CN106619685A - Oral solid preparation containing ivermectin medicine - Google Patents
Oral solid preparation containing ivermectin medicine Download PDFInfo
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- CN106619685A CN106619685A CN201710033270.6A CN201710033270A CN106619685A CN 106619685 A CN106619685 A CN 106619685A CN 201710033270 A CN201710033270 A CN 201710033270A CN 106619685 A CN106619685 A CN 106619685A
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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
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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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
- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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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
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
Abstract
The invention provides an oral solid preparation containing an ivermectin medicine, and the oral solid preparation is prepared by combining the ivermectin medicine with a selected nonionic surfactant and other adjuvant. The oral solid preparation mainly solves the technical problems of increasing the dissolution rate of the ivermectin medicine in the preparation in water and overcoming the shortcoming that the ivermectin medicine is easy to hydrolyze under an acidic condition, so as to fulfill the aims of increasing the dissolution rate of the medicine in the body and protecting the medicine from being damaged or guaranteeing less damage to the medicine in the acidic gastric liquid; furthermore, the problems of acid/alkali catalytic degradation and oxidizing degradation of active components of the preparation in the storage period are solved, so that less effective components in the medicine are degraded. According to the oral solid preparation containing the ivermectin medicine, by the particular use of a polyoxyethylene hydrogenated castor oil condensation compound and benzyl benzoate or azone or octanoic/capric acid triglyceride or isopropyl myristate for combination, the oral solid preparation containing the ivermectin medicine, which is higher in resistance to acidic/alkaline catalytic degradation, is prepared.
Description
Technical field
The invention belongs to veterinary drug preparation technology of preparing, and in particular to a kind of system of ivermectin class drug oral solid preparation
Standby technology, the preparation prepared with this technology has dissolution high and more tolerant to the characteristic of acid/base catalytic degradation.
Background technology
Ivermectin class medicine is a kind of high-efficiency broad spectrum anti-parasite medicine, and it is to parasitic nematicide in animal body and outer
Parasite have it is very strong kill effect, they are widely used in animal parasitosis and prevent and treat.Commercially available product for animals has
Injection, oral liquid, dashing agent, unguentum, granule, slow release bolus, tablet, powder, pre-mixing agent etc..Wherein pre-mixing agent is main
It is used for the preventing and treating verminosis of pig and horse.At home at this stage there is 0.6% ivermectin pre-mixing agent of import commercially available prod (such as
Ivomec), domestic ivermectin/Albendazole's compound recipe pre-mixing agent and powder, domestic albendazole oxide/ivermectin compound recipe
Pre-mixing agent, the single preparations of ephedrine also without domestic powder or pre-mixing agent is commercially available.
The slightly solubility of medicine and the sensitivity on acid are all the key factors for affecting oral type drug bioavailability.Test
Show with data：(1) ivermectin class medicine is not almost dissolved in water.Such as it is only capable of dissolving the Yi Wei of 6-9 micrograms in 1 liter of water
Rhzomorph.Therefore, when the oral solid formulation of the medicine of class containing ivermectin is prepared, in order to ensure that medicine can more be absorbed,
The water solubility problems for improving medicine are the sport technique segments for needing to consider.(2) there are 2 in the molecular structure of ivermectin class medicine
Glycosidic bond, it is easily catalyzed by acids hydrolysis and loses saccharide residue.Such as ivermectin is easily catalyzed by acids hydrolysis and conversion is Viability very
Low monosaccharide ivermectin B1a(MS H2B1And H a)2B1A aglycones (are shown in Table 1).And the gastric juice of the animal such as pig, chicken is most in acid
Property, its acidity most can reach by force pH value 1 or so (being approximately equivalent to the acidity of 0.1M hydrochloric acid).This points out us：By improving preparation
Acid resistance, to reduce hydrolysis of the acidic gastric juice to ivermectin class medicine, can be this kind of medicine oral formulations energy
Probability is provided by more absorption.We are detected to domestic commercially available prod, are as a result shown, 0.6% Yi Wei of import
Rhzomorph pre-mixing agent (Ivomec) has the performance (being shown in Table 2) of the high and tolerable acid-catalyzed hydrolysis of drug dissolution.And it is nearly all
The dissolution of ivermectin is zero in domestic compounding powder and pre-mixing agent.Clinical practice shows, just kills Sarcoptes suis and pig is sucked blood
For the effect of louse, imported product determined curative effect, undulatory property is little.Show according to correlational study, the oral ivermectin formulation of pig, it is biological
Availability is only 41% or so.It is believed that dissolution of the ivermectin in water and tolerance acid-catalyzed hydrolysis effect in preparation
Power be affect ivermectin oral administration biaavailability key factor.Therefore, by the dissolution and acid-catalyzed hydrolysis of product
Rate is of practical significance as the quality index for weighing this quasi drugss quality, this can further monitor from another side and
Reflect the quality of product, you can enable the control of this kind of drug quality more scientific, accurately and comprehensive.
Test shows, C2 position of the ivermectin class medicine in the basic conditions in its molecular structure easily there is epimerism and
It is converted into 2- epimer H2B1a(2-epimer H2B1A), its anthelmintic activity is only H2B11% or so of a activity；C3=
C4The double bond of position is easily subjected to displacement, and is converted into the very low Δ of activity2,3H2B1A (is shown in Table 3)；Have in ivermectin molecular structure
Lactone bond is equally easily by OH-Attack and destroyed.In fact, degraded of the ivermectin class medicine during preserving, except oxygen
Change degraded outer, also there are problems that acid/base catalytic degradation.Open source information shows, ivermectin class medicine under the conditions of slant acidity more
Stable, suitable pH range is between 4-6.We work as composition by being shown with the test that carries out of preparation containing ivermectin
When the PH of the carrier material of preparation is more than 6.2, the impurity produced in the shelf-life is more 2- epimer ivermectins
B1a；When the pH value of carrier material is less than 4.3, the impurity produced in the shelf-life is more monosaccharide ivermectin B1a.Test is aobvious
Show, the oral formulations of the medicine of class containing ivermectin prepared with the selected nonionic surfactant of the present invention, its carrier material
, in 4.8-5.3, stability is more preferably (with the relative percentage content of the 2- epimer ivermectins of storage life increase for pH value
With MS H2B1The relative percentage content of a is used as Index for examination).
It is visible in sum, prepare containing ivermectin medicine preparation when, need to solve the problems, such as medicine water-insoluble and
Overcome the acid/base catalytic degradation problem of medicine.Because ivermectin class medicine also has the double bond that can be oxidized, therefore, prepare
The preparation of the medicine of class containing ivermectin is it is also necessary to take into account that its oxidative degradation problem.
Surfactant can not only improve the water dissolvable of some hydrophobic drugs as solubilizing agent or cosolvent, and
The presence of specific surfactant, can strengthen some preparation stablizing in acid or alkaline environment for containing facile hydrolysiss medicine
Property, " this is because surfactant can form in the solution micelle, that is, defining a kind of barrier ", this " glue for wrapping up in medicine
Beam barrier " hinders H+、OH-Attack to facile hydrolysiss medicine.But if it is improper that surfactant is selected, on the contrary medicine can be made more
Easily by acid/base catalytic degradation.Such as sodium lauryl sulphate (abbreviation SDS), its acid-catalyzed hydrolysis to ivermectin have aobvious
The potentiation (being shown in Table 5) of work.Therefore, by improving dissolution of the insoluble drug in water using the method for surfactant
(dissolving) speed or meltage, while requiring that there are preparation the sour catalyzing hydrolysis of tolerance to act on and raising preparation is during preserving
Stability (including opposing acid or destruction and the oxidative degradation of alkali), the selection of kinds of surfactants and using method
Foundation undoubtedly it is critical that sport technique segment.
The content of the invention
The invention mainly solves the technical problem of improving dissolution of the ivermectin class medicine in water in solid preparation
With the defect for overcoming ivermectin class medicine facile hydrolysiss in acid condition, to reach medicine i.e. dissolution in gastric juice, while and
Not by acidic gastric juice destruction or less destroyed purpose；Next to that overcome preparation during preserving, the acid/base of its active ingredient
Catalytic degradation problem and oxidative degradation problem, make that the active component of medicament degrades is less.The present invention is more preferably by surface activity
Agent and hydrophobic solvent (the benzyl benzoate or pungent/capric acid triglyceride or isopropyl myristate or azone) combination for selecting make
With come prepare more resistant to acid/base catalytic degradation effect oral solid formulation, target of the present invention is realized with this.
Following each component is included in preparation of the present invention：
(1) active component, its content in per kilogram preparation is 0.1-20 gram；Described active component includes Avermectin
One kind in element, ivermectin, doractin, moxidectin, Eprinomectin, department's drawing rhzomorph.They are belonged to greatly
Cyclic lactone class anti-parasite medicine.
(2) nonionic surfactant of the hydrophile-lipophile balance value (HLB value) more than or equal to 12, it is in the formulation most
Big content is 20%, and suitable content is 3-20 times of anti-parasite medicine weight, and content preferably is anti-parasite medicine
6-14 times of weight.The surfactant of selection includes Tweenses, Myrij class, brejses, peregal, polyethylene glycol hydrogenated Semen Ricini
Oily condensation substance, Polyethylene Glycol vegetable oil condensation substance.The surfactant for further selecting includes Polyethylene oxide (35) hydrogenated castor
Oily (HEL-35), Polyethylene oxide (40) castor oil hydrogenated (HEL-40), Polyethylene oxide (50) castor oil hydrogenated (HEL-50), polyoxy
Ethylene (60) castor oil hydrogenated (HEL-60), Polyethylene Glycol (40) palm-kernel oil, Polyethylene Glycol (60) Semen Maydis oil, Polyethylene Glycol
(60) corn oil glyceride, Polyethylene Glycol (60) almond oil, Polyethylene Glycol (50) Oleum Ricini, hydrophile-lipophile balance value (HLB value)
One or more the compositionss in Brij58, Brij -35 more than 12；Still more preferably HEL-
35th, HEL-40 or HEL-60 is used for the preparation of invention formulation.
