EP0880354A1 - Compositions destinees au traitement de troubles urogenitaux et intestinaux - Google Patents

Compositions destinees au traitement de troubles urogenitaux et intestinaux

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Publication number
EP0880354A1
EP0880354A1 EP97904914A EP97904914A EP0880354A1 EP 0880354 A1 EP0880354 A1 EP 0880354A1 EP 97904914 A EP97904914 A EP 97904914A EP 97904914 A EP97904914 A EP 97904914A EP 0880354 A1 EP0880354 A1 EP 0880354A1
Authority
EP
European Patent Office
Prior art keywords
acid
lactobacillus
species
group
mixtures
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.)
Withdrawn
Application number
EP97904914A
Other languages
German (de)
English (en)
Inventor
Paul Joseph Sagel
Anne Marie Carella
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Procter and Gamble Co
Original Assignee
Procter and Gamble Co
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Procter and Gamble Co filed Critical Procter and Gamble Co
Publication of EP0880354A1 publication Critical patent/EP0880354A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K36/13—Coniferophyta (gymnosperms)
    • A61K36/14—Cupressaceae (Cypress family), e.g. juniper or cypress
    • 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
    • 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
    • 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)
    • A61K36/88—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
    • 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
    • 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
    • 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

Definitions

  • compositions useful in preventing and/or treating urogenital and intestinal disorders This application relates to compositions useful in preventing and/or treating urogenital and intestinal disorders.
  • Deviations from this delicate flora balance have been etiologically linked to a number of urogenital and/or gastrointestinal tract disorders; such imbalances usually resulting in the proliferation and predominance of pathogenic species. Establishing and/or preserving such a delicate flora balance is, therefore, essential to maintaining optimal health.
  • lactobacillus One way of establishing or maintaining the body's flora is by administering lactobacillus.
  • lactobacillus to treat urogenital and intestinal disorders has been proposed, for instance, in Canadian 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 January 5, 1995, to Tosi et al.
  • lactobacillus provide host protection via adherence to intestinal or vaginal epithelial cells.
  • Bifidobacterium provide improved compositions for treating and/or preventing urogenital and gastrointestinal 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 Vaccinium (e.g. cranberry 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.
  • Vaccinium e.g. cranberry and blueberry
  • compositions of the present invention provide improved environments more conducive to the colonization of lactic acid bacteria. Accordingly, it is an object of the present invention to provide compositions for dietary supplementation.
  • Another object of the present invention is to provide improved compositions comprising a viable colony of microencapsulated lactobacillus and/or bifidobacteria.
  • a further object of the present invention is to provide compositions effective in preventing and/or treating urogenital and intestinal disorders.
  • 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 intestinal disorders.
  • the present invention relates to compositions for the treatment or prevention of 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
  • the present invention also relates to the above compositions further comprising a growth factor for facilitating the growth of lactic acid bacteria.
  • urogenital and intestinal compositions means a product which in the ordinary course of usage may be retained in the oral cavity, swallowed or applied topically to provide urogenital and/or intestinal activity.
  • antiadhesive amount means an amount effective to reduce the number of pathogenic microorganisms on the epithelial and/or mucosal lining of the urogenital and/or intestinal tract.
  • urogenital means that system of organs concerned with the production and excretion of urine and reproduction.
  • intestinal means of or relating to the intestines.
  • nonpathogenic means substantially lacking the ability to cause disease or abnormality in healthy mammals.
  • health means free of underlying disease and/or immunosuppression
  • the Ericaceae (heath) family consisting of about 1 10 genera and 4,000 species, is by far the most important family of the Ericales order, encompassing a wide variety of fruit producing shrubbery and evergreen plants.
  • Genera falling under Ericaceae family include Vaccinium, Arctostaphylos, Gaultheria, and Gaylussacia.
  • the Arctostaphylos genus includes such species as the checkerberry and bearberry (Uva rsi).
  • Other edible fruits such as the creeping snowberry or moxie plum fall under the genus Gaultheria.
  • Huckleberries are a well known species of the genus Gaylussacia.
