CN107625810B - Compound macleaya cordata composition preparation for treating animal diarrhea diseases - Google Patents
Compound macleaya cordata composition preparation for treating animal diarrhea diseases Download PDFInfo
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Abstract
The invention discloses a compound macleaya cordata composition preparation for treating animal diarrhea diseases and application thereof, belongs to the field of veterinary drugs, and particularly relates to a pharmaceutical composition containing macleaya cordata total alkaloid extract and quinolone compounds, wherein the active ingredients of the pharmaceutical composition comprise the following components in parts by mass: 1-1,000 parts of macleaya cordata total alkaloid extract and 1-2,000 parts of quinolone compounds. The pharmaceutical dosage form can be one or more of liquid preparations such as injection, syrup, oral solution, etc., solid preparations such as common tablet, dispersible tablet, sustained release tablet, capsule, granule, powder, etc., and semi-solid preparations such as ointment, paste, gel, etc. The compound macleaya cordata composition preparation has obvious synergistic effect on the aspect of treating animal diarrhea diseases, can effectively control the infection of the diseases, has obvious treatment effect, stable quality, high safety and simple preparation method, and is suitable for industrial production.
Description
Technical Field
The invention relates to a veterinary compound macleaya cordata composition preparation for treating animal diarrhea diseases and application thereof. Belongs to the field of veterinary drugs.
Background
The national people are the basis and the people eat the food as the day, and at present, due to the continuous occurrence and variation of various animal pathogens, the development of the livestock and poultry industry in China causes serious harm and has potential influence on the life and health of the national people to a certain extent. Various pathogens such as bacteria can cause diarrhea diseases of animals, the main target organs of the infection of the diseases are digestive tracts and gastrointestinal tracts, the nutrition absorption of the animals is caused, the intestinal contents are increased, clinical symptoms such as vomit, diarrhea and dehydration appear, and the death rate of young animals is extremely high.
The yellow-white scour of piglets is a common disease and frequently encountered disease widely existing in pig farms, and an acute digestive tract infectious disease of newborn piglets is caused by pathogenic escherichia coli, so that a large amount of medicament expenses are brought to the breeding industry, the growth and development of the piglets are directly influenced, if the piglets are not treated in time, the piglets are easily killed, and huge economic losses are brought to the pig farms and farmers.
Papaveraceae plant called as "Lapachyrhizus", Horn tube, Horn bamboo, mountain fire tube, cavitate grass, Horn rod, tuba tube, Horn tree, Horn grass, Macleaya cordata contains sanguinarine, chelerythrine, protopine, alpha-allocryptopine, macleaya cordata alkali, oxerucidine, macleaya cordata alcaline, dehydrocheilanthifoline, etc. The macleaya cordata injection recorded in the veterinary drug quality standard of Ministry of agriculture is a sterilized aqueous solution of alkaloid sulfate prepared by extracting and separating macleaya cordata fruits, has the functions of resisting bacteria and diminishing inflammation, can be used for treating animal diarrhea diseases and mainly treats yellow and white scour of piglets.
Patent CN101347512A discloses a macleaya cordata injection and its preparation method, the injection is composed of the following raw materials in parts by weight: 30-40 parts of macleaya cordata extract, 0-30 parts of cosolvent, 0.5-5 parts of analgesic and 25-70 parts of dispersion medium.
Patent CN103919862A discloses a microemulsion injection containing macleaya cordata extract and a preparation method thereof, wherein the microemulsion injection comprises the following components: macleaya cordata extract, diacetin, polysorbate-80, polyethylene glycol 600, glycerol, vitamin E and water for injection.
Patent CN105267309A discloses an oral liquid medicine for treating canine parvovirus disease and a preparation method thereof, wherein the main component of the medicine is a plurality of isoquinoline alkaloids of traditional Chinese medicine macleaya cordata.
The effective components of the three patents are only single macleaya cordata, and the macleaya cordata only has an antibacterial effect on certain bacterial fungi and has a narrow antibacterial spectrum, so the three preparations in the three patents have weak effects.
Patent CN1682863A discloses a veterinary macleaya cordata injection, which is composed of 60% of macleaya cordata and 40% of common andrographis herb, and is a pure natural green Chinese herbal medicine compound preparation for veterinary use.
Patent CN103623078A discloses a powder of Macleaya cordata and Coptis chinensis, which comprises raw materials of 8-12 parts of Macleaya cordata, 4-6 parts of Coptis chinensis and 4-6 parts of licorice, and is used for treating infectious gastroenteritis of livestock and the like.
Patent CN103655881A discloses a veterinary drug for treating livestock dysentery, which comprises the following raw material medicines in parts by weight: 50-60 parts of macleaya cordata, 60-80 parts of polygonum hydropiper, 40-50 parts of common andrographis herb, 40-50 parts of heartleaf houttuynia herb, 5-10 parts of radix scutellariae, 10-20 parts of honeysuckle, 10-20 parts of fructus forsythiae, 15-30 parts of purslane, 15-20 parts of Chinese pulsatilla root, 20-30 parts of coptis chinensis, 20-30 parts of cortex fraxini, 15-25 parts of costustoot, 5-10 parts of liquorice and 10-20 parts of hydroxypropyl methyl cellulose.
The three patents are all that the macleaya cordata and other Chinese herbal medicine components are combined together, the components are mutually synergistic, but according to the records of data of medicinal plant science, raw pharmacy and the like, the antibacterial spectrums of the andrographis paniculata and the macleaya cordata are similar, and the antibacterial spectrums of the coptis chinensis and the liquorice are narrow, so the combined effect of the medicines in the patent CN1682863A and the patent CN103623078A is unsatisfactory; the prescription of patent CN103655881A is composed of a plurality of Chinese herbal medicines, although the antibacterial spectrum is increased, the components are various, the preparation process is complex, and the compatibility risk is increased.
