CN108785681B - Compound antipyretic analgesic anti-inflammatory composition preparation for livestock and application thereof - Google Patents
Compound antipyretic analgesic anti-inflammatory composition preparation for livestock and application thereof Download PDFInfo
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
The invention discloses a veterinary compound antipyretic-analgesic-anti-inflammatory composition preparation and application thereof, belongs to the field of veterinary medicines, and particularly relates to a pharmaceutical composition containing a non-steroidal anti-inflammatory drug and a honeysuckle extract (chlorogenic acid of a honeysuckle extract and baicalin of a scutellaria baicalensis extract), wherein the active ingredients of the pharmaceutical composition consist of the following components in parts by mass: 1-1,000 parts of non-steroidal anti-inflammatory drugs and 1-100 parts of honeysuckle flower and scutellaria baicalensis extracts. 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 antipyretic analgesic anti-inflammatory composition preparation has obvious synergistic effect on the aspects of animal antipyretic analgesic anti-inflammatory, can effectively and effectively reduce adverse drug reactions, 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 antipyretic analgesic and anti-inflammatory composition preparation and application thereof. Belongs to the field of veterinary drugs.
Background
Antipyretic analgesic anti-inflammatory drugs, also known as nonsteroidal anti-inflammatory drugs (NSAIDs), are drugs with antipyretic and analgesic effects, and most of them also have anti-inflammatory and antirheumatic effects. NSAIDs have been marketed by hundreds or thousands of brands over 100 years since the first synthesis of aspirin in 1898; according to the chemical structure, the compounds can be divided into salicylic acids, anilines, pyrazolones, indoleacetic acids, anthranilic acids and arylalkanoic acids, wherein the anilines basically have no anti-inflammatory and antirheumatic effects. NSAIDs have different chemical structures, but inhibit cyclooxygenase in the metabolic process of arachidonic acid, so as to reduce synthesis of prostaglandin and exert the effects of antipyresis, analgesia and anti-inflammation.
NSAIDs are currently one of the most used drugs worldwide, with approximately 3000 million people using them around the world every day; NSAIDs are also widely used in the field of animal medicine. Flunixin meglumine is a novel antipyretic analgesic drug special for non-steroidal animals. The flunixin meglumine injection and the flunixin meglumine particles are developed by the company Xianlingbao (United states) in the 90 th century (the trade name of Banamine), are widely applied to a plurality of countries such as the United states, France, Switzerland, Germany, England and the like, and are also recorded in the pharmacopoeia of the people's republic of China (2005 edition).
In recent three years, 5 kinds of new NSAIDs for animals in China are meloxicam tablets (5 kinds of new veterinary drugs), meloxicam oral suspension (5 kinds of new veterinary drugs), acetaminophen and diclofenac sodium injection (5 kinds of new veterinary drugs), diclofenac sodium injection (5 kinds of new veterinary drugs) and vitacoxib tablets (1 kind of new veterinary drugs).
Patent CN1533764A discloses a sustained-release injection containing non-steroidal anti-inflammatory drugs, which uses hydrophobic liquid with sustained-release effect as medium, or prepares NSAIDs into micro powder state to be dispersed in the medium of the preparation, and has good sustained-release effect.
Patent CN104288096A and patent CN104337759A disclose a preparation method of diclofenac sodium injection for animals; patent CN104337763A and patent CN104337764A disclose a suspension containing diclofenac sodium; patent CN104337776A discloses an analgesic diclofenac sodium-containing tablet for pets and a preparation method thereof.
Patent CN101267807A discloses a veterinary composition comprising a non-steroidal anti-inflammatory drug and paracetamol, which synergistically enhance the therapeutic effect.
Patent CN1530096A discloses a veterinary powder injection containing non-steroidal anti-inflammatory drugs, which is prepared by mixing NSAIDs and antimicrobial drugs and combining the drugs.
Patent CN101219130A and patent CN1887285A disclose a veterinary compound pharmaceutical composition, a preparation method and application thereof, the composition consists of diclofenac sodium and naproxen or barbital, and the antipyretic effect is more thorough than that of a single preparation.
Patent CN101647804A discloses a compound amoxicillin soluble powder for treating duck serositis and a preparation method thereof, and diclofenac sodium and amoxicillin are combined to improve the curative effect; patent CN106727299A discloses a veterinary compound ceftiofur hydrochloride suspension, which is added with diclofenac sodium to achieve synergistic effect; patent CN105727249A discloses an external ointment for treating joint diseases of cats and dogs and a preparation method thereof, and diclofenac sodium is combined with traditional Chinese medicine components such as cogongrass rhizome, teasel root, rhizoma drynariae and the like, so that the curative effect is enhanced.
With the increased use of NSAIDs, the problem of safe use of such drugs has also become of increasing concern to clinicians, pharmacists, patients, society and government. In particular, the company majorit announced an active withdrawal of wanluo (rofecoxib) from the global market in 2004 at 10 months; the U.S. Food and Drug Administration (FDA), considering potential cardiovascular and gastrointestinal bleeding risks for NSAIDs, requires that these drug manufacturers provide warnings in their specifications, which makes the safe administration of NSAIDs a current global medical community hot issue.
Patent CN101439038A discloses a pharmaceutical preparation comprising a non-steroidal anti-inflammatory drug and misoprostol; patent CN107224585A discloses a composition comprising a non-steroidal anti-inflammatory drug and a proton pump inhibitor. By means of drug combination, the adverse reaction of the digestive tract is reduced.
Patent CN105456289A discloses a western medicine compound formula for treating gout, which comprises sulphoaluminate, diclofenac sodium, magnesium oxide, benzbromarone and chitin, wherein the sulphoaluminate has the effect of protecting gastric mucosa.
Patent CN104095867A discloses an oral preparation for analgesia and its preparation method; patent CN104147007A discloses a pharmaceutical composition for relieving pain and its use, comprising diclofenac sodium, rosmarinic acid, tetrahydropalmatine and mangiferin, wherein the rosmarinic acid component can protect cardiovascular system and gastrointestinal tract.
Patent CN106511862A and patent CN106344905A disclose a medicine for treating rheumatoid diseases and a preparation method thereof, the medicine comprises diclofenac sodium and a stomach nourishing preparation, wherein the stomach nourishing preparation comprises: radix astragali, rhizoma Dioscoreae, fructus oryzae Germinatus, flos Caryophylli, cortex Cinnamomi Japonici, semen Alpiniae, folium Camelliae sinensis, herba Polygoni Avicularis, Zingiberis rhizoma, rhizoma Cyperi, Tremella, and fructus Foeniculi.
