CN107595871A - Compound preparation containing ivermectin and preparation method thereof - Google Patents
Compound preparation containing ivermectin and preparation method thereof Download PDFInfo
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- CN107595871A CN107595871A CN201711048950.1A CN201711048950A CN107595871A CN 107595871 A CN107595871 A CN 107595871A CN 201711048950 A CN201711048950 A CN 201711048950A CN 107595871 A CN107595871 A CN 107595871A
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- ivermectin
- compound preparation
- preparation containing
- containing ivermectin
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- AZSNMRSAGSSBNP-UHFFFAOYSA-N 22,23-dihydroavermectin B1a Natural products C1CC(C)C(C(C)CC)OC21OC(CC=C(C)C(OC1OC(C)C(OC3OC(C)C(O)C(OC)C3)C(OC)C1)C(C)C=CC=C1C3(C(C(=O)O4)C=C(C)C(O)C3OC1)O)CC4C2 AZSNMRSAGSSBNP-UHFFFAOYSA-N 0.000 title claims abstract description 217
- 229960002418 ivermectin Drugs 0.000 title claims abstract description 217
- SPBDXSGPUHCETR-JFUDTMANSA-N 8883yp2r6d Chemical compound O1[C@@H](C)[C@H](O)[C@@H](OC)C[C@@H]1O[C@@H]1[C@@H](OC)C[C@H](O[C@@H]2C(=C/C[C@@H]3C[C@@H](C[C@@]4(O[C@@H]([C@@H](C)CC4)C(C)C)O3)OC(=O)[C@@H]3C=C(C)[C@@H](O)[C@H]4OC\C([C@@]34O)=C/C=C/[C@@H]2C)/C)O[C@H]1C.C1C[C@H](C)[C@@H]([C@@H](C)CC)O[C@@]21O[C@H](C\C=C(C)\[C@@H](O[C@@H]1O[C@@H](C)[C@H](O[C@@H]3O[C@@H](C)[C@H](O)[C@@H](OC)C3)[C@@H](OC)C1)[C@@H](C)\C=C\C=C/1[C@]3([C@H](C(=O)O4)C=C(C)[C@@H](O)[C@H]3OC\1)O)C[C@H]4C2 SPBDXSGPUHCETR-JFUDTMANSA-N 0.000 title claims abstract description 208
- 238000002360 preparation method Methods 0.000 title claims abstract description 175
- 150000001875 compounds Chemical class 0.000 title claims abstract description 127
- RJMUSRYZPJIFPJ-UHFFFAOYSA-N niclosamide Chemical compound OC1=CC=C(Cl)C=C1C(=O)NC1=CC=C([N+]([O-])=O)C=C1Cl RJMUSRYZPJIFPJ-UHFFFAOYSA-N 0.000 claims abstract description 51
- JFIOVJDNOJYLKP-UHFFFAOYSA-N bithionol Chemical compound OC1=C(Cl)C=C(Cl)C=C1SC1=CC(Cl)=CC(Cl)=C1O JFIOVJDNOJYLKP-UHFFFAOYSA-N 0.000 claims abstract description 49
- 229960002326 bithionol Drugs 0.000 claims abstract description 49
- 239000000945 filler Substances 0.000 claims abstract description 42
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- 239000000314 lubricant Substances 0.000 claims abstract description 25
- 239000002994 raw material Substances 0.000 claims abstract description 21
- 239000002245 particle Substances 0.000 claims description 33
- 238000007873 sieving Methods 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 29
- 239000008101 lactose Substances 0.000 claims description 26
- 229960001375 lactose Drugs 0.000 claims description 26
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 25
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 25
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 23
- 239000007962 solid dispersion Substances 0.000 claims description 23
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
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- 239000001856 Ethyl cellulose Substances 0.000 claims description 5
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 5
- 229920001249 ethyl cellulose Polymers 0.000 claims description 5
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 4
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- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 claims description 3
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims description 3
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims description 3
- 229940043253 butylated hydroxyanisole Drugs 0.000 claims description 3
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 3
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- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 claims description 2
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- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
Abstract
The present invention relates to a kind of compound preparation containing ivermectin and preparation method thereof.The compound preparation containing ivermectin is mainly prepared by each raw material of following parts by weight：2 parts of 0.05 part of ivermectin 0.01 part, 30 parts of niclosamidum 10 part, 15 parts of bithionol 6 part, 10 parts of disintegrant 3 part, 91 parts of filler 49 part, 3 parts of lubricant 1 part and adhesive 0.8 part.The uniformity of the compound preparation containing ivermectin is high and using effect is good.
Description
Technical field
The present invention relates to anti-parasite medicine technical field, more particularly to a kind of compound preparation containing ivermectin and its system
Preparation Method.
Background technology
With the raising of economic capability, increasing people raises dog, cat etc. and is used as pet.As canine can not only give people
Flat life increase enjoyment, and the lonely and pressure of people's heart can be alleviated.But Canis is in mammal, easily
Suffer from the parasitic diseases such as nematode, tapeworm, fluke, if can not get timely medical treatment, not only influence the health of canine, can also increase the mankind
Infect the risk of parasitic disease.Further, since cross-infection also easily occurs in daily life for canine and other mammals
Germ parasite, and can mutually be infected between different germ parasites, so as to which the illness of Different types of etiopathogenises can be suffered from.
Ivermectin is new less toxic antibioticses antiparasitic agent, has to nematode and arthropod and kills effect.
The anticestodal agent that niclosamidum belongs in anti parasitic disease medicine, toxicity is relatively low, has to tapeworm and kills effect.Bithionol pair
Fluke and tapeworm kill effect.But the Traits change between ivermectin, niclosamidum and bithionol is larger, and
Its Traits change between each excipient substance is also larger.Therefore, ivermectin, niclosamidum and bithionol are difficult to multiple
Close and tablet is made.
The content of the invention
Based on this, it is necessary to provide the compound preparation containing ivermectin and its preparation that a kind of uniformity is high and using effect is good
Method.
A kind of compound preparation containing ivermectin, is mainly prepared by each raw material of following parts by weight：Ivermectin 0.01
- 0.05 part of part, 10 parts -30 parts of niclosamidum, 6 parts -15 parts of bithionol, 3 parts -10 parts of disintegrant, 49 part -91 of filler
0.8 part -2 parts of part, 1 part -3 parts of lubricant and adhesive.
In one of the embodiments, in addition to flavor enhancement and parts by weight that parts by weight are 1 part -4 parts be 0.01 part -
0.04 part of preservative.
In one of the embodiments, it is prepared by each raw material of following parts by weight：0.04 part -0.05 of ivermectin
Part, 15 parts -25 parts of niclosamidum, 10 parts -15 parts of bithionol, 5 parts -8 parts of disintegrant, 50 parts -70 parts of filler, lubricant
0.01 part -0.03 part of 1 part -2 parts, 1.5 parts -2 parts of adhesive, 1 part -2 parts of flavor enhancement and preservative.