The prescription of the compound macleaya cordata preparation of the invention comprises quinolone compounds. The quinolone compounds are also called pyridone acids or pyridone acids, and are artificially synthesized antibacterial drugs containing 4-quinolone basic structures. Quinolones target bacterial deoxyribonucleic acid (DNA), interfere with DNA gyrase, further cause irreversible damage to bacterial DNA, and achieve antibacterial effects. Quinolone antibiotics are a class of drugs commonly used by humans and animals. The antibacterial agent has the characteristics of wide antibacterial spectrum, strong antibacterial activity, no cross drug resistance with other antibacterial drugs, small toxic and side effects and the like, and is widely applied to livestock breeding, aquatic product breeding and other breeding industries, including disease control in breeding of chickens, ducks, geese, pigs, cattle, sheep, fish, shrimps, crabs and the like.
According to the latest data of the information base of the State food and drug administration, the number of quinolone drugs for human beings who have been on the market and are clinically used in China is up to 22, the total number of the national drug production documents is 4042, and the number of the imported drug registration documents is 93.
The quinolone medicines special for animals comprise ebafloxacin, sarafloxacin, enrofloxacin, marbofloxacin, orbifloxacin, danofloxacin and the like. Heretofore, there have been marketed quinolone drug products for veterinary use useful for antibacterial use, such as ebafloxacin (trade name: Ibalfingel, Intervet), orbifloxacin (trade name: Victas S MT, Dainippon), marbofloxacin (trade name: austrazon, Vetoquinol), etc., but there is a need to evaluate the safety of quinolone drugs specific to animals for human beings. When people eat animal food, Chinese patent medicine health food and the like containing low-concentration quinolone medicines for a long time, the transfer of drug resistance is easily induced, so that the clinical curative effect of the medicines is influenced. In order to avoid the harm to human body caused by eating animal-derived food containing quinolone medicine residue. The food additive expert council and the European Union of the food and agriculture organization/world health organization of the United nations have established the maximum residual limits of various quinolone drugs in animal tissues. In 2002, China stipulates that the maximum residual limit of 7 quinolone drugs such as ciprofloxacin, mononoxacin, enrofloxacin, sarafloxacin, difloxacin, oxolinic acid, flumequine and the like in animal muscle tissues is 10-500 mu g/kg.
The total alkaloid extract of the macleaya cordata and the quinolone drugs are combined, so that the antibacterial spectrum can be expanded, and a better treatment effect can be obtained; meanwhile, after the two medicines are used together, the dosage of the quinolone medicines can be reduced, the residual quantity of the quinolone medicines in animal muscle tissues can be controlled, and the quinolone medicines are safer and healthier.
Based on the defects of the prior art, the invention aims to provide a compound macleaya cordata composition preparation which has wide antimicrobial spectrum and small side effect and can effectively treat animal diarrheal diseases.
Disclosure of Invention
The invention relates to a compound macleaya cordata composition preparation based on the defects of single antibacterial spectrum and limited treatment effect of macleaya cordata in treating animal diarrhea diseases including piglet yellow-white dysentery.
The invention aims to solve the first technical problem of providing a compound macleaya cordata composition preparation for treating animal diarrhea diseases.
The second technical problem to be solved by the invention is to provide a drug administration dosage form of the compound macleaya cordata composition preparation for treating animal diarrhea diseases.
The third technical problem to be solved by the invention is to provide the application of the compound macleaya cordata composition preparation for treating animal diarrhea diseases.
In order to solve the first technical problem, the inventor finds that the antibacterial spectrum can be expanded and better treatment effect can be obtained by combining the traditional Chinese medicine component macleaya cordata total alkaloid extract and quinolone medicines, particularly specific quinolone medicines; meanwhile, after the two medicines are used together, the dosage of the quinolone medicines can be reduced, the residual quantity of the quinolone medicines in animal muscle tissues can be controlled, and the quinolone medicines are safer and healthier.
The technical scheme provided by the invention is as follows:
the invention provides a compound macleaya cordata composition preparation for treating animal diarrhea diseases, which is characterized in that the active ingredients of the pharmaceutical composition consist of the following components in parts by mass: 1-1,000 parts of macleaya cordata total alkaloid extract, 1-2,000 parts of quinolone compounds and other necessary auxiliary materials.
The invention provides a compound macleaya cordata composition preparation for treating animal diarrhea diseases, which is characterized in that the active ingredients of the pharmaceutical composition consist of the following components in parts by mass: macleaya cordata total alkaloid extract: the carbostyril compound is 1:200-100:1, and other necessary auxiliary materials are added.
The macleaya cordata total alkaloid extract is total alkaloid in the macleaya cordata fruits, and mainly comprises sanguinarine, chelerythrine and macleaya cordata alkali; the main existing forms are benzyl isoquinoline alkaloid and salts thereof.
The macleaya cordata total alkaloid extract is obtained by adopting an extraction method of acid extraction and alkali precipitation and alcohol reflux collection of a conventional alkaloid extraction method, and the total alkaloid extraction rate is not lower than 60 percent; the selected acid is preferably sulfuric acid, hydrochloric acid and phosphoric acid, the base is preferably ammonia water, sodium hydroxide, calcium hydroxide and potassium hydroxide, and the alcohol is preferably ethanol.
The quinolone compound can be ciprofloxacin, sparfloxacin, levofloxacin, difloxacin, fleroxacin, enoxacin, ebaxacin, sarafloxacin, marbofloxacin, orbifloxacin and danofloxacin, or can be one or more of the salts of the quinolone medicines or the esters of the quinolone medicines. One or more of ciprofloxacin, sparfloxacin and levofloxacin are preferred.
The mass percentage of the carbostyril compound in the pharmaceutical composition is not more than 1%. The pharmaceutical composition is characterized in that, the macleaya cordata total alkaloid extract is 0.5 percent by mass; the ciprofloxacin content is 1%. The compound macleaya cordata injection for treating animal diarrhea diseases is characterized in that the auxiliary materials are an antioxidant, a metal ion chelating agent, a bacteriostatic agent, an analgesic, a freezing point regulator, a pH regulator, a solubilizer and water for injection.
In order to solve the second technical problem, the invention provides the following technical scheme:
the pharmaceutical preparation of the composition can be any one of liquid preparations such as injection, syrup, oral solution and the like, solid preparations such as common tablets, dispersible tablets, sustained-release tablets, capsules, granules, powder and the like, and semi-solid preparations such as ointment, paste, gel and the like.
