CN118078761A - Laxaloxycine sodium micropill and preparation method thereof - Google Patents

Abstract

The solid lasalocid sodium micropill comprises the following components in parts by weight per 100 g: 1.0 to 25.0g of lasalox sodium, 0.1 to 1.0g of vitamin E oil, 4.0 to 10.0g of solid paraffin, 2.0 to 20.0g of ragweed fat, 5.0 to 15.0g of triglycerin monostearate, 10.0 to 20.0g of poloxamer 237 and the balance of polyethylene glycol 12000. The lasalocid sodium micropill is spherical solid, has the particle size of 600-1000 mu m, is not broken or dissolved in rumen fluid for 8 hours continuously, can maintain the inherent shape, can pass through the rumen after being orally taken, does not influence the flora in the rumen, and has high safety and good stability. The invention further discloses a preparation method, the process operability is strong, the conversion can be realized in a common GMP production workshop, and the market prospect is wider.

Description

Laxaloxycine sodium micropill and preparation method thereof

Technical Field

The invention belongs to the technical field of medicine preparation, and in particular relates to lasalocid sodium micropills and a preparation method thereof.

Background

Lasalox sodium (Lasalocid Sodium) is a chemical drug with strong inhibition and killing effects on livestock coccidium, and is clinically used for procedural prevention of the sensitive period of coccidium outbreak. Meanwhile, the lasalongz sodium is used as a growth promoter, has a certain growth promoting effect on beef cattle fattening, can obviously improve the feed conversion rate, promote the in-vivo conversion and deposition of nutrients, reduce the feed conversion ratio and help cattle to go out of the fence in advance. However, when the compound is used as a growth promoter, due to the antimicrobial effect of the compound, the compound can have certain influence on flora and ciliate in gastric juice after entering rumen, so that local microecological environment is unbalanced, cows can easily suffer from diarrhea, reduced feed intake, dyspepsia, ruminant disorder and other symptoms, and especially the side effect is most obvious in the first few days of use, so that the popularization of the lasalongxisodium in ruminant culture is hindered.

The lasalongz sodium prepared by the prior art has the dosage forms of premix, microemulsion and the like. The premix is mixed with materials, and if the main components are not coated, the medicine can still be quickly released into rumen fluid after entering the rumen orally, so that the digestive function is affected. The microemulsion is obtained by dissolving the medicine in an oil phase, and then emulsifying and coating the oil phase by a surfactant (cosurfactant), wherein the coating process is involved in the process, but the coating material is easy to damage after entering rumen fluid, so that the medicine is released due to the conditions of layering, demulsification and the like, and finally the side effect cannot be avoided. In addition, the drug loading rate of the dosage form prepared by the microemulsion technology is low and is generally not higher than 6.0%, so that the final product has lower cost performance, and the emulsion is a liquid preparation, and has certain requirements on transportation and storage environments in the later period, so that the popularization of the drug is not facilitated, and the application of the drug in the market is limited.

Disclosure of Invention

Aiming at the defects and shortcomings of the prior preparation technology, the lasalongxi sodium pellet is prepared by the technical improvement, the main component of the lasalongxi sodium pellet is lasalongxi sodium, the rumen bypass characteristic is achieved, the rumen flora is not damaged by oral administration, compared with the prior art, the side effect is obviously reduced, the drug safety is improved, the substantial progress is achieved, meanwhile, the pellet has good palatability after mixing materials, no influence on ingestion is achieved, and the rapid market popularization is facilitated. In addition, the process has strong operability, can realize production conversion in common GMP production workshops, and has a large market application space.

Specifically, the invention adopts the following technical scheme: the lasalongz sodium micropill comprises the following components in parts by weight per 100g of micropill: 1.0 to 25.0g of lasalox sodium, 0.1 to 1.0g of vitamin E oil, 4.0 to 10.0g of solid paraffin, 2.0 to 20.0g of ragweed fat, 5.0 to 15.0g of triglycerin monostearate, 10.0 to 20.0g of poloxamer 237 and the balance of polyethylene glycol 12000.