In one of the embodiments, the disintegrant is sodium carboxymethyl starch, PVPP, cross-linked carboxymethyl fiber
One or more in plain sodium, ethyl cellulose, methylcellulose, lauryl sodium sulfate and polyvinylpyrrolidone.
In one of the embodiments, the filler is anhydrous Icing Sugar, lactose, sucrose, starch, microcrystalline cellulose and wheat
One or more in bud dextrin.
In one of the embodiments, the filler is lactose, microcrystalline cellulose and maltodextrin, wherein, the breast
The mass ratio of sugared, described microcrystalline cellulose and the maltodextrin is (40-73)：(5-10)：(4-8).
In one of the embodiments, the lactose, the mass ratio of the microcrystalline cellulose and the maltodextrin are
42：7：5.
In one of the embodiments, the flavor enhancement is beef flavor and/or chicken essence；The lubricant is tristearin
One or more in sour magnesium, talcum powder and superfine silica gel powder；Described adhesive is sodium carboxymethylcellulose, starch slurry, hydroxypropyl first
One or more in cellulose or PVP；The preservative is parabens, butylated hydroxy anisole or two
One or more in butylated hydroxytoluene.
Compound preparation containing ivermectin in the present invention is the sheet system being processed into by main ingredient and suitable excipient substance
Agent.Count in parts by weight, the main ingredient includes the double dichloros of 0.01 part -0.05 part of ivermectin, 10 parts -30 parts of niclosamidum and sulphur
6 parts -15 parts of phenol, the excipient substance include 3 parts -10 parts of disintegrant, 49 parts -91 parts of filler, 1 part -3 parts of lubricant and bonding
0.3 part -1 part of agent.Ivermectin, niclosamidum and bithionol in the compound preparation containing ivermectin can be compound,
And preferably collaboration wide spectrum expelling parasite insecticidal effect is produced, it can effectively kill the parasites such as nematode, tapeworm, fluke disease.This contains her
Dimension rhzomorph compound preparation is by controlling ivermectin, niclosamidum, bithionol, disintegrant, filler, lubricant and gluing
The ratio of mixture, it is ensured that ivermectin, niclosamidum, bithionol can be evenly dispersed in each excipient substance,
The compound preparation containing ivermectin of the uniformity preferably can be made, and there is preferable using effect and security performance.
In addition, the filler in the present invention uses lactose, microcrystalline cellulose and maltodextrin, and by controlling lactose, micro-
The mass ratio of crystalline cellulose and maltodextrin is (40-73)：(5-10)：(1-10), its filler being collectively forming have suitable
Suitable caking property and mobility, it is ensured that ivermectin, niclosamidum and bithionol can be dispersed, and then prepare shape
Into the compound preparation containing ivermectin the uniformity it is preferable.In addition, the filler that lactose, microcrystalline cellulose and maltodextrin are formed
Hardness it is suitable, it is preferable to prepare the dissolving out capability of main ingredient in the compound preparation containing ivermectin of formation, and then this contains ivermectin
The using effect and security performance of compound preparation are all preferable.
The disintegrant of the present invention is from sodium carboxymethyl starch, PVPP, Ac-Di-Sol, ethyl cellulose
During one or more in element, methylcellulose, lauryl sodium sulfate and polyvinylpyrrolidone, it is preferable that it is disintegrated effect,
The dissolution of ivermectin is helped lend some impetus to, and then further increases the using effect and security of the compound preparation containing ivermectin
Energy.When disintegrant is PVPP, it can make disintegration of tablet rapid, not only be easier to soak medicaments uniformity, Er Qieneng
Hydrophobic drug surface is changed into hydrophily, further promote the dissolution of medicine and the disintegration of tablet.
A kind of preparation method of the compound preparation containing ivermectin is provided in addition, there is a need to.
A kind of preparation method of compound preparation containing ivermectin, comprises the following steps：
By parts by weight described above weigh respectively ivermectin, niclosamidum, bithionol, disintegrant, filler,
Lubricant and adhesive；
Each raw material weighed is subjected to pulverization process respectively, and handled by the mesh sieve of 60 mesh -120；
The ivermectin after sieving is added in absolute ethyl alcohol and is completely dissolved, is added described after the sieving of part
Filler is well mixed, and drying, crushing and sieving processing, ivermectin solid dispersion body is made, wherein, the ivermectin
The content of ivermectin described in solid dispersions is 1%-5%；
Described adhesive after sieving is added in solvent, it is 0.1% (w/v's) -10% (w/v) to prepare and obtain concentration
Binder solution；
By the niclosamidum after sieving, the bithionol after sieving, the disintegrant after sieving, residue
Sieving after the filler and the ivermectin solid dispersion body be well mixed by the equivalent method of progressively increasing, and add institute
Binder solution is stated, softwood is made；
The softwood is pelletized, dry and whole grain, particle is made, wherein, the water content of the particle is 2%-
7%；
The lubricant after sieving is well mixed with the particle, through compressing tablet process, produces compound containing ivermectin
Preparation, wherein, the hardness of the compound preparation containing ivermectin is 1kgf-7kgf.
In one of the embodiments, the mass ratio of the ivermectin and the absolute ethyl alcohol is 1：(20-40).
The preparation method of the heretofore described compound preparation containing ivermectin, can significantly improve compound containing ivermectin
The uniformity and dissolution rate of preparation, effectively improve the effectiveness and reliability of medicine.Contain ivermectin of the present invention
In the preparation method of compound preparation, by ivermectin, niclosamidum, bithionol, disintegrant, filler, lubricant and
Adhesive is handled after crushing respectively with the mesh sieve of 60 mesh -120, to ensure that the particle diameter of each raw material is smaller and uniform, it is ensured that mixing
The content of ivermectin, niclosamidum and bithionol is uniform afterwards, and fine and smooth uniform compound containing ivermectin can be made
Preparation, the dissolution rate of its active ingredient are accelerated.In addition, the particle diameter of ivermectin, niclosamidum, bithionol is relatively
Small, surface area is larger, and its solubility property is preferable.
By the way that the ivermectin after sieving is added in absolute ethyl alcohol, ivermectin can be filled in absolute ethyl alcohol
Divide dissolving, then be well mixed with the filler after the sieving of part, drying, crushing and sieving processing, obtained ivermectin
Solid dispersions.Ivermectin can be dispersed in the ivermectin solid dispersion body, expands its mixing with each raw material
It contact surface, can uniformly be distributed in auxiliary material, effectively increase the uniformity of the compound preparation containing ivermectin.By using etc.
The amount method of progressively increasing is well mixed niclosamidum, bithionol, filler and ivermectin solid dispersion body, further effectively
Improve the uniformity of the compound preparation containing ivermectin.
By controlling the concentration of binder solution it is 0.1% (w/v) -10% (w/v) in the present invention, it is ensured that containing ivermectin
Compound preparation has suitable viscosity, can reduce the contact angle of the compound preparation containing ivermectin, make it easier to soak, effectively change
The secondary disintegration of the kind compound preparation containing ivermectin, so as to significantly improve the dissolution rate of the compound preparation containing ivermectin.