(3) carrier material, adds to 1 kilogram.Described carrier material include maize cob meal, zeolite powder, stone powder, kieselguhr,
One or more compositionss in Gypsum Fibrosum powder, starch, fish flour, beef powder, Carnis Gallus domesticus powder, pork liver powder, chicken liver meal.By 4 grams
Carrier material, with 20-40 milliliters water 10-30 minutes are soaked, and are then determined with acidometer, and described carrier material pH value should be
In the range of 4.4-5.7, suitable pH range is 4.7-5.3.
Hydrophobic solvent (medium), the hydrophobic solvent can be also added to include Benzyl Benzoate in the above preparation
Ester, pungent/capric acid triglyceride, isopropyl myristate, ethyl oleate, azone, dipropylene glycol dibenzoate, diethylene glycol benzene
One or more compositionss in formic acid esters；Content of the hydrophobic solvent in per kilogram preparation is the surface activity
The 10-110% of agent weight.The common feature of hydrophobic solvent of the present invention is that have preferably molten to ivermectin class medicine
Agent ability, has very strong affinity with preferred surfactant.This is that they can form closely " micelle barrier ", to hinder
H+、OH-With primary chemical basis of the oxygen to medicaments target.
Also comprising 10-220 gram of solid dispersion medium (also referred to as firming agent), institute in described per kilogram preparation
The pharmaceutic adjuvant that solid dispersion medium is stated for fusing point more than 45 DEG C less than 100 DEG C, preferred solid dispersion medium includes single Hard Fat
Acid glyceride, glyceryl tristearate, the Polyethylene Glycol of solid state, stearic acid, the fatty alcohol of solid state, animal wax, bar
One or more compositionss in western wax, castor oil hydrogenated, behenic acid or Glyceryl Behenate.What is added in preparation consolidates
Body disperse medium can be such that the surfactant and anti-parasite medicine of liquid condition dissolves in wherein, be fixed on solid dispersion medium
In, so as to can more effectively hinder attack (oxidative degradation) of the oxygen in air to medicine.Test shows, when solid in preparation
When the content of body disperse medium exceedes 10 times of medicament contg, even if being added without antioxidant, preparation is still very stable, and the shelf-life is reachable
More than 2 years, solid dispersion medium content more shelf-lifves were longer.
Also comprising 10-120 gram of arabic gum or polyvinylpyrrolidone in described per kilogram preparation.
Also comprising 0.2-5 gram of antioxidant in described per kilogram preparation, the antioxidant includes butylated hydroxy-a
One or more compositionss in benzene, tertiary butyl-4-hydroxy methoxybenzene, propylgallate.The addition of antioxidant can
Further reduce the probability that preparation occurs to degrade because of oxidation.
10-100 gram of other anti-parasite medicine, the anti-parasitism of other described can be also added in described per kilogram preparation
Worm medicine includes the one kind in Albendazole, albendazole oxide, Phenbendasol, oxfendazole, insect growth regulator, IGR.
The solid preparation may be selected one of following methods and prepare：
The solution of the medicine of class containing ivermectin that method a. dissolves by ivermectin class medicine or with solvent is non-with described
Ionic surface active agent mixes, and adds or be added without 1,2-PD, described hydrophobic solvent is added or be added without, in 70-
Stir under the conditions of 85 DEG C, make complete drug dissolution, obtain the liquid of the medicine of class containing ivermectin；To the liquid under the conditions of 70-85 DEG C
Described carrier material is added in body, is sufficiently stirred for, mix homogeneously, afterwards temperature of charge is down to into room temperature, remove the solvent,
24 mesh sieves are crossed, described solid preparation is obtained final product；The solvent is ethanol or ethyl acetate or combinations thereof.
The solution of the medicine of class containing ivermectin that method b. dissolves by ivermectin class medicine or with solvent is non-with described
Ionic surface active agent mixes, and adds or be added without 1,2-PD, described hydrophobic solvent is added or be added without, in 70-
Stir under the conditions of 85 DEG C, make complete drug dissolution, add described solid dispersion medium, continue to stir, make solid dispersion medium
Melt and mix, described carrier material is added under the conditions of 70-85 DEG C, be sufficiently stirred for, mix homogeneously, afterwards by temperature of charge
Room temperature is down to, is treated that material is fully cured or is dried and is removed the solvent, cross 24 mesh sieves, siftage is described solid preparation；
The solvent is ethanol or ethyl acetate or combinations thereof.
Method c. by ivermectin class medicine, described nonionic surfactant and 1,2-PD mix, add or
Described hydrophobic solvent is not added with, is stirred under the conditions of 70-85 DEG C, make complete drug dissolution, be cooled to 30-45 DEG C, in stirring
Under the conditions of, the water equivalent to ivermectin class 5-70 times of weight of medicine is added, it is prepared into emulsion；Then will be with emulsion equivalent to 5
The carrier material and emulsion mixing of times weight, is sufficiently stirred for, and then mix homogeneously is dried, and obtains final product described solid preparation；
Method d. by ivermectin class medicine, described nonionic surfactant and 1,2-PD mix, add or
Described hydrophobic solvent is not added with, is stirred under the conditions of 70-85 DEG C, make complete drug dissolution, be cooled to 30-45 DEG C, in stirring
Under the conditions of, the water equivalent to ivermectin class 5-70 times of weight of medicine is added, it is prepared into emulsion；Then will be with emulsion equivalent to 5
The carrier material and emulsion mixing of times weight, is sufficiently stirred for, mix homogeneously, is dried, and must carry medicine granule；Solid dispersion is situated between
Matter melts under the conditions of 70-95 DEG C, and obtained load medicine granule is added under this temperature conditions, is sufficiently stirred for, mix homogeneously, drops
To room temperature, it is allowed to solidify, crosses 24 mesh sieves, obtains final product described solid preparation.
Method e. by ivermectin class medicine, described nonionic surfactant and 1,2-PD mix, add or
Described hydrophobic solvent is not added with, is stirred under the conditions of 70-85 DEG C, make complete drug dissolution, be cooled to 30-45 DEG C, in stirring
Under the conditions of, add containing polyvinylpyrrolidone or the aqueous solution containing arabic gum, fully mix, it is prepared into sticky emulsion；So
To mix with emulsion to the maize cob meal of 5 times of weight with emulsion equivalent afterwards, stirring and evenly mixing, be dried, obtain final product described solid preparation.
Method f. by ivermectin class medicine, described nonionic surfactant and 1,2-PD mix, add or
Described hydrophobic solvent is not added with, is stirred under the conditions of 70-85 DEG C, make complete drug dissolution, be cooled to 30-45 DEG C, in stirring
Under the conditions of, the aqueous solution containing polyvinylpyrrolidone or ethanol solution are added, or the aqueous solution containing arabic gum is added, it is fully mixed
It is even, it is prepared into slightly sticky emulsion or solution；Then by with the carrier material of emulsion or solution even to 5 times of weight and emulsion or
Solution mixes, stirring and evenly mixing, is dried, and must carry medicine granule；Described solid dispersion medium is melted under the conditions of 70-95 DEG C, and
Obtained load medicine granule is added under this temperature conditions, is sufficiently stirred for mixing, be down to room temperature, be allowed to solidify, sieved, obtained final product described
Solid preparation.
Dissolution Rate Testing shows, after solid preparation mixes with water obtained in above method, Jing vibration medicines are dissolved,
In the form of emulsion droplet in system.This points out our said preparations under body temperature, and meeting can be in gastrointestinal motility after body fluid
Promoting under spontaneously form emulsion, it is therefore contemplated that prepared above-mentioned preparation is a kind of self-emulsifying drug delivery system (Jia Wei, Gao Wen
Remote chief editor, Qiu Mingfeng associate editors, medicine controlled releasing novel form, Chemical Industry Press, April the 1st edition, the 71-83 page in 2005),
I.e. said preparation is a kind of self-emulsification solid preparation.
Test shows, by the oral solid formulation containing ivermectin prepared by above-mentioned formula and method, is in concentration of hydrochloric acid
In the solution of 0.09-0.11M, under the conditions of 36-37 DEG C 3 hours are incubated, are detected with HPLC, particularly preferred preparation its monosaccharide she
Dimension rhzomorph B1The chromatographic peak area of a and ivermectin B1The ratio of the chromatographic peak area of a is less than 2% (embodiment 2 is to embodiment 4).Enter
, more than 5% (be shown in Table 12 and table 15), sample is (in embodiment 3 obtained in the technology as disclosed in Patents for mouthful product ratio
M-102-1, M-105-1) its area ratio is also greater than 5%.This explanation, this preparation has higher preventing to the catalytic degradation of acid
Effect.This preparation equally has higher inhibitory action (be shown in Table 16 and table 17) to the catalytic degradation of alkali.
By the apparent essential characteristics for illustrating the present invention described above and progress.
