WO2008151502A1

WO2008151502A1 - Enrofloxacin microcapsule formulation and preparation method thereof

Info

Publication number: WO2008151502A1
Application number: PCT/CN2008/000632
Authority: WO
Inventors: Yuyan Zhou
Original assignee: Hainapharm Pharmaceutical Co., Ltd. Foshan
Priority date: 2007-06-08
Filing date: 2008-03-31
Publication date: 2008-12-18
Also published as: KR20090122466A; CN101273980A; KR101148501B1; CN101273980B

Abstract

An enrofloxacin microcapsule formulation and preparation method thereof. The enrofloxacin formulation is prepared from 5%-90% of enrofloxacin and 95%-10% of adjuvant. The adjuvant is one of C12-18 fatty acid, calcium glyceryl monostearate, stearyl alcohol, saturated triglyceride, monoglyceride, paraffin wax, animal wax, vegetable wax, fatty powder or combination thereof. The appearance of said enrofloxacin microcapsule formulation is white or pale yellow particle.

Description

Enrofloxacin microcapsule preparation and preparation method thereof

The invention belongs to the field of medicine, in particular to an enrofloxacin microcapsule preparation and a preparation method thereof. Background technique

Enrofloxacin is a synthetic antibacterial drug for animals. It is a third-generation quinolone preparation. Enrofloxacin has a broad-spectrum bactericidal effect and is effective against both stationary and growing bacteria. It has a good killing effect on a variety of Gram-positive and Gram-negative bacteria, as well as mycoplasma, such as Pseudomonas aeruginosa. , Escherichia coli, Salmonella, Shigella, Klebsiella, Pasteurella, Proteus, Staphylococcus, Chlamydia, etc. are effective.

Since enrofloxacin acts on the bacterial cell DNA helicase, the bacteria can not form a supercoil, and the stain is damaged, thereby producing a bactericidal effect. Because its bactericidal mechanism is different from other drugs, the chance of cross-resistance is small, and the toxicity of enrofloxacin is extremely small. The therapeutic dose is not teratogenic and mutagenic, and it is safe for clinical use.

In actual production, Enrofloxacin is trusted by the majority of farmers because of its good use. At present, the most common forms of enrofloxacin preparations on the market are: tablets, soluble powders, solutions, injections and the like. Among them, the injection dosage form belongs to the individual, and its disadvantage is that it is not suitable for intensive large-scale breeding; other dosage forms are oral, suitable for individual administration, however, since enrofloxacin is very bitter and odorous, when administered orally On the one hand, it will affect palatability. On the other hand, it will stimulate the stomach of livestock and poultry. In severe cases, it will cause vomiting. Even some pigs will not eat the feed if they smell the enrofloxacin.

Therefore, the research on how to eliminate the bitterness and odor of enrofloxacin and not affect the therapeutic effect of enrofloxacin has attracted people's attention. At present, there are several related researches in China:

First, the molecular structure is changed by a chemical reaction. For example, enrofloxacin hydrochloride, enrofloxacin sodium, enrofloxacin lactate, etc., but this method will lead to an increase in pharmaceutical costs, and the improvement of the drug is not obvious.

Second, it is made into a coating, microcapsule or taste masking dosage form. Patent No. ZL200510050039.5 discloses a coated dosage form of nosoxacin microcapsules and a preparation method thereof, which is mainly coated with a coating agent twice in the outer layer of enrofloxacin particles, and a sweetener can be added. This masks the bitterness of Enrofloxacin. The dust in the production process is relatively large. Except for the poor production environment of the workers, through the analysis of the products on the market, it is found that most of the defects are incomplete package and low coating rate. Chinese Patent Application No. 200610049243.X discloses a method for preparing a taste-masking enrofloxacin, which is prepared by mixing gelatin with glycerin, forming a gelatin-plasticizer composite solution, and then enrolling enrofloxacin. Mixed

1

Confirmation The suspension, after which the suspension is spray dried, the process is very complicated and inconvenient to handle. ' Invention content

One of the technical problems to be solved by the present invention is to provide a novel enrofloxacin microcapsule preparation which effectively eliminates the bitterness and odor of enrofloxacin without affecting the use effect of enrofloxacin.

