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WO2022255959A1 - Compositions pharmaceutiques de globules de matière grasse du lait - Google Patents

Compositions pharmaceutiques de globules de matière grasse du lait Download PDF

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Publication number
WO2022255959A1
WO2022255959A1 PCT/TR2021/050537 TR2021050537W WO2022255959A1 WO 2022255959 A1 WO2022255959 A1 WO 2022255959A1 TR 2021050537 W TR2021050537 W TR 2021050537W WO 2022255959 A1 WO2022255959 A1 WO 2022255959A1
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pharmaceutical composition
acid
disease
treatment
mfgs
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Kasim FERDUSI
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS OR COOKING OILS
    • A23D7/00—Edible oil or fat compositions containing an aqueous phase, e.g. margarines
    • A23D7/005—Edible oil or fat compositions containing an aqueous phase, e.g. margarines characterised by ingredients other than fatty acid triglycerides
    • A23D7/0053—Compositions other than spreads
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/158—Fatty acids; Fats; Products containing oils or fats
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/70—Feeding-stuffs specially adapted for particular animals for birds
    • A23K50/75—Feeding-stuffs specially adapted for particular animals for birds for poultry
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1276—Globules of milk; Constituents thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A61K9/0017—Non-human animal skin, e.g. pour-on, spot-on
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0041—Mammary glands, e.g. breasts, udder; Intramammary administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention generally relates to a pharmaceutical composition which comprises of milk fat globules as an active ingredient.
  • Influenza is an infectious respiratory disease. In humans it is caused by influenza A and influenza B viruses. Symptoms associated with influenza virus infection vary from a mild respiratory disease confined to the upper respiratory tract and characterized by fever, sore throat, runny nose, cough, headache, muscle pain and fatigue to severe and in some cases lethal pneumonia owing to influenza virus or to secondary bacterial infection of the lower respiratory tract. Influenza virus infection can also lead to a wide range of non-respiratory complications in some cases-affecting the heart, central nervous system and other organ systems. Although characterized by annual seasonal epidemics, sporadic and unpredictable global pandemic outbreaks also occur that involve influenza A virus strains of zoonotic origin.
  • Pandemic influenza occurs every 10-50 years and is characterized by the introduction of a new influenza A virus strain that is antigenically very different from previously circulating strains; the lack of pre- existing immunity in humans is often associated with the severity of the infection and an increase in mortality.
  • All influenza viruses are enveloped negative-sense single-strand RNA viruses with a segmented genome.
  • a unique characteristic of influenza A viruses is that they circulate not only in humans but also in domestic animals, pigs, horses and poultry and in wild migratory birds (>100 species of ducks, geese, swans, gulls, waders and wild aquatic birds are considered natural reservoirs).
  • Current seasonal influenza vaccines have only suboptimal effectiveness across all age groups, particularly in elderly individuals (a high- risk group for severe influenza virus infection). Thus, there is a major need to better understand the biology of influenza virus infections to develop new and more effective antiviral agents.
  • Coronaviruses are known to cause disease in humans and animals. Among these, four (human coronaviruses 229E, NL63, OC43 and HKU1 ) typically infect only the upper respiratory tract and cause relatively minor symptoms. However, there are three coronaviruses i.e. severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2) that can replicate in the lower respiratory tract and cause pneumonia, which can be fatal. SARS-CoV-2 belongs to the betacoronavirus genus. Its closest relative among human coronaviruses is SARS-CoV, with 79% genetic similarity.
  • SARS-CoV Middle East respiratory syndrome coronavirus
  • SARS-CoV-2 is most similar to bat coronavirus RaTG13, with 98% similarity, and coronavirus sequences in the pangolin (a scaly anteater) also share high similarity.
  • SARS-CoV- 2 is transmitted primarily via respiratory droplets, with a possible, but unproven, faecal-oral transmission route.
  • SARS-CoV-2 is a highly transmissible and pathogenic coronavirus that emerged in late 2019 and has caused a pandemic of acute respiratory disease, named ‘coronavirus disease 2019’ (COVID-19), which threatens human health and public safety.
  • the median incubation period is approximately 4-5 days before symptom onset, with 97.5% of symptomatic patients developing symptoms within 11 .5 days.
  • patients with COVID-19 typically exhibit a fever and dry cough; less commonly, patients also experience difficulty in breathing, muscle and/or joint pain, headache/dizziness, diarrhoea, nausea and the coughing up of blood.
  • SARS- CoV-2 viral load reaches its peak- significantly earlier than that of the related SARS-CoV, where viral load peaks at about 10 days after symptom onset.
  • Severe COVID-19 cases progress to acute respiratory distress syndrome (ARDS), on average around 8-9 days after symptom onset.
  • ARDS acute respiratory distress syndrome
  • SARS-CoV-2 infection closely resembles that of SARS-CoV infection, with aggressive inflammatory responses strongly implicated in the resulting damage to the airways. Therefore, disease severity in patients is due to not only the viral infection but also the host response. The pattern of increasing severity with age is also broadly consistent with the epidemiology of SARS-CoV and MERS-CoV. ARDS seen in severe COVID-19 is characterized by difficulty in breathing and low blood oxygen level. As a result, some patients may succumb to secondary bacterial and fungal infections. ARDS may lead directly to respiratory failure, which is the cause of death in 70% of fatal COVID-19 cases.
  • Newcastle disease ND
  • the disease was named after a place known as Newcastle Upon Tyne, in England where it was reported for the first time in 1926.
  • the disease was also reported around the same time in Java, Indonesia.
  • Anthony its geographic distribution slowly expanded, leading to a well-established pandemic of the disease barely two decades after its novel emergence.
  • the second pandemic of the disease occurred with an incredibly high speed, taking only four years to spread throughout the world, probably due to extensive commercialization of poultry production and the improvement of air transport systems which facilitated the exchange of exotic birds into new areas.
  • Newcastle disease caused by infections with virulent viruses from the genus Avulavirus and species avian avulavirus 1 , commonly known as Newcastle disease virus (NDV) and abbreviated as avian paramyxovirus 1 (APMV 1 ).
  • the control of ND must include strict biosecurity that prevents virulent NDV from contacting poultry, and also proper administration of efficacious vaccines.
  • improvements are still needed. Impediments to prevent outbreaks include uneven vaccine application when using mass administration techniques in larger commercial settings, the difficulties associated with vaccinating free-roaming, multi-age birds of village flocks, and difficulties maintaining the cold chain to preserve the thermo-labile antigens in the vaccines. Incomplete or improper immunization often results in the disease and death of poultry after infection with virulent NDV.
  • Coronaviruses also infect a wide range of animals and cause respiratory, enteric, hepatic, and neurological diseases of varying severity. They cause severe diseases in livestock animals and thereby lead to high economic losses. Based on genotypic and serological characterization, coronaviruses are divided into 4 distinct groups. Their tendency for recombination and high mutation rates may allow their adaptation to new hosts and ecological niches. Infectious bronchitis virus (IBV), the coronavirus of chickens, is one of the foremost causes of economic losses for the poultry industry, affecting the performance of meat and egg- laying birds, mainly through respiratory signs and severe egg drop and poor quality, respectively; kidney damage can also occur. Infectious bronchitis virus has the ability to change rapidly.
  • IBV Infectious bronchitis virus
  • Leishmania is a parasitic disease transmitted by a sand-fly vector and it is one of the most neglected diseases in the world, affecting the poorest of the poor.
  • CL Cutaneous leishmaniasis
  • the lesion starts as an erythema that gradually transforms to a papule and later to a nodule. The nodule then increases in volume and progressively ulcerates. The whole process generally takes between two and six months.
  • CL lesions are slowly self-healing but they often lead to scar tissue. They pose major public health problems mainly in tropical and sub-tropical regions of the globe which affect about 12 million people worldwide. Disease manifestations range from self-healing benign cutaneous to non-healing mucocutaneous leishmaniasis (MCL).
