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WO2014097044A1 - Compositions équibiotiques et méthodes de traitement d'une maladie parodontale et de l'halitose chez des animaux - Google Patents

Compositions équibiotiques et méthodes de traitement d'une maladie parodontale et de l'halitose chez des animaux Download PDF

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WO2014097044A1
WO2014097044A1 PCT/IB2013/060715 IB2013060715W WO2014097044A1 WO 2014097044 A1 WO2014097044 A1 WO 2014097044A1 IB 2013060715 W IB2013060715 W IB 2013060715W WO 2014097044 A1 WO2014097044 A1 WO 2014097044A1
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mammals
halitosis
extract
extracts
periodontal disease
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Xavier Lozoya Legorreta
Juan AGÜERO AGÜERO
Erika Rivera Arce
Patricia FACI VILLALOBOS
Maricela GASCÓN MURO
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9728—Fungi, e.g. yeasts
    • 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)
    • A61K36/57—Magnoliaceae (Magnolia family)
    • A61K36/575—Magnolia
    • 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)
    • A61K36/61—Myrtaceae (Myrtle family), e.g. teatree or eucalyptus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • 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
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q11/00—Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses

Definitions

  • the present invention relates to sanitary-veterinary products. It particularly relates to compositions formulated based on two plant extracts, in which the content of active ingredients is appropriately standardized in a mixture exerting synergistic antimicrobial activity over the range of microorganisms that cause halitosis, gingivitis, and periodontal disease in animals, more particularly to compositions containing standardized extracts of Psidii pu mil urn var. guadalupense (D. C.) and Houpoea officinalis ⁇ Render & E.H. Wilson) for the treatment of periodontal disease and/or animal halitosis.
  • the objective of the present invention is to provide suitable compositions and methods for the treatment of periodontitis in animals. Background of the invention.
  • toothed animals In the market there are various products, which are used to treat oral microorganisms that cause oral disease in toothed animals. However, their application is complicated and risky because of the toxicity degree of these products when they are swallowed. Halitosis or bad breath is not unique to humans. Generally, toothed animals with are susceptible to suffer from it when microbiota of the oral cavity is altered producing the growth of pathogenic microorganisms that are hosted on the gingiva, teeth, tongue and oral mucosa.
  • the oral cavity is the gateway of food, where the process of transformation of nutrients is started by chewing (grinding the food with the teeth to reduce it to chemically attackable particles) and bolus formation (impregnating the food with water and enzymes from salivary glands and its modeling, by the tongue, of the shape and size) for swallowing it into the stomach.
  • chewing grinding the food with the teeth to reduce it to chemically attackable particles
  • bolus formation imppregnating the food with water and enzymes from salivary glands and its modeling, by the tongue, of the shape and size
  • Residues in the transformation process by the enzymatic action of the saliva become an ideal substrate for feeding millions of microorganisms commonly found in the oral cavity in addition to those acquired by food itself and opportunistic pathogens.
  • Physiological and biochemical responses happen in the oral cavity to combat the presence of pathogenic microorganisms; this occurs through various mechanisms, such as changes in volume and saliva enzyme content, changes in the pH medium, increasing the activity of immune cells (macrophages, mainly), the production of bacteriocins (compounds produced by other bacteria), and biochemical reactions that hinder the adhesion of certain strains of the mucous membranes etc.
  • These responses seek to maintain the equilibrium established between the oral microbiota and the host. When this set of responses does not achieve its purpose, the microbiotic equilibrium is upset starting the colonization, which involves the establishment of the infectious process.
  • Residues adhered to the tongue, teeth and mucous facilitate the retention and growth of microorganisms in the oral cavity, and the accumulation of bacteria that in the medium term will produce a chronic infectious process beginning with halitosis, generalized gingival inflammation or gingivitis, and ultimately, periodontitis. Also, cavities develop and, in later stages, produce the loss of bone and the loosening of teeth.
  • the plaque increases in volume, elevating to cover the teeth and colonizing the gingiva.
