CN116392507A - Fullerene-containing composition and application thereof - Google Patents
Fullerene-containing composition and application thereof Download PDFInfo
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- CN116392507A CN116392507A CN202211697457.3A CN202211697457A CN116392507A CN 116392507 A CN116392507 A CN 116392507A CN 202211697457 A CN202211697457 A CN 202211697457A CN 116392507 A CN116392507 A CN 116392507A
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- preservative
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Classifications
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- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/44—Elemental carbon, e.g. charcoal, carbon black
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/40—Cyclodextrins; Derivatives thereof
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- 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
- Y02A40/00—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production
- Y02A40/70—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production in livestock or poultry
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Abstract
The invention relates to application of a fullerene-containing composition in preparing a medicament for treating or preventing livestock and poultry animal diseases, wherein the livestock and poultry animals are selected from cattle, sheep, horses, chickens, ducks, geese, rabbits and pigs, and the diseases are selected from diarrhea and airway inflammation. The pharmaceutical preparation prepared from the composition has good prevention and treatment effects on inflammatory bowel disease diarrhea and acute diarrhea of livestock and poultry, is safe and reliable, and can replace antibiotic medicines.
Description
Technical Field
The present disclosure relates to the field of medicine, and in particular to the use of fullerene-containing compositions in the manufacture of a medicament for the treatment or prevention of animal diseases.
Background
Diarrhea in animals is one of the common diseases of farms, and especially in young calves/piglets. Symptoms are mainly fecal character change, dehydration and eating difficulty, the disease is developed all the year round, the disease is developed in winter and spring Ji Duo, the disease course is short, the death rate is high, and the serious loss of the breeding industry is easy to cause. The environmental conditions are changed, the organism of the newborn animals is dyspepsia, the feeding management is not in place, the environment of the colony house is poor, and the epidemic prevention and disinfection measures are not strict, so that the newborn animals can be seriously diarrhea and die. Bacteria and viruses can also cause severe diarrhea in animals, including Escherichia coli, clostridium perfringens type B (Clostridium perfringens), salmomlla (Salmonella), rotavirus (Rotavirus RV), bovine viral diarrhea (Bonvine viral diarrheavirus, BVDV), and other pathogens. Animal diarrhea is common throughout the world, and in recent years, animal diarrhea caused by bacterial and viral infections is most severe, and clinical and pathological changes are not significantly different after animals are infected by different pathogens.
According to the different etiology, the clinical symptoms are various, and the treatment principle is different. The conventional diarrhea treating method in clinical practice includes oral antidiarrheal, anti-inflammatory, spasmolytic, nourishing tonic, etc. and has the advantages of short-term curative effect, and different side effects and contraindications. The conventional means is antibiotic therapy, the short-term curative effect is still available, but the long-term use can generate drug resistance, so that the curative effect is poor, the malignant circulation with larger and larger doses is formed, and the antibiotics remained in the animal body can finally enter the human body along with the food chain, so that the potential hidden trouble of human health is necessarily caused.
Therefore, by combining the pathogenesis characteristics of animal diarrhea, the research and development of a drug which can replace antibiotics to treat diarrhea, has obvious effect, less contraindications and low side effects has important clinical significance.
Disclosure of Invention
In view of one of the above problems in the prior art, the present invention provides a composition containing fullerene, wherein the composition uses fullerene as an active ingredient, and the composition is combined with inert, nontoxic and pharmaceutically compatible auxiliary materials suitable for enema administration, so that the prepared pharmaceutical preparation can effectively treat and/or prevent diarrhea and airway inflammation of animals.
In order to achieve the above purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a composition comprising fullerenes and one or more excipients selected from the group consisting of fillers, adhesion agents, preservatives, stabilizers and suspending agents.
According to some embodiments of the invention, the fullerene content of the composition is 0.5% to 5%, for example 0.5%, 0.8%, 1%, 1.2%, 1.5%, 1.8%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5%, preferably 0.5% to 2% by weight.
According to some embodiments of the invention, the fullerene content of the composition is 0.5% to 2%, for example 0.55% to 1.95%, 0.6% to 1.9%, 0.65% to 1.85%, 0.7% to 1.8%, 0.75% to 1.75%, 0.8% to 1.7% or 0.85% to 1.65% by weight.
According to some embodiments of the invention, the fullerene is selected from C 60 And derivatives, C thereof 70 And one or more of its derivatives. In some preferred embodiments, the derivative is selected from one or more of an amino acid derivative, a hydroxyl derivative, a carboxyl derivative, an amino derivative. In some preferred embodiments, the amino acid is selected from one or more of alanine, glycine, serine, arginine, lysine, aspartic acid.
