobacterium is grown in a sterile nutrient media ~e.g. Trypticase Soy agar broth). The media is removed by centrifugation. The bacteria isolates are washed using a sterile b~l~nced salt and 5% glucose solution. The bacteria are then "snap frozen" with liquid nitrogen and vacuum freeze dried. The freeze dried product is then checked for 5 bacterial plate count and then diluted so that the plate count per unit dose composition is from about 103 to about 1012.
Example II
The freshly obtained, washed and Iyophilized bacteria obtained as described above are suspended in 10 ml of 5% glucose saline solution in such volume so as to obtain a 10 heavy suspension of bacteria which contains between one to 101~ organisms per ml, at 0-4~C. All of these procedures are performed in the 0-4~C temperature range unlessotherwise noted, in order to "~ viability of the lactobacilli bacteria which at room temperature lose viability. The suspension of bacteria is rapidly, but gently, stirred while 0.2-0.4 ml of sodium alginate solution (1.5% weight by volume) is added. The above 15 rnixture is then transferred into a 4 liter round bottom flask by using a nitrogen stream through a ~he~thec~ 14 gauge needle. The 4 liter round bottom flask was previously washed with a 5% albumin solution, and thereafter heated for at least 10 hours at 6~~C, and the needle and the tubing used in the process have also been treated this way.
Thereafter the above mixture is forced through a 30 gauge multi-beveled needle 20 under pressure using a large syringe and nitrogen stream. Very small droplets are generated at the end of the needle which are dried by the nitrogen and air stream around the 30 gauge needle, and the droplets are collected in an aqueous solution of 1.3-2%
calcium chloride where they gel. Thereafter, they are washed at least three times with 0.08-0.13% 2-(N-cyclohexyl-amino) ethanesulfonic acid (CHES) solution and 1.0-1.5%
25 calcium chloride solution.
The gelled droplets or little spheres are further washed with at least a five fold excess of the 0.1% CHES 1.1% calcium chloride, and norrnal saline solution. The rçslllt~nt spheres are then "snap frozen" in liquid nitrogen and then Iyophilized. After these steps, the encapsulated org~nicm~ can be used in the forrnulations of the present 30 invention.
Example III
A tablet forrn of the present invention is made by combining the following components using conventional mixing and tableting technology.
Ingredient % Weight Concentrated Cranberry Extract 37 300%
W O 97/29762 PCTrUSg7/01662 Lactobacillusl 29.900%
~, K2932 (5% ethanol soln)2 13.4.00%
Avicel (pH 101)3 13.400%
~, Explotab4 1.8%
Talc 3.600%
~ne~il-m stearate 0.6û0%
1 Microencapsulated ~.actobnr~ 2~ Caseii l~ar. rhamnosus (108 cfu/g).
2 Polyv~ py~ ollidone 3 TM for microcrystalline cellulose, a highl)~ purified particulate form of cellulose 10 4 Abrandofsodiumstarchglycolate The cranberry extract is gr~n~ ted with half the Avicel and the K2932 in ethanol.
The granl~l~tin~n is then passed through a I2 mesh screen and dried at 120~F. The dried granulation mixture is passed through a 20 mesh screen. To the sieved granulation is added the lactobacill--~, re~inin~ Avicel, Explotab and talc and mixed until uniform.
15 ~gn~cillm stearate is then added to the uniforrn mixture with mixing. The resultant granulation mixture is then con,pressed using conventional tableting processes.
Example IV
A oral capsule form of the present invention is made by combining the following components using conventional mixing techr~ology.
Ingredient % Weight Conce"Ll~led Cl~l.l,~.ly Extract 29.900%
Bifidobacteriuml 15.000%
fructooligosaccharide2 29.900%
Avicel3 22.400%
Ac Di Sol4 2.800%
Microencapsulated Lactobacillus bif dus subsp pennsylvanicus ( 108 cfu/g).
2 Available as NutraFlora FOS from Golden Technologies Company, Inc.
3 TM for microcrystalline cellulose, a highly purified particulate form of cellulose.
4 A brand of a cross-linked form of sodium carboxymethylcellulose.
Combine and mix the cranberry extract, fructooligosaccharide, Lactobacillus culture, Avicel and Act Di Sol in a V-blender until uniro~ . Unit dose amounts of the res~lt~nt mixture is then placed into suitably sized hard gelatin capsules.
