CN103316005B - Praziquantel-mebendazole nanoemulsion oral liquid and preparation method thereof - Google Patents
Praziquantel-mebendazole nanoemulsion oral liquid and preparation method thereof Download PDFInfo
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- CN103316005B CN103316005B CN201310246303.7A CN201310246303A CN103316005B CN 103316005 B CN103316005 B CN 103316005B CN 201310246303 A CN201310246303 A CN 201310246303A CN 103316005 B CN103316005 B CN 103316005B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- 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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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K9/00—Medicinal preparations characterised by special physical form
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- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention discloses a praziquantel-mebendazole nanoemulsion oral liquid. The liquid drop practical size of the nanoemulsion oral liquid is within 10-100nm, and the nanoemulsion oral liquid is prepared from the following raw materials in percentage by weight: 15.00-30.00% of a surfactant, 15.23-24.00% of a cosurfactant, 5.00-15.00% of ethyl acetate, 5.00-18.00% of N,N-dimethylacetamide, 0.10-1.50% of praziquantel, 0.10-1.50% of mebendazole and 5.80-53.40% of distilled water, and the total components are 100%. By utilizing the praziquantel-mebendazole nanoemulsion oral liquid, the medicament stabilities of the praziquantel and the mebendazole in the machining process are improved, the bioavailability is improved, the medicament metabolism time in vivo is prolonged, the use amount of auxiliary materials is reduced, the production cost is lowered, and the praziquantel-mebendazole nanoemulsion oral liquid has a wide market prospect in the medicine field.
Description
Technical field
The invention belongs to field of medicaments, relate to a kind of novel form of praziquantel-mebendazole, particularly a kind of praziquantel-mebendazole nanometer emulsion oral liquid of transparent and stable.
Background technology
Parasitic disease is a kind of common zoonosis, the new drug of development treatment parazoon disease, for ensureing the healthy of wholly human and promoting that the development of animal husbandry has necessarily important effect.
Praziquantel is a kind of broad-spectrum anti-parasite medicine.Its anthelmintic spectrum is very wide, also has killing action to Schistosoma japonicum, Schistosoma haematobium, Schistosoma mansoni, lung fluke, clonorchis sinensis, Echinococcus hydatid cyst, cysticercosis, Zhen Shi pleroceroid, fasciloopsis, cestode etc.Since appearance, because efficient, low toxicity, the advantage such as inexpensive are treated in schistosomicide and be used widely in preventing and controlling.Praziquantel has now become the choice drug for the treatment of multiple endoparasite.But it has water insoluble, the shortcoming of bioavailability difference.Mebendazole is a wide spectrum anthelmintic, in body or in vitro tests all prove directly to suppress nematicide to the absorption of glucose, cause glycogen depletion, make it survive, there is the effect killed larva significantly, suppress ovulation development, but do not affect blood in human body in sugar level.Can be used for the intestinal parasitical diseases such as control ancylostome, ascarid, pinworm, whipworm, excrement class loop line worm.But it has water insoluble, the shortcoming of bioavailability difference.
Utilizing nano fabrication technique, take nano-emulsion as carrier, and praziquantel and mebendazole are prepared into Nano medication.The new drug prepared can overcome praziquantel and mebendazole dissolubility is low, bioavailability is low shortcoming, and has easy absorption, the advantage that therapeutic effect improves greatly.Combined with mebendazole nanotechnology by praziquantel, develop a kind of wide spectrum, efficient, safe new drug, to reach the object to treatment parasites in animals disease, for the meaning overcoming animal parasitosis and have important production and apply.
Summary of the invention
For above-mentioned problems of the prior art and defect, the object of the present invention is to provide a kind of content evenly accurately, steady quality, bioavailability be high, and prepares easy praziquantel-mebendazole nanometer emulsion oral liquid.
The technical scheme realizing foregoing invention object is praziquantel-mebendazole nanometer emulsion oral liquid, comprises mass percent and is:
Surfactant 15.00 ﹪ ~ 30.00 ﹪, cosurfactant 15.23 ﹪ ~ 24.00 ﹪, ethyl acetate 5.00 ﹪ ~ 15.00 ﹪, N, N-dimethyl acetylamide 5.00 ﹪ ~ 18.00 ﹪, praziquantel 0.10 ﹪ ~ 1.50 ﹪, mebendazole 0.10 ﹪ ~ 1.50 ﹪ and distilled water 5.80% ~ 53.40% form, and total component is 100 ﹪
Praziquantel of the present invention-mebendazole nanometer emulsion oral liquid, its optimization formula comprises mass percent and is:
Surfactant 20.00 ﹪ ~ 30.00 ﹪, cosurfactant 18.00 ﹪ ~ 24.00 ﹪, ethyl acetate 6.00 ﹪ ~ 15.00 ﹪, N, N-dimethyl acetylamide 6.50 ﹪ ~ 18.00 ﹪, praziquantel 0.50 ﹪ ~ 1.50 ﹪, mebendazole 0.30 ﹪ ~ 1.50 ﹪ and distilled water 5.80% ~ 48.00% form, and total component is 100 ﹪.