According to some embodiments of the invention, the composition comprises fullerenes, fillers, adhesion agents, preservatives, stabilizers, and suspending agents. Preferably, water is also included in the composition.
According to some embodiments of the invention, the composition comprises, in weight percent: 0.5 to 5 percent of fullerene, 15 to 32 percent of filler, 0.1 to 4 percent of adhesive, 0.01 to 10 percent of preservative, 0.1 to 1.5 percent of stabilizer and/or 0.1 to 2.5 percent of suspending agent and water.
According to some embodiments of the invention, the composition comprises, in weight percent: 0.5 to 2 percent of fullerene, 15 to 32 percent of filler, 0.1 to 4 percent of adhesive, 0.01 to 10 percent of preservative, 0.1 to 1.5 percent of stabilizer and/or 0.1 to 2.5 percent of suspending agent and water.
According to some embodiments of the invention, the composition consists of fullerenes, fillers, adhesion agents, preservatives, stabilizers, suspending agents and water.
According to some embodiments of the invention, the composition consists of, in weight percent: 0.5 to 5 percent of fullerene, 15 to 32 percent of filler, 0.1 to 4 percent of adhesive, 0.01 to 10 percent of preservative, 0.1 to 1.5 percent of stabilizer, 0.1 to 2.5 percent of suspending agent and the balance of water.
According to a preferred embodiment of the invention, the composition consists of the following components in weight percent: 0.5 to 2 percent of fullerene, 15 to 32 percent of filler, 0.1 to 4 percent of adhesive, 0.01 to 10 percent of preservative, 0.1 to 1.5 percent of stabilizer, 0.1 to 2.5 percent of suspending agent and the balance of water.
According to some embodiments of the invention, the filler is selected from one or more of methylcellulose, hypromellose, hydroxypropyl- β -cyclodextrin, polyvinylpyrrolidone, sodium hyaluronate, carboxymethylcellulose, or sodium carboxymethylcellulose.
According to a preferred embodiment of the invention, the filler is selected from one or more of hypromellose, hydroxypropyl-beta-cyclodextrin, polyvinylpyrrolidone, sodium hyaluronate. Preferably, the hydroxypropyl-beta-cyclodextrin has an average molecular weight of 10000-30000.
According to some embodiments of the invention, the adhesive is selected from one or more of sodium hyaluronate, carboxymethyl cellulose, or sodium carboxymethyl cellulose. Preferably, the adhesive is sodium hyaluronate.
According to some embodiments of the invention, the preservative is selected from one or more of glycerol, propylene glycol, methylparaben, sodium benzoate. Preferably, the preservative is glycerol.
According to some embodiments of the invention, the stabilizer is selected from nonionic surfactants.
According to a preferred embodiment of the present invention, the nonionic surfactant is tween 80.
According to some embodiments of the invention, the suspending agent is selected from one or more of sodium carboxymethyl cellulose, tragacanth, acacia, hydroxypropyl cellulose, povidone, carbomers.
According to a preferred embodiment of the invention, the suspending agent is sodium carboxymethyl cellulose. Preferably, the viscosity of the sodium carboxymethyl cellulose is 600-1000 mPa.s.
In a second aspect, the present invention provides a pharmaceutical preparation prepared from the composition according to the first aspect of the present invention.
According to some embodiments of the invention, the pharmaceutical is in the form of a suspension, tablet, powder, granule, capsule, solution, emulsion or suppository, preferably a suspension.
According to some embodiments of the invention, the preparation of the pharmaceutical formulation comprises the steps of:
mixing a raw material comprising fullerene and one or more selected from a filler, an adhesive, a preservative, a stabilizer and a suspending agent with water to obtain the pharmaceutical preparation.
Preferably, the pharmaceutical formulation is stored at a temperature of not more than 20 ℃.
In the invention, in the process of mixing the raw materials with water, each component is added, the raw materials are continuously stirred until dissolved, then the other component is added, and finally pure water is used for supplementing the weight.
Preferably, the preparation further comprises a step of pretreatment of the fullerene. The pretreatment is to establish an H bond reconstruction structure through high-speed shearing to form a nest structure, so that fullerene is distributed in the nest structure and is not easy to settle.