Example V
A topical gel form of the present invention is made by colllbilfing the following 35 components using conventional mixing technolog,v.
CA 0224~810 1997-08-lO
W O 97/29762 PCTrUS97/01662 Ingredient % Weight Concentrated (~ranberry Extract 0.50%
Lactobacillus 1 2.50%
fructooligosaccharide2 6.00%
Polyacrylamide and C 13-14 Isoparaffin and Laureth-73 4.00%
PPG-14 Butylether 8.00%
Water, Purified q.s.
Microencapsulated Lactobacillus Caseii var. rhamnost~s (108 cfu/g).
10 2 Available as NutraFlora FOS from Golden Technologies Company, Inc.
3 Available as Sepigel from Seppic Corporation.
Water is added to a suitable size container. While mixing at a moderate speed (300 rpm), the Polyacrylamide and C13 14 Isoparaffln 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 15 covered. Using a r.i~htnin' Mixer with a 3 blade paddle prop, the cranberry extract and fructooligos~cch~ride are added to the PPG-14 Butyl ether and mixed at a low speed (100 rpm) until the el ~nbe- l y extract and fructooligosaccharide are dissolved. Thelactobacillus culture is added to the water phase and mixed at low speed (100 rpm) until a uniform solution results. The PPG-14 Butyl ether is slowly added to the water phase to 20 form a gel. The reslllting gel is mixed at moderate speed until uniform.
Claims (10)
1. A composition for treating or preventing urogenital and intestinal disorders, comprising:
a.) an antiadhesive amount of at least one plant species of the Ericaceae family or its extract; and b.) a viable culture of at least one species of microencapsulated bacteria selected from the group consisting of lactobacillus, bifidobacterium and mixtures thereof.
a.) an antiadhesive amount of at least one plant species of the Ericaceae family or its extract; and b.) a viable culture of at least one species of microencapsulated bacteria selected from the group consisting of lactobacillus, bifidobacterium and mixtures thereof.
2. A composition according to Claim 1, further comprising a growth factor wherein the growth factor is selected from the group consisting of lactulose, rhamnose, oligosaccharides, glycogen and mixtures thereof.
3. A composition according to Claim 1 or 2, further comprising a coating material having an A w of less than about 0.6 and having suspended therein the microencapsulated bacteria.
4. A composition according to any one of the preceding Claims, further comprising a carrier selected from group consisting of suppository, tablet, troche, oral liquid, suspension, capsule, gelatin capsule.
5. A composition according to any one of the preceding Claims, wherein the species of lactobacillus is selected from the group consisting of L. acidophilus, L. gasseri, L. catenaforme, L. casei, L. crispatus, L. defbrueckii, L. jensenii, L rogosae, L.
fermentum, L. plantarum and mixtures thereof and wherein the species of bacteriais present at a level of 10 4 to 10 12 lactobacillus cells per unit dose of the composition, preferably 10 6 to 10 10 lactobacillus cells per unit dose of the composition.
fermentum, L. plantarum and mixtures thereof and wherein the species of bacteriais present at a level of 10 4 to 10 12 lactobacillus cells per unit dose of the composition, preferably 10 6 to 10 10 lactobacillus cells per unit dose of the composition.
6. A composition according to any one of the preceding Claims. wherein the plant or extract is a species selected from the genus Vaccinium.
7. A composition according to any one of the preceding Claims, further comprising nutritional additives selected from the group consisting of vitamins, minerals, amino acids, phytochemicals and mixtures thereof and/or an additional plant extract selected from the group consisting of echinacea, allium, bucha, juniper ginseng allicin, chlorella, algin and mixtures thereof and/or a pharmaceutical active selected from the group of consisting of analgesics, gastrointestinal actives and mixtures thereof.
8. A topically administered composition for treating or preventing urogenital disorders, comprising:
a.) an antiadhesive amount of at least one plant species of the Ericaceae family or its extract; and b.) a viable culture of at least one species of microencapsulated bacteria selected from the group consisting of lactobacillus, bifidobacterium and mixtures thereof.
a.) an antiadhesive amount of at least one plant species of the Ericaceae family or its extract; and b.) a viable culture of at least one species of microencapsulated bacteria selected from the group consisting of lactobacillus, bifidobacterium and mixtures thereof.