  • the primary immune response to this aggression is inflammation of the gums or gingivitis. If the inflammatory defense process is not effective and a macrobiotic imbalance is created in the system, colonization continues to advance destroying gum tissue, retracting the gingiva, making it prone to bleeding and producing a purulent infection in form of periodontal pockets.
  • Streptococcus mutans and Fusobacterium nucleatum associated with other bacteria such as Escherichia coli, Staphylococcus aureus, Staphylococcus fecalis, yeasts such as Candida albicans, and opportunistic actinomycetes such as Trichophyton rubrum, and Trichophyton mentagrophytes, among others.
  • the pathogenesis of the more virulent strains is related to their capacity to adhere to the biofilm that constantly forms on the surface of the teeth and mucous membranes of the oral cavity.
  • the microorganisms find in this layer the ideal feeding conditions and metabolizing sucrose in organic acids and polysaccharides. In this enriched medium proliferates Gram-positive and Gram-negative bacteria, resulting in multiple colonization of microorganisms.
  • Halitosis in animals is the first symptom of microbiota imbalance of the oral cavity resulting from the accelerate reproduction of various microbial strains, generating sulfur gases produced by the microorganisms because of its metabolism; these are incorporated to the breath, which consequently acquires an unpleasant odor (halitosis).
  • the animals suffer primary gingivitis, periodontal pocket formation (larger than 3 mm in dogs, or 5 mm in cats), in which the infectious material accumulates, and they eventually suffer the loss of teeth.
  • Some conditions such as uremia, hypothyroidism, feline leukemia, feline immunodeficiency, pemphigus vulgaris, and lupus erythematosus are associated with halitosis and gingivitis, which highlights the intimate relationship between the immune status of the animal and the equilibrium of its oral microbiota.
  • the brush cleaning of the denture after each meal remains the paradigmatic principle of prophylaxis of periodontal disease as it allows the removal of food debris on teeth and gums by the mechanical action of the brushing.
  • the use of toothpastes, mouthwashes with chemical antiseptics and other abrasives help to prevent the formation of plaque as long as frequency of use does not cause toxic effects or abrasion, and gingival and mucosal lesions.
  • Bactericidal effect The destruction of microorganisms by the action of specific chemical compounds altering the permeability of their membrane;
  • Anti-adherent effect The prevention of adhesion of microorganisms to the biofilm.
  • the significant global growth of herbal medicine in preventive and curative programs in dental care has stimulated scientific research to substantiate the antimicrobial activity of various plant extracts to help in controlling plaque and decreasing caries incidence and periodontal disease.
  • the first hypothesis assumes the universal presence of potentially pathogenic microorganisms in dental plaque and all accumulation of it is pathogenic, giving rise to the hypothesis of non-specific plaque hypothesis.
  • a model of surgical management of dental treatment was created in which the diagnosis was not considered important since all teeth were affected by a plaque of odonto-pathogenic bacteria and therefore, all individuals were prone to develop the disease.
  • the problem with this hypothesis is that it implies the need to completely remove the plaque in all patients. This goal is unrealistic and difficult to achieve even in better-disposed individuals.
  • Its main weakness lies in the fact that it minimizes the evidence that different microbial ecosystems are always present in the oral cavity. So, to the decade of the nineties of the last century this hypothesis was widely questioned.
  • the second hypothesis is based on the observation that bacterial plaque is not always accompanied by alterations of the dental enamel, assuming that the plaque is pathogenic only when there are other changes in the ecosystem, since only a limited number of microorganisms, mainly bacteria, are capable of causing dental caries and periodontal disease, and that in the plaque are other microorganisms present in equilibrium with the host. This is the specific plaque hypothesis. Treatment based on this second hypothesis is aimed at eliminating specific pathogens, not all the plaque, for which the pre-clinical microbiological diagnosis is essential.
  • the goal of the treatment is to remove the cariogenic plaque and replace it with plaque free from pathogenic microorganisms, achieving this by applying "soft" antibacterial measures but hard enough to procure some sterility in the tooth surface for short periods of time.
  • harmless strains of, e.g., Streptococcus sanguis and Streptococcus mitis should predominate over smaller proportions of Streptococcus mutans.
