CN108295038B - Veterinary enteric composition and preparation method thereof - Google Patents
Veterinary enteric composition and preparation method thereof Download PDFInfo
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- CN108295038B CN108295038B CN201810201203.5A CN201810201203A CN108295038B CN 108295038 B CN108295038 B CN 108295038B CN 201810201203 A CN201810201203 A CN 201810201203A CN 108295038 B CN108295038 B CN 108295038B
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- enteric
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- toltrazuril
- bioadhesive
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 239000000463 material Substances 0.000 claims abstract description 81
- 229960000898 toltrazuril Drugs 0.000 claims abstract description 48
- OCINXEZVIIVXFU-UHFFFAOYSA-N 1-methyl-3-[3-methyl-4-[4-(trifluoromethylthio)phenoxy]phenyl]-1,3,5-triazinane-2,4,6-trione Chemical compound CC1=CC(N2C(N(C)C(=O)NC2=O)=O)=CC=C1OC1=CC=C(SC(F)(F)F)C=C1 OCINXEZVIIVXFU-UHFFFAOYSA-N 0.000 claims abstract description 47
- 230000001070 adhesive effect Effects 0.000 claims abstract description 31
- 239000000853 adhesive Substances 0.000 claims abstract description 28
- 239000002702 enteric coating Substances 0.000 claims abstract description 21
- 238000009505 enteric coating Methods 0.000 claims abstract description 21
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- 230000007227 biological adhesion Effects 0.000 claims abstract description 12
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- 238000002156 mixing Methods 0.000 claims description 18
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 18
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- 238000000034 method Methods 0.000 claims description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
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- 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 2
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- 235000019425 dextrin Nutrition 0.000 claims description 2
- 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 2
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
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- 239000008101 lactose Substances 0.000 claims description 2
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- 238000009395 breeding Methods 0.000 description 2
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- -1 Toltrazuril triazinone compounds Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 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
- 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/736—Glucomannans or galactomannans, e.g. locust bean gum, guar gum
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Biophysics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a veterinary enteric composition, which comprises a bioadhesive inner core and an enteric outer layer; the bioadhesive inner core comprises toltrazuril, a framework material and an adhesive material, and the enteric outer layer comprises an enteric coating material; the composition also comprises pharmaceutically acceptable auxiliary materials. The invention also provides a preparation method of the composition, and toltrazuril enteric-coated bioadhesive sustained-release tablets are prepared by combining the bioadhesive technology and the enteric-coated sustained-release technology. The veterinary enteric-coated composition provided by the invention can directly reach the focus, can stay in the bodies of livestock for a long time after being taken once, has dual performances of intestinal tract positioning and biological adhesion, provides an enteric-coated veterinary composition which is slow-released in the intestines, long in action time and high in stability, reduces the administration frequency and is convenient to administer.
Description
Technical Field
The invention relates to the field of veterinary medicines, and in particular relates to a veterinary enteric composition and a preparation method thereof.
Background
Coccidiosis is a common parasitic protozoa in intestinal tracts of livestock, mainly parasitizes in intestinal epithelial cells of chickens, pigeons, rabbits, pigs and dogs, and as the intestinal tracts are important digestion and absorption organs, parasites multiply to cause damage to intestinal tissues and thickening of intestinal walls of the livestock, and the specific disease symptoms are as follows: poor spirit, abdominal distension, diarrhea, hematochezia, cramps and even death. The coccidiosis seriously affects the digestion and absorption of the livestock on the feed, so that the feeding efficiency is reduced, the feed reward is reduced, and huge economic loss is caused to livestock breeding. The larger harm is that the infection rate of the coccidiosis in different kinds of livestock is as high as 60-100%, and the death rate is 50-80%. Especially in areas of poor environmental hygiene, the rate of coccidia proliferation is quite dramatic, resulting in higher rates of infection and mortality, and even population-wide coverage. Coccidiosis causes great harm to animal husbandry and becomes one of parasitic diseases which have the greatest harm to livestock breeding.
Toltrazuril triazinone compounds having a broad spectrum of anticoccidial activity. Can be widely used for treating coccidiosis. Toltrazuril has a wide range of action sites on coccidia and has effects on both asexual cycles of coccidia, such as inhibition of schizonts, nuclear division of gametophytes and wall formers of gametophytes. The product has coccidiostat effect because it interferes with coccidian nucleus division and mitochondria, affects the respiratory and metabolic functions of the body, and can enlarge endoplasmic reticulum of cells to cause severe vacuolation.
Toltrazuril is mainly taken orally, active ingredients of the existing common toltrazuril oral preparation cannot directly reach focuses, and the digestive tracts of livestock are short, so that the digestive absorption is insufficient, the bioavailability is greatly reduced, the cure rate is reduced, and the medication time is prolonged; on the other hand, toltrazuril has poor water solubility, is unstable and is easy to separate out when being dissolved in water, while powder is not easy to be uniformly dispersed in feed in the process of mixing the powder with the feed, and the intestinal tracts of livestock suffering from coccidiosis are damaged, so that the food intake is obviously reduced; inconvenience in many aspects and difficulty in administration. Therefore, a medicine which can directly reach the focus and stay in the bodies of the livestock and poultry for a long time after being taken once is needed to prevent and treat the coccidiosis of the livestock and poultry.
Bioadhesive Drug Delivery Systems (BDDS) utilize the adhesive properties of materials to the surface of biological mucous membranes to extend the residence time of the drug delivery system at a specific location in the biological membrane, thereby achieving the purpose of drug absorption at a specific location. The system can adhere to target site, prolong the retention time of medicine in the focus part, and improve the effect of treating local diseases. Less bioadhesive drug delivery systems have been studied in livestock. Due to the complexity of the intestinal tract, the role and effect of bioadhesive drug delivery systems vary widely. The digestive tract of the livestock is short, the biological adhesive sheet is required to be quickly adhered after entering the intestinal tract, the intestinal tract of the livestock suffering from coccidiosis is damaged, the intestinal tract is further damaged due to too strong adhesion of the biological adhesive sheet, on the other hand, the intestinal tract of the livestock suffering from coccidiosis produces more secreted mucus and even bleedings, the continuously secreted mucus in the environment is easy to shorten the adhesion time of the biological adhesive sheet, and more obstruction is brought to biological adhesion. At present, no research report of a biological adhesion drug delivery system with strong pertinence for treating livestock coccidiosis exists.
Disclosure of Invention
The invention aims at the problems and provides a veterinary enteric composition and a preparation method thereof.
The first object of the invention is to provide a veterinary enteric composition, which comprises a bioadhesive inner core and an enteric outer layer; the bioadhesive inner core comprises toltrazuril, a framework material and an adhesive material, and the enteric outer layer comprises an enteric coating material; the composition also comprises pharmaceutically acceptable auxiliary materials; the mass ratio of toltrazuril to the framework material to the adhesive material is (2.0-4.0): (3.0-6.5): (1.0-5.5), the dosage of the enteric coating material is 2-6% of the bioadhesive type inner core according to the weight percentage. Under the proportion, the adhesive property, the water absorption rate and the release degree of the toltrazuril, the framework material and the adhesive material are excellent.
Further, the framework material is a mixture of octadecanol and PEG6000, and the mass ratio of octadecanol to PEG6000 is (0.5-2): (2-5). The octadecanol and the PEG6000 are mixed, heated and melted according to the proportion, the fusion of the octadecanol and the PEG6000 with toltrazuril has good intersolubility, after entering the intestinal tracts of the livestock, the framework material can continuously and stably release the toltrazuril, and the effective blood concentration can be maintained within 48 hours.
Further, the adhesive material is one or a mixture of more of carbopol934, fenugreek gum and hydroxypropyl methyl cellulose. The invention applies the fenugreek gum to the biological adhesive material, and provides a new choice for the biological adhesive material. The fenugreek gum has the effects of relieving pain, sterilizing, clearing away toxic materials and expelling parasites, has stable gel strength in a slightly alkaline environment of an intestinal tract, is adhered to the intestinal tract to stably release toltrazuril, has an adhesion effect and also can expel parasites in cooperation with the toltrazuril, and on the other hand, after being degraded in vivo, the fenugreek gum can form a soluble complex with fibrin to clear harmful substances accumulated in the intestinal tract, help livestock to expel coccidian out of bodies while treating coccidiosis, and has strong pertinence in treating the coccidiosis of the livestock.
Furthermore, as the carbopol934 has polar groups such as hydroxyl, amino and the like, the adhesive can be quickly swelled when meeting water, and can interact with toltrazuril in the slightly alkaline environment of intestinal tracts to form an insoluble compound, so that the toltrazuril can be slowly released, and the adhesive is a better choice for adhesive materials. However, carbopol934 has strong adhesion, and even if the livestock suffering from coccidiosis has damage or bleeding in the intestinal tract, simply using carbopol934 as an adhesive material will further damage the surface of the intestinal mucosal wall due to too strong adhesion. In response to this problem, the present invention provides a preference for carbopol934 mixed with fenugreek gum, which, in addition to its adhesive strength-regulating effect, synergistically repels insects in conjunction with toltrazuril, and at the same time helps to clean up harmful substances accumulated in the intestine. The ratio of carbopol934 to fenugreek gum has a large effect on the adhesion and release of the adhesive sheet when carbopol 934: the mass ratio of the fenugreek gum is (4-6) to (2-3), the biological adhesion type inner core can rapidly expand in the intestinal tract to form a mesh gel structure along with the dissolution of the enteric coating outer layer, so that the water infiltration and the drug release are slowed down, the stable release of toltrazuril is kept, meanwhile, the biological adhesion type inner core still has enough adsorption capacity under the condition that more mucus is secreted in the intestinal tract of livestock suffering from coccidiosis, the biological adhesion type inner core is fully adhered to the intestinal mucosa wall to release the drug, and the intestinal mucosa wall is not damaged.
Further, the carbopol 934: the mass ratio of the fenugreek gum is 6: 2.5.
Further, the enteric coating material is acrylic resin solution or ethyl cellulose solution.
Furthermore, the auxiliary materials are one or a mixture of more of magnesium stearate, aerosil, talcum powder, lactose, microcrystalline cellulose and dextrin.
The second purpose of the invention is to provide a preparation method of the enteric composition for livestock, which comprises the following steps:
s1: weighing toltrazuril, a framework material, an adhesive material, an enteric coating material and auxiliary materials according to a proportion;
s2: mixing and heating framework material at 60-90 deg.C for melting, adding toltrazuril fine powder, stirring for 1h, mixing, cooling to completely solidify, vacuum drying to water content of 2-3%, grinding, and sieving with 80 mesh sieve to obtain dispersed powder;
s3: uniformly mixing the adhesive material and the auxiliary material, uniformly mixing the adhesive material and the auxiliary material with the dispersed powder obtained in S2 by an equivalent progressive method, sieving the mixture by a 40-mesh sieve, adding the auxiliary material, and directly tabletting the powder to prepare the biological adhesive inner core;
s4: preparing enteric coating material, spraying the enteric coating material on the surface of the bioadhesion type inner core obtained in S3, and drying to obtain the finished product.
Further, the tablet strength of S3 is 4 to 11 kN. The preferred tablet strength is 8 kN.
Further, the bioadhesive core described in S3 had a diameter of 7 mm.
The invention has the beneficial effects that:
(1) the biological adhesion technology and the enteric-coated sustained-release technology are combined, and the prepared toltrazuril enteric-coated biological adhesion sustained-release tablet has the dual performance of intestinal positioning and biological adhesion. The coccidiosis lesion parts of the livestock are mainly in intestinal tracts, and the proper enteric coating layer is selected to ensure that the adhesive inner core directly reaches the intestinal tracts, so that the effective components are not damaged in gastric acid and can safely reach and adhere to a focus area to play a role in treatment, thereby achieving the purposes of targeted drug delivery and long-acting release, having long action time and high stability, reducing the drug administration frequency and facilitating the drug administration.
(2) The types and the proportions of the skeleton material, the adhesive material and the slow-release material are improved by combining the characteristics of the gastrointestinal tract of the sick livestock, so that the toltrazuril bioadhesive slow-release tablet with excellent adhesive property, water absorption and release degree is obtained.
(3) The composite skeleton material is fused with toltrazuril, so that after entering the intestinal tracts of livestock, the skeleton material can continuously and stably release toltrazuril, and effective blood concentration can be maintained for a long time.
(4) The invention applies the fenugreek gum to the biological adhesive material, and provides a new choice for the biological adhesive material. The fenugreek gum has the effects of relieving pain, sterilizing, clearing away toxic materials and expelling parasites, has stable gel strength in a slightly alkaline environment of an intestinal tract, is adhered to the intestinal tract to stably release toltrazuril, has an adhesion effect and also can expel parasites together with the toltrazuril, and on the other hand, can form a soluble complex with fibrin after being degraded in vivo to clear harmful substances accumulated in the intestinal tract and help livestock to expel coccidian out of bodies while treating coccidiosis, is an adhesive material and a treatment medicament, so that the composition has strong pertinence to the treatment of the coccidiosis of the livestock.
(5) The composite adhesive material is preferably provided, can rapidly expand in the intestinal tract to form a reticular gel structure along with the dissolution of the enteric outer layer, so that the water infiltration and the drug release are slowed down, the stable release of toltrazuril is kept, and meanwhile, the composite adhesive material still has enough adsorption capacity for the condition that more mucus is secreted in the intestinal tract of livestock suffering from coccidiosis, fully adheres to the intestinal mucosa wall to release the drug, and does not damage the intestinal mucosa wall.
Detailed Description
Example 1
Weighing toltrazuril, a framework material and an adhesive material according to the mass ratio of 2:6: 5. The framework material is octadecanol and PEG6000 with the mass ratio of 1:3, the adhesion material is carbopol934 and fenugreek gum with the mass ratio of 5:2, and the enteric coating material is acrylic resin solution; mixing octadecanol and PEG6000, mixing at 85 deg.C, heating for melting, adding toltrazuril fine powder, stirring for 1 hr, mixing, cooling to completely solidify, vacuum drying to water content of 3%, grinding, and sieving with 80 mesh sieve to obtain dispersed powder; uniformly mixing carbopol934 and fenugreek gum powder, uniformly mixing with the dispersed powder by an equivalent progressive method, sieving with a 40-mesh sieve, adding 2% of microcrystalline cellulose and 1.5% of magnesium stearate, and tabletting at 8 kN, wherein the powder is directly tabletted to prepare a bioadhesive type inner core with the diameter of 7 mm; preparing an enteric coating material acrylic resin solution, spraying the enteric coating material on the surface of the bioadhesive type inner core, increasing the weight by 3 percent by the coating layer, and drying to obtain the veterinary enteric composition.
Example 2
Weighing toltrazuril, a framework material and an adhesive material according to the mass ratio of 3:5: 4. The framework material is octadecanol and PEG6000 with the mass ratio of 1.5:5, the adhesion material is fenugreek gum, and the enteric coating material is acrylic resin solution; mixing octadecanol and PEG6000, mixing at 90 deg.C, heating for melting, adding toltrazuril fine powder, stirring for 1 hr, mixing, cooling to completely solidify, vacuum drying to water content of 2%, grinding, and sieving with 80 mesh sieve to obtain dispersed powder; taking fenugreek gum powder, mixing with the dispersed powder by an equivalent progressive method, sieving with a 40-mesh sieve, adding 5% of microcrystalline cellulose and 0.5% of magnesium stearate, and tabletting with 11kN, wherein the powder is directly tabletted to form a biological adhesion type inner core with the diameter of 7 mm; preparing an enteric coating material acrylic resin solution, spraying the enteric coating material on the surface of the bioadhesive type inner core, increasing the weight by 2 percent by the coating layer, and drying to obtain the veterinary enteric composition.
EXAMPLE 3 in vitro bioadhesive Performance test of the veterinary enteric compositions prepared according to the examples of the invention
The test method comprises the following steps:
1. in vitro adhesion experiments:
one rabbit fasted for 24h was sacrificed by intravenous air injection to the ear, the small intestine was removed, washed with phosphate buffer solution of pH6.8 to remove the content, cut into small pieces, stored in a refrigerator at-20 deg.C, thawed in a refrigerator at 4 deg.C overnight before the experiment, and allowed to stand at room temperature before the experiment.
The experiments were divided into 7 groups: 1 control group (toltrazuril general formulation) and 6 experimental groups (composition 3 group prepared in example 1, composition 3 group prepared in example 2). And 7 intestinal mucosa sheets are respectively fixed on 7 sheets A provided with hooks. Taking 1 toltrazuril common preparation, 3 toltrazuril common preparation tablets, 3 tablets of composition prepared in example 1 and 3 tablets of composition prepared in example 2, adhering the cores, respectively fixing the cores on 7 sheets B provided with hooks, hanging the sheets B on a bracket, wetting the surfaces of the adhered cores with simulated intestinal juice for 5min, contacting small intestines on the sheets A, applying 100g of pressure, and maintaining the pressure for 2 min. On the sheet AThe hook is a plastic bag which naturally hangs down, water is added into the plastic bag at the speed of 5ml/min until the plastic bag is separated due to overlarge pulling force, and the weight of the sheet A, the plastic bag and the water in the plastic bag is weighed, namely the tissue adhesion force. The average adhesion force of the adhesion inner core provided by the embodiment 1 of the invention reaches 152.21g/cm2Example 2 provides an adherent core having an average adhesion of 114.50g/cm2While the common tablet adhesion is 14.74g/cm2。
2. In vitro adhesion time experiments:
the experiments were divided into 7 groups: 1 control group (toltrazuril general formulation) and 6 experimental groups (composition 3 group prepared in example 1, composition 3 group prepared in example 2). Taking 1 toltrazuril common preparation, 3 toltrazuril inner cores prepared in example 1 and 3 adhesive inner cores prepared in example 2, wetting the toltrazuril common preparation with simulated intestinal juice for 10min respectively, contacting with the mucosa of the small intestine, soaking the toltrazuril inner cores in the simulated intestinal juice without applying force, and observing the separation time of the adhesive inner cores from the intestinal membrane at room temperature, namely the adhesion time. The average adhesion time of the inner core provided in example 1 of the present invention reached 31h, the average adhesion time of the inner core provided in example 2 reached 26h, and the general tablet was immediately separated from the intestinal membrane and administered.
Example 4 results of experiments on administration of the veterinary enteric composition prepared according to the present invention
The experiments were divided into 5 groups: infected control group, negative control group, toltrazuril common preparation control group, composition experimental group in example 1 and composition experimental group in example 2, and the animals infected with coccidian are randomly grouped into 4 animals each. The weights before the experiment were recorded separately and rabbits were infected orally with the mixed coccidia oocysts with infectivity. After infection, the mental state, feed intake, water intake and feces of the rabbits of each group are observed every day, the animals of the infected control group and the negative control group are not administrated from 5 days of infection, the veterinary enteric-coated compositions prepared in the examples 1 and 2 are administrated 3 times on empty stomach (1 time respectively on 5 days, 7 days and 9 days of infection), the drug and the feed are uniformly mixed according to the ratio of 1:100 in the control group of toltrazuril common preparation for continuous administration for 6 days, the toltrazuril common preparation is administrated for the last day, weighing each group of rabbits 10 days after challenge, calculating weight gain rate and survival rate, performing autopsy on all the rabbits with challenge, taking out intestinal tracts, observing the change conditions of small intestines and cecum, scoring lesion, and recording a lesion value according to the scoring condition, respectively collecting the contents of the small intestine and the caecum, collecting oocysts in the small intestine and the caecum, and respectively recording the specific conditions of each group of experimental rabbits.
The effect of each experimental group on the treatment of coccidian infected rabbits is shown in table 1.
Anticoccidial index (ACI) = (relative weight gain + survival) × 100- (lesion value + oocyst value) was calculated.
The coccidiosis resistant index is more than 180 and is a high-efficiency coccidiosis resistant drug; those with anticoccidial index of 160-; those with anticoccidial index 120-; those with an anticoccidial index of < 120 are ineffective anticoccidial agents.
Table 1: treatment effect of each experimental group on coccidian infected rabbit
| Group of | Survival rate (%) | Relative weight gain (%) | Value of the disease | Oocyst value | ACI |
| Totrazuril general formulation | 98 | 97.13 | 7.5 | 0 | 187.53 |
| Example 1 composition | 100 | 99.27 | 6.0 | 0 | 193.27 |
| Example 2 composition | 99 | 98.85 | 6.5 | 0 | 191.35 |
| Infection control | 75 | 39.23 | 37.5 | 1 | 75.73 |
| Negative control | 100 | 100 | 0.0 | 0 | 200 |
The experimental results show that the veterinary enteric-coated compositions prepared by the methods in the examples 1 and 2 can keep high blood concentration in rabbits for a long time only by feeding the compositions 1 time every other day, the survival rate reaches 100%, the relative weight gain rate reaches 99.27%, and the ACI reaches 193.27, which are higher than those of a toltrazuril ordinary preparation control group continuously taking the compositions and feed every day after being uniformly mixed, after intestinal tract dissecting, the conditions of intestinal tract bleeding and intestinal wall thickening are obviously lighter than those of the toltrazuril ordinary preparation control group, so that the fenugreek gum can synergistically expel parasites with the toltrazuril except for the adhesion effect, the bioavailability is high, and the coccidiosis can be effectively prevented and treated for a long time after feeding the veterinary enteric-coated compositions once.
Claims (8)
1. An enteric composition for veterinary use, comprising a bioadhesive inner core and an outer enteric layer; the biological adhesion type inner core comprises the following components in percentage by mass (2.0-4.0): (3.0-6.5): (1.0-5.5) toltrazuril, a framework material, an adhesive material; the enteric outer layer comprises an enteric coating material, and the dosage of the enteric coating material is 2-6% of the bioadhesive inner core in percentage by weight; the composition also comprises pharmaceutically acceptable auxiliary materials;
the framework material comprises the following components in percentage by mass (0.5-2): (2-5) octadecanol and PEG 6000;
the adhesive material is one or a mixture of more of carbopol934, fenugreek gum and hydroxypropyl methyl cellulose.
2. The enteric veterinary composition of claim 1, wherein the adhesive material is carbopol934 and fenugreek gum at a mass ratio of (4-6) to (2-3).
3. The enteric veterinary composition according to claim 1, wherein the adhesive material is carbopol934 and fenugreek gum at a mass ratio of 6: 2.5.
4. The veterinary enteric composition according to claim 1, wherein the enteric coating material is an acrylic resin solution or an ethylcellulose solution.
5. The enteric composition for veterinary use according to claim 1, wherein the auxiliary material is one or more of magnesium stearate, aerosil, talcum powder, lactose, microcrystalline cellulose and dextrin.
6. A process for the preparation of a veterinary enteric composition according to any of claims 1 to 5, characterized in that it comprises the following steps:
s1: weighing toltrazuril, a framework material, an adhesive material, an enteric coating material and auxiliary materials according to a proportion;
s2: mixing and heating framework material at 60-90 deg.C for melting, adding toltrazuril fine powder, stirring for 1h, mixing, cooling to completely solidify, vacuum drying to water content of 2-3%, grinding, and sieving with 80 mesh sieve to obtain dispersed powder;
s3: uniformly mixing the adhesion material and the dispersed powder obtained in the step S2 by an equivalent progressive method, sieving by a 40-mesh sieve, adding auxiliary materials, uniformly mixing, and directly tabletting the powder to prepare the biological adhesion type inner core;
s4: preparing enteric coating material, spraying the enteric coating material on the surface of the bioadhesion type inner core obtained in S3, and drying to obtain the finished product.
7. The method according to claim 6, wherein the tablet strength of S3 is 4 to 11 kN.
8. The method of claim 6, wherein the bioadhesive core of S3 is 7mm in diameter.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6004585A (en) * | 1996-02-05 | 1999-12-21 | Bayer Aktiengesellschaft | Granular composition of a triazine compound |
| CN1331561A (en) * | 1998-10-08 | 2002-01-16 | 高新研究公司 | Novel compsns. and methods for prevention and treatment of protozoal disease |
| CN101491497A (en) * | 2008-12-26 | 2009-07-29 | 天津瑞普生物技术股份有限公司 | Toltrazuril suspension preparation capable of being effectively uniformly dispersed in water and preparation method thereof |
| BRPI0901058A2 (en) * | 2008-03-19 | 2009-11-03 | Adolfo Augusto Aubinel | oral bioadhesive formulation based on triazine-derived compounds and the procedure for obtaining it |
| CN103070844A (en) * | 2013-01-28 | 2013-05-01 | 万平 | Locating quick-release biological adhesive and application thereof |
| CN103083272A (en) * | 2013-01-22 | 2013-05-08 | 上海应用技术学院 | Levetiracetam bioadhesive sustained-release tablet and preparation method thereof |
-
2018
- 2018-03-12 CN CN201810201203.5A patent/CN108295038B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6004585A (en) * | 1996-02-05 | 1999-12-21 | Bayer Aktiengesellschaft | Granular composition of a triazine compound |
| CN1331561A (en) * | 1998-10-08 | 2002-01-16 | 高新研究公司 | Novel compsns. and methods for prevention and treatment of protozoal disease |
| BRPI0901058A2 (en) * | 2008-03-19 | 2009-11-03 | Adolfo Augusto Aubinel | oral bioadhesive formulation based on triazine-derived compounds and the procedure for obtaining it |
| CN101491497A (en) * | 2008-12-26 | 2009-07-29 | 天津瑞普生物技术股份有限公司 | Toltrazuril suspension preparation capable of being effectively uniformly dispersed in water and preparation method thereof |
| CN103083272A (en) * | 2013-01-22 | 2013-05-08 | 上海应用技术学院 | Levetiracetam bioadhesive sustained-release tablet and preparation method thereof |
| CN103070844A (en) * | 2013-01-28 | 2013-05-01 | 万平 | Locating quick-release biological adhesive and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 地克珠利肠溶微囊的制备及其特性的研究;符华林等;《中国兽医科学》;20111231;第41卷(第3期);308-313 * |
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Denomination of invention: A veterinary enteric composition and its preparation method Granted publication date: 20200828 Pledgee: Bank of Nanjing Co.,Ltd. Changzhou Branch Pledgor: JIANGSU LINGYUN PHARMACEUTICAL CO.,LTD. Registration number: Y2024980019202 |