Praziquantel of the present invention-mebendazole nanometer emulsion oral liquid, its optimum formula comprises mass percent and is:
Surfactant mutually 20.38 ﹪, cosurfactant 20.00 ﹪, ethyl acetate 10.00 ﹪, N,N-dimethylacetamide 10.00 ﹪, praziquantel 1.00 ﹪, mebendazole 1.00 ﹪ and distilled water 37.62% forms, and total component is 100 ﹪.
Described surface active agent tween-80;
Described cosurfactant is ethanol.
The present invention, in the selection of surfactant, selects the nonionic surfactant of avirulence and good biocompatibility.Nonionic surfactant is more stable in the solution, is not subject to the impact of strong electrolyte, inorganic salts, is not also subject to the impact of soda acid, and good with the compatibility of other surfactants, and haemolysis is less.In theory, the preparation of O/W type nanometer emulsion needs the HLB value of surfactant between 8 ~ 18, consider the simplicity of preparation technology, the i.e. easy formative of nano-emulsion and the stability of the nano-emulsion prepared, the present invention selects the liquid nonionic type surfactant of HLB between 10 ~ 15.Surfactant is tween 80.
In order to the hydrophilic and oleophilic value (HLB) of adjustment form surface-active agent, interfacial tension can be reduced further, increase flexibility and the rigidity of film, be inserted in interfacial film, promote the formation of the film that radius of curvature is very little, expand nano-emulsion forming region, the present invention selects bland cosurfactant, mainly contains ethanol.
The present invention is according to when the HLB of the surfactant needed for emulsifying oil phase is close with surfactant, and the principle of the emulsion stabilization formed, the oils and fats selected is ethyl acetate, N, N-dimethyl acetylamide.Be in a liquid state under this oily room temperature.
The preparation method of praziquantel of the present invention-mebendazole nanometer emulsion oral liquid, specifically comprises step as follows:
(1) preparation of surfactant phase takes surfactant by formula proportion, and helps surface activity composite in proportion, calculates the HLB value of this system, stirs.The HLB value of common emulsifying agent can be found in some chemical industry handbooks, as " the chemical products handbook " of chemical industry publishing house.Because hydrophile-lipophile balance (HLB) value of surfactant has additive properties, available quality averaging method obtains the HLB value of surfactant.Such as, after two kinds of surfactant A, B mix, the hydrophile-lipophile balance HLBAB value of its mixed surfactant is
HLBAB＝（WAHLBA＋WBHLBB）/（WA＋WB）
WA, WB in formula---the quality of blend surfactants A, B;
The HLB value of HLBA, HLBB---surfactant A, B.
(2) preparation of oil phase is according to the HLB value of surfactant phase, selects oil, adjusts its ratio, make the HLB value needed for its emulsifying close with the HLB of surfactant phase.
(3) ratio of surfactant phase and oil phase is changed in the rule of 9:1 ~ 1:9, add the praziquantel of formula proportion, mebendazole wherein, stirring makes it whole dissolving, fully stir at 20 DEG C ~ 25 DEG C slow adding distil waters, until form clear, viscosity is little and there is the flaxen nanometer emulsion of mobility.
Outward appearance of the present invention is light yellow transparent liquid, has good stability.When ageing stability refers to that nanometer emulsion oral liquid is preserved under room temperature natural trend condition, the degree that outward appearance extends in time and changes.This praziquantel-mebendazole nanometer emulsion oral liquid is transparent lastingly, does not find muddiness or precipitation, then illustrate that ageing stability is good.This is the important indicator evaluating nanometer emulsion oral liquid.Praziquantel-mebendazole nanometer emulsion oral liquid is placed in test tube, sealing, under the rotating speed of 12000r/min centrifugal 20 minutes, there is no layering, still clear.
Praziquantel of the present invention-mebendazole nanometer emulsion oral liquid, compared with prior art, has the following advantages:
1) thermodynamic stability is high.Operate fairly simple during preparation, not phase-splitting, not precipitate, bin stability improves;
2) light transmission is good, and any inhomogeneities or sedimentary existence are easily found, and sensible quality improves;
3) antiseptic property improves, because dispersion fluid is smaller, can prevent the intrusion of antibacterial, increase the dissolubility of some active ingredients simultaneously;
4) there is good solubilization, effectively can improve the dissolubility of insoluble drug;
5) dissolubility of praziquantel, mebendazole can be improved, delay the regression time of praziquantel, mebendazole, thus improve the bioavailability of praziquantel-mebendazole;
6) method technique is simple, is applicable to large-scale production.
