CN113230233A - Florfenicol solid dispersion inclusion microcapsule and preparation method and application thereof - Google Patents
Florfenicol solid dispersion inclusion microcapsule and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a florfenicol solid dispersion inclusion microcapsule and a preparation method thereof, wherein the main raw materials comprise florfenicol, cyclodextrin, hydroxypropyl-beta-cyclodextrin, polyethylene glycol 6000, copovidone, poloxamer, sodium dodecyl sulfate and the like. Aiming at the difficult-soluble florfenicol, the invention combines the cyclodextrin inclusion technology with the solid dispersion microcapsule technology, the florfenicol solid dispersion inclusion microcapsule is prepared by a cold spraying mode, the water solubility of the obtained inclusion microcapsule is as high as 10000ppM, and the solubility, the dissolution and the bioavailability of the florfenicol are greatly improved. By comparing the product of the invention with a commonly-used imported product of 'nifirole' in the market, research shows that the oral bioavailability of the florfenicol solid dispersion inclusion microcapsule and the 'nifurole' in target animal pigs is consistent, and the long-acting property of in vivo release is shown. The preparation method is simple and convenient to operate, low in cost, safe, environment-friendly, good in stability and suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of veterinary preparations, and particularly relates to a florfenicol solid dispersion inclusion microcapsule, and a preparation method and application thereof.
Background
Florfenicol is an antibacterial drug special for animals, is used for treating bacterial diseases of pigs, chickens and fishes caused by sensitive bacteria, has obvious curative effects on respiratory system infection and intestinal tract infection, and comprises various gram-positive bacteria, gram-negative bacteria, mycoplasma and the like. The sensitive bacteria comprise haemophilus bovis and pigs, shigella dysenteriae salmonella, escherichia coli, pneumococcus, influenza bacillus, streptococcus, staphylococcus aureus, chlamydia, rickettsia and the like, and have extremely wide application prospect in animal health care. With the popularization of large-scale animal breeding, aiming at the demand of centralized feeding of florfenicol, the solid mixing materials in clinic are found to have a plurality of influence factors such as poor mixing uniformity, inconvenient feeding, high drug stability and the like, drinking water is needed for administration in the first production line for reducing the adverse factors, but the florfenicol has low solubility in water and slow dissolution speed, so that the drinking water administration application is limited. There is an urgent need to develop high water-soluble florfenicol formulations suitable for first-line clinical use.
The literature examination shows that in order to ensure that florfenicol meets the better dissolution requirement at present, some cases are that raw materials or preparations are directly subjected to superfine grinding and then added with a cosolvent to improve the solubility of the florfenicol, and the effect is very little; in other cases, the florfenicol and the solvent are stirred at a high temperature of 80-90 ℃ for heat preservation, dissolved for 6-8 hours and then spray-dried to prepare the drug inclusion compound, although the solubility is greatly improved, the high solvent dosage, the high temperature and the long-time stirring are needed, and the disadvantages of the spray-drying manufacturing process are high cost, large energy consumption and poor drug stability.
Therefore, the preparation of new florfenicol preparation with high water solubility, high stability, low cost and easy industrial production is imminent.
Disclosure of Invention
In view of the above, the invention aims to prepare the florfenicol solid dispersion inclusion microcapsule by combining two technologies of solid dispersion and cyclodextrin inclusion according to the characteristics of the florfenicol, adopting a nuisanceless and liquid-state solvent-free technology and using a convenient cold spraying technology in the preparation process. The preparation process has the advantages of low energy consumption, low cost, large production batch, no environmental pollution and the like, and the florfenicol solubility of the finished product in water can reach 10000ppM, and the stability is good.
In order to achieve the purpose, the invention adopts the following technical scheme:
the florfenicol solid dispersion inclusion microcapsule comprises the following components in parts by weight: 10-30 parts of florfenicol, 40-70 parts of solid dispersing agent, 5-30 parts of inclusion agent and 1-5 parts of wetting agent.
It is worth mentioning that the solid dispersion technology is a new technology for highly dispersing the poorly soluble drug in another solid carrier in a molecular, colloidal, microcrystalline or amorphous state, and the commonly used carriers for solubilization are polyethylene glycol 6000, polyethylene glycol 8000, poloxamer 188, copovidone, etc. The main technical characteristics are that the dissolution rate and the solubility of the indissolvable drug are improved so as to improve the absorption and the bioavailability of the drug.