In a third aspect, the present invention provides the use of a fullerene-containing composition according to the first aspect for the manufacture of a medicament for the treatment or prophylaxis of a disease in a livestock animal selected from the group consisting of cattle, sheep, horses, chickens, ducks, geese, rabbits and pigs, said disease being selected from the group consisting of diarrhea and respiratory inflammation.
According to some embodiments of the invention, the fullerene content of the composition is 0.5% -5%, for example 0.5%, 0.8%, 1%, 1.2%, 1.5%, 1.8%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% by weight.
According to some embodiments of the invention, the fullerene is selected from C 60 And derivatives, C thereof 70 And one or more of its derivatives. Preferably, the derivative is selected from one or more of amino acid derivatives, hydroxyl derivatives, carboxyl derivatives and amino derivatives. More preferably, the amino acid is selected from one or more of alanine, glycine, serine, arginine, lysine, aspartic acid.
According to some embodiments of the invention, the composition further comprises one or more of a filler, an adhesive, a preservative, a stabilizer, and a suspending agent. Preferably, the composition further comprises fillers, adhesion agents, preservatives, stabilizers and suspending agents.
According to some embodiments of the invention, the composition comprises, in weight percent: 0.5 to 5 percent of fullerene, 15 to 32 percent of filler, 0.1 to 4 percent of adhesive, 0.01 to 10 percent of preservative, 0.1 to 1.5 percent of stabilizer and/or 0.1 to 2.5 percent of suspending agent and water.
Preferably, the composition consists of the following components in weight percent: 0.5 to 5 percent of fullerene, 15 to 32 percent of filler, 0.1 to 4 percent of adhesive, 0.01 to 10 percent of preservative, 0.1 to 1.5 percent of stabilizer, 0.1 to 2.5 percent of suspending agent and the balance of water.
According to some embodiments of the invention, the composition comprises, in weight percent: 0.5 to 2 percent of fullerene, 15 to 32 percent of filler, 0.1 to 4 percent of adhesive, 0.01 to 10 percent of preservative, 0.1 to 1.5 percent of stabilizer and/or 0.1 to 2.5 percent of suspending agent and water.
Preferably, the composition consists of the following components in weight percent: 0.5 to 2 percent of fullerene, 15 to 32 percent of filler, 0.1 to 4 percent of adhesive, 0.01 to 10 percent of preservative, 0.1 to 1.5 percent of stabilizer, 0.1 to 2.5 percent of suspending agent and the balance of water.
According to some embodiments of the invention, the filler is selected from one or more of methylcellulose, hypromellose, hydroxypropyl- β -cyclodextrin, polyvinylpyrrolidone, carboxymethyl cellulose or sodium carboxymethyl cellulose, preferably one or more of hypromellose, hydroxypropyl- β -cyclodextrin, polyvinylpyrrolidone. Preferably, the hydroxypropyl-beta-cyclodextrin has an average molecular weight of 10000-30000.
According to some embodiments of the invention, the adhesive is selected from one or more of sodium hyaluronate, carboxymethyl cellulose, or sodium carboxymethyl cellulose. Preferably, the adhesive is sodium hyaluronate.
According to some embodiments of the invention, the preservative is selected from one or more of glycerol, propylene glycol, methylparaben, sodium benzoate. Preferably, the preservative is glycerol.
According to some embodiments of the invention, the stabilizer is selected from nonionic surfactants. Preferably, the nonionic surfactant is tween 80.
According to some embodiments of the invention, the suspending agent is selected from one or more of sodium carboxymethyl cellulose, tragacanth, acacia, hydroxypropyl cellulose, povidone, carbomers. Preferably, the suspending agent is sodium carboxymethyl cellulose. Preferably, the viscosity of the sodium carboxymethyl cellulose is 600-1000 mPa.s.
According to some embodiments of the invention, the pharmaceutical is in the form of a suspension, tablet, powder, granule, capsule, solution, emulsion or suppository, preferably a suspension.
According to some embodiments of the invention, the preparation of the medicament comprises the steps of:
mixing a raw material comprising fullerene and one or more selected from a filler, an adhesive, a preservative, a stabilizer and a suspending agent with water to obtain the pharmaceutical preparation.
According to a preferred embodiment of the invention, the livestock and poultry animal is selected from cattle and sheep.
According to a preferred embodiment of the invention, the diarrhea is an inflammatory bowel disease type diarrhea.
According to a preferred embodiment of the present invention, the diarrhea is acute diarrhea caused by bacteria or viruses, including but not limited to diarrhea caused by escherichia coli, clostridium perfringens type B, salmonella, rotavirus or bovine viral diarrhea virus.