  • dental plaque is always produced, even after thoroughly brushing the teeth; its formation begins within a few minutes after the brushing when an acellular mucinous layer free of bacteria, called dental cuticle, or acquired dental pellicle (APD), or biofilm.
  • APD acquired dental pellicle
  • various forms of bacteria adhere to it by ionic, electrolyte or ligand-lectin type bonds, colonizing it and producing dextran, a high-weight extracellular polysaccharide, which is viscous and very adhesive and is produced exclusively from the transformation of food into sucrose that is performed by some bacteria.
  • Streptococcus mutans and Fusobacterium nucieatum are particularly known to be capable of adhering to the oral mucosa and teeth, because they produce dextran.
  • these adherent bacteria have special receivers to the viscose matrix of dextran, allowing them to agglutinate tightly with each other.
  • these pioneer microorganisms proliferate and extend laterally forming a layer on the tooth surface, similar to a mat, and allowing the agglutination of other microbes. Subsequent bacterial growth is, therefore, of mixed colonies of different microorganisms.
  • the resulting combined layer allows other weaker microorganisms to concatenate, such as filamentous and spiral bacteria, yeasts, and fungi, which could not otherwise fix themselves. Accordingly, the formation of a mature plaque involves a series of molecular exchange between the cumulative microbiota, which, initially, will depend on the preparatory stage of the local conditions modified by the bacteria with adhesive capacity. The formation of a mature dental plaque takes an average of 4 to 5 days.
  • Patent application WO2007133721 discloses a composition that includes natural ingredients including the use of pomegranate extract, green tea extract, rosemary, quercetin, amla extract, and kakadu extract.
  • the patent US626501 1 relates to compositions for treating and preventing oral disease in animals and humans, consisting of 8 to 12 parts by weight of whole wheat flour, 4 to 6 parts of oat bran, 2 to 3 parts of dry nonfat milk, and 2 to 3 parts of whole rice flour.
  • the composition further includes water, vanilla extract, parsley, alfalfa powder, vegetable oil, peppermint extract, tarragon, mint leaf and green tea powder.
  • the vegetal oil includes an antioxidant, preferably sunflower oil.
  • the patent document EP0951838 discloses a cat food to prevent oral malodor containing 0.03 to 0.1 % by weight of green tea extract in which said extract contains 40 to 50% by weight of tannin.
  • the document ES2052406 discloses a hygiene product for oral deodorization of domestic animals comprising an assimilable protein carrier impregnated with a deodorant substance associated with an inhibitor of proteolytic enzymes and a natural antimicrobial product.
  • the document US3936527 describes a method for treating oral malodor in dogs and cats daily administering to the animal 50 to 500 mg of methionine in tablet form, further containing concentrated proteins, among which is a mixture of soy and fish flour.
  • the document CN 102327594 describes a composition for the treatment of periodontitis and halitosis in dogs, which consists of 10 parts of dried orange peel, 5 to 30 parts of ginger, 5 to 30 parts of odor clove, 5 to 30 parts of mint, and 5 to 30 parts of Aucklandia root, which is applied as an ointment, spray, tincture, or mixture.
  • the present invention provides equibiotic compositions whose formulation is based on two extracts obtained from plants (Psidii pumilum var. guadalupense (D. C.) and Houpoea officinalis (Rehder & E.H. Wilson)) whose content is appropriately standardized into a synergistic mix possessing an increased antimicrobial activity on the range of microorganisms that cause halitosis, gingivitis, and periodontal disease in animals. Strains of the most common microorganisms present in the formation of dental plaque and gingivitis in domestic animals, were used; e.g.
  • compositions of the invention comprising two concentrated extracts: 1 ) a standardized concentration mixture of glycosyl benzochromones obtained from Psidii pumilum var. guadalupense (D. C.) (Extract A), and 2) a standardized concentration of dialkylphenols obtained from Houpoea officinalis (Rehder & E.H.
  • Wilson (Extract B) by the method of diffusion in agar plate.
  • the extracts were dissolved in DMSO (dimethyl sulfoxide) centrifuged and filtered (0.22 pm) to achieve its sterility and obtain greater homogeneity when mixed with the culture medium.