  • the Vaccinium genus best known for its fruits, contain some of the most common of berries, including the blueberry (e.g., V. australe), cranberry (e.g., V. macrocarpori) and bilberry (e.g., V. myrtillus).
  • blueberry e.g., V. australe
  • cranberry e.g., V. macrocarpori
  • bilberry e.g., V. myrtillus
  • E. coli adherence results primarily from adhesins on the raised hair like fimbriae (or pili) of the microorganism. These adhesins are designated MS (mannose-sensitive) and MR (mannose-resistent).
  • Plants or extracts useful in the compositions of the present invention come from a wide range of Ericaceae genera including, but not limited to, Vaccinium, Arctostaphylos, Gaultheria, and Gaylussacia.
  • Preferred species include, V. australe, V. corymbosum, V. occidental, V. ova turn, V. myrtillus, V. parvifolium, V. uliginosum, V. macrocarpon, V. oxycoccus, V. erythrocarpum, V. vitis-idaea.
  • Vaccinium species most preferred for use in the present invention include V. australe, V. macrocarpon, and V. myrtillus.
  • 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 50 pounds of plant concentrate or extracts per pound of concentrate.
  • the Ericaceae extracts are preferably present at a level of at least 1 Omg, more preferably from about lOOmg to about 18g, most preferably 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.
  • 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 to about 4g.
  • Preferred levels of the Ericaceae plants or extracts provide urinary and/or intestinal tract fluid concentrations of the above mentioned unidentified, non-dialyzable polymeric compound of from about 12 to about 25 micrograms per milliliter.
  • the plants or extracts of the present invention preferably retain greater than 2.5% of their total acid content and greater than about 0.1% of their benzoic acid content.
  • the level is selected to provide the desired level of anti-adhesin activity and can be modified as desired.
  • Cranberries and cranberry extracts are useful in the treatment and/or prophylaxis of urinary tract infections and are also useful as vaginal deodorants. Species of Lactobacillus or Bifidobacterium
  • Lactobacillus Another essential component of the present invention is a viable colony of microencapsulated Lactobacillus or Bifidobacterium.
  • Bacteria of the Lactobacillus genus are characterized as rod-shaped, gram-positive and non-spore-forming bacteria.
  • Lactobacillus inhabit the urogenital and gastrointestinal tracts of animals and humans and are important members of lactic acid producing group of bacteria.
  • Various species of Lactobacillus are used commercially in the production of sour milks, cheeses and yogurt. Lactobacilli also share an important role in the manufacture of fermented vegetables (e.g., pickles and sauerkraut), beverages (e.g., beer, wine and juices), sourdough breads, and some sausages.
  • Lactobacillus species suitable for use in the present invention are those which 1.) readily adhere to the epithelial cells of either the urogenital or gastrointestinal tracts of mammals; 2.) produce hydrogen peroxide; 3.) promote low pH; and produce bacteriocins.
  • bacteriocins means proteinaceious, bacteriocidal substances synthesized by bacteria, which usually have a narrow spectrum of activity, inhibiting strains of the same or closely related species. Bacteriocins appear to be capable of displacing or suppressing the growth of other bacteria, and as such may provide an advantage to microorganisms in fermenting the female genital tract ecosystem.
  • Preferred species of Lactobacillus include L. acidophilus, L. catenqforme, L.
  • Lactobacillus species of the present invention are hydrogen peroxide producing such as L. acidophilus, L. catenqforme, L. casei, L.
  • Bifidobacterium family Actinomycetaceae
  • Lactic and acetic acid producing Bifidobacteria are also considered important regulators of the urogenital and intestinal flora of mammals
  • Species suitable for use in the present compositions include, but are not limited to, B.
  • B. breve Lactobacillus Bifidus and Lactobacillus bifidus subsp pennsylvanicus.
  • Preferred for use in the present compositions is B. Bifidum, most preferred B. Bifidum subsp. Pennsylvanicus.
  • Lactobacillus and/or Bifidobacterium species may also be used Any of the above species may be obtained either commercially or through laboratory cultures.