Detailed description of the invention
The embodiment provided below by way of inventor sets forth the preparation method of praziquantel of the present invention-mebendazole nanometer emulsion oral liquid further.
embodiment 1
Accurately take tween 80 30.00g, ethanol 15.23g, ethyl acetate 15.00g, N, N-dimethyl acetylamide 15.15 puts into beaker, under 20 DEG C of room temperature conditions, hand operated mixing is by its abundant mix homogeneously, by 1.5g praziquantel, 1.5g mebendazole directly adds, stir fully, then slowly distilled water is added wherein, adding distil water limit, limit hand operated mixing, during beginning, system viscosity is less, along with the increase of the distillation water yield, system can become sticky, continue to drip and constantly stir, when system unexpected thinning time, namely what now produce is stable pale yellow transparent praziquantel-mebendazole nanometer emulsion oral liquid, its gross weight is claimed to be 100.0g.
embodiment 2
Accurately take tween 80 30.00g, ethanol 24.00g, ethyl acetate 15.00g, N, N-dimethyl acetylamide 18.00, put into beaker, under 20 DEG C of room temperature conditions, hand operated mixing is by its abundant mix homogeneously, by 0.1g praziquantel, 0.1g mebendazole directly adds, stir until all dissolve, then slowly distilled water is added wherein, adding distil water limit, limit hand operated mixing, during beginning, system viscosity is less, along with the increase of the distillation water yield, system can become sticky, continue to drip and constantly stir, when system unexpected thinning time, namely what now produce is stable pale yellow transparent praziquantel-mebendazole nanometer emulsion oral liquid, its gross weight is claimed to be 100.0g.
embodiment 3
Accurately take tween 80 21.00g, ethanol 21.00g, ethyl acetate 7.00g, N, N-dimethyl acetylamide 7.00, put into beaker, under 20 DEG C of room temperature conditions, hand operated mixing is by its abundant mix homogeneously, by 0.2g praziquantel, 0.2g mebendazole directly adds, stir until all dissolve, then slowly distilled water is added wherein, adding distil water limit, limit hand operated mixing, during beginning, system viscosity is less, along with the increase of the distillation water yield, system can become sticky, continue to drip and constantly stir, when system unexpected thinning time, namely what now produce is stable pale yellow transparent praziquantel-mebendazole nanometer emulsion oral liquid, its gross weight is claimed to be 100.0g.
embodiment 4
Accurately take tween 80 15.00g, ethanol 20.00g, ethyl acetate 6.00g, N, N-dimethyl acetylamide 5.00, put into beaker, under 20 DEG C of room temperature conditions, hand operated mixing is by its abundant mix homogeneously, by 0.3g praziquantel, 0.3g mebendazole directly adds, stir until all dissolve, then slowly distilled water is added wherein, adding distil water limit, limit hand operated mixing, during beginning, system viscosity is less, along with the increase of the distillation water yield, system can become sticky, continue to drip and constantly stir, when system unexpected thinning time, namely what now produce is stable pale yellow transparent praziquantel-mebendazole nanometer emulsion oral liquid, its gross weight is claimed to be 100.0g.
embodiment 5
Accurately take tween 80 18.00g, ethanol 24.00g, ethyl acetate 5.00g, N, N-dimethyl acetylamide 6.50, put into beaker, under 20 DEG C of room temperature conditions, hand operated mixing is by its abundant mix homogeneously, by 0.4g praziquantel, 0.4g mebendazole directly adds, stir until all dissolve, then slowly distilled water is added wherein, adding distil water limit, limit hand operated mixing, during beginning, system viscosity is less, along with the increase of the distillation water yield, system can become sticky, continue to drip and constantly stir, when system unexpected thinning time, namely what now produce is stable pale yellow transparent praziquantel-mebendazole nanometer emulsion oral liquid, its gross weight is claimed to be 100.0g.
embodiment 6
Accurately take tween 80 30.00g, ethanol 20.00g, ethyl acetate 15.00g, N, N-dimethyl acetylamide 8.33, put into beaker, under 20 DEG C of room temperature conditions, hand operated mixing is by its abundant mix homogeneously, by 0.5g praziquantel, 1.5g mebendazole directly adds, stir until all dissolve, then slowly distilled water is added wherein, adding distil water limit, limit hand operated mixing, during beginning, system viscosity is less, along with the increase of the distillation water yield, system can become sticky, continue to drip and constantly stir, when system unexpected thinning time, namely what now produce is stable pale yellow transparent praziquantel-mebendazole nanometer emulsion oral liquid, its gross weight is claimed to be 100.0g.