  • DMSO dimethyl sulfoxide
  • the compositions of the invention were clinically tested in domestic animals (dogs) afflicted with periodontitis with excellent results in the treatment of this disease.
  • Figure 1 Shows the different stages of periodontal infection in dogs. Shows (a) initiation of plaque formation; (b) gingivitis; (c) retraction of the gum; and d) periodontitis with dental attachment loss.
  • Figure 2 Shows the effect of the composition of the present invention on 8 cases of halitosis in dogs. Time 1 corresponds to 8 days of treatment.
  • Figure 3 Shows the effect of the composition of the present invention on 8 cases of gingivitis in dogs. Timel corresponds to 8 days of treatment. Detailed description of the invention.
  • the present invention provides equibiotic compositions whose formulation is based on two extracts obtained from plants (Psidii pumilum var. guadalupense (D. C.) and Houpoea officinalis (Rehder & E.H. Wilson)), whose content of active principles is appropriately standardized in a synergistic mixture possessing an increased antimicrobial activity on the range of microorganisms that cause halitosis, gingivitis, and periodontal disease in animals, for example in domestic species such as, for example, domestic cats and dogs.
  • compositions of the present invention comprise two extracts of plants: one of them obtained from Folium Psidii pumilum var. guadalupense (D. C.) (Extract A), whose content of glycosyl benzochromones was standardized; and the other obtained from Cortex Houpoea officinalis (Rehder & E.H. Wilson) (Extract B) whose content of dialkylphenols was standardized; both of them form a mixture having a synergistic antimicrobial activity on the range of microorganisms that cause halitosis, gingivitis, and periodontal disease in animals, wherein the above extracts can be present as fluid and/or dry extracts.
  • the extract A is obtained from leaves (Folium) of Psidii pumilum var. guadalupense (D.C), while the extract B is obtained from bark of Houpoea officinalis (Rehder & E.H. Wilson), although other parts of the plants mentioned above can be used to obtain the active principles mentioned for each (glycosyl benzochromones for extract A and dialkylphenols for extract B), and the proper amount of such actives to standardize both extracts.
  • standardized extracts of Psidii pumilum var. guadalupense (D. C.) and Houpoea officinalis (Rehder & E.H. Wilson) are provided, so these extracts contain determined and standardized quantities of the active principles responsible for their therapeutic efficacy.
  • This characteristic of the standardized extracts of the invention allows its use for obtaining frequent and controlled pharmaceutical compositions, by that allowing to control the quantity of active principles in such compositions. Accordingly, it is possible to obtain pharmaceutical compositions with known predetermined doses, which can be administered by different routes to the subject in need of treatment in a right volume.
  • compositions by administering such compositions it is assured that the subject will receive controlled and constant quantities of the active principles contained for different treatment regimes.
  • these extracts allow the physician to design controlled treatments for the subjects suffering from, e.g., periodontal disease, gingivitis, and/or halitosis, as it is possible to administer controlled doses of the drug and a suitable follow up treatment.
  • standardized extracts of the invention allow to easily combining multiple compounds useful for manufacturing various conventional dosage forms, either in powder or liquid depending on the needs and administration and therapeutic regimen.
  • the extracts retain their pharmacological properties, despite the process that is subjected for obtaining suitable dosage forms, which allows great versatility in their management.
  • the standardized extracts described herein contain predetermined quantities of their standardized active principles such as glycosyl benzochromones for Psidii pumilum var. guadalupense (D. C.) extracts and of Houpoea officinalis (Rehder & E.H. Wilson) for dialkylphenol extracts, using the quantitative determination of said active principles by methods known in the art for identifying molecules, such as; e.g., high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • compositions using the extracts of the invention or combinations thereof as therapeutic agents can be prepared according to any of the methods and procedures known in the art.
  • the active ingredient is mixed or diluted with a carrier, or is preferably included within a carrier, which may be in various forms, such as capsules, bags, or in other packings.
  • the carrier serves as a diluent, it can be a solid, semisolid, or liquid material, which acts as a vehicle, excipient, or medium for the active ingredient.
  • the compositions can be in a tablet, pill, powder, bag, elixir, suspension, emulsion, gel, solution, syrup, aerosol, soft and hard gelatin capsule, sterile injectable solution, sterile packaged powder, and the like.