  • the Lactobacillus and/or Bifidobacterium species are present as core and/or coating components at levels of at least about 10 ⁇ cells per unit dose, preferably at levels of from about 10"* to about 1012 cells per unit dose and most preferably at levels of from about 10 > to about 10 * ⁇ cells per unit dose
  • unit dose means physically discrete units suitable as unitary dosages for administration to mammals, each such unit containing a predetermined quantity of an active ingredient calculated to produce the desired therapeutic effect in association with pharmaceutically acceptable carriers.
  • the level is selected to provide the desired level of urogenital and gastrointestinal activity and can be modified as desired.
  • Lactobacillus may loose 4-6 fold of its viability at room temperature and during manufacturing, so depending on the manufacturing conditions, an excess of Lactobacillus is added to maintain an adequate number of viable organisms per final unit dose form.
  • a patient can be administered the equivalent of these concentrations of organisms where the values are expressed by some other measurement such as, for example, total protein concentration
  • the Lactobacillus and/or Bifidobacterium species of the present invention must also be microencapsulated.
  • Viable Lactobacillus and/or Bifidobacterium bacteria that have been lyophilized 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 strains.
  • Suitable media include MRS, Thayer-Martin media, Trypticase Soy, Brain-Heart Infusion Broth, or any other enriched media suitable for the cultivation of these organisms, as no particular media is critical to the success of this suppository
  • the only important factors are the viability and quantity of the micro-organisms that are always determined by standard clinical laboratory dilution methods, 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 performing a colony count
  • the removal of the nutrient media is done by centrifugation at 14,000 x g at 0°-4°C, and then washing with sterile, balanced salts and 5% glucose solution at least three times after the initial centrifugation.
  • compositions of the present invention is a growth factor for facilitating the growth of lactic acid bacteria.
  • a growth factor for facilitating the growth of lactic acid bacteria is meant a nutrient source or media which supplies a necessary source of food and/or energy for facilitating the growth of lactic acid producing bacteria.
  • the growth factor is preferably selective for establishing and maintaining the growth of lactic acid bacteria, preferably Lactobacillus and/or Bifidobacterium, without facilitating extreme growth of pathogenic bacteria
  • the various nutritional requirements essential for bacterial and/or colony growth are normally met when the growth factor contain fermentable carbohydrate, peptone, meat and yeast extract.
  • 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- ⁇ -D-mannoside, p-nitrophenol- ⁇ -D-mannoside, maltose, maltodextrin, dextrin, dextran, levan, sialic acid and acetylglucosamine as well as oligosaccharides such as, but not limited to, fructooligosaccharides, galactooligosaccharides and soybean oligosaccharides.
  • yeast extracts such as glycogen, glucose, fructose, rhamnose, lactulose, methyl- ⁇ -D-mannoside, p-nitrophenol- ⁇ -D-mannoside, maltose, maltodextrin, dextrin, dextran, levan, sialic acid and acety
  • Fiber or fermentable substrates such as psyllium may be used in the present compositions as may gums such as guar gum and xanthum gum.
  • proteinacious materials such as, peptone, keratin; vegetable; soy and unsaturated fatty acids such as lauric acid and teichoic acids such as lipoteichoic acid and esters such as glycerophosphates or ⁇ -glycerophosphates are also useful as growth factors.
  • the growth factor is preferably selective for establishing and maintaining 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 nutrients may also be used.
  • the growth factor of the present invention is an oligosaccharide such 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 preferred for use herein are fructooligosaccharides. Lactic acid bacteria, such as Lactobacillus and Bifidobacterium, partially utilize fructooligosaccharides as an energy source by converting it, via fermentation, 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 maintenance of low pH which is an important control mechanism for preventing colonization of pathogens.
  • oligosaccharide such as, but not limited to, galactooligosaccharides, soybean oligosaccharides and fructooligosaccharides. Oligosaccharides
  • Inulin is prepared by hot water extraction of chicory roots and is composed of molecules 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.
  • Non-fructosyl units may include, but are not limited to, polyalcohols such as xylitol, mannitol, and sorbitol.
  • Fructooligosaccharides most preferred for use in the present compositions are inulin or oligofructose. Mixtures of these nutrients may also be used
  • Growth factors are preferably inco ⁇ orated into the compositions of the present invention at from about 5% to about 75%, more preferably from about 20% to about 70%, and most preferably 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 (A w ) of less than about 0.6, more preferably less than about 0 45, most preferably less than about 0.3.