In order to solve the third technical problem, the invention carries out the research on the treatment of yellow and white scour of piglets on the compound macleaya cordata composition preparation for treating the animal diarrhea diseases. The total amount of macleaya cordata and ciprofloxacin in the injection formulas of the experimental group (except the 6 th to 8 th groups) and the comparative group used in the research is constant, and the specification is 75mg of the total amount of the active ingredients of each 5 mL; the total amount of the effective components in each 5mL of the groups 6 to 8 is shown in the following table; in addition, single component macleaya cordata and single component ciprofloxacin lactate injection are prepared by the method with the total amount of 75mg and without adding macleaya cordata total alkaloid extract or ciprofloxacin lactate. 360 piglets which appear within 15 days of birth and are characterized by discharging yellow and white liquid excrement are selected, and the piglets are respectively half female and half male, and are confirmed to have coliform diarrhea, namely yellow and white scour of the piglets through a bacteria separation identification experiment; the groups were randomized into 12 groups, and the grouping and dosing schedule is shown in the table below; intramuscular injection was performed at 0.1mL/kg per body weight, and each group was administered once a day for three consecutive days.
TABLE 1 Experimental groups and dosing schedules
From the day before the test to the fifth day after the test, observing and recording the total stool number of each group of piglets and the stool number of yellow and white dysentery twice in the morning and afternoon every day; and (4) whether dead pigs appear or not. As diarrhea verification cannot be carried out on each piglet, the diarrhea condition and diarrhea index of the excrement in the litter are counted before and after the test, and the reduction of the diarrhea rate is used as an index for judging the curative effect: diarrhea index is the number of diarrhea stools/total number of stools x 100%.
In order to solve the third technical problem, the invention carries out treatment research on controlling infection of yellow and white scour of piglets on the compound macleaya cordata preparation for treating yellow and white scour of piglets. The total amount of macleaya cordata and ciprofloxacin in the injection formulas of the experimental group (except the 8 th to 10 th groups) and the comparative group used in the research is constant, and the specification is 75mg of the total amount of the active ingredients of each 5 mL; the total amount of the effective components in each 5mL of the groups 8-10 is shown in the following table; in addition, the single-component macleaya cordata and single-component ciprofloxacin lactate injection are prepared by the same total amount and method without adding the total alkaloid extract of the macleaya cordata or ciprofloxacin lactate. The affected piglets were randomly divided into 23 groups, wherein the first to tenth groups were experimental groups, the tenth to twentieth groups were control groups, and the twentieth group was 0.9% physiological saline, each group was intramuscularly injected with 0.1mL/kg by body weight, and each group was continuously administered for three days. Specific groups and dosing regimens are shown in table 2.
TABLE 2 Experimental animal groups and dosing regimens
Collecting the feces of each group of piglets three times every day in three time periods from the day of administration, detecting the activity of pathogenic escherichia coli in the feces, taking the Most Probable Number of the coliform group MPN (Most Probable Number) as a measurement index, wherein the MPN is the Most Probable Number of the coliform group in the sample calculated according to the Number of tested positive tubes by applying a statistical principle and a method, and reporting the Most Probable Number of the coliform group per 100mL (g). After the test, feces with the same bacterial activity were selected in each group for subsequent tests.
690 healthy piglets within 15 days of birth are selected, the male and female parts of the piglets are randomly divided into twenty-three captive breeding groups, and the excrement with the same quantity and the same bacterial activity in each group is respectively placed in each captive breeding group to ensure that the placed areas are the same and the piglets are easy to contact; observing the health condition of piglets in each captive group the next day, carrying out bacteria separation and identification experiments on feces of each piglet, confirming the number of piglets infected with colibacillary diarrhea (namely yellow and white scour of piglets), and calculating the infection rate of each group: the infection rate is the total number of sick (dead) pigs/30 × 100%.
In order to solve the third technical problem, the invention performs safety evaluation on the compound macleaya cordata preparation for treating yellow and white scour of piglets. Selecting 360 healthy piglets within 15 days of birth, wherein the male and female parts are divided into twelve groups randomly, the first group to the seventh group are experimental groups and are all compound macleaya cordata injection, and the contained quinolone medicaments are respectively ciprofloxacin, sparfloxacin, enoxacin, fleroxacin, difloxacin, sarafloxacin and ebaxacin; the eighth group to the tenth group are comparison groups, are compound macleaya cordata injection, and contain quinolone drugs of ofloxacin, norfloxacin, normethacin and pefloxacin respectively; the tenth group is 0.9% normal saline, each group is injected intramuscularly with 0.1mL/kg according to body weight, and each group is administered continuously for three days; during the dosing period, the physiological and mental status of the piglets was observed and recorded daily; and detecting the residual quantity of the quinolone medicaments in each group in animal muscle tissues by using high performance liquid chromatography on the 2 nd day after the administration is finished.
In order to solve the third technical problem, the compound macleaya cordata preparation for treating piglet yellow-white dysentery is subjected to a campylobacter drug resistance investigation experiment generated during piglet yellow-white dysentery treatment. 110 piglets which appear within 15 days of birth and are characterized by discharging yellow and white liquid excrement are selected, and the piglets are respectively half female and half male, and are confirmed to have coliform diarrhea, namely yellow and white scour of the piglets through a bacteria separation identification experiment; randomly dividing the sick piglets into eleven groups, wherein the first group to the ninth group are experimental groups, all are compound macleaya cordata injection, and the contained quinolone drugs are respectively ciprofloxacin, sparfloxacin, enoxacin, levofloxacin, fleroxacin, difloxacin, marbofloxacin, orbifloxacin and danofloxacin; the tenth group is a comparison group, which is a compound macleaya cordata injection and contains quinolone drugs enrofloxacin; the tenth group was 0.9% physiological saline, each group was injected intramuscularly at body weight of 0.1mL/kg, and each group was administered for three consecutive days. During the administration period, anal cotton swabs and intestinal fecal samples of each group of piglets were collected, 60 samples per group. The cotton swab samples were transported to the culture medium or directly to the laboratory for testing. The separation and identification of campylobacter are carried out according to the standard GB/T4789.9-2008; then 20 positive campylobacter strains were selected for each group, and drug susceptibility test was performed with reference to the agar diffusion method recommended by the american Clinical Laboratory Standards Institute (CLSI). 100 mu L of campylobacter culture solution with the concentration of 0.5 McLee unit is evenly coated on an MH agar plate with the diameter of 9cm, an antibiotic paper sheet is pasted on the surface of the agar after being sucked dry, whether a bacteriostatic ring exists or not and the size of the bacteriostatic ring are observed after incubation for 48h at 42 ℃, and the edge of the bacteriostatic ring is limited to the condition that bacteria can not obviously grow by naked eyes. The diameter (mm) of each bacteriostatic ring of the paper sheet is respectively measured, and the paper sheet is judged to be sensitive, medium sensitive or drug resistant according to the CLSI M100-S20 judgment standard and the judgment standard in the specification of the drug sensitive paper sheet product of OXOID company.