In garbled surfactant, there are some surfactants because of the acid catalyzed degradation to ivermectin class medicine
Show obvious facilitation and be abandoned.Such as sodium lauryl sulphate, although it has very to ivermectin class medicine
Good solubilising/emulsification, but because the acid-catalyzed hydrolysis effect that it has stronger promotion ivermectin (is shown in Table 4 Hes simultaneously
Table 5), therefore, it is not appropriate for for preparing invention formulation.Equally, ivermectin class medicine and sodium lauryl sulphate group
Into solid dispersion, although good water solubility, but for oral formulations preparation still suffer from being more easy to by acidic gastric juice destroy can
Can property.
Although also some surfactants have extraordinary solubilising/emulsification and suppression to ivermectin class medicine
The catalyzing hydrolysis effect of acid, but this does not imply that they are applied to the preparation of invention formulation.Such as Poloxamer 188 and poly-
The surfactants such as ethylene glycol (12) stearic acid acid esters, the acid that the Emulsion or microemulsion prepared with them and ivermectin is carried out is urged
Change Degrading experiment to show, these surfactants have ivermectin good solubilising/emulsification and suppress the catalysis of acid
Hydrolysis.But the carrier material that they are adopted with the present invention is combined, the obtained solid preparation containing ivermectin, even if
The content of surfactant is 10-33 times of ivermectin in preparation, and dissolution of the ivermectin in water be not still in medicament
To 20%.Therefore, this kind of surfactant is not suitable for the preparation of invention formulation yet.
From the above, this technology of preparing is understanding in depth to ivermectin physicochemical property, and to commercially available phase
Propose on the basis of the understanding of the problem for closing product presence.Therefore, in order to be able to apparent explanation the technology of the present invention feature.
It is necessary that pair main foundation test closely related with the present invention is described by.
1. hydrolysis experiment of the ivermectin in variable concentrations hydrochloric acid solution (with methanol/water as solvent).Test method is：
Sample places 0-3 hours in 36-37 DEG C of insulation.The MS H in reactant liquor are determined with HPLC methods2B1A and H2B1A, hydrolysis degree with
MS H2B1The peak area of a accounts for 0 hour ivermectin B1a(H2B1A) peak area (%) is represented.Result of the test is shown in Table 1.
Hydrolysis of the ivermectin of table 1. in variable concentrations hydrochloric acid solution (with methanol/water as solvent)
2. the hydrolysis degree and dissolution determination of imported product ivermectin in variable concentrations hydrochloric acid/aqueous solution.Test
Method is：1 gram of import sample is taken in 20 milliliters of hydrochloric acid/aqueous solutions, is placed 3 hours at 36-37 DEG C.Determined with HPLC methods, with
MS H2B1The peak area value and H of a2B1The ratio (%) of the peak area value of a weighs the hydrolysis degree of ivermectin.* the survey of 0 hour
It is fixed：1 gram of sample is placed 3 hours in 20 milliliters of water at 36-37 DEG C；Thereafter operate ibid.Result of the test is shown in Table 2.
The hydrolysis degree and dissolution of the imported product of table 2. ivermectin in variable concentrations hydrochloric acid/aqueous solution
3. ivermectin is in 0.1M NaOH solutions (methanol/water=1: the Degrading experiment in 1)：Take containing 0.6% Yi Wei bacterium
10 milliliters of element/methanol solution, mixes with 10 milliliters of the sodium hydroxide solution of 0.2M, and at 21-24 DEG C 0-930 minutes are placed.With
HPLC methods determine 2-epimer H in reactant liquor2B1a、Δ2,3H2B1A and H2B1A, calculates 2-epimer H2B1A and H2B1A peaks face
The ratio (%) of product value, Δ2,3H2B1A and H2B1The ratio (%) of a peak area values, H2B1A and 0 minute H2B1The ratio of a peak area values
(%).Result of the test is shown in Table 3.
The ivermectin of table 3. is in 0.1M NaOH solutions (methanol/water=1: the degraded in 1)
In sum, main points of the present invention and it has an advantage that：(1) preparation prepared with this technology, because the surface for selecting is lived
Property agent/benzyl benzoate or azone have and form the performance of " micelle barrier " so that the ivermectin class medicine for wherein including is not
Easily by H+Attack, this reduces to a certain extent degree or the probability that medicine is hydrolyzed by acidic gastric juice, so as to reduce because of stomach
Acid effect causes the tendentiousness that drug absorption rate is reduced.(2) oral solid formulation prepared with the technology of the present invention has higher
Barrier H+、OH-The performance of attack.Therefore, the present invention preferably solves the acid/base catalysis of ivermectin class pharmaceutical solid preparation
Degradation problem so that it is less that preparation active ingredient during preserving is degraded, so as to improve product quality and the market competitiveness.
Specific embodiment
Embodiment 1. carries out the screening of surfactant by taking ivermectin as an example
When carrying out the screening of surfactant, except investigating its emulsifying/solubilizing effect to ivermectin, further define with
The acid catalyzed degradation rate of ivermectin has carried out acid catalyzed hydrolysis as screening index, the emulsion to being prepared with surfactant
Reaction test.Primary dcreening operation is to combine screened surfactant with ivermectin to be prepared into microemulsion or submicronized emulsion, with table
The consumption of face activating agent judges its emulsifying/solubilizing effect, and (Ms is used with the acid catalyzed degradation rate in 0.1M aqueous hydrochloric acid solutions
H2B1A and H2B1The peak area ratio of a is represented) weigh resistance inhibitor action power of the surfactant to the acid catalyzed degradation of ivermectin.
Concrete test and result are as follows.
1 milliliter of emulsion in table 4 is taken, is mixed with 19 milliliters of the aqueous hydrochloric acid solution of 0.1M, reacted 1 hour at 36-37 DEG C, used
HPLC determines the MS H in reactant liquor2B1a、H2B1A, records peak area, calculates MS H2B1A chromatographic peak areas and H2B1A chromatographic peaks
The ratio (%) of area, result of the test is shown in Table 4.
To the ivermectin microemulsion containing SDS, the microemulsion containing Polyethylene oxide (40) castor oil hydrogenated in table 4 and containing pool
The test sample of Luo Shamu 188 further detected in terms of acid degradation rate and dissolution, the results are shown in Table 5, table 6.
Data described in table 5 are obtained by tests below method：(a). the preparation containing SDS microemulsions and acid catalyzed
Hydrolysis：0.7g SDS, 1 milliliter of 1,2-PD, 0.75 milliliter of the ethyl acetate solution containing 0.15 gram of ivermectin are taken, is stirred
Mixing is mixed, 25 milliliters are added water to, is sufficiently stirred for, obtain final product the microemulsion of clear；Take 1 milliliter of microemulsion plus 0.01M hydrochloric acid/water
19 milliliters of solution, 36-37 DEG C is reacted 3 hours.(b). reference substance is prepared and acid catalyzed hydrolysis：Take containing 6 milligrams of Yi Wei bacterium
0.5 milliliter of the ethyl acetate solution of element, mixes with 9.5 ml methanols, adds 10 milliliters of hydrochloric acid/aqueous solution that concentration is 0.02M,
Mix, 36-37 DEG C is reacted 3 hours.The MS H in reactant liquor are determined with HPLC methods2B1a、H2B1a AG、H2B1A, records peak area,
Calculate H2B1A degradation rates (%), MS H2B1A and H2B1The ratio (%) of the peak area of a, H2B1aAG(H2B1A aglycones) and H2B1a
Peak area ratio (%).
Its acid catalyzed hydrolysis test of ivermectin emulsion of the table 4. containing different surfaces activating agent and result
| Surfactant | MS H2B1a/H2B1A% | H2B1A degradation rate % |
| Polyethylene oxide (40) Oleum Ricini | 3.7-4.1 (has interference, inaccurate) | 3.3-4.3 |
| Polyethylene oxide (90) Oleum Ricini | 5-6 (has interference, inaccurate) | 4.5-7.2 |
| NPE (OP-10) | 2.3-2.6 | 2.1-2.8 |
| Polyethylene oxide (23) lauryl alcohol (Brij35) | 2.9-3.8 | 3.1-3.6 |
| Polyethylene oxide (20) spermaceti alcohol ether (Brij58) | 2.2-2.8 | 2.3-3.2 |
| Polyglycol distearate SG-40 | 2.8-3.5 | 4.9-5.3 |
| Polyglycol distearate SG-100 | 3.1-3.3 | 4.6-5.3 |
| Polyethylene oxide (9) laurate LAE-9 | 3.3-3.5 | 4.2-4.8 |
| Cithrol 4ML | 1.4-1.6 | 2.7-3.1 |
| Polyethylene Glycol (50) Oleum Ricini | 1.5-1.9 | 1.0-1.4 |
| Tween 80 | 1.7-2.1 (has interference) | 1.9-2.4 |
| Polyethylene oxide (35) castor oil hydrogenated HEL-35 | 1.4-1.7 | 2.8-3.3 |
| Polyethylene oxide (40) castor oil hydrogenated HEL-40 | 1.4-1.7 | 2.7-3.1 |
| Polyethylene oxide (50) castor oil hydrogenated HEL-50 | 1.4-1.7 | 2.9-3.4 |
| Polyethylene oxide (60) castor oil hydrogenated HEL-60 | 2.0-2.2 | 3.6-3.9 |
| Sodium lauryl sulphate | 79.66 | 96.07 |
Facilitation of the sodium lauryl sulphate of the table 5. (SDS) to ivermectin acid-catalyzed hydrolysis
The acid catalyzed degradation test of ivermectin micro emulsion of the table 6. containing HEL-40
Table 4 is compared into visible with table 1, in the surfactant described in table 4, except SDS, other are to ivermectin
Acid catalyzed degradation has different degrees of inhibitory action；Table 4 and table 5 show that the ivermectin microemulsion containing SDS is in 0.1M salt
1 hour H is reacted in acid solution2B1A degradation rates reach 96.07%, and 3 hours H are reacted in 0.01M hydrochloric acid solutions2B1A degradation rates
Reach 99.81%.As can be seen here, SDS has extremely significant facilitation to ivermectin acid catalyzed degradation, is not suitable as Yi Wei
Emulsifying/the solubilizing agent of rhzomorph oral formulations.Table 4 and table 6 show, HEL-40 and its homologue (, HEL-35, HEL-50, HEL-
60) there is significant inhibitory action to ivermectin acid catalyzed degradation, its inhibitory action is better than other surfactants.