  • MCL mucocutaneous leishmaniasis
  • Sarcoptic mange is a common, widespread disease of domestic and wild mammals.
  • the causative agent is Sarcoptes scabiei, a microscopic mite that infests the skin of its host by burrowing into the epidermis. It is an acarid that belongs to the order Sarcoptiformes, which includes other mites of veterinary importance such as Psoroptes, Knemicodoptes, and Notoedres, among others.
  • the lesions most commonly associated with sarcoptic mange include alopecia, hyperkeratosis, and erythema often accompanied by intense pruritus.
  • Mange epizootics have been reported in a variety of host species worldwide. These events are often associated with high morbidity and mortality in wildlife populations, including Cantabrian chamois (Rupicapra pyrenaica parava) in Spain, red foxes (Vulpes vulpes) in Fennoscandia, and wombats.
  • Cattle lice are obligatory blood-sucking ectoparasites, which is an obstacle in the health and product performance of livestock.
  • Two major families of lice have been found on cattle; Haematopinidae family, including Haematopinus eurysternus, H. quadripertusus, H. tuberculatus and Linognatidae family; Linognathus vituli and Solenopotes capillatus.
  • H. quadripertusus is commonly found to infest on the cattle tail hair and is widespread in tropical and subtropical regions.
  • Lice infestation are a common cause of animal health and they can be responsible for economic losses by inducing pathophysiological changes in their hosts, including weight loss, skin infections and damage, loss of wool or hair due to scratching, and can cause mild to severe anemia.
  • T. orientalis can be separated into several genotypes, namely, type 1 (Chitose), type 2 (Ikeda), type 3 (Buffeli), types 4-8 and types N1 -N3. The emergence of the pathogenic genotype T.
  • Babesia ovata which is transmitted by Haemaphysalis longicornis, is an intraerythrocytic protozoan parasite of cattle. Based on its morphology, B. ovata is classified as a large-type Babesia. The developmental stages of B. ovata have been described both in cattle and the tick vector. In infected adult female ticks, the parasite is transovarially transmitted to the tick eggs. The sexual reproduction of B. ovata has been demonstrated in the tick midgut.
  • the diagnostic tools that are currently available for the specific detection of B. ovata in cattle include microscopy and polymerase chain reaction assays. The development of improved molecular and serological diagnostic tools has been constrained by the limited availability of genetic data.
  • B. ovata was thought to be a benign parasite however, infections in immuno compromised or Theileria orientalis-infected animals are clinically significant. Thus, control strategies aimed at minimizing the prevalence of B. ovata are vital. The taxonomy of B. ovata is unclear, and the phylogenetic position has not been well defined. Consequently, non-B. ovata species have sometimes been classified as B. ovata.
  • Coccidiosis is a parasitic disease caused by seven species of the genus Eimeria with different localizations within the intestinal tract of chickens. Eimeria acervulina, E. maxima and E. tenella are the most prevalent species in broilers in the intensive poultry management system. The disease represents a serious threat for the poultry industry, affecting the production, and causing high morbidity, mortality and significant economic loss due to the associated costs of treatment and prophylaxis. Global financial losses due to coccidiosis have been estimated at three billion USD per annum. In-feed anticoccidials have been used for decades for managing avian coccidiosis and they were very effective until drug resistance emerged.
  • D. gallinae is a small ectoparasite (approximately 1 .5 mm in length) that is characterized by five developmental stages: egg, larva, protonymph, deutonymph, and adult. To develop from the protonymph to adult stage, and to lay eggs thereafter, these mites need to feed on blood meals. During these developmental stages, D. gallinae causes several adverse effects in host birds, including anemia in hens, reduced egg quality, and increased feed and water intake. Moreover, given that the life cycle of this mite can be completed within 1 week, heavy infestations of D.
  • D. gallinae in layer poultry farms can occur within a short time period (30-70 days).
  • D. gallinae is also known as a vector of avian pathogens, including paramyxovirus, Escherichia coli, Salmonella Enteritidis, and avian influenza A virus, that can infect animals and humans.
  • avian pathogens including paramyxovirus, Escherichia coli, Salmonella Enteritidis, and avian influenza A virus, that can infect animals and humans.
  • IPM integrated pest management
  • IPM comprises the following five stages: 1) prevention, 2) monitoring for diagnosis, 3) application of non-chemical control strategies, 4) application of chemical control strategies, and 5) monitoring the effects of control strategy application.
  • monitoring is a key component for the appropriate application of IPM programs for D. gallinae.
  • D. gallinae notably the fact that it lives off-host and feeds only intermittently during the night, the monitoring of this mite tends to be difficult.
  • Metritis MET
  • clinical endometritis CE
  • SE subclinical endometritis
  • SE subclinical endometritis
  • MET Metritis
  • CE clinical endometritis
  • SE subclinical endometritis
  • MET uterine pathogens isolated from cows with MET, CE, and in some cases SE are Escherichia coli and Trueperella pyogenes.
  • Other frequently isolated pathogens are Prevotella species, Fusobacterium necrophorum, and Fusobacterium nucleatum.
  • Most practitioners perform antibiotic treatment of bovine uterine infections without sampling for bacteriological testing because it is time-consuming and costly.
  • Routine methods of bacteriological identification are based on colony characteristics, Gram staining, morphology, hemolytic ability and biochemical profile. Although these methods are useful to identify bacteria, they have some limitations. The time consumed to achieve a result, the difficulty to identify some bacteria, and the need for more accurate identification of bacteria are some of these limitations.
  • Mastitis is an inflammation of the mammary gland caused mainly by bacteria that made incursion of the udder through the teat canal.
  • the disease has negative economic impact to the dairy producers as it causes reduction of not only the milk yield and quality (change of milk composition and palatable leading to un-salability of the milk), but also the cow fertility by causing irregular/extended estrus cycle and hence the calving problem.
  • Mastitis also incurs the expense on treatment, intervention and control of the infection in the herd.
  • BM can be classified based on clinical manifestations into clinical mastitis (CM) and subclinical bovine mastitis (SCM); of which the latter is the more common entity.
  • CM clinical mastitis
  • SCM subclinical bovine mastitis
  • the affected udder shows inflammation including heat, swelling, discoloration as well as abnormal secretion; the infected cow may exhibit systemic reactions such as fever, loss of appetite and sometimes death.
  • SCC somatic cell counts
  • CMT California mastitis/milk test
  • Staphylococcus spp. including S. aureus and coagulase-negative staphylococci (CoNS) are the most common pathogens associated with SCM.
  • Mycoplasma gallisepticum is an important avian pathogen that commonly induces chronic respiratory disease in chickens and sinusitis in turkeys. This avian mycoplasma is responsible for considerable economic losses worldwide, and consequently a large number of studies have been dedicated to better understand its biology and the factors involved in host interactions.
  • M. gallisepticum colonizes its host mainly via the mucosal surfaces of the respiratory tract, causing air sacculitis within a few days, and disseminates throughout the body. This systemic infection is reflected by the high rate of M. gallisepticum reisolation from inner organs such as the liver, heart, spleen, or kidney and by its detection inside and at the surface of red blood cells of experimentally infected birds.
  • M. gallisepticum may rely on two independent phenomena that provide the pathogen with defensive measures against host defenses. These are the high versatility of its surface architecture via phase-variable expression of surface antigens and the ability to establish facultative intracellular residence in nonphagocytic host cells.
  • Colibacillosis is a syndromic disease of birds characterised by fibrinous lesions around visceral organs caused by a group of extraintestinal pathogenic Escherichia coli (ExPEC) known as avian pathogenic E. coli (APEC). Airsacculitis, cellulitis, pericarditis, perihepatitis and respiratory distress are among the most commonly associated signs of colibacillosis in broiler (meat producing) chickens. Extraintestinal E. coli infections are a considerable economic burden on the global poultry industry due to increased mortality rates during rearing and rejection of carcasses at slaughter. Despite a number of studies aimed at elucidating the APEC pathotype, it remains poorly defined.