Compared with the application of single component in the pharmaceutical composition, the compound macleaya cordata preparation (the main components are the macleaya cordata total alkaloid extract and the quinolone compound) prepared by the invention can obviously improve the curative effect of the medicine and effectively control the infection of diseases; the toxic and side effects of the carbostyril compound in the prior patent in the pharmaceutical composition can be remarkably reduced, so that the problem of high residual quantity of the carbostyril compound in animal muscle tissues is solved, and the quality safety of animal food is improved; meanwhile, the possibility of drug resistance of the quinolone drugs can be reduced, and the safety and practicability of the compound preparation are obviously improved.
The invention has the advantages that:
1. in the field of veterinary medicines, a compound macleaya cordata composition preparation for treating animal diarrhea diseases is provided for the first time.
2. In the field of veterinary medicines, provides a compound macleaya cordata composition preparation administration preparation for treating animal diarrhea diseases for the first time.
3. In the field of veterinary medicines, the application of a compound macleaya cordata composition preparation for treating animal diarrhea diseases is provided for the first time.
4. The additive of the prescription of the compound macleaya cordata composition liquid preparation comprises the freezing point regulator, so that the freezing point of the injection can be effectively reduced, the quinolone medicaments are prevented from being crystallized and separated out at a lower temperature, and the quality of the preparation is stable.
5. The invention combines the macleaya cordata total alkaloid extract and the quinolone medicaments for human or veterinary use at present for the first time, and the antibacterial spectra of the macleaya cordata total alkaloid extract and the quinolone medicaments for human or veterinary use are superposed, thereby expanding the applicable diseases of the compound macleaya cordata composition preparation.
6. Compared with the application of single component in the pharmaceutical composition, the compound macleaya cordata composition preparation (the main components of which are the macleaya cordata total alkaloid extract and the quinolone compound) prepared by the invention can obviously improve the curative effect of the medicine and effectively control the infection of diseases.
7. Due to the addition of the antibacterial quinolone drugs, compared with the single application of the macleaya cordata total alkaloid extract, the compound macleaya cordata composition preparation has the advantages of quicker response and longer duration of the drug effect.
8. The compound macleaya cordata composition preparation prepared by the invention can obviously reduce the toxic and side effects of the quinolone compounds in the existing patent in the pharmaceutical composition when applied, namely the problem of high residual quantity of the quinolone compounds in animal muscle tissues is solved, and the quality safety of animal food is improved; meanwhile, the possibility of drug resistance of the quinolone drugs can be reduced, and the safety and practicability of the compound preparation are obviously improved.
9. The compound macleaya cordata composition preparation can be prepared into different administration formulations, and can be any one of liquid preparations such as injection, syrup, oral solution and the like, solid preparations such as common tablets, dispersible tablets, sustained-release tablets, capsules, granules, powder and the like, and semi-solid preparations such as ointments, pastes, gels and the like; the administration dosage is flexible and changeable, so as to achieve different treatment purposes, including long-acting and slow-release treatment, and can also be suitable for different treatment environments and treatment requirements.
10. The compound macleaya cordata composition preparation has simple extraction and production processes, is easy to automate in production flow, and is suitable for industrial expanded production.
Detailed Description
Examples 1 to 10
The prescription (5mL) of the compound macleaya cordata injection for treating animal diarrhea diseases is as follows:
TABLE 3 formulations of examples 1-10
Note: q.s. means proper amount, sufficient amount.
The preparation method comprises the following steps:
(1) dissolving antioxidant, metal ion chelating agent, antibacterial (analgesic) agent, and freezing point regulator in water for injection saturated with carbon dioxide or nitrogen, adding quinolone drugs, and stirring to dissolve.
(2) Extracting with 20 times of 0.5% acid water solution, adjusting pH to 8-10 with base, separating precipitate, and extracting with 90% ethanol to obtain herba Macleayae Cordatae total alkaloids with extraction rate not less than 60%;
(3) dissolving herba Macleayae Cordatae total alkaloid extract and polysorbate 80 in carbon dioxide or nitrogen saturated water for injection. Mixing the above solutions, diluting with carbon dioxide or nitrogen saturated water for injection, adjusting pH to 4.2-5 with hydrochloric acid, filtering, bottling, sealing, and sterilizing with 100 deg.C flowing steam for 30 min.
Examples 11 to 20
The prescription (100 mL of emulsion injection) of the compound macleaya cordata injection for treating yellow and white scour of piglets is as follows:
TABLE 4 formulations of examples 11 to 20
Note: q.s. means proper amount, sufficient amount.
The preparation method comprises the following steps:
(1) extracting with 20 times of 0.5% acid water solution, adjusting pH to 8-10 with alkali, separating precipitate, and extracting with 90% ethanol to obtain herba Macleayae Cordatae total alkaloids with extraction rate not less than 60%; (2) preparation of oil phase: adding herba Macleayae Cordatae total alkaloid extract and antioxidant into soybean oil, stirring to dissolve completely to transparent state as oil phase;
(3) preparation of the aqueous phase: adding metal ion chelating agent, bacteriostatic (analgesic) agent, freezing point regulator, emulsifying (solubilizing) agent and polyethylene glycol 400 into water for injection, and adding quinolone drugs while stirring to dissolve the quinolone drugs into a transparent state to serve as a water phase for later use;
(4) emulsification: slowly adding the water phase into the oil phase while vigorously stirring to obtain primary emulsion, and adjusting pH to 4.2-5 with hydrochloric acid;
(5) continuously homogenizing the prepared primary emulsion for 5 times at a primary pressure of 1000Pa and a secondary pressure of 5000Pa, and homogenizing for one time at a low pressure of 120 Pa;
(6) filtering, bottling, sealing, and sterilizing with 100 deg.C flowing steam for 30 min.