The inclusion technology is that one molecule is embedded in a cavity structure of another molecule, and after a medicine is included as a guest molecule, multiple purposes can be achieved. And the common main molecules of the inclusion compound are cyclodextrin, hydroxypropyl-beta-cyclodextrin and the like, and the main technical characteristics are that the stability of the medicine is improved, the solubility of the medicine is increased, the irritation and the adverse reaction of the medicine are reduced, the dissolution rate of the medicine is adjusted, the bioavailability is improved and the like.
Further, the solid dispersant is at least one of polyethylene glycol 6000, polyethylene glycol 8000, poloxamer 188 and copovidone; preferably, the solid dispersing agent is a mixture formed by mixing polyethylene glycol 6000 and poloxamer according to a mass ratio of 2: 1.
The inclusion agent is one or a mixture of two of beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin; preferably, the inclusion agent is hydroxypropyl-beta-cyclodextrin.
The wetting agent is at least one of hydroxypropyl methyl cellulose, polyoxyethylene hydrogenated castor oil, sodium dodecyl sulfate and propylene glycol; preferably, the wetting agent is sodium lauryl sulfate.
The second purpose of the invention is to provide a preparation method of the florfenicol solid dispersion inclusion microcapsule.
In order to achieve the above purpose, the invention provides the following technical scheme:
a preparation method of florfenicol solid dispersion inclusion microcapsules comprises the following steps:
(1) weighing the solid dispersing agent according to the mass part, heating to 60-90 ℃, dissolving and clarifying to obtain a solution 1 for later use;
(2) weighing the inclusion agent according to the mass part, then adding the inclusion agent into the solution 1, and uniformly stirring and dissolving to obtain a solution 2 for later use;
(3) weighing florfenicol according to the weight parts, adding the florfenicol into the solution 2, and stirring and dissolving the florfenicol uniformly to obtain a solution 3 for later use;
(4) weighing the wetting agent according to the parts by weight, adding the wetting agent into the solution 3, and uniformly stirring and dissolving to obtain a solution 4 for later use;
(5) and stirring the solution 4 at the constant temperature for 30-120 minutes, and then carrying out cold spraying by a high-speed atomizer to prepare the florfenicol solid dispersion inclusion microcapsule.
It is worth to be noted that the florfenicol solid dispersion inclusion microcapsule prepared by the invention has the florfenicol solubility reaching 10000ppM in water and good stability. The preparation process has the advantages of low energy consumption, low cost, large production batch, no environmental pollution and the like, and is suitable for popularization and application in the market.
The third purpose of the invention is to provide the application of the florfenicol solid dispersion inclusion microcapsule.
In order to achieve the above purpose, the invention provides the following technical scheme:
the florfenicol solid dispersion inclusion microcapsule is applied to veterinary preparations.
Compared with the prior art, the invention discloses and provides a florfenicol solid dispersion inclusion microcapsule and a preparation method and application thereof, and has the advantages that:
(1) the invention discloses a preparation method of florfenicol solid dispersion inclusion microcapsules, which combines a solid dispersion technology and an inclusion technology, adopts a solid dispersion inclusion preparation process without using a liquid solvent, has short heat preservation time, does not need heat energy during spraying, is prepared only by a cold spraying mode, has simple and convenient operation, low cost and no solvent recovery and environmental pollution problems compared with similar preparations, and is suitable for large-scale industrial production.
(2) The florfenicol solid dispersion inclusion microcapsule provided by the invention has water solubility as high as 10000ppm, dissolution rate in water for 15 minutes as high as more than 90%, and a sample after dissolution is clear and transparent, can simultaneously meet various requirements of clinical material mixing, drinking water and concentrated preparation application, and is convenient for clinical application and popularization.
(3) The florfenicol solid dispersion inclusion microcapsule provided by the invention uses the solid dispersing agent, the inclusion agent, the wetting agent and the like which are green and safe, does not contain ingredients which influence food safety, such as hormone, antibiotic and the like, and is suitable for popularization and application and industrialization of large-scale pig farms.
(4) The florfenicol solid dispersion inclusion microcapsule disclosed by the invention is compared with a sample of a certain well-known enterprise in the market in solubility and dissolution by the same method, and the solubility and the dissolution of the sample are obviously superior to those of the similar products in the market.