According to some embodiments of the invention, the diarrhea is acute diarrhea caused by gastrointestinal dysfunction.
According to a preferred embodiment of the invention, the respiratory tract inflammation comprises upper respiratory tract inflammation and pneumonia.
Compared with the prior art, the invention has the beneficial technical effects that:
1. the fullerene-containing pharmaceutical preparation provided by the invention has the advantages of quick response, strong effect, obvious and durable curative effect, no irritation, safety and reliability in the aspect of preventing and treating animal diarrhea and respiratory tract inflammation, can overcome the defects that the medicine damages intestinal health and generates medicine residues in intestinal tracts, solves the problem of drug resistance caused by excessive abuse of antibiotics for preventing and treating animal diarrhea, and can replace antibiotics.
2. The fullerene is used for preparing the medicine for treating and/or preventing the livestock and poultry diseases, and the H bond reconstruction structure is established through high-speed shearing to form the nest structure, so that the fullerene is distributed in the nest structure and is not easy to settle, the particle size of the fullerene is reduced, the water solubility of the fullerene and the quality stability of a pharmaceutical preparation are obviously improved, and the pharmaceutical application value of the fullerene is expanded.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. The specific embodiments described herein are for purposes of illustration only and are not to be construed as limiting the invention in any way. In addition, in the following description, descriptions of well-known structures and techniques are omitted so as not to unnecessarily obscure the concepts of the present disclosure.
The term "amino acid derivative, hydroxy derivative, carboxyl derivative, amino derivative" as used herein refers to a fullerene modified with amino acid or hydroxy, carboxyl and amino functional groups. The modification method can be conventional modification methods disclosed in the prior art.
The term "treatment" as used herein refers to obtaining a desired pharmacological and/or physiological effect. Comprising the following steps: inhibiting the disease, i.e., preventing an increase in the severity or extent of the disease; alternatively, the disease is alleviated, even if the disease is partially or completely ameliorated; alternatively, the recurrence of the disease is prevented, i.e., the recovery of the disease to an active state after a previous successful treatment of the disease symptoms or treatment of the disease.
The term "inflammatory bowel disease" as used herein refers to chronic digestive system diseases, including a variety of chronic inflammatory diseases, such as crohn's disease, gastroduodenal crohn's disease, crohn's (granulomatous) colitis, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, behcet's disease, microscopic colitis, ulcerative proctitis, proctositis, jejunum ileitis, left-hand proctitis, holotontitis, ileitis and indeterminate colitis.
As used herein, the term "Escherichia coli" is a normal resident bacterium in the intestinal tract of humans and animals, also known as E.coli, and is a gram-negative bacillus-free bacterium that is an aerobic or facultative anaerobic bacterium capable of fermenting lactose, acid and gas. Diarrhea-causing escherichia coli is classified into 5 species of enterotoxigenic escherichia coli, enteroinvasive escherichia coli, enteropathogenic escherichia coli, enteroadhesive escherichia coli, and enterohemorrhagic escherichia coli, according to the pathogenicity.
The term "clostridium perfringens type B" as used herein is a gram positive, rod-shaped, anaerobic, sporulation pathogenic bacterium of the genus clostridium, capable of causing lamb dysentery and necrotic enteritis in lambs, calves, piglets, rabbits, chickens, etc.
The term "Salmonella" as used herein belongs to the Enterobacteriaceae family, gram-negative Enterobacter, and can cause food poisoning.
The term "rotavirus" as used herein is a double stranded ribonucleic acid virus belonging to the reoviridae family, which primarily infects small intestine epithelial cells, thereby causing cell damage and causing diarrhea.
The term "bovine viral diarrhea virus" as used herein is the pathogen that causes an infectious disease in cattle characterized by inflammation, erosion, necrosis and diarrhea of the mucous membrane.
The term "upper respiratory tract inflammation" as used herein refers to inflammation of the nose, throat, and larynx, and is divided into infectious inflammation and non-infectious inflammation.
The filler used in the following examples was hydroxypropyl-beta-cyclodextrin having an average molecular weight of 15000; the suspending agent is sodium carboxymethyl cellulose, and the viscosity is 800 mPa.s; the stabilizer is Tween 80; the adhesive is sodium hyaluronate; the preservative is glycerol.