It is 1%- by controlling the water content of particle in the heretofore described preparation method of compound preparation containing ivermectin
5%.The particle has the preferable uniformity and mobility, and ivermectin content distribution is uniform, and then effectively increases containing Yi Wei
The uniformity of rhzomorph compound preparation.
In the heretofore described preparation method of compound preparation containing ivermectin, by controlling compound preparation containing ivermectin
Hardness be 1kgf-7kgf, it is ensured that compound preparation containing ivermectin has preferable specific surface area, porosity and duct rate,
The disintegration efficiency of the compound preparation containing ivermectin can be effectively improved, and then with dissolving out capability preferably.
In the heretofore described preparation method of compound preparation containing ivermectin, by control ivermectin with it is described anhydrous
The mass ratio of ethanol is 1：(20-40), it is ensured that absolute ethyl alcohol can preferably dissolve ivermectin, and then ensure ivermectin compared with
It is uniformly dispersed in auxiliary material, obtained compound preparation containing ivermectin has the preferable uniformity, and then the usability of medicine
Can be preferably.
Therefore, the uniformity of the compound preparation produced by the present invention containing ivermectin and dissolution rate are preferable, and then effectively improve
The effectiveness and reliability of medicine.
Compound preparation containing ivermectin in the present invention can be used for outer expelling parasite inside the animals such as canine.As this contains Yi Wei
Rhzomorph compound preparation is chewable tablets, and animal carries out internal expelling parasite by being swallowed after the compound preparation containing ivermectin is chewed.Should
The using effect and security performance of the compound preparation containing ivermectin are all preferable.
Embodiment
For the ease of understanding the present invention, the present invention is described more fully below in conjunction with embodiment.But this hair
It is bright to realize in many different forms, however it is not limited to embodiment described herein.On the contrary, provide these embodiments
Purpose be to make the understanding more thorough and comprehensive to the disclosure.
Unless otherwise defined, all of technologies and scientific terms used here by the article is with belonging to technical field of the invention
The implication that technical staff is generally understood that is identical.Term used in the description of the invention herein 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
The arbitrary and all combination of the Listed Items of pass.
The test method of unreceipted actual conditions in the following example, conventionally and condition, or said according to commodity
The condition of bright book suggestion is selected.Agents useful for same or the unreceipted production firm person of instrument, it is that can be obtained by commercially available purchase
Conventional products.
The compound preparation containing ivermectin is to pass through the Formulation being processed into by main ingredient and suitable auxiliary material.This contains her
Dimension rhzomorph compound preparation is mainly prepared by each raw material of following parts by weight：0.01 part -0.05 part of ivermectin, such as can be with
For, but it is not limited to 0.01 part, 0.02 part, 0.03 part, 0.04 or 0.05 part；10 parts -30 parts of niclosamidum, such as can be, but
Be not limited to 10 parts, 15 parts, 20 parts, 25 parts or 30 parts, 6 parts -15 parts of bithionol, such as can be, but be not limited to 6 parts, 8
Part, 10 parts, 12 parts, 12.5 parts or 15 parts, 3 parts -10 parts of disintegrant, such as can be, but be not limited to 3 parts, 4 parts, 5 parts, 6 parts, 7
Part, 8 parts or 10 parts；49 parts -91 parts of filler, such as can be, but be not limited to 49 parts, 53.73 parts, 60 parts, 65 parts, 70 parts,
73 parts, 80 parts, 85 parts or 91 parts；1 part -3 parts of lubricant, such as can be, but it is not limited to 1 part, 2 parts or 3 parts；Adhesive 0.8
- 2 parts of part, such as can be, but it is not limited to 0.8 part, 1 part, 1.2 parts, 1.4 parts, 1.6 parts, 1.8 parts or 2 parts.
In one embodiment, 1 part -4 parts of flavor enhancement, such as can be, but it is not limited to 1 part, 2 parts, 3 parts or 4 parts；Anti-corrosion
0.01 part -0.04 part of agent, such as can be, but it is not limited to 0.01 part, 0.02 part, 0.03 part or 0.04 part.
In one embodiment, this contain ivermectin compound preparation mainly by following parts by weight each raw material prepare and
Into：0.04 part -0.05 part of ivermectin, 15 parts -25 parts of niclosamidum, 10 parts -15 parts of bithionol, 5 parts -8 parts of disintegrant,
0.01 part of 50 parts -70 parts of filler, 1 part -2 parts of lubricant, 1.5 parts -2 parts of adhesive, 1 part -2 parts of flavor enhancement and preservative -
0.03 part.
In one embodiment, it is prepared by each raw material of following parts by weight：0.05 part of ivermectin, niclosamidum
20 parts, 12.5 parts of bithionol, 5 parts of disintegrant, 53.73 parts of filler, 1 part of flavor enhancement, 1 part of lubricant, 1.7 parts of adhesive
And 0.02 part of preservative.
The disintegrant refers to the material that tablet can be made to split into fine particle rapidly in gastro-intestinal Fluid, so that main ingredient composition
Dissolve and absorb and play a role rapidly.The disintegrant needs have good water imbibition and dilatancy, so as to realize collapsing for tablet
Solution.Alternatively, the disintegrant is sodium carboxymethyl starch, PVPP, Ac-Di-Sol, ethyl cellulose, first
One or more in base cellulose, lauryl sodium sulfate and polyvinylpyrrolidone etc., its disintegration effect is preferable, contributes to
Promote the dissolution of ivermectin, and then further increase the using effect and security performance of the compound preparation containing ivermectin.Enter
Alternatively, the disintegrant is PVPP to one step, and it can make disintegration of tablet rapid, not only be easier to soak medicaments uniformity,
And hydrophobic drug surface can be made to be changed into hydrophily, further promote the dissolution of medicine and the disintegration of tablet.
The weight or volume for being mainly used in filling tablet of the filler, so as to dilute main ingredient, being easy to, which increases volume, helps it
Shaping.Alternatively, the filler be lactose, anhydrous Icing Sugar, sucrose, starch, microcrystalline cellulose, maltodextrin, inorganic salts and
One or more in amylum pregelatinisatum etc..Wherein, sucrose refers to the white that crystallinity sucrose forms after low temperature drying crushes
Powder, its bonding force are strong, by increasing capacitance it is possible to increase the hardness of tablet, and make the surface smooth and beautiful appearance of tablet.The compressibility energy of anhydrous Icing Sugar
Good, property is stable, and chemically reactive, the tablet being pressed into be not bright and clean attractive in appearance with most drug.The property of starch is stable, and most
Number medicine does not work, and price is also relatively cheap, and hygroscopicity is small, appearance luster is good.Microcrystalline cellulose is cellulosic sections hydrolysis
Prepared by the less crystallinity cellulose of the degree of polymerization, there is good compressibility, have stronger adhesion, the tablet being pressed into has
It is larger to have hardness.Amylum pregelatinisatum has good mobility, compressibility, self-lubricity and dry adhesive.Dextrin is starch
The general name of intermediate product is hydrolyzed, maltodextrin forms using starch as raw material through enzyme method technique control hydrolysis.