9. A composition according to Claim 8, further comprising an oligosaccharide growth factor selected from the group consisting of galactooligosaccharides, soybean oligosaccharides, fructooligosaccharides and mixtures thereof and/or a bufferingagent selected from the group consisting of boric acid, hippuric acid, tartaric acid, sorbic acid, benzoic acid, lactic acid, ascorbic acid, citric acid, acetic acid,proprionic acid, pharmaceutically acceptable salts thereof and mixtures thereof.
10. A composition according to Claim 8 or 9, further comprising a carrier selected from group consisting of suppository, vaginal tablet, vaginal gelatin capsules, vaginal troche, cream, gel, ointment, lotion, irrigant, douche, tissue, wipe, panty liner, feminine napkin, tampon, diaper and incontinent care product.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US60148096A | 1996-02-14 | 1996-02-14 | |
US08/601,480 | 1996-02-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2245810A1 true CA2245810A1 (en) | 1997-08-21 |
Family
ID=24407644
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002245810A Abandoned CA2245810A1 (en) | 1996-02-14 | 1997-02-06 | Urogenital and intestinal compositions |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0880354A1 (en) |
JP (1) | JPH11504048A (en) |
CN (1) | CN1211188A (en) |
AU (1) | AU1758197A (en) |
CA (1) | CA2245810A1 (en) |
WO (1) | WO1997029762A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015173693A1 (en) * | 2014-05-16 | 2015-11-19 | Pizeta Group Srl | Compositions containing boric acid and a mixture of lactobacillus |
Families Citing this family (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU754615B2 (en) * | 1997-07-05 | 2002-11-21 | Australasian Food Group Pty Ltd | Frozen dessert |
AU744527B2 (en) * | 1997-09-09 | 2002-02-28 | Rutgers, The State University Of New Jersey | Plant proanthocyanidin extract effective at inhibiting adherence of bacteria with P-type fimbriae to surfaces |
SE519648C2 (en) * | 1998-03-06 | 2003-03-25 | Essum Ab | New strain of Lactobacillus plantarum |
DK0956858T3 (en) * | 1998-04-30 | 2002-01-28 | Vesely Renata Maria Cavaliere | Pharmaceutical preparations containing lactobacilli for the treatment of vaginal infections |
US7767203B2 (en) | 1998-08-07 | 2010-08-03 | Ganeden Biotech, Inc. | Methods for the dietary management of irritable bowel syndrome and carbohydrate malabsorption |
US6461607B1 (en) | 1998-08-24 | 2002-10-08 | Ganeden Biotech, Inc. | Probiotic, lactic acid-producing bacteria and uses thereof |
US6080401A (en) * | 1998-11-19 | 2000-06-27 | Reddy; Malireddy S. | Herbal and pharmaceutical drugs enhanced with probiotics |
CA2379040C (en) * | 1999-03-05 | 2010-01-26 | Shanbrom Technologies, Llc | Soluble plant derived natural color concentrates and antimicrobial nutraceuticals |
CA2374937A1 (en) * | 1999-05-25 | 2000-11-30 | Gregor Reid | Oral administration of lactobacillus for the maintenance of health in women |
IT1306716B1 (en) * | 1999-06-21 | 2001-10-02 | Mendes S U R L | ASSOCIATION OF LACTIC BACTERIA AND ITS USE FOR THE PREVENTION AND / OR THERAPEUTIC TREATMENT OF INFECTIONS AND INFLAMMATORY STATES. |
JP4603116B2 (en) * | 1999-12-02 | 2010-12-22 | わかもと製薬株式会社 | Lactic acid bacteria-containing composition, medicine and food |