  • Necrotic enteritis is an acute clostridial disease of economic importance to the poultry industry. NE is caused by Clostridium perfringens, a Gram-positive, rod-shaped, spore forming, and oxygen-tolerant anaerobe . C. perfringens is a normal component of the chicken gut microbiota and the alterations in the host-pathogen relationship that regulate the development of NE remain to be determined. A variety of predisposing factors, however, are known to promote disease, including diets containing high levels of wheat, barley, or poorly digestible proteins and co-infection by the apicomplexan protozoa, Eimeria, the etiologic agent of avian coccidiosis.
  • C. perfringens Because of the risk of transmission to humans through the food chain, C. perfringens also is important for public health. Traditionally, prophylactic in-feed antibiotics have proven effective for control of clostridial field infections in chickens. However, NE has recently emerged as a significant problem as a result of decreased antibiotic usage amid concerns over the appearance of antibiotic-resistant human pathogens.
  • Salmonella is a major foodborne pathogen that causes an estimated 153 million enteric infections and 56,969 diarrheal deaths each year worldwide. Chicken meat and eggs have been reported as a major source of Salmonella contamination. Therefore, it is important to control Salmonella in chicken- and egg-containing food products. Despite significant improvements in technology and hygienic practices at all stages of chicken production, salmonellosis and Salmonella infections remain an intransigent threat to human and animal health. In many countries the high incidence of salmonellosis in humans appears to be caused by infection derived from contaminated eggs, poultry meat and meat-containing products. The contaminated products cause disease as a result of inadequate cooking or cross contamination of working surfaces in the kitchen environment.
  • Salmonella Schwarengrund is one of the Salmonella serovars responsible for human and poultry infections in some countries, for sample, the United States, Denmark and Thailand. Antimicrobial resistance is becoming an increasingly important issue in salmonellosis in both animals and human. In poultry production, antimicrobial agents are widely used for growth promotion, or treatment purposes. As a consequence, chicken and chicken meat can harbor antimicrobial resistant strains and function as a vehicle for dissemination of these to human. Today, antimicrobial resistant of Salmonella strains are frequently encountered in most of the world and the proportion of antimicrobial resistant dramatically increased over the past decade.
  • Dermatophytes are fungi that invade and multiply within keratinized tissues (skin, hair, and nails) causing infection. Based upon their genera, dermatophytes can be classified into three groups: Trichophyton (which causes infections on skin, hair, and nails), epidermophyton (which causes infections on skin and nails), and Microsporum (which causes infections on skin and hair). Based upon mode of transmission, these have been classified as anthropophillic, zoophilic, and geophilic.
  • tinea capitis head
  • tinea faciei face
  • tinea barbae beard
  • tinea corporis body
  • tinea manus hand
  • tinea cruris groin
  • tinea pedis foot
  • tinea unguium unguium
  • Other clinical variants include tinea imbricata, tinea pseudoimbricata, and Majocchi granuloma.
  • Dermatophytosis is one of the most frequent skin diseases of pets and livestock. Contagiousness among animal communities, high cost of treatment, difficulty of control measures, and the public health consequences of animal ringworm explain their great importance.
  • a wide variety of dermatophytes have been isolated from animals, but a few zoophilic species are responsible for the majority of the cases, viz. Microsporum canis, Trichophyton mentagrophytes, Trichophyton equinum and Trichophyton verrucosum, as also the geophilic species Microsporum gypseum. According to the host and the fungal species involved, the typical aspect of dermatophytic lesions may be modified. As a consequence, an accurate clinical examination, a good differential diagnosis and laboratory analyses are required for a correct identification.
  • RA Rheumatoid arthritis
  • Hands, wrists, and knees are most commonly bilaterally affected causing inflammation, pain, and eventually permanent joint damage.
  • Genetic factors may account for a portion of risk, while the rest might be linked to environmental factors or a combination of genetic and environmental factors.
  • Infectious diseases, tobacco smoking, and gut bacteria have all been considered to play a role in the development or progression of RA.
  • Medications are a mainstay of treatment, but have unwanted side effects or are often expensive. Thus, changes in diet might be an easy and economical intervention in the management of RA.
  • Peyronie’s disease is a connective tissue disorder involving the tunica albuginea of the corpora cavernosa of the penis. It occurs in 3.2%-13% of adult males.
  • the disease consists of a thickening of a small area of tissue that gradually turns into an inelastic plaque, which can cause penile deformity (penile curvature, shortening, divot, hourglass deformity, etc), pain during erection, erectile dysfunction [ED], and psychological disorders (psychosexual impact).
  • penile deformity penile curvature, shortening, divot, hourglass deformity, etc
  • ED erectile dysfunction
  • an initial active inflammatory remodeling phase lasting 12-18 months (actually preceded by a brief, acute posttraumatic period, lasting 2 weeks wherein powerful recruitment of inflammatory cells occurs), and a second stage in which both tissue damage and deformation stabilize.
  • Medical treatment is mainly indicated in the first stage of PD.
  • oral therapy potaba, colchicine, tamoxifen, vitamin E, carnitine, etc
  • intralesional injections verapamil, steroids, interferon, and, recently, collagenase Clostridium histolyticum [CCH, Xiaflex]
  • physical treatment iontophoresis, extracorporeal shock wave therapy [ESWT], penile extender.
  • Gastric acid secretion is largely controlled by cholinergic, histaminergic and peptidergic (especially gastrin) pathways. Disorders in a number of these pathways can lead to gastric acid hypersecretion, which primarily mediate the hypersecretion by causing hypergastrinemia, causing hyperhistaminemia or by an unknown etiology. While these disorders may have different etiologies, they frequently share similar clinical features [i.e., peptic ulcer disease (PUD), gastroesophageal reflux disease (GERD)] due to the effects of the acid hypersecretion on the esophagus, stomach and the duodenum.
  • PID peptic ulcer disease
  • GTD gastroesophageal reflux disease
  • the PUD/GERD may be refractory and severe enough to lead to compilations such as PUD penetration, perforation, and bleeding or esophageal strictures.
  • ZES Zollinger-Ellison syndrome
  • the acid hypersecretion can result in diarrhea and malabsorption of nutrients, particularly vitamin B12 and iron.
  • the gastric acid hypersecretion mediated by these different disorders can all be treated by gastric antisecretory agents.
  • EP0306971A2 discloses the use of milk fat globules as a lipid matrix for the delivery of liposoluble active drugs.
  • MFGs as an active ingredient, namely a drug, is not disclosed.
  • EP1453526A2 discloses the use of milk fat globules in pharmaceutical compositions for the topical treatment of skin disorders, skin burns and skin wounds.
  • Said compositions are an oil- in- water emulsions containing ZnO and further antibiotic, bactericidal drug, sulphonamide or a retinoid.
  • WO2014/016647A1 discloses the use of milk fat globules in pharmaceutical compositions for the topical treatment of skin disorders. It has been disclosed that the topical treatment of burned rabbit skin with cream containing MFGs inhibited release of PGE2, TXB2 and LTB4 from the thermally injured area.
  • antibiotic residue contamination in food animals is alarming: a recent study of over 1000 8 ⁇ 11 -year-old children in Shanghai, China, detected in 58% of the urine samples multiple antibiotics that are only used in food animals (i.e., tylosin, chlortetracycline, and enrofloxacin).
  • tylosin i.e., tylosin, chlortetracycline, and enrofloxacin
  • Antibiotic residues in food animals is a consequence of antibiotic overuse in animal feed. Bacterial and protozoal diseases are continually diagnosed and new diseases have emerged in poultry, but there is a lack of newer efficacious antimicrobials to treat these diseases.