  • examples of pharmaceutical carriers, excipients, and diluents suitable are for example, lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia gum, alginates, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, hydroxymethyl benzoates, hydroxyprophyl benzoates, talc, magnesium stearate, and mineral oil, and others known in the art for the same purpose.
  • the compositions may additionally include fillers, anti- agglutinative agents, flavoring agents, lubricants, wetting agents, emulsifiers, preservatives, and the like.
  • compositions of the invention may be formulated to provide quick, sustained, or delayed release of the active ingredients after administration to a mammal by employing any of the procedures and/or methods well known in the art.
  • Synergistic pharmaceutical compositions of the present invention contain an amount of 0.4 to 1 .91 mg of glycosyl benzochromones from extract A, and an amount of 300 to 463 mg of dialkylphenols from extract B.
  • concentration of the active principles can vary within the ranges mentioned depending on the pharmaceutical in question.
  • compositions of the invention can be administered topically, administering them directly to the gums in subjects suffering for example, periodontal disease, gingivitis, and/or halitosis, in a dose containing at least 0.4 mg of glycosyl benzochromones from extract A in combination with at least 300 mg of dialkylphenols from extract B.
  • Such doses may be administered as a single dose or daily in divided doses up to the complete disappearance of clinical symptoms.
  • the extract amount of the compositions to be administered to the subject in treatment may vary according to age, sex, body weight, severity of the disease, and the formulation used.
  • One embodiment of the present invention is to provide a semi-solid equibiotic product such as gel, which is formulated based on two plant extracts whose content of active principles is appropriately standardized in a synergistic mixture having antimicrobial activity on the range of microorganisms causing halitosis, gingivitis, and periodontal disease in animals.
  • a second modality of the present invention is to provide a veterinary hygiene product for major species, such as domestic dogs and cats, to eliminate bad breath, the formation of dental plaque, and combat and prevent gingivitis and periodontal diseases, which are difficult to treat in animals.
  • compositions disclosed in the present invention can be in various dosage forms; however, gel is the preferred form of the product, because in contrast to other products manufactured with the purpose of eliminating halitosis and decrease inflammation of the gums, such as, e.g., solutions and antibiotic ointments, antiseptic mouthwashes, abrasive toothpastes, etc., the gel form of the compositions in the present invention is easy to use, and its pleasant taste makes dogs and cats to distribute it with their own tongue in the oral cavity. Additionally, the gel form increases the permanence of the actives of the formulation in the site of action (oral cavity). For purposes of the invention, the application of the pharmaceutical gel form after each meal guarantees its effect for more than 12 hours.
  • Equibiotics act simultaneously in two modality, such as auferobiotic and alerebiotic. In the auferobiotic modality the antimicrobial and/or antibiotic activity is developed, whereas in the alerebiotic modality the restoration of the microbiota is developed. Equibiotics are unique in that their action influences and strengthens the immunological regulatory capacity of the host itself.
  • the active principles of equibiotics propel bactericidal modalities and pharmacological properties that interfere with the pH medium, inhibit bacterial adhesion, reduce the inflammation, and restore tissues and mucous, among other properties, what distinguishes and constitutes them a superior alternative than traditional antibiotics and simple phytomedicines. Additionally, being complex extracts of medicinal plants simplifies or significantly improves the absorption, diffusion, transport, and general bioavailability of the active compositions present in the original medium.
  • a further embodiment of the present invention is to provide an equibiotics-based compositions, which are effective and safe as topical treatment to significantly reduce the symptoms of halitosis and gingivitis in animals.
  • compositions of the invention in its gel form comprise an equibiotic product formulated based on two plant extracts (Extract A and Extract B), whose active principles content are appropriately standardized in a synergistic mixture showing antimicrobial activity on the range of microorganisms causing halitosis, gingivitis, and periodontal disease.
  • the compositions here disclosed can be administered topically in the oral cavity of the animal at least one time per day, preferably after food ingestion.
  • the compositions of the invention can be administered 2 to 3 times daily up to observing the reduction of the disease and according to the attending veterinarian who can subsequently decrease the rate of administration at a lower dose; for example 1 time per day to complete the treatment.