An enrofloxacin microcapsule preparation is prepared mainly from 5% to 60% of enrofloxacin starting material and 40-95% auxiliary material, and the auxiliary material is twelve to eighteen carbon fatty acids. One or a mixture of monostearic acid glyceride, stearyl alcohol, saturated triglyceride, monoglyceride, paraffin, animal wax, vegetable wax, fat powder, and the like.

Preferably, the enrofloxacin raw material is contained in an amount of 10% to 50%, and accordingly, the auxiliary material is 50 to 90%, more preferably 10% or 50% of the enrofloxacin raw material, and the auxiliary material is 90%. % or 50%.

Preferably, the auxiliary material is one or more of stearic acid, fat powder, monostearic acid glyceride and paraffin wax. Another technical problem to be solved by the present invention is to provide a method for preparing the above-described enrofloxacin microcapsule.

A method for preparing the above enrofloxacin microcapsules mainly comprises the following steps:

(1) heating, melting, and stirring the auxiliary materials, the auxiliary materials are twelve to eighteen carbon fatty acids, monostearic acid glycerides, stearyl alcohols, saturated triglycerides, monoglycerides, paraffins, animal waxes, One or a mixture of vegetable wax, fat powder, and the like;

(2) mixing enrofloxacin raw materials with the melted auxiliary materials, wherein the enrofloxacin raw material content is 5%-60%, the auxiliary material content is 40-95%, the shearing stirring is 5-60 minutes, and the temperature control is 65~120 °C;

(3) heating and heating the material after the stirring in step (2), the temperature is 65 ° C - 120 ° C;

(4) Spray granulation;

(5) Cooling, oscillating and sifting, collecting.

Preferably, the temperature at which the auxiliary material is heated and melted is 55 ° C to 120 ° C, more preferably 65 to 90 ° C; and the heat insulating temperature in the step (3) is 65 ° C to 100 ° C.

The enrofloxacin microcapsule preparation of the invention has the advantages of simple preparation method, low cost, easy operation, less loss, and total product yield, and the produced enrofloxacin microcapsule preparation has a white or yellowish or yellow appearance. Spherical particles, which are translucent under the microscope, have a particle size of 200μηη - 850μηη, which is good in fluidity and is more conducive to mixing with food. According to the preparation method provided by the invention, combined with the selected auxiliary materials, the obtained enrofloxacin microcapsule preparation has a great improvement compared with the ordinary particles, mainly: the auxiliary materials used are simple, no additional sweetener is added, and the animal is safe. Poultry without toxic side effects; It completely masks the bitter taste of enrofloxacin and is easily accepted by livestock and poultry. It changes the current situation that enrofloxacin oral solid preparation is difficult to apply to pigs, and expands its use range. It has good stability and can be slowly released in the gastrointestinal tract. Maintain the long-lasting effect of the drug, and maintain the peak concentration of the effective blood drug for a longer period of time and longer lasting effect. DRAWINGS

1 is a flow chart of preparation of enrofloxacin microcapsules of the present invention

Figure 2 is a schematic illustration of the enrofloxacin microcapsule microscope (40 times) of the present invention.

Excipient

2. Enrofloxacin raw materials;

3. Chemical tanks;

4. Batching tank;

5. Storage tanks;

6. Spray device;

7. Cooling system;

8. Vibrating screen. detailed description

Embodiment 1

Excipient 1 stearic acid (according to the Chinese Pharmacopoeia or the United States Pharmacopoeia, the European Pharmacopoeia, the British Pharmacopoeia, the quality standard of stearic acid) 225kg into the chemical tank 3, as shown in Figure 1. Show, heat to 80 ° C, keep stirring, until the excipient 1 is completely melted; pump the melted stearic acid from the chemical tank into the dosing tank 4, and simultaneously put the accurately weighed 25kg enrofloxacin raw material 2 into the batching tank 4, high-speed emulsion shear mixing for 10 minutes, the temperature should be controlled at 80 ° C; the prepared materials are introduced into the storage tank 5, and the temperature is heated to 80 ° C -10 (rC _; start the feed spray device 6, The spraying device 6 can be a high-speed centrifugal spray dryer, and the materials in the storage tank 5 are granulated by spray cooling (cooling system 7); the granules of the finished product are collected by sifting through a sieve of 200 μm - 850 μηι. 303 kg of finished enrofloxacin microcapsule preparation (10% content) was obtained, and the particle size was 200 μm - 700 μιη, and the yield was 97%. As shown in Fig. 2, the enrofloxacin microcapsule preparation was half under a 40-fold microscope. Transparent, light yellow spherical particles. Example 2 selection of auxiliary materials 120kg of stearic acid glyceride is put into the chemical tank, heated to 70 ° C, stirring constantly, waiting for the whole material 2008/000632 Melting; pumping the melted calcium stearate monoglyceride from the chemical tank into the batching tank, and at the same time, 80kg of enrofloxacin, which has been accurately weighed, is put into the batching tank and sheared and stirred for 8 minutes. Keep at 80 Ό; introduce the prepared materials into the storage tank, and heat the temperature to 8{TC-10 (rC _; start the feed spray device, granulate the materials in the storage tank through the spray freezing equipment; The finished product granules were collected by oscillating sieve with 200 μπι-850 μηι. Finally, 190 kg of the finished enrofloxacin microcapsule preparation (40%) was obtained, and the particle size was 200 μm-850 μm, and the yield was 95%.