Example 1: fullerene suspension
The embodiment provides a fullerene suspension, which comprises the following components in percentage by mass:
example 2: fullerene suspension
The embodiment provides a fullerene suspension, which comprises the following components in percentage by mass:
the preparation method of the fullerene suspension in the above example is as follows:
1. pretreatment of fullerene: and (3) processing the bulk drug fullerene by adopting a high-speed shearing method, controlling the feeding pressure to be 0.25-0.45MPa by using an instrument model SIM-50, and shearing once to obtain the final bulk drug fullerene powder.
2. Preparing a suspension: according to the prescription, adding the components with corresponding amounts into pure water, wherein the addition sequence is preservative, sodium carboxymethyl cellulose, sodium hyaluronate, tween 80, adhesive and pretreated fullerene, each component is required to be continuously stirred, and after being uniformly mixed, the other component is added, and a homogenization method is adopted, wherein the homogenization speed is 20000rpm, and the homogenization time is 10min, so that the fullerene suspension is obtained.
Experimental example 1: fullerene suspension for treating chronic diarrhea of mice caused by senna leaves
The test verifies the effect of the fullerene suspension on preventing and treating chronic diarrhea by constructing a senna leaf induced mouse diarrhea model, observing small intestine peristalsis, small intestine effusion, mice disease activity (scoring on rat weight change, diarrhea condition and the like) and small intestine histopathology, and the specific test process is as follows:
(1) Establishment of diarrhea mouse model
Weighing 300g of folium sennae, adding 3000mL of water, heating and boiling for 30min, cooling, filtering, concentrating the filtrate to 300mL to obtain 1g/mL of folium sennae extract, and storing in a refrigerator at 4 ℃ for standby. Heat to 25 ℃ before use.
60 clean-grade Kunming mice were randomly divided into diarrhea model control group, positive control group, fullerene suspension high dose group, medium dose group, low dose group and blank control group, each group comprising 10 mice. Diarrhea model control group, positive control group, fullerene suspension high dose group, medium dose group and low dose group, and the mice were fasted for 12h before molding, and were free to drink water. The senna leaf extract was infused once daily at 0.5mL/20g, and the empty group was infused with the same amount of distilled water for 5 days.
(2) Sampling and processing
Fullerene suspensions were high, medium and low dose group lavage fullerene suspensions, and the administration doses were 71, 143 and 260mg/kg of the fullerene suspension of example 1, respectively.
The administration amount of berberine hydrochloride in the positive control group is 40mg/kg.
The diarrhea model control group is filled with distilled water with the dosage of 40mg/kg.
Mice were kept in a single cage, filter paper was laid under the cage, and total stool number, loose stool number and loose stool level were recorded. The filter paper was changed every 1 hour, and observation was continued for 5 hours. After the experiment is finished, the cervical dislocation method of the mice is used for killing, the abdominal cavity is opened, fresh small intestines at the position of 2-4 cm close to the duodenal end of the jejunum are taken, intestinal cavity contents are cleaned in normal saline and are placed in 10% formaldehyde solution for fixation, and the method is used for analyzing the pathological morphology of the small intestines.
Clean-grade Kunming male mice were taken at a weight of 20.+ -.3 g for 30. Randomly dividing into a blank control group, a positive control group, a fullerene suspension high-dose group, a fullerene suspension medium-dose group and a fullerene suspension low-dose group, wherein six fullerene suspension medium-dose groups are used in each group. Fasted for 20 hours before the experiment, and the water is freely drunk. The positive control group, the fullerene suspension high dose group, the medium dose group and the low dose group are subjected to gastric lavage administration according to the doses, and the empty group is subjected to abdominal lavage with distilled water in the same amount as the other groups. After 40min of gastric lavage, 0.2ml of 5% carbon powder suspended in 0.5% CMC-Na was administered. After 30min, the mice were sacrificed, the small intestine was removed, and the total length of the small intestine and the advancing distance of the carbon ink were measured.
Male rats with body weight (200+ -20 g) were selected, fasted for 20h, and randomly divided into 5 groups after free drinking, which were model control group, positive control group, fullerene suspension high dose, medium dose, and low dose groups, respectively. Physiological saline (1 mL), castor oil (1 mL) and loperamide (10 mg/kg) were administered separately, and the formulations were as described above. After 1h, each group of rats was fed 1m L castor oil. After 3h, the intestines were removed, weighed by ligation at the pyloric sphincter and the ileocecal junction, respectively, and the intestinal contents were collected into a 5mL graduated cylinder for measuring volume. The intestines were reweighed and the small intestine content weight calculated.
(3) Experimental results
The data obtained were statistically processed and each dose group was represented by mean ± standard deviation, and the inter-group significance test was determined by t-test. The calculation method of the P value is as follows: comparison of the test drug group with the diarrhea model group resulted in a very significant difference (< 0.01 for P and a significant difference for P < 0.05).