The screening test of the hydrophobic medium of embodiment 2. (oil phase)
In self-emulsifying drug delivery system in addition to containing surfactant, also need containing oil-phase component and co-emulsifier.Properly
Oil phase have stable emulsion drop act on.Therefore, during recipe determination, the hydrophobic medium to being likely to become oil phase enters
Screening is gone, acid catalyzed degradation when high spot review adds different hydrophobic mediums or is added without hydrophobic medium to ivermectin
The impact of rate.Test sample containing hydrophobic medium composition is included：0.6% ivermectin, 10%HEL-40,16%1,2- the third two
Alcohol, hydrophobic medium are added by the amount of Table 7, and isopropanol adds to 100%.
Screening test method：Take 1 milliliter of the emulsion containing the hydrophobic medium shown in table 7, the aqueous hydrochloric acid solution with 0.1M
19 milliliters of mixing, react 2 hours at 36-37 DEG C, and with HPLC the MS H in reactant liquor are determined2B1a、H2B1A, records peak area value,
Calculate MS H2B1A and H2B1The ratio (%) of the peak area of a, result of the test is shown in Table 7.
The impact that the hydrophobic medium of table 7. is acted on the acid-catalyzed hydrolysis of ivermectin
| Hydrophobic medium and content | MSH2B1A peak area values/H2B1A peak area value % |
| Oleum Ricini 2% | 3.1-4.4 |
| Soybean oil 3% | 3.1-4.1 |
| Sucrose stearate 2% | 4.3-4.5 (has interference) |
| Glycerol monostearate 3.3% | 3.5-4.2 |
| Glyceryl triacetate 3.3% | 2.9-3.5 |
| Ethyl oleate 9% | 1.6-2.1 |
| Isopropyl myristate 9% | 1.7-2.4 |
| Pungent/capric acid triglyceride 10% | 1.4-1.8 |
| Azone 5.5% | 1.3-1.8 |
| Arlacel-60 3% | 1.6-2.1 |
| Arlacel-80 3% | 2.8-3.1 |
| Benzyl benzoate 3.3% | 1.1-1.6 |
| Dipropylene glycol dibenzoate 4.5% | 1.2-1.6 |
| Ethyl acetate 3.3% | 3.5-4.2 |
| Hexadecanol 5% | 2.5-3.1 |
| It is not added with hydrophobic medium | 3.5-4.2 |
The impact (repetition) that the hydrophobic medium of table 8. is acted on the acid-catalyzed hydrolysis of ivermectin
| Preparation is numbered | NO.35 | NO.43 | NO.44 | NO.131 | NO.12-2 | NO.342 |
| Ivermectin g | 0.134 | 0.132 | 0.13 | 0.13 | 0.13 | 0.13 |
| HEL-40g | 1.2 | 1.2 | 1.2 | 1.55 | 1.20 | 1.63 |
| Monoglyceride g | 1.2 | 1.2 | 1.2 | - | - | - |
| Pungent/capric acid triglyceride g | - | 0.81 | - | - | - | - |
| Isopropyl myristate g | - | - | 0.9 | - | - | - |
| Ethyl oleate g | 0.99 | - | - | - | - | - |
| Azone g | - | - | - | 0.78 | - | - |
| Benzyl benzoate g | - | - | - | - | 0.56 | - |
| Dipropylene glycol dibenzoate g | - | - | - | - | - | 0.92 |
| 1,2-PD g | 0.2 | 0.3 | 0.3 | 0.39 | 0.2 | |
| Maize cob meal g | 16.28 | 16.36 | 16.35 | 16.67 | 18 | 17.76 |
| MS H2B1a/H2B1a% | 1.45 | 1.39 | 1.73 | 1.39 | 1.12 | 1.21 |
As seen from Table 7, benzyl benzoate, dipropylene glycol dibenzoate, azone and HEL-40 are applied in combination to Yi Wei bacterium
The resistance inhibitor action of the acid catalyzed degradation of element is most strong, next to that pungent/capric acid triglyceride, isopropyl myristate and ethyl oleate.
Repeat test and show (being shown in Table 8), test sample (1 gram of test sample in 0.1M hydrochloric acid solutions：20 milliliters of acid solutions) reaction 2 hours, still
It is so strong to the acid catalyzed degradation inhibitory action of ivermectin with benzyl benzoate, dipropylene glycol dibenzoate, azone.
With benzyl benzoate, azone and ethyl oleate as hydrophobic medium, their containing with HEL-40 have further been inquired into
Impact of the amount ratio to the acid catalyzed degradation rate of ivermectin.Test method is as follows with result：
Test sample containing benzyl benzoate composition：1% ivermectin, 16%1,2- Propylene Glycol, benzyl benzoate and HEL-
40 content calculates (being shown in Table 9) by the weight ratio meter of ivermectin, and isopropanol adds to 100%.
Acid catalyzed hydrolysis experiment：Take 0.3 milliliter of test sample in table 9 to mix for 4.7 milliliters with 0.1M aqueous hydrochloric acid solutions, in
36.5-37.5 DEG C is reacted 2 hours, plus about 230 microlitres of 10% sodium hydroxide solution, is mixed, plus methanol constant volume is to 10 milliliters, is filtered
Detect the Ms H in reactant liquor with HPLC afterwards2B1a、H2B1A, records peak area, calculates H2B1The percent hydrolysiss of a, with Ms H2B1A with
H2B1The ratio (%) of the peak area of a weighs the size of percent hydrolysiss.Result of the test is shown in Table 9.
Ivermectin/benzyl benzoate/HEL-40 the preparations of the different proportion of table 9. its acid catalyzed hydrolysis experiments
| Preparation is numbered | The weight ratio of ivermectin/benzyl benzoate/HEL-40 | MS H2B1a/H2B1A% |
| Test sample 1 | 1∶1∶6 | 2.23 |
| Test sample 2 | 1∶2∶6 | 1.94 |
| Test sample 3 | 1∶3∶6 | 1.67 |
| Test sample 4 | 1∶4∶6 | 1.29 |
| Test sample 5 | 1∶3∶9 | 2.01 |
| Test sample 6 | 1∶4.5∶9 | 1.58 |
| Test sample 7 | 1∶2∶9 | 2.31 |
| Reference substance -1 | Ethyl acetate substitutes benzyl benzoate, and ratio is 1: 3: 9 | 4.27 |
| Reference substance -2 | Ethyl acetate substitutes benzyl benzoate, and ratio is 1: 4: 6 | 4.22 |
As seen from Table 9, (test sample 4) MS H when the weight ratio of benzyl benzoate/HEL-40 is 1 to 1.52B1A and H2B1a
Ratio it is minimum.The ratio of MS H2B1a and H2B1a is maximum when substituting benzyl benzoate with ethyl acetate.
Test sample containing azone is constituted：The content of 1% ivermectin, 3%1,2- Propylene Glycol, azone and HEL-40 presses Yi Wei bacterium
The weight ratio meter of element calculates (being shown in Table 10), and isopropanol adds to 100%.
Acid catalyzed hydrolysis experiment：Test method and the acid catalyzed hydrolysis experiment method phase of test sample containing benzyl benzoate
Together.Result of the test is shown in Table 10.
Ivermectin/azone/HEL-40 the test samples of the different proportion of table 10. its acid catalyzed hydrolysis experiments
| Preparation is numbered | The weight ratio of ivermectin/azone/HEL-40 | MS H2B1a/H2B1A% |
| Test sample 8 | 1∶1∶6 | 2.86 |
| Test sample 9 | 1∶2∶6 | 1.99 |
| Test sample 10 | 1∶3∶6 | 1.72 |
| Test sample 11 | 1∶4∶6 | 1.46 |
| Test sample 12 | 1∶3∶9 | 2.20 |
| Test sample 13 | 1∶6∶9 | 1.62 |
| Test sample 14 | 1∶4.5∶9 | 1.85 |
| Reference substance -3 | Ethyl acetate substitutes azone, and ratio is 1: 3: 9 | 4.23 |
From table 10, (test sample 11) MS H when the weight ratio of azone/HEL-40 is 1 to 1.52B1A and H2B1The ratio of a
Value is minimum.MS H when substituting azone with ethyl acetate2B1A and H2B1The ratio of a is maximum.
Test sample containing ethyl oleate is constituted：0.6% ivermectin, 1.8%1,2- Propylene Glycol, ethyl oleate and HEL-40's
Content is shown in Table 11, and isopropanol adds to 100%.
Acid catalyzed hydrolysis experiment：Take 0.3 milliliter of test sample to mix for 4.7 milliliters with 0.1M aqueous hydrochloric acid solutions, in 36.5-
37.5 DEG C are reacted 1 hour, plus about 230 microlitres of 10% sodium hydroxide solution, are mixed, plus 5 milliliters of methanol, after filtration
The MS H in reactant liquor are detected with HPLC methods2B1a、H2B1A, records peak area, calculates H2B1The percent hydrolysiss of a, with MS
H2B1A and H2B1The ratio (%) of the peak area value of a weighs the size of percent hydrolysiss.Result of the test is shown in Table 11.