(5) Compared with the imported product 'neoflurane', the florfenicol solid dispersion inclusion microcapsule provided by the invention has similar bioavailability, and has the characteristics of long-acting property and stable in-vivo release.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts
Figure 1 is a graph comparing the dissolution curve of florfenicol in water as a solid dispersion inclusion microcapsule.
Fig. 2 is a blood concentration-time curve of the florfenicol solid dispersion inclusion microcapsule and the neoflurron which are orally taken by pigs.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The present invention will be further specifically illustrated by the following examples for better understanding, but the present invention is not to be construed as being limited thereto, and certain insubstantial modifications and adaptations of the invention by those skilled in the art based on the foregoing disclosure are intended to be included within the scope of the invention.
Example 1
A florfenicol solid dispersion inclusion microcapsule comprises the following components in percentage by mass: 20 parts of florfenicol, 600046 parts of polyethylene glycol, 23 parts of poloxamer, 10 parts of hydroxypropyl-beta-cyclodextrin and 1 part of sodium dodecyl sulfate.
The preparation method of the florfenicol solid dispersion inclusion microcapsule comprises the following steps:
(1) weighing 23 kg of poloxamer and 600046 kg of polyethylene glycol, heating to 75 +/-5 ℃, and dissolving to obtain a clear solution 1;
(2) weighing 10 kg of hydroxypropyl-beta-cyclodextrin, adding into the solution 1, stirring, heating and dissolving to obtain a solution 2;
(3) weighing 20 kg of florfenicol, adding into the solution 2, stirring, heating and dissolving to obtain a solution 3;
(4) weighing 1 kg of sodium dodecyl sulfate, adding the sodium dodecyl sulfate into the solution 3, stirring, heating and dissolving to obtain a solution 4;
(5) stirring the solution 4 at 75 +/-5 ℃, preserving heat for 30 minutes, filtering under stirring and heat preservation, pumping into an atomizer through a conveying pipeline, controlling the cold spraying air inlet temperature to be 5 ℃, and performing cold spraying to prepare the florfenicol solid dispersion inclusion microcapsule.
99.1 kg of florfenicol solid dispersion inclusion microcapsules are collected, and the yield is 99.1%.
Example 2
A florfenicol solid dispersion inclusion microcapsule comprises the following components in percentage by mass: 10 parts of florfenicol, 25 parts of poloxamer, 800045 parts of polyethylene glycol, 15 parts of hydroxypropyl-beta-cyclodextrin and 5 parts of propylene glycol.
The preparation method of the florfenicol solid dispersion inclusion microcapsule comprises the following steps:
(1) weighing 25 kg of poloxamer and 800045 kg of polyethylene glycol, heating to 70 +/-5 ℃, and dissolving to obtain a clear solution 1;
(2) weighing 15 kg of hydroxypropyl-beta-cyclodextrin, adding into the solution 1, stirring, heating and dissolving to obtain a solution 2;
(3) weighing 10 kg of florfenicol, adding into the solution 2, stirring, heating and dissolving to obtain a solution 3;
(4) weighing 5kg of propylene glycol, adding the propylene glycol into the solution 3, stirring, heating and dissolving to obtain a solution 4;
(5) stirring the solution 4 at 70 +/-5 ℃, preserving heat for 50 minutes, filtering under stirring and heat preservation, pumping into an atomizer through a conveying pipeline, controlling the cold spraying air inlet temperature to be 8 ℃, and performing cold spraying to prepare the florfenicol solid dispersion inclusion microcapsule.
98.8 kg of florfenicol solid dispersion inclusion microcapsules are collected, and the yield is 98.8 percent.
Example 3
A florfenicol solid dispersion inclusion microcapsule comprises the following components in percentage by mass: 20 parts of florfenicol, 23 parts of poloxamer, 600019 parts of polyethylene glycol, 800019 parts of polyethylene glycol, 5 parts of copovidone, 12 parts of beta-cyclodextrin and 2 parts of sodium dodecyl sulfate.
The preparation method of the florfenicol solid dispersion inclusion microcapsule comprises the following steps:
(1) weighing 23 kg of poloxamer, 600019 kg of polyethylene glycol, 800019 kg of polyethylene glycol and 5kg of polyvidone, heating to 85 +/-5 ℃, and dissolving to obtain a clear solution 1;
(2) weighing 12 kg of beta-cyclodextrin, adding into the solution 1, stirring, heating and dissolving to obtain a solution 2;
(3) weighing 20 kg of florfenicol, adding into the solution 2, stirring, heating and dissolving to obtain a solution 3;
(4) weighing 2 kg of dodecane-grade sodium sulfate, adding the dodecane-grade sodium sulfate into the solution 3, stirring, heating and dissolving to obtain a solution 4;
(5) stirring the solution 4 at 85 +/-5 ℃, preserving heat for 40 minutes, filtering under stirring and heat preservation, pumping into an atomizer through a conveying pipeline, cold spraying at the air inlet temperature of 6 ℃, and cold spraying to prepare the florfenicol solid dispersion inclusion microcapsule.
99.6 kg of florfenicol solid dispersion inclusion microcapsules are collected, and the yield is 99.6%.
In order to further prove the beneficial effects of the present invention and to better understand the present invention, the properties and application properties of the florfenicol solid dispersion inclusion microcapsule of the present invention are further illustrated by the following test experiments, but the present invention is not to be understood as being limited thereto, and the properties of the product obtained by other determination experiments performed by those skilled in the art according to the above summary of the invention and the applications performed according to the above properties are also considered to fall within the protection scope of the present invention.
The florfenicol solid dispersion inclusion microcapsule solubility test, the dissolution test and the drug time curve test are as follows:
1. solubility comparison test:
the test method comprises the following steps: taking 5 g of a florfenicol solid dispersion inclusion microcapsule (specification is 20%) in example 1 and a florfenicol powder (specification is 20%) product of an enterprise known as A, B on the market, respectively weighing the sample, placing the sample in a beaker, adding 100 ml of water, diluting to 10000PPM, selecting a stirring speed of 300r/min, stirring for 60 seconds, observing the dissolution phenomenon after stirring is stopped, and placing for 4 hours to observe the dissolution phenomenon, wherein the results are shown in Table 1 below.
TABLE 1 florfenicol solid Dispersion Inclusion microcapsules solubility comparative test results
And (4) analyzing results: the florfenicol solid dispersion inclusion microcapsule (specification 20%) has the concentration up to 10000PPM, the dissolution time is fast, no precipitate is separated out after the microcapsule is placed for 4 hours, and all indexes are obviously superior to enterprise products in market A and B.
2. Dissolution rate comparison test:
the test method comprises the following steps: according to a florfenicol powder content determination method and a dissolution determination method in the first part of China veterinary pharmacopoeia 2015 edition, the florfenicol solid dispersion inclusion microcapsule in the example 1 and samples from different manufacturers are weighed and operated in the same method, the dissolution in water is determined, and the dissolution results are respectively obtained by sampling and determining at 0, 15, 30, 45, 75 and 120 minutes and are shown in the following table 2 and figure 1.
TABLE 2 results of comparative tests on the dissolution rate of florfenicol in water in solid dispersion inclusion microcapsule
And (4) analyzing results: it can be seen from table 2 and fig. 1 that the florfenicol solid dispersion inclusion microcapsule has a dissolution rate of more than 90% in water within 15 minutes, and the dissolution rate is obviously superior to that of market sample A and sample B.
3. Comparative bioavailability test:
the test method comprises the following steps: the design score is 2 groups, namely a newflounder (import) group and a florfenicol solid dispersion inclusion microcapsule group in the embodiment 1; the pigs are 24 heads, the weight is 27.67 plus or minus 2.45kg, and the pigs are randomly divided into two groups; fasting for 12 hours, orally feeding by intragastric administration, and calculating the dosage according to the weighing; collecting blood of 5ml in the anterior vena cava according to the time of 0h, 0.25h, 0.5h, 0.75h, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 36h, 48h and 72 h; and (4) processing the blood sample, measuring the blood concentration by an HPLC method, and calculating a drug time curve. The results are shown in Table 3 below and FIG. 2.
TABLE 3 pharmacokinetic parameters of florfenicol solid dispersion inclusion microcapsules and "niflurol" porcine oral drug
And (4) analyzing results: it can be seen from table 3, fig. 2 that the florfenicol solid dispersion inclusion microcapsules are consistent with the bioavailability of imported neoflurane.
4. And (3) stability test:
the test method comprises the following steps: 3 batches of florfenicol solid dispersion inclusion microcapsules were prepared according to example 1, and the room temperature storage test and the thermal acceleration (40 ± 2 ℃) test were performed according to the guidelines of the drug stability test under the section of "Chinese veterinary drug dictionary 2015", and the results are shown in tables 4 and 5 below.
TABLE 4 florfenicol solid Dispersion Inclusion microcapsules (accelerated 40 + -2 deg.C.) stability test
TABLE 5 florfenicol solid Dispersion Inclusion microcapsules (Normal temperature) stability test
And (4) analyzing results: the florfenicol solid dispersion inclusion microcapsule is observed in an accelerated test for 6 months and a normal temperature for 24 months, and all quality indexes are in a qualified range.
In conclusion, the florfenicol solid dispersion inclusion microcapsule prepared by the invention has the advantages of excellent water solubility, water solubility of 10000ppm, simple and convenient preparation method, low cost and good stability, and is suitable for large-scale industrial production. Compared with similar products, the neoflurandrum officinale total liposome has extremely high solubility and dissolution speed, is convenient for various administration modes required clinically, has similar bioavailability compared with an imported product of neoflurandrum officinale, and has the characteristics of long-acting property and stable in-vivo release.
Therefore, the implementation and popularization of the scheme of the invention can certainly promote the revolution of florfenicol preparation technology in the animal and security industry, and has good clinical application and market prospect.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. The florfenicol solid dispersion inclusion microcapsule is characterized by comprising the following components in parts by weight: 10-30 parts of florfenicol, 40-70 parts of solid dispersing agent, 5-30 parts of inclusion agent and 1-5 parts of wetting agent.
2. The florfenicol solid dispersion inclusion microcapsule according to claim 1, wherein the solid dispersion agent is at least one of polyethylene glycol 6000, polyethylene glycol 8000, poloxamer 188, copovidone.
3. A florfenicol solid dispersion inclusion microcapsule according to claim 1, wherein the inclusion agent is one or a mixture of two of β -cyclodextrin and hydroxypropyl- β -cyclodextrin.
4. A florfenicol solid dispersion inclusion microcapsule according to claim 1, wherein the wetting agent is at least one of hydroxypropyl methylcellulose, polyoxyethylene hydrogenated castor oil, sodium lauryl sulfate, propylene glycol.
5. The florfenicol solid dispersion inclusion microcapsule according to claim 2, wherein the solid dispersant is a mixture of polyethylene glycol 6000 and poloxamer in a mass ratio of 2: 1.
6. A florfenicol solid dispersion inclusion microcapsule according to claim 3, wherein the inclusion agent is hydroxypropyl- β -cyclodextrin.
7. A florfenicol solid dispersion inclusion microcapsule according to claim 4, wherein the wetting agent is sodium lauryl sulfate.
8. A method for preparing florfenicol solid dispersion inclusion microcapsules according to claim 1, comprising the steps of:
(1) weighing the solid dispersing agent according to the mass part, heating to 60-90 ℃, dissolving and clarifying to obtain a solution 1 for later use;
(2) weighing the inclusion agent according to the mass part, then adding the inclusion agent into the solution 1, and uniformly stirring and dissolving to obtain a solution 2 for later use;
(3) weighing florfenicol according to the weight parts, adding the florfenicol into the solution 2, and stirring and dissolving the florfenicol uniformly to obtain a solution 3 for later use;
(4) weighing the wetting agent according to the parts by weight, adding the wetting agent into the solution 3, and uniformly stirring and dissolving to obtain a solution 4 for later use;
(5) and stirring the solution 4 at the constant temperature for 30-120 minutes, and then carrying out cold spraying by a high-speed atomizer to prepare the florfenicol solid dispersion inclusion microcapsule.
9. The method of claim 8, wherein the stirring temperature in steps (1) - (5) is 60-90 ℃.
10. Use of the florfenicol solid dispersion inclusion microcapsule according to claim 1 or the florfenicol solid dispersion inclusion microcapsule prepared according to the method of claim 8 in veterinary formulations.
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| CN116036020A (en) * | 2022-08-31 | 2023-05-02 | 瑞普（天津）生物药业有限公司 | Florfenicol powder with high bioavailability and preparation method thereof |
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