  • water activity is well known in 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 temperature. A more detailed description of water activity is found in U.K. Patent 2,014,429.
  • Water soluble coatings useful to the compositions of the present invention may include sugar or organic coatings.
  • Sugar coatings useful to the present compositions may be syrupy materials containing monosaccharides or polymers of two or more saccharide units.
  • Organic coatings are also useful to the compositions of the present invention.
  • Useful organic polymers or copolymers used include those having a plurality of carboxylic acid and ester groups. Such groups are largely responsible for physical or chemical interactions with an active ingredient for effective taste masking properties.
  • the preferred 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 ascertained by one of ordinary skill in the art.
  • polymers/copolymers that are pharmaceutically acceptable in terms of safety and toxicity may be used. It is preferred that such polymers copolymers be soluble in a solvent or a mixture of solvents
  • Such 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 cellulose, cellulose acetates, cellulose acetate phthallates, ethyl vinyl acetates and/or phthalates, polyvinyl acetates and/or phthalates, ethyl and/or methyl methacrylic acids, esters and co-polymers, hydroxy alkyl cellulose acetates and/or phthalates
  • Such compounds include commercially available materials sold under trade names such as Eudragit S
  • One particular embodiment of the present invention comprises a core containing at least one species of the Ericaceae family and a coating material containing a viable culture of at least one species of the above described microencapsulated bacteria
  • the microencapsulated Lactobacillus can reside in the core coated with a coating material containing 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.
  • Protein-like coating components may be included Useful for improvement of gastrointestinal 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 L-vahne (10 2 parts), cysteine hydrochloride (1 5 parts), and sodium carbonate (26 parts) in water at 40°C for 20 minutes to manufacture coated powders containing 10% free amino acids and 43% branched amino acids
  • the branched amino acid-modified powders can be mixed with fats, dextrins, salts, vitamins, and the like to make tablets
  • a tablet coating materials are zeolites and clays to make tablets more palatable Zeolites have found use as bacterial feed coatings for domestic animals
  • tiamulin fumarate is dissolved in methanol, supported on mordenite-type zeolite or starch, dried and further premixed with the supports to produce sustained-release, coated granules
  • Still other examples of tablet coatings include complex carbohydrate and inclusion complexes
  • the sugar and/or organic coatings of the present invention may be applied by conventional means including mechanical methods such as pan coating, air suspension techniques, multiorifice centrifugal techniques and spray drying techniques as well as physicochemical methods such as coacervation-phase separation. Coating procedures are more fully discussed in Remington's Pharmaceutical Sciences (Alfonso Gennarol, editor), 1666-1675 (1990), herein inco ⁇ orated by reference. Buffering Agents The compositions of the present invention may also contain a buffering agent.
  • buffering agents suitable for use in the compositions of the present invention are those capable of maintaining a urogenital pH of about 3 0 to about 5.5.
  • Any mild pharmaceutically acceptable acid other than those found in the Ericaceae species disclosed herein, can be used.
  • Suitable acids include boric 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 combination with their respective sodium or other pharmaceutically acceptable salt (to the extent necessary to achieve the desired pH).
  • 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 preferably using lactic acid with sodium lactate or a combination 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 inco ⁇ orated into the compositions of the present invention. Such plants or extracts include echinacea, allium, bucha, juniper ginseng, allicin, chlorella, algin and the like. Mixtures of these additional plants or extracts may also be used.
  • Nutritional additives may also be inco ⁇ orated into the compositions of the present invention.
  • Such additives include, but are not limited to, proteins and carbohydrates other than those mentioned herein as growth factors, vitamins, minerals, amino acids such as glycine, phytochemicals and mixtures thereof. These additives may, alternatively, be first inco ⁇ orated into the Lactobacillus and/or Bifidobacterium of the present invention.
  • Pharmaceutical Actives include, but are not limited to, proteins and carbohydrates other than those mentioned herein as growth factors, vitamins, minerals, amino acids such as glycine, phytochemicals and mixtures thereof.