Ivermectin/ethyl oleate/HEL-40 the test samples of the different proportion of table 11. its acid catalyzed hydrolysis experiments
| Preparation is numbered | Ethyl oleate/HEL-40 | MS H2B1a | H2B1a | MS H2B1a/H2B1a% |
| N0.32 | 1∶0.77 | 33989 | 4280211 | 0.79 |
| NO.30 | 1∶1 | 40122 | 4837012 | 0.83 |
| N0.31 | 1∶1 | 34998 | 4029734 | 0.87 |
| N0.33 | 1∶1 | 32735 | 4268351 | 0.77 |
| N0.34 | 1∶2.4 | 46420 | 4057935 | 1.14 |
From table 11, MS H when ethyl oleate/HEL-40 weight ratio is 1: 0.77-12B1A and H2B1The ratio of a is minimum.
The impact of test sample acid resistance of the addition of benzyl benzoate to being prepared with different emulsifiers
Trying test method is：40 grams of test sample is taken, in putting into the aqueous hydrochloric acid solution that 800 milliliters of concentration are 0.1M, is being stirred
Mix rotating speed 50r/min, 36.5-37.5 DEG C reacts 1-3 hours, samples 5 milliliters, plus 10% sodium hydroxide at 1,2,3 hours respectively
About 250 microlitres of solution, mixes, plus methanol constant volume is to 10 milliliters, and the MSH in reactant liquor is detected with HPLC methods after filtration2B1a、
H2B1A, records peak area, calculates H2B1The percent hydrolysiss of a, with MS H2B1A and H2B1The ratio (%) of the peak area value of a weighs percent hydrolysiss
Size.Result of the test is shown in Table 12.
The impact of containing ivermectin test sample acid resistance of the benzyl benzoate of table 12. to being prepared with different emulsifiers
Note：0 hour all test sample Ms H2B1a is 0.31-0.34% with H2B1a peak area ratios；MS/H2B1a represents MS
H2B1a and H2B1a peak area ratios (%).Reference substance is imported product.
Testing result shown in table 12 is further demonstrated that：Benzyl benzoate and different surfaces activating agent combination application, all have
There is the resistance inhibitor action significantly strengthened to acid catalyzed degradation.It is also shown from table 12, benzyl benzoate is combined with different emulsifiers should
Used time, to H2B1The impact significant difference of a dissolutions；When with HEL-40 or HEL-35 as emulsifying agent, with or without Benzyl Benzoate
The preparation of ester, its H2B1A dissolutions are almost consistent.
Embodiment 3. prepares the solid preparation containing ivermectin 0.6% with HEL-40
1. preparation is constituted and preparation method：The active ingredient of preparation is ivermectin, and its content in the formulation is
0.66-0.68 gram；Other compositions are shown in Table 13 in preparation；The end weight of preparation is added to the maize cob meal that particle diameter is 140-420 microns
Amount (100 grams).By above-mentioned【0018】Section methods described prepares NO.12-2, N0.12-2-1 and NO.13-1 preparation, by above-mentioned
【0019】Section methods described prepares M-102 to M-109 preparations.
2. acid catalyzed degradation test：1.00 grams of samples are taken in 25 milliliters of tool plug test tubes, 18 milliliters of water are added, 5 points are vibrated
Clock, adds afterwards 2 milliliters of 1M hydrochloric acid solutions, mixes, and in 36-37 DEG C of insulation to sample time, draws 4 milliliters of reactant liquors and adds
About 0.2 milliliter of 10% sodium hydroxide solution, mixes, and adds 4 ml methanols, mixes, and uses 0.45um membrane filtrations, filtered solution HPLC
Detection (20 microlitres of sample introduction), records chromatogram, calculates MS H2B1A peak areas and H2B1The ratio (%) of a peak areas.Result of the test is shown in
Table 14.
Table 13.0.6% ivermectin solid preparation compositions and content
The acid catalyzed degradation result of the test of the preparation of table 14.
" reference substance -1 " in table 14 is imported product (0.6% ivermectin pre-mixing agent)；The preparation side of " reference substance -2 "
Method is：5.0 grams of reference substance -1 are taken, in 50 milliliters of beakers, after adding 0.2 milliliter of benzyl benzoate, in moving into 85 DEG C of water-baths, is filled
Divide stirring, mix, then remove from water-bath, be cooled to room temperature, obtain final product described reference substance -2；The preparation and acid of reference substance -3
Catalyzing hydrolysis test method：1.00 grams of reference substances -1 are taken in 25 milliliters of tool plug test tubes, 37 microlitres of benzyl benzoate is added, afterwards
18 milliliters of water are added, after fully vibrating 5 minutes, 2 milliliters of 1M hydrochloric acid solutions is added, is operated and the above acid catalyzed degradation thereafter
Test method it is identical.
Table 14 is compared with table 1, be will be obvious, by the use of HEL-40 as solubilizing agent, not only can be made in preparation
Ivermectin have higher dissolution in water, and HEL-40 has significant suppression to the acid catalyzed degradation of ivermectin
Effect.Table 14 also shows, does not contain the preparation of benzyl benzoate, MS H2B1A and H2B1The peak area ratio (%) of a be containing
2-3 times of Benzyl Benzoate ester formulation.As can be seen here, benzyl benzoate is applied in combination with HEL-40, can more effectively suppress acid right
The catalyzing hydrolysis effect of ivermectin.The acid catalysiss drop done by the addition benzyl benzoate in imported product (reference substance -1)
Solution test (reference substance -2 and reference substance -3 in table 14), further demonstrates acid catalysiss of the benzyl benzoate in ivermectin
Inhibitory action played in degradation process.
Using several representational preparations in table 14 as test sample, the dissolution determination method as described in pharmacopeia enters one
Step determines their H in 0.1M hydrochloric acid solutions2B1The dissolution of a and acid catalyzed degraded situation.As a result it is shown in table 15.
The test sample of table 15. dissolution of ivermectin and hydrolysis situation in 0.1M hydrochloric acid solutions
3. base catalysiss Degrading experiment：1.00 grams of samples are taken in 25 milliliters of tool plug test tubes, 18 milliliters of water are added, 5 points are vibrated
Clock, adds afterwards 2 milliliters of 1M sodium hydroxide solutions, mixes, and reacts at 20-23 DEG C 2 hours, and 4 milliliters of reactant liquors are drawn immediately, plus
Enter about 0.4 milliliter of 1M hydrochloric acid solutions, mix, add 4 ml methanols, mix, with 0.45 um membrane filtrations, filtered solution is examined with HPLC
Survey, record peak area, calculate 2- epimer H2B1A peak areas account for H2B1A peak area percents (%), the results are shown in Table 16.
The base catalysiss Degrading experiment of table 16.
By table 16 and【0037】The table 3 of section is compared, and will be obvious, base catalysiss of the HEL-40 to ivermectin
Degraded equally has significant inhibitory action.Detection data shown in table 16 also shows, does not contain the preparation of benzyl benzoate,
Its 2-epimer H2B1A accounts for H2B1The peak area percent (%) of a is 3-4 times containing Benzyl Benzoate ester formulation.As can be seen here,
Benzyl benzoate is applied in combination with HEL-40, can more effectively suppress alkali to act on the catalytic degradation of ivermectin.By right
Done according to addition benzyl benzoate in product-1 (imported product) base catalysiss Degrading experiment (reference substance-2 and reference substance in table 16-
3) resistance inhibitor action of the benzyl benzoate played in the base catalysiss degradation process of ivermectin, has further been affirmed.
In order to exclude test error, further have selected from above-mentioned formula M102, M103, M104, M105, M106,
N0.12-2, N0.13-1 have carried out the repetition test of base catalysiss degraded as test sample, and test method is：Test sample is added
To in 0.1M NaOH solutions, react 2 hours and 20 hours at 20-22 DEG C, with H in HPLC detection reactant liquors2B1A and 2- are differed to different
Structure body H2B1A, records chromatogram, calculates 2- epimer H2B1A peak areas account for H2B1A peak area percents (%).Test knot
Fruit is shown in table 17.
The repetition result of the test of the base catalysiss of table 17. degraded
M103-1 is free from the test sample of benzyl benzoate in table 17, is prepared by the formula in Patent Application Publication
, control -5 and control -6 are that benzyl benzoate is with the addition of in reference substance (imported product), M102, M103, M104, M105,
N0.12-2, N0.13-1 are the test samples containing benzyl benzoate.From table numeral, it is apparent that reaction 2 hours, contain
There is the test sample of benzyl benzoate its 2- epimer H2B1The yield of a is far below the test sample for not containing benzyl benzoate,
3-8 times of difference.Reaction 20 hours, the 2- epimer H that M105 is produced2B1A and H2B1A peak area ratios are only imported product
42%.The alkaline degradation test display that product are carried out is crystallized with ivermectin, 28-33 minutes, 2- epimers in reactant liquor is reacted
H2B1A and H2B1A peak area ratios are 44.60%, by the H of reaction primary quantity2B1A is calculated, 2- epimer H2B1A and H2B1A peaks
Area ratio is 18-25%, also, H2B1A oneself degradeds 50% or so are (see the【0037】The table 3 of section).
Visible according to above-mentioned test result analysis, the HEL-40 in (1) preparation has to the catalytic degradation of alkali and significantly prevents
Effect；(2) HEL-40 and benzene methyl benzyl ester combination application, can make resistance inhibitor action higher.
