CN105687196A - Itraconazole-terbinafine compound injection for dogs and cats and preparation method of compound injection - Google Patents
Itraconazole-terbinafine compound injection for dogs and cats and preparation method of compound injection Download PDFInfo
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- CN105687196A CN105687196A CN201610004215.XA CN201610004215A CN105687196A CN 105687196 A CN105687196 A CN 105687196A CN 201610004215 A CN201610004215 A CN 201610004215A CN 105687196 A CN105687196 A CN 105687196A
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- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 claims description 24
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Classifications
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- 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
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Emergency Medicine (AREA)
- Dermatology (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to the field of veterinary drugs, and discloses an itraconazole-terbinafine compound injection for dogs and cats and a preparation method of the compound injection.The novel compound preparation prepared by taking hydroxypropyl-beta-cyclodextrin as a carrier has the advantages of being wide in antibacterial spectrum, high in treatment effect, low in cost and the like; the product is high in inclusion rate and drug concentration, capable of meeting the treatment requirement and good in stability; the compound injection is low in toxicity, good in absorption and capable of achieving the better treatment effect on fungal skin diseases of the dogs and the cats.
Description
Technical field
The present invention relates to veterinary medicine field, particularly a kind of dog cat itraconazole-Terbinafine compound injection and preparation method thereof。
Background technology
The control release of medicine is the multi-crossed disciplines frontier of period of expansion in recent decades。With macromolecular material emerge in multitude, its application in the researching and producing of pharmaceutical preparation is increasingly extensive。It may be said that, the development of pharmaceutical preparation can be produced great motive force with each progress of macromolecular material, pharmaceutical preparation is made to have had qualitative leap in quality, the appearance of these materials makes the controlled release of medicine, slow release be achieved, and has important advantage with conventional common drug formulations。Simultaneously also in that clinic it is required that medicine controlled releasing, slow release method become the focus of research。Clinically, the poor stability of many medicines, bioavailability is not high, drug effect plays the fastoperation time and short etc. is not suitable for people's medication custom, therefore, limiting the use of these medicines, the defect that medicine controlled releasing slow release method is these medicines provides good solution。For Drug therapy disease, promote the well-being of mankind and play indelible effect。
Summary of the invention
It is an object of the invention to provide a kind of dog cat itraconazole-Terbinafine compound injection and preparation method thereof, this compound injection has has a broad antifungal spectrum, curative effect height, drug effect length, lower-price characteristic, and the treatment for dog cat dermatomycosis provides one more preferably compound recipe novel form。
For realizing above-mentioned technical purpose, reach above-mentioned technique effect, the invention discloses a kind of dog cat itraconazole-Terbinafine compound injection, compound injection includes itraconazole 1.0g, Terbinafine 1.0g, HP-β-CD 35g, dehydrated alcohol 3.0mL, propylene glycol 5mL, 12mol/L concentrated hydrochloric acid 370 μ L, distilled water 42mL。
The preparation method that the invention also discloses a kind of dog cat itraconazole-Terbinafine compound injection, preparation method specifically comprises the following steps that
Step 1: the itraconazole accurately weighed and Terbinafine are respectively put in beaker A and beaker B, HP-β-CD is divided into two parts, is respectively put in beaker C and beaker D, adds propylene glycol, then be slowly added dropwise 12mol L in beaker A-1Concentrated hydrochloric acid, makes itraconazole be completely dissolved；In beaker B, add dehydrated alcohol, make Terbinafine be completely dissolved；Distilled water is injected in beaker C and beaker D, make HP-β-CD dissolve；
Step 2: when magnetic agitation, itraconazole solution in beaker A is slowly added dropwise in beaker C, mix with HP-β-CD solution, time for adding is every gram of itraconazole 15min, beaker C is placed in thermostat water bath, inclusion under 40 DEG C of conditions, the inclusion time is 24～36h, obtains clathrate E solution；Same when magnetic agitation, Terbinafine solution in beaker B is slowly added dropwise in beaker D, mix with HP-β-CD solution, time for adding is every gram of Terbinafine 20min, beaker D is placed in thermostat water bath, inclusion under 40 DEG C of conditions, the inclusion time is 24～36h, obtains clathrate F solution；
Step 3: by clathrate E solution 0.8mol L-1Sodium hydroxide solution carry out pH value adjustment, pH value is 5.5, clathrate F solution in beaker D is poured in the beaker C equipped with clathrate E solution having regulated pH value, mixing liquid in beaker C is with 0.45 μm of filtering with microporous membrane, carry out 100 DEG C of flowing steam sterilizations after bottling, obtain dog cat itraconazole-Terbinafine compound injection。
The method have the advantages that
1. a kind of novel compound preparation that the present invention is prepared as carrier by HP-β-CD, has the features such as has a broad antifungal spectrum, curative effect is high, price is low。
2. product inclusion rate of the present invention is high, and drug level is high, reaches treatment requirement, and stability is better。
3. the product of the present invention is compound injection, and toxicity is low, absorbs good, the dermatomycosis of dog cat can be played better therapeutic effect。
Accompanying drawing explanation
Fig. 1 is the uv absorption figure of invention formulation。
Detailed description of the invention
In order to make the purpose of the present invention, technical scheme and advantage clearly understand, below in conjunction with drawings and Examples, the present invention is further elaborated。
Embodiment 1
The invention discloses a kind of dog cat itraconazole-Terbinafine compound injection liquid and preparation method thereof, specifically comprise the following steps that
Step 1: accurately weigh itraconazole 1.0g and Terbinafine 1.0g and be respectively put in beaker A and beaker B, HP-β-CD is divided into two parts, it is respectively put in beaker C (containing HP-β-CD 20～25g) and beaker D (containing HP-β-CD 10～15g), in beaker A, add propylene glycol 5mL, then be slowly added dropwise 12mol L-1Concentrated hydrochloric acid 370 μ L, makes itraconazole be completely dissolved；In beaker B, add dehydrated alcohol 3mL, make Terbinafine be completely dissolved；Distilled water is injected in beaker C (containing distilled water 24～30mL) and beaker D (containing distilled water 12～18mL), make HP-β-CD dissolve。
Step 2: when magnetic agitation, itraconazole solution in beaker A is slowly added dropwise in beaker C, mix with HP-β-CD solution, time for adding is every gram of itraconazole 15min, beaker C is placed in thermostat water bath, inclusion under 40 DEG C of conditions, the inclusion time is 24～36h, obtains clathrate E solution；Same when magnetic agitation, Terbinafine solution in beaker B is slowly added dropwise in beaker D, mix with HP-β-CD solution, time for adding is every gram of Terbinafine 20min, beaker D is placed in thermostat water bath, inclusion under 40 DEG C of conditions, the inclusion time is 24～36h, obtains clathrate F solution。
Step 3: by clathrate E solution 0.8mol L-1Sodium hydroxide solution carry out pH value adjustment, pH value is 5.5, clathrate F solution in beaker D is poured in the beaker C equipped with clathrate E solution having regulated pH value, mixing liquid in beaker C is with 0.45 μm of filtering with microporous membrane, carry out 100 DEG C of flowing steam sterilizations after bottling, obtain dog cat itraconazole-Terbinafine compound injection。
In the compound injection that this enforcement is prepared, itraconazole inclusion rate reaches 80%, and Terbinafine inclusion rate reaches 70%, prepared injection clarification, faint yellow, modest viscosity。
Embodiment 2
Experiment purpose and method: in order to characterize the chemical relationship of HP-β-CD and itraconazole and Terbinafine, the present embodiment adopts the mode that ultraviolet absorpting spectrum characterizes synthesising preparation is carried out uv absorption sign and analyzes, specific experiment operation is consistent with relevant criterion operation, repeats no more herein。
Experimental result: as shown in Figure 1, use microplate reader to carry out compound injection length scanning and carry out absorption band scanning in 250nm to 310nm (λ) scope, medicine in compound injection forms peak value at 262nm and 289nm place as shown in Figure 1, illustrate that itraconazole does not react with Terbinafine, but define clathrate with HP-β-CD respectively。
Embodiment 3
Experiment purpose and method: in order to characterize the bio-toxicity of the application preparation, the present embodiment is by setting up mouse model, and carried out acute toxicity test and subchronic toxicity test, specific experiment method is as follows: acute toxicity test: through preliminary experiment, in compound injection, the median lethal dose(LD 50) (LD50) of Terbinafine is higher than itraconazole, therefore dosage calculates with itraconazole。70 white mice are randomly divided into 7 groups, often group 10, male and female half and half, sub-cage rearing。Wherein, the 7th group is matched group (injecting normal saline)。Determining the dosage of each group of mice on the basis of trial test, between two adjacent groups, the ratio of dosage is 1.4, and each group concrete dosage of mice is as shown in table 1。Every white mice presses 0.03mL g-1Body weight dorsal sc injection, medicinal liquid normal buffered saline dilutes, and various dose group volume injected same concentrations is different。Disposable to white mice subcutaneous administration, Continuous Observation 7d after injection, record each group of mice dying time and quantity, adopt the karber's method improved to calculate LD50 and 95% fiducial limit。Result is in Table 2。
Subchronic toxicity test: 80 white mice are randomly divided into 4 groups, often group 20, male and female half and half。Wherein, 1～3 group is test group, namely low dose group, middle dosage group, high dose group。Dosage (calculates) respectively 20mg kg with itraconazole gauge-1·d-1, 40mg kg-1·d-1With 60mg kg-1·d-1。4th group is blank group。Adopting dorsal sc dose regimen, medicinal liquid normal saline dilution, by 0.01mL g-1Body weight successive administration one month, blank group injects the normal saline of same volume。In process of the test, mice ad lib and freely intaking。Every day weighs, and adjusts dosage。29d after medication carries out blood parameters mensuration。Weigh each group of Mouse Weight every day, and observe the changes such as the diet of mice, behavioral activity and clinical symptoms。Using Spss software data processing, result is in Table 3。Detection alanine aminotransferase (ALT), glutamic oxaloacetic transaminase, GOT (GOT), alkali phosphatase (ALP), serum creatinine (Scr) and serum urea nitrogen (BUN)。Using Spss software data processing, result is in Table 4。Experimental result:
White mice dosage respectively organized by table 1
Note: * is in itraconazole
Table 2 respectively organizes dosage and mice dying situation
Note: * is with itraconazole content meter
The change of white mice body weight respectively organized by table 3
Note: represent significant difference (P < 0.05) with column data Superscript letters difference person
The change of table 4 mice Liver and kidney index
Note: represent significant difference (P < 0.05) with column data Superscript letters difference person
As shown in table 1-4: the LD50 of white mice is 84.22mg kg by compound injection-1, the 95% of LD50 credible is limited to 69.32～102.431mg kg-1；In subchronic toxicity test, to 28d weigh time, the average weight of high dose group compares with other three groups, significant difference (P < 0.05), illustrates that high dose medicament affects the weightening finish of mice；The ALT of high dose group compared with other 3 groups, significant difference (P < 0.05), illustrate that continuously heavy dose of administration affects the function of liver。
Embodiment 4
Experiment purpose and method: in order to study and evaluate the present invention therapeutic effect to Dog fungus skin disease, the present embodiment has chosen obvious Fungal Skin disease symptoms, and (forelimb, affected part, back are become subcircular to come off by hair, there is erythema, skin is covered with a large amount of squama) 12 dogs, through scraping blade microscopy, find that the main pathogenic fungi is Sabouraudites lanosus and tinea bacterium, 12 dogs are randomly divided into 3 groups, often group 4。First group of dosage: 4 dogs press 4mg kg-1Subcutaneous injection itraconazole is administered；Second group of dosage: 4 dogs press 4mg kg-1Subcutaneous injection Terbinafine is administered；3rd group of dosage: 4 dogs press 2mg kg-1(itraconazole amount) subcutaneous injection compound injection。Each group is administered 1 time every day, and after successive administration 3d, drug withdrawal 1 week is 1 course for the treatment of, after treating two courses for the treatment of, disease sites is evaluated。
Experimental result: after treating two courses for the treatment of, 2 dog recoveries from illness in the 3rd group, 1 dog is effective, and the erythema of dog disease sites disappears, and has grown new hair gradually, without gargalesthesia, checks and does not find spore；1 dog recovery from illness in first group, 1 effective；In second group, 1 dog occurs effective, and 2 dogs are got better and turn, and 1 dog is invalid。Effective dog erythema disappears, and affected part has grown the hair of light, and microscopy finds a small amount of spore, and the dog affected part taking a turn for the better and failing to respond to any medical treatment grows virgin wool, but dog back still has gargalesthesia, sometimes rubs wall, and microscopy finds have a number of spore to exist。From the treatment situation of above-mentioned three groups, the therapeutic effect of the 3rd group of compound injection is better than other two groups of folk prescription injection。
Embodiment 5
Experiment purpose and method: the clinical efficacy in order to study and analyze invention formulation is tested, the present embodiment adopts and has carried out clinical group expanding therapeutic test and popularization and application in Qiqihar pets hospital and six branches thereof, Qiqihar and the dog field of surrounding area, cat field。
Experimental result: dog cat itraconazole-Terbinafine compound injection of the present invention is that antifungal drug provides a new combination dosage forms, dog cat dermatomycosis there is remarkable result, obtain higher economic benefit and social benefit, it is subject to pet owner and the favorable comment of vast dog field master, there is wide market application foreground。
The above; being only the present invention preferably detailed description of the invention, but protection scope of the present invention is not limited thereto, any those familiar with the art is in the technical scope that the invention discloses; the change that can readily occur in or replacement, all should be encompassed within protection scope of the present invention。
Claims (2)
1. dog cat itraconazole-Terbinafine compound injection, it is characterised in that described compound injection includes itraconazole 1.0g, Terbinafine 1.0g, HP-β-CD 35g, dehydrated alcohol 3.0mL, propylene glycol 5mL, 12mol/L concentrated hydrochloric acid 370 μ L, distilled water 42mL。
2. the preparation method of dog cat itraconazole-Terbinafine compound injection, it is characterised in that: described preparation method specifically comprises the following steps that
Step 1: the itraconazole accurately weighed and Terbinafine are respectively put in beaker A and beaker B, HP-β-CD is divided into two parts, is respectively put in beaker C and beaker D, adds propylene glycol, then be slowly added dropwise 12mol L in beaker A-1Concentrated hydrochloric acid, makes itraconazole be completely dissolved；In beaker B, add dehydrated alcohol, make Terbinafine be completely dissolved；Distilled water is injected in beaker C and beaker D, make HP-β-CD dissolve；
Step 2: when magnetic agitation, itraconazole solution in beaker A is slowly added dropwise in beaker C, mix with HP-β-CD solution, time for adding is every gram of itraconazole 15min, beaker C is placed in thermostat water bath, inclusion under 40 DEG C of conditions, the inclusion time is 24～36h, obtains clathrate E solution；Same when magnetic agitation, Terbinafine solution in beaker B is slowly added dropwise in beaker D, mix with HP-β-CD solution, time for adding is every gram of Terbinafine 20min, beaker D is placed in thermostat water bath, inclusion under 40 DEG C of conditions, the inclusion time is 24～36h, obtains clathrate F solution；
Step 3: by clathrate E solution 0.8mol L-1Sodium hydroxide solution carry out pH value adjustment, pH value is 5.5, clathrate F solution in beaker D is poured in the beaker C equipped with clathrate E solution having regulated pH value, mixing liquid in beaker C is with 0.45 μm of filtering with microporous membrane, carry out 100 DEG C of flowing steam sterilizations after bottling, obtain dog cat itraconazole-Terbinafine compound injection。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610004215.XA CN105687196B (en) | 2016-01-05 | 2016-01-05 | A kind of dog cat Itraconazole-Terbinafine compound injection and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610004215.XA CN105687196B (en) | 2016-01-05 | 2016-01-05 | A kind of dog cat Itraconazole-Terbinafine compound injection and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105687196A true CN105687196A (en) | 2016-06-22 |
| CN105687196B CN105687196B (en) | 2019-04-09 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101889979A (en) * | 2010-07-05 | 2010-11-24 | 东北农业大学 | Itraconazole injection for dogs and preparation method thereof |
| CN101889973A (en) * | 2010-07-05 | 2010-11-24 | 东北农业大学 | Itraconazole gel for dogs and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101889979A (en) * | 2010-07-05 | 2010-11-24 | 东北农业大学 | Itraconazole injection for dogs and preparation method thereof |
| CN101889973A (en) * | 2010-07-05 | 2010-11-24 | 东北农业大学 | Itraconazole gel for dogs and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| JOSEPH MELETIADIS等: "In vitro interaction of terbinafine with itraconazole against clinical isolates of Scedosporium prolificans", 《ANTIMICROBIAL AGENTS AND CHEMOTHERAPY》 * |
| 国家药典委员会编: "《中华人民共和国药典 2010年版 第二增补本》", 30 September 2013, 中国医药科技出版社 * |
| 张敏等: "特比奈芬和伊曲康唑单独及联合应用对暗色真菌的体外药敏试验研究", 《第二届全国深部真菌感染学术会议论文集》 * |
| 殷凯生，殷民生主编: "《实用抗感染药物手册》", 31 August 2001, 人民卫生出版社 * |
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