120kg of excipient monostearate was put into the chemical tank, heated to 70 ° C, stirring constantly, all the excipients were melted; the melted calcium stearate monoglyceride was pumped from the chemical tank into the batching tank, and at the same time Accurately weigh 80kg of enrofloxacin into the batching tank, shear and stir for 8 minutes, the temperature should be kept at 80 °C _; the prepared materials are introduced into the storage tank, and the temperature is heated to 80 °C-10 (TC _The feed spray device is started, and the materials in the storage tank are granulated by a spray freezing device; the granules of the finished product are collected by a 200 μm η-850 μηη sifting sieve, and finally 190 kg of the finished enrofloxacin microcapsule preparation is obtained. 40%), the particle size is 20 (^m-85 (^m, yield up to 95%).

Embodiment 3

Use 60kg of monostearic acid glyceride, 60kg of fatty powder, 20kg of paraffin, put into the chemical tank, heat to 90 °C, stir constantly, and all the auxiliary materials are melted; pump the melted auxiliary material from the chemical tank to the batching tank At the same time, 60kg of enrofloxacin which has been accurately weighed is put into the batching tank, and the mixture is sheared and stirred for 8 minutes, and the temperature is kept at 80 其; the prepared material is introduced into the storage tank, and the temperature is heated to 80 ° C-100. °C _; start the feed spray device, the material in the storage tank is granulated by spray freezing; the granules of the finished product are collected by 20(^m-85(^m oscillating sieve). Finally, 190kg finished product is obtained. Nosastar microcapsule preparation (30%), particle size of 200μιη-850μηι, yield up to 95%.

Use the auxiliary material 1 fat powder 100kg into the chemical tank 3, heat to 80 °C, keep stirring, wait until the auxiliary material 1 is completely melted; pump the melted fat powder from the chemical tank into the batching tank, and at the same time, accurately weigh 100kg Norostar raw material 2 is put into the batching tank 4, and is stirred by high-speed emulsification for 10 minutes, during which the temperature is kept at 8 (TC _; the prepared material is introduced into the storage tank 5, and the temperature is heated to 80 ° C -10 ( TC _; start the feed spray device 6, the spray device 6 can be a high-speed centrifugal spray cooler, the material in the storage tank 5 is granulated by spray cooling; the granules of the finished product are sifted through a sieve of 200 μm - 850 μπι Screen collection. Finally, 194kg of finished enrofloxacin microcapsule preparation (50% content) was obtained. Amount), the particle size is 200μιη-850μηι, and the yield is up to 97%. Enrofloxacin microcapsule preparations are translucent, yellow spherical particles under a 40x microscope. Experimental example five

The enrofloxacin microcapsules prepared in Example 4 were fed to pigs in need of treatment. The pharmacokinetics of enrofloxacin microcapsules demonstrated that the blood concentration of enrofloxacin microcapsules and enrofloxacin in pigs are shown in Tables 1 and 2, respectively. The pharmacokinetic parameters of the two preparations in pigs are shown in Tables 3 and 4.