In one embodiment, the filler is lactose, microcrystalline cellulose and maltodextrin, wherein, the lactose, the crystallite
The mass ratio of cellulose and the maltodextrin is (40-73)：(5-10)：(1-10).Alternatively, the lactose, the microcrystalline cellulose
The mass ratio of element and the maltodextrin is 42：7：5.The filler that lactose, microcrystalline cellulose and malt paste are collectively forming has
Suitable caking property and mobility, it is ensured that each main ingredient can be dispersed, and then prepares the compound preparation containing ivermectin formed
The uniformity it is preferable.In addition, the hardness for the filler that lactose, microcrystalline cellulose and maltodextrin are formed is suitable, formation is prepared
The dissolving out capability of medicine is preferable in compound preparation containing ivermectin, and then this contains ivermectin compound preparation using effect and safety
Performance is all preferable.
The flavor enhancement is used for the organoleptic properties for improving food, makes food tastier, and can promote point of digestive juice
Secrete and orectic food additives.Alternatively, the flavor enhancement be beef flavor, chicken essence, dog taste flavouring agent, milk powder or
One or more in chicken liver meal etc..
The lubricant is used to reduce frictional force between particle, improves powder flowbility, prevents auxiliary material from sticking at punch head surface, drops
Frictional force between low tablet and punch die hole wall.Alternatively, the lubricant is one in magnesium stearate, talcum powder and superfine silica gel powder etc.
Kind is a variety of.
The adhesive is the sticking material of tool, and drug material can link together by its viscosity.Alternatively, this is viscous
Mixture is in sodium carboxymethylcellulose, starch slurry, hydroxypropyl methylcellulose, methylcellulose or ethyl cellulose, PVP etc.
It is one or more.During using adhesive, it can be added into or be scattered in water, in ethanol equal solvent, to be configured to required concentration
Binder solution.Alternatively, the concentration of binder solution is 0.6% (w/v) -10% (w/v).As starch slurry be in tablet it is more normal
Adhesive, the concentration of its starch slurry solution matched somebody with somebody are generally 2% (w/v) -10% (w/v)；When material compressibility can it is poor,
The starch slurry using higher concentration may be selected；If material compressibility can be good, the starch slurry of low concentration may be selected.According to carboxylic first
When base sodium cellulosate is as adhesive, the concentration of its sodium carboxymethyl cellulose solution prepared is generally 0.1% (w/v) -4%
(w/v).During according to hydroxypropyl methylcellulose as adhesive, the concentration of its hydroxypropyl methylcellulose aqueous solution prepared is generally
1% (w/v) -6% (w/v).During according to PVP as adhesive, the concentration of its PVP aqueous solution prepared is generally
2% (w/v) -5% (w/v).
The preservative is used to keep the drug effect of medicine and using quality.Alternatively, the preservative is p-hydroxybenzoate
One or more in class, butylated hydroxy anisole or dibutyl hydroxy toluene etc..
The absolute ethyl alcohol is used to dissolve ivermectin.The ivermectin can carry out preferably scattered in absolute ethyl alcohol.Its
In, by the dosage for adjusting absolute ethyl alcohol, it is ensured that ivermectin can be completely dissolved.Alternatively, the dosage of the absolute ethyl alcohol is
20 times -40 times of ivermectin dosage.When absolute ethyl alcohol can be completely dissolved ivermectin, the ivermectin can be equably
Mixed with auxiliary material, the uniformity of the compound preparation containing ivermectin of formation is preferable.
Compound preparation containing ivermectin in the present invention is the sheet system being processed into by main ingredient and suitable excipient substance
Agent.Count in parts by weight, the main ingredient includes the double dichloros of 0.01 part -0.05 part of ivermectin, 10 parts -30 parts of niclosamidum and sulphur
6 parts -15 parts of phenol, the excipient substance include 3 parts -10 parts of disintegrant, 49 parts -91 parts of filler, 1 part -3 parts of lubricant and bonding
0.3 part -1 part of agent.Ivermectin, niclosamidum and bithionol in the compound preparation containing ivermectin can be compound,
And preferably collaboration wide spectrum expelling parasite insecticidal effect is produced, it can effectively kill the parasites such as nematode, tapeworm, fluke disease.This contains her
Dimension rhzomorph compound preparation is by controlling ivermectin, niclosamidum, bithionol, disintegrant, filler, lubricant and gluing
The ratio of mixture, it is ensured that ivermectin, niclosamidum, bithionol can be evenly dispersed in each excipient substance,
The compound preparation containing ivermectin of the uniformity preferably can be made, and there is preferable using effect and security performance.
In addition, the filler in the present invention uses lactose, microcrystalline cellulose and maltodextrin, and by controlling lactose, micro-
The mass ratio of crystalline cellulose and maltodextrin is (40-73)：(5-10)：(1-10), its filler being collectively forming have suitable
Suitable caking property and mobility, it is ensured that ivermectin, niclosamidum and bithionol can be dispersed, and then prepare shape
Into the compound preparation containing ivermectin the uniformity it is preferable.In addition, the filler that lactose, microcrystalline cellulose and maltodextrin are formed
Hardness it is suitable, it is preferable to prepare the dissolving out capability of main ingredient in the compound preparation containing ivermectin of formation, and then this contains ivermectin
The using effect and security performance of compound preparation are all preferable.
A kind of preparation method of the compound preparation containing ivermectin is provided in addition, there is a need to.
A kind of preparation method of compound preparation containing ivermectin, comprises the following steps：
1) weigh and sieve：Ivermectin, niclosamidum, bithionol and disintegration are weighed by above-mentioned parts by weight point
The auxiliary materials such as agent, filler, lubricant, adhesive, by the ivermectin weighed, niclosamidum, bithionol and auxiliary material point
Do not crushed and handled by the mesh sieve of 60 mesh -120.Alternatively, the auxiliary material also includes flavor enhancement and preservative, and by upper
State parts by weight and weigh flavor enhancement and preservative respectively.
2) ivermectin solid dispersion body is prepared：Ivermectin after sieving is added in absolute ethyl alcohol and is completely dissolved,
The filler added after the sieving of part is well mixed, and drying, crushing and sieving processing, ivermectin solid dispersion is made
Body, wherein, the content of ivermectin described in ivermectin solid dispersion body is 1%-5%.
In one embodiment, the temperature of drying is 50 DEG C -60 DEG C, and the mesh number of sieving is the mesh of 60 mesh -120.
In one embodiment, can also include adding preservative into absolute ethyl alcohol the step dissolved in step 2)
Suddenly.
Specifically, ivermectin, preservative are dissolved in ethanol in tubbing, ensure that dissolving is complete, added part and fill out
Agent mixing is filled, about 4-5 hours is dried in 55 DEG C in baking oven -60 DEG C of drying, crushes, cross 100 mesh sieves, be made and contain 1% ivermectin
Solid dispersions.