The invention preferably comprises the following components by weight per 100g of the pellets: 6.0 to 20.0g of lasalocid sodium, 0.2 to 0.8g of vitamin E oil, 5.0 to 9.0g of solid paraffin, 3.0 to 19.0g of ragweed fat, 8.0 to 12.0g of triglycerin monostearate, 12.0 to 18.0g of poloxamer 237 and the balance of polyethylene glycol 12000.

As a further preferred aspect of the invention, the composition by weight per 100g of the pellets is: 13.0g of lasalox sodium, 0.5g of vitamin E oil, 7.0g of solid paraffin, 11.0g of ragweed fat, 10.0g of triglycerol monostearate, 15.0g of poloxamer 237 and 12000.5 g of polyethylene glycol.

The invention discloses a preparation method of lasalongz sodium pellets, which comprises the following steps:

(a) Under normal temperature and normal pressure, mixing the solid paraffin and the ragfat, heating to 70-78 ℃, completely converting the system from solid to liquid at the moment, and sequentially adding vitamin E oil and sodium lasalongxite for dissolution to obtain a system 1;

(b) Mixing triglycerin monostearate, poloxamer 237 and polyethylene glycol 12000, heating to 70-78 ℃, and adding into the system 1 after completely converting into liquid, and mixing to obtain a system 2;

(c) Adding ethanol aqueous solution into the system 2, stirring and mixing, maintaining the system temperature at 70-78 ℃, performing spray freeze drying after the whole mixed system is converted into milky liquid, and performing vacuum drying on the obtained freeze-dried product to constant weight.

As a further preferred aspect of the present invention, in step (c), absolute ethanol in aqueous ethanol solution by weight: water=1:9, and the amount of aqueous ethanol solution is 3 to 5 times by weight of the system 2.

As a further preferred aspect of the present invention, in step (c), 40KHz ultrasonic treatment is performed while stirring and mixing.

The lasaloside sodium pellets prepared by the invention are orally taken in a stirring mode, are mainly used for beef cattle cultivation production, can last for 8 hours in rumen fluid without rupture and dissolution, do not harm rumen flora, have good rumen bypass effect, can avoid the consumption of medicine by rumen microorganisms, and have no palatability problem at the same time, and do not influence food intake. Compared with the prior art, the beef cattle can obviously improve the feed conversion rate during the use period, and the fattening period of the pellets is shorter and the growth promoting effect is better under the same administration dosage and administration method.

The formula of the invention comprises main components and auxiliary materials, wherein lasalongxi sodium is the main components, the balance is the auxiliary materials, and the other auxiliary materials have the following effects compared with the main components:

1) The vitamin E oil is selected as the component of the invention, mainly has good antioxidation effect, can prevent oxidation degradation of lasalongy sodium, ragfat and the like, and is beneficial to keeping the medicine stable. Meanwhile, vitamin E belongs to one of fat-soluble vitamins, and daily use is also beneficial to preventing the organism from lacking vitamin E, and free radicals generated in the tissue metabolic process can be removed, so that the disease incidence rate is reduced.

2) The solid paraffin and the rag fat are selected as the components of the invention, the solid paraffin and the rag fat are used as the solvent of the lasalocid sodium, the solvent of the lasalocid sodium and the solvent are converted into liquid state under the heating state, the medicine is quickly dissolved, the solid shape is recovered after cooling, and the inertness of the solid paraffin and the rag fat is proved to be very strong by experiments, and the solid paraffin and the rag fat do not chemically react with other components, thus the solvent is excellent;

3) The triglycerin monostearate is selected as the component of the invention, and mainly has good fusion effect on the mixture of the solid paraffin and the ragfat, can be better emulsified and molded in a heating state, can keep inert with the main component, does not generate chemical reaction, and finally forms the pellets with regular shape and stability;

4) Poloxamer 237 is selected as the component of the invention, because the compound of the poloxamer 237 and the triglycerin monostearate can better emulsify a system consisting of solid paraffin and ragfat into balls, and can also maintain the shape to be stable. Poloxamers commonly used in pharmaceutics have the types of 124, 188, 237, 338, 407 and the like, but not all the types can meet the requirements of the invention, the poloxamer 124 has a low melting point and can not be formed into pills, and the prepared product is easy to deform; poloxamer 188 has a low viscosity number, which is not beneficial to forming spherical pellets; poloxamers 338 and 407 had too high a viscosity number and could be pelleted, but the drug was prone to breakage during low temperature storage (figure 2). Through experimental screening (comparative example 1), poloxamer 237 was finally selected as the adjuvant component of the present invention.