Examples 21 to 30
The prescription (suspension type injection or sterile powder for injection, 20mL) of the compound macleaya cordata injection for treating yellow and white scour of piglets is as follows:
TABLE 5 formulations of examples 21 to 30
The preparation method comprises the following steps:
(1) extracting with 20 times of 0.5% acid water solution, adjusting pH to 8-10 with alkali, separating precipitate, and extracting with 90% ethanol to obtain herba Macleayae Cordatae total alkaloids with extraction rate not less than 60%;
(2) adding antioxidant, metal ion chelating agent, antibacterial (analgesic) agent, buffer salt ion pair, freezing point regulator or powder injection filler, suspending agent, and wetting agent into water for injection to 20mL, dissolving, filtering, sterilizing with 100 deg.C flowing steam for 30min, cooling, adding Macleaya cordata total alkaloid extract and quinolone drugs in sterile room, and making into suspension injection.
(3) Or mixing antioxidant, metal ion chelating agent, antibacterial (analgesic) agent, buffer salt ion pair, freezing point regulator or powder injection filler, suspending agent, wetting agent, herba Macleayae Cordatae total alkaloid extract and quinolone drugs under sterile condition, and packaging to obtain sterile powder for injection. Before use, sterile water for injection is added to 20mL to prepare suspension.
Examples 31 to 40
The prescription (powder, 100g) of the compound macleaya cordata composition preparation for treating yellow and white scour of piglets is as follows:
TABLE 6 formulation of examples 31 to 40
The preparation method comprises the following steps:
(1) extracting with 20 times of 0.5% acid water solution, adjusting pH to 8-10 with alkali, separating precipitate, and extracting with 90% ethanol to obtain herba Macleayae Cordatae total alkaloids with extraction rate not less than 60%;
(2) placing herba Macleayae Cordatae total alkaloid extract and quinolone drugs, antioxidant, metal ion chelating agent, beef essence or fish essence, and lactose in oven, drying at 40 deg.C for 2 hr, taking out, and sieving with 120 mesh nylon sieve respectively. Grinding appropriate amount of lactose in a mortar to saturate the inner wall and pouring out, mixing herba Macleayae Cordatae total alkaloid extract and quinolone drugs in the mortar, gradually adding antioxidant, metal ion chelating agent and beef essence (fish essence) according to an equivalent progressive mixing method, grinding completely, gradually adding required lactose according to an equivalent progressive mixing method, grinding uniformly, subpackaging into single-dose powder by weight method, and packaging.
Examples 41 to 50
The prescription (oral solution, 1L) of the compound macleaya cordata composition preparation for treating yellow and white scour of piglets is as follows:
TABLE 7 formulation of examples 41-50
The preparation method comprises the following steps:
(1) extracting with 20 times of 0.5% acid water solution, adjusting pH to 8-10 with alkali, separating precipitate, and extracting with 90% ethanol to obtain herba Macleayae Cordatae total alkaloids with extraction rate not less than 60%;
(2) preparing enough 0.9 percent sodium chloride solution or 5 percent glucose solution by using distilled water under the normal temperature condition (25 ℃); dissolving weighed macleaya cordata total alkaloid extract, quinolone drugs, an antioxidant, a metal ion chelating agent, a preservative, a flavoring agent and a solubilizer in a certain amount of the solution, dissolving under stirring at normal temperature, supplementing to a required volume, filtering to be clean, stirring, subpackaging in time and sealing in a dry light-proof container.
Example 51
Treatment experiment of compound macleaya cordata injection for treating yellow and white scour of piglets
1. Selection and confirmation of experimental piglets suffering from yellow-white dysentery
1.1 Experimental methods
1.1.1 preliminary screening
500 piglets which are characterized by discharging yellow-white liquid excrement within 15 days of birth, male and female ginseng halves are initially selected and then are subjected to bacteria separation and identification.
1.1.2 fecal sampling and testing
And collecting a feces sample from a rectum of a suspected pig with yellow-white dysentery by using a sterile cotton swab, and placing the feces sample in a sterilization tube for marking. Suspending the cotton swab in each sterile test tube filled with sterile physiological saline, fully eluting excrement by vortex oscillation, taking 1-3 rings of the suspension by using an inoculating ring, streaking and inoculating the suspension on a Mackanka agar plate, culturing for 18-24h at 37 ℃, observing and collecting bacterial colonies for detecting and identifying whether the bacterial colonies are infected by escherichia coli, and selecting experimental piglets suffering from yellow-white dysentery.
Whether piglets are infected by escherichia coli is determined by the following four experiments: morphological identification of bacteria, biochemical identification of pathogenic bacteria, serological detection and pathogenicity test.
1.2 results of the experiment
1.2.1 morphological identification of bacteria
Differential media isolation and gram stain microscopy were performed on 500 samples.
(1) The separated escherichia coli strain is in a round shape with regular edges, a little bulge, smooth and moist surface and pink color on the Macconkey agar, and the separated escherichia coli strain is in a purplish black shape on an eosin methylene blue agar plate and has a metal luster bacterial colony, and a round bulge, smooth, moist, semitransparent and approximately grey-white bacterial colony is formed on the nutrient agar.
(2) The separated escherichia coli is gram-stained, and gram-negative bacilli with thick short bacilli and blunt round bacilli at two ends can be seen through microscopic examination.
Obtaining 475 strains which accord with the culture characteristics and morphological characteristics of the escherichia coli.
1.2.2 Biochemical identification of pathogenic bacteria
The result of biochemical identification of the separated strains completely accords with the majority of the biochemical characteristics of the escherichia coli, and only a few separated strains do not accord with individual projects. See table 8 for details.
