CN108653262B - Ketoprofen external medicine and preparation method and application thereof - Google Patents

Ketoprofen external medicine and preparation method and application thereof Download PDF

Info

Publication number
CN108653262B
CN108653262B CN201810721306.4A CN201810721306A CN108653262B CN 108653262 B CN108653262 B CN 108653262B CN 201810721306 A CN201810721306 A CN 201810721306A CN 108653262 B CN108653262 B CN 108653262B
Authority
CN
China
Prior art keywords
ketoprofen
parts
external
external medicine
medicine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201810721306.4A
Other languages
Chinese (zh)
Other versions
CN108653262A (en
Inventor
寇贺红
李成应
江国亮
谢志恒
叶伟庆
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Foshan Nanhai Eastern Along Pharmaceutical Co ltd
Original Assignee
Foshan Nanhai Eastern Along Pharmaceutical Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Foshan Nanhai Eastern Along Pharmaceutical Co ltd filed Critical Foshan Nanhai Eastern Along Pharmaceutical Co ltd
Priority to CN201810721306.4A priority Critical patent/CN108653262B/en
Publication of CN108653262A publication Critical patent/CN108653262A/en
Application granted granted Critical
Publication of CN108653262B publication Critical patent/CN108653262B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dermatology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pregnancy & Childbirth (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention provides a ketoprofen external medicine and a preparation method and application thereof, relating to the technical field of medicinal preparations. Through the synergistic cooperation of the specific components and the proportion, the ketoprofen external medicine provided by the invention can reduce the degree of allodynia, shorten the time for pain and recovery and avoid the occurrence of irreversible injury, thereby greatly improving the treatment effect and having the advantages of convenient use and low cost. According to the preparation method provided by the invention, the ketoprofen external medicine with good analgesic effect can be obtained through the steps of adding the specific components in sequence, uniformly mixing, dissolving and the like. The external analgesic drug provided by the invention comprises the analgesic drug combination provided by the invention, can obviously reduce animal pain, has the effect of eliminating swelling, improves animal welfare, accelerates animal recovery and improves economic benefits.