  • compositions of the present invention may also be used in combination with pharmaceutical actives.
  • the pharmaceutical active is preferably selected from at least one of an analgesic agent and or a gastrointestinal agent.
  • appropriate measures should be taken to avoid contact with the microorganisms of 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 .
  • analgesics preferred for use in the present invention include acetaminophen, acetyl salicylic acid, indomethacin and optically active isomers or racemates of ibuprofen, naproxen, flurbiprofen, carprofen, tiaprofenic acid, cicloprofen, ketoprofen, ketorolac, etodolac, indomethacin, sulindac, fenoprofen, diclofenac, piroxicam, benzydomine, nabumetone, their pharmaceutically acceptable salts and mixtures thereof.
  • gastrointestinal agents preferred for use in the present invention include anticholinergics including atropine, clidinium and dicyclomine; antacids including aluminum hydroxide, bismuth subsalicylate, bismuth subcitrate, simethicone, calcium carbonate and magaldrate; H2-receptor antagonists including cimetidine, famotidine, nizatidine and ranitidine; laxatives including: docusate, phenolphthalein and casanthrol; gastroprotectants including sucralfate and sucralfate humid gel; gastrokinetic agents including metoclopramide and cisapride; proton pump inhibitors including omeprazole and antidiarrheals including: diphenoxylate, kaolin pectin, attapulgite and loperamide.
  • Carrier Materials including atropine, clidinium and dicyclomine; antacids including aluminum hydroxide, bismuth subsalicylate, bismuth subcitrate, simethi
  • compositions of the present invention may be inco ⁇ orated are many and varied and depend largely upon the end use of the compositions. These carriers are pharmaceutically 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 compatible with the herein disclosed compositions.
  • compatible means that the carrier components are capable of being commingled with the components of the present invention, and with each other, in a manner such that there is no interaction which would substantially reduce the activity or viability of the compositions under ordinary use situa ⁇ tions.
  • Carrier materials must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human being treated.
  • the compositions of the present invention comprise from about 0.01% to about 99.99% of one or more carrier materials.
  • Carriers suitable for topical administration of the present compositions include suppositories, vaginal tablets or capsules, ovules, creams, solutions for lavages, emulsions, foams, gels, liniments, oils and ointments, douches.
  • Creams, gels and other base formulations may be used in topical administration of the present compositions to, for example, male or female genitalia (including the vulva 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, acrylamides, methacrylamides, 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, magnesium stearate, glycol.
  • the effervescent tablets contain chemical components (i.e. sodium bicarbonate with citric acid or tartaric acid), which are necessary to develop carbon dioxide in order to produce effervescence.
  • compositions of the present invention may also be incorporated into and topically applied by woven or nonwoven fabric materials such as tissues, wipes, feminine napkins, panty liners, tampons, diapers, incontinent care products and the like.
  • woven or nonwoven fabric materials such as tissues, wipes, feminine napkins, panty liners, tampons, diapers, incontinent care products and the like.
  • Preferred for use herein are nonwoven fabrics.
  • Nonwoven fabrics suitable for inco ⁇ orating the present compositions are described in U.S. Patent 4,891,227 to Thaman et al., herein inco ⁇ orated by reference.
  • Oral dosage forms are also useful as carriers for the present invention. These dosage forms contain compatible solid or liquid filler diluents or encapsulating substances which are suitable for oral administration to a human or lower animal.
  • Liquid dosage forms for oral administration may comprise dissolving or suspending the compositions of the present invention in a potable liquid, such as sterile or purified water.
  • liquid or dry oral administration forms can comprise an enterically coated capsule containing the dosage forms.
  • Suitable forms include emulsions, suspensions, solutions, syrups, and elixirs containing inert diluents commonly used in the art, such as purified water, sugars, polysaccharides, silicate gels, gelatin, or an alcohol. These inert diluents 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 fermentation or degradation of the Lactobacillus.
  • compositions can also contain wetting agents, emulsifying agents, suspending agents, as well as additional therapeutic actives
  • wetting agents emulsifying agents
  • suspending agents emulsifying agents
  • additional therapeutic actives emulsifying agents
  • Tablets can be compressed, molded, triturated, enteric-coated, sugar-coated, film- coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, and flow-inducing agents.