Ivermectin formulation of the embodiment 4. containing arabic gum and its dissolution and acid-catalyzed hydrolysis test
1. prepared by preparation：0.66 gram of ivermectin, 6 grams of HEL-40,2 grams of benzyl benzoate, 2.1 grams of 1,2-PDs are mixed
Close, in 60-65 DEG C of stirring and dissolving, be cooled to 40 DEG C or so, add 30 milliliters of the aqueous solution containing 20% arabic gum, fully mix,
Add 83 grams of maize cob meal, stirring and evenly mixing, drying obtain final product this agent (preparation numbering is M-113).Comparative formulation (M-113-1) is no
Containing benzyl benzoate, other are identical with M-113.
2. the test method of acid catalyzed degradation：800 milliliters of the hydrochloric acid solution of 0.1M, control stirring is added to turn in stripping rotor
Speed be 49-51 rev/min, stirring be warming up to dissolution medium temperature stabilization 36-37 DEG C, pH value be 0.85-0.87 when, to dissolution
40.00 grams of sample is added in medium, is 0.85- temperature 36-37 DEG C, speed of agitator is controlled for 49-51 rev/min, pH value
React 3 hours under conditions of 0.87.1 hour, 2 hours, 3 hours separately sampled 4 milliliters, with 10% sodium hydroxide solution about
0.2 milliliter is adjusted after PH, adds 4 ml methanols, is mixed, and uses 0.45 Mm filter, takes 20 microlitres of filtered solution, is detected with HPLC, note
Record chromatogram, calculates MS H2B1A peak areas and the H of dissolution2B1The ratio (%) of a peak areas, calculates H2B1The dissolution (%) of a.
Result of the test is shown in Table 18.
The acid catalyzed degradation result of the test of table 18.M-113 and M-113-1 preparations
From table 18, the preparation dissolution prepared with arabic gum, benzyl benzoate and HEL-40 is high, and with right
The acid catalyzed degradation of ivermectin has very strong resistance inhibitor action.It is believed that the preparation containing arabic gum, is worth further system
Research (including the test such as clinical efficacy and pharmacokineticss), it has the possibility for becoming classic medicine in similar drug.
The stability examination of the representative preparation of embodiment 5
(1) hot test：Test sample is placed 14 days in 60 DEG C of constant temperature, is materialsed 1 gram, with 20 ml methanol mechanical shaking extractions
10 minutes, with 0.22 μm of membrane filtration, take filtrate and detect MS H with HLPC2B1a、2-epimer H2B1A (abbreviation 2- in table 19
) and H epimer2B1A, records peak area, calculates MS H2B1A peak areas and H2B1A peak area ratios (%), 2-epimer peaks face
Product and H2B1A peak area ratios (%) and the H of 14 days2B1A peak areas and the H of 0 day2B1The ratio (%) of a peak areas.Result of the test
It is shown in Table 19.
As seen from Table 19, sample is processed 14 days in 60 DEG C of constant temperature, the preferred preparation 2- containing benzyl benzoate
epimerH2B1The yield of a is significantly less than the preparation without benzyl benzoate.And containing benzyl benzoate, but do not contain
The preparation (NO.12-2 and NO.13-1) of solid dispersion medium (glyceryl monostearate or PEG-6000 etc.), its 2-epimer
H2B1The yield of a is few.
The hot test result of table 19.
(2) Accelerated stability test of 3 months is placed in 40 DEG C of constant temperature
It is generally believed that medicine places the degraded of 1-2.5 in the degradation rate that 40 DEG C of constant temperature are placed 3 months equivalent to room temperature
Rate.Therefore, we examine representational preparation and place 2-3 month in 40 DEG C of constant temperature, MS H in test sample2B1a、2-
epimeH2B1A and H2B1The changes of contents situation of a.Result of the test is shown in Table 20-1 to 20-3.
20-1.40 DEG C of table 1 month
20-2.40 DEG C of table 2 months
20-3.40 DEG C of table 3 months
As seen from Table 20, sample is placed 90 days in 40 DEG C of constant temperature, the preferred preparation 2- containing benzyl benzoate
epimerH2B1The yield of a is significantly less than the preparation without benzyl benzoate.And containing benzyl benzoate, but do not contain
The preparation (NO.12-2 and NO.13-1) of solid dispersion medium (glyceryl monostearate or PEG-6000 etc.), its 2-epimer
H2B1The yield of a is less.Except NO.35-1 preparations, other preparations are placed 90 days in 40 DEG C of constant temperature, its H2B1The degradation rate of a is little
In 3%.This preferred better stability of preparation of explanation.From stability approach consider, they all reached become commodity quality will
Ask.If comprehensive consideration (including dissolution problem, the degradation problem in acidic gastric juice, stability problem), as commodity
In terms of quality, still there is each other very big difference in them.
Difference of the embodiment 6. containing its stability of the preparation of different PH carrier material
It with maize cob meal is prepared by carrier material that commercially available Ivomec product is, after testing, its particle diameter is neat, active component
Homogeneity is good, dissolution is high, and with the performance of tolerance acid/base catalytic degradation.Described according to Patents, constitute its preparation
Major auxiliary burden composition be water soluble nonionic surfactant and water insoluble non-ionic surfactant, also contain antioxidant
And co-emulsifier, a small amount of organic acid (such as citric acid) is also added in pre-mixing agent, to suppress 2-epimer H2B1The product of a
It is raw, in order to make the extended shelf-life of preparation.4 grams of imported product is taken, is soaked with 20 milliliters of water, detection shows：PH value is
4.47-4.53.Investigation and detection of the Jing to the maize cob meal of sale on domestic market, as a result shows, the jade of different manufacturers production
Rice core powder, its PH differs greatly.Therefore, in order to inquire into the pH value of carrier material and the relation of ivermectin degraded, this research is adopted
With the maize cob meal of two kinds of commercially available different PHs as carrier material, Brij -35 is employed in solubilizing agent, and preparation
The acid/base regulator such as citric acid is added without, be also added without benzyl benzoate etc. has stronger obstruction to make to the catalytic degradation of acid/base
Material.Concrete process of the test is as follows：
1. the preparation of test specimen M-79 and M-80
(1) preparation of sample M-79：1.5 grams of Brij -35,0.13 gram of monoglyceride, 0.16 gram of PEG-6000 are taken, is melted in 80 DEG C
Change, add 0.3 milliliter of the ethyl acetate solution containing 0.061 gram of ivermectin, mix, plus 3 milliliters of water, stirring and evenly mixing, add PH
It is worth 8.2 grams of the maize cob meal (particle diameter is between 30-80 mesh sieves hole) for 6.2-6.4, fully mixes, drying at room temperature obtains 10.39 grams
Sample (M-79).(2) preparation of sample M-80：1.5 grams of Brij -35,0.13 gram of monoglyceride, 0.16 gram of PEG-6000 are taken, in 80
DEG C melt, add 0.3 milliliter of the ethyl acetate solution containing 0.061 gram of ivermectin, mix, plus 3 milliliters of water, stirring and evenly mixing, plus
Enter 8.2 grams of the maize cob meal (particle diameter is between 30-80 mesh sieves hole) that pH value is 4.9-5.1, fully mix, drying at room temperature is obtained
10.32 grams of samples (M-80).
2. hot test
Accurately weigh sample M-79 and M-80 each 3 parts, sample weighting amount is 1.0000 grams/part, in 25 milliliters of test tubes, after sealing
In being placed in 59-61 DEG C of proof box, constant temperature is placed 15 days, then with 20 ml methanol mechanical shaking extraction 10 minutes, with 0.22 μm of film mistake
Filter, takes filtrate and detects MS H with HLPC2B1a、2-epimer H2B1A and H2B1A, records peak area value, calculates MS H2B1A peaks face
Product value and H2B1The ratio (%) of a peak area values, 2-epimer peak area values and H2B1The ratio (%) of a peak area values and 15 days
H2B1A peak area values and the H of 0 day2B1The ratio (%) of a peak area values.Testing result is shown in table 21.
The hot test result of table 21.
The data from table 21, sample is processed 15 days in 60 DEG C of constant temperature, is prepared with the maize cob meal that pH value is 4.9-5.1
Sample (M-80), its 2-epimer H2B1The yield of a, MS H2B1The yield and H of a2B1The degradation amount of a is significantly low
In the sample (M-79) prepared with the maize cob meal that pH value is 6.2-6.4.This result of the test shows that the pH value of carrier material is to system
The stability of agent has significant impact.Accordingly, we are analyzed the medical additive further to commonly using, and are as a result shown,
Gypsum Fibrosum powder and starch all apply to prepare the carrier material of invention formulation, and the typical additives such as glucose, Calcium Carbonate are not
It is suitable for preparing invention formulation.
Embodiment 7. prepares 0.6% ivermectin solid preparation
Take ivermectin that 0.66 gram of purity is 90%, 0.75 gram of benzyl benzoate, 3 grams of HEL-35,0.6 gram of 1,2- the third two
Alcohol, in 500 milliliters of beakers, in 80-85 DEG C of stirred in water bath dissolving, is cooled to 40 DEG C or so, adds 20 milliliters of water, fully stirs
Mixing is mixed, 30 grams of maize cob meals (particle diameter is between 40-100 mesh sieves hole) are subsequently adding, after being sufficiently stirred for mixing, is dried, must be carried
Medicine microgranule；5 grams of glyceryl monostearates are taken, in 80-85 DEG C of thawing, medicine carrying microgranule is added, is fully mixed, then add corn cob
To 100 grams, stirring and evenly mixing obtains final product 0.6% ivermectin solid preparation to powder.