TABLE 8 Biochemical identification of isolated strains
| Authentication program | Reaction of | Positive rate (%) |
| Indoles | + | 100 |
| Methyl Red | + | 100 |
| VP | - | 0 |
| Lactose | + | 84.63 |
| Maltose | + | 84.63 |
| Mannitol | + | 100 |
| Hydrogen sulfide | - | 0 |
VP：Voges-Proskauer test
According to Bergey's Manual of identification of bacteria, 402 isolated strains of 475 strains meet biochemical identification indexes of Escherichia coli, and are judged as Escherichia coli.
1.2.3 serological assays
Coli standard anti-O serum agglutination tests were performed. Through the serological type identification, the serotype of the pathogen isolated strain is O889 strains and O10196 strains, O11524 strains, O14185 strains, O15798 strains.
1.2.4 pathogenicity test
The identified Escherichia coli are respectively inoculated into nutrient broth culture media, cultured orally, and diluted into a strain solution for counteracting toxic substances by using sterilized broth. 20 mice were divided into 5 groups of 4 mice each. 4 groups are used as a test group, 1 group is used as a control group, the intraperitoneal injection of the test group is performed with 0.2 mL/body of suspension, the intraperitoneal injection of the control group is performed with 0.2 mL/body of sterilized broth, 1 time of observation is performed every 6h after injection, continuous observation is performed, dead mice are subjected to autopsy, a liver smear is aseptically taken, and gram staining microscopy is performed. The judgment standard can lead the mouse to be judged as a pathogenic strain when the mouse dies within 24h under the normal feeding condition.
6h after inoculation, inoculation O8、O157All mice had the diseaseThen; after 12h, inoculate O141All mice had disease; after 14h, inoculate O101All mice developed disease. The sick mice had loose stools, depressed spirit, accelerated respiration and died from the test. Control and inoculation O115Group mice did not die. The white mouse died by the autopsy has gastrointestinal swelling, the intestinal cavity is filled with yellow water sample and is diluted, the liver smear of the dead mouse is smeared, gram staining is carried out, and microscopic examination is carried out. The result is the same as the result of microscopic examination of the isolated strain. Thus, 378 of the 402 isolated E.coli strains were pathogenic E.coli.
From the above experimental results, 378 piglets identified as suffering from yellow-white dysentery.
2. Administration scheme and curative effect evaluation of compound macleaya cordata injection for treating yellow and white scour of piglets
2.1. Drug, experimental animal grouping and dosing regimen
The total amount of macleaya cordata and ciprofloxacin in the injection formulas of the experimental group (except the 6 th to 8 th groups) and the comparative group used in the research is constant, and the specification is 75mg of the total amount of the active ingredients of each 5 mL; the total amount of the effective components in each 5mL of the groups 6 to 8 is shown in the following table; in addition, single component macleaya cordata and single component ciprofloxacin lactate injection are prepared by the method with the total amount of 75mg and without adding macleaya cordata total alkaloid extract or ciprofloxacin lactate.
360 piglets which are identified as suffering from yellow-white dysentery are selected, and the number of the piglets is half that of the piglets. Randomly divided into 12 groups, and the grouping and dosing schedule are shown in table 1; intramuscular injection was performed at 0.1mL/kg per body weight, and each group was administered once a day for three consecutive days.
From the day before the test to the fifth day after the test, observing and recording the total stool number of each group of piglets and the stool number of yellow and white dysentery twice in the morning and afternoon every day; and (4) whether dead pigs appear or not. As diarrhea verification cannot be carried out on each piglet, the diarrhea condition and diarrhea index of the excrement in the litter are counted before and after the test, and the reduction of the diarrhea rate is used as an index for judging the curative effect: diarrhea index is the number of diarrhea stools/total number of stools x 100%.
2.2 results and discussion
2.2.1 clinical effects of Compound Macleaya cordata injection for treating diarrhea of piglets
TABLE 9 diarrhea and mortality in the treated piglets
After the treatment of each group of medicines, the diarrhea condition of piglets has great change. As shown in table 10, the diarrhea rates of the experimental group and the comparative group are generally decreased compared to the diarrhea rates of the pre-administration and the normal saline control group, wherein the decrease of each experimental group is most obvious and the drug effect is rapid, the effect of the comparative group is relatively slow and the therapeutic effect is weak, and the diarrhea rate of the normal saline control group is increased to 63.89%. It can be seen that the difference between each experimental group and the control group is significant, and the diarrhea rate can be reduced to different degrees, and the disease condition can be controlled rapidly.
From the mortality data (%) in table 10, it can be seen that the piglets suffering from yellow-white dysentery without effective treatment suffer from a great deal of death, and the experimental injection can effectively control the mortality of the sick piglets, and the mortality does not exceed 10%; in the control group, the death rate of the sick pigs is also reduced, and compared with the normal saline group, the death rate of the sick pigs is obviously different, but partial sick pigs still die.
2.2.2 Compound Macleaya cordata injection for treating yellow and white scour of piglets
According to the disease characteristics and the age of the day, the diarrhea is divided into yellow dysentery and white dysentery, and the treatment effect of the medicine on the yellow dysentery and the white dysentery of the piglets is analyzed (the numerical value in the table is the diarrhea frequency).
TABLE 10 diarrhea frequency of yellow-white scour of piglets
As can be seen from Table 10, after piglets are treated by the macleaya cordata injection of the experimental group, the diarrhea frequency is obviously reduced, and the diarrhea frequency of yellow-white dysentery shows an obvious reduction trend; the change trend of the diarrhea frequency of the white dysentery of the comparison group is consistent with that of the macleaya cordata injection of the experimental group, while the yellow dysentery shows the trend of descending first and then rising and descending again, and the effect is inferior to that of the latter.
The data show that the compound macleaya cordata injection in a certain proportion range can effectively treat yellow and white scour of piglets and control the death rate of sick pigs, and the treatment effect is obviously superior to that of a single-component medicine group and an injection group in the proportion range.
Example 52.
Compound macleaya cordata injection liquid controlled piglet yellow-white dysentery infection treatment experiment
1. Selecting and confirming experimental piglets suffering from yellow-white dysentery
Experimental methods and experimental results as described in examples 1.1 and 1.2 of example 51, 230 piglets confirmed to have colibacillary diarrhea (i.e., yellow and white scour of piglets) were selected, and hermaphrodite piglets were selected.