(1) Influence of senna-leaf-induced diarrhea model in mice
Mice with diarrhea model were perfused with senna leaf extract once daily for five consecutive days. By the fifth day, diarrhea was significantly aggravated, urine was yellow, mice appeared lassitude, listlessness, significantly reduced activity, and weight loss. The change in body weight is shown in Table 1.
TABLE 1 weight changes in mice before and after diarrhea modeling and before and after drug administration treatment (unit: g)
Note that: the level values of the factors are recorded as follows: mean ± variance; comparison to the blank: * Represents P <0.05, significant difference; * P <0.01, very significant difference.
And after the senna leaves of 0.5mL are irrigated to the stomach of the mice on the fifth day of establishing the diarrhea model for 30min, the low dose group, the medium dose group, the high dose group, the positive control group and the model control group of the fullerene suspension are respectively irrigated to the stomach for administration. The mice of each group were observed for changes in mental state, behavior and bowel movements. The total stool number, the stool dilution number and the stool dilution level of the mice per 1 hour were recorded, and continuous observation was performed for 4 hours. Diarrhea evaluation indexes such as loose stool grade, defecation inhibition rate, diarrhea inhibition rate, loose stool rate, diarrhea index and the like are calculated, and the results are shown in table 2.
Thin stool grade: to indicate the degree of urination of each animal, the size of the area diameter of the thin stool-contaminated paper mat was classified into four stages. Stage 1: diameter <1cm;2 stages: 1cm < diameter <2cm;3 stages: 2cm < diameter <3cm;4 stages: 3cm < diameter. The stain is a diameter of a more regular circle, the longest length of the stain is measured by an irregular shape, and the diameter of the approximate circle is calculated by the two numbers and divided. The calculation formula is as follows: rare earth level = the sum of rare earth levels/rare earth times.
Defecation inhibition rate: an index of reducing the number of bowel movements was suppressed, and the reduction in the amount of bowel movements was observed by the bowel movement suppression ratio.
The percent of inhibition of defecation = [ average number of defecations in model group-average number of defecations in dosing group ]/average number of defecations in model group ].
Diarrhea inhibition rate: an index for inhibiting the reduction of the number of loose stools, a reduction in the number of loose stools was observed by the diarrhea inhibition rate, and an important index for treating diarrhea was observed.
The diarrhea inhibition ratio = [ average of the loose stool in the model group-average of the loose stool in the administration group)/average of the loose stool in the model group ].
TABLE 2 Effect of Fullerene suspension on stool in senna laxative mice
Note that: the level values of the factors are recorded as follows: mean ± variance; comparison to model set: * Represents P <0.05, significant difference; * P <0.01, very significant difference.
Diarrhea rate: is the proportion of diarrhea mice in the total mice.
Thin feces rate: ratio of the number of bowel movements per mouse to the total number of bowel movements. The feces were discharged once per granule or per stack on the filter paper.
Dilute rate= (number of loose stools/total number of loose stools) ×100%.
Diarrhea index: is the product of the loose stool rate and the loose stool progression.
Diarrhea index = runny bowel rate x runny bowel progression.
The diarrhea index per hour was calculated separately and the results are shown in table 3.
At the first 1h, the diarrhea rate reached 89% in the model group, and the diarrhea index was 0.58±0.33. While the diarrhea rate was less than 89% for the positive and fullerene suspension groups, as well as the diarrhea index was much lower than for the model group. The fullerene suspension has a certain diarrhea inhibiting effect. By 2h and 3h, the diarrhea index was significantly lower than in the model group, although the diarrhea rate of the positive group and the fullerene suspension was 100% as in the model group. By 4h, the diarrhea rate was 100% for the model group, but both the positive group and the fullerene suspension group were less than 89%. The diarrhea index was also lower compared to the model group (1.19.+ -. 0.24), both below 0.88.+ -. 0.47. The diarrhea index was significantly reduced in the positive group compared to the model group. Fullerene suspension has a certain effect of treating diarrhea.
TABLE 3 Effect of Fullerene suspensions on diarrhea Rate and diarrhea index in mice
Note that: the level values of the factors are recorded as follows: mean ± variance; comparison to model set: * Represents P <0.05, significant difference; * P <0.01, very significant difference.
(2) Fullerene suspension to small intestine histopathological results
The total length of the small intestine is from the pylorus to the ileocecum, and the distance from the pylorus to the front end of the carbon end is the carbon end propulsion distance.