  • Avian viral diseases caused by avian influenza Al, infectious bronchitis (IB), infectious bursal disease (IBD), and Newcastle disease (ND) viruses are a major obstacle in the poultry industry worldwide and result in substantial economic losses, especially in broilers, due to respiratory distress, high mortality, impaired growth or immune suppression. Furthermore, they have the capability of inducing diseases independently or in concurrent infection with each other.
  • Avian influenza viruses are classified in the genus Influenza virus of Orthomyxoviridae family, while the etiology of IBD or Gumboro disease is the infectious bursal disease virus that is a member of genus Avibirnavirus of Birnaviridae family.
  • Infectious bronchitis virus is belonging to Coronavirus genus of family Coronaviridae, while the cause of ND is Newcastle disease virus, belonging to genus Avulavirus of Paramyxoviridae family. All of these viruses have RNA genome enclosed within either enveloped (Al, IB and ND viruses) or non-enveloped (IBD virus) capsid. Their outbreaks still occur in the field, though several live, inactivated, or recombinant vaccines are commercially available, and different vaccination programs are applied for each disease. Many factors are related to this problem, one of them is the immune suppression or an immature immune system. Moreover, if a virus is endemic in a region, its elimination is difficult, so additional methods are required to combat these viruses along with vaccination.
  • EDS Egg drop syndrome
  • FE Feed efficiency
  • Feed efficiency can be measured using the feed conversion ratio (FCR), which is a composite trait defined as feed intake per unit of body weight gain (BWG) during a specified period of time.
  • FCR feed conversion ratio
  • FCR feed efficiency metric metric ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • One object of the present invention is to provide a pharmaceutical composition for use in the treatment of bacterial, viral, fungal and parasitic diseases which do not comprise metallic chemicals and which are based on abundant natural sources which are inexpensive.
  • Another object of the present invention is to provide a pharmaceutical composition for the treatment of diseases which decrease the antibiotic, antibacterial, antiviral, antifungal and antiparasitic intake of subjects including humans and animals.
  • the present invention provides a pharmaceutical composition comprising 5 to 70 wt% of milk fat globules and at least one added C4-C20 fatty acid for use in the treatment of a viral infection disease.
  • the present invention provides a pharmaceutical composition comprising 5 to 70 wt% of milk fat globules and at least one added C4-C20 fatty acid for use in the treatment of a parasitic disease.
  • the present invention provides a pharmaceutical composition comprising 5 to 70 wt% of milk fat globules and at least one added C4-C20 fatty acid for use in the treatment of a bacterial infection disease selected from metritis (MET), mastitis (BM), mycoplasma gallisepticum infection, Escherichia coli infections, necrotic enteritis (NE), Salmonella infections, Pseudomonas aeruginosa and Staphylococcus aureus.
  • a bacterial infection disease selected from metritis (MET), mastitis (BM), mycoplasma gallisepticum infection, Escherichia coli infections, necrotic enteritis (NE), Salmonella infections, Pseudomonas aeruginosa and Staphylococcus aureus.
  • the present invention provides a pharmaceutical composition comprising 5 to 70 wt% of milk fat globules and at least one added C4-C20 fatty acid for use in the treatment of a fungal disease.
  • the present invention provides a pharmaceutical composition comprising 5 to 70 wt% of milk fat globules and at least one added C4-C20 fatty acid for use in the treatment of cartilage damage.
  • the present invention provides a pharmaceutical composition comprising 5 to 70 wt% of milk fat globules and at least one added C4-C20 fatty acid for use in the treatment of rheumatoid arthritis (RA).
  • RA rheumatoid arthritis
  • the present invention provides a pharmaceutical composition comprising 5 to 70 wt% of milk fat globules and at least one added C4-C20 fatty acid for use in the treatment of Peyronie’s disease (PD).
  • PD Peyronie’s disease
  • the present invention provides a pharmaceutical composition comprising 5 to 70 wt% of milk fat globules and at least one added C4-C20 fatty acid for use in the treatment of flatulence.
  • the present invention provides a pharmaceutical composition comprising 5 to 70 wt% of milk fat globules and at least one added C4-C20 fatty acid for use in the treatment of gastric acid hypersecretory states.
  • the present invention provides a pharmaceutical composition comprising 5 to 70 wt% of milk fat globules and at least one added C4-C20 fatty acid for use as a strong expectorant.
  • the present invention provides a complementary animal food supplement comprising 5 to 70 wt% of milk fat globules and at least one added C4-C20 fatty acid for use in protecting the animals from bacterial, viral, parasitic, fungal diseases and improving feed conversion ratio, egg shell and albumen quality.
  • the present invention provides a pharmaceutical composition comprising 5 to 70 wt% of milk fat globules and at least one added C4-C20 fatty acid for use in the treatment of egg drop syndrome disease in chickens.
  • Figure 1 shows photographs taken on week 1 , 2, 3, 4, 5, 6, 8, 10, 12 and 14 after wounding and treatment for reconstruction of cartilage defects in rabbit’s ear as described in Example 24.
  • Figure 2 shows a photograph taken after the end of the treatment as described in Example 24.
  • Figure 3 shows a photograph A in which the treated ear as described in Example 24 is shown and a photograph B in which a normal ear is shown.
  • the milk fat globules comprise a triglyceride core surrounded by a lipid bilayer containing integral membrane proteins (Mather and Keenan, J. Membrane Biol. 21 : 65, 1975). They comprise the cream fraction milk and consist of fat droplets that are stabilized by an external membrane derived mainly from the apical plasma membrane of mammary secretory cells. This membrane (approximately 10 nm in cross-section) consists of a complex mixture of proteins, phospholipids, glycoproteins, triglycerides, cholesterol, enzymes and other minor components (McPherson, et al. J. Dairy Research (1983) 50 :107-133).
  • the milk fat globules are composed of 99% triglycerides which are synthesized in the mammary gland secretory cell from precursors in the blood such as glucose, acetate, low density lipoproteins.
  • the triglyceride core of the MFGs is surrounded by a lipid bilayer containing integral membrane proteins.
  • the triglyceride core is composed of polysaturated fatty acids (butyric acid, caproic acid, caprylic acid, cupric acid, lauric acid, myristic acid, palmitic acid, stearic acid, and arachidic acid) and polyunsaturated fatty acids (oleic acid, linoleic acid and arachidonic acid) attached to glycerine groups.
  • the lipid bilayer surrounding the triglyceride core which is called milk fat globule membrane (MFGM) consists of a complex mixture of proteins, phospholipids, glycoproteins, lactadherin, annexin V, RGD, cholesterol, enzymes, carotenes, vitamins and other minor components (Hamosh M, Peterson JA, Henderson TR, Scallan CD, Kiwan R, Ceriani RL, Armand M, Mehta NR, Hamosh P. Protective function of human milk: the milk fat globule. Semin Perinatol.1999 Jun; 23(3):242- 9. Peterson JA, Scallan CD, Ceriani RL, Hamosh M. Structural and functional aspects of three major glycoproteins of the human milk fat globule membrane. AdvExp Med Biol.2001 ; 501 : 179-87).
  • Weight % means percentage by weight of the composition.
  • oral administration includes oral, buccal, enteral and intragastric administration.
  • parenteral administration includes but is not limited to topical (including administration to any dermal, epidermal or mucosal surface), subcutaneous, intravenous, intraperitoneal and intramuscular administration.
  • subject is intended to refer to an animal, preferably a mammal, more preferably an animal or human.
  • the present invention is directed to a composition comprising 5 to 70 wt% of milk fat globules and at least one added C4-C20 fatty acid for use in the treatment of diseases of the present invention.
  • the amount of at least 5 wt% of MFGs in the composition is sufficient to provide an efficient treatment of the diseases of the present invention without the presence of additional protective, preservative or anti- infectious medium or as an additional active ingredient.
  • compositions consist of MFGs as the sole active ingredient.
  • compositions of the present invention provide an effective treatment without the addition of anti-infectious drugs and prevents the infectious agent from becoming drug resistant.