  • the gelatin shell is essentially transparent 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 manufacture of these capsules is obtained by the partial hydrolysis of collagenous material
  • Gelatin suitable for capsule manufacture is commercially available from the Sigma Chemical Company, St. Louis, Mo
  • One or more plasticizers is inco ⁇ orated to produce a gelatin shell
  • Useful plasticizers of the present invention include glycerin, sorbitan, sorbitol, or similar low molecular weight polyols, and mixtures thereof.
  • compositions of the present invention may be achieved by inco ⁇ orating the compositions of the present invention into freeze-dried or lyophilized tablets. Freeze-drying or lyophilization facilitates disintegration of the composition by forming the dried composition into an open matrix network. In most cases, this results in rapid permeation by the aqueous media, promoting timely delivery of the product Suitable methods of freeze drying are well known in the art and commonly employed Any suitable conventional method of freeze-drying may be utilized. A preferable method of freezing and drying is to fast freeze the composition and then dry the composition to a final moisture content of about 2% to about 5%.
  • 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 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 inco ⁇ orated by reference
  • ingredients well known to the pharmacist's art may also be included in amounts generally known for these ingredients, for example, natural or artificial sweeteners, flavoring agents, colorants, perfuming agents, buffering agents and the like to 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 paraben, potassium sorbate, or sodium benzoate, to prolong and enhance shelf life
  • a preferred optional component is also caffeine
  • Lactobacillus and/or Bifidobacterium species cultures can be freeze dried (or purchased freeze dried)
  • an inoculum of Lactobacillus 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 balanced 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 bacterial plate count and then diluted so that the plate count per unit dose composition is from about IO 3 to about IO 12
  • the freshly obtained, washed and lyophilized bacteria obtained as described above are suspended in 10 ml of 5% glucose saline solution in such volume so as to obtain a heavy suspension of bacteria which contains between one to 10 ⁇ organisms per ml, at 0-
  • 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 normal saline solution
  • the resultant spheres are then "snap frozen" in liquid nitrogen and then lyophilized After these steps, the encapsulated organisms can be used in the formulations of the present invention.
  • Example III A tablet form of the present invention is made by combining the following components using conventional mixing and tableting technology
  • the cranberry extract is granulated with half the Avicel and the K2932 in ethanol
  • the granulation is then passed through a 12 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 -lactobacillus, remaining Avicel, Explotab and talc and mixed until uniform.
  • Magnesium stearate is then added to the uniform mixture with mixing.
  • the resultant granulation mixture is then compressed using conventional tableting processes.
  • Example IV A oral capsule form of the present invention is made by combining the following components using conventional mixing technology. Ingredient % Weight
  • Example V A topical gel form of the present invention is made by combining the following components using conventional mixing technology. Ingredient % Weight
  • Water is added to a suitable size container. While mixing at a moderate speed (300 ⁇ m), the Poiyacrylamide and C13.J4 Isoparaffin and Laureth-7 is added to the water to form a water phase. Separately, the PPG- 14 Butyl ether is placed in a container and covered. Using a Lightnin' Mixer with a 3 blade paddle prop, the cranberry extract and fructooligosaccharide are added to the PPG-14 Butyl ether and mixed at a low speed (100 ⁇ ) until the cranberry extract and fructooligosaccharide are dissolved.
  • the lactobacillus culture is added to the water phase and mixed at low speed ( 100 ⁇ m) until a uniform solution results
  • the PPG- 14 Butyl ether is slowly added to the water phase to form a gel.
  • the resulting gel is mixed at moderate speed until uniform

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Abstract

Compositions utiles pour prévenir et/ou traiter des troubles urogénitaux et intestinaux, qui contiennent une quantité efficace d'au moins une espèce de plante de la famille des Ericaceae ou de son extrait, et une culture d'au moins une espèce de bactéries microencapsulées choisies dans le groupe constitué de lactobacillus, bifidobacterium et de mélanges desdites bactéries.