Description

Ketoprofen external medicine and preparation method and application thereof
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a ketoprofen external medicine and a preparation method and application thereof.
Background
With the rapid development of economy, the intensification degree of animal breeding is higher and higher, and animal diseases are more and more complicated. Especially infectious diseases. Such as pneumonia, enteritis, mastitis, metritis, etc., and finally, the symptoms of inflammation, fever, pain, etc. appear in animals.
Ketoprofen belongs to a high-efficiency non-steroidal anti-inflammatory drug (NSAIDs), has the effects of resisting inflammation, relieving pain and relieving fever, and mainly inhibits the biosynthesis of inflammatory substances Prostaglandin (PGs), Leukotriene (LTs) and Thromboxane (TXs) by reversibly inhibiting the activity of Cyclooxygenase (COXs), proinflammatory peptide or Lipoxygenase (LOXs), so that the release of bradykinin is reduced, and further plays good anti-inflammatory, analgesic and antipyretic roles. The traditional Chinese medicine composition is mainly applied to treating rheumatic or rheumatoid arthritis, ankylosing spondylitis, osteoarthritis and other related inflammatory diseases in human clinical practice; and pain caused by trauma, postoperative pain, acute renal colic, intestinal colic, gout attack, etc. The traditional Chinese medicine composition is mainly applied to veterinary clinic for treating inflammatory diseases such as mastitis, mammary gland edema, pneumonia, arthritis and the like of dairy cows, horses and pig animals, intestinal colic, skeletal muscle trauma and the like.
In recent years, animal welfare has received much attention and there have been organizations focusing on the study of animal pain, including pain due to illness and the effect of pain on productivity. For example, the treatment of postoperative pain of pets, the treatment of intestinal colic of racehorses, traumatic pain of skeletal muscles and the like, and the treatment of mastitis of cows and sows has allodynia. However, the existing drugs applied to animals for relieving pain often have the problems of long effect taking time, high cost, side effect and the like.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The first purpose of the present invention is to provide a ketoprofen external-use drug to alleviate the technical problems of long effective time, high cost or side effects of the drugs for relieving pain in the prior art.
The second purpose of the invention is to provide the preparation method of the ketoprofen external medicine, the method has simple process and convenient operation, can save a large amount of manpower and material resources, effectively improves the production efficiency, and the prepared ketoprofen external medicine has good analgesic effect.
The third purpose of the invention is to provide the application of the ketoprofen external medicine in preparing an external analgesic.
The fourth purpose of the invention is to provide an external analgesic drug to relieve the technical problems of long effective time, high cost or side effect of the drugs for relieving pain in the prior art.
The invention provides a ketoprofen external medicine, which comprises the following components in parts by weight based on 100 parts by weight:
0.1-30 parts of ketoprofen, 0.1-20 parts of cosolvent, 0.1-2 parts of transdermal absorption enhancer, 0.1-5 parts of stabilizer and the balance of water.
Further, the ketoprofen external medicine comprises the following components in parts by weight based on 100 parts by weight:
1-30 parts of ketoprofen, 2-20 parts of cosolvent, 0.1-1.5 parts of transdermal absorption enhancer, 0.1-4 parts of stabilizer and the balance of water;
preferably, the ketoprofen external use medicine comprises the following components in parts by weight based on 100 parts by weight:
5-30 parts of ketoprofen, 3-15 parts of cosolvent, 0.1-1 part of transdermal absorption enhancer, 1-3 parts of stabilizer and the balance of water.
Further, the cosolvent is selected from one or more of arginine, meglumine, histidine, methionine, betacyclodextrin, tween 80, polyethylene glycol 400 or polyethylene glycol 600;
preferably, the cosolvent is arginine and polyethylene glycol 600;
preferably, the mass ratio of the arginine to the polyethylene glycol 600 is 1-30: 1-30.
Further, the transdermal absorption enhancer is selected from one or more of laurocapram, menthol, propylene glycol or eucalyptus oil;
preferably, the transdermal absorption enhancer is laurocapram;
preferably, the stabilizer is selected from citric acid;
preferably, the ketoprofen external medicine further comprises 0.001-5 parts of pigment, preferably 0.001-1 part, more preferably 0.005-0.1 part;
preferably, the pigment is a food grade pigment, preferably brilliant blue.
Further, the ketoprofen external medicine also comprises 0.1-10 parts of an emollient, preferably 1-5 parts, and more preferably 1-3 parts;
preferably, the emollient comprises glycerin.
Further, the ketoprofen external medicine also comprises 0.1-20 parts of penetration enhancer, preferably 1-15 parts, more preferably 5-10 parts;
preferably, the penetration aid is an organic solvent, preferably a C1-C4 alcohol, more preferably ethanol.
The invention also provides a preparation method of the ketoprofen external medicine, which comprises the following steps:
taking the components according to the formula amount, adding the cosolvent into water, uniformly mixing until the cosolvent is dissolved, then adding the ketoprofen, uniformly mixing until the ketoprofen is dissolved, then adding the stabilizer and the transdermal absorption enhancer, uniformly mixing, finally adding the pigment, and fixing the volume to obtain the ketoprofen external medicine.
Further, before adding the cosolvent, heating the solvent;
preferably, the temperature of the heat treatment is 50 to 70 ℃, preferably 55 to 65 ℃.
The invention also provides the ketoprofen external medicine or the application of the ketoprofen external medicine prepared by the preparation method in preparing external analgesic medicines;
preferably, the external analgesic drug is an external analgesic spray.
In addition, the invention also provides application of the ketoprofen external medicine or the ketoprofen external medicine prepared by the preparation method in preparation of a medicine for adjuvant treatment of cow mastitis.