  • the compositions are advantageously used for the treatment of the diseases showing drug resistance.
  • the added C4-C20 fatty acid is selected from the group consisting of butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, palmitic acid, stearic acid, oleic acid, isosteric acid, linoleic acid and myristic acid.
  • said added C4-C20 fatty acid is selected from the group consisting oleic acid and stearic acid.
  • said added C4-C20 fatty acid is oleic acid or stearic acid.
  • C4-C20 fatty acids present in the composition with the active ingredient namely MFGs provide a synergistic effect in the treatment of diseases of the present invention with the active ingredient, namely MFGs.
  • Fatty acids also act as an auxiliary emulsifying agent and increase the emulsion stability.
  • compositions of the present invention may comprise at least one emulsifier.
  • the emulsifier may be selected from alkyl alcohols, alkyl polyglucosides, polyglycerol alkyl esters, C1-C4 esters of alkyl alcohols, C1 -C4 esters of alkyl carboxylates, alkyl amides, alkyl betaines and alkyl phosphates or phospholipids, alkyl quaternary amines, alkyl amine oxides, polyoxyethylene castor oil derivatives, polyethoxylated alkyl alcohols, alkyl esters of polyethylene glycol, triethanolamine, oleic acid and mixtures thereof.
  • the emulsifier is preferably ethoxylated castor oil, also known by the name of glyceryl polyethylene glycol ricinoleate or glycerol polyethylene glycol ricinoleate (E484) having an FILB 12.6 and/or oleic acid such as liquid emulsion,
  • the emulsifier is preferably ethoxylate castor oil surfactant having an FILB from 4 to 18 and a molar ratio of 1 molecule of castor oil to 1 - 200 molecules of ethylene oxide and/or oleic acid such as emulsifiable concentrate (EC).
  • EC emulsifiable concentrate
  • the emulsifier is preferably triethanolamine and/or stearic acid acid for topical compositions such as cream.
  • compositions of the present invention may further comprise at least one pharmaceutically acceptable carrier including an excipient which is selected from, mineral oils, isopropyl myristate, sunflower oil, corn oil, olive oil, soybean oil, canola oil, ethyl oleate, sesame oil, cotton seed oil, lanolin alcohols, hydrous lanolin and polyethylene glycol and/or other substance.
  • an excipient which is selected from, mineral oils, isopropyl myristate, sunflower oil, corn oil, olive oil, soybean oil, canola oil, ethyl oleate, sesame oil, cotton seed oil, lanolin alcohols, hydrous lanolin and polyethylene glycol and/or other substance.
  • compositions of the present invention may be formulated to allow for administration to a subject by any chosen route, including but not limited to oral or parenteral (including topical, subcutaneous, intramuscular and intravenous) administration.
  • the composition is preferably administered via rectal, nasal and intraocularly.
  • the compositions of the present invention may be formulated as a food, drink, food additive, drink additive, dietary supplement, nutritional product, medical food, nutraceutical, medicament or pharmaceutical.
  • nutraceutical or pharmaceutical composition may be formulated by a skilled worker according to known formulation techniques.
  • Topical formulations may be prepared as lotions, creams, ointments, pastes or salves by a skilled worker according to known formulation techniques.
  • the composition may further comprise oily excipients selected from liquid paraffin and isopropyl myristate in cream.
  • the liquid paraffin and isopropyl myristate synergistically reduce the cream absorption by gauze and prevent gauze adhering to the affected area.
  • topical cream preparations are more preferable than topical ointment preparations by patients than cream formulations as cream is perceived to be easier to apply and to cause less garment soiling than ointments.
  • the pharmaceutical composition comprises 20 wt% of MFGs as the active ingredient and 10 wt% of stearic acid.
  • the combination provides effective stabilization and structure thickening.
  • the composition also has a synergistic effect in the treatment of skin parasitic diseases (cutaneous leishmaniasis), skin bacterial diseases (Escherichia coli infections and Staphylococcus aureus infections), skin fungal diseases (dermatophyte infections such as dermatophytic lesions, Candida albican infections) and cartilage regeneration when administered topically.
  • the pharmaceutical composition comprises 40 to 50 wt% of MFGs as the active ingredient and 10 wt% of oleic acid.
  • the composition is synergistically stable; this is probably due to oleic acid acting as an auxiliary emulsifying agent.
  • the composition has a synergistic effect in the treatment of viral infection diseases (infections by influenza viruses, corona viruses including SARS-CoV-2 infection, virulent Newcastle disease virus and virulent avian infectious bronchitis virus), parasitic diseases (cutaneous leishmaniasis, sarcoptic mange, lice infestation, infection by species of theileria, babesiosis, coccidiosis and red mite), bacterial diseases selected (metritis, mastitis, mycoplasma infection, E.
  • viral infection diseases infections by influenza viruses, corona viruses including SARS-CoV-2 infection, virulent Newcastle disease virus and virulent avian infectious bronchitis virus
  • parasitic diseases cutaneous leishmaniasis, sarcoptic mange, lice infestation, infection by species of theileria, babesiosis, coccidiosis and red mite
  • bacterial diseases selected metritis, mastitis, mycoplasma infection, E.
  • the composition forms an oil-in-water or water-in-oil emulsion together with the emulsifier.
  • the composition may be in the form of a liquid emulsion.
  • the composition may be in the form of emulsifiable concentrate.
  • the present invention is also directed to a complementary animal food supplement composition
  • a complementary animal food supplement composition comprising 5 to 70 wt% of milk fat globules and at least one added C4-C20 fatty acid for use in protecting the animals from bacterial, viral, parasitic, fungal diseases and improving feed conversion ratio (FCR), egg shell and albumen quality.
  • the animal food supplement may be used for all species.
  • the composition comprises MFGs in an amount of 40 to 50 wt% and oleic acid in an amount of 10 wt%.
  • the composition is synergistically stable; this is probably due to oleic acid acting as an auxiliary emulsifying agent.
  • the composition has a synergistic effect in protecting the animals from bacterial, viral, parasitic, fungal diseases and improving feed conversion ratio (FCR), egg shell and albumen quality.
  • the composition forms an oil-in-water emulsion together with the emulsifier.
  • the composition may be in the form of a liquid emulsion.
  • the composition may further comprise oily excipient such as sunflower oil.
  • MFGs Milk Fat Globules
  • Methods commonly used for the preparation of MFGs are disclosed in EP0306971A2, incorporated herein in its entirety. It is well known in the state of the art that MFGs may be obtained from ghee, butter oil, clarified butter or anhydrous milk fat. MFGs are insulated from ruminants milk and produced commercially all over the world. MFGs insulated from raw milk contain approximately 3.3 % fat, into > fresh cream contains approximately 40% fat, into > butter contains 82% fat, into > butter ghee contains 99.9% fat.
  • the extraction process of the milk fat globules from the raw starting material, namely milk is carried out under gentle conditions, avoiding especially too high temperatures and excessive centrifugation speeds. Ruminants milk was found to be a preferred starting material for preparing the pharmaceutical composition of the invention.
  • Example 1 Inviolability emulsion - Liquid emulsion containing 40% MFGs
  • the formulation of the Inviolability - liquid emulsion containing 40% MFGs is shown in Table
  • the emulsion is prepared as follows:
  • the water is put in a mixer and heated up to 60°C.
  • the oily materials, MFGs, emulsifying agent and oleic acid are heated up to the melting point.
  • the melted oily materials are slowly added to the mixer in water.
  • the mixing is continued at a speed of 3000 rotations per minute for about 1 hours.
  • the process was carried out under sterile conditions.
  • the sterile emulsion is packaged in a sterile bottle.
  • Example 2 Mifago concentrate - Water emulsifiable concentrate containing 50% MFGs
  • the oily materials, MFGs, emulsifying agent and oleic acid are heated up to the melting point.
  • the melted oily materials are slowly added to the mixer.
  • the mixing is continued at a speed of 3000 rotations per minute for about 1 hours.