  • the extracts used for obtaining the equibiotic compositions of the present invention are obtained for example by hydroalcoholic percolation and subsequent concentration up to obtaining fluid extracts for extract A and dry extracts for extract B.
  • solvents known in the art to obtain the active principles in extracts A and B can be used.
  • critical variables are controlled, such as temperature and time of extraction, solvent extraction ratio, and initial and final content of active ingredients in the plant material and the final extract, respectively.
  • extract A must contain at least 0.5% (w/v) of glycosyl benzochromones, while for extract B the contents of dialkylphenols must be of at least 80% w/w.
  • Separate quality control of each extract and the mixture thereof in the bulk and in the finished product is generally performed by analytical methods known in the art; for example, by HPLC (high performance liquid chromatography), employing gradients of mobile phases consisting of acidified aqueous mixtures of an organic modifier, although other methods known in the art to allow the characterization of the active principles can also be used.
  • HPLC high performance liquid chromatography
  • compositions of the invention comprising mixtures of the extracts A and B in a w/w interval of 10:90 to 40:60 respectively, showed a significant synergistic activity in the antimicrobial effect, allowing to enhance their effect when applied in animal models; for example; in domestic dogs previously diagnosed with periodontal disease, gingivitis, and/or halitosis, wherein after their application in gel form we observed dramatic effects of improvement in dental and oral conditions of the animals treated, eliminating the halitosis and significantly reducing the periodontal disease in the period of clinical evaluation.
  • the mixtures of extracts A and B that showing a synergistic effect in their antimicrobial activity can be used effectively for the treatment of periodontal disease
  • the concentration of the extract glycosyl benzochromones in extract A is in an interval of 0.4 to 1 .91 mg
  • the dialkylphenols concentration in extract B is in an interval of 300 to 463 mg.
  • compositions of the present invention are evident when used in the treatment of periodontal disease in animals. Aside from showing an effective antimicrobial activity at a very low concentration of their active principles because to their synergistic activity, they also restore oral microbiota equilibrium in animals, influencing and strengthening its immunological regulation capacity, so that the animal recovers efficiently and quickly. Also, the compositions described herein are safe and non-toxic to animals treated, substantially improving their health condition.
  • Example 1 Obtaining and standardization of the extracts A and B of the invention.
  • Extracts of Folia Psidii pumilum var. guadalupense (D. C.) (extract A) and of Cortex Houpoea officinalis (Rehder & E.H. Wilson) (extract B) were obtained by hydroalcoholic percolation and subsequent concentration from leaves (extract A) and bark (extract B) to obtain fluid extracts (extract A) and dry extracts (extract B).
  • critical variables such as temperature and time of extraction, extraction solvent ratio, initial and final content of active principles were controlled in the plant material and the final extract.
  • the extraction was performed to obtain an extract A with a content of at least 0.5% (w/v) of glycosyl benzochromones and extract B with a contents of at least 80% (w/w) of dialkylphenols.
  • strains of the microorganisms most commonly present in dental plaque formation and responsible for causing gingivitis and periodontal disease such as Streptococcus mutans, Fusobacterium nucleatum, Escherichia coli, Staphylococcus aureus, Staphylococcus fecalis, Candida albicans, Trichophyton rubrum, and Trichophyton mentagrophytes.
  • Streptococcus mutans Fusobacterium nucleatum
  • Escherichia coli Staphylococcus aureus
  • Staphylococcus fecalis Candida albicans
  • Trichophyton rubrum Trichophyton mentagrophytes
  • extract A extract A
  • extract B extract B
  • concentrations from 3.0 to 0.2 mg/ml_ considered in the range of antimicrobial activity of natural products for in vitro tests.
  • the Minimal Inhibitory Concentration (MIC) was determined in each case, defined as the lowest concentration able to inhibit 100% the growth and development of colonies. The reading was performed at 48 and 72 hrs of incubation, conducting triplicate incubation assays.