EP97904914A 1996-02-14 1997-02-06 Compositions destinees au traitement de troubles urogenitaux et intestinaux Withdrawn EP0880354A1 (fr)

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US601480 1984-04-18
US60148096A 1996-02-14 1996-02-14
PCT/US1997/001662 WO1997029762A1 (fr) 1996-02-14 1997-02-06 Compositions destinees au traitement de troubles urogenitaux et intestinaux

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JP (1) JPH11504048A (fr)
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AU (1) AU1758197A (fr)
CA (1) CA2245810A1 (fr)
WO (1) WO1997029762A1 (fr)

Families Citing this family (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0994656B1 (fr) 1997-07-05 2006-04-19 Societe Des Produits Nestle S.A. dessert congelé avec bactéries lactiques et fibres fermentescibles
ES2318874T3 (es) * 1997-09-09 2009-05-01 Rutgers, The State University Of New Jersey Extracto de proantocianidina vegetal eficaz para inhibir la adherencia a superficies de bacterias con fimbrias de tipo p.
SE519648C2 (sv) * 1998-03-06 2003-03-25 Essum Ab Ny stam av Lactobacillus plantarum
ES2165139T3 (es) * 1998-04-30 2002-03-01 Vesely Renata Maria Cavaliere Composiciones farmaceuticas que contienen lactobacillus brevis y lactobacillus salivarius para el tratamiento de infecciones vaginales.
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
WO2000051445A2 (fr) * 1999-03-05 2000-09-08 Shanbrom Technologies Llc Concentres solubles de couleurs naturelles et nutraceutiques antimicrobiens a base de plantes
AU4905300A (en) * 1999-05-25 2000-12-12 Andrew W. Bruce Oral administration of lactobacillus for the maintenance of health in women
IT1306716B1 (it) * 1999-06-21 2001-10-02 Mendes S U R L Associazione di batteri lattici e suo uso per la prevenzione e/o iltrattamento terapeutico di infezioni e di stati infiammatori.
JP4603116B2 (ja) * 1999-12-02 2010-12-22 わかもと製薬株式会社 乳酸菌含有組成物、医薬及び食品
SE518097C2 (sv) 2000-10-03 2002-08-27 Ellen Ab Förfarande för framställning av en absorberande sanitetsartikel som innefattar mjölksyraproducerande bakterier samt sådant alster
GB2369777B (en) * 2000-10-05 2004-10-27 St Ivel Ltd Food products with antimicrobial lactic acid bacteria
FI109602B (fi) 2001-01-25 2002-09-13 Valio Oy Probioottiyhdistelmä
EP1228769A1 (fr) * 2001-02-02 2002-08-07 Jörg-Peter Prof. Schür Preparation symbiotique regénératrice
FR2827774B1 (fr) * 2001-07-30 2005-06-24 Dolisos Lab Preparations pharmaceutiques et/ou dietetiques contenant un extrait vegetal titre en composes actifs et des micro-organismes probiotiques
US20030143262A1 (en) 2001-12-13 2003-07-31 Brusk Ulla Forsgren Hygiene tissue
SE0104199L (sv) * 2001-12-13 2003-06-14 Sca Hygiene Prod Ab Ny produkt
RU2316586C2 (ru) * 2002-03-21 2008-02-10 Бифодан А/С ПРОБИОТИЧЕСКИЕ ШТАММЫ Lactobacillus (ВАРИАНТЫ) И ИХ ПРИМЕНЕНИЕ
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 (fr) * 2004-09-08 2006-12-22 Pharmatoka Soc Par Actions Sim Nouveaux dispositifs chirurgicaux et/ou medicaux et leur mode d'utilisation
FR2875406B1 (fr) * 2004-09-21 2007-01-05 Danisco Souche de lactobacillus acidophilus ayant des proprietes analgesiques au niveau du systeme gastro-intestinal
US20090036849A1 (en) * 2005-12-22 2009-02-05 Sca Hygiene Products Ab Absorbent Article
JP4800393B2 (ja) * 2005-12-22 2011-10-26 エスセーアー・ハイジーン・プロダクツ・アーベー 吸収物品
DK2211626T3 (da) 2007-08-29 2019-10-21 Ganeden Biotech Inc Bagværk
CN101642189B (zh) * 2008-08-07 2012-05-30 北京大北农科技集团股份有限公司 一种微囊化复合饲料添加剂及其制备方法
BR122017003315B1 (pt) 2008-10-16 2018-01-16 Ganeden Biotech, Inc. Composições alimentícias compreendendo grãos e esporos isolados de bacillus coagulans, bem como seu método de preparação
EP2210505A1 (fr) * 2009-01-27 2010-07-28 Nestec S.A. Composition comportant de l'acide caftarique et/ou dérivés associés
EP2424550B1 (fr) 2009-04-29 2017-06-07 Ganeden Biotech, Inc. Composition bactérienne de type cellulaire membranaire
IT1403661B1 (it) * 2011-01-28 2013-10-31 Probiotical Spa Composizione effervescente in forma solida per uso in applicazioni vaginali per il trattamento di infezioni vaginali.