  • the process was carried out under sterile conditions.
  • the sterile oil is packaged in a sterile bottle.
  • Example 3 Mifago cream - Cream containing 20% MFGs
  • the Mifago cream is formulated as a cream containing MFGs as an active ingredient in the form of an oil-in-water emulsion which is suitable for topical administration.
  • stearic acid is preferred because it gives the creamy form to the preparation.
  • the cream is prepared as follows:
  • the water is put in a mixer and heated up to 90°C. At this stage, the materials which are able to melt in water are added. 2.
  • the oily materials, MFGs, stearic acid, isopropyl myristate, VaselineTM and liquid paraffin are heated up to melting point.
  • the melted oily materials are slowly added to the mixture in water.
  • the mixing is continued at a speed of 3000 rotations per minute for about 50 minutes.
  • the process was carried out under sterile conditions and after cooling the cream is filled in tubes.
  • Example 4 Effect of compositions of the present invention on influenza disease virus in humans
  • the pharmaceutical composition of the invention i.e. Mifago concentrate containing 50% MFGs is orally administered to patients suffering from influenza.
  • This experiment was carried out in Aleppo region, an area of situated in north Iraq. The experiment was conducted on 5 patients with influenza virus infection. Patients were interviewed with structured questionnaires and clinically-examined by a specialist. Symptoms associated with influenza virus infection vary from a mild respiratory disease confined to the upper respiratory tract and characterized by fever, sore throat, runny nose, cough, headache, muscle pain and fatigue to severe.
  • Mifago concentrate containing 50% MFGs was administered orally 2 times daily for 7 days at a dose of 1 ml per 10 kg of body weight.
  • Example 5 Effect of compositions of the present invention on Corona disease virus (COVID- 19) in humans
  • the Inviolability emulsion 40% MFGs is orally administered to patients suffering from corona disease (COVID-19).
  • Example 6 Effect of compositions of the present invention in broiler chickens infected with infectious Newcastle disease virus
  • compositions according to present invention are assessed in vivo as a preventive measure and as a therapy for vNDv (virulent Newcastle disease virus) infection in broiler chickens.
  • Mifago water emulsifiable concentrate containing 50% MFGs was supplemented through the drinking water at a dose of 1 ml_/L.
  • a previously isolated and characterized virulent genotype VII ND virus was used for challenging experimental groups.
  • the challenge was performed on the 28th day of age (d) with 106.3 EID50 /100 pL/bird via eye drop (50 pl_) and the intranasal (50 mI_) route.
  • the negative control group was sham challenged with similar volumes and routes using phosphate-buffered saline (PBS).
  • PBS phosphate-buffered saline
  • NC non-vaccinated, non-treated and non-challenged (Negative control)
  • PC non-vaccinated, non-treated and vNDv challenged (Positive control)
  • VC vaccinated, non-treated and vNDv challenged (Vaccinated, challenged)
  • VTC vaccinated, treated (MFGs treatment was started after each vaccine and continued for 3 days), and vNDv challenged (Vaccinated, treated and challenged)
  • PRV vaccinated and treated (MFGs treatment was started one day before vNDv challenge and continued for 5 days) (Preventive group)
  • TTT vaccinated and treated (MFGs treatment was started two days after vNDv challenge and continued for 5 days) (Therapeutic group)
  • Vaccinated groups (VC, VTC, PRV and TTT) received the vaccination program shown in Table 5 against ND, IB, IBD and Al. Food and water were provided to all birds with free access. The chicks were received at 32°C on day 1 and then the temperature was decreased linearly by 2°C per week.
  • PC post challenge
  • NC negative control group
  • vNDv challenge resulted in depression, swollen head, conjunctivitis, rales, sneezing and nasal discharge beginning at the 2nd day post challenge (PC) in three experimentally challenged group (PC, VC and TTT).
  • PC 2nd day post challenge
  • PC three experimentally challenged group
  • Table 6 Diarrhoea was also recorded in PC and TTT (Table 5).
  • Table 5 Upon examination of dead birds, congestion of the pectoral muscles and trachea, proventricular haemorrhage, button-like ulcers on the small intestine, and a mottled enlarged spleen were observed (Table 5).
  • Data are an average of clinical signs and the post mortem lesion score, as follows: 0: No; 1 : Mild; 2: Moderate and 3: Severe signs or lesions.
  • supplemental Mifago water emulsifiable concentrate 50% MFGs had a positive effect on broiler chickens infected with NDV. They decreased the severity of Newcastle disease virus (NDV) and had a strong antiviral activity.
  • NDV Newcastle disease virus
  • Example 7 Effect of compositions of the present invention in broiler chickens infected with infectious bronchitis disease virus
  • compositions of the present invention are assessed in vivo as a preventive measure and as a therapy for vIBv infection in broiler chickens.
  • IBV TN20/00 strain virus was used for challenging experimental groups.
  • the challenge was performed on the 28th day of age (d) with 106.3 EID50 /100 pL/bird via eye drop (50 pl_) and the intranasal (50 mI_) route.
  • the negative control group was sham challenged with similar volumes and routes using phosphate-buffered saline (PBS).
  • PBS phosphate-buffered saline
  • NC non-vaccinated, non-treated and non-challenged (Negative control)
  • PC non-vaccinated, non-treated and vIBv challenged (Positive control)
  • VC vaccinated, non-treated and vIBv challenged (Vaccinated, challenged)
  • VTC vaccinated, treated (MFGs treatment was started after each vaccine and continued for 3 days), and vIBv challenged (Vaccinated, treated and challenged)
  • PRV vaccinated and treated (MFGs treatment was started one day before vIBv challenge and continued for 5 days) (Preventive group)
  • TTT vaccinated and treated (MFGs treatment was started two days after vIBv challenge and continued for 5 days) (Therapeutic group)
  • Vaccinated groups (VC, VTC, PRV and TTT) received the vaccination program shown in Table 5 against ND, IB, IBD and Al. Feed and water were provided to all birds with free access. The chicks were received at 32°C on day 1 and then the temperature was decreased linearly by 2°C per week.
  • Data are an average of clinical signs and the post mortem lesion score, as follows: 0: No; 1 : depression; 2: sick, coughing, sneezing, nasal, discharge and 3: Severe respiratory distress, death.
  • Mifago cream containing 20% MFGs is topically administered to patients suffering from non healing cutaneous leishmania (CL).
  • This experiment was carried out in Aleppo region, an area of situated in north Iraq.
  • the experiment was conducted on 10 patients with active skin lesions suspicious for CL. Patients were interviewed with structured questionnaires and clinically-examined by a specialized dermatologist.
  • the lesion’s evolution time was calculated by the time interval from the lesion’s eruption day till the patient’s consultation day.
  • the clinical examination involved tissue- affected, lesion characteristics (number, size, site and appearance).
  • the lesion’s size was measured through 2 crossing diameters by a metric calliper.
  • Patients eligible for treatment were selected and Mifago cream containing MFGs 20% was administered topically 2 times daily for 35 days.
  • the inventors observed that healing was observed after the administration of the Mifago cream containing MFGs 20% on ulcerative lesions.
  • Resolution signs of the lesions included inflammatory signs (skin erythema, edema and hardening) and size regression 100% without scar formation.
  • Example 9 Efficacy of compositions of the present invention on treatment of Sarcoptic mange in camel.
  • Mifago water emulsifiable concentrate containing 50% MFGs is topically administered to camels suffering from sarcoptic mange in skin.
  • Mifago water emulsifiable concentrate 50% MFGs Twenty camels suffering from Sarcoptic mange were treated with Mifago water emulsifiable concentrate 50% MFGs. It is administered with spray locally on the affected area on skin once a day for 5 days with light massage. Before use each 1 liter of Mifago concentrate was mixed with 1 liter of water.
  • Example 10 Efficacy of compositions of the present invention on treatment of Lice in cattle.