The average total length of the small intestine and the average carbon powder stacking distance of each group of mice were calculated. The small intestine peristalsis index and small intestine propulsion inhibition rate were calculated according to the following formulas. The results are shown in Table 4.
Small intestinal motility index% = (carbon ink push distance/small intestinal length) ×100%.
Small intestine propulsion inhibition% = (carbon ink movement distance of blank control group-carbon ink movement distance of test drug group)/carbon ink movement distance of blank control group × 100%.
TABLE 4 Effect of Fullerene suspensions on small intestine peristalsis
Note that: the level values of the factors are recorded as follows: mean ± variance; comparison to model set: * Represents P <0.05, significant difference; * P <0.01, very significant difference.
(3) Effect of fullerene suspension on small intestine effusion
The small intestine hydrops inhibition rate is the small intestine hydrops weight difference between the blank control group and the tested drug group divided by the small intestine hydrops weight of the blank control group. The results are shown in Table 5.
Small intestine hydrops inhibition ratio = [ model group small intestine hydrops weight-test drug group small intestine hydrops weight ]/model group small intestine hydrops weight ] ×100%.
TABLE 5 influence of Fullerene suspensions on the volume of rat intestinal effusion
| Grouping | volume/mL | Content weight/g | Hydrops inhibition/% |
| Model control group | 3.25±0.28 | 3.18±0.27 | —— |
| Positive control group | 2.39±0.56** | 2.34±0.48** | 26.41 |
| Fullerene low dose | 2.53±0.30** | 2.68±0.20** | 15.72 |
| Dosage in fullerenes | 2.51±0.19** | 2.50±0.36** | 21.38 |
| High dosage of fullerenes | 2.26±0.28** | 2.39±0.37** | 24.84 |
Note that: the level values of the factors are recorded as follows: mean ± variance; p <0.01 represents a very significant difference compared to the model group,
* P <0.05 significance difference.
From the results, the fullerene suspension has good control effect on chronic diarrhea of mice, so that the fullerene can be used as an active component in chronic diarrhea medicines.
Test example 2: fullerene suspension for treating acute diarrhea of calf
The method comprises the steps of selecting acute diarrhea calves of a farm caused by escherichia coli infection, verifying the prevention and treatment effect of fullerene suspension on the acute diarrhea through the activity degree and symptom change of the calves, and specifically testing the method as follows:
(1) Selection of diarrhea calves
5 heads of the sick calves in Guanzhong Jia, 5 heads of the sick calves in Keqi forest land and 6 heads of the sick calves in Keqi mountain area;
fasted for 12 hours before treatment, and the water is freely drunk.
(2) Experimental results
The fullerene suspension of example 1 was administered at a dose of 1g/kg twice daily, and continued until the symptoms were significantly improved. Changes in calf symptoms were observed as shown in Table 6.
TABLE 6 therapeutic Effect of Fullerene suspensions on calf diarrhea
(3) Discussion of the invention
The results show that the fullerene suspension has remarkable treatment effect on acute diarrhea of calves caused by bacterial infection.
Test example 3: fullerene suspension for treating acute diarrhea of lambs
The diarrhea lamb in the farm is selected, the prevention and treatment effect of the fullerene suspension on acute diarrhea is verified through the activity degree and symptom change of the disease of the lamb, and the specific test process is as follows:
(1) Selection of diarrhea lambs
Gangqi Gangan check lamb 12 heads: diarrhea caused by cold in the shade due to the humid environment of the sheepfold;
lamb 3 heads of Raymond animal husbandry: diarrhea caused by overfeeding milk or weak intestinal function or catching cold;
fasted for 12 hours before treatment, and the water is freely drunk.
(2) Experimental results
The fullerene suspension of example 1 was administered at a dose (4 to 6) g/kg twice daily, and continued until the symptoms were significantly improved. The observed lamb symptom changes are shown in Table 7.
TABLE 7 therapeutic Effect of Fullerene suspensions on lamb diarrhea
(3) Discussion of the invention
The results show that the fullerene suspension has remarkable treatment effect on acute diarrhea of lambs caused by gastrointestinal dysfunction or catching cold and the like.
Test example 4: therapeutic effect of fullerene suspension on calf respiratory tract inflammation
Selecting a disease calf of a farm, verifying the control effect of the fullerene suspension on the respiratory tract inflammation through the disease activity and symptom change of the calf, wherein the specific test process is as follows:
(1) Selection of diseased calves
10 calves (15-40 days) are fasted for 12 hours before treatment and are free to drink water.