Embodiment 8. prepares 0.1% department and draws rhzomorph powder
Rhzomorph, 0.8 gram of pungent/capric acid triglyceride, 1.1 grams of HEL-60,0.4 gram of PEG- draw in the department for taking 0.11 gram 90%
6000th, 0.6 gram of glyceryl monostearate, in 200 milliliters of beakers, in 80-85 DEG C of stirred in water bath dissolving, adds 88 grams and fries
Fish flour (particle diameter is between 24-60 mesh sieves hole), be sufficiently mixed uniform, be cooled to room temperature, cross 18 mesh sieves, obtain 0.1% department and draw rhzomorph
Powder.This product is used for dog, cat preventing and treating verminosis, disposably feeds, and per kilogram of body weight takes 0.2 gram of this product, monthly.
Embodiment 9. prepares 0.1% ivermectin granule
Ivermectin, 0.2 gram of azone, 0.6 gram of HEL-40,0.1 gram of 1,2-PD that 0.11 gram of purity is 90% are taken, in
In 100 milliliters of beakers, in 80-85 DEG C of stirred in water bath dissolving, when being cooled to 35-40 DEG C, 4-5 milliliter water is added, be sufficiently stirred for
Into emulsion, 8 grams of maize cob meals (particle diameter is between 100-200 mesh sieves hole) are added, fully mixed, in 25-35 DEG C of drying, obtain her
Dimension rhzomorph/maize cob meal medicine carrying microgranule.Take and fry 30 grams of beef powder, 40 grams of starch, 10 grams of polyvinylpyrrolidone, medicine is micro- with carrying
Grain is mixed, and adds dehydrated alcohol, granulation to cross 12 mesh sieve granulate, be dried, and obtains 0.1% ivermectin granule.This agent be used for dog,
Cat preventing and treating verminosis, per kilogram of body weight feeds 0.2 gram of this product, monthly feeds once.
Embodiment 10. prepares 0.6% ivermectin solid preparation
Take ivermectin, 2.5 grams of benzyl benzoate, 8 grams of HEL-60,3 grams of PEG-6000 and 8 that 0.66 gram of purity is 90%
Gram monoglyceride, in 500 milliliters of beakers, in 80-85 DEG C of dissolving, adds 77.8 grams of 40-100 mesh maize cob meal, is sufficiently stirred for, and mixes
It is cooled to room temperature after closing uniformly, crosses 30 mesh sieves, obtains final product 0.6% ivermectin solid preparation.This agent is used for pig preventing and treating verminosis, often
Ton feedstuff adds 1 kilogram of body of this product, continuous feeding 7-10 days.
Embodiment 11. prepares 0.3% doractin solid preparation
Take doractin that 0.33 gram of purity is 90%, 2 grams of benzyl benzoate, 2.4 grams of HEL-60,1.2 grams of PEG, 1.2 grams
Glyceryl monostearate, in 500 milliliters of beakers, in 80-85 DEG C of dissolving, adds 92.8 grams of 40-100 mesh maize cob meal, fully
Stirring, is cooled to room temperature after mix homogeneously, cross 30 mesh sieves, obtains final product 0.3% doractin solid preparation.
Embodiment 12. prepares 0.3% ivermectin solid preparation
0.33 gram 90% of ivermectin, 0.75 gram of benzyl benzoate, 2.1 grams of HEL-60,0.3 gram of 1,2-PD are taken,
In 200 milliliters of beakers, in 80-85 DEG C of stirred in water bath dissolving, when being cooled to 35-40 DEG C, 20 milliliters of water are added, be sufficiently stirred for
Extremely into emulsion, 50 grams of maize cob meals (particle diameter is between 40-100 mesh sieves hole), stirring and evenly mixing, in naturally dry are added in emulsion
It is dry, after removing moisture, add maize cob meal ad pond om and mix for 100 grams, obtain final product 0.3% ivermectin solid preparation.
Embodiment 13. prepares 0.6% ivermectin solid preparation
Take ivermectin that 0.66 gram of purity is 90%, 0.75 gram of benzyl benzoate, 3 grams of HEL-40,0.6 gram of 1,2- the third two
Alcohol, in 500 milliliters of beakers, in 80-85 DEG C of stirred in water bath dissolving, (particle diameter is in 40-100 mesh sieves to add 30 grams of maize cob meals
Between hole), after being sufficiently stirred for mixing, room temperature is down to, maize cob meal is added to 100 grams, stirring and evenly mixing obtains final product 0.6% Yi Wei bacterium
Plain solid preparation.
Embodiment 14. prepares 0.25% ivermectin, 6% Albendazole's solid preparation
Take ivermectin, 0.15 gram of benzyl benzoate, 3.25 grams of HEL-40,3.25 grams of lists that 0.27 gram of purity is 90% hard
Glycerol, 0.2 gram of 1,2-PD, in 100 milliliters of beakers, in 80-85 DEG C of water-bath, stirring and dissolving adds 20 grams
Maize cob meal (particle diameter is between 100-200 mesh sieves hole), is sufficiently stirred for mixing, and is down to room temperature, obtains final product ivermectin/maize cob meal
Medicine carrying microgranule；6 grams of Albendazoles, 0.5 gram of polyvinylpyrrolidone are taken, is added water 20 milliliters, add 60 grams after being sufficiently stirred for by several times
Maize cob meal, mixes, and mixes with ivermectin/maize cob meal medicine carrying microgranule and 6 grams of iron oxide black micropowders after being dried, and obtains final product
0.25% ivermectin, 6% Albendazole's solid preparation.
Embodiment 15. prepares 0.2% ivermectin, 5% albendazole oxide solid preparation
Take ivermectin, 0.15 gram of benzyl benzoate, 3.25 grams of HEL-40,3.25 grams of lists that 0.22 gram of purity is 90% hard
Glycerol, 0.2 gram of 1,2-PD, in 100 milliliters of beakers, in 80-85 DEG C of stirred in water bath dissolving, add 20 grams of jade
Rice core powder (particle diameter is between 100-200 mesh sieves hole), is sufficiently stirred for mixing, and is down to room temperature, obtains final product ivermectin/maize cob meal and carries
Medicine microgranule；5 grams of albendazole oxides, 0.5 gram of polyvinylpyrrolidone are taken, is added water 20 milliliters, add 61 grams after being sufficiently stirred for by several times
Maize cob meal, fully mixes, and mixes with ivermectin/maize cob meal medicine carrying microgranule and 5 grams of iron oxide black micropowders after being dried, and obtains final product
0.2% ivermectin, 5% albendazole oxide solid preparation.
Embodiment 16. prepares 0.2% avilamycin solid preparation
Take avilamycin, 0.9 gram of benzyl benzoate, 2.86 grams of HEL-40,6.6 grams of single Hard Fat that 0.22 gram of purity is 90%
Acid glyceride, in 200 milliliters of beakers, in 80-85 DEG C of stirred in water bath dissolving, (particle diameter is in 40- to add 50 grams of maize cob meals
Between 100 mesh sieve holes), be sufficiently stirred for mix, be down to room temperature, add maize cob meal to whole weight be 100 grams, obtain final product 0.2% Ah
Dimension rhzomorph solid preparation.
Embodiment 17. prepares 0.3% doramectin solid preparation
By 0.33 gram of doramectin, 10 grams of HEL-35,1 milliliter of 1,2-PD and 9 grams of pungent/capric acid triglyceride mixing,
Stir under the conditions of 75-85 DEG C, make complete drug dissolution, then add maize cob meal to 100 grams in the liquid, fully stir
Mix, temperature of charge is down to room temperature by mix homogeneously afterwards, obtain final product 0.3% doramectin solid preparation.
Embodiment 18. prepares 1% moxidectin solid preparation
1 gram of moxidectin, 10 grams of HEL-35,1 milliliter of 1,2-PD and 5 grams of pungent/capric acid triglyceride are mixed,
Stir under the conditions of 75-85 DEG C, make complete drug dissolution, add 8 grams of glyceryl monostearates, continue to stir, be allowed to melt and mix
It is even, add maize cob meal to 100 grams under the conditions of 75-85 DEG C, it is sufficiently stirred for, temperature of charge is down to room by mix homogeneously afterwards
Temperature is waited to be fully cured, as 1% moxidectin solid preparation.
Embodiment 19. prepares 0.1% department and draws rhzomorph powder
By 0.11 Ke Sila rhzomorphs, 0.3 gram of HEL-40,0.5 milliliter of 1,2-PD, 0.2 gram of pungent/capric acid triglyceride,
Stir under the conditions of 75-85 DEG C, make complete drug dissolution, be cooled to 40 DEG C or so, under agitation, add 7 milliliters of water, system
For into emulsion；Then emulsion is mixed homogeneously with 14 grams of maize cob meals, penetrates into emulsion or partly penetrate into the hole of maize cob meal
In gap, then it is dried, mix homogeneously with the 2 grams of glyceryl monostearates for melting, it is cooled to room temperature, beef powder is added to 100
Gram, obtain final product this agent.This agent is applied to dog, cat preventing and treating verminosis.
Embodiment 20. prepares 0.3% ivermectin solid preparation
By 0.3 gram of ivermectin, 3 grams of HEL-40,0.5 milliliter of 1,2-PD, 1 gram of benzyl benzoate and pyrroles containing polyethylene
20 milliliters of mixing of the ethanol solution that 1.5 grams of pyrrolidone, stir under the conditions of 60-70 DEG C, make complete drug dissolution, add 40-80
Maize cob meal between mesh sieve hole, is sufficiently stirred for, mix homogeneously, is dried, and obtains medicine carrying microgranule.By glyceryl monostearate in 80-
Melt under the conditions of 85 DEG C, and obtained medicine carrying microgranule is added under this temperature conditions, be sufficiently stirred for mixing, be down to room temperature, be allowed to
Solidification, obtains final product 0.3% ivermectin solid preparation.