  • Mifago water emulsifiable concentrate containing 50% MFGs is topically administered to bovines suffering from lice in skin.
  • Mifago water emulsifiable concentrate containing 50% MFGs Five cows suffering from lice were treated with Mifago water emulsifiable concentrate containing 50% MFGs. It is administered with spray locally on the affected area on skin once a day for 2 days. Before use each 1 liter of Mifago concentrate was mixed with 1 liter of water.
  • Example 11 Efficacy of compositions of the present invention on treatment of Theileria in bovine
  • Inviolability emulsion containing 40% MFGs was intramuscular administered to animals suffering from theileria.
  • Example 12 Efficacy of compositions of the present invention on treatment of Babesia in bovine
  • Inviolability emulsion containing 40% MFGs was intramuscular administered to animals suffering from bovine Babesia.
  • Example 13 Efficacy of compositions of the present invention on coccidiosis in broiler chicken
  • ROSS 308 hybrid broiler chickens infected with Coccidiosis are the most prevalent species in broilers in the intensive poultry management system. They were randomly divided in two groups, 200 of each. Group one treated with Inviolability emulsion administration 1 ml per litter of drinking water for 5 days. Group two treated with traditional medicine left as control.
  • Example 14 Efficacy of compositions of the present invention on red mite (Dermanyssus gallinae) in layer chicken
  • Inviolability emulsion containing 40% MFGs was orally administered to animals with red mite.
  • the inventors observed after oral administration of MFGs emulsion that red mite disappeared from body of birds after end of the treatment.
  • Example 15 The effects of compositions of the present invention on bacteria and fungus in vitro The objective of this experiment is to assess the antibacterial effect of Mifago cream containing 20% MFGs on bacteria (Pseudomonas aeruginosa, Staphylococcus aureus and E. coli and fungus (Candida albicans) in vitro. The cream was free of preservatives and antioxidants.
  • the experiments consists of challenging the preparation, with a prescribed inoculum of suitable micro-organisms, storing the inoculated preparation at ambient temperature, avoiding sunlight, withdrawing samples from the container at specified intervals of time and counting the organisms in the samples so removed.
  • Mifago cream containing 20% MFGs has antibacterial activity against a Pseudomonas aeruginosa, Staphylococcus aureus and E. coli and antifungal activity (Candida albicans) in vitro as shown in Table 7.
  • Example 16 Efficacy of compositions of the present invention on treatment of metritis
  • Mifago cream containing 20% MFGs and Inviolability emulsion containing 40% MFGs were administered locally and intramuscularly respectively to animals suffering from metritis.
  • Mifago cream containing 20% MFGs. It is administered by uterine suppositories or metritis tubes containing Mifago cream twice a day for 5 days. Generally the metritis tubes contain 10 gram Mifago cream. Inviolability emulsion by intramuscular injections at a dose of 0.5 ml/10 kg body weight/day for 5 days is also administered to accelerate the healing and prevent the transmission of infection to the blood.
  • the inventors observed healing of all animals and disappearance of the signs of metritis after the end of the treatment.
  • Example 17 Efficacy of compositions of the present invention on treatment of mastitis
  • Mifago cream containing 20% MFGs and Inviolability emulsion containing 40% MFGs were administered locally and intramuscularly respectively to animals suffering from mastitis.
  • Ten dairy cows suffering from mastitis were treated with MFGs.
  • the treatment is started with offloading the milk from the inflamed quarter then inserting the Mifago cream inside the mastitis tube in the teat channel and emptying the entire tube within the affected quarter. This process was repeated twice a day for 5 days.
  • the Mifago cream in the mastitis tube is usually 10 g.
  • the inventors observed healing of all animals and disappearance of the signs of mastitis after the end of the treatment.
  • Example 18 Efficacy of compositions of the present invention on treatment of mycoplasma gallisepticum in chicken
  • Example 19 Efficacy of compositions of the present invention on treatment of Escherichia Coli in broiler chicken
  • Example 20 Efficacy of compositions of the present invention on treatment of necrotic enteritis (NE) in broiler chicken
  • Example 21 Efficacy of compositions of the present invention on treatment of Salmonella in broiler chicken. The purpose of the present experiment was to assess the effect of Inviolability emulsion containing 40% MFGs on Salmonellas in broiler chickens.
  • Example 22 Efficacy of compositions of the present invention on treatment of tinea pedis (foot)
  • Mifago cream containing 20% MFGs is topically administered to patients suffering from tinea pedis between the foot fingers.
  • Mifago cream containing 20% MFGs was administered topically 2 times daily until healing.
  • the inventors observed that administration of the Mifago cream containing 20% MFGs on affected areas stopped scratching within 24 hours after the administration and healing of skin started during the administration of the Mifago cream. The signs of fungi disappeared at day 30 from the treatment.
  • Example 23 Efficacy of compositions of the present invention on treatment of fungi in cattle
  • Mifago cream containing 20% MFGs is locally administered to animals suffering from fungal lesions.
  • Mifago cream containing 20% MFGs.
  • the Mifago cream administered three times on the lesions every day up to the appearance of hair.
  • Inviolability emulsion instead of cream may be used instead of cream can be used for a big livestock.
  • Example 24 The effects of compositions of the present invention on reconstruction of cartilage defects in rabbit’s ear.
  • the purpose of the experiment was further to investigate the effects of Mifago cream containing 20% MFGs on the regeneration/restoration of tissue function of a large hole in a rabbit's ear when it is administered topically.
  • Figure 2 shows that the cartilage in treated group was thicker of the cartilage in normal ear.
  • Figure 3 shows (A) group, the treated ear was approximately normal and the cartilage structure was normal compared to skin and cartilage structure in normal ear in (B) group.
  • (A) group consists of treated animals with the pharmaceutical composition of the invention.
  • the animals were anaesthetized with intramuscular ketamine (40 mg/kg) and Xylazine (4mg/kg). Cleaning of the ears was done with iodine. No local anesthesia was used. A punch 2x3 cm, which of the full thickness of the one ear per rabbit was excised in mid ear. Bleeding was stopped by inserting a plug of sterilized gauze in the hole.
  • the animals were divided into two groups (G1 , G2) ten of each.
  • G1 had twice-daily application of Mifago cream preparation containing 20% MFGs.
  • G2 left as a control group in which the wounds were covered by simple saline twice daily without any kind of cream.
  • the dressings were changed twice daily. All wounds were covered with a self-adhering wrap around ear. The wounds were covered with dry gauze. The dressing wrap-around ear in all groups, Mefix from (Molnlycke health care company Sweden). The animals were checked 2 times daily to ensure that the wounds were always covered.
  • regenerated tissue was harvested from mid wounds; the specimen was fixed in 10% paraformaldehyde, embedded in paraffin, and sectioned. Sections were stained with Hematoxylin-eosin H&E stain.
  • cartilage in the treated group was the same as those cartilage found in the normal ear.
  • the cartilage was thicker in G1 ear than cartilage in the normal ear.
  • MFGs cream when topically applied led reconstruction of full-thickness defects in rabbit ear compared to normal ear by active positive contraction for skin without scar formation and promoted cartilage regeneration in the treated group as shown in Fig.2.
  • Histology The sections stained with H&E consisted of epidermis, dermis and cartilage, although these were the same as those tissues compared to normal ear as shown in Fig.3.
  • Example 25 The effects of compositions of the present invention as an anti-inflammatory agent in rheumatoid arthritis in human
  • Inviolability emulsion containing 40% MFGs is orally administered to patients suffering from rheumatoid arthritis and cartilage damage.
  • the aim of this experiment was to clarify the role of the compositions of the present invention in the pathogenesis of RA, in particular focusing on the progress of inflammation and cartilage repair.
  • the experiment included 5 cases. All patients were suffering from rheumatoid arthritis and cartilage damage. Patients eligible for treatment were selected and Inviolability emulsion containing MFGs containing 40% was administered orally 1 ml/10 kg body weight every 72 hours for 6 month.