(2) Experimental results
The fullerene suspension of example 1 was administered at a dose (0.5-1) g/kg 2-3 times daily, and continued until symptoms were significantly improved. Changes in calf symptoms were observed as shown in Table 8.
TABLE 8 therapeutic Effect of Fullerene suspensions on calf respiratory inflammation
(3) Discussion of the invention
The results show that the fullerene suspension has remarkable treatment effect on inflammation and pneumonia caused by calf respiratory tract infection.
In conclusion, the fullerene suspension has remarkable curative effects on both mouse inflammatory diarrhea and calf and lamb diarrhea and respiratory tract inflammation.
The technical scheme of the invention is not limited to the specific embodiment, and all technical modifications made according to the technical scheme of the invention fall within the protection scope of the invention.
Claims (10)
1. Use of a fullerene-containing composition for the manufacture of a medicament for the treatment or prophylaxis of a disease in a livestock animal selected from the group consisting of cattle, sheep, horses, chickens, ducks, geese, rabbits and pigs, said disease being selected from the group consisting of diarrhea and respiratory inflammation.
2. Use according to claim 1, characterized in that the fullerene content of the composition is 0.5% to 5%, preferably 0.5% to 2% by weight;
and/or the enrichmentThe luxene is selected from C 60 And derivatives, C thereof 70 And one or more of its derivatives, preferably the derivatives are selected from one or more of amino acid derivatives, hydroxy derivatives, carboxy derivatives, amino derivatives, more preferably the amino acids are selected from one or more of alanine, glycine, serine, arginine, lysine, aspartic acid.
3. The use according to claim 1 or 2, wherein the composition further comprises one or more of a filler, an adhesive, a preservative, a stabilizer and a suspending agent, preferably a filler, an adhesive, a preservative, a stabilizer and a suspending agent.
4. Use according to any one of claims 1 to 3, characterized in that the composition comprises, in weight percent: 0.5 to 2 percent of fullerene, 15 to 32 percent of filler, 0.1 to 4 percent of adhesive, 0.01 to 10 percent of preservative, 0.1 to 1.5 percent of stabilizer and/or 0.1 to 2.5 percent of suspending agent and water;
preferably, the composition consists of the following components in weight percent: 0.5 to 2 percent of fullerene, 15 to 32 percent of filler, 0.1 to 4 percent of adhesive, 0.01 to 10 percent of preservative, 0.1 to 1.5 percent of stabilizer, 0.1 to 2.5 percent of suspending agent and the balance of water.
5. The use according to any one of claims 1 to 4, wherein the filler is selected from one or more of methylcellulose, hypromellose, hydroxypropyl- β -cyclodextrin, polyvinylpyrrolidone, carboxymethyl cellulose or sodium carboxymethyl cellulose, preferably one or more of hypromellose, hydroxypropyl- β -cyclodextrin, polyvinylpyrrolidone;
and/or the adhesive is selected from one or more of sodium hyaluronate, carboxymethyl cellulose or sodium carboxymethyl cellulose, preferably the adhesive is sodium hyaluronate.
6. The use according to any one of claims 1 to 5, wherein the preservative is selected from one or more of glycerol, propylene glycol, methylparaben, sodium benzoate, preferably the preservative is glycerol;
and/or the stabilizer is selected from nonionic surfactants, preferably the nonionic surfactant is tween 80;
and/or the suspending agent is selected from one or more of sodium carboxymethyl cellulose, tragacanth, acacia, hydroxypropyl cellulose, povidone, carbomer, preferably the suspending agent is sodium carboxymethyl cellulose.
7. The use according to any one of claims 1 to 6, wherein the medicament is in the form of a suspension, tablet, powder, granule, capsule, solution, emulsion or suppository, preferably a suspension.
8. The use according to any one of claims 1 to 7, wherein the preparation of the medicament comprises the steps of:
mixing a raw material comprising fullerene and one or more selected from a filler, an adhesive, a preservative, a stabilizer and a suspending agent with water to obtain the pharmaceutical preparation.
9. The use according to claims 1-8, wherein the animal is selected from cattle and sheep.
10. The use according to any one of claims 1 to 9, wherein the diarrhea is selected from diarrhea caused by inflammatory bowel disease, acute diarrhea caused by bacteria or viruses, or acute diarrhea caused by gastrointestinal dysfunction; and/or the respiratory tract inflammation includes upper respiratory tract inflammation and pneumonia.
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