  • the two extracts (A) and (B) exhibited antimicrobial activity in vitro, preventing the growth of all the strains used since the first 48 hours of incubation with MIC values ranging from 0.03 and 2.0 mg/ml_, depending on the sensitivity of each strain, being Trichophyton the most sensitive and Fusobacterium the most resistant.
  • Some of the mixtures under test demonstrated a strong synergistic effect producing complete growth inhibition of microorganisms with up to 1 ,000 times less than the concentration quantity required of each one of the extracts separately, obtaining, for example, MIC values for mixture A+B (30:70) equivalent to those described for pure antibiotics used as controls (table 1 ).
  • Example 3 Composition of de invention in gel form.
  • the topical formulation was prepared by dispersing the standardized extracts A and B in a mixture of glycerin/propylene glycol previously hydrated; we integrated the mixture of the extracts with the carbomer, and finally added the rest of the excipients to produce the formulation.
  • Table 2 shows the results obtained with such a formulation.
  • the fluid extracts prepared from a mixture of dialkylphenols and glycol benzochromones have strong antimicrobial activity in vitro on major organisms responsible for periodontal disease.
  • the combination A+B (30:70) has synergistic properties, which increase their antibiotic potency dramatically.
  • the gel formulations of said mixture retain its antimicrobial properties and synergistic effect.
  • Example 4 Treatment of periodontal disease in dogs with the compositions of the invention.
  • NT gingival inflammation
  • NT gingival inflammation
  • a scale to assess gingival inflammation and other typical parameters of periodontal disease. It was determined that the duration of the treatment would be 8 days, using the composition of the invention in gel form described in example 3, 1 to 2 times a day depending on the possibility of dog owners of applying the gel in gums 10 to 15 min after the dog's meal.
  • the entire group of animals was clearly diagnosed with halitosis with an average time of evolution of the disease of about 5 years.
  • the halitosis degree was qualified by each owner in a scale of 0 to 5, giving a range of 3 to 5.
  • the average obtained for the group was 4.5 at the beginning of the study (time 0).
  • the initial values ranged from 1 to 4 on the scale of 0 to 5, with 2.62 as an average value.
  • composition of the present invention proved to be a safe and effective equibiotic as an 8-day treatment of topic application to clearly reduce the symptoms of halitosis and gingivitis in dogs.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Oral & Maxillofacial Surgery (AREA)
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Abstract

La présente invention concerne des compositions équibiotiques efficaces pour le traitement d'une maladie parodontale, d'une gingivite et/ou de l'halitose chez des animaux, par exemple chez des animaux domestiques y compris les chiens et les chats, les compositions équibiotiques ayant une activité antimicrobienne synergique et comprenant des extraits standardisés de Psidii pumilum var. guadalupense (D.C.) et de Houpoea officinalis (Rehder & E.H. Wilson). Les compositions de l'invention sont des produits équibiotiques, puisqu'elles présentent une action antimicrobienne et/ou antibiotique contre les micro-organismes responsables d'une maladie parodontale et de l'halitose, tout en restaurant également, en même temps, l'équilibre du microbiota oral chez les animaux. Les compositions équibiotiques de l'invention sont uniques en ce que leur action influence et renforce la régulation immunologique de l'hôte.
PCT/IB2013/060715 2012-12-07 2013-12-07 Compositions équibiotiques et méthodes de traitement d'une maladie parodontale et de l'halitose chez des animaux Ceased WO2014097044A1 (fr)

Applications Claiming Priority (2)

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MX2012014315A MX345485B (es) 2012-12-07 2012-12-07 Composiciones equibióticas y métodos para el tratamiento de enfermedad periodontal y/o halitosis en animales.
MXMX/A/2012/014315 2012-12-07

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WO2014097044A1 true WO2014097044A1 (fr) 2014-06-26

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US20220005607A1 (en) * 2018-11-15 2022-01-06 Mars, Incorporated Method or system for diagnosing periodontal disease

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220005607A1 (en) * 2018-11-15 2022-01-06 Mars, Incorporated Method or system for diagnosing periodontal disease
US12322513B2 (en) * 2018-11-15 2025-06-03 Mars, Incorporated Method or system for diagnosing periodontal disease

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MX345485B (es) 2017-01-31

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