2. Test scheme and effect evaluation for compound macleaya cordata injection liquid for controlling yellow-white dysentery infection of piglets
2.1 grouping and dosing regimens in test animals
The total amount of macleaya cordata and ciprofloxacin in the injection formulas of the experimental group (except the 8 th to 10 th groups) and the comparative group used in the research is constant, and the specification is 75mg of the total amount of the active ingredients of each 5 mL; the total amount of the effective components in each 5mL of the groups 8-10 is shown in the following table; in addition, the single-component macleaya cordata and single-component ciprofloxacin lactate injection are prepared by the same total amount and method without adding the total alkaloid extract of the macleaya cordata or ciprofloxacin lactate.
The affected piglets were randomly divided into 23 groups, wherein the first to tenth groups were experimental groups, the tenth to twentieth groups were control groups, and the twentieth group was 0.9% physiological saline, each group was intramuscularly injected with 0.1mL/kg by body weight, and each group was continuously administered for three days. Specific grouping and dosing regimens table 2.
2.2 Collection and detection of test feces
Collecting the feces of each group of piglets three times every day in three time periods from the day of administration, detecting the activity of pathogenic escherichia coli in the feces, taking the Most Probable Number of the coliform group MPN (Most Probable Number) as a measurement index, wherein the MPN is the Most Probable Number of the coliform group in the sample calculated according to the Number of tested positive tubes by applying a statistical principle and a method, and reporting the Most Probable Number of the coliform group per 100mL (g). After the test, feces with the same bacterial activity were selected in each group for subsequent tests.
2.3 yellow-white dysentery infection test for piglets
690 healthy piglets within 15 days of birth are selected, the male and female parts of the piglets are randomly divided into twenty-three captive breeding groups, and the excrement with the same quantity and the same bacterial activity in each group is respectively placed in each captive breeding group to ensure that the placed areas are the same and the piglets are easy to contact; observing the health condition of piglets in each captive group the next day, carrying out bacteria isolation and identification experiments on feces of each piglet, confirming the number of piglets infected with colibacillary diarrhea (namely piglet yellow-white dysentery), and calculating the infection rate of each group: the infection rate is the total number of sick (dead) pigs/30 × 100%.
2.4 results and discussion
The experimental procedure for isolation and identification of bacteria was as described in 1 of example 51.
TABLE 11 therapeutic results for controlling yellow-white dysentery infection in piglets
As can be seen from Table 11, 25 sick piglets and 5 dead piglets in the physiological saline group on the second day have the infection rate of 100 percent; the infection rates of the control group (except the 11 th group) are all more than 65%, and different numbers of dead pigs appear, and the infection rate of the 11 th group (single-component ciprofloxacin) is close to that of the 3 rd group of the experimental group; wherein the infection rate of group 22 (monocomponent macleaya cordata group) is 100%; the infection rates of the groups 15-17 were all greater than 90%, and as seen from comparison of the groups 1-3 with the groups 12 and 13, when the ciprofloxacin and macleaya cordata ratios were not within the effective ranges, the infection rates were significantly increased, and no good infection control effect was exhibited; the infection rates of the compound macleaya cordata injection containing different quinolone drugs in the experimental group are different, and compared with the control group (except the 11 th group) and the normal saline group, the infection rates of the groups are obviously reduced and are controlled within 50 percent (including 50 percent) and no dead piglets appear.
The data show that the compound macleaya cordata injection in a certain proportion range effectively controls the infection of diseases, and the effect is obviously superior to that of a contrast group.
Example 53
Safety evaluation of compound macleaya cordata injection for treating yellow and white scour of piglets
1. Drug, experimental animal grouping and protocol
1.1 healthy piglets within 15 days of birth were selected from 360, half each male and female, and randomly divided into twelve groups.
1.2 the compound macleaya cordata injection of the experimental group and the comparative group used in the research is prepared according to the prescription proportion in the example 1, namely, the ciprofloxacin is replaced by other quinolone medicaments with the same quantity according to the grouping requirement.
The first group to the seventh group are experimental groups, which are all compound macleaya cordata injection, and the contained quinolone drugs are respectively ciprofloxacin, sparfloxacin, enoxacin, fleroxacin, difloxacin, sarafloxacin and ebaxacin; the eighth group to the tenth group are comparison groups, are compound macleaya cordata injection, and contain quinolone drugs of ofloxacin, norfloxacin, normethacin and pefloxacin respectively; the tenth group is 0.9% normal saline, each group is injected intramuscularly with 0.1mL/kg according to body weight, and each group is administered continuously for three days; during the dosing period, the physiological and mental status of the piglets was observed and recorded daily; and detecting the residual quantity of the quinolone medicaments in each group in animal muscle tissues by using high performance liquid chromatography on the 2 nd day after the administration is finished.
2. Results and discussion
TABLE 12 physiological and mental status of piglets after administration and drug residue results
Note: the sign of "+" indicates that adverse symptoms appear, such as physiological reactions like inappetence and the like, mental reactions like fatigue and weakness and the like, and the more the number of "+" indicates more serious; "-" indicates no adverse reaction occurred.
From the results in table 13, it can be known that the drug residue of each group of compound macleaya cordata injections containing different quinolone drugs in the experimental group is significantly lower than that of the comparative group under the same administration dosage; on the other hand, although the physiological and mental conditions of the piglets in the experimental group are influenced by the medicament, the influence is weaker than that of the comparative group through overall analysis, and the appetite of the piglets is obviously reduced and the piglets are fatigued and weak as the administration time is prolonged. The results show that the compound macleaya cordata injection of the experimental group solves the problem of high residual quantity of quinolone drugs in animal muscle tissues, controls the occurrence of adverse reactions and increases the quality safety of animal food.
Example 54
Research on drug resistance of campylobacter for treating yellow and white scour of piglets by using compound macleaya cordata injection
1. Selecting and confirming experimental piglets suffering from yellow-white dysentery
Experimental methods and experimental results as described in examples 1.1 and 1.2 of example 51, 110 piglets were selected from the group, both male and female, which were confirmed to have colibacillary diarrhea (i.e. yellow-white dysentery in piglets).