The ketoprofen external medicine provided by the invention comprises the components of ketoprofen, a cosolvent, a transdermal absorption enhancer and a stabilizer. Wherein, the ketoprofen belongs to NSAIDs and is used as an active ingredient of the ketoprofen external-use medicine, the degree of allodynia can be reduced, the effects of analgesia and inflammation diminishing can be achieved, the compatibility of each component can be better by adding the cosolvent, the external ketoprofen drug provided by the invention can be absorbed by skin more easily when being used externally by adding the transdermal absorption enhancer, the aim of good absorption and good curative effect can be achieved, the stability of the external ketoprofen drug can be stronger by adding the stabilizer, the external ketoprofen drug is not easy to denaturalize and deteriorate, is convenient to store and saves the cost, through the synergistic cooperation of the specific components and the proportion, the ketoprofen external medicine provided by the invention can reduce the degree of allodynia, shorten the time of pain and recovery, avoid the occurrence of irreversible injury, thereby greatly improving the treatment effect and having the advantages of convenient use and lower cost.
The preparation method of the ketoprofen external medicine provided by the invention is simple to operate, and can enable the components to be matched with each other through specific operation steps such as specific component adding sequence, uniform mixing and dissolving of the components and the like, so that the ketoprofen external medicine with good analgesic effect, quick response, convenient use and low cost is obtained.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The invention provides a ketoprofen external medicine, which comprises the following components in parts by weight based on 100 parts by weight:
0.1-30 parts of ketoprofen, 0.1-20 parts of cosolvent, 0.1-2 parts of transdermal absorption enhancer, 0.1-5 parts of stabilizer, 0.001-5 parts of pigment and the balance of water.
Ketoprofen belongs to high-efficiency non-steroidal anti-inflammatory drugs (NSAIDs), has the effects of resisting inflammation, relieving pain and relieving fever, and mainly inhibits the biosynthesis of inflammatory substances Prostaglandin (PGs), Leukotriene (LTs) and Thromboxane (TXs) by reversibly inhibiting the activity of Cyclooxygenase (COXs), proinflammatory peptide or Lipoxygenase (LOXs), so that the release of bradykinin is reduced, and the good effects of resisting inflammation, relieving pain and relieving fever are exerted. In the present invention, ketoprofen is used as the external pharmaceutical active ingredient of ketoprofen, which can reduce the degree of allodynia and has analgesic and anti-inflammatory effects. The amount may be, for example, but is not limited to, 0.1 part, 1 part, 5 parts, 10 parts, 15 parts, 20 parts, 25 parts, or 30 parts.
The cosolvent is soluble in water, is mostly a low-molecular compound, and can form soluble intermolecular complexes, associations, double salts and the like with a poorly soluble component in water so as to increase the solubility of the drug in the solvent. In the invention, the cosolvent is added, so that the compatibility of each component can be better. The amount may be, for example, but is not limited to, 0.1 part, 1 part, 5 parts, 10 parts, 15 parts, or 20 parts.
Transdermal absorption enhancers (transdermal enhancers for short) are substances which increase the rate at which a drug penetrates the skin without causing severe irritation and damage to the skin. The transdermal enhancer has an action mechanism which mainly changes the structure of the skin through reversibility to permeate into the skin and reduce the resistance of the drug passing through the skin, thereby achieving the purpose of promoting the systemic absorption or the local treatment of the drug. In the invention, the skin penetration enhancer is added, so that the ketoprofen external medicine provided by the invention can be absorbed by skin more easily when being used externally, and the purposes of good absorption and good curative effect are achieved. The amount may be, for example, but is not limited to, 0.1 part, 0.5 part, 1 part, 1.5 parts, or 2 parts.
The stabilizer can increase the stability of the solution or mixture, slow down the reaction, maintain chemical equilibrium, reduce surface tension, and prevent light, thermal or oxidative decomposition. In the invention, the stabilizer is added in a matching way, so that the ketoprofen external medicine has stronger stability, is not easy to denaturize and deteriorate, is convenient to store and saves the cost. The amount may be, for example, but is not limited to, 0.1 part, 1 part, 2 parts, 3 parts, 4 parts, or 5 parts.
The ketoprofen external medicine provided by the invention can reduce the degree of allodynia, shorten the time for pain and recovery and avoid the occurrence of irreversible injury by the synergistic cooperation of the specific components and the proportion, thereby greatly improving the treatment effect and having the advantages of convenient use and low cost.
In a preferred embodiment, the ketoprofen external application medicine comprises the following components in parts by weight based on 100 parts by weight:
1-30 parts of ketoprofen, 2-20 parts of cosolvent, 0.1-1.5 parts of transdermal absorption enhancer, 0.1-4 parts of stabilizer, 0.001-1 part of pigment and the balance of water.
Preferably, the ketoprofen external use medicine comprises the following components in parts by weight based on 100 parts by weight:
5-30 parts of ketoprofen, 3-15 parts of cosolvent, 0.1-1 part of transdermal absorption enhancer, 1-3 parts of stabilizer, 0.005-0.1 part of pigment and the balance of water.
By further adjusting and optimizing the mixture ratio of the components, the ketoprofen external medicine provided by the invention has better analgesic effect, better curative effect and quicker response, and saves the cost to the greatest extent.
In a preferred embodiment, the co-solvent is selected from one or more of arginine, meglumine, histidine, methionine, betacyclodextrin, tween 80, polyethylene glycol 400 or polyethylene glycol 600.
Preferably, the co-solvents are arginine and polyethylene glycol 600.
When arginine and polyethylene glycol 600 are selected as the cosolvent in the invention, the solubility of each component in the solvent can be better increased, and the compatibility of each component in the ketoprofen external medicine can be improved.
Preferably, the mass ratio of arginine to polyethylene glycol 600 is 1-30:1-30, and may be, for example, but not limited to, 1:1, 1:2, 1:3, 1:5, 1:10, 1:15, 1:20, 1:30, 30:1, 20:1, 15:1, 10:1, 5:1, 3:1, or 2: 1.
In a preferred embodiment, the transdermal absorption enhancer is selected from one or more of laurocapram, menthol, propylene glycol or eucalyptus oil.
Preferably, the transdermal absorption enhancer is laurocapram.
When laurocapram is selected as the transdermal absorption enhancer, the ketoprofen external medicament provided by the invention can be absorbed by skin more easily when being used externally, and the aim of good absorption and good curative effect is fulfilled.
Preferably, the stabilizer is selected from citric acid.
When citric acid is selected as the stabilizing agent, the ketoprofen external medicine has stronger stability, is not easy to denaturize and deteriorate, is convenient to store and saves the cost.
Preferably, the ketoprofen external medicine further comprises a pigment.
Pigments are substances that can color an object or solution. In the invention, the pigment is added, so that the observation of whether the medicine completely covers tissues, particularly the positions of mammitis, bone trauma and the like of large animals is more convenient during clinical use.
The amount is 0.001 to 5 parts, and may be, for example, but not limited to, 0.001 part, 0.005 part, 0.01 part, 0.1 part, 1 part, 2 parts, 3 parts, 4 parts or 5 parts; preferably 0.001 to 1 part, more preferably 0.005 to 0.1 part.
Preferably, the pigment is a food grade pigment, preferably brilliant blue.
The food-grade pigment is selected, so that the food-grade pigment can be ensured to be safe and harmless even if being eaten by animals by mistake, and potential safety hazards are not caused to users.
In a preferred embodiment, the ketoprofen external agent further comprises an emollient.
Emollients refer to agents that help the skin maintain a soft, smooth, and elastic appearance. Emollients function by virtue of their ability to reside on the surface of the skin or in the stratum corneum. The emollient is added into the ketoprofen external medicine provided by the invention, so that the irritation of the ketoprofen external medicine to the skin can be effectively reduced, and the comfort level of a user is greatly improved.
The content of the emollient is 0.1 to 10 parts, and may be, for example, but not limited to, 0.1 part, 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, or 10 parts, preferably 1 to 5 parts, and more preferably 1 to 3 parts.
Preferably, the emollient comprises glycerin.
In a preferred embodiment, the ketoprofen topical medicament further comprises a permeation aid.
The penetration assisting agent can be used in combination with the penetrating agent, and the transdermal effect of the medicine is enhanced through the synergistic effect of the penetration assisting agent and the penetrating agent, so that the waste is reduced while the curative effect is enhanced.
Wherein, the content of the permeation assistant agent is 0.1 to 20 parts, such as but not limited to 0.1 part, 1 part, 3 parts, 5 parts, 7 parts, 10 parts, 12 parts, 15 parts, 18 parts or 20 parts, preferably 1 to 15 parts, more preferably 5 to 10 parts;
preferably, the penetration aid is an organic solvent, preferably a C1-C4 alcohol, more preferably ethanol.
When ethanol is selected as the permeation promoter, it works best synergistically with the penetrant to maximize the transdermal effect.
The invention also provides a preparation method of the ketoprofen external medicine, which comprises the following steps:
taking the components according to the formula amount, adding the cosolvent into water, uniformly mixing until the cosolvent is dissolved, then adding the ketoprofen, uniformly mixing until the ketoprofen is dissolved, then adding the stabilizer and the transdermal absorption enhancer, uniformly mixing, finally adding the pigment, and fixing the volume to obtain the ketoprofen external medicine.
The preparation method of the ketoprofen external medicine provided by the invention is simple to operate, and can enable the components to be matched with each other through specific operation steps such as specific component adding sequence, uniform mixing and dissolving of the components and the like, so that the ketoprofen external medicine with good analgesic effect, quick response, convenient use and low cost is obtained.
In a preferred embodiment, the water is heated prior to addition of the co-solvent.
The water is heated in advance, so that the dissolution of the cosolvent is better facilitated, and the time is saved.
Preferably, the temperature of the heat treatment is 50 to 70 ℃, for example, but not limited to, 50 ℃, 55 ℃, 60 ℃, 65 ℃ or 70 ℃, preferably 55 to 65 ℃.
In a preferred embodiment, the blending is carried out by stirring or ultrasound, preferably by stirring.
The mode of utilizing the stirring carries out the mixing and can effectively practice thrift instrument cost when reaching the mixing effect.
Preferably, the stirring is carried out at a speed of 70-90r/min, which may be, for example, but not limited to, 70r/min, 75r/min, 80r/min or 85r/min, preferably 75-85 r/min.
The invention also provides the ketoprofen external medicine or the application of the ketoprofen external medicine prepared by the preparation method in preparing external analgesic medicines. The external analgesic drug may be, for example, but not limited to, an external analgesic spray or an external analgesic paint.
Preferably, the external analgesic drug is an external analgesic spray, and the spray can ensure that the drug can be uniformly and comprehensively applied and covered on the affected part without the help of a smearing tool, so that the action area of the drug is ensured. In addition, the spray is not required to be actually contacted with an affected part when being applied, so that the stress reaction caused by contact pain is avoided, the treatment effect is improved, and the treatment time is shortened.
In addition, the invention also provides application of the ketoprofen external medicine or the ketoprofen external medicine prepared by the preparation method in preparation of a medicine for adjuvant treatment of cow mastitis.
The present invention will be further described with reference to specific examples and comparative examples.
Example 1
The embodiment provides a ketoprofen external medicine which comprises the following components in parts by weight:
0.1 part of ketoprofen, 20 parts of betacyclodextrin, 0.1 part of menthol and 74.8 parts of water.
Example 2
The embodiment provides a ketoprofen external medicine which comprises the following components in parts by weight:
30 parts of ketoprofen, 0.1 part of histidine, 2 parts of propylene glycol and 67.8 parts of water.
Example 3
The embodiment provides a ketoprofen external medicine which comprises the following components in parts by weight:
15 parts of ketoprofen, 8 parts of arginine, 6002 parts of polyethylene glycol, 0.5 part of laurocapram, 2 parts of citric acid and 72.5 parts of water.
Example 4
The embodiment provides a ketoprofen external medicine which comprises the following components in parts by weight:
0.1 part of ketoprofen, 20 parts of betacyclodextrin, 0.1 part of menthol, 10 parts of glycerol, 0.1 part of ethanol and 64.699 parts of water.
Example 5
The embodiment provides a ketoprofen external medicine which comprises the following components in parts by weight:
30 parts of ketoprofen, 0.1 part of histidine, 2 parts of propylene glycol, 0.1 part of glycerol, 20 parts of ethanol and 47.6 parts of water.
Example 6
The embodiment provides a ketoprofen external medicine which comprises the following components in parts by weight:
15 parts of ketoprofen, 8 parts of arginine, 6002 parts of polyethylene glycol, 0.5 part of laurocapram, 2 parts of citric acid, 0.01 part of brilliant blue, 5 parts of glycerol, 10 parts of ethanol and 57.49 parts of water.
Example 7
The embodiment provides a ketoprofen external medicine, which is prepared by the following preparation method:
(a) taking the ketoprofen external medicine provided by the embodiment 3, heating 72.5 parts of water to 60 ℃, adding 8 parts of arginine, and stirring at 80r/min for 8-10min until complete dissolution;
(b) adding 6002 parts of polyethylene glycol, and uniformly stirring;
(c) adding 15 parts of ketoprofen, and stirring at 80r/min for 15-20min until complete dissolution;
(d) stopping heating, sequentially adding 2 parts of citric acid and 0.5 part of laurocapram, stirring uniformly for later use, fixing the volume, sterilizing and filling.
Example 8
The embodiment provides a ketoprofen external medicine, which is prepared by the following preparation method:
(a) taking the ketoprofen external medicine provided in example 6, heating 57.49 parts of water to 60 ℃, adding 8 parts of arginine, and stirring at 80r/min for 8-10min until complete dissolution;
(b) adding 6002 parts of polyethylene glycol, and uniformly stirring;
(c) adding 15 parts of ketoprofen, and stirring at 80r/min for 15-20min until complete dissolution;
(d) stopping heating, sequentially adding 2 parts of citric acid, 0.5 part of laurocapram, 5 parts of glycerol and 10 parts of ethanol, and uniformly stirring for later use;
(e) dissolving 0.01 part of brilliant blue in alcohol, adding the solution, diluting to a constant volume, sterilizing and filling.
Comparative example 1
The comparative example provides a ketoprofen external-use medicine, which comprises the following components in parts by weight:
0.05 part of ketoprofen, 22 parts of betacyclodextrin, 0.05 part of menthol and 70.9 parts of water.
Comparative example 2
The comparative example provides a ketoprofen external-use medicine, which comprises the following components in parts by weight:
15 parts of ketoprofen, 0.5 part of laurocapram, 2 parts of citric acid and 82.5 parts of water.
Comparative example 3
The comparative example provides a ketoprofen external-use medicine, which comprises the following components in parts by weight:
15 parts of ketoprofen, 8 parts of arginine, 6002 parts of polyethylene glycol, 2 parts of citric acid and 73 parts of water.
To further illustrate the ketoprofen external-use drug provided by the present invention, the following experiment was performed:
experimental example 1 pharmaceutical stability test
1. Test by intense light irradiation
The results of the sample hard light test are shown in table 1 below:
TABLE 1 test results of intense light irradiation (1000 ml/bottle)
Figure BDA0001717579510000111
Figure BDA0001717579510000121
Figure BDA0001717579510000131
As can be seen from the experimental results in table 1, the stability of the properties, pH and content of ketoprofen prepared by using the components and ratios provided in examples 1 to 8 of the present invention under strong light irradiation is much higher than that of the ketoprofen prepared by using the components and ratios provided in comparative examples 1 to 3, which indicates that the pharmaceutical stability of the ketoprofen external medicine provided by the present invention is greatly enhanced by the synergistic interaction between the specific components and ratios, and is suitable for clinical application. Meanwhile, the effects of the example 7 and the example 8 prepared by the preparation method provided by the invention are slightly better than those of the example 3 and the example 6, which shows that the ketoprofen external medicine prepared by the preparation method provided by the invention has better effects.
2. High temperature test
In order to save the experiment cost, the examples 3 and 6 with stronger chemical stability in the strong light irradiation test are selected to be used for high temperature test, and the comparative example 1 is selected to be used for comparison. The sample high temperature test results are shown in table 2 below:
TABLE 2 high temperature test investigation results (1000 ml/bottle)
Figure BDA0001717579510000132
Figure BDA0001717579510000141
As can be seen from the experimental results in table 2, the properties, pH values and stability of the content of ketoprofen prepared by using the components and ratios provided in examples 3 and 6 of the present invention at high temperature are much higher than those of the ketoprofen prepared by using the components and ratios provided in comparative example 1, which indicates that the pharmaceutical stability of the ketoprofen external medicine provided by the present invention is greatly enhanced by the synergistic interaction between the specific components and ratios, and the ketoprofen external medicine is suitable for clinical application.
3. Accelerated test
In order to save the experiment cost, the examples 3 and 6 with stronger chemical stability in the strong light irradiation test are selected to be used for high temperature test, and the comparative example 1 is selected to be used for comparison. The sample high temperature test results are shown in table 3 below:
TABLE 3 accelerated test investigation results (1000 ml/bottle)
Figure BDA0001717579510000142
As can be seen from the experimental results in table 3, the stability of the property, pH and content of ketoprofen after long-term storage, of the external ketoprofen prepared by using the components and ratios provided in examples 3 and 6 of the present invention, is much higher than that of the external ketoprofen prepared by using the components and ratios provided in comparative example 1, which indicates that the pharmaceutical stability of the external ketoprofen provided by the present invention is greatly enhanced by the synergistic interaction between the specific components and ratios, and is suitable for clinical application.
Experimental example 2 clinical efficacy test
Mastitis of dairy cattle
1. Test animal selection criteria
The cow enrollment standard is as follows: clinical diagnosis shows that the breast of the dairy cow in the lactation period with acute clinical mastitis has clinical symptoms such as flushing, swelling, fever and pain.
2. Grouping and administration of test animals
30 test cattle were randomly assigned to 2 test groups (I, II, 15 in each group) in an effort to make the severity of the disease in each group substantially consistent.
Uniformly spraying the whole cow breast tissue with the ketoprofen external medicine provided by the embodiment 3 of the invention for 1 day and 2 times for 3 days; 1 cefquinome sulfate breast injection (in lactation period) is administered for 1 time and 1 time at intervals of 12 hours, and the cefquinome sulfate breast injection is administered for 6 times continuously, wherein specific administration information of each group is shown in table 4. All test sick cattle were not given any further antibacterial and anti-inflammatory drugs throughout the test period.
3. Experimental grouping and administration
Table 4 test grouping and dosing
Figure BDA0001717579510000151
4. Clinical symptom observation and evaluation of experimental cattle
The cows were observed for mental status, local symptoms in the breasts, and milk characteristics 0 days before administration, before each administration, and on days 1, 3, 7, and 14 after the last administration, respectively, and scored according to the following clinical symptom scoring criteria (table 5).
TABLE 5 clinical symptom Scoring criteria
Figure BDA0001717579510000161
5. Milk cow pain response observation and evaluation
Each group selected 15 cows, and 0h before ketoprofen administration, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, and 24h after each administration, and 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 36h, and 48h after the last administration, the cows were observed for their pain response and scored according to the pain response scoring criteria (table 6).
TABLE 6 pain response Scoring criteria
Figure BDA0001717579510000162
Figure BDA0001717579510000171
6. Test results and analysis
6.1 clinical manifestations of sick cattle
All affected cows were observed for mental status, local symptoms in the breast, and milk status 0 day before administration, before each administration, and on days 1, 3, 7, and 14 after the last administration, and scored according to the above criteria. Statistical analysis was performed on the breast local symptoms, milk traits, and mental status scores of each group of test cows, and the results are shown in tables 7, 8, and 9, respectively.
TABLE 7 statistics of local symptom scores of cow breasts tested at different time points
Observation time (sky) Group I Group II
Administration for 0 day 2.60±0.62 2.63±0.56
Administration for 1 day 2.27±0.52 2.43±0.50
The administration is carried out for 2 days 1.67±0.61* 1.97±0.41*
The administration is carried out for 3 days 0.83±0.75* 1.13±0.57*
Stop taking medicine for 1 day 0.39±0.50* 0.61±0.50*
Stop taking medicine for 3 days 0.11±0.42* 0.32±0.55*
Stop the medicine for 7 days 0.04±0.19* 0.08±0.27*
Stop taking medicine for 14 days 0.00±0.00* 0.00±0.00*
Note: the difference is obvious by the same lower case letters (p is less than or equal to 0.05); "+" indicates significant difference (p ≦ 0.05).
The results show that the topical ketoprofen medicament for treating acute mastitis can quickly and effectively improve the local symptoms of the breasts of sick cattle after the acute mastitis cattle are treated by the ketoprofen medicament.
TABLE 8 statistics of milk character scoring results of test cows at different time points
Figure BDA0001717579510000172
Figure BDA0001717579510000182
Note: the difference is obvious by the same lower case letters (p is less than or equal to 0.05); "+" indicates significant difference (p ≦ 0.05).
The results show that the milk property of the sick cattle can be quickly and effectively improved after the acute mastitis sick cattle are treated by the ketoprofen external medicine provided by the invention.
TABLE 8 statistics of scoring results of bovine mental states tested at different time points
Observation time (sky) Group I Group II
Administration for 0 day 1.47±0.51 1.53±0.51
Administration for 1 day 1.03±0.41 1.20±0.41
The administration is carried out for 2 days 0.67±0.55* 0.83±0.53*
The administration is carried out for 3 days 0.47±0.63* 0.57±0.57*
Stop taking medicine for 1 day 0.18±0.39* 0.39±0.50*
Stop taking medicine for 3 days 0.07±0.26* 0.25±0.52*
Stop the medicine for 7 days 0.04±0.19* 0.08±0.27*
Stop taking medicine for 14 days 0.00±0.00* 0.00±0.00*
Note: the difference is obvious by the same lower case letters (p is less than or equal to 0.05); "+" indicates significant difference (p ≦ 0.05).
The results show that after the ketoprofen external medicine provided by the invention is applied to acute mastitis cattle, the mental states of the acute mastitis cattle can be quickly and effectively improved.
6.2 test sick cattle pain response score results
TABLE 9 statistics of the pain response scores of the test cattle at different time points
Figure BDA0001717579510000181
Figure BDA0001717579510000191
The results show that the pain of the sick cattle can be quickly and effectively relieved after the acute mastitis sick cattle are treated by the ketoprofen external medicine provided by the invention.
7. Conclusion of the experiment
Compared with the single application of the cefquinome sulfate breast injectant, the ketoprofen external medicine provided by the invention can be used for effectively relieving the lassitude and appetite reduction of the dairy cows and enhancing the milking compliance; the ketoprofen external medicine provided by the invention can be used for more quickly and thoroughly relieving the breast swelling of the sick cattle and eliminating the breast lumps caused by mastitis; the ketoprofen external medicine provided by the invention can be used together to effectively reduce the abnormalities of milk floc, milk clotting and the like, so that the milk and the lactation capacity can be recovered more quickly; the ketoprofen external medicine provided by the invention can be used for effectively recovering the milk production performance of the cows in the lactation period, improving the recovery speed of the milk yield and the ratio before the onset of diseases, and increasing the economic benefit of a pasture.
Secondly, pet postoperative analgesia
1. 10 cases of surgery (fracture and other cases) of dogs in a certain pet hospital of Guangzhou are counted, and the medication scheme is as follows:
Figure BDA0001717579510000201
2. pain scoring table
Figure BDA0001717579510000202
3. Pain score sheet results statistics
Figure BDA0001717579510000203
Figure BDA0001717579510000211
As can be seen from the above table, the analgesic effect of the morphine hydrochloride combined with the ketoprofen external medicine provided by the invention is better than that of the morphine hydrochloride alone. The ketoprofen external medicine provided by the invention can reduce the degree of allodynia, shorten the time for pain and recovery and avoid the occurrence of irreversible injury by the synergistic cooperation of the specific components and the proportions, thereby greatly improving the treatment effect and having the advantages of convenient use and low cost.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

Claims (8)

1. The ketoprofen external medicine is characterized by comprising the following components in parts by weight:
15 parts of ketoprofen, 8 parts of arginine, 6002 parts of polyethylene glycol, 0.5 part of laurocapram, 2 parts of citric acid and 72.5 parts of water; or the like, or, alternatively,
15 parts of ketoprofen, 8 parts of arginine, 6002 parts of polyethylene glycol, 0.5 part of laurocapram, 2 parts of citric acid, 0.01 part of brilliant blue, 5 parts of glycerol, 10 parts of ethanol and 57.49 parts of water.
2. The method for preparing a ketoprofen external use drug according to claim 1, comprising:
taking the components according to the formula amount, adding arginine and polyethylene glycol 600 into water, uniformly mixing until the arginine and the polyethylene glycol are dissolved, then adding ketoprofen, uniformly mixing until the ketoprofen is dissolved, adding citric acid and laurocapram, uniformly mixing, and fixing the volume to obtain the ketoprofen external medicine; or the like, or, alternatively,
taking the components according to the formula amount, adding arginine and polyethylene glycol 600 into water, uniformly mixing until the arginine and the polyethylene glycol are dissolved, then adding ketoprofen, uniformly mixing until the ketoprofen is dissolved, then adding citric acid, laurocapram, glycerol and ethanol, uniformly mixing, finally adding brilliant blue, and fixing the volume to obtain the ketoprofen external medicine.
3. The method of claim 2, wherein the water is heated before the polyethylene glycol 600 is added.
4. The production method according to claim 3, wherein the temperature of the heat treatment is 50 to 70 ℃.
5. The production method according to claim 4, wherein the temperature of the heat treatment is 55 to 65 ℃.
6. Use of the ketoprofen topical medicament according to claim 1 in the preparation of a topical analgesic.
7. The use of claim 6, wherein the analgesic drug is a topical analgesic spray.
8. Use of the ketoprofen topical medicament according to claim 1 in the preparation of a medicament for the adjunctive treatment of bovine mastitis.
CN201810721306.4A 2018-06-29 2018-06-29 Ketoprofen external medicine and preparation method and application thereof Active CN108653262B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201810721306.4A CN108653262B (en) 2018-06-29 2018-06-29 Ketoprofen external medicine and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201810721306.4A CN108653262B (en) 2018-06-29 2018-06-29 Ketoprofen external medicine and preparation method and application thereof

Publications (2)

Publication Number Publication Date
CN108653262A CN108653262A (en) 2018-10-16
CN108653262B true CN108653262B (en) 2021-02-26

Family

ID=63773649

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810721306.4A Active CN108653262B (en) 2018-06-29 2018-06-29 Ketoprofen external medicine and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN108653262B (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1671369A (en) * 2002-08-01 2005-09-21 阿麦里尼工业药物联合中心科学研究室 Topical formulations containing ketoprofen stabilised with sulisobenzone
CN1738612A (en) * 2001-12-11 2006-02-22 埃斯蒂文博士实验室股份有限公司 Drinkable preparation comprising ketoprofen and the use thereof in the simultaneous treatment of a group of animals for processes which are accompanied by fever, inflammation and/or pain
CN103156803A (en) * 2011-12-08 2013-06-19 杭州赛利药物研究所有限公司 Ketoprofen gel and preparation method thereof
CN107007574A (en) * 2017-05-16 2017-08-04 蔡志浩 A kind of Ketoprofen Babu cream

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1738612A (en) * 2001-12-11 2006-02-22 埃斯蒂文博士实验室股份有限公司 Drinkable preparation comprising ketoprofen and the use thereof in the simultaneous treatment of a group of animals for processes which are accompanied by fever, inflammation and/or pain
CN1671369A (en) * 2002-08-01 2005-09-21 阿麦里尼工业药物联合中心科学研究室 Topical formulations containing ketoprofen stabilised with sulisobenzone
CN103156803A (en) * 2011-12-08 2013-06-19 杭州赛利药物研究所有限公司 Ketoprofen gel and preparation method thereof
CN107007574A (en) * 2017-05-16 2017-08-04 蔡志浩 A kind of Ketoprofen Babu cream

Also Published As

Publication number Publication date
CN108653262A (en) 2018-10-16

Similar Documents

Publication Publication Date Title
US7052715B2 (en) Alcohol-free transdermal analgesic composition and processes for manufacture and use thereof
CN103690471B (en) Be used for the treatment of pharmaceutical composition and the method for cattle and other Ii _ i_iLLci _ i_
KR20040074999A (en) Drinkable preparation comprising ketoprofen and the use thereof in the simultaneous treatment of a group of animals for processes which are accompanied by fever, inflammation and/or pain
RU2455992C1 (en) Preparation for treatment and prevention of postpartum endometritis in cows
CN102688483A (en) Composition for treating dermatosis, preparation containing composition and preparation method thereof
TW201513854A (en) A medicament formulation for treating inflammation of horse
CN108653262B (en) Ketoprofen external medicine and preparation method and application thereof
RU2464979C1 (en) Medicine for treatment and prevention of postnatal endometritis and syndrome of metritis-mastitis-agalactia in sows
RU2316329C2 (en) Method for manufacturing preparation for preventing and treating diseases of viral etiology in cattle and method for treating such diseases
BRPI0902699A2 (en) Chemical Method for Sexual Sterilization and Libido Elimination in Male Mammals
CN104906132B (en) A kind of plaster for preventing and treating lamb stomatitis
CN1806850A (en) Transdermal drug delivery intensifier composition and its application in externally applied medicine
RU2475244C1 (en) Agent antiactinomycilline for treating actinomycosis and necrobacillosis in farm animals
CN104906131B (en) A kind of preparation method preventing and treating lamb stomatitis plaster
RU2381802C1 (en) Preparation for treatment and prevention of infectious keratoconjunctivitis in cattle and method for application thereof
JP2009508853A (en) Anthelmintic preparation
RU2280458C1 (en) Anti-inflammatory ointment
CN104288096A (en) Injection for treating pyrexia and hoof disease of dairy cows, and its preparation method
CN108451902A (en) Treat the Ketoprofen dip and preparation method thereof of mammitis of animal
US20060263439A1 (en) Alcohol-free transdermal analgesic composition and processes for manufacture and use thereof
RU2768589C1 (en) Method for prevention of acute postpartum endometritis in cows
RU2722162C1 (en) Method of treating tendon-ligamentous apparatus injuries in horses
RU2447894C1 (en) Veterinary homeopathic agent for external application in musculoskeletal diseases
Vijayasarathi et al. Therapeutic management of bovine calf papillomatosis
WO2001058464A1 (en) Water dispersed ivermectin dosage form used for curing ecto- and endoparasitic diseases

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant