CN117257986A - Dinitrotolamine solid dispersion and preparation method thereof - Google Patents
Dinitrotolamine solid dispersion and preparation method thereof Download PDFInfo
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- CN117257986A CN117257986A CN202311260388.4A CN202311260388A CN117257986A CN 117257986 A CN117257986 A CN 117257986A CN 202311260388 A CN202311260388 A CN 202311260388A CN 117257986 A CN117257986 A CN 117257986A
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- solid dispersion
- dinitrate
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- amine
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- 238000002360 preparation method Methods 0.000 title abstract description 21
- 239000000463 material Substances 0.000 claims abstract description 106
- 238000000498 ball milling Methods 0.000 claims abstract description 64
- ZEFNOZRLAWVAQF-UHFFFAOYSA-N Dinitolmide Chemical compound CC1=C(C(N)=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O ZEFNOZRLAWVAQF-UHFFFAOYSA-N 0.000 claims abstract description 47
- 229960003934 dinitolmide Drugs 0.000 claims abstract description 47
- 150000001412 amines Chemical class 0.000 claims abstract description 45
- 239000011324 bead Substances 0.000 claims abstract description 22
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000011049 filling Methods 0.000 claims abstract description 11
- 238000000227 grinding Methods 0.000 claims abstract description 9
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 49
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- 239000001116 FEMA 4028 Substances 0.000 claims description 32
- 229960004853 betadex Drugs 0.000 claims description 32
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 23
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 20
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- 238000007873 sieving Methods 0.000 claims description 16
- 239000003085 diluting agent Substances 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 8
- 239000000969 carrier Substances 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims 1
- 229940089206 anhydrous dextrose Drugs 0.000 claims 1
- 229910021487 silica fume Inorganic materials 0.000 claims 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 24
- 239000000203 mixture Substances 0.000 abstract description 15
- 239000003814 drug Substances 0.000 abstract description 11
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 16
- 229960001031 glucose Drugs 0.000 description 16
- 238000005303 weighing Methods 0.000 description 15
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- 241000287828 Gallus gallus Species 0.000 description 11
- 235000013330 chicken meat Nutrition 0.000 description 11
- 239000002671 adjuvant Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 5
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 5
- 238000012216 screening Methods 0.000 description 5
- 208000003495 Coccidiosis Diseases 0.000 description 4
- 206010023076 Isosporiasis Diseases 0.000 description 4
- 238000003801 milling Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000004584 weight gain Effects 0.000 description 4
- 235000019786 weight gain Nutrition 0.000 description 4
- 241000224483 Coccidia Species 0.000 description 3
- VDQQXEISLMTGAB-UHFFFAOYSA-N chloramine T Chemical compound [Na+].CC1=CC=C(S(=O)(=O)[N-]Cl)C=C1 VDQQXEISLMTGAB-UHFFFAOYSA-N 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
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- 239000010871 livestock manure Substances 0.000 description 2
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- 239000002994 raw material Substances 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- 229920000856 Amylose Polymers 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000561734 Celosia cristata Species 0.000 description 1
- 241000223932 Eimeria tenella Species 0.000 description 1
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- 230000002354 daily effect Effects 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 230000013872 defecation Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 208000035861 hematochezia Diseases 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
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- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
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- 230000017448 oviposition Effects 0.000 description 1
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- 229910002027 silica gel Inorganic materials 0.000 description 1
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Classifications
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Tropical Medicine & Parasitology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a dinitrate amine solid dispersion and a preparation method thereof. According to the invention, the particle size of the material is reduced to the nano-scale by mechanical ball milling assistance, so that the material enters into a gap between auxiliary material solubilizers with solubilization to form inclusion compound, and the solubility of the inclusion compound is increased. The specific process comprises the following steps: and (3) placing the dinitolmide and the auxiliary materials into a ball milling tank, and adding ball milling beads with a certain proportion for grinding. And the formulation proportion, grinding time, grinding speed, filling rate and the like of the polishing composition are examined. Obtaining a set of material formula and ball milling process with better quality. The invention has the characteristics of simple preparation method, no need of organic solvent, good uniformity of drug content, increased solubility in water of the obtained solid dispersion, good anticoccidial effect and the like, and has potential prospects in the fields of veterinary drug production and application.
Description
Technical Field
The invention belongs to the field of veterinary medicine preparations, and particularly relates to a method for preparing dinitolmide solid dispersion by mechanochemistry.
Background
Chicken coccidiosis (Coccidiosis in Chicken) is a common and serious parasitic disease of chickens, and can seriously damage intestinal mucosa of poultry, so that symptoms such as bloody stool, feed stool, water stool and the like appear, and the serious people can die in a large area; in addition, poor uniformity of the population, repeated occurrence of necrotic enteritis, reduced feed return, color differences in cockscomb, paw, leg, poor sales, and dramatic economic losses. The incidence and mortality rate of chicks are high. The growth of the healed chicks is blocked, and the weight gain is slow; adult chickens are mostly with insects, and do not develop diseases but have reduced weight and egg laying capacity.
Dinitrotolamine, also known as globfurazolidone, has special effect on preventing and treating coccidiosis of livestock and poultry. The product has high dosage, no side effect, low toxicity, and stable performance, and can not be decomposed when added into feed. Besides preventing and treating coccidiosis, the feed can promote the weight gain (weight gain rate is 13.8%) of poultry and improve the utilization rate of the feed. After the product is dissolved in water, the product has the flavor of food calling for the anorexia of the chickens, and has excellent administration effect. But its solubility in water is very low and thus greatly influences its bioavailability.
Cyclodextrin (CD) is a generic term for a series of cyclic oligosaccharides produced by amylose under the action of Cyclodextrin glucosyltransferase produced by Bacillus, and generally contains 6 to 12D-glucopyranose units. The space structure of cyclodextrin is not cylindrical molecule but is a slightly conical ring, which contains middle cavity structure and outer circle contains hydrophilic hydroxyl group, so that it can wrap medicine molecule with proper size and increase water solubility. Among them are the α -, β -and hydroxypropyl- β - (HP- β -) cyclodextrins used in the formulation field.
At present, most of dinitolmide products sold in the market are subjected to simple physical mixing after auxiliary materials are added, so that the uniformity and the solubility of the materials are poor, and the effects of drug residues caused by overhigh local drug concentration or too low drug residues can not achieve the prevention and treatment effects all the time are easily caused. Therefore, the solubility is high, the biological safety is high, the animal absorption is good, and the economical and practical dinitolamine solid dispersion has good market popularization prospect.
Disclosure of Invention
The invention aims to provide a uniform and stable dinitrate amine solid dispersion with good solubility in water and a preparation method thereof.
The solid dispersion of dinitrate amine is composed of dinitrate amine, diluent and solubilizer in the mass ratio of 0.5-1:2-3:0.5-1.5. Dinitolmide is used as an active ingredient, and a diluent and a solubilizer are used as carriers. Further preferably, the aqueous dispersion consists of dinitrate amine, diluent and solubilizer in the mass ratio of 1:3:1.
Furthermore, the invention also defines that the diluent is one of light calcium carbonate, anhydrous glucose and micro powder silica gel; the solubilizer is one of beta-cyclodextrin and hydroxypropyl-beta- (HP-beta-) cyclodextrin.
Furthermore, the invention also provides a preparation process of the dinitrate amine solid dispersion, which comprises the following steps: and weighing the dinitrate amine, the diluent and the solubilizer, placing the dinitrate amine, the diluent and the solubilizer into a ball milling tank, adding ball milling beads for grinding together, and sieving and collecting materials after grinding is finished to obtain the dinitrate amine solid dispersion which is uniformly mixed.
Further, the invention also defines a ball milling speed of 100 to 300rpm, preferably 150 to 200rpm.
Further, the invention defines a ball milling time of 1 to 12 hours, preferably 5 to 8 hours.
Further, the invention defines a ball-milling bead to material mass ratio of 8-16:1, preferably 12-14 times.
Further, the invention defines a ball milling pot fill of 35% to 95%, preferably 65% to 85%.
Compared with the prior art, the invention has the following advantages:
1) According to the invention, the active ingredient is wrapped by utilizing the structural characteristic of the solubilizer, so that the water solubility of the active ingredient is increased, the problem of indissolvable active ingredient is solved, and the bioavailability of the active ingredient in a human body is higher;
2) The invention promotes the solubilizer to clathrate active ingredient molecules by the aid of ball milling mechanical force, so that the solubility of insoluble and indissoluble active ingredients in water is increased;
3) The preparation method of the dinitolmide solid dispersion has simple equipment operation, avoids using an organic solvent, namely avoids the problems of solvent residues, environmental pollution and the like possibly generated in the process of removing the organic solvent. Is easy to realize industrialized mass production.
Drawings
FIG. 1 shows the relationship between the material ratio and the solubility.
FIG. 2 is a graph showing the relationship between content uniformity and solubility and ball milling time
FIG. 3 is a graph showing content uniformity and solubility versus ball-to-material ratio.
FIG. 4 is a graph showing content uniformity and solubility versus ball mill rotational speed.
Fig. 5 is a graph of content uniformity and solubility versus fill rate.
Detailed Description
Example 1: preparation of dinitrate amine solid dispersion with light calcium carbonate as auxiliary material (dinitrate amine: light calcium carbonate=1:3)
Weighing 5g of dinitolmide, placing 15g of light calcium carbonate in a ball milling tank, adding ball milling beads with the mass 15 times of that of the materials, setting parameters of an instrument, setting the rotating speed to 150rpm, mixing the materials, respectively taking 3 samples at different positions after 7 hours of equipment operation, stopping the equipment, sieving the materials, and collecting the materials to obtain the prepared dinitolmide solid dispersion, and detecting the content of the dinitolmide solid dispersion by using a high-performance liquid phase according to a detection method of animal pharmacopoeia. The solid dispersion obtained in this example was subjected to a solubility test, 0.5g of the solid dispersion was weighed, placed in a conical flask, 50mL of distilled water was added, and the flask was shaken at 37℃and 160rpm for 24 hours, after the completion of which the supernatant was taken and passed through a 0.45 μm needle filter, and then the solubility was measured by using high performance liquid chromatography. Experimental results show that the content of the dinitrate amine in the solid dispersion sampling sample of the formula is 25.78%, 26.14% and 24.36%, and the solubility is 491.14 mug/mL.
Example 2: preparation of solid dispersion of dinitrate amine with anhydrous glucose as adjuvant (dinitrate amine: anhydrous glucose=1:3)
Weighing 5g of dinitolmide, placing 15g of anhydrous glucose in a ball milling tank, adding ball milling beads with the mass 15 times of that of the materials, starting equipment, setting the rotation speed of the instrument to 150rpm, sampling after 7 hours of equipment operation, taking 3 samples at different positions, stopping the equipment, sieving the materials, collecting the materials, and detecting the content of the dinitolmide solid dispersion in a liquid phase. The solid dispersion obtained in this example was subjected to a solubility test: 0.5g of solid dispersion was weighed, placed in a conical flask, 50ml of distilled water was added, and the flask was shaken at 37℃and 160rpm for 24 hours, after the completion of which the supernatant was taken and passed through a 0.45 μm needle filter, and then the solubility was measured by HPLC. The content and solubility test result of the liquid phase test shows that the content of the dinitrate amine in the solid dispersion sample of the formula is 24.66%, 25.23% and 23.48%, and the solubility is 486.35 mug/mL.
Example 3: preparation of solid dispersion of dinitrate with light calcium carbonate and beta-cyclodextrin as adjuvants (dinitrate: light calcium carbonate: beta-cyclodextrin=1:3:0.5)
Weighing 5g of dinitolmide, 15g of light calcium carbonate and 2.5g of beta-cyclodextrin, placing in a ball milling tank, adding ball milling beads with the mass of 15 times of that of the materials, setting parameters of an instrument, mixing the materials at the rotating speed of 150rpm, sampling after 7 hours of operation of equipment, taking 3 samples at different positions, stopping the equipment, sieving the materials, and collecting the materials to obtain the prepared dinitolmide solid dispersion, and detecting the content of the dinitolmide solid dispersion by using a high-efficiency liquid phase according to a detection method of animal pharmacopoeia. The solid dispersion obtained in this example was subjected to a solubility test, 0.5g was weighed, placed in a conical flask, 50mL of distilled water was added, and the mixture was shaken at 37℃and 160rpm of a shaker for 24 hours, and after the completion, the supernatant was collected, and after passing through a 0.45 μm needle filter, the solubility was measured by using high performance liquid chromatography. The content and solubility test result of the liquid phase test shows that the content of dinitrate amine in the solid dispersion sample of the formula is 22.27%, 21.77% and 22.14%, and the solubility is 527.15 mug/mL.
Example 4: preparation of solid dispersion of dinitrate with light calcium carbonate and beta-cyclodextrin as adjuvants (dinitrate: light calcium carbonate: beta-cyclodextrin=1:3:1)
Weighing 5g of dinitolmide, 15g of light calcium carbonate, placing 5g of beta-cyclodextrin in a ball milling tank, adding ball milling beads with the mass of 15 times of the mass of the materials, setting parameters of an instrument, mixing the materials at the rotating speed of 150rpm, sampling after 7 hours of equipment operation, taking 3 samples at different positions, stopping the equipment, sieving the materials, and collecting the materials to obtain the prepared dinitolmide solid dispersion, and detecting the content of the dinitolmide solid dispersion by using a high-performance liquid phase according to a detection method of animal pharmacopoeia. The solid dispersion obtained in this example was subjected to a solubility test, 0.5g was weighed, placed in a conical flask, 50mL of distilled water was added, and the mixture was shaken at 37℃and 160rpm of a shaker for 24 hours, and after the completion, the supernatant was collected, and after passing through a 0.45 μm needle filter, the solubility was measured by using high performance liquid chromatography. The content and solubility test result of the liquid phase test shows that the content of dinitrate amine in the solid dispersion sample of the formula is 20.14%, 20.09% and 19.37%, and the solubility is 543.37 mug/mL.
Example 5: preparation of solid dispersion of dinitrate with light calcium carbonate and HB-beta-cyclodextrin as adjuvants (dinitrate amine: light calcium carbonate: HB-beta-cyclodextrin=1:3:0.5)
Weighing 5g of dinitolmide, 15g of light calcium carbonate and 2.5g of HB-beta-cyclodextrin, placing in a ball milling tank, adding ball milling beads with the mass of 15 times of the materials, setting parameters of an instrument, rotating at 150rpm, mixing the materials, sampling after 7 hours of equipment operation, taking 3 samples at different positions, stopping the equipment, sieving the materials, and collecting the materials to obtain the prepared dinitolmide solid dispersion, and detecting the content of the dinitolmide solid dispersion by using a high-efficiency liquid phase according to a detection method of animal pharmacopoeia. The solid dispersion obtained in this example was subjected to a solubility test, 0.5g was weighed, placed in a conical flask, 50mL of distilled water was added, and the mixture was shaken at 37℃and 160rpm of a shaker for 24 hours, and after the completion, the supernatant was collected, and after passing through a 0.45 μm needle filter, the solubility was measured by using high performance liquid chromatography. The content and solubility test result of the liquid phase test shows that the content of dinitrate amine in the solid dispersion sample of the formula is 22.67%, 22.14% and 22.09%, and the solubility is 521.36 mug/mL.
Example 6: preparation of solid dispersion of dinitrate with light calcium carbonate and HB-beta-cyclodextrin as adjuvants (dinitrate: light calcium carbonate: HB-beta-cyclodextrin=1:3:1)
Weighing 5g of dinitolmide, 15g of light calcium carbonate, 5g of HB-beta-cyclodextrin, placing in a ball milling tank, adding ball milling beads with the mass of 15 times of the mass of the materials, setting parameters of an instrument, mixing the materials at the rotating speed of 150rpm, sampling after 7 hours of operation of equipment, taking 3 samples at different positions, stopping the equipment, sieving the materials, and collecting the materials to obtain the prepared dinitolmide solid dispersion, and detecting the content of the dinitolmide solid dispersion by using a high-efficiency liquid phase according to a detection method of animal pharmacopoeia. The solid dispersion obtained in this example was subjected to a solubility test, 0.5g was weighed, placed in a conical flask, 50mL of distilled water was added, and the mixture was shaken at 37℃and 160rpm of a shaker for 24 hours, and after the completion, the supernatant was collected, and after passing through a 0.45 μm needle filter, the solubility was measured by using high performance liquid chromatography. The content and solubility test result of the liquid phase test shows that the content of dinitrate amine in the solid dispersion sample of the formula is 19.14%, 19.48% and 20.37%, and the solubility is 537.39 mug/mL.
Example 7: preparation of solid dispersion of dinitrate amine with anhydrous glucose and beta-cyclodextrin as adjuvants (dinitrate amine: anhydrous glucose: beta-cyclodextrin=1:3:0.5)
Weighing 5g of dinitolmide, 15g of anhydrous glucose and 2.5g of beta-cyclodextrin, placing in a ball milling tank, adding ball milling beads with the mass of 15 times of the mass of the materials, setting parameters of an instrument, mixing the materials at the rotating speed of 150rpm, sampling after 7 hours of operation of equipment, taking 3 samples at different positions, stopping the equipment, sieving the materials, and collecting the materials to obtain the prepared dinitolmide solid dispersion, and detecting the content of the dinitolmide solid dispersion by using a high-efficiency liquid phase according to a detection method of animal pharmacopoeia. The solid dispersion obtained in this example was subjected to a solubility test, 0.5g was weighed, placed in a conical flask, 50mL of distilled water was added, and the mixture was shaken at 37℃and 160rpm of a shaker for 24 hours, and after the completion, the supernatant was collected, and after passing through a 0.45 μm needle filter, the solubility was measured by using high performance liquid chromatography. The content and solubility test result of the liquid phase test shows that the content of dinitrate amine in the solid dispersion sample of the formula is 22.51%, 22.07% and 21.92%, and the solubility is 516.65 mug/mL.
Example 8: preparation of solid dispersion of dinitrate amine with anhydrous glucose and beta-cyclodextrin as adjuvants (dinitrate amine: anhydrous glucose: beta-cyclodextrin=1:3:1)
Weighing 5g of dinitolmide, 15g of anhydrous glucose and 5g of beta-cyclodextrin, placing in a ball milling tank, adding ball milling beads with the mass of 15 times of the mass of the materials, setting parameters of an instrument, mixing the materials at the rotating speed of 150rpm, sampling after 7 hours of equipment operation, taking 3 samples at different positions, stopping the equipment, sieving the materials, and collecting the materials to obtain the prepared dinitolmide solid dispersion, and detecting the content of the dinitolmide solid dispersion by using a high-performance liquid phase according to a detection method of animal pharmacopoeia. The solid dispersion obtained in this example was subjected to a solubility test, 0.5g was weighed, placed in a conical flask, 50mL of distilled water was added, and the mixture was shaken at 37℃and 160rpm of a shaker for 24 hours, and after the completion, the supernatant was collected, and after passing through a 0.45 μm needle filter, the solubility was measured by using high performance liquid chromatography. The content and solubility test result of the liquid phase test shows that the content of dinitrate amine in the solid dispersion sample of the formula is 20.08%, 20.11% and 19.87%, and the solubility is 534.37 mug/mL.
Example 9: preparation of solid dispersion of dinitrate with anhydrous glucose and HB-beta-cyclodextrin as adjuvants (dinitrate amine: anhydrous glucose: HB-beta-cyclodextrin=1:3:0.5)
Weighing 5g of dinitolmide, 15g of anhydrous glucose and 2.5g of HB-beta-cyclodextrin, placing in a ball milling tank, adding ball milling beads with the mass of 15 times of the mass of the materials, setting parameters of an instrument, rotating at 150rpm, mixing the materials, sampling after 7 hours of operation of equipment, taking 3 samples at different positions, stopping the equipment, sieving the materials, and collecting the materials to obtain the prepared dinitolmide solid dispersion, and detecting the content of the dinitolmide solid dispersion by using a high-efficiency liquid phase according to a detection method of animal pharmacopoeia. The solid dispersion obtained in this example was subjected to a solubility test, 0.5g was weighed, placed in a conical flask, 50mL of distilled water was added, and the mixture was shaken at 37℃and 160rpm of a shaker for 24 hours, and after the completion, the supernatant was collected, and after passing through a 0.45 μm needle filter, the solubility was measured by using high performance liquid chromatography. The content and solubility test result of the liquid phase test shows that the content of dinitrate amine in the solid dispersion sample of the formula is 22.36%, 22.14% and 21.79%, and the solubility is 518.36 mug/mL.
Example 10: preparation of solid dispersion of dinitrate with anhydrous glucose and HB-beta-cyclodextrin as adjuvants (dinitrate amine: anhydrous glucose: HB-beta-cyclodextrin=1:3:1)
Weighing 5g of dinitolmide, 15g of anhydrous glucose, 5g of HB-beta-cyclodextrin, placing in a ball milling tank, adding ball milling beads with the mass of 15 times of the mass of the materials, setting parameters of an instrument, mixing the materials at the rotating speed of 150rpm, sampling after 7 hours of operation of equipment, taking 3 samples at different positions, stopping the equipment, sieving the materials, and collecting the materials to obtain the prepared dinitolmide solid dispersion, and detecting the content of the dinitolmide solid dispersion by using a high-efficiency liquid phase according to a detection method of animal pharmacopoeia. The solid dispersion obtained in this example was subjected to a solubility test, 0.5g was weighed, placed in a conical flask, 50mL of distilled water was added, and the mixture was shaken at 37℃and 160rpm of a shaker for 24 hours, and after the completion, the supernatant was collected and was subjected to a 0.45 μm needle filter, and then analyzed by high performance liquid chromatography. The content and solubility test result of the liquid phase test shows that the content of dinitrate amine in the solid dispersion sample of the formula is 20.01%, 19.67% and 20.27%, and the solubility is 534.34 mug/mL.
Example 11: the solid dispersion is preferably
In examples 1-10, different carriers are respectively selected to obtain solid dispersion of dinitolmide, the solubility of each solid dispersion and raw materials is plotted to obtain a preferable auxiliary material formula which is light calcium carbonate and beta-cyclodextrin, the ratio of dinitolmide to the solid dispersion is 1:3:1, and the solubility of the dinitolmide is 543.37 mug/mL.
Example 12: ball milling time screening for preparation of dinitrate amine solid dispersion
Preparing a dinitrate amine solid dispersion according to the preferred auxiliary material proportion in the embodiment 11, weighing 5g of dinitrate amine, 15g of light calcium carbonate and 5g of beta-cyclodextrin, placing in a ball milling tank, adding ball milling beads with the mass 15 times of that of the materials, setting the parameters of an instrument with the rotating speed of 150rpm, mixing the materials, sampling at the ball milling time of 1, 3, 5, 7 and 9 hours, taking 3 samples at different positions, stopping the equipment, sieving the materials, collecting the materials, and detecting the content of each group by using a high-efficiency liquid phase according to the detection method of animal pharmacopoeia. The solid dispersion obtained in this example was subjected to a solubility test, 0.5g was weighed, placed in a conical flask, 50mL of distilled water was added, and the mixture was shaken at 37℃and 160rpm of a shaker for 24 hours, and after the completion, the supernatant was collected and was subjected to a 0.45 μm needle filter, and then analyzed by high performance liquid chromatography. The experimental results of liquid phase detection on the content and the solubility show that the materials tend to be uniform after 5 hours along with the increase of the ball milling time, the wall sticking phenomenon is more serious when the ball milling time is longer, the material receiving is influenced, the solubility is increased along with the increase of the time, and the amplification is slowed down after 5 hours, so the ball milling time is preferably 5 hours. The contents of the components are 19.90%, 20.19% and 20.78%, respectively, and the solubility is 561.59 mug/mL.
Example 13: ball-to-charge ratio screening for preparation of dinitolmide-solid dispersion
Weighing 5g of dinitolmide, 15g of light calcium carbonate and 5g of beta-cyclodextrin, placing the dinitolmide, the light calcium carbonate and the 5g of beta-cyclodextrin in a ball milling tank, adding ball milling beads with the mass of 8-16 times of the materials, taking five groups of balls with the mass of 8-10 times, 12 times, 14 times and 16 times of the balls, starting equipment, setting the ball milling rotation speed to 150rpm, sampling after the equipment operates for 5 hours, taking 3 samples at different positions from each group, stopping the equipment, sieving the materials, and collecting the materials to obtain the prepared dinitolmide solid dispersion, and detecting the content of the dinitolmide solid dispersion by using a high-efficiency liquid phase according to a detection method of animal pharmacopoeia. Several groups of solid dispersions obtained in this example were subjected to solubility experiments: each group was weighed by 0.5g, placed in a conical flask, added with 50ml of distilled water, shaken for 24 hours at 37℃and 160rpm on a shaker, and after the completion of the shaking, the supernatant was collected, passed through a 0.45 μm needle filter and then analyzed and detected by high performance liquid chromatography. The content and solubility test result of the liquid phase test shows that the material uniformity is better and the solubility is increased along with the increase of the ball-to-material ratio. However, the ball-to-material ratio is increased, the phenomenon that the material sticks to the wall and beads is more and more serious, the material yield of the material is affected, and in consideration of the use cost of consumable materials, the preferable steel ball addition amount is 12 times of the material mass. The content of the composition was 20.03%, 20.14% and 19.85%, and the solubility was 561.48. Mu.g/mL.
Example 14: dinitolmide solid dispersion ball milling rotational speed screening
5g of dinitolmide, 15g of light calcium carbonate and 5g of beta-cyclodextrin are weighed and placed in a ball milling tank, ball milling beads with the mass 12 times of that of the materials are added, equipment is started, the rotating speed is set to be 100, 150, 200, 250 and 300rpm for 5 groups, the equipment is operated for 5 hours, and then sampling is carried out, and 3 samples at different positions are taken from each group. Stopping the equipment, sieving and collecting the materials to obtain the prepared dinitrate-tolamine solid dispersion. The liquid phase is used for detecting the content of the liquid phase. The solid dispersion samples obtained in this example were subjected to solubility experiments: each group was weighed by 0.5g, placed in a conical flask, added with 50ml of distilled water, shaken for 24 hours at 37℃and 160rpm on a shaker, and after the completion of the shaking, the supernatant was collected, passed through a 0.45 μm needle filter and then analyzed and detected by high performance liquid chromatography. The liquid phase detection of the content and the solubility test result shows that the uniformity of the materials is advanced to be uniform and then tends to be nonuniform along with the increase of the rotating speed. The analysis reason is that the materials are not easy to rotate along with the ball milling tank at a small ball milling rotating speed, and the steel balls are not easy to mix the materials. When the rotating speed is too high, the materials are adhered to the wall under the influence of centrifugal force, and the materials are not uniform. The solubility increases with the increase in the milling speed, but the overall expansion is gentle, so that the milling speed is preferably 200rpm. The content of the group is 20.832%, 19.952% and 20.272%, and the solubility is 552.36 mug/mL.
Example 15: filling rate screening for preparation of dinitrate amine solid dispersion
Weighing materials according to the following proportion:
TABLE 1 filling ratios corresponding to different Material additions
| Group of | Dinitolmide (g) | Calcium carbonate (g) | Beta-cyclodextrin (g) | Filling ratio (%) |
| 1 | 5 | 15 | 5 | 35 |
| 2 | 10 | 30 | 10 | 50 |
| 3 | 15 | 45 | 15 | 65 |
| 4 | 20 | 60 | 20 | 85 |
| 5 | 25 | 75 | 25 | 95 |
Adding ball-milling beads with the mass 12 times of that of the materials into a ball-milling tank, starting equipment, setting the rotating speed of the instrument to 200rpm, sampling after the equipment operates for 5 hours, taking 3 samples at different positions from each group, stopping the equipment, sieving the materials, collecting the materials, and obtaining the prepared dinitrate tolamine solid dispersion, and detecting the content of the dinitrate tolamine solid dispersion in a liquid phase. The solid dispersion samples obtained in this example were subjected to solubility experiments: each group was weighed by 0.5g, placed in a conical flask, added with 50ml of distilled water, shaken for 24 hours at 37℃and 160rpm on a shaker, and after the completion of the shaking, the supernatant was collected, passed through a 0.45 μm needle filter and then analyzed and detected by high performance liquid chromatography. The liquid phase detection shows that the content and the solubility of the material are improved, the uniformity of the material is reduced after the material is first uniform along with the increase of the filling rate, and the solubility change is not obvious. It can be seen that as the filling rate increases, the space for grinding the material decreases, but the uniformity of the material decreases, and from the viewpoint of production efficiency, the filling rate is preferably 85%, the group contents are 20.376%, 20.312%, 19.952%, and the solubility is 556.78 μg/mL.
As shown in fig. 1, it is shown that the solubility of example 4 is highest among the formulations of the respective examples and the solubilities of the raw materials, and the formulations are preferably subjected to screening in the subsequent process.
As shown in fig. 2, it is shown that under different ball milling time, the solubility gradually increases along with time, the materials also tend to be more uniform, and the economy and effect are comprehensively judged, and preferably 5h is the optimal ball milling time.
As shown in fig. 3, it is shown that under different ball-to-material ratio conditions, the material uniformity is better and the solubility is increased as the ball-to-material ratio is increased. However, the ball-material ratio is increased, the phenomenon that the material sticks to the wall and beads is more and more serious, the material yield of the material is affected, and in consideration of the use cost of consumable materials, the material is preferably 12 times.
As shown in fig. 4, it is shown that the material uniformity tends to be uniform with increasing rotation speed, and then tends to be nonuniform. The analytical reasons may be that both small and excessive ball mill speeds are insufficient to make the material uniform. The solubility increases with the increase in the milling speed, but the overall expansion is gentle, so that the milling speed is preferably 200rpm.
As shown in fig. 5, the material precursor became uniform and then started to decrease in uniformity with increasing filling rate, and the solubility change was not obvious. It can be seen that as the filling rate becomes higher and higher, the space for grinding the material becomes smaller and smaller, but the uniformity of the material is reduced, and from the viewpoint of production efficiency, the filling rate is preferably 85%.
Example 16: examination of anticoccidial effect of dinitrate-amine solid dispersion
The anticoccidial effect was evaluated by SPF green-shelled black-bone chickens, and 50 green-shelled black-bone chickens with uniform weight were equally divided into 5 groups of 10 animals each, which were respectively a commercial product of globalpine, a solid dispersion of dinitolmide, a sensitive drug control, an infection control and a blank control group. Respectively inoculating chicken eimeria tenella soft capsules into groups 1-4, adding medicines with corresponding concentrations into drinking water of a medicine group on days 1-6 after coccidian inoculation, wherein the medicine use concentration of the globarium is 0.5 g/kg of material, and according to the daily average feed intake of each chicken, sterilizing water, uniformly mixing, inoculating orally every day, and the sensitive medicine use concentration is 0.5 ml/l of water; weighing every 2 days, observing the condition of defecation and photographing and recording at the 5 th to 6 th days after coccidian infection, collecting the chicken manure of each group at the 7 th to 9 th days after coccidian infection, storing and checking in a refrigerator at the temperature of 4 ℃, and counting the chicken manure oocyst number (OPG) of each group by a Mastery counting method. The relevant original data is input into EXCEL for analysis, the anticoccidial index of the medicine is calculated according to the following formula,
aci= (survival + relative weight gain) - (lesion + oocyst) values), ACI values greater than 180 were judged to be high efficacy, 160-179 were judged to be medium efficacy, and less than 160 were judged to be ineffective.
The results obtained are given in the following table:
TABLE 2 anticoccidial index (ACI) for different drugs
According to ACI value, the dinitrate tolamine solid dispersion prepared by the invention has better anticoccidial effect than the commercial product.
Finally, it should be noted that: the embodiment of the invention is disclosed only as a preferred embodiment of the invention, and is only used for illustrating the technical scheme of the invention, but not limiting the technical scheme; although the invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art will understand that; the technical scheme recorded in the various embodiments can be modified or part of technical features in the technical scheme can be replaced equivalently; these modifications or substitutions do not make the essence of the corresponding technical solutions deviate from the spirit and scope of the technical solutions of the embodiments of the present invention, and these embodiments all belong to the protection scope of the present invention.
Claims (10)
1. The solid dispersion of dinitrate amine is characterized by comprising dinitrate amine, a diluent and a solubilizer in a mass ratio of 0.5-1:2-3:0.5-1.5, wherein the dinitrate amine is used as an active ingredient, and the diluent and the solubilizer are used as carriers.
2. The dinitrate amine solid dispersion of claim 1, which is composed of dinitrate amine, diluent and solubilizer in a mass ratio of 1:3:1.
3. The solid dispersion of dinitolmide according to claim 1, wherein said diluent is one of light calcium carbonate, anhydrous dextrose and micro silica gel.
4. The solid dispersion of dinitrate amine according to claim 1, wherein said solubilizing agent is one of beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin.
5. The method for preparing a solid dispersion of dinitolmide according to any one of claims 1 to 4, characterized by comprising the steps of:
and (3) placing the dinitrate amine, the diluent and the solubilizer in a ball milling tank, adding ball milling beads for grinding together, and sieving and collecting materials after grinding is finished to obtain the dinitrate amine solid dispersion which is uniformly mixed.
6. The method for preparing a dinitrate amine solid dispersion according to claim 5, wherein the ball milling speed in the ball milling tank is 100-300 rpm, and the ball milling time is 1-12 h.
7. The method for preparing a dinitrate amine solid dispersion according to claim 6, wherein the ball milling speed in the ball milling tank is 150-200 rpm, and the ball milling time is 5-8 hours.
8. The method for preparing a dinitrate-tolamine solid dispersion of claim 5, wherein the mass ratio of ball-milling beads to materials in the ball-milling tank is 8-16:1.
9. The method for preparing a dinitrate-tolamine solid dispersion of claim 8, wherein the mass ratio of ball-milling beads to materials in the ball-milling tank is 12-14:1.
10. The method for preparing a dinitrate amine solid dispersion according to claim 5, wherein the filling rate of the ball milling tank is 35% -95%.
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