  • the inventors observed that the administration of the Inviolability emulsion containing 40% MFGs orally led the abolishment of pain within one hour after administration of MFGs and a gradual cartilage damage repair within 6 months after starting treatment.
  • Example 26 The effects of compositions of the present invention on Peyronie’s disease
  • Inviolability emulsion containing 40% MFGs is orally administered to patients suffering from Peyronie’s disease.
  • IIEF International Index of Erectile Function
  • PI-NRS Pain Assessment questionnaire
  • BMI body mass index
  • color Doppler analysis included three- dimensional study of the plaque’s measurements (length, width, and thickness), with imaging of the penis at maximum erection and photographic poses according to Kelami for goniometric measurement of penile curvature. Plaque volume was measured in cubic centimeters using the ellipsoid formula.
  • the inventors observed that the administration of the Inviolability emulsion containing 40% MFGs orally led degradation of the connective tissue and the abolishment of pain.
  • Example 27 Prevention and treatment of flatulence with compositions of the present invention
  • Mifago a water emulsifiable concentrate containing 50% MFGs is orally administered to patients suffering from flatulence.
  • This experiment was conducted on 5 patients suffering from flatulence. Patients were interviewed with structured questionnaires and clinically-examined by a specialist.
  • Mifago water emulsifiable concentrate containing 50% MFGs was administered orally one time daily at dose of 3 ml per patient in the first week, one time every 48 hour in the second week and on time every 72 hours in the third week.
  • the inventors observed that within half an hour after administering Mifago water emulsifiable concentrate orally, gas formation was reduced and gas repellent in the first day and pain were removed in the second day. The results in this experiment indicated that anti-flatulence activity of compositions of the present invention led to healing of patients.
  • Example 28 Prevention and Treatment of gastric acid hypersecretory with compositions of the present invention
  • Mifago a water emulsifiable concentrate containing 50% MFGs is orally administered to patients suffering from gastric acid hypersecretory.
  • This experiment was conducted on 4 patients suffering from gastric acid hypersecretory. Patients were interviewed with structured questionnaires and clinically-examined by a specialist. Patients eligible for treatment were selected and Mifago a water emulsifiable concentrate containing 50% MFGs was administered orally one time daily at dose of 3 ml per patient in the first week, one time every 48 hours in the second week and on time every 72 hours in the third week.
  • Example 29 Compositions of the present invention protecting broiler chicken from bacterial diseases and improving growth performance
  • T vaccinated, non-treated with traditional medicines, treated (Inviolability emulsion was supplemented through the drinking water at a dose of 1 mL/L at 1 , 6, 11 , 16, 21 , 26, 31 day of bird’s life.
  • the feeding program consisted of starter feed (crumbles) for the first 12 days with 23% crude protein and metabolizable energy (ME) of 3008 Kcal/kg diet, grower feed (pellets) (21% crude protein and 3080 Kcal/kg diet ME) up to 26th day, followed by finisher (pellets) feed till end of the experiment (35 days) with 19% crude protein and 3190 Kcal/kg diet ME. Feed and water were provided to all birds with free access. The chicks were received at 32°C on day 1 and then the temperature was decreased linearly by 2°C per week.
  • starter feed crumbles
  • ME metabolizable energy
  • FCR feed conversion ratio
  • the experimental groups resulted in the death of 26/300 birds (8.66%) in the Control group (C) that received treatment by traditional medicines. The death was reduced to 4.33% (13/300) in the Therapeutic Group (T) that received treatment by Inviolability emulsion 40% MFGs. All birds in the therapeutic group (T) appeared clinically normal, while the Control Group (C) showed clinical signs for infection with Mycoplasma gallisepticum, E. coli, Salmonella, Enteritis, fungal diseases and coccidiosis. The inventors found that the oral administration of the Inviolability emulsion containing 40% MFGs improved feed conversion ratio in the therapeutic group compared to the control group as summarized in Table 7.
  • Example 30 Compositions of the present invention protecting Laying hens from bacterial diseases and improve performance
  • This experiment was designed to evaluate the effect of Mifago water emulsifiable concentrate containing 50% MFGs supplementation to laying hens’ diets to protect the hens from bacterial diseases and improve the growth performance.
  • T vaccinated, non-treated with traditional medicines, treated with Mifago concentrate supplemented through the drinking water at a dose of 1 mL/L ever 5 days of bird life.
  • This Mifago water emulsifiable concentrate 50% MFGs treated group is the therapeutic group.
  • Example 31 Compositions of the present invention protecting laying hens from egg drop syndrome disease
  • This experiment was designed to evaluate the effect of Mifago concentrate containing 50% MFGs efficacy in protecting layering hens from EDS virus.
  • NC non-vaccinated EDS, non-treated MFGs (Negative control)
  • Example 32 Compositions of the present invention protecting broiler chickens from virus diseases
  • the objectives of this experiment was to evaluate Inviolability emulsion containing 40% MFGs for supplementation efficacy for protecting the broiler chickens from viral diseases.
  • NC non-vaccinated, non-treated with milk fat globules (negative control)
  • TTG non-vaccinated, treated (Inviolability emulsion was supplemented through the drinking water at a dose of 1 mL/L at 1 ,6,11 ,16,21 ,26,31 day of bird’s life. (Therapeutic group)
  • the feeding program consisted of starter feed (crumbles) for the first 12 days with 23% crude protein and metabolizable energy (ME) of 3008 Kcal/kg diet, grower feed (pellets) (21% crude protein and 3080 Kcal/kg diet ME) up to 26th day, followed by finisher (pellets) feed till end of the experiment (35 days) with 19% crude protein and 3190 Kcal/kg diet ME. Feed and water were provided to all birds with free access. The chicks were received at 32°C on day 1 and then the temperature was decreased linearly by 2°C per week. The experiment was repeated six times.
  • Inviolability emulsion containing 40% MFGs and Mifago concentrate containing 50% MFGs have protection effects for animals from bacterial, viral, parasites, fungal diseases and improve feed conversion ratio, egg shell and albumen quality.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant de 5 à 70 % en poids de globules de matière grasse du lait et au moins un acide gras en C4-C20 ajouté destiné à être utilisé dans le traitement de maladies bactériennes, virales, fongiques et parasitaires.
PCT/TR2021/050537 2021-06-04 2021-06-04 Compositions pharmaceutiques de globules de matière grasse du lait Ceased WO2022255959A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023104402A1 (fr) * 2021-12-09 2023-06-15 Frieslandcampina Nederland B.V. Fraction de lait qui inhibe une infection par la covid-19

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1319407A1 (fr) * 2001-12-14 2003-06-18 Montoie Import-Export S.A. Composition pharmaceutique pour le traitement topique des affections cutanées et des blessures cutanées
US20150216902A1 (en) * 2012-07-27 2015-08-06 Kassem Khal Fardoussi PHARMACEUTICAL COMPOSITION OF MILK FAT GLOBULES (MFGs) ZINC FREE
US20170312322A1 (en) * 2014-11-19 2017-11-02 San Diego State University (Sdsu) Foundation Antibacterial and protective formulations and methods for making and using them

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1319407A1 (fr) * 2001-12-14 2003-06-18 Montoie Import-Export S.A. Composition pharmaceutique pour le traitement topique des affections cutanées et des blessures cutanées
US20150216902A1 (en) * 2012-07-27 2015-08-06 Kassem Khal Fardoussi PHARMACEUTICAL COMPOSITION OF MILK FAT GLOBULES (MFGs) ZINC FREE
US20170312322A1 (en) * 2014-11-19 2017-11-02 San Diego State University (Sdsu) Foundation Antibacterial and protective formulations and methods for making and using them

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023104402A1 (fr) * 2021-12-09 2023-06-15 Frieslandcampina Nederland B.V. Fraction de lait qui inhibe une infection par la covid-19

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