5) Polyethylene glycol 12000 is selected as the component of the invention, and can be used as a framework auxiliary material of the pellets, so that the lasalocid sodium product can keep good stability, and has good resistance to rumen fluid, and the medicine does not break and dissolve after entering the rumen. Polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000 and polyethylene glycol 12000, which are commonly used, were screened (comparative example 2) by experiments, and polyethylene glycol 12000 was found to be the optimal adjuvant choice.

Poloxamer 237 is an essential component of the present invention and is not replaced by other poloxamer types. Taking the sample prepared in example 1 as an example, after poloxamer 237 is replaced by poloxamers 124, 188, 338 and 407, the sample is either pasty, the properties of the sample are changed after being placed, or the sample is difficult to prepare into a sphere, or the viscosity is increased, the dispersibility is poor, the sample is difficult to disperse uniformly during mixing, or unstable phenomena such as fragmentation occur in a low-temperature environment. After poloxamer 237 is removed, regular spherical pellets (irregular particles or ellipsoids) cannot be obtained, and the obtained samples have poor dispersibility and serious adhesion and cannot meet clinical use requirements.

Compared with the prior art, the invention achieves the following technical effects by improving the formula and the process:

(1) The lasaloside sodium micropill can be kept in rumen for 8 hours without rupture and dissolution after being orally taken, the medicine can not damage rumen flora, the lasaloside sodium micropill has good rumen bypass performance, and the symptoms such as diarrhea, food intake reduction, dyspepsia, ruminant disorder and the like of cattle can not occur during the use period;

(2) The feed additive is used according to the specified dosage, so that animal feeding is not affected, the palatability is good, and the safety is high;

(3) Compared with the medicines of common preparations sold in the market, the preparation has higher relative bioavailability, the same dosage has more remarkable growth promoting effect on animals, and the feed conversion rate is higher;

(4) The product of the invention has stable property, the medicine particles are in a sphere shape, the medicine particles are easier to mix uniformly, the specific surface area is large, the preparation process has no special requirements, and the invention is beneficial to the efficient conversion of technology and the popularization of products.

Drawings

FIG. 1 is a micrograph of lasalongz sodium micropills prepared in example 1 of the present invention;

FIG. 2 is a micrograph of a sample obtained after substitution of poloxamer 237 with poloxamer 338 showing fragmentation in a low temperature environment according to the method of preparation of example 1;

fig. 3 is a micrograph of a sample obtained after complete removal of poloxamer 237 according to the preparation method of example 1.

Detailed Description

The invention will be further illustrated by the following specific examples, which are not intended to limit the scope of the invention in any way.

Examples 1 to 10

For simplicity of description, the weight composition of the lasalongz sodium micropills of the present invention described in examples 1-10 is shown in table 1.

Table 1 weight composition of pellets of the invention per 100g in examples 1-10

The preparation method of the lasalopecuroide sodium pellets in the embodiment 1 comprises the following steps:

(a) Under the normal temperature and pressure environment, 7.0g of solid paraffin and 11.0g of rag fat are uniformly mixed and then heated to 72 ℃, at this time, the system is completely converted into liquid from solid, 0.5g of vitamin E oil and 13.0g of lasalongxi sodium are respectively added, and the system 1 is obtained by stirring and dissolving;

(b) 10.0g of triglycerin monostearate, 15.0g of poloxamer 237 and 43.5g of polyethylene glycol 12000 are mixed, heated to 72 ℃ to convert the system into liquid, and then added into the system 1 to be uniformly stirred to obtain a system 2;

(c) Adding 400g of 10% ethanol solution (containing 40g of absolute ethanol and 360g of water) into a system 2, stirring and mixing, performing ultrasonic treatment (frequency: 40 KHz) while stirring, maintaining the system temperature at 72 ℃, performing spray freeze drying treatment after the whole mixed system is converted into uniform milky liquid, and finally placing the obtained freeze-dried product into a vacuum drying oven for further dehydration and drying, and packaging after the weight is kept constant.

The preparation method of the lasalox sodium micropills in examples 2-10 is the same as that in example 1, except that the weight compositions are different, and the weights of the compositions are shown in table 1.

In other embodiments, the heating temperatures involved in steps (a), (b) and (c) are between 70 and 78 ℃, and the 10% ethanol solution used in step (c) is 3 to 5 times the weight of the system 2, so that the preparation effect of the invention can be achieved.

Performance characterization and testing:

Comparative example 1: poloxamer 237 was replaced with poloxamers 124, 188, 338 and 407 and the effect on the invention after removal alone

Samples of lasalongxi sodium pellets, designated as sample a, sample B, sample C and sample D, were prepared by substituting poloxamer 237 with poloxamers 124, 188, 338 and 407 according to the formulation and preparation method of example 1. Meanwhile, poloxamer 237 is removed to prepare a Laxaloxy sodium pellet sample, which is denoted as sample E. The final samples A to D and pellet products obtained in example 1 were subjected to stability studies at 40℃at 25℃at 4℃and at-20℃at a relative humidity of 60.+ -. 5%, respectively, for a period of one week, and the results are shown in Table 2 below.

Table 2 examination of samples of sodium Laxaloxite pellets prepared from different poloxamers

Comparison from table 2 shows that: the present invention replaces poloxamer 237 with poloxamers 124, 188, 338 and 407. In the same preparation method, the sample obtained by using poloxamer 124 is in the shape of ointment or block, and has poor dispersibility and serious adhesion. Samples obtained with poloxamer 188 were ellipsoidal and showed sticking at high temperature and room temperature. Samples obtained with poloxamer 338 and poloxamer 407 were normal in shape, good in dispersibility, and free of sticking, but cracked in low temperature environment, as shown in fig. 2.

The samples were irregularly granular or oval after the poloxamer 237 was completely removed, and had poor dispersibility and severe adhesion, as shown in fig. 3.

The above results indicate that: poloxamer 237 used in the present invention is an essential component of the present invention and is not replaced by another type of poloxamer.

Comparative example 2: rumen bypass in vitro verification and influence of different polyethylene glycol types on the invention

To verify the rumen bypass effect of the present invention, the present inventors took rumen contents at slaughterhouse site, and then forcefully squeeze the rumen contents after wrapping the rumen contents with gauze, thereby obtaining natural rumen fluid. Meanwhile, comparative samples were prepared on the basis of example 1, except that polyethylene glycol 12000 was replaced with polyethylene glycol 4000, polyethylene glycol 6000 and polyethylene glycol 8000, which were designated as sample 1, sample 2 and sample 3, respectively, and were immersed in natural rumen fluid together with the samples prepared in example 1, and observed at 0.5h, 1.0h, 2.0h, 4.0h and 8.0h, respectively, after immersion, and detailed records were made, and the results are shown in table 3.

Table 3 sample tumor gastric fluid soaking test prepared with different polyethylene glycols

	Sample 1	Sample 2	Sample 3	Example 1
					0.5h	√	√	√	√
1.0h	×	×	√	√
					2.0h	××	×	√	√
4.0h	××	××	×	√
					8.0h	×××	××	×	√

( And (3) injection: "v" indicates no change in pellet shape, no chipping or dissolution; "×" indicates that the pellet has cracks on its surface, but the whole is still spherical and the drug is slightly dissolved; "×" represents that the pellets are broken, severely deformed, changed in appearance, and the drug dissolved; "×" represents complete disintegration of the pellets into powder and substantial dissolution. )

As can be seen from Table 3, the lasaloside sodium micropills prepared from polyethylene glycol 4000, polyethylene glycol 6000 and polyethylene glycol 8000 were disintegrated and dissolved within 8 hours, and had poor stability in rumen fluid, and could not exhibit rumen bypass effect, and the sample of example 1 prepared from polyethylene glycol 12000 was kept relatively stable.

The results show that: polyethylene glycol 12000 is the best choice for the lasalocid sodium micropellets of the present invention.

Test examples 1 to 3:

test example 1

Property stability test of the inventive product

Examples 1-10 of the present invention were sampled and tested for accelerated stability (40 ℃), long-term stability (25 ℃), refrigerated stability (4 ℃) and freeze stability (-20 ℃) at different ambient temperatures, respectively, according to the requirements of the veterinary pharmacopoeia.

Accelerated stability test: and placing the prepared lasalox sodium micropill sample in an accelerating box, adjusting the temperature of the accelerating box to 40 ℃, controlling the relative humidity to be 70%, and accelerating degradation and deterioration under a high-temperature and high-humidity environment. A stable condition is considered if the pharmaceutical properties have not changed during the period of investigation and the sodium content of lasalosidate is still within a acceptable range (between 90 and 110% of the indicated amount). The test has the accelerated investigation period of 6 months, and the accelerated investigation period is respectively sampled and inspected at 15d, 1 month, 2 months, 3 months and 6 months, so that the properties of the medicine are not changed, the appearance is still in the shape of a sphere pill, the surface is smooth and has no cracks, the particles of the pellet have no adhesion, and the content is also in the specified value range, thereby proving that the medicine has good stability.

The samples were then placed in 25 ℃,4 ℃ and-20 ℃ environments, and were sampled and inspected at 15d, 1 month, 3 months, 6 months, 12 months and 24 months, respectively. The results prove that all samples have no change in appearance, no phenomena such as inferior pills, deformation and adhesion, and the like, are qualified in content and good in stability.

The results show that: the lasaloside sodium micropill samples in examples 1 to 10 of the invention have no unstable conditions such as fragmentation, deformation, adhesion and the like after the inspection is finished, the content is always qualified, and the stability is good.

Test example 2 safety and palatability test evaluation

In order to rapidly popularize and apply the product in a farm, the inventor uses Simendal beef cattle 50 with the weight of 250-270 kg as a test object to carry out safety application evaluation. Cattle are randomly divided into 5 groups, 10 cattle are respectively divided into male and female halves, wherein groups 1, 2 and 3 are respectively high-dose, medium-dose and low-dose groups of the lasalongz sodium micropills, samples prepared in the example 1 are taken and evenly mixed into feed according to doses of 1538 g/ton, 769 g/ton and 385g/kg for feeding of the cattle; group 4 is a drug control group, and the raw material of the lasalongxi sodium is uniformly mixed into the feed according to the dosage of 100 g/ton (calculated by the lasalongxi sodium) for cattle to feed; group 5 was a blank control group and was fed normally without any drug. All cattle were kept in the same environment and managed by the same breeder, and the whole test period was 1 week, during which feeding and drinking conditions of each group of cattle were recorded, and observation records of clinical behaviors were made, with the results shown in the following table.

Table 4 safety and palatability tests of lasalongxisodium micropills

Analysis of results:

1) The high-dose, medium-dose and low-dose application of the lasalongxi sodium micropill disclosed by the invention has no influence on feeding and drinking of cattle, has normal clinical behavior, has no symptoms such as diarrhea, overfeeding, food retention and ruminant disorder, and has no obvious difference compared with a blank control, and the palatability and the safety are qualified.

2) The cattle in the drug control group have reduced feeding rate during the test period, diarrhea and yellow feces, contain undigested corn and soybean meal particles, and have food retention in the later period of the test, and the ruminant is obstructed, so that the lasalongxi sodium can actually produce certain toxic and side effects on the digestive system of the cattle in the early period of use, and has potential safety hazards.

The results show that: the lasalocid sodium micropill has good safety and palatability.

