KR101509168B1 - Sustained-release preparations of cephalosporin antibiotic and Sustained-release pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention relates to a sustained-release preparation of cephalosporin antibiotics, a sustained-release pharmaceutical composition comprising the same, and a method for producing the sustained-release formulation. The suspension injections containing the sustained-release preparation of cephalosporin antibiotic of the present invention can solve the inconvenience of the conventional formulation for three consecutive days because the efficacy is continuously exhibited even with a single administration, and it is left for a long time The stability is high. Therefore, the present invention can be usefully used as a therapeutic agent for antibiotics and respiratory diseases of animals.

Description

[0001] Sustained-release preparations of cephalosporin antibiotic and sustained-release pharmaceutical composition comprising the sustained-release preparations of cephalosporin antibiotics,

The present invention relates to a sustained-release preparation of cephalosporin antibiotics, a sustained-release pharmaceutical composition comprising the same, and a method for producing the sustained-release formulation.

Cephalosporin antibiotics are third-generation antibiotics that act extensively on Gram-positive and Gram-negative bacteria. They are resistant to actinomycetes such as Actinobacillus, Salmonella, Pasteurella, Streptococcus, Mycoplasma or Hemophilus, Diarrhea, pneumonia, infectious gastroenteritis or mastitis in domestic animals or poultry (Brown, SA, J. Vet. Pharmacol. Therap ., 22, 35-40, 1999; RJ Yancey et al., Am. Vet Res 48,1050).

Cephalosporin antibiotics are easily broken down in the body, or are rapidly released through the kidneys, so they are characterized by a short half-life in the body from several minutes to several hours. Therefore, injections must be given at least twice a day or at least once a week in order to obtain a sustained therapeutic effect.

In order to solve these problems and to facilitate the patient's convenience, there is a need for a formulation that inhibits degradation by the body's enzymes and inhibits absorption in the kidney and blood vessels to prolong the blood residence time. Since cephalosporin drugs are poorly soluble in water, they are prepared as suspensions and injected into the animals. In general, the suspending agent should have properties such as efficacy of treatment, physical / chemical stability of the pharmaceutical composition, durability of the preparation, and apparent beautification, and the sustained-release suspension of the currently available cephalosporin- There is an inconvenience that it is necessary to frequently administer the drug for a short period of time, and there is a problem that the sedimentation rate of the particles is so fast that it is difficult to regenerate the drug.

Background Art [0002] An aqueous composition (Korean Patent Laid-Open Publication No. 10-1994-0013512) has been proposed as a dissolving aid for nicotinamide to improve the solubility of ceftiofur. Further, there is a persistent formulation technique (International Patent Publication WO 94/20505) in which an active ingredient is dispersed in vegetable oil as a non-aqueous suspension injectable agent, and a method of dissolving lecithin and a surfactant, Hydrochloride (WO 98/25621).

However, these preparations are disadvantageous in that they are difficult to be stored for a long time due to precipitation of main components and difficulty in redispersing, and the viscosity of the vegetable oil used as a dispersion medium is high and inconvenient to use. On the other hand, there is a disadvantage in that the commercially available Septioedip sodium preparation has disadvantages in that it is dissolved in water when it is used as a powdered preparation freeze-dried in an aseptic condition for stabilization of an active ingredient, and the manufacturing process is complicated.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

The present inventors have conducted studies to develop a sustained-release preparation of cephalosporin antibiotics which maintains the drug efficacy of cephalosporin antibiotics and provides ease of administration and has excellent redispersibility and bioavailability. As a result, it has been found that a complex of alginate and cephalosporin antibiotics is prepared, and each of the alginates of the complex is ion-crosslinked with each other to develop a preparation, and then the preparation is sustained release of cephalosporin antibiotic And that the present invention has been completed.

It is therefore an object of the present invention to provide a sustained release formulation of cephalosporin antibiotic.

It is another object of the present invention to provide a sustained release pharmaceutical composition comprising a sustained release formulation of cephalosporin antibiotic.

It is yet another object of the present invention to provide a process for the preparation of a sustained release formulation of cephalosporin antibiotic.

Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, the present invention comprises a cephalosporin antibiotic and an alginate, wherein the alginate is cross-linked to each other by a divalent cation to form particles, wherein the cephalosporin antibiotic is cross-linked Wