CN107375205B - Non-oily Doramectin injection fluid and its preparation method and application - Google Patents
Non-oily Doramectin injection fluid and its preparation method and application Download PDFInfo
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- CN107375205B CN107375205B CN201710640385.1A CN201710640385A CN107375205B CN 107375205 B CN107375205 B CN 107375205B CN 201710640385 A CN201710640385 A CN 201710640385A CN 107375205 B CN107375205 B CN 107375205B
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- oily
- doractin
- propylene glycol
- injection fluid
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—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
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- 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
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- 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
Abstract
The present invention relates to a kind of non-oily Doramectin injection fluids and its preparation method and application.The non-oily Doramectin injection fluid includes following components: doractin, glycerol formal and propylene glycol；Wherein, the weight percent of the doractin is 0.1%-10%, the mass ratio of the glycerol formal and propylene glycol composition mixed solvent, glycerol formal described in the mixed solvent and the propylene glycol is (4-8): (2-6).The stability of the non-oily Doramectin injection fluid is good and irritation is low.
Description
Technical field
Anti-parasite medicine technical field of the present invention, more particularly to a kind of non-oily Doramectin injection fluid and its preparation
Methods and applications.
Background technique
Doractin (CAS accession number is 11774-25-3) is macrolides anti-parasite medicine of new generation, chemical name
Referred to as 25- cyclohexyl -5-0- demethyl -25- removes (1- methyl-propyl) avermectin Ala, chemical formula C50H74O14.With tradition
Avermectin drug is compared, and doractin has good Pharmacokinetic Characteristics, and duration of efficacy is relative to Yi Wei bacterium
Element improves 30%.Therefore, doractin has market prospects preferably as antiparasite drugs for animals.
The insecticidal mechanism of doractin class drug is mainly the nervous physiology activity for interfering polypide, and segmental appendage can be stimulated dynamic
Released in the helminths such as object, nematode inhibiting nerve transmitting medium (such as aminobutyric acid), so benumb and kill arthropod,
The helminths such as nematode.It, can be auxiliary by doractin class drug and solvent etc. in order to adapt to treat or prevent the needs of parazoon
Helping property ingredient is prepared by mixing into anti-parasite medicine preparation.Solubility is very low in water for doractin, at 20 DEG C only
0.025mg/L.Doractin is dissolved using oil for injection when traditional technology prepares Doramectin injection fluid.But grease is light-exposed
Or rancid or discoloration is easy when ingress of air, cause its stability poor.In addition, the viscosity of Doramectin injection fluid is very big,
Filtration sterilization difficulty is higher, and drawn needle is difficult in use process, is easy to accumulate bulge in injection site, can cause pain reaction,
With intense stimulus, application effect is poor.
Summary of the invention
Based on this, it is necessary to provide a kind of stability preferably and the non-oily Doramectin injection fluid without intense stimulus and its
Preparation method and application.
A kind of non-oily Doramectin injection fluid, including following components: doractin, glycerol formal and propylene glycol；Its
In, the weight percent of the doractin is 0.1%-10%, and the glycerol formal and propylene glycol composition mixing are molten
The mass ratio of agent, glycerol formal described in the mixed solvent and the propylene glycol is (4-8): (2-6).
The glycerol formal and the mass ratio of the propylene glycol are (5-7): (3-5) in one of the embodiments,.
The glycerol formal and the mass ratio of the propylene glycol are 6:4 in one of the embodiments,.
The non-oily Doramectin injection fluid further includes each group of following weight percent in one of the embodiments,
Point: benzyl alcohol 0.1%-5%, antioxidant 0.05%-1%, preservative 0.01%-1%；Respectively by above-mentioned weight percent
The doractin, the benzyl alcohol, the antioxidant, the preservative, the glycerol formal and the propylene glycol are mixed
It closes, non-oily doractin mixed solution is made in total weight percent 100%, adds pH adjusting agent, and adjusting pH value is 3-
7 to get the non-oily Doramectin injection fluid.
The weight percent of the doractin is 0.5%-5%, the weight of the benzyl alcohol in one of the embodiments,
Amount percentage is 0.1%-1%.
In one of the embodiments, the non-oily Doramectin injection fluid be according to following preparation steps prepare and
: first respectively by the doractin, the benzyl alcohol, the antioxidant, the preservative, the glycerol formal and institute
It states propylene glycol to mix according to the ratio that weight percent is 1%, 0.2%, 0.1%, 0.1%, 60%, 38.6%, is made non-oil
Property doractin mixed solution, then pH adjusting agent will be added in the non-oily doractin mixed solution, adjusts pH to 3-7.
The antioxidant is vitamin A, carotenoid, ascorbic acid, flavonoids in one of the embodiments,
Close one of object, polyphenol, isothiocyanates, cysteine, tocopherol and Renascin or a variety of.
The preservative is phenylethanol, phenol, metacresol, zephiran, para hydroxybenzene first in one of the embodiments,
One of acid esters, butylated hydroxyanisole (BHA), butylated hydroxytoluene, propyl gallate and benzaldehyde are a variety of.
Solvent in the present invention uses glycerol formal and propylene glycol, and the mass ratio of the glycerol formal and the propylene glycol
Example is (4-8): (2-6).By compounding between glycerol formal and propylene glycol, the mixing of glycerol formal and propylene glycol composition
Solvent can preferably dissolve doractin, and have preferable compatibility with doractin, being capable of injection in use process
It can smoothly flow out, it is lower to the irritation of animal.In addition, propylene glycol can be combined with glycerol formal, it is molten after mixing
The stability of liquid is preferable.And glycerol formal and the mixed solvent of propylene glycol are non-oily solvent, and stability is relatively high.Cause
This preferably can promote doractin to dissolve, can not only protect by controlling the proportionate relationship of glycerol formal and propylene glycol
The injection irritation for demonstrate,proving the non-oily doractin of preparation is lower, and guarantees the injection of the non-oily doractin of preparation
Stability it is preferable.
Doractin preparation in the present invention passes through control doractin, benzyl alcohol, antioxidant, preservative, glycerol acetonide
The weight percent of formaldehyde and the mixed solvent of propylene glycol, each component are used cooperatively jointly, can generate preferable synergy,
The stability of its injection for effectively increasing doractin, and irritation is reduced, using effect is preferable.In addition, passing through
Using benzyl alcohol as analgestic, it can reduce the irritation of preparation and reduce caused pain reaction when injection.
In addition, we there is a need to provide a kind of preparation method of non-oily Doramectin injection fluid.
A kind of preparation method of non-oily Doramectin injection fluid, comprising the following steps:
The doractin of 0.1%-10% is taken by weight percentage, and is added to glycerol formal and is mixed with what propylene glycol formed
In bonding solvent, wherein the mass ratio of the glycerol formal and the propylene glycol is (4-8): (2-6)；
The mixed solvent and the doractin are mixed, stirred evenly, through nitrogen flushing packing, rolls lid, sterilizing, lamp inspection conjunction
Lattice and packaging are to get non-oily Doramectin injection fluid.
The preparation method of the non-oily Doramectin injection fluid is simple and efficient, and industrialization is suitble to generate, and has wide answer
Use prospect.
It is posted in addition, there is a need to provide a kind of non-oily Doramectin injection fluid for preventing, treating or controlling in animal
Infested application.
Non-oily Doramectin injection fluid in the present invention can be used for the inside and outside expelling parasite of the animals such as poultry, domestic animal.Such as
The subcutaneously or intramuscularly injection that the injection can be used for animal carries out internal expelling parasite, or the injection is applied to helminth and is posted
External expelling parasite is carried out at raw.The non-oily Doramectin injection fluid stability is preferably and without intense stimulus.
Specific embodiment
To facilitate the understanding of the present invention, below in conjunction with embodiment to invention is more fully described.But this hair
It is bright to realize in many different forms, however it is not limited to embodiment described herein.On the contrary, providing these embodiments
Purpose be to make the disclosure of the present invention more thorough and comprehensive.
Unless otherwise defined, all technical and scientific terms used herein and belong to technical field of the invention
The normally understood meaning of technical staff is identical.Term as used herein in the specification of the present invention is intended merely to description tool
The purpose of the embodiment of body, it is not intended that in the limitation present invention.Term as used herein "and/or" includes one or more phases
Any and all combinations of the listed item of pass.
The test method of actual conditions is not specified in the following example, according to conventional methods and conditions, or says according to commodity
The adjusting of bright book suggestion is selected.Reagents or instruments used without specified manufacturer is that can be obtained by commercially available purchase
Conventional products.
The non-oily Doramectin injection fluid is using doractin as anti parasitic inside and outside the animal body of main pharmacodynamics ingredient
Preparation.The non-oily Doramectin injection fluid includes each component of following weight percent: doractin 0.1%-10%, such as
It can be, but be not limited to 0.5%, 1%, 2%, 3%, 4%, 5%, 6% or 8% etc..Solvent be glycerol formal and propylene glycol,
Weight percent is maintained at 100% by solvent.The quality of the glycerol formal and the propylene glycol in solvent in the present invention
Ratio is (4-8): (2-6).Such as can be, but be not limited to 4:2,4:4,5:3,4:6,6:1,6:2,6:4,6:5,7:3,7:5,
8:2,8:3 or 8:6 etc..Optionally, the glycerol formal and the mass ratio of the propylene glycol are (5-7): (3-5).Further may be used
The mass ratio of selection of land, the glycerol formal and the propylene glycol is 6:4.Optionally, the pH of the non-oily Doramectin injection fluid
Value is 3-7.Still optionally further, the pH value of the non-oily Doramectin injection fluid is 4-6.
Pass through compounding for glycerol formal and propylene glycol, it is ensured that the solvent being made of glycerol formal and propylene glycol can be compared with
Doractin is dissolved well, and all has preferable compatibility, can not only guarantee the injection of the non-oily doractin of preparation
Liquid stability is preferable, and the effect of injection of the non-oily doractin of guarantee preparation is preferable.And the glycerol formal
It is non-oily solvent with propylene glycol, it is easier to store, stability is higher.Therefore, pass through control glycerol formal and propylene glycol
Proportionate relationship, preferably doractin can be promoted to dissolve, can not only guarantee preparation non-oily doractin injection
Liquid irritation is lower, and guarantees that the stability of the injection of the non-oily doractin of preparation is preferable.
In one embodiment, which further includes each component of following weight percent: more
Drawing rhzomorph is 0.1%-10%, such as can be, but be not limited to 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 8%
Or 10% etc..Benzyl alcohol is 0.1%-5%, such as can be, but be not limited to 0.1%, 0.5%, 1%, 2%, 3%, 4% or
5% etc..Antioxidant is 0.05%-1%, such as can be, but is not limited to 0.05%, 0.2%, 0.4%, 0.6%, 0.8%
Or 1% etc..Preservative is 0.01%-1%, such as can be, but be not limited to 0.01%, 0.05%, 0.2%, 0.4%,
0.6%, 0.8% or 1% etc..Solvent is glycerol formal and the propylene glycol, and total weight percent is maintained at 100%.It is optional
Ground, respectively by the doractin of above-mentioned weight percent, the benzyl alcohol, the antioxidant, the preservative, the glycerol formal and
The mixed with propylene glycol, total weight percent 100% obtain the non-oily doractin mixed solution, add pH adjusting agent,
3-7 is adjusted to get non-oily Doramectin injection fluid.
In one embodiment, the weight percent of the doractin is 1%, and the weight percent of the benzyl alcohol is
0.2%, the weight percent of the antioxidant is 0.1%, and the weight percent of the preservative is 0.1%, the glycerol formal
Weight percent be 60%, the weight percent of the propylene glycol is 38.6%.Respectively by above-mentioned weight percent doractin,
It is mixed that non-oily doractin is made in the benzyl alcohol, the antioxidant, the preservative, the glycerol formal and the mixed with propylene glycol
Solution is closed, pH adjusting agent is added, adjusting pH value is 3-7 to get the non-oily Doramectin injection fluid.
Doractin preparation in the present invention passes through control doractin, benzyl alcohol, antioxidant, preservative, solvent
Weight percent, each component are used cooperatively jointly, can generate preferable synergy, effectively increase the note of doractin
The stability of liquid is penetrated, and reduces irritation, using effect is preferable.When the pH value of the non-oily Doramectin injection fluid controls
It is lower to the irritation of animal in 3-7, and effect is preferable.In addition, by using benzyl alcohol as analgestic, it can
It reduces the irritation of preparation and reduces caused pain reaction when injection.
In one embodiment, the antioxidant be vitamin A, carotenoid, ascorbic acid, flavone compound,
Polyphenol, isothiocyanates, cysteine, tocopherol (one in such as alpha-tocopherol, betatocopherol, Gamma-Tocopherol and Delta-Tocopherol
Kind or it is a variety of) and one of Renascins such as tocopherol acetate, tocopherol succinate or a variety of.Such as the antioxidant can
Think tocopherol acetate, or be the mixture of vitamin A and carotenoid, or is vitamin A, carotenoid and anti-bad
The mixture etc. of hematic acid.
Wherein, flavone compound to be with flavones (2- phenyl chromone) be parent nucleus and derivative a kind of yellow pigment,
In include the isomer and its hydrogenation and reduzate of flavones, namely take C6-C3-C6 as a series of chemical combination of basic carbon skeleton
Object.Flavone compound is distributed very wide, most of form that glycoside or carbon glycosyl are combined into sugar in plant in plant kingdom
In the presence of also some exists in a free form.Such as flavones, flavonols, flavanones, flavanonol, isoflavones, isoflavanones, look into ear
Ketone, dihydrochalcone, aurones, flavane, flavanols and flavane glycol (3,4).
Carotenoid can be classified as two classes according to the difference of chemical structure, and one kind is carrotene, containing only carbon
Two kinds of elements of hydrogen are free of oxygen element, such as lycopene, ɑ-carrotene, beta carotene and gamma carotene.It is another kind of to be
Lutein, containing oxygen-containing functional groups such as hydroxyl, ketone group, carboxyl, methoxyl groups, such as lutein and astaxanthin.
In one embodiment, the preservative be phenylethanol, phenol, metacresol, zephiran, p-hydroxybenzoate,
One of butylated hydroxyanisole (BHA), butylated hydroxytoluene, propyl gallate, benzaldehyde are a variety of.If preservative can be butyl
Hydroxyanisol (BHA) or the preservative are butylated hydroxytoluene (BHT) or the preservative is butylated hydroxyanisole (BHA) and fourth
The mixture of base hydroxy-methylbenzene, or the mixture etc. for p-hydroxybenzoate, butylated hydroxyanisole (BHA) and butylated hydroxytoluene.
By the present invention in that with maleic acid, hydrochloric acid, tartaric acid, sodium hydroxide, acetic acid, acetate, phosphoric acid, phosphate, lemon
Lemon acid, citrate, ethanol amine, triethanolamine and the medium pH adjusting agent of diethanol amine are by the note of the non-oily doractin of preparation
The pH for penetrating liquid is controlled in 3-7, has preferable synergy between each component at this time, and the effect of anti parasitic is preferable, and stimulates
Property is lower.
In addition, we there is a need to provide a kind of preparation method of non-oily Doramectin injection fluid.
A kind of preparation method of above-mentioned non-oily Doramectin injection fluid, comprising the following steps:
The doractin of 0.1%-10% is taken by weight percentage, and is added to the molten of glycerol formal and mixed with propylene glycol
In agent, wherein the mass ratio of the glycerol formal and the propylene glycol is (4-8): (2-6)；
The solvent and the doractin are mixed, stirred evenly, through nitrogen flushing packing, rolls lid, sterilizing, lamp inspection qualification and packet
Dress is to get non-oily Doramectin injection fluid.
It is posted in addition, there is a need to provide a kind of non-oily Doramectin injection fluid for preventing, treating or controlling in animal
Infested application.
Non-oily Doramectin injection fluid in the present invention can be used for the inside and outside expelling parasite of the animals such as poultry, domestic animal.Such as
The subcutaneously or intramuscularly injection that the injection can be used for animal carries out internal expelling parasite, or the injection is applied to helminth and is posted
External expelling parasite is carried out at raw.The non-oily Doramectin injection fluid stability is preferably and without intense stimulus.Non-oily doractin
The dosage of injection and specific form of therapy can be selected according to the case where zoogenetic infection helminth.
The following are specific embodiments:
Embodiment 1
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 1%, glycerol formal 59.4% and propylene glycol 39.6%.
1) agitator tank is added in glycerol formal and propylene glycol, be uniformly mixed；
2) doractin is added in the agitator tank in step 1), stirring 15 minutes to being completely dissolved；
3) step 2) acquired solution dispensed through nitrogen flushing, roll lid, sterilizing, lamp inspection is qualified and packaging is to get non-oily Duola
Rhzomorph injection 1.
Embodiment 2
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 1%, glycerol formal 39.7% and propylene glycol 59.3%.
The preparation method of the non-oily Doramectin injection fluid 2 is same as Example 1.
Embodiment 3
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 5%, glycerol formal 76% and propylene glycol 19%.
The preparation method of the non-oily Doramectin injection fluid 3 is same as Example 1.
Embodiment 4
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 10%, glycerol formal 54% and propylene glycol 36%.
The preparation method of the non-oily Doramectin injection fluid 4 is same as Example 1.
Embodiment 5
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 0.1%, glycerol formal 59.9% and propylene glycol 40%.
The preparation method of the non-oily Doramectin injection fluid 5 is same as Example 1.
Embodiment 6
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 5%, benzyl alcohol 2.5%, tocopherol acetate 0.5%, butylated hydroxyanisole (BHA) 0.5%, glycerol acetonide
Formaldehyde 54.6% and the propylene glycol 36.9%.
1) agitator tank is added in propylene glycol and glycerol formal, be uniformly mixed.
2) doractin is added in the agitator tank in step 1), stirring 15 minutes to being completely dissolved.
3) benzyl alcohol, tocopherol acetate and butylated hydroxyanisole (BHA) are added in the agitator tank in step 2), are stirred
Mixed solution is obtained to uniformly mixed within 10 minutes.
4) pH adjusting agent is added in the mixed solution obtained by step 3), adjusting pH value is 3-7.
5) step 4) acquired solution nitrogen flushing dispensed, roll lid, sterilizing, lamp inspection is qualified and packaging is to get non-oily Doramectin
Plain injection 6.
Embodiment 7
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
It is doractin 0.1%, benzyl alcohol 0.1%, tocopherol acetate 0.05%, butylated hydroxyanisole (BHA) 0.01%, sweet
Oily formal 59.84% and the propylene glycol 39.9%.
The preparation method of the non-oily Doramectin injection fluid 7 is same as Example 6.
Embodiment 8
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 10%, benzyl alcohol 5%, tocopherol acetate 1%, butylated hydroxyanisole (BHA) 1%, glycerol formal
49.2% and the propylene glycol 33.8%.
The preparation method of the non-oily Doramectin injection fluid 8 is same as Example 6.
Embodiment 9
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 1%, benzyl alcohol 0.2%, tocopherol acetate 0.05%, butylated hydroxyanisole (BHA) 0.05%, glycerol
Formal 63.6% and the propylene glycol 35.1%.
The preparation method of the non-oily Doramectin injection fluid 9 is same as Example 6.
Embodiment 10
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 1%, benzyl alcohol 0.2%, tocopherol acetate 0.1%, butylated hydroxyanisole (BHA) 0.1%, glycerol acetonide
Formaldehyde 60% and propylene glycol 38.6%.
The preparation method of the non-oily Doramectin injection fluid 10 is same as Example 6.
Embodiment 11
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 4%, benzyl alcohol 3%, flavonols 0.5%, phenol 0.5%, glycerol formal 61% and the propylene glycol
31%.
The preparation method of the non-oily Doramectin injection fluid 11 is same as Example 6.
Embodiment 12
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 8%, benzyl alcohol 4%, vitamin A 0.8%, p-hydroxybenzoate 0.8%, glycerol formal
65.2% and the propylene glycol 22.2%.
The preparation method of the non-oily Doramectin injection fluid 12 is same as Example 6.
Embodiment 13
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 9%, benzyl alcohol 5%, alpha-tocopherol 0.5%, zephiran 0.5%, glycerol formal 68.1% and should
Propylene glycol 16.9%.
The preparation method of the non-oily Doramectin injection fluid 13 is same as Example 6.
Embodiment 14
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 0.5%, benzyl alcohol 0.1%, alpha-tocopherol 0.05%, zephiran 0.01%, glycerol formal
59.6% and propylene glycol 39.74%.
The preparation method of the non-oily Doramectin injection fluid 14 is same as Example 6.
Embodiment 15
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 5%, benzyl alcohol 5%, alpha-tocopherol 5%, zephiran 5%, glycerol formal 50% and propylene glycol
30%.
The preparation method of the non-oily Doramectin injection fluid 15 is same as Example 6.
Comparative example 1
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 1%, ethyl oleate 21%, phenol 0.5%, butylated hydroxyanisole (BHA) 0.5% and soybean oil 77%.
1) agitator tank is added in soybean oil and ethyl oleate, be uniformly mixed.
2) doractin and butylated hydroxyanisole (BHA) are added in the agitator tank in step 1), are uniformly mixed.
3) phenol is added in the agitator tank in step 2), is uniformly mixed to obtain solution.
4) step 3) acquired solution nitrogen flushing is dispensed, rolls lid, sterilized, lamp inspection is qualified and packs to get doractin injection
Liquid 1.
Comparative example 2
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 5%, glycerol formal 85.5% and propylene glycol 9.2%.
The preparation method of the Doramectin injection fluid 2 is same as Example 1.
Comparative example 3
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 5%, glycerol formal 31.7% and propylene glycol 63.3%.
The preparation method of the Doramectin injection fluid 3 is same as Example 1.
Comparative example 4
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 1%, benzyl alcohol 0.2%, tocopherol acetate 0.1%, butylated hydroxyanisole (BHA) 0.1%, glycerol acetonide
Formaldehyde 88.65% and the propylene glycol 9.95%.
The preparation method of the Doramectin injection fluid 4 is same as Example 6.
Comparative example 5
Weigh each raw material by following weight percent (by taking total amount 100ml as an example)
Doractin 1%, benzyl alcohol 0.2%, tocopherol acetate 0.1%, butylated hydroxyanisole (BHA) 0.1%, glycerol acetonide
Formaldehyde 32.9% and propylene glycol 65.7%.
The preparation method of the Doramectin injection fluid 5 is same as Example 6.
Effete test embodiment 1
In order to verify stability of the non-oily Doramectin injection fluid under extraordinary environment in the present invention, Example 1, reality
It is appropriate to apply doractin preparation prepared by example 10 and comparative example 1, simulation listing packing instructions carry out hot test, Qiang Guang respectively
It is as follows according to test and high humidity test, specific test method:
1.1 hot test
It is sealed in brown sodium calcium injection bottle, is placed 10 days at a temperature of 60 DEG C, in the 5th day and the 10th day sampling analysis.
The test of 1.2 intense light irradiations
It is sealed in brown sodium calcium injection bottle and is placed in the stable case of sample, placed under the conditions of 4500 ± 500lx of Yu Zhaodu
10 days, the 5th day and the 10th day sampling analysis.
1.3 high humidity test
It is sealed in brown sodium calcium injection bottle and is placed in 25 DEG C, placed 10 days under the conditions of relative humidity 70% ± 5%,
5 days and the 10th day sampling analysis.
Each samples taken presses the quality mark of " veterinary medical quality standard compendium " (2006-2011) Doramectin injection fluid
Standard is tested and analyzed, and is compared with 0 day result, and table 1 is stability of the Doramectin injection fluid under extraordinary environment
Test result.
Stability test result of 1 Doramectin injection fluid of table under extraordinary environment
Conclusion: according to 1 detection data of table it is found that the non-oily Doramectin injection fluid of embodiment 1 and embodiment 10 is 60
DEG C high temperature, the intense light irradiation of 4500 ± 500lx and 75% ± 5% high humidity environment under every Testing index have no significant change, matter
It measures relatively stable.And Doramectin injection fluid prepared by comparative example 1 is in 60 DEG C of high temperature, the intense light irradiation and 90% of 4500 ± 500lx
Changes of contents is larger in every Testing index under ± 5% high humidity environment, in the intense light irradiation face of 60 DEG C of high temperature, 4500 ± 500lx
Color change is bigger, unstable quality.Therefore, stability of the non-oily Doramectin injection fluid under extraordinary environment in the present invention
It significantly improves.
Effete test embodiment 2
In order to verify the stability of non-oily Doramectin injection fluid in normal circumstances in the present invention, Example 1, reality
It is appropriate to apply example 2, embodiment 6, embodiment 10 and the doractin preparation of comparative example 1-5 preparation, simulation listing packing instructions, respectively
6 months progress accelerated stability tests are placed under conditions of 40 ± 2 DEG C of temperature, relative humidity 75% ± 5%, during test
1st month, 2 months, 3 months, the 6 months the end of month it is separately sampled primary, each samples taken presses " veterinary medical quality standard compendium "
The quality standard of (2006-2011) Doramectin injection fluid is tested and analyzed, and is compared with 0 day result, and table 2 is
The accelerated stability test result of Doramectin injection fluid in normal circumstances.
The accelerated stability test result of 2 Doramectin injection fluid of table in normal circumstances
Conclusion: according to 2 detection data of table it is found that prepared by the embodiment of the present invention 1, embodiment 2, embodiment 6, embodiment 10
After non-oily Doramectin injection fluid accelerated stability test 6 months, content declines within 3%, and color is without significant change, surely
It is qualitative preferable.Comparative example 1 prepares the Doramectin injection fluid accelerated stability test 6 of formation using oily injection solvent
After a month, content decrease beyond 15%, and color has significant change after 3 months, and stability is poor.And comparative example 2, comparative example 3,
Doramectin injection fluid prepared by comparative example 4, after stability test 6 months, the content decline later face more than 10%, 6 month
Color has significant change, and stability is poor.
Because glycerol formal and mixed with propylene glycol mass ratio are (4-8): when (2-6), dissolving the property of doractin
Can be preferable and also preferable with the compatibility of doractin, the stability of the non-oily Doramectin injection fluid formed at this time is preferable.
When glycerol formal and excessive or too small mixed with propylene glycol mass ratio, it can all inhibit the dissolution of doractin, and each component
Between matching property it is also poor, and then the stability of Doramectin injection fluid prepared is significantly deteriorated.Therefore, prepared by the present invention
Non-oily Doramectin injection fluid stability it is preferable.
Effete test embodiment 3
In order to verify the long-time stability of non-oily Doramectin injection fluid in normal circumstances, Example in the present invention
1, embodiment 2, embodiment 6, embodiment 10 and the doractin preparation of comparative example 1-5 preparation are appropriate, simulation listing packing instructions,
24 months progress long-term stable experiments, In are placed under conditions of 25 DEG C ± 2 DEG C of temperature, relative humidity 60% ± 10% respectively
1st month during test, 2 months, 3 months, 6 months, 12 months, 24 the end of month it is separately sampled primary, each samples taken is equal
Tested and analyzed by the quality standard of " veterinary medical quality standard compendium " (2006-2011) Doramectin injection fluid, and with 0 day
Result be compared, table 3 be the long-term stable experiment result of Doramectin injection fluid in normal circumstances.
The long-term stable experiment result of 3 Doramectin injection fluid of table in normal circumstances
Conclusion: according to 3 detection data of table it is found that prepared by the embodiment of the present invention 1, embodiment 2, embodiment 6, embodiment 10
Non-oily Doramectin injection fluid long term test 24 months after, content declines within 3%, and color has no significant change, long
Phase stability is preferable.And the Doramectin injection fluid long term test in comparative example 1-5 is after 24 months, content decline is more than
15%, color also has significant change, and long-time stability are poor.Therefore, non-oily Doramectin injection fluid prepared by the present invention
Long-time stability in normal circumstances are also preferable.
Effete test embodiment 4
Doramectin injection fluid prepared by non-oily Doramectin injection fluid and comparative example 1 prepared by Example 10 is appropriate
Carry out animal irritation test and anti parasitic efficacy test.
In dog farm, Huadu, Guangdong Province, itch is chosen, local skin dothienesis, hair follicle inflammation, hair of leafing through is visible
The dog of black helminth excreta or helminth polypide only 20, it is judged as parasitic disease dog, every 10 are included into one group.A group is
Experimental group, the 0.6mg/kg weight based on doractin, injection in every 7 days use the non-oily Doramectin injection fluid of embodiment 10；B
Group is control group, uses the Doramectin injection fluid of comparative example 1 with injection in A group Isodose every 7 days.Embodiment 10 and comparative example
1 injection is combined three times, and A group and the stable breeding of B component field avoid cross infection.
Combination injection after non-oily Doramectin injection fluid, observes the dog skin conditions of A group and B group, A group dog is only three times
Significant red and swollen and bulge is not found all, it is good to test dog spirit without special change for injection site；And the note of 6 dogs only in B group
Penetrating position has red and swollen and bulge, the lassitude of the dog only.Therefore, non-oily Doramectin injection fluid of the invention is relative to oil
The irritation of property Doramectin injection fluid is low, using effect is good.In addition, the whole dog skin conditions of A group are obviously improved, inflammation disappears
It loses, opens hair without discovery black helminth excreta, also without discovery helminth living body.2 dog inflammation of B group do not disappear, turn over
Wool opening has returned black helminth excreta, it has been found that helminth living body.Therefore, non-oily Doramectin injection fluid of the invention
Also has effects that preferably anti parasitic.
Each technical characteristic of embodiment described above can be combined arbitrarily, for simplicity of description, not to above-mentioned reality
It applies all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited
In contradiction, all should be considered as described in this specification.
The embodiments described above only express several embodiments of the present invention, and the description thereof is more specific and detailed, but simultaneously
It cannot therefore be construed as limiting the scope of the patent.It should be pointed out that coming for those of ordinary skill in the art
It says, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection of the invention
Range.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.
Claims (9)
1. a kind of non-oily Doramectin injection fluid, which is characterized in that be made of following raw material components: doractin, glycerol acetonide
Formaldehyde and propylene glycol；Wherein, the weight percent of the doractin is 0.1%-10%, the glycerol formal and described third
Glycol forms mixed solvent, and glycerol formal described in the mixed solvent and the mass ratio of the propylene glycol are (4-8):
(2-6)；Or
It is made of following raw material components: doractin, glycerol formal and propylene glycol, benzyl alcohol, antioxidant and preservative；Its
In, the weight percent of the doractin is 0.1%-10%, and the weight percent of the benzyl alcohol is 0.1%~5%, institute
The weight percent for stating antioxidant is 0.05%~1%, and the weight percent of the preservative is 0.01%~1%, described
Glycerol formal and the propylene glycol form mixed solvent, glycerol formal described in the mixed solvent and the propylene glycol
Mass ratio is (4-8): (2-6).
2. non-oily Doramectin injection fluid according to claim 1, which is characterized in that the glycerol formal with it is described
The mass ratio of propylene glycol is (5-7): (3-5).
3. non-oily Doramectin injection fluid according to claim 2, which is characterized in that the glycerol formal with it is described
The mass ratio of propylene glycol is 6:4.
4. non-oily Doramectin injection fluid according to claim 1, which is characterized in that the weight hundred of the doractin
Divide than being 0.5%-5%, the weight percent of the benzyl alcohol is 0.1%-1%.
5. non-oily Doramectin injection fluid according to claim 4, which is characterized in that the non-oily doractin note
Penetrate liquid be according to following preparation steps prepare and obtain: first respectively by the doractin, the benzyl alcohol, the antioxidant,
The preservative, the glycerol formal and the propylene glycol according to weight percent be 1%, 0.2%, 0.1%, 0.1%,
60%, non-oily doractin mixed solution is made in 38.6% ratio mixing, then the non-oily doractin mixing is molten
PH adjusting agent is added in liquid, adjusts pH to 3-7.
6. non-oily Doramectin injection fluid according to claim 1, which is characterized in that the antioxidant is vitamin
A, carotenoid, ascorbic acid, flavone compound, polyphenol, isothiocyanates, cysteine, tocopherol and Renascin
One of or it is a variety of.
7. non-oily Doramectin injection fluid according to claim 1, which is characterized in that the preservative is phenyl second
Alcohol, phenol, metacresol, zephiran, p-hydroxybenzoate, butylated hydroxyanisole (BHA), butylated hydroxytoluene, propyl gallate and benzene
One of formaldehyde is a variety of.
8. a kind of preparation method of such as described in any item non-oily Doramectin injection fluids of claim 1-7, which is characterized in that
The following steps are included:
The doractin for taking 0.1%-10% by weight percentage is added to the mixed solvent of glycerol formal and propylene glycol composition
In, wherein the mass ratio of the glycerol formal and the propylene glycol is (4-8): (2-6)；
The mixed solvent and the doractin are mixed, stirred evenly, through nitrogen flushing packing, roll lid, sterilizing, lamp inspection it is qualified and
Packaging is to get non-oily Doramectin injection fluid.
9. a kind of as the described in any item non-oily Doramectin injection fluids of claim 1-7 prevent, treat in animal in preparation
Application in the drug of helminth.
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| IT202000009577A1 (en) * | 2020-04-30 | 2021-10-30 | Fatro Spa | INJECTABLE LIPOIC ACID FORMULATIONS FOR THE TREATMENT OF OXIDATIVE STRESS AND METABOLIC DISORDERS |
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