At present, the drug combination is the best means for solving the adverse reaction of NSAIDs. When the misoprostol and the proton pump inhibitor are used in combination, the misoprostol and the proton pump inhibitor are recommended in the prescription of NSAIDs; the sulpho-aluminous saccharide is also a common gastric mucosa protective agent, but the combined mode only can relieve gastrointestinal adverse reactions, but has no obvious effect on protecting the cardiovascular system. The addition of a series of traditional Chinese medicine components can reduce adverse reactions of gastrointestinal tract and cardiovascular system, but most of the traditional Chinese medicine components in the formula are redundant and have poor curative effect, so that the search for traditional Chinese medicine monomers or traditional Chinese medicine compositions which can be well compatible with NSAIDs, reduce adverse reactions and even exert synergistic effect and have simple and definite components is necessary.
Honeysuckle, also known as honeysuckle, has a chlorogenic acid compound as a main active ingredient; the scutellaria baicalensis, also known as camellia root and golden camellia root, has the main active component of baicalin compounds. Honeysuckle and scutellaria baicalensis extracts (chlorogenic acid and baicalin) are commonly used in combination, are called ' honeysuckle-scutellaria ', are used as common Chinese patent medicines for human, and are marketed in dosage forms of honeysuckle-scutellaria granules, honeysuckle-scutellaria oral liquid, honeysuckle-scutellaria tablets, honeysuckle-scutellaria capsules, honeysuckle-scutellaria injection and the like at present, and the first part of the 2015 edition of the pharmacopoeia of the people's republic of China records two dosage forms of the honeysuckle-scutellaria granules and the honeysuckle-scutellaria oral liquid. Animal-used honeysuckle extract injection, a honeysuckle extract (calculated as chlorogenic acid) and a radix scutellariae extract (calculated as baicalin) are also recorded in the second part of 2005 edition of the people's republic of China pharmacopoeia, and the animal-used honeysuckle extract injection is used for clearing heat and dispelling wind, relieving sore throat and detoxifying.
Patent CN104666791A discloses a compound aqueous solution for preventing and treating upper respiratory tract infection of cats and a preparation method thereof, comprising chrysanthemum flower powder, houttuynia cordata powder, tobacco leaf powder, lotus plumule powder, pseudo-ginseng powder, coffee powder, rhubarb powder, honeysuckle powder, tobacco leaf powder, garlic powder, diclofenac sodium, vitamins and the like, wherein the honeysuckle powder is a good medicine for clearing heat and removing toxicity.
Patent CN102188436A discloses an injection for treating pig mixed infection, the effective components are sulfamonomethoxine sodium, ofloxacin, diclofenac sodium, baicalin and trimethoprim, wherein the baicalin plays the roles of antivirus, anti-inflammation and antioxidation.
Patent CN106668268A discloses a pharmaceutical composition suitable for treating toothache, which comprises Chinese medicinal components and western medicinal components, wherein the Chinese medicinal components comprise herba Senecionis Scandentis, herba asari, radix Angelicae Dahuricae, Notoginseng radix, cortex Phellodendri, Scutellariae radix, flos Chrysanthemi, flos Lonicerae, herba Menthae and Glycyrrhrizae radix; the western medicines comprise metronidazole tablet, diclofenac sodium tablet, dexamethasone tablet and vitamin B group. The honeysuckle, the baical skullcap root and other Chinese medicinal components have the functions of purging fire, detoxifying, clearing heat and diminishing inflammation.
According to the data, the honeysuckle flower and the scutellaria baicalensis can not only clear heat, expel wind, relieve sore throat and detoxify, but also chlorogenic acid can be used as a free radical scavenger and an antioxidant, can generate a protection effect on cardiovascular systems, and has strong effects of promoting the release of prostacyclin and resisting platelet aggregation; baicalin has platelet aggregation inhibiting and anticoagulant effects, and can inhibit platelet aggregation induced by arachidonic acid.
Based on the analysis, the honeysuckle flower and the scutellaria baicalensis have the capability of relieving cardiovascular and digestive adverse reactions caused by NSAIDs, and the components are clear and simple; can be used in combination with NSAIDs to enhance antipyretic, analgesic and anti-inflammatory effects.
Therefore, in order to further enrich the variety of veterinary drugs, increase the safety of the preparation and improve the curative effect of the existing drugs, the invention discloses a compound antipyretic analgesic and anti-inflammatory composition preparation for veterinary use and application thereof. The invention combines the Chinese medicine component 'honeysuckle flower and scutellaria root' extract (calculated by chlorogenic acid and baicalin) with specific NSAIDs for use, the Chinese medicine and western medicine components are synergistic, the quick-acting antipyretic analgesic and anti-inflammatory effects are achieved, and the effect is long; meanwhile, through compatibility, the risk of cardiovascular and gastrointestinal bleeding possibly generated when the pharmaceutical composition preparation is used is greatly reduced, and the prescription of the preparation is safer and more reasonable.
Disclosure of Invention
Based on the risk of cardiovascular and gastrointestinal bleeding caused by application of NSAIDs, the invention aims to provide a compound antipyretic-analgesic anti-inflammatory composition preparation with high safety factor for animals and application thereof.
The invention aims to solve the first technical problem of providing an antipyretic, analgesic and anti-inflammatory medicine composition preparation for animals.
The invention aims to solve the second technical problem of providing a veterinary antipyretic-analgesic and anti-inflammatory composition preparation administration dosage form.
The third technical problem to be solved by the invention is to provide the application of the antipyretic analgesic and anti-inflammatory medicine composition preparation for livestock.
In order to solve the first technical problem, the invention provides the technical scheme that.
The invention provides a veterinary antipyretic, analgesic and anti-inflammatory drug composition preparation which is characterized in that the active ingredients of the drug composition comprise the following components in parts by mass: 1-1,000 parts of non-steroidal anti-inflammatory drugs, 1-100 parts of honeysuckle flower and scutellaria baicalensis extracts and other necessary auxiliary materials. The honeysuckle extract is a mixture of chlorogenic acid of a honeysuckle extract and baicalin of a scutellaria baicalensis extract, and is subjected to multiple dipping extraction and recovery by adopting ethanol to obtain a reddish brown liquid; extracting Scutellariae radix with alkali, precipitating with acid, and collecting light yellow powder. The honeysuckle extract and the honeysuckle extract can also be purchased from finished products of the honeysuckle extract and can be purchased from Sanjie Biotech limited company in Guanghan.
The veterinary compound antipyretic-analgesic anti-inflammatory composition is characterized in that the active ingredients of the pharmaceutical composition consist of the following components in percentage by mass: non-steroidal anti-inflammatory drugs: honeysuckle extract =1:100 and 1000: 1.
The veterinary compound antipyretic-analgesic anti-inflammatory composition is characterized in that the active ingredients of the honeysuckle and scutellaria baicalensis extract in the pharmaceutical composition consist of the following components in percentage by mass: chlorogenic acid in honeysuckle extract: baicalin =10:1-1:100 of scutellaria baicalensis extract.
The compound antipyretic-analgesic anti-inflammatory composition for livestock is characterized in that the non-steroidal anti-inflammatory drug is selected from salicylic acid, indoleacetic acid, anthranilic acid, aryl alkanoic acid, enolic acid and a selective cyclooxygenase 2 inhibitor, or is one or more of salts of the non-steroidal anti-inflammatory drug or esters of the non-steroidal anti-inflammatory drug; preferably flunixin meglumine, diclofenac, ibuprofen, naproxen, indomethazine, ketoprofen, piroxicam and meloxicam, or as a salt of the aforementioned non-steroidal anti-inflammatory drugs, or as one or more of the aforementioned esters of non-steroidal anti-inflammatory drugs. More preferably, diclofenac or a salt thereof.
In order to solve the second technical problem, the invention provides the technical scheme that.
The medicament can be liquid preparation, injection, syrup, oral solution; can be solid preparation, such as common tablet, dispersible tablet, sustained release tablet, capsule, granule, and powder; can be semisolid preparation, and can be ointment, paste, and gel; any of the above formulations may be used.
A veterinary compound antipyretic analgesic and anti-inflammatory composition preparation is characterized in that the pharmaceutical preparation can be veterinary compound antipyretic analgesic and anti-inflammatory composition injection, and comprises a non-steroidal anti-inflammatory drug, a honeysuckle extract, an antioxidant, a metal ion chelating agent, a bacteriostatic agent, an analgesic, a freezing point regulator, a pH regulator, a solubilizer and an injection solvent; wherein, the non-steroidal anti-inflammatory drug is selected from diclofenac sodium according to the parts by weight, and the dosage of the non-steroidal anti-inflammatory drug is 2.5 percent; the dosage of the honeysuckle flower and scutellaria baicalensis extract is 0.24 percent (calculated by chlorogenic acid), wherein the content of the chlorogenic acid: baicalin =1: 10.
The composition medicine injection is characterized in that the antioxidant is selected from one or more of sodium sulfite, sodium metabisulfite, sodium bisulfite, sodium thiosulfate and vitamin C; the metal ion chelating agent is one or more of sodium calcium ethylene diamine tetracetate, disodium ethylene diamine tetracetate and dicalcium ethylene diamine tetracetate; the bacteriostatic and analgesic agents are selected from one or two of chlorobutanol and benzyl alcohol; the pH regulator is selected from one or more of tartaric acid-tartrate, citric acid-sodium citrate, disodium hydrogen phosphate-sodium dihydrogen phosphate, sodium hydroxide, and hydrochloric acid; the injection solvent is selected from one or more of ethanol, propylene glycol, PEG400, Dimethylformamide (DMF) and Dimethylacetamide (DMA) with different proportions, preferably 40% DMF.
[14] The preparation method of the composition medicine injection comprises the following steps: adding Scutellariae radix extract (calculated as baicalin) into injection solvent containing pH regulator buffer solution, dispersing, adjusting pH to 6.5, boiling for 3min, cooling filtrate to below 60 deg.C, adding flos Lonicerae extract (calculated as chlorogenic acid), dissolving completely, adjusting value to 7.0 with 8% sodium hydroxide solution, settling overnight, and filtering to obtain solution A. Adding the non-steroidal anti-inflammatory drug in the prescription amount into an injection solvent for dispersion, stirring and dissolving, and adjusting the pH to 7.0 to obtain a solution B. The solution A was slowly added to the solution B while stirring, and the pH was adjusted to 7.0. Diluting with injection solvent to desired volume, filtering, packaging, and bottling.
The influence of the stability of the composition medicine injection on the quality of the preparation is very important, and the invention researches the preparation stability of the veterinary compound antipyretic-analgesic and anti-inflammatory medicine composition injection. Adding Scutellariae radix extract (calculated as baicalin) into injection solvent containing pH regulator buffer solution, dispersing, adjusting pH to 6.5, boiling for 3min, cooling filtrate to below 60 deg.C, adding flos Lonicerae extract (calculated as chlorogenic acid), dissolving completely, adjusting value to 7.0 with 8% sodium hydroxide solution, settling overnight, and filtering to obtain solution A. Adding flunixin meglumine, diclofenac sodium, ibuprofen, indomethacin, meloxicam, nimesulide, analgin or antipyrine with prescription dose into injection solvent for dispersion, stirring for dissolution, and adjusting pH to 7.0 with 1mol/L hydrochloric acid to obtain solution B. The solution A was slowly added to the solution B while stirring, and the pH was adjusted to 7.0. Diluting with injection solvent to desired volume, filtering, packaging, and bottling. Taking several prepared injections of each prescription, treating with boiling water for 10min and 30min, and measuring the content of chlorogenic acid, baicalin and non-steroidal anti-inflammatory drug in the injections by high performance liquid chromatography.
The application objects of the compound antipyretic-analgesic-anti-inflammatory medicine composition preparation for livestock are livestock, poultry and pets.
In order to solve the third technical problem, the invention performs rabbit antipyretic contrast test on the veterinary compound antipyretic-analgesic and anti-inflammatory drug injection. 150 New Zealand rabbits with normal body temperature of 38.0-39.6 ℃ and body temperature difference of not more than 1 ℃ are selected, 6 rabbits in each group are injected subcutaneously with boiled peptone solution with concentration of 20% at a dose of 5mL/kg, the body temperature of the rabbits is measured with an anal thermometer after 2 hours and recorded after the onset of fever, after marking, the rabbits are randomly divided into 25 groups, the grouping and administration scheme is as the following Table 6, and the body temperature of the rabbits in each group is measured and recorded after 0.5, 1.0, 1.5, 2, 2.5 and 3.0 hours of drug injection, respectively.
In order to solve the third technical problem, the invention performs a mouse analgesic test on the veterinary compound injection of antipyretic analgesic and anti-inflammatory drug. The test adopts an acetic acid twisting method, 250 Kunming mice are selected, each half of male and female mice is selected, 10 mice are selected in each group, the grouping and administration scheme is as shown in the following table 7, after administration, glacial acetic acid is injected into the abdominal cavity of each mouse, the animals are observed and recorded after the glacial acetic acid is injected into the abdominal cavity, the limbs stretch, the abdomen contract and the inner recess and the hip are lifted after the animal has twisted body reaction, the times of animal twisting body reaction within 10min are recorded, the difference between groups is compared, and the inhibition percentage, namely the inhibition rate (%) = (the number of twisting body average times of the normal saline group-the number of twisting body average times of the administration group)/the number of twisting body average times.
In order to solve the third technical problem, the invention performs rat anti-inflammatory tests on the veterinary compound antipyretic-analgesic and anti-inflammatory drug injection. SD rats of 250 animals, each half of male and female, were selected and 10 animals were selected, and the group and administration schedule were as follows in Table 8. After the administration, fresh egg white was injected on the right rear foot side, and the circumferences of the right rear foot of the rats were measured by a soft skin ruler (not elastic) at 1, 2, 3, and 4 hours before and after the inflammation, so that the swelling ratio (%) was calculated as the circumference value before and after the inflammation, which was formulated as swelling ratio (%) = (circumference after the inflammation-circumference before the inflammation)/circumference before the inflammation x 100%, and the differences between the groups were compared.
In order to solve the third technical problem, the invention carries out adverse reaction-cardiovascular risk monitoring test on the veterinary compound antipyretic-analgesic and anti-inflammatory drug composition preparation. When the prostaglandins are reduced, the blood flow of renal medulla is reduced, the excretion of natrium is reduced, the retention of water and sodium is increased, congestive heart failure and hypertension are aggravated, thrombosis is increased, patients are easy to have adverse reactions of heart and cerebral vessels, and even cerebral apoplexy, myocardial infarction and aggravation of heart failure are caused. Therefore, the compound honeysuckle and scutellaria baicalensis composition injection for animal antipyretic, analgesic and anti-inflammatory is subjected to blood pressure change monitoring test. Taking 75 beagle dogs, and taking 3 beagle dogs each; the grouping and dosing regimen is shown in table 9 below. The basal blood pressure level before dosing was used as a negative control for each dog. Each group of dogs was injected intravenously at a time of 3 mL/min, and after administration for 10min, Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), mean arterial pressure (MBP) and Heart Rate (HR) of each dog were measured with a sphygmomanometer, respectively, 5 times, and averaged and recorded.
In order to solve the third technical problem, the invention carries out adverse reaction-gastrointestinal bleeding risk monitoring test on the veterinary compound antipyretic-analgesic and anti-inflammatory drug composition preparation. Taking 125 mice, 5 mice in each group; the grouping and dosing regimen is shown in table 10 below. Before the experiment began, the weight of each group of mice was weighed and recorded. Six consecutive days were given at the same time and the body weight of the mice before each administration was weighed and recorded. Weighing the body weight of the mouse the next day after the last administration, dissecting, soaking all the stomachs in 10% neutral formalin, and preserving at normal temperature; the stomach tissue of the mouse was sampled, paraffin sections were prepared, and then photographed under a microscope at 200 times.
Compared with a single component of the non-steroidal anti-inflammatory drug in the pharmaceutical composition, the veterinary compound antipyretic-analgesic anti-inflammatory drug composition preparation prepared by the invention can obviously improve the curative effect of the drug, greatly reduce the risk of cardiovascular and gastrointestinal bleeding easily caused by the use of the non-steroidal anti-inflammatory drug, and ensure that the prescription of the preparation is safer and more reasonable.
The invention has the advantages.
1. In the field of veterinary medicines, a veterinary compound antipyretic analgesic anti-inflammatory composition preparation combining a non-steroidal anti-inflammatory drug and a honeysuckle extract is provided for the first time.
2. In the field of veterinary medicine, the veterinary compound antipyretic-analgesic-anti-inflammatory medicine composition preparation combined by the non-steroidal anti-inflammatory medicine and the honeysuckle extract is provided for the first time.
3. In the field of veterinary medicines, the application of a veterinary compound antipyretic analgesic anti-inflammatory composition preparation combining a non-steroidal anti-inflammatory drug and a honeysuckle extract is provided for the first time.
4. The invention combines the non-steroidal anti-inflammatory drug and the honeysuckle extract (chlorogenic acid and baicalin) for the first time, is used for animal antipyretic, analgesic and anti-inflammatory, can obviously improve the drug effect, and effectively reduces the risk of cardiovascular and gastrointestinal bleeding easily caused by the use of the non-steroidal anti-inflammatory drug.
5. The compound antipyretic analgesic anti-inflammatory drug composition injection prepared by the invention adopts a compound solvent to effectively solve the problems of drug solubility and preparation stability.
6. The invention considers the antipyretic, analgesic and anti-inflammatory treatment effects of the prescription, and does not contain aniline non-steroidal anti-inflammatory drug with almost no anti-inflammatory effect; based on the results of the formulation stability test, the praziquantel nonsteroidal anti-inflammatory drug with unqualified stability is not included.
7. The compound antipyretic analgesic anti-inflammatory 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.
8. The extraction and production process of the compound antipyretic-analgesic-anti-inflammatory medicine composition preparation is simple and convenient, the production flow is easy to automate, and the preparation method is suitable for industrial expanded production.
Detailed Description
Examples 1 to 8.
Examples used raw materials honeysuckle extract and honeysuckle flower extract were purchased from samsung biotechnology limited, guanghan.
The prescription (5 mL) of the compound antipyretic-analgesic and anti-inflammatory medicine composition injection for livestock is as follows.
TABLE 1 examples 1-8.
Note: (1) the dosage of the honeysuckle flower and scutellaria baicalensis extract is calculated by chlorogenic acid, wherein the weight ratio of the chlorogenic acid: baicalin =10:1-1: 100;
(2) q.s. means proper amount, sufficient amount.
The preparation method comprises the following steps.
Adding Scutellariae radix extract (calculated as baicalin) into injection solvent containing pH regulator buffer solution, dispersing, adjusting pH to 6.5, boiling for 3min, cooling filtrate to below 60 deg.C, adding flos Lonicerae extract (calculated as chlorogenic acid), dissolving completely, adjusting value to 7.0 with 8% sodium hydroxide solution, settling overnight, and filtering to obtain solution A. Adding the non-steroidal anti-inflammatory drug in the prescription amount into an injection solvent for dispersion, stirring and dissolving, and adjusting the pH to 7.0 to obtain a solution B. The solution A was slowly added to the solution B while stirring, and the pH was adjusted to 7.0. Diluting with injection solvent to desired volume, filtering, packaging, and bottling.
Example 9.
And (3) investigating the preparation stability of the veterinary compound antipyretic-analgesic and anti-inflammatory drug composition injection.
1. The experimental method comprises the following steps: adding Scutellariae radix extract (calculated as baicalin) into injection solvent containing pH regulator buffer solution, dispersing, adjusting pH to 6.5, boiling for 3min, cooling filtrate to below 60 deg.C, adding flos Lonicerae extract (calculated as chlorogenic acid), dissolving completely, adjusting value to 7.0 with 8% sodium hydroxide solution, settling overnight, and filtering to obtain solution A. Adding flunixin meglumine, diclofenac sodium, ibuprofen, indomethacin, meloxicam, nimesulide, analgin or antipyrine with prescription dose into injection solvent for dispersion, stirring for dissolution, and adjusting pH to 7.0 with 1mol/L hydrochloric acid to obtain solution B. The solution A was slowly added to the solution B while stirring, and the pH was adjusted to 7.0. Diluting with injection solvent to desired volume, filtering, packaging, and bottling. Taking several prepared injections of each prescription, treating with boiling water for 10min and 30min, respectively, measuring pH, observing properties, and measuring chlorogenic acid, baicalin and nonsteroidal anti-inflammatory drug content in the injection by high performance liquid chromatography.
Table 2 formulation stability study formula of veterinary compound antipyretic analgesic and anti-inflammatory injection.
2. And (5) experimental results.
And 3, a preparation stability investigation result of the veterinary compound antipyretic-analgesic and anti-inflammatory drug composition injection.
The experimental results show that the praziquantel nonsteroidal anti-inflammatory drugs analgin and antipyrine have obvious degradation effect on chlorogenic acid; diclofenac sodium (different proportions), flunixin meglumine, ibuprofen, indomethacin, meloxicam and nimesulide are added into the injection, the hydrolysis of chlorogenic acid is not remarkably promoted, and other effective components in the prescription are kept stable; in the prescription with the same medicine proportion, the chlorogenic acid in the diclofenac sodium group has the lowest hydrolysis degree, namely is more stable. At the same time, we found that the addition of baicalin contributes to the stability of chlorogenic acid. Based on the above analysis, the nsaid of the present invention does not contain praziquantel-based drugs in consideration of the stability of the formulation.
Examples 10 to 19.
The invention relates to a prescription (powder, 100 g) of a compound antipyretic-analgesic and anti-inflammatory medicine composition preparation for livestock.
TABLE 4 formulation of examples 10-19.
Note: the dosage of the honeysuckle flower and scutellaria baicalensis extract is calculated by chlorogenic acid, wherein the weight ratio of the chlorogenic acid: baicalin =10:1-1: 100.
The preparation method comprises the following steps.
Placing the crude drug powder of YINHUANG extract, non-steroidal anti-inflammatory drug, 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 the YINHUANG extract and the non-steroidal anti-inflammatory drug 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 the required lactose according to an equivalent progressive mixing method, grinding uniformly, subpackaging into single-dose powder by weight method, and packaging.
Examples 20 to 29.
The invention relates to a single dose prescription (tablet) of a veterinary compound antipyretic-analgesic anti-inflammatory composition preparation.
TABLE 5 examples 20-29.
Note: the dosage of the honeysuckle flower and scutellaria baicalensis extract is calculated by chlorogenic acid, wherein the weight ratio of the chlorogenic acid: baicalin =10:1-1: 100.
The preparation method comprises the following steps: putting the crude drug powder of the honeysuckle flower and the scutellaria baicalensis extract, the non-steroidal anti-inflammatory drug, the filling agent, the lubricant magnesium stearate and the glidant micropowder silica gel into an oven to be dried for 2 hours at 40 ℃, taking out, and respectively sieving by a 120-mesh sieve. And (3) fully and uniformly mixing the powder according to the prescription amount, and directly tabletting the powder.
The prescription (oral solution, 1L) of the compound antipyretic-analgesic and anti-inflammatory medicine composition preparation for livestock is as follows.
TABLE 6 examples 30-39.
Note: the dosage of the honeysuckle flower and scutellaria baicalensis extract is calculated by chlorogenic acid, wherein the weight ratio of the chlorogenic acid: baicalin =10:1-1: 100.
The preparation method comprises the following steps.
At normal temperature (25 deg.C), adding Scutellariae radix extract (calculated as baicalin) into solvent containing pH regulator buffer solution, dispersing, adjusting pH to 6.5, boiling for 3min, cooling filtrate to below 60 deg.C, adding flos Lonicerae extract (calculated as chlorogenic acid), dissolving completely, adjusting value to 7.0 with 8% sodium hydroxide solution, settling overnight, and filtering to obtain solution A. Dissolving the non-steroidal anti-inflammatory drug, the antioxidant, the metal ion chelating agent, the preservative and the flavoring agent in the prescription amount in a solvent, dispersing, stirring and dissolving to obtain solution B. Slowly adding the solution A into the solution B which is stirring. Fixing volume with solvent, filtering, packaging, and bottling.
Example 40.
The veterinary compound antipyretic analgesic and anti-inflammatory drug composition injection is used for rabbit antipyretic contrast tests.
The dosage of the non-steroidal anti-inflammatory drugs in the formulas of the experimental group and the control group containing the non-steroidal anti-inflammatory drugs used in the research is constant, the specification is 25mg/mL, and the dosage of chlorogenic acid and baicalin in the formula of the control group only containing the silver yellow extract is consistent with that of the experimental group with the corresponding proportion; the auxiliary materials are prepared into injections according to the formula of the example 1 and only the dosage of the chlorogenic acid and the baicalin is adjusted. Wherein the non-steroidal anti-inflammatory drug is selected from diclofenac sodium, flunixin meglumine, meloxicam and indomethacin.
1. Experimental methods.
150 New Zealand rabbits with normal body temperature of 38.0-39.6 ℃ and body temperature difference of not more than 1 ℃ are selected, 6 rabbits in each group are injected subcutaneously with boiled peptone solution with the concentration of 20% at the dose of 5mL/kg, the body temperature of the rabbits is measured by an anal thermometer after 2 hours and recorded after the fever is induced, after marking, the rabbits are randomly divided into 25 groups, the grouping and administration scheme is as the following table 6, and the body temperature of the rabbits in each group is measured and recorded after 0.5, 1.0, 1.5, 2, 2.5 and 3.0 hours of medicine injection respectively.
And (5) experimental results.
Table 7 shows the comparative test results of the compound antipyretic analgesic and anti-inflammatory injection for rabbit antipyretic.
The body temperature change of each group of rabbits at each time point before and after administration is shown in the table above, and the normal body temperature range of the rabbits is 38.0-39.6 ℃. The results show that the body temperature of the rabbits in the blank group given physiological saline did not change significantly, while the body temperatures of the other groups all tended to decrease to different degrees within 3 hours after the administration. As can be seen from the data in the table, in 3h, the body temperatures of the rabbits of the experimental group and the control group containing different kinds of NSAIDs are all reduced to be within a normal range, the antipyretic effect of the compound antipyretic-analgesic and anti-inflammatory drug composition injection of the experimental group is superior to that of the corresponding single-component NSAIDs injection, the antipyretic effect of the group containing diclofenac sodium is most obvious, and when the diclofenac sodium: when the honeysuckle and scutellaria baicalensis extract (calculated by chlorogenic acid) =1:100-10:1, the antipyretic effect of the compound antipyretic-analgesic and anti-inflammatory medicine composition injection is superior to that of other proportion ranges; yinhuang injection with different proportions also has antipyretic effect, but the effect intensity is weaker than that of injection containing NSAIDs. The above results indicate that the addition of the honeysuckle flower and scutellaria extract can enhance the antipyretic effect of the NSAIDs injection.
Example 41.
The veterinary compound antipyretic analgesic and anti-inflammatory drug composition injection is used for a mouse analgesic test.
The dosage of the non-steroidal anti-inflammatory drugs in the formulas of the experimental group and the control group containing the non-steroidal anti-inflammatory drugs used in the research is constant, the specification is 25mg/mL, and the dosage of chlorogenic acid and baicalin in the formula of the control group only containing the silver yellow extract is consistent with that of the experimental group with the corresponding proportion; the auxiliary materials are prepared into injections according to the formula of the example 1 and only the dosage of the chlorogenic acid and the baicalin is adjusted. Wherein the non-steroidal anti-inflammatory drug is selected from diclofenac sodium, flunixin meglumine, meloxicam and indomethacin.
1. Experimental methods.
80 Kunming mice are selected, each male and female is half, each group is 10, the grouping and administration scheme is as the following table 7, after administration, glacial acetic acid is injected into the abdominal cavity of each mouse, the animals are observed and recorded after the glacial acetic acid is injected into the abdominal cavity, the limbs stretch, the abdomen contract and the inner concave and the hip are raised after the writhing reaction, the times of the writhing reaction of the animals within 10min are recorded, the differences among the groups are compared, and the inhibition percentage, namely the inhibition ratio (%) = (the average times of writhing of the normal saline group-the average times of writhing of the administration group)/the average times of writhing of the normal saline group is multiplied by 100 percent.
And (5) experimental results.
Table 8 shows the results of the analgesic and antipyretic compound injection for mice.
Note: 1. in comparison with the blank set, the results,p*＜0.1，p #less than 0.05; as compared with the group 21, it is,p a< 0.01, and compared to group 22,p bless than 0.01; as compared with the case of the group 23,p c＜0.01，p dless than 0.05; in comparison with the 24 th group,p e＜0.01。
the recorded writhing times of the mice injected with glacial acetic acid solution after administration are shown in the table. According to statistical analysis, the times of writhing of the mice in the experimental group are obviously reduced, and compared with the corresponding single-component NSAIDs injection group, the analgesic capacity is obviously enhanced, and the obvious difference is achieved; different NSAIDs have different analgesic effects, and the results in the table show that: diclofenac sodium, flunixin meglumine, meloxicam and indomethacin, namely the analgesic effect of the group containing diclofenac sodium is most obvious, when the ratio of diclofenac sodium: when the honeysuckle and scutellaria baicalensis extract (calculated by chlorogenic acid) =1:100-1-10:1, the analgesic effect of the compound antipyretic-analgesic and anti-inflammatory medicine composition injection is superior to that of other proportion ranges; the number of writhing times of the mice in the Yinhuang injection group with different proportions is also reduced to different degrees. The above results indicate that the addition of the honeysuckle flower and scutellaria extract can enhance the analgesic effect of the NSAIDs injection.
Example 42.
The veterinary compound antipyretic-analgesic and anti-inflammatory drug composition injection is used for anti-inflammatory tests of rats.
The dosage of the non-steroidal anti-inflammatory drugs in the formulas of the experimental group and the control group containing the non-steroidal anti-inflammatory drugs used in the research is constant, the specification is 25mg/mL, and the dosage of chlorogenic acid and baicalin in the formula of the control group only containing the silver yellow extract is consistent with that of the experimental group with the corresponding proportion; the auxiliary materials are prepared into injections according to the formula of the example 1 and only the dosage of the chlorogenic acid and the baicalin is adjusted. Wherein the non-steroidal anti-inflammatory drug is selected from diclofenac sodium, flunixin meglumine, meloxicam and indomethacin.
1. Experimental methods.
80 SD rats, male and female halves, 10 rats each, were selected, and the grouping and dosing schedule was as follows in Table 8. After the administration, fresh egg white was injected on the right rear foot side, and the circumferences of the right rear foot of the rats were measured by a soft skin ruler (not elastic) at 1, 2, 3, and 4 hours before and after the inflammation, so that the swelling ratio (%) was calculated as the circumference value before and after the inflammation, which was formulated as swelling ratio (%) = (circumference after the inflammation-circumference before the inflammation)/circumference before the inflammation x 100%, and the differences between the groups were compared.
And (5) experimental results.
TABLE 9 Compound antipyretic analgesic and anti-inflammatory injection for rat anti-inflammatory test results.
The results are shown in the above table, and the swelling rate of the mice in the experimental group and the control group is reduced to different degrees compared with the blank group at different time points after administration; the foot swelling condition of the mice in the experimental group and the single-component non-steroidal anti-inflammatory drug comparison group is obviously weaker, and compared with the corresponding single-component NSAIDs injection, the anti-inflammatory capacity of the experimental group is stronger, wherein the anti-inflammatory effect of the experimental group containing diclofenac sodium is most obviously enhanced; different NSAIDs have different anti-inflammatory capabilities, and the results are shown in the table: indomethacin > meloxicam > diclofenac sodium > flunixin meglumine, diclofenac sodium has slightly weaker anti-inflammatory effect than the former two, when diclofenac sodium: when the honeysuckle and scutellaria baicalensis extract (calculated by chlorogenic acid) =1:100-10:1, the anti-inflammatory effect of the compound antipyretic analgesic and anti-inflammatory drug composition injection is superior to that of other proportion ranges; the above results show that the addition of the honeysuckle flower and scutellaria baicalensis extract can enhance the swelling eliminating effect of the non-steroidal anti-inflammatory drug on the swelling of feet caused by egg white.
Example 43.
The veterinary compound antipyretic-analgesic and anti-inflammatory medicine composition preparation is subjected to adverse reaction-cardiovascular risk monitoring test.
The dosage of the non-steroidal anti-inflammatory drugs in the formulas of the experimental group and the control group containing the non-steroidal anti-inflammatory drugs used in the research is constant, the specification is 25mg/mL, and the dosage of chlorogenic acid and baicalin in the formula of the control group only containing the silver yellow extract is consistent with that of the experimental group with the corresponding proportion; the auxiliary materials are prepared into injections according to the formula of the example 1 and only the dosage of the chlorogenic acid and the baicalin is adjusted. Wherein the non-steroidal anti-inflammatory drug is selected from diclofenac sodium, flunixin meglumine, meloxicam and indomethacin.
1. Experimental methods.
Taking 75 beagle dogs, and taking 3 beagle dogs each; the grouping and dosing regimen is shown in table 9 below. The basal blood pressure level before dosing was used as a negative control for each dog. Each group of dogs was injected intravenously at a time of 3 mL/min, and after administration for 10min, Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), mean arterial pressure (MBP) and Heart Rate (HR) of each dog were measured with a sphygmomanometer, respectively, 5 times, and averaged and recorded.
And (5) experimental results.
TABLE 10 cardiovascular risk monitoring test results for the compound antipyretic analgesic and anti-inflammatory composition injection.
As shown in the above table, when the NSAIDs exert antipyretic, analgesic and anti-inflammatory effects, the prostaglandins are decreased, so that the blood pressure is easily increased, and the risk of blood pressure increase caused by different NSAIDs is different, and the results are shown in the table: the meloxicam and flunixin meglumine are greater than the diclofenac sodium and not less than indometacin, and the risks of the two are relatively low; the honeysuckle and scutellaria baicalensis extracts can reduce blood pressure to a certain extent, and the data results of experimental groups reflect that the honeysuckle and scutellaria baicalensis extracts with different proportions can be combined with non-steroidal anti-inflammatory drugs to effectively control cardiovascular risks possibly caused by NSAIDs, so that the prescription of the preparation is safer and more reasonable, wherein when the diclofenac sodium is combined with the honeysuckle and scutellaria baicalensis extracts with different proportions, the change of each index is minimum, namely the safety coefficient is high, and when the diclofenac sodium: when the honeysuckle and scutellaria baicalensis extract (calculated by chlorogenic acid) =1:100-10:1, the safety of the compound antipyretic analgesic and anti-inflammatory medicine composition injection is superior to that of other proportion ranges.
Example 44.
The veterinary compound antipyretic-analgesic and anti-inflammatory medicine composition preparation is subjected to adverse reaction-gastrointestinal bleeding risk monitoring test.
The dosage of the non-steroidal anti-inflammatory drugs in the formulas of the experimental group and the control group containing the non-steroidal anti-inflammatory drugs used in the research is constant, the specification is 25mg/mL, and the dosage of chlorogenic acid and baicalin in the formula of the control group only containing the silver yellow extract is consistent with that of the experimental group with the corresponding proportion; the auxiliary materials are prepared into injections according to the formula of the example 1 and only the dosage of the chlorogenic acid and the baicalin is adjusted. Wherein the non-steroidal anti-inflammatory drug is selected from diclofenac sodium, flunixin meglumine, meloxicam and indomethacin.
1. Experimental methods.
Taking 125 mice, 5 mice in each group; the grouping and dosing regimen is shown in table 10 below. Before the experiment began, the weight of each group of mice was weighed and recorded. Six consecutive days were given at the same time and the body weight of the mice before each administration was weighed and recorded. Weighing the body weight of the mouse the next day after the last administration, dissecting, soaking all the stomachs in 10% neutral formalin, and preserving at normal temperature; the stomach tissue of the mouse was sampled, paraffin sections were prepared, and then photographed under a microscope at 200 times.
And (5) experimental results.
TABLE 11 gastrointestinal bleeding risk monitoring test results of the compound antipyretic analgesic and anti-inflammatory injection.
Note: "-" no lesions; "+" with visible lesions; "x" with obvious lesions; "x" had severe lesions.
Results as shown in the table above, the body weight of the blank group of mice increased day by day; the body weight of the mice of the non-steroidal anti-inflammatory drug injection control group is obviously reduced, and the body weight of the mice of the different proportions of the honeysuckle extract injection control group is also increased; the mice in the experimental group showed a slower increase in body weight compared to the blank group. Meanwhile, in the experimental process, except for the steroidal anti-inflammatory drug injection control group, the mental state of each group of mice was good. Observing the gastric section condition of each group of mice, wherein the blank group, each experimental group and the comparison group of the honeysuckle extract injection with different proportions have complete tissue forms of the mice, the thickness of the gastric basal layer and the mucous layer is larger and complete, the external villi are arranged orderly, and no lesion and damage exist; the gastric mucosa of the mice of the non-steroidal anti-inflammatory drug injection control group is subjected to tissue lesion to different degrees, and particularly, the outermost part of the mucosal layer of the mice of the indomethacin control group is infiltrated by a large amount of inflammatory cells. Therefore, the damage of the honeysuckle and the scutellaria baicalensis to the stomach can be effectively reduced by adding the honeysuckle and the scutellaria baicalensis extract into the non-steroidal anti-inflammatory drug, so that the preparation prescription is safer and more reasonable.