3) binder solution is prepared：Adhesive after step 1) is sieved is added in solvent, is prepared into binder solution.Can
Selection of land, the concentration of the binder solution is 0.1% (w/v) -10% (w/v).
Specifically, by step 1) sieve after PVP be added to the water with concentration be 3% (w/v) PVP it is water-soluble
Liquid.
4) softwood is prepared：By the niclosamidum after sieving, the bithionol after sieving, the disintegrant after sieving, residue
Filler and ivermectin solid dispersion body after sieving are well mixed by the equivalent method of progressively increasing, and it is molten to add described adhesive
Liquid, softwood is made.Alternatively, the softwood can be held agglomerating, and light pressure dissipates.
In one embodiment, step 4) also includes flavor enhancement being added to the step of being mixed in preparing tank.
Specifically, by bithionol, niclosamidum, disintegrant, remaining filler, flavor enhancement, ivermectin solid
Dispersion etc. is progressively increased by equivalent to be mixed in method input mixer, and adds binder solution, softwood is made.
5) pelletize：Softwood prepared by step 4) is pelletized, dry and whole grain, particle is made.Wherein, particle contains
Water is 2%-7%.
Specifically, softwood is crossed into 20 mesh sieves through oscillating granulator and grain is made, and be put into baking oven 55 DEG C of -60 DEG C of dryings about
3-4 hours, drying course will stir back and forth, be heated evenly it, avoid the phenomenon of overdrying or overly moist, make moisture control 5%.
After 24 mesh sieves, particle is made.
6) film-making：Lubricant after step 1) is sieved is added in particle prepared by step 5), and is mixed, tabletting,
Produce compound preparation containing ivermectin.Wherein, the hardness for containing ivermectin compound preparation is 1kgf-7.0kgf.As this contains her
Dimension rhzomorph compound preparation hardness can be, but be not limited to 1kgf, 1.5kgf, 2kgf, 2.5kgf, 3kgf, 3.5kgf,
4kgf, 4.5kgf, 5kgf, 5.5kgf, 6kgf, 6.5kgf or 7kgf.
Specifically, particle is added lubricant and knocks down two-dimensional motion mixer and always mix timing, then by total mixed particle
It is transferred between tabletting and carries out tabletting, produces compound preparation containing ivermectin.
The preparation method of the heretofore described compound preparation containing ivermectin, compound rhzomorph tablet can be significantly improved
The uniformity and dissolution rate, effectively improve the effectiveness and reliability of medicine.In the compound system of the present invention containing ivermectin
In the preparation method of agent, by ivermectin, niclosamidum, bithionol, disintegrant, filler, lubricant and adhesive
Handled after crushing respectively with the mesh sieve of 60 mesh -120, to ensure that the particle diameter of each raw material is smaller and uniform, it is ensured that Yi Wei after mixing
The content of rhzomorph, niclosamidum and bithionol is uniform, and obtained compound preparation containing ivermectin is more fine and smooth uniform, its
The dissolution rate of active ingredient is accelerated.In addition, the particle diameter of ivermectin, niclosamidum, bithionol is relatively small, surface area
Larger, its solubility property is preferable.
By the way that the ivermectin after sieving is added in absolute ethyl alcohol, ivermectin can be filled in absolute ethyl alcohol
Divide dissolving, then be well mixed with the filler after the sieving of part, drying, crushing and sieving processing, obtained ivermectin
Solid dispersions.Ivermectin can be dispersed in the ivermectin solid dispersion body, expands its mixing with each raw material
It contact surface, can uniformly be distributed in auxiliary material, effectively increase the uniformity of the compound preparation containing ivermectin.By using etc.
The amount method of progressively increasing is well mixed niclosamidum, bithionol, filler, disintegrant and ivermectin solid dispersion body, enters
One step effectively increases the uniformity that the compound preparation containing ivermectin is made.
By controlling the concentration of binder solution it is 0.1% (w/v) -10% (w/v) in the present invention, it is ensured that containing ivermectin
Compound preparation has suitable viscosity, can reduce the contact angle of the compound preparation containing ivermectin, make it easier to soak, effectively change
The secondary disintegration of the kind compound preparation containing ivermectin, so as to significantly improve the dissolution rate of the compound preparation containing ivermectin.
It is 1%- by controlling the water content of particle in the heretofore described preparation method of compound preparation containing ivermectin
5%.The particle has the preferable uniformity and mobility, and ivermectin content distribution is uniform, and then effectively increases containing Yi Wei
The uniformity of rhzomorph compound preparation.
In the heretofore described preparation method of compound preparation containing ivermectin, by controlling compound preparation containing ivermectin
Hardness be 1kgf-7kgf, it is ensured that compound preparation containing ivermectin has preferable specific surface area, porosity and duct rate,
The disintegration efficiency of the compound preparation containing ivermectin can be effectively improved, and then with dissolving out capability preferably.
Therefore, the uniformity by the compound preparation containing ivermectin made from the preparation method is preferable, effectively improves medicine
The effectiveness and reliability of thing, and the preparation method is simply efficient, is adapted to industrialization to produce, has broad application prospects.
Compound preparation containing ivermectin in the present invention can be used for outer expelling parasite inside the animals such as canine.As this contains Yi Wei
Rhzomorph compound preparation is chewable tablets, and animal carries out internal expelling parasite by being swallowed after this contains the chewing of ivermectin compound preparation.Should
The using effect and security performance of the compound preparation containing ivermectin are all preferable.
It is specific embodiment below：
Embodiment 1-13
The composition of the compound preparation containing ivermectin is as shown in table 1 in embodiment 1-13.Numerical value corresponding to various raw materials in table 1
For the parts by weight of the raw material.
The composition of the compound preparation containing ivermectin of table 1
1. embodiment 1-7 preparation method is as follows：
1) ivermectin, niclosamidum, bithionol, PVPP, breast are weighed respectively by the above-mentioned parts by weight
Sugar, microcrystalline cellulose, maltodextrin, beef flavor, magnesium stearate, PVP and ethyl-para-hydroxybenzoate.By what is weighed
Each raw material is crushed and handled by 100 mesh sieves respectively.
2) ivermectin and ethyl-para-hydroxybenzoate are added in absolute ethyl alcohol is completely dissolved it, and adds
Portion of Lactose is well mixed, the drying process 4-5 hours at a temperature of in baking oven 55 DEG C -60 DEG C, is crushed, and through 100 mesh sieve mistakes
Sieve processing, is made the ivermectin solid dispersion body containing 1% ivermectin.
3) PVP by step 1) sieving is added in purified water, and it is water-soluble to be prepared into the PVP that concentration is 3% (w/v)
Liquid.
4) by step 1) sieve after niclosamidum, bithionol, PVPP, remaining lactose, maltodextrin,
Ivermectin solid dispersion body prepared by microcrystalline cellulose, beef flavor and step 2) is mixed by the equivalent method of progressively increasing, and
Add the PVP aqueous solution that concentration prepared by step 3) is 3% (w/v) to be mixed in preparing tank, softwood is made.This is soft
Material can be held agglomerating, and light pressure dissipates.