Test example 3 clinical efficacy comparative test

The lasalongxi sodium micropill has rumen bypass characteristic, can avoid interaction between medicine and rumen flora, and has obvious growth promoting effect. To verify the clinical effect of the invention, the applicant selected 60 beef cattle weighing about 400kg for the test, randomly divided the beef cattle into 3 groups, and each group of 20 beef cattle were fed under the same environment and fed and managed by the same manager. The group 1 is a lasalox sodium micropill group (example 1) according to the invention, the lasalox sodium micropill group is evenly mixed into feed according to 769 g/ton of feed, the group 2 is a commercially available 20% premix group, the lasalox sodium micropill group is continuously fed into the feed according to 500 g/ton of feed every day, the group 3 is a blank control group, the lasalox sodium micropill group is normally fed, and no growth-promoting medicine is added into the feed. The test period was 3 months, during which time weighing was performed periodically and recorded, and finally data comparison was performed, and the results are shown in table 5.

Table 5 comparative test of growth promoting effect of laxalomic sodium micropellet beef cattle of the invention

Analysis of results:

1) The final average weight of the cattle in the test group 1 and the cattle in the test group 2 is 20.7kg and 13.1kg higher than that of the cattle in the control group 3, and the average feed conversion ratio is 1.21 and 0.69, which shows that the lasalongxi sodium has good growth promoting effect on the beef cattle, can improve the feed conversion rate and help reduce the feed conversion ratio;

2) The final average weight of the cattle in the test group 1 is 7.6kg higher than that of the cattle in the test group 2, and the average feed conversion rate is 0.52 lower, so that the growth promoting effect of the lasalocid sodium micropill is better than that of a common preparation prepared in the prior art on the premise of the same dosage, and the feed conversion rate is higher.

The results show that: the clinical growth promoting effect of the lasalocid sodium micropill is superior to that of the prior art.

Claims (7)

1. Lasalongz sodium micropills, characterized in that the weight composition per 100g of micropills is: 1.0 to 25.0g of lasalox sodium, 0.1 to 1.0g of vitamin E oil, 4.0 to 10.0g of solid paraffin, 2.0 to 20.0g of ragweed fat, 5.0 to 15.0g of triglycerin monostearate, 10.0 to 20.0g of poloxamer 237 and the balance of polyethylene glycol 12000.

2. A lasalox sodium pellet as claimed in claim 1, wherein the weight composition per 100g of said pellet is: 6.0 to 20.0g of lasalocid sodium, 0.2 to 0.8g of vitamin E oil, 5.0 to 9.0g of solid paraffin, 3.0 to 19.0g of ragweed fat, 8.0 to 12.0g of triglycerin monostearate, 12.0 to 18.0g of poloxamer 237 and the balance of polyethylene glycol 12000.

3. A lasalox sodium pellet as claimed in claim 2, wherein the weight composition per 100g of said pellet is: 13.0g of lasalox sodium, 0.5g of vitamin E oil, 7.0g of solid paraffin, 11.0g of ragweed fat, 10.0g of triglycerol monostearate, 15.0g of poloxamer 237 and 12000.5 g of polyethylene glycol.

4. A lasalopecuroide sodium micropellet as claimed in claim 1 or 2 or 3, wherein the micropellet has a particle size distribution of between 600 and 1000 μm.

5. A process for the preparation of lasalopecuroide sodium micropellets as claimed in claim 1 or 2 or 3, characterised in that it comprises the steps of:

Under normal temperature and normal pressure, mixing the solid paraffin and the ragfat, heating to 70-78 ℃, completely converting the system from solid to liquid at the moment, and sequentially adding vitamin E oil and sodium lasalongxite for dissolution to obtain a system 1;

Mixing triglycerin monostearate, poloxamer 237 and polyethylene glycol 12000, heating to 70-78 ℃, and adding into the system 1 after completely converting into liquid, and mixing to obtain a system 2;

Adding ethanol aqueous solution into the system 2, stirring and mixing, maintaining the system temperature at 70-78 ℃, performing spray freeze drying after the whole mixed system is converted into milky liquid, and performing vacuum drying on the obtained freeze-dried product to constant weight.

6. The process for preparing lasalocid sodium micropellets of claim 5, wherein in step (c), absolute ethanol is present in aqueous ethanol solution by weight: water=1:9, and the amount of aqueous ethanol solution is 3 to 5 times by weight of the system 2.

7. The process for preparing lasalocid sodium micropill according to claim 5, wherein in step (c), 40KHz ultrasonic treatment is performed while stirring and mixing.