SE518097C2 (en) | 2000-10-03 | 2002-08-27 | Ellen Ab | Process for the preparation of an absorbent sanitary article comprising lactic acid producing bacteria as well as such |
GB2369777B (en) * | 2000-10-05 | 2004-10-27 | St Ivel Ltd | Food products with antimicrobial lactic acid bacteria |
FI109602B (en) | 2001-01-25 | 2002-09-13 | Valio Oy | Probiotkombination |
EP1228769A1 (en) * | 2001-02-02 | 2002-08-07 | Jörg-Peter Prof. Schür | Symbiotic regenerative composition |
FR2827774B1 (en) * | 2001-07-30 | 2005-06-24 | Dolisos Lab | PHARMACEUTICAL AND / OR DIETARY PREPARATIONS CONTAINING ACTIVE PLANT VEGETABLE EXTRACT AND PROBIOTIC MICROORGANISMS |
SE0104199L (en) * | 2001-12-13 | 2003-06-14 | Sca Hygiene Prod Ab | New product |
US20030143262A1 (en) | 2001-12-13 | 2003-07-31 | Brusk Ulla Forsgren | Hygiene tissue |
DE60323734D1 (en) | 2002-03-21 | 2008-11-06 | Bifodan As | Lactobacillus strains |
US20030229335A1 (en) * | 2002-04-30 | 2003-12-11 | Payne Richard Grady | Apparatus and method for delivery of constrained beneficial bacteria to the vaginal tract |
US7785640B2 (en) * | 2004-01-16 | 2010-08-31 | Amerilab Technologies, Inc. | Effervescent composition including cranberry extract |
GB0410785D0 (en) * | 2004-05-14 | 2004-06-16 | Glycologic Ltd | Improved prebiotic |
FR2874826B1 (en) * | 2004-09-08 | 2006-12-22 | Pharmatoka Soc Par Actions Sim | NEW SURGICAL AND / OR MEDICAL DEVICES AND THEIR USE |
FR2875406B1 (en) * | 2004-09-21 | 2007-01-05 | Danisco | STRAIN OF LACTOBACILLUS ACIDOPHILUS HAVING ANALGESIC PROPERTIES AT THE GASTROINTESTINAL SYSTEM LEVEL |
EP1965840A4 (en) * | 2005-12-22 | 2011-10-19 | Sca Hygiene Prod Ab | Absorbent article |
EP1965839B1 (en) * | 2005-12-22 | 2012-07-25 | SCA Hygiene Products AB | Absorbent article |
SI2211626T1 (en) | 2007-08-29 | 2019-12-31 | Ganeden Biotech, Inc. | Baked goods |
CN101642189B (en) * | 2008-08-07 | 2012-05-30 | 北京大北农科技集团股份有限公司 | Microcapsule compound feed additive and preparation method thereof |
AU2009305668B2 (en) | 2008-10-16 | 2015-11-26 | Ganeden Biotech, Inc. | Probiotic grain-based compositions |
EP2210505A1 (en) * | 2009-01-27 | 2010-07-28 | Nestec S.A. | Composition comprising caftaric acid and/or derivatives thereof |
US8568743B2 (en) | 2009-04-29 | 2013-10-29 | Ganeden Biotech, Inc. | Inactivated bacterial cell formulation |
IT1403661B1 (en) * | 2011-01-28 | 2013-10-31 | Probiotical Spa | EFFERVESCENT COMPOSITION IN THE SOLID FORM FOR USE IN VAGINAL APPLICATIONS FOR THE TREATMENT OF VAGINAL INFECTIONS. |
US11235008B2 (en) | 2011-03-31 | 2022-02-01 | Ganeden Biotech, Inc. | Probiotic sports nutrition compositions |
ITMI20110791A1 (en) | 2011-05-09 | 2012-11-10 | Probiotical Spa | BACTERIA OF BACTERIA ABLE TO METABOLIZE THE OXALATES. |
ITMI20110793A1 (en) | 2011-05-09 | 2012-11-10 | Probiotical Spa | STRAINS OF PROBIOTIC BACTERIA AND SYNBIOTIC COMPOSITION CONTAINING THEMSELVES INTENDED FOR THE BABY FOOD. |
ITMI20110792A1 (en) | 2011-05-09 | 2012-11-10 | Probiotical Spa | STRAINS OF BACTERIA BELONGING TO THE BIFIDOBACTERIUM TYPE FOR USE IN THE TREATMENT OF HYPERCOLESTEROLEMIA. |
ITRM20110477A1 (en) | 2011-09-09 | 2013-03-10 | Giovanni Mogna | COMPOSITION INCLUDING N-ACETYLCISTEIN AND / OR LYSOZYME MICROINCAPSULATE GASTROPROTECT IN ASSOCIATION WITH PROBIOTIC BACTERES ABLE TO RESTORE THE BARRIER EFFECT OF THE STOMACH THAT IS LOST DURING THE PHARMACOLOGICAL TREATMENT OF |