5) softwood is crossed into the processing of 20 mesh sieves through oscillating granulator, wet granular is made.Wet granular is placed on baking again
55 DEG C of -60 DEG C of dryings -4 hours about 3 hours in case, drying course will stir back and forth, be heated evenly it, avoid overdrying or overly moist
Phenomenon, make moisture control 5%.The particle dried is crossed into 24 mesh sieves again, carries out whole grain, particle is made.
6) magnesium stearate after step 1) is sieved is added in particle, and is knocked down two-dimensional motion mixer and always mixed, then will
Total mixed particle carries out tabletting between being transferred to tabletting, produces the 1-7 of compound preparation containing ivermectin.Wherein, this contains ivermectin
The hardness of compound preparation is 5.5 ± 1kgf.
2. embodiment 8-10 preparation method is as follows：
1) ivermectin, niclosamidum, bithionol, PVPP, breast are weighed respectively by the above-mentioned parts by weight
Sugar, magnesium stearate and PVP.Each raw material weighed is crushed respectively and handled by 100 mesh sieves.
2) ivermectin is added in absolute ethyl alcohol and be completely dissolved, and added portion of Lactose and be well mixed, in baking
Drying process 4-5 hours at a temperature of 55 DEG C -60 DEG C in case, crush, and handled through 100 mesh sieves, be made and contain 1% Yi Wei bacterium
The ivermectin solid dispersion body of element.
3) PVP after step 1) is sieved is added in purified water, and it is water-soluble to be prepared into the PVP that concentration is 3% (w/v)
Liquid.
4) niclosamidum, bithionol, PVPP, remaining lactose and step 2) after step 1) is sieved
The ivermectin solid dispersion body of preparation is mixed by the equivalent method of progressively increasing, and the concentration for adding step 3) preparation is 3% (w/v)
The PVP aqueous solution mixed in preparing tank, be made softwood.The softwood can be held agglomerating, and light pressure dissipates.
5) softwood is crossed into the processing of 20 mesh sieves through oscillating granulator, wet granular is made.Wet granular is placed on baking again
55 DEG C of -60 DEG C of dryings -4 hours about 3 hours in case, drying course will stir back and forth, be heated evenly it, avoid overdrying or overly moist
Phenomenon, make moisture control 5%.The particle dried is crossed into 24 mesh sieves again, carries out whole grain, particle is made.
6) magnesium stearate after step 1) is sieved is added in particle, and is knocked down two-dimensional motion mixer and always mixed, then will
Total mixed particle carries out tabletting between being transferred to tabletting, produces the 8-10 of compound preparation containing ivermectin.Wherein, this contains ivermectin
The hardness of compound preparation is 5.5 ± 1kgf.
3. embodiment 11-13 preparation method is as follows：
1) ivermectin, niclosamidum, bithionol, PVPP, breast are weighed respectively by the above-mentioned parts by weight
Sugar, beef flavor, magnesium stearate, ethyl-para-hydroxybenzoate and PVP.Each raw material weighed is crushed simultaneously respectively
Handled by 100 mesh sieves.
2) ivermectin and ethyl-para-hydroxybenzoate are added in absolute ethyl alcohol and are completely dissolved, and add part
Lactose is well mixed, the drying process 4-5 hours at a temperature of in baking oven 55 DEG C -60 DEG C, crush, and through 100 mesh sieves at
Reason, the ivermectin solid dispersion body containing 1% ivermectin is made.
3) PVP after step 1) is sieved is added in purified water, and it is water-soluble to be prepared into the PVP that concentration is 3% (w/v)
Liquid.
4) niclosamidum, bithionol, PVPP, beef flavor, remaining lactose after step 1) is sieved
And ivermectin solid dispersion body prepared by step 2) is mixed by the equivalent method of progressively increasing, and add the concentration of step 3) preparation
The PVP aqueous solution for 3% (w/v) is mixed in preparing tank, and softwood is made.The softwood can be held agglomerating, and light pressure is
Dissipate.
5) softwood is crossed into the processing of 20 mesh sieves through oscillating granulator, wet granular is made.Wet granular is placed on baking again
55 DEG C of -60 DEG C of dryings -4 hours about 3 hours in case, drying course will stir back and forth, be heated evenly it, avoid overdrying or overly moist
Phenomenon, make moisture control 5%.The particle dried is crossed into 24 mesh sieves again, carries out whole grain, particle is made.
6) magnesium stearate after step 1) is sieved is added in particle, and is knocked down two-dimensional motion mixer and always mixed, then will
Total mixed particle carries out tabletting between being transferred to tabletting, produces the 11-13 of compound preparation containing ivermectin.Wherein, this contains Yi Wei bacterium
The hardness of plain compound preparation is 5.5 ± 1kgf.
Comparative example 1
This comparative example is tablet 1, and the difference of the component and the component of embodiment 8 of comparative example 1 is：With following weight percent
Than weighing each raw material：0.05 part of ivermectin, 50 parts of niclosamidum, 30 parts of bithionol, 125 parts of lactose, PVPP
2 parts of 18 parts, 15 parts of PVP and magnesium stearate.The preparation method of the comparative example 1 is identical with the preparation method of embodiment 8.
Comparative example 2
This comparative example is tablet 2, and the difference of the component and the component of embodiment 8 of comparative example 2 is：It is not added with niclosamidum
And bithionol, other components and proportioning are same as Example 8.The preparation method of the comparative example 2 and the preparation of embodiment 8
Method is identical.
Comparative example 3
This comparative example is tablet 3, and the difference of the component and the component of embodiment 8 of comparative example 3 is：It is not added with ivermectin
And bithionol, other components are same as Example 8 with matching.The preparation method of the comparative example 3 and the preparation of embodiment 8
Method is identical.
Comparative example 4
This comparative example is tablet 4, and the difference of the component and the component of embodiment 8 of comparative example 4 is：It is not added with ivermectin
And niclosamidum, other components are same as Example 8 with matching.The preparation method of the comparative example 4 and the preparation side of embodiment 8
Method is identical.
Comparative example 5
This comparative example is tablet 5, the component and proportioning of comparative example 5 and the component of embodiment 8 and proportioning all same.Difference exists
In：Ivermectin and being added in absolute ethyl alcohol is not completely dissolved in preparation method, but the Yi Wei after step 1) is sieved
Rhzomorph, niclosamidum, bithionol, PVPP and lactose are directly mixed, and the concentration for adding preparation is 3%
(w/v) the PVP aqueous solution is mixed in preparing tank, and softwood is made.
The dissolution rate test of effete test embodiment 1
What respectively prepared by 6 in the compound preparation containing ivermectin 1 of the preparation of Example 1, embodiment 8 contains ivermectin
6 progress dissolutions in tablet 5 prepared by 6 in compound preparation 8,6 in the tablet 1 for preparing of comparative example 1 and comparative example 5
Degree test.Test method：According to dissolution rate and drug release determination method (《Republic of China Veterinary Pharmacopoeia version in 2015》(one)
Annex 0931) the second method carries out, and by external standard method with the stripping quantity of calculated by peak area every, limit is the 75% of labelled amount.Test
As a result it is as shown in table 1.
The dissolution rate test result of table 1
Conclusion：It can be seen from the data of table 1, prepared by compound preparation containing ivermectin 1 and embodiment 8 prepared by embodiment 1
The dissolution rate of compound preparation containing ivermectin 8 be all higher than 75%, meet dissolution specification, and the piece prepared relative to comparative example 1
The equal conspicuousness of each composition dissolution rate of tablet 5 prepared by agent 1 and comparative example 5 improves, and tablet prepared by comparative example 1, comparative example 5
1 and tablet 5 in three kinds of compositions (ivermectin, niclosamidum, bithionol) dissolution rate it is unqualified.
The uniformity of effete test embodiment 2 is tested
10 in the compound preparation containing ivermectin respectively prepared by embodiment 11, the bacterium containing Yi Wei for preparing of embodiment 8
10 progress uniformity tests in tablet 1 prepared by 10 in plain compound preparation 8 and comparative example 1, test method：According to containing
Amount uniformity test method (《Republic of China Veterinary Pharmacopoeia version in 2015》(one) annex 0941) carry out, by external standard method with peak
The content of areal calculation every.Test result is as shown in table 2.
The uniformity test result of table 2
Conclusion：It can be seen from the data of table 1, prepared by compound preparation containing ivermectin 1 and embodiment 8 prepared by embodiment 1
Compound preparation containing ivermectin 8 in three kinds of compositions (ivermectin, niclosamidum, bithionol) uniformity of dosage units compared with
Good, its uniformity (A+2.2S) is respectively less than 15, meets uniformity requirements, and the uniformity of the tablet 1 prepared relative to comparative example 1
Equal conspicuousness improves, and the uniformity of dosage units of three kinds of compositions (ivermectin, niclosamidum, bithionol) is equal in comparative example 1
It is unqualified.
The influence factor of effete test embodiment 3 is tested
In order to verify that the influence factor of the compound preparation containing ivermectin in the present invention is tested, prepared by Example 1 contains her
Rhzomorph compound preparation 1 and the compound preparation containing ivermectin 8 of the preparation of embodiment 8 are tieed up, carries out hot test, intense light irradiation experiment respectively
And the experiment of the influence factor such as high wet test, test method is according to the medicine under material medicine and preparation stability test direction principle item
Thing preparation influence factor test method (《Republic of China Veterinary Pharmacopoeia (version in 2015)》(one) annex 9001) carry out, tool
Body test method is as follows：
3.1 hot test
The good sample of bubble-cap is placed 10 days at a temperature of 60 DEG C, in the 5th day and the 10th day sampling analysis.
3.2 intense light irradiations are tested
The good sample of bubble-cap is placed in the stable case of sample, placed 10 days under the conditions of 4500 ± 500lx of illumination, the 5th
It and the 10th day sampling analysis.
3.3 high wet tests
The good sample of bubble-cap is placed under 90% damp condition and places the decentralization of 10 days conditions and puts 10 days, at the 5th day and the 10th
Its sampling analysis.
Character, content, dissolution rate to samples taken etc. carry out observation detection, and compared with the result of 0 day, table 3
For the influence factor result of the test of compound preparation containing ivermectin.
The influence factor result of the test of table 3
Conclusion：It can be seen from table 3 detects data, compound preparation containing ivermectin prepared by embodiment 1 and embodiment 8 is 60
Every Testing index has no significant change under DEG C high temperature, 4500 ± 500lx intense light irradiation and 90% ± 5% high humidity environment, matter
Measure relatively stable, meet stability requirement.
The accelerated stability of effete test embodiment 4 is tested
In order to verify the accelerated stability test of the compound preparation containing ivermectin in the present invention, prepared by Example 1 contains
Compound preparation containing ivermectin 8 prepared by ivermectin compound preparation 1 and embodiment 8 is appropriate, respectively in 40 ± 2 DEG C of temperature, phase
To placed under conditions of humidity 73% ± 5% 6 months carry out accelerated stability test, 1st month during experiment, 2 months, 3
Individual month, the 6 months the end of month it is separately sampled once, character and each component to samples taken (including ivermectin, niclosamidum, sulphur
Double Dichlorophenols) content and each component dissolution rate etc. carry out observation detection, and compared with the result of 0 day, test method according to
Under material medicine and preparation stability test direction principle item pharmaceutical preparation accelerated test method (《People's Republic of China (PRC) beast
Pharmacopeia (version in 2015)》(one) annex 9001) carry out.Table 4 is the accelerated stability test knot of the compound preparation containing ivermectin
Fruit.
The accelerated stability test result of table 4
Conclusion：According to table 4 detect data understand, embodiment 1 and embodiment 8 preparation compound preparation containing ivermectin
Every Testing index has no significant change under conditions of 40 ± 2 DEG C of temperature, relative humidity 73% ± 5%, and quality is relatively stable, symbol
Close stability requirement.
The efficacy test of effete test embodiment 5
The compound preparation containing ivermectin 8 and right that Example 1 prepares compound preparation containing ivermectin 1, prepared by embodiment 8
Tablet 1-5 prepared by ratio 1-5 carries out anti parasitic efficacy test.
It is visible in dog plant of Huadu of Guangdong Province, selection itch, local skin dothienesis, hair follicle inflammation, hair of leafing through
The dog of black parasite excreta or parasite polypide only 80, is judged as parasitic disease dog, and every 10 are included into one group, are respectively
A, B, C, D, E, F, G and H group.By 1/5kg, orally compound preparation containing ivermectin 1, B groups orally contain Yi Wei to A groups by 1/5kg
Rhzomorph compound preparation 7, C groups press tablet 1 prepared by 1/5kg oral contrasts example 1, and D groups are prepared by 1/5kg oral contrasts example 2
Tablet 2, E groups press 1/5kg oral contrasts example 3 prepare tablet 3, F groups by 1/5kg oral contrasts example 4 preparation tablet
4, G groups press tablet 5 prepared by 1/5kg oral contrasts example 5, and H groups are not administered, as blank control group.A groups, B groups, C groups, D
Group, E groups, F groups, G groups and the field stable breeding of H components avoid cross infection.The 5th day after administration, each group is gathered respectively within the 10th day, the 15th day
Fecal specimens carry out microscopy.Testing result is as shown in table 5.
The excrement testing result of table 5
Redution of eggs (%)={ worm's ovum number before [worm's ovum number after worm's ovum number-administration before administration]/administration } * 100%
Worm's ovum is with respect to slip (%)={ [not administration group nematode worm's ovum number-administration group nematode worm's ovum number]/not administration group line
Worm worm's ovum number } * 100%
Conclusion：The compound system containing ivermectin that the embodiment 1 prepares compound preparation containing ivermectin 1 and prepared by embodiment 8
Agent 8 is significantly increased relative to the comparative example 1-5 tablet 1-5 prepared anthelminthic effect, especially to nematode, tapeworm and suction
The purge ratio performance of worm is good.In addition, in the process using compound preparation containing ivermectin 1 and compound preparation containing ivermectin 8
In, animal does not occur obvious uncomfortable reaction.Therefore, this of the invention contains ivermectin, the chlorine in ivermectin compound preparation
Nitre willow amine and bithionol are compound, can produce preferably collaboration wide spectrum expelling parasite insecticidal effect, can effectively kill nematode,
The parasites such as tapeworm, fluke, this, which contains ivermectin compound preparation, has preferably anti parasitic effect.
Each technical characteristic of embodiment described above can be combined arbitrarily, to make description succinct, not to above-mentioned reality
Apply 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, the scope that this specification is recorded all is considered to be.
Embodiment described above only expresses the several embodiments of the present invention, and its description is more specific and detailed, but simultaneously
Can not therefore it be construed as limiting the scope of the patent.It should be pointed out that come for one of ordinary skill in the art
Say, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the protection of the present invention
Scope.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
Claims (10)
1. a kind of compound preparation containing ivermectin, it is characterised in that be mainly prepared by each raw material of following parts by weight：Yi Wei
0.01 part -0.05 part of rhzomorph, 10 parts -30 parts of niclosamidum, 6 parts -15 parts of bithionol, 3 parts -10 parts of disintegrant, filler
0.8 part -2 parts of 49 parts -91 parts, 1 part -3 parts of lubricant and adhesive.
2. compound preparation containing ivermectin according to claim 1, it is characterised in that also including parts by weight be 1 part -4 parts
Flavor enhancement and parts by weight be 0.01 part -0.04 part of preservative.
3. compound preparation containing ivermectin according to claim 2, it is characterised in that by each raw material system of following parts by weight
It is standby to form：0.04 part -0.05 part of ivermectin, 15 parts -25 parts of niclosamidum, 10 parts -15 parts of bithionol, 5 parts of disintegrant -
8 parts, 50 parts -70 parts of filler, 1 part -2 parts of lubricant, 1.5 parts -2 parts of adhesive, 1 part -2 parts of flavor enhancement and preservative 0.01
- 0.03 part of part.
4. according to the compound preparation containing ivermectin described in claim any one of 1-3, it is characterised in that the disintegrant is carboxylic
Methyl starch sodium, PVPP, Ac-Di-Sol, ethyl cellulose, methylcellulose, lauryl sodium sulfate
With the one or more in polyvinylpyrrolidone.
5. according to the compound preparation containing ivermectin described in claim any one of 1-3, it is characterised in that the filler is nothing
One or more in molasses sugar powder, lactose, sucrose, starch, microcrystalline cellulose and maltodextrin.
6. compound preparation containing ivermectin according to claim 5, it is characterised in that the filler is lactose, crystallite
Cellulose and maltodextrin, wherein, the lactose, the mass ratio of the microcrystalline cellulose and the maltodextrin are (40-
73)：(5-10)：(4-8).
7. compound preparation containing ivermectin according to claim 6, it is characterised in that the lactose, the microcrystalline cellulose
The plain and mass ratio of the maltodextrin is 42：7：5.
8. according to the compound preparation containing ivermectin described in claim any one of 2-3, it is characterised in that the flavor enhancement is ox
Meat essence and/or chicken essence；The lubricant is the one or more in magnesium stearate, talcum powder and superfine silica gel powder；It is described
Adhesive is the one or more in sodium carboxymethylcellulose, starch slurry, hydroxypropyl methylcellulose or PVP；The preservative is
One or more in parabens, butylated hydroxy anisole or dibutyl hydroxy toluene.
9. the preparation method of a kind of compound preparation containing ivermectin, it is characterised in that comprise the following steps：
Ivermectin, niclosamidum, bithionol, disintegration are weighed respectively by any one of the claim 1-8 parts by weight
Agent, filler, lubricant and adhesive；
Each raw material weighed is subjected to pulverization process respectively, and handled by the mesh sieve of 60 mesh -120；
The ivermectin after sieving is added in absolute ethyl alcohol and is completely dissolved, the filling added after the sieving of part
Agent is well mixed, and drying, crushing and sieving processing, ivermectin solid dispersion body is made, wherein, the ivermectin solid
The content of ivermectin described in dispersion is 1%-5%；
Described adhesive after sieving is added in solvent, prepares and obtains the bonding that concentration is 0.1% (w/v) -10% (w/v)
Agent solution；
By the niclosamidum after sieving, the bithionol after sieving, the disintegrant after sieving, remaining mistake
The filler and the ivermectin solid dispersion body after sieve are well mixed by the equivalent method of progressively increasing, and are added described viscous
Mixture solution, softwood is made；
The softwood is pelletized, dry and whole grain, particle is made, wherein, the water content of the particle is 2%-7%；
The lubricant after sieving is well mixed with the particle, through compressing tablet process, produces compound preparation containing ivermectin,
Wherein, the hardness of the compound preparation containing ivermectin is 1kgf-7kgf.
10. the preparation method of the compound preparation according to claim 9 containing ivermectin, it is characterised in that the Yi Wei bacterium
The plain and mass ratio of the absolute ethyl alcohol is 1：(20-40).
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108261401A (en) * | 2018-01-31 | 2018-07-10 | 佛山市南海东方澳龙制药有限公司 | Ivermectin solid dispersion body and ivermectin tablet |
| WO2021201805A1 (en) * | 2020-04-01 | 2021-10-07 | Imuneks Farma Ilac San. Ve Tic. A.S. | Niclosamide compositions with high solubility and bioavailability |
| WO2022101623A1 (en) * | 2020-11-10 | 2022-05-19 | The University Of Liverpool | Pharmaceutically active compound formulations |
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| CN101703776A (en) * | 2009-09-28 | 2010-05-12 | 洛阳惠中兽药有限公司 | Method for preparing anti-infective agent long-acting injection |
| CN105267230A (en) * | 2015-10-12 | 2016-01-27 | 青岛农业大学 | A kind of compound recipe fenbendazole tablet |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101703776A (en) * | 2009-09-28 | 2010-05-12 | 洛阳惠中兽药有限公司 | Method for preparing anti-infective agent long-acting injection |
| CN105267230A (en) * | 2015-10-12 | 2016-01-27 | 青岛农业大学 | A kind of compound recipe fenbendazole tablet |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108261401A (en) * | 2018-01-31 | 2018-07-10 | 佛山市南海东方澳龙制药有限公司 | Ivermectin solid dispersion body and ivermectin tablet |
| CN108261401B (en) * | 2018-01-31 | 2021-01-08 | 佛山市南海东方澳龙制药有限公司 | Ivermectin solid dispersion and ivermectin tablet |
| WO2021201805A1 (en) * | 2020-04-01 | 2021-10-07 | Imuneks Farma Ilac San. Ve Tic. A.S. | Niclosamide compositions with high solubility and bioavailability |
| WO2022101623A1 (en) * | 2020-11-10 | 2022-05-19 | The University Of Liverpool | Pharmaceutically active compound formulations |
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