2. Test scheme and result for investigating drug resistance of campylobacter generated by treating yellow and white scour of piglets by using compound macleaya cordata injection
2.1 grouping and dosing regimens in test animals
The compound macleaya cordata injection of the experimental group and the comparative group used in the research is prepared according to the prescription proportion in the embodiment 1, namely, the ciprofloxacin is replaced by other quinolone medicaments with the same quantity according to the grouping requirement.
Randomly dividing the sick piglets into eleven groups, wherein the first group to the ninth group are experimental groups, all are compound macleaya cordata injection, and the contained quinolone drugs are respectively ciprofloxacin, sparfloxacin, enoxacin, levofloxacin, fleroxacin, difloxacin, marbofloxacin, orbifloxacin and danofloxacin; the tenth group is a comparison group, which is a compound macleaya cordata injection and contains quinolone drugs enrofloxacin; the tenth group was 0.9% physiological saline, each group was injected intramuscularly at body weight of 0.1mL/kg, and each group was administered for three consecutive days.
2.2 test feces Collection, Strain isolation identification
During the administration period, anal cotton swabs and intestinal fecal samples of each group of piglets were collected, 60 samples per group. The cotton swab samples were transported to the culture medium or directly to the laboratory for testing. The separation and identification of campylobacter are carried out according to the standard GB/T4789.9-2008; then 20 positive campylobacter strains were selected for each group, and drug susceptibility test was performed with reference to the agar diffusion method recommended by the american Clinical Laboratory Standards Institute (CLSI). 100 mu L of campylobacter culture solution with the concentration of 0.5 McLee unit is evenly coated on an MH agar plate with the diameter of 9cm, an antibiotic paper sheet is pasted on the surface of the agar after being sucked dry, whether a bacteriostatic ring exists or not and the size of the bacteriostatic ring are observed after incubation for 48h at 42 ℃, and the edge of the bacteriostatic ring is limited to the condition that bacteria can not obviously grow by naked eyes. The diameter (mm) of each bacteriostatic ring of the paper sheet is respectively measured, and the paper sheet is judged to be sensitive, medium sensitive or drug resistant according to the CLSI M100-S20 judgment standard and the judgment standard in the specification of the drug sensitive paper sheet product of OXOID company.
2. Results and discussion
2.1 isolation and identification of Campylobacter
246 campylobacter isolates are obtained by separating 660 samples, and the separation rate of the total samples is 37.27%; ensures that at least 20 positive campylobacter strains in each group are obtained.
2.2 results of drug susceptibility test
In this test, the resistance of clinically used quinolone drugs (ofloxacin and norfloxacin) was investigated for each isolated group of Campylobacter strain.
TABLE 13 results of drug resistance experiments
From the results, the comparative group, namely the compound macleaya cordata injection containing enrofloxacin, generates obvious drug resistance, and the drug resistance to ofloxacin and norfloxacin is respectively as high as 75 percent and 85 percent; the drug resistance of each group of the experimental group to the two drugs is obviously weaker than that of the comparative group. The compound macleaya cordata injection in the experimental group is difficult to cause the campylobacter to generate drug resistance to other quinolone drugs, and reduces the possibility of infecting drug-resistant bacteria and the risk of generating complications for human beings.
The above-mentioned embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Various other modifications and alterations will occur to those skilled in the relevant art based on the foregoing description and examples. This description is not intended to be exhaustive of all embodiments. All obvious modifications and variations of the present invention are intended to fall within the scope of the present invention.
Claims (7)
1. The compound macleaya cordata injection for treating animal diarrhea diseases is characterized by comprising a pharmaceutical active ingredient and auxiliary materials, wherein the pharmaceutical active ingredient comprises the following components in parts by weight: macleaya cordata total alkaloid extract: ciprofloxacin is 1:2, and the extraction method of the macleaya cordata total alkaloid extract comprises the following steps: the method comprises extracting fruit pods of Macleaya cordata with 20 times of 0.5% acid water solution, adjusting pH to 8-10 with alkali, separating precipitate, and extracting with 90% ethanol to obtain Macleaya cordata total alkaloids with extraction rate not less than 60%.
2. The compound macleaya cordata injection for treating animal diarrhea diseases according to claim 1, wherein the macleaya cordata total alkaloid extract is 0.5 percent by mass; the ciprofloxacin content is 1%.
3. The compound macleaya cordata injection for treating animal diarrhea diseases according to claim 1 or 2, wherein the auxiliary materials are antioxidant, metal ion chelating agent, bacteriostatic agent and analgesic, freezing point regulator, pH regulator, solubilizer and water for injection.
4. A method for preparing the compound macleaya cordata injection for treating animal diarrhea according to claim 3,
1) dissolving antioxidant, metal ion chelating agent, bacteriostatic, analgesic, and freezing point regulator in water for injection saturated with carbon dioxide or nitrogen, adding ciprofloxacin, and stirring to dissolve;
2) in addition, the extraction method of acid-extraction-alkali precipitation and alcohol reflux collection is adopted to obtain the macleaya cordata total alkaloids, and the extraction rate is not lower than 60%; dissolving herba Macleayae Cordatae total alkaloid extract and polysorbate 80 in carbon dioxide or nitrogen saturated water for injection;
3) then combining the solutions obtained in 1) and 2), diluting with carbon dioxide or nitrogen saturated water for injection to full volume, adjusting pH to 4.2-5 with hydrochloric acid, filtering, bottling, sealing, and sterilizing with 100 deg.C flowing steam for 30 min.
5. The compound macleaya cordata injection for treating animal diarrhea diseases according to claim 1 or 2, wherein the injection is applied to piglets.
6. Use of an injection according to any one of claims 1 to 3 or prepared by the process according to claim 4 for the preparation of a medicament for the treatment of diarrheal diseases in an animal.
7. Use of the injection according to any one of claims 1 to 3 or the injection prepared by the preparation method according to claim 4 for veterinary use in the treatment of bacterial infectious diseases of the digestive tract and for effective control of the transmission of diseases.
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