ITMI20111718A1 (en) | 2011-09-23 | 2013-03-24 | Probiotical Spa | A WATERPROOF MOISTURE AND OXYGEN MATERIAL FOR PACKAGING DIETARY, COSMETIC AND MEDICINAL PRODUCTS. |
WO2013113767A1 (en) | 2012-01-31 | 2013-08-08 | Bioclin Bv | Method for administration of a probiotic |
ITMI20130793A1 (en) | 2013-05-14 | 2014-11-15 | Probiotical Spa | COMPOSITION INCLUDING LACTIC BACTERIA FOR USE IN THE PREVENTIVE AND / OR CURATIVE TREATMENT OF THE RECURRENT CYCLES. |
WO2017058175A1 (en) | 2015-09-29 | 2017-04-06 | Kimberly-Clark Worldwide, Inc. | Synergistic composition for maintenance of healthy balance of microflora |
JP7118594B2 (en) * | 2016-03-31 | 2022-08-16 | 小林製薬株式会社 | antidiarrheal composition |
EP3320897A1 (en) * | 2016-11-14 | 2018-05-16 | Dompè Primary S.r.l | Process for the preparation of coated cranberry granules with stable proanthocyanidine content |
US10258567B1 (en) | 2016-11-17 | 2019-04-16 | Grace Procurements Llc | Vaginal probiotic products and related processes |
CN110234325A (en) | 2017-02-28 | 2019-09-13 | 金伯利-克拉克环球有限公司 | For safeguarding the cooperative compositions in a healthy and balanced way of microbiologic population |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2421066A1 (en) * | 1974-05-02 | 1976-03-25 | Solco Basel Ag | Bifido bacterial preparations - additionally contg. Lactobacillus casei var. rhamnosus |
SE446940B (en) * | 1983-02-16 | 1986-10-20 | Carl Axel Virdalm | MEASURES FOR FIGHTING DISEASE CONDITIONS IN THE FOOD MELTER CONTAINING SHALL OR OUTSIDE OF BEERS OR FRUITS |
DE3404474A1 (en) * | 1983-04-06 | 1984-10-11 | James Gorden Belleair Fla. Roberts | METHOD FOR PRODUCING A MULTIPLE FERMENTED DAIRY PRODUCT |
IT1227154B (en) * | 1988-08-05 | 1991-03-19 | A Tosi Farmaceutici S R L Nova | PHARMACEUTICAL COMPOSITIONS FOR GYNECOLOGICAL USE BASED ON LATTOBACILLI |
US5219842A (en) * | 1989-08-29 | 1993-06-15 | Nihon Shokuhin Kako Co., Ltd. | Method of improving intestinal floras |
GB2261372A (en) * | 1991-11-15 | 1993-05-19 | Gregor Reid | Lactobacillus and skim milk compositions for prevention of urogenital infection |
US5525341A (en) * | 1992-10-09 | 1996-06-11 | Jlb, Inc. | Partially purified cranberry anti-adhesion activity |
US5474774A (en) * | 1994-03-25 | 1995-12-12 | Jlb, Inc. | Adhesion inhibiting composition |
-
1997
- 1997-02-06 JP JP9529373A patent/JPH11504048A/en active Pending
- 1997-02-06 AU AU17581/97A patent/AU1758197A/en not_active Abandoned
- 1997-02-06 CN CN97192254A patent/CN1211188A/en active Pending
- 1997-02-06 WO PCT/US1997/001662 patent/WO1997029762A1/en not_active Application Discontinuation
- 1997-02-06 CA CA002245810A patent/CA2245810A1/en not_active Abandoned
- 1997-02-06 EP EP97904914A patent/EP0880354A1/en not_active Withdrawn
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2015173693A1 (en) * | 2014-05-16 | 2015-11-19 | Pizeta Group Srl | Compositions containing boric acid and a mixture of lactobacillus |
Also Published As
Publication number | Publication date |
---|---|
CN1211188A (en) | 1999-03-17 |
JPH11504048A (en) | 1999-04-06 |
WO1997029762A1 (en) | 1997-08-21 |
AU1758197A (en) | 1997-09-02 |
EP0880354A1 (en) | 1998-12-02 |
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