In conclusion, the non-steroidal anti-inflammatory drug and the honeysuckle extract in the compound antipyretic-analgesic anti-inflammatory drug composition can play a synergistic role, the antipyretic-analgesic anti-inflammatory effect is increased, and meanwhile, adverse reactions caused by the non-steroidal anti-inflammatory drug can be reduced. When the non-steroidal anti-inflammatory drug is diclofenac sodium, the compound antipyretic analgesic anti-inflammatory drug composition has the best antipyretic analgesic effect, and when the compound antipyretic analgesic anti-inflammatory drug composition is used together with the honeysuckle flower and scutellaria baicalensis extract, the anti-inflammatory effect is enhanced most obviously compared with that of a single preparation; the honeysuckle and scutellaria baicalensis extract can effectively control adverse reactions caused by diclofenac sodium medication.
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 (9)
1. The veterinary compound antipyretic-analgesic anti-inflammatory composition is characterized in that active ingredients of the pharmaceutical composition consist of 1-1,000 parts of diclofenac sodium and 1-100 parts of a honeysuckle extract, the honeysuckle extract is a combination of chlorogenic acid and baicalin, and the weight ratio of the diclofenac sodium: the ratio of the honeysuckle extract to the scutellaria baicalensis extract is 1:100-10: 1; the ratio of chlorogenic acid to baicalin is 1: 10-1: 100.
2. the veterinary compound antipyretic-analgesic and anti-inflammatory composition according to claim 1, wherein the dosage form of the pharmaceutical composition is selected from liquid preparation, solid preparation or semisolid preparation, and the liquid preparation is selected from injection, syrup or oral solution; the solid preparation is selected from common tablets, dispersible tablets, sustained release tablets, capsules, granules and powder; the semisolid preparation is selected from ointment, paste and gel.
3. A veterinary compound antipyretic-analgesic and anti-inflammatory injection comprising the veterinary compound antipyretic-analgesic and anti-inflammatory composition according to claim 1, an antioxidant, a metal ion chelating agent, a bacteriostatic agent, an analgesic, a freezing point regulator, a pH regulator, a solubilizer and an injection solvent.
4. The veterinary compound antipyretic-analgesic and anti-inflammatory injection as claimed in claim 3, wherein the antioxidant is selected from one or more of sodium sulfite, sodium metabisulfite, sodium bisulfite, sodium thiosulfate and vitamin C; the metal ion chelating agent is selected from one or more of calcium ethylene diamine tetracetate, disodium ethylene diamine tetracetate and dicalcium ethylene diamine tetracetate; the bacteriostatic agent and the analgesic agent are selected from one or two of chlorobutanol and benzyl alcohol; the pH regulator is one or more selected from tartaric acid-tartrate, citric acid-sodium citrate, disodium hydrogen phosphate-sodium dihydrogen phosphate, sodium hydroxide and hydrochloric acid; the injection solvent is selected from one or more of ethanol, propylene glycol, PEG400, Dimethylformamide (DMF) and Dimethylacetamide (DMA) in different proportions.
5. The veterinary compound antipyretic-analgesic and anti-inflammatory injection according to claim 4, wherein the injection solvent is 40% DMF.
6. The veterinary compound injection of antipyretic analgesic and anti-inflammatory drug as claimed in claim 3, characterized in that, in percentage by weight, diclofenac sodium is 2.5%; the dosage of the honeysuckle flower and scutellaria baicalensis extract is 0.24%, wherein the weight ratio of chlorogenic acid: baicalin 1: 10.
7. The veterinary compound antipyretic-analgesic and anti-inflammatory injection as claimed in claim 3, characterized in that the preparation method of the injection comprises the following steps: adding the Scutellariae radix extract into injection solvent containing pH regulator buffer solution, dispersing, adjusting pH to 6.5, boiling for 3min, cooling filtrate to below 60 deg.C, adding flos Lonicerae extract, dissolving completely, adjusting pH to 7.0 with 8% sodium hydroxide solution, settling overnight, and filtering to obtain solution A; adding diclofenac sodium in the prescription amount into an injection solvent for dispersion, stirring and dissolving, and adjusting the pH to 7.0 to obtain a solution B; slowly adding the solution A into the solution B while stirring, and adjusting the pH value to 7.0; diluting with injection solvent to desired volume, filtering, packaging, and bottling.
8. The veterinary compound antipyretic-analgesic and anti-inflammatory composition according to claim 1 or 2 or the veterinary compound antipyretic-analgesic and anti-inflammatory injection according to any one of claims 3 to 7, which is applied to livestock, poultry and pets.
9. Use of the veterinary compound antipyretic-analgesic and anti-inflammatory composition according to claim 1 or 2 or the veterinary compound antipyretic-analgesic and anti-inflammatory injection according to any one of claims 3 to 7 in preparing antipyretic-analgesic and anti-inflammatory drugs for animals or other diseases accompanied by obvious pain.
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| KR20100008548A (en) * | 2008-07-16 | 2010-01-26 | (주) 서울바이오메드 | A composition for treatment of choroidal neovascular diseases comprising chlorogenic acid |
| CN102188436A (en) * | 2011-03-28 | 2011-09-21 | 郑州百瑞动物药业有限公司 | Injection for treating porcine mixed infection |
| CN102198167A (en) * | 2011-06-07 | 2011-09-28 | 重庆巴仕迪动物药业有限公司 | Pharmaceutical composition for treating flu or hyperpyrexia caused by bacterial virus |
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| CN105106935A (en) * | 2015-08-31 | 2015-12-02 | 河南亚卫动物药业有限公司 | Compound Flunixin meglumine injection and preparation method thereof |
| CN107648215A (en) * | 2017-09-27 | 2018-02-02 | 成都导飞科技有限公司 | A kind of compound silver yellow composition injection for animal antipyretic-antalgic anti-inflammatory |
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| KR20100008548A (en) * | 2008-07-16 | 2010-01-26 | (주) 서울바이오메드 | A composition for treatment of choroidal neovascular diseases comprising chlorogenic acid |
| CN102188436A (en) * | 2011-03-28 | 2011-09-21 | 郑州百瑞动物药业有限公司 | Injection for treating porcine mixed infection |
| CN102198167A (en) * | 2011-06-07 | 2011-09-28 | 重庆巴仕迪动物药业有限公司 | Pharmaceutical composition for treating flu or hyperpyrexia caused by bacterial virus |
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