Table 1 Determination of blood concentration of enrofloxacin microcapsules in pigs (ϋ^ ug/ml)

Note: ND is not detected, below detection limit 0. 02 ug/ml

Determination of the blood concentration of enrofloxacin powder in pigs X Shi SD, g/ml)

Pharmacokinetic parameters of enrofloxacin microcapsule preparation in pigs soil sm time pig number

Unit

(h) Al A2 A3 A4 A5 Bl B2 B3 B4 B5 X S.D

D mg/kg 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 10.0 0.00

Co ug/ml 1.31 1.51 3.05 3.70 3.84 1.60 1.95 1.87 2.24 1.90 2.30 0.86

Ka / h 1.07 0.59 0.25 0.32 0.23 0.60 0.50 0.53 0.46 0.98 0.55 0.22

K 1 h 0.03 0.05 0.08 0.05 0.04 0.04 0.03 0.05 0.05 0.03 0.04 0.01 t l h 0.65 1.17 2.81 2.18 3.02 1.15 1.40 1.32 1.50 0.71 1.59 0.71 tl h 27.29 13.38 8.86 12.85 15.88 18.12 21.14 14.72 15.11 21.88 16.92 3.15

Tp h 3.59 4.51 6.82 6.72 8.93 4.87 5.86 5.04 5.93 3.84 5.61 1.51

Oisz ug/ml 1.20 1.20 1.79 2.58 2.60 1.33 1.61 1.48 1.74 1.70 1.72 0.48

AUC tng/1. h 51.69 29.17 39.03 68.63 87.89 41.86 59.59 39.81 48.92 60.07 52.67 15.64 lagtime h 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.38 0.22 0.06 0.14

Table 4 Pharmacokinetic parameters of enrofloxacin powder in pigs w soil sm

The above data shows that:

1. The peak concentrations of enrofloxacin microcapsule preparation and the original powder were 1.72 h and 2.53 h, respectively. Compared to the original powder, the microcapsule preparation of the present invention has a lower concentration in pigs but lasts longer. The blood concentration of the microcapsule preparation group and the original powder group at the 72h after administration was 0.11 g/ml and 0.04 g/ml, respectively, and the microcapsule preparation group was 0.05 g/ml at the 96h after administration. The blood concentration of the powder group was not detected.

2. Taking the original powder of enrofloxacin as a control, enrofloxacin microcapsule preparation was completely absorbed after oral administration, and its relative bioavailability was as high as 115.8 %.

The enrofloxacin microcapsule preparation prepared in the above Examples 1-3 had the same effects as described above, and detailed data was omitted. The detailed description of the present invention is intended to be illustrative of the preferred embodiments of the present invention, and is not intended to limit the scope of the invention. in.

Claims

Rights request

An enrofloxacin microcapsule preparation, which is prepared from an enrofloxacin raw material having a content of 5-60% and an auxiliary material having a content of 40-95%, wherein the auxiliary material is twelve to ten One or more of octacarbon fatty acid, monostearic acid glyceride, stearyl alcohol, saturated triglyceride, monoglyceride, paraffin wax, animal wax, vegetable wax, and fat powder.

The enrofloxacin microcapsule preparation according to claim 1, wherein the enrofloxacin raw material is contained in an amount of 10% to 50%, and the auxiliary material is contained in an amount of 50 to 90%.

The enrofloxacin microcapsule preparation according to claim 1, wherein the enrofloxacin raw material is contained in an amount of 10% or 50%, and the auxiliary material is contained in an amount of 90% or 50%.

The enrofloxacin microcapsule preparation according to claim 1, wherein the enrofloxacin microcapsule preparation has a particle diameter of 200 μm to 850 μm, and has a white or pale yellow or yellow spherical particle appearance.

The enrofloxacin microcapsule preparation according to claim 1, wherein the excipient is one or more of stearic acid, fat powder, monostearic acid glyceride and paraffin wax.

6. A method of preparing enrofloxacin microcapsules according to claim 1 or 2, characterized in that it comprises the following steps:

(1) heating, melting, and stirring the auxiliary materials;

(2) mixing enrofloxacin raw materials with the melted auxiliary materials, shearing and stirring for 5-60 minutes, and controlling the temperature at

65-100 °C ;

(3) heating and heating the material after the stirring in step (2), the temperature is 65 ° C - 100 ° C;

(4) Material spray granulation;

(5) Cooling, oscillating and sifting, collecting and getting.

The preparation method according to claim 6, wherein the temperature at which the auxiliary material is heated and melted in the step (1) is 55 ° C - 120. C.

The preparation method according to claim 6, wherein the heating temperature in the step (3) is from 80 ° C to 100 ° C.