US11235008B2 (en) 2011-03-31 2022-02-01 Ganeden Biotech, Inc. Probiotic sports nutrition compositions
ITMI20110791A1 (it) 2011-05-09 2012-11-10 Probiotical Spa Ceppi di batteri in grado di metabolizzare gli ossalati.
ITMI20110793A1 (it) 2011-05-09 2012-11-10 Probiotical Spa Ceppi di batteri probiotici e composizione sinbiotica contenente gli stessi destinata alla alimentazione dei neonati.
ITMI20110792A1 (it) 2011-05-09 2012-11-10 Probiotical Spa Ceppi di batteri appartenenti al genere bifidobacterium per uso nel trattamento della ipercolesterolemia.
ITRM20110477A1 (it) 2011-09-09 2013-03-10 Giovanni Mogna Composizione comprendente n-acetilcisteina e/o lisozima microincapsulato gastroprotetto in associazione con batteri probiotici in grado di ripristinare l'effetto barriera proprio dello stomaco che viene perso durante il trattamento farmacologico dell
ITMI20111718A1 (it) 2011-09-23 2013-03-24 Probiotical Spa Un materiale impermeabile alla umidita e allo ossigeno per confezionare prodotti dietetici, cosmetici e specialita medicinali.
EP2809301A1 (fr) 2012-01-31 2014-12-10 Biosoma B.V. Méthode d'administration d'un probiotique
ITMI20130793A1 (it) 2013-05-14 2014-11-15 Probiotical Spa Composizione comprendente batteri lattici per uso nel trattamento preventivo e/o curativo delle cistiti ricorrenti.
EP3142675A1 (fr) * 2014-05-16 2017-03-22 Pizeta Group S.r.l. Compositions contenant de l'acide borique et un mélange de lactobacilles
MX2018002533A (es) 2015-09-29 2018-06-27 Kimberly Clark Co Composicion sinergica para el mantenimiento de un equilibrio saludable de la microflora.
JP7118594B2 (ja) * 2016-03-31 2022-08-16 小林製薬株式会社 止瀉剤組成物
EP3320897A1 (fr) * 2016-11-14 2018-05-16 Dompè Primary S.r.l Préparation de granules de cranberry enrobés à teneur stable en proanthocyanidines
US10258567B1 (en) 2016-11-17 2019-04-16 Grace Procurements Llc Vaginal probiotic products and related processes

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2421066A1 (de) * 1974-05-02 1976-03-25 Solco Basel Ag Bifidobakterien enthaltendes praeparat
SE446940B (sv) * 1983-02-16 1986-10-20 Carl Axel Virdalm Medel for bekempande av sjukdomstillstand i matsmeltningsapparaten innehallande skal eller ytterdelar av ber eller frukter
DE3404474A1 (de) * 1983-04-06 1984-10-11 James Gorden Belleair Fla. Roberts Verfahren zur herstellung eines mehrfach fermentierten molkereiproduktes
IT1227154B (it) * 1988-08-05 1991-03-19 A Tosi Farmaceutici S R L Nova Composizioni farmaceutiche per uso ginecologico a base di 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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9729762A1 *

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CN1211188A (zh) 1999-03-17
AU1758197A (en) 1997-09-02
JPH11504048A (ja) 1999-04-06
WO1997029762A1 (fr) 1997-08-21

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