Claims (9)
1. a kind of oral solid formulation containing anti-parasite medicine, it is characterised in that the solid preparation includes following each component：
A, in per 1 kilogram of solid preparation include 0.1-20 gram of active component, the active component include avilamycin, she
One kind in dimension rhzomorph, doractin, moxidectin, Eprinomectin, department's drawing rhzomorph；
B, hydrophile-lipophile balance value are equal to or more than 12 nonionic surfactant, and its content in the formulation is the activity
3 to 20 times of component content, by weight calculating, most additions are less than the 20% of weight of formulation；Described hydrophilic and oleophilic
Nonionic surfactant of the equilibrium valve more than or equal to 12 includes Tweenses, Myrij class, brejses, peregal, Polyethylene oxide
Castor oil hydrogenated condensation substance, Polyethylene Glycol vegetable oil condensation substance, polyoxyethylene castor oil condensation substance；
C, carrier material, add to 1 kilogram；The carrier material include maize cob meal, zeolite powder, stone powder, kieselguhr, Gypsum Fibrosum powder,
One or more compositionss in starch, fish flour, beef powder, Carnis Gallus domesticus powder, pork liver powder, chicken liver meal；
D, in per 1 kilogram of oral solid formulation do not include or comprising 2-10 gram of 1,2-PD；
E, in per 1 kilogram of oral solid formulation do not include or comprising equivalent to the nonionic surfactant weight
The hydrophobic medium of 10-110%, percentage by weight；Described hydrophobic medium includes benzyl benzoate, dipropylene glycol hexichol first
One kind in acid esters, diethylene glycol benzoate, pungent/capric acid triglyceride, isopropyl myristate, ethyl oleate, azone or
More than one compositionss.
2. the solid preparation as described in claim 1, it is characterised in that it is described per 1 kilogram of oral solid formulation in include
10-220 gram of solid dispersion, the solid dispersion is pharmaceutic adjuvant of the fusing point more than 45 DEG C less than 100 DEG C.
3. the solid preparation as described in claim 1, it is characterised in that it is described per 1 kilogram of oral solid formulation in include
10-100 gram of other anti-parasite medicine, other described anti-parasite medicines include that Albendazole, albendazole oxide, fragrant benzene are rattled away
One kind in azoles, oxfendazole, insect growth regulator, IGR.
4. the solid preparation as described in claim 1, it is characterised in that described hydrophile-lipophile balance value is more than or equal to 12
Nonionic surfactant includes Polyethylene oxide (35) castor oil hydrogenated, Polyethylene oxide (40) castor oil hydrogenated, Polyethylene oxide
(50) castor oil hydrogenated, Polyethylene oxide (60) castor oil hydrogenated, Polyethylene Glycol (40) palm-kernel oil, Polyethylene Glycol (60) Semen Maydiss
Oil, Polyethylene Glycol (60) corn oil glyceride, Polyethylene Glycol (60) almond oil, Polyethylene Glycol (50) Oleum Ricini, hydrophilic and oleophilic are put down
Weighing apparatus value is more than one or more in 12 Brij58, polyglycol distearate SG-40, Brij -35
Compositionss.
5. the solid preparation as described in claim 1, it is characterised in that comprising benzyl benzoate or azone in described preparation,
The content of benzyl benzoate or azone in solid preparation is nonionic of the described hydrophile-lipophile balance value more than or equal to 12
The 1/5 to 1/2 of surfactant weight.
6. the solid preparation as described in claim 2, it is characterised in that described solid dispersion include glyceryl monostearate,
Glyceryl tristearate, the Polyethylene Glycol of solid state, stearic acid, the fatty alcohol of solid state, animal wax, brazil wax, hydrogenation
One or more compositionss in Oleum Ricini, behenic acid Huo behenic acid glyceride.
7. the solid preparation as described in claim 1, it is characterised in that comprising 10-150 gram in described per kilogram preparation
Arabic gum or polyvinylpyrrolidone.
8. the solid preparation as described in claim 1, it is characterised in that the pH value of described maize cob meal is 4.4-5.7.
9. the solid preparation as described in claim 1 to claim 8 any one, it is characterised in that the solid preparation is optional
Select the preparation of one of following methods：
The solution and described nonionic of the medicine of class containing ivermectin that method a. dissolves by ivermectin class medicine or with solvent
Surfactant mixes, and adds or be added without 1,2-PD, described hydrophobic medium is added or be added without, at 70-85 DEG C
Under the conditions of stir, make complete drug dissolution, obtain the liquid of the medicine of class containing ivermectin；Under the conditions of 70-85 DEG C in the liquid
Described carrier material is added, is sufficiently stirred for, mix homogeneously, afterwards temperature of charge is down to into room temperature, remove the solvent, cross 24
Mesh sieve, obtains final product described solid preparation；The solvent is ethanol or ethyl acetate or combinations thereof；
The solution and described nonionic of the medicine of class containing ivermectin that method b. dissolves by ivermectin class medicine or with solvent
Surfactant mixes, and adds or be added without 1,2-PD, described hydrophobic medium is added or be added without, at 70-85 DEG C
Under the conditions of stir, make complete drug dissolution, add described firming agent, continue to stir, firming agent is melted and is mixed, in 70-
Described carrier material is added under the conditions of 85 DEG C, is sufficiently stirred for, temperature of charge is down to room temperature by mix homogeneously afterwards, treats material
It is fully cured or is dried and remove the solvent, cross 24 mesh sieves, siftage is described solid preparation；The solvent be ethanol or
Ethyl acetate or combinations thereof；
Method c. mixes ivermectin class medicine, described nonionic surfactant and 1,2-PD, adds or is not added with
Described hydrophobic medium, stirs under the conditions of 70-85 DEG C, makes complete drug dissolution, 30-45 DEG C is cooled to, in stirring condition
Under, the water equivalent to ivermectin class 5-70 times of weight of medicine is added, it is prepared into emulsion；Then will be with emulsion equivalent to 5 times of weights
The carrier material and emulsion mixing of amount, is sufficiently stirred for, and then mix homogeneously is dried, and obtains final product described solid preparation；
Method d. mixes ivermectin class medicine, described nonionic surfactant and 1,2-PD, adds or is not added with
Described hydrophobic medium, stirs under the conditions of 70-85 DEG C, makes complete drug dissolution, 30-45 DEG C is cooled to, in stirring condition
Under, the water equivalent to ivermectin class 5-70 times of weight of medicine is added, it is prepared into emulsion；Then will be with emulsion equivalent to 5 times of weights
The carrier material of amount and emulsion mix, and are sufficiently stirred for, mix homogeneously, are dried, and must carry medicine granule；By the firming agent in 70-95
Melt under the conditions of DEG C, and obtained load medicine granule is added under this temperature conditions, be sufficiently stirred for, mix homogeneously is down to room temperature, makes
Solidification, cross 24 mesh sieves, obtain final product described solid preparation；
Method e. mixes ivermectin class medicine, described nonionic surfactant and 1,2-PD, adds or is not added with
Described hydrophobic medium, stirs under the conditions of 70-85 DEG C, makes complete drug dissolution, 30-45 DEG C is cooled to, in stirring condition
Under, add containing polyvinylpyrrolidone or the aqueous solution containing arabic gum, fully mix, it is prepared into sticky emulsion；Then will
Mix with emulsion to the maize cob meal of 5 times of weight with emulsion equivalent, stirring and evenly mixing, be dried, obtain final product described solid preparation；
Method f. mixes ivermectin class medicine, described nonionic surfactant and 1,2-PD, adds or is not added with
Described hydrophobic medium, stirs under the conditions of 70-85 DEG C, makes complete drug dissolution, 30-45 DEG C is cooled to, in stirring condition
Under, the aqueous solution containing polyvinylpyrrolidone or ethanol solution are added, or the aqueous solution containing arabic gum is added, fully mix,
It is prepared into slightly sticky emulsion or solution；Then by with the carrier material of emulsion or solution even to 5 times of weight and emulsion or molten
Liquid mixes, stirring and evenly mixing, is dried, and must carry medicine granule；Described firming agent is melted under the conditions of 70-95 DEG C, and in this temperature
Under the conditions of add it is obtained carry medicine granule, be sufficiently stirred for mixing, be down to room temperature, be allowed to solidify, sieve, obtain final product described solid system
Agent.
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| CN108066767A (en) * | 2016-11-17 | 2018-05-25 | 北京科百大科技有限责任公司 | A kind of self-emulsification solid composition of the drug of class containing ivermectin of stabilization |
| EP4062907A1 (en) | 2021-03-23 | 2022-09-28 | Substipharm | Formulation for oral administration of ivermectin and uses thereof |
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| CN108066767A (en) * | 2016-11-17 | 2018-05-25 | 北京科百大科技有限责任公司 | A kind of self-emulsification solid composition of the drug of class containing ivermectin of stabilization |
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Effective date of registration: 20181207 Address after: Room 006, 3rd floor, Lishizhen Avenue Building, Caohe Town, Qichun County, Hubei Province Applicant after: Zhongnong Huawei Biopharmaceutical (Hubei) Co., Ltd. Address before: 102206 Block C 510, Zhongguancun Life Science Park, Beiqing Road, Changping District, Beijing Applicant before: Beijing Zhongnonghuawei Biological Medicine Research Institute |
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