embodiment 7
Accurately take tween 80 21.00g, ethanol 16.00g, ethyl acetate 7.00g, N, N-dimethyl acetylamide 7.00, put into beaker, under 20 DEG C of room temperature conditions, hand operated mixing is by its abundant mix homogeneously, by 0.6g praziquantel, 0.6g mebendazole directly adds, stir until all dissolve, then slowly distilled water is added wherein, adding distil water limit, limit hand operated mixing, during beginning, system viscosity is less, along with the increase of the distillation water yield, system can become sticky, continue to drip and constantly stir, when system unexpected thinning time, namely what now produce is stable pale yellow transparent praziquantel-mebendazole nanometer emulsion oral liquid, its gross weight is claimed to be 100.0g.
embodiment 8
Accurately take tween 80 22.00g, ethanol 18.00g, ethyl acetate 7.00g, N, N-dimethyl acetylamide 7.00, put into beaker, under 20 DEG C of room temperature conditions, hand operated mixing is by its abundant mix homogeneously, by 0.7g praziquantel, 0.7g mebendazole directly adds, stir until all dissolve, then slowly distilled water is added wherein, adding distil water limit, limit hand operated mixing, during beginning, system viscosity is less, along with the increase of the distillation water yield, system can become sticky, continue to drip and constantly stir, when system unexpected thinning time, namely what now produce is stable pale yellow transparent praziquantel-mebendazole nanometer emulsion oral liquid, its gross weight is claimed to be 100.0g.
embodiment 9
Accurately take tween 80 24.00g, ethanol 21.00g, ethyl acetate 12.00g, N, N-dimethyl acetylamide 12.00, put into beaker, under 20 DEG C of room temperature conditions, hand operated mixing is by its abundant mix homogeneously, by 0.8g praziquantel, 0.8g mebendazole directly adds, stir until all dissolve, then slowly distilled water is added wherein, adding distil water limit, limit hand operated mixing, during beginning, system viscosity is less, along with the increase of the distillation water yield, system can become sticky, continue to drip and constantly stir, when system unexpected thinning time, namely what now produce is stable pale yellow transparent praziquantel-mebendazole nanometer emulsion oral liquid, its gross weight is claimed to be 100.0g.
Claims (3)
1. praziquantel-mebendazole nanometer emulsion oral liquid, it is characterized in that, be made up of the raw material of following weight percentage ratio: surfactant 15.00 ﹪ ~ 30.00 ﹪, cosurfactant 15.23 ﹪ ~ 24.00 ﹪, ethyl acetate 5.00 ﹪ ~ 15.00 ﹪, N, N-dimethyl acetylamide 5.00 ﹪ ~ 18.00 ﹪, praziquantel 0.10 ﹪ ~ 1.50 ﹪, mebendazole 0.10 ﹪ ~ 1.50 ﹪ and distilled water 5.80% ~ 53.40% form, and total component is 100 ﹪; Described surface active agent tween-80;
Described cosurfactant is ethanol.
2. praziquantel according to claim 1-mebendazole nanometer emulsion oral liquid, it is characterized in that, be made up of the raw material of following weight percentage ratio: surfactant 20.00 ﹪ ~ 30.00 ﹪, cosurfactant 18.00 ﹪ ~ 24.00 ﹪, ethyl acetate 6.00 ﹪ ~ 15.00 ﹪, N, N-dimethyl acetylamide 6.50 ﹪ ~ 18.00 ﹪, praziquantel 0.50 ﹪ ~ 1.50 ﹪, mebendazole 0.30 ﹪ ~ 1.50 ﹪ and distilled water 5.80% ~ 48.00% form, and total component is 100 ﹪.
3. a kind of praziquantel-mebendazole nanometer emulsion oral liquid according to claim 1, it is characterized in that, be made up of the raw material of following weight percentage ratio: surfactant is 20.38 ﹪, cosurfactant 20.00 ﹪, ethyl acetate 10.00 ﹪, N mutually, N-dimethyl acetylamide 10.00 ﹪, praziquantel 1.00 ﹪, mebendazole 1.00 ﹪ and distilled water 37.62% form, and total component is 100 ﹪.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201310246303.7A CN103316005B (en) | 2013-06-20 | 2013-06-20 | Praziquantel-mebendazole nanoemulsion oral liquid and preparation method thereof |
| PCT/CN2014/076699 WO2014201914A1 (en) | 2013-06-20 | 2014-05-03 | Praziquantel-mebendazole nanoemulsion oral liquid medication and preparation method therefor |
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| CN201310246303.7A CN103316005B (en) | 2013-06-20 | 2013-06-20 | Praziquantel-mebendazole nanoemulsion oral liquid and preparation method thereof |
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| CN103316005B true CN103316005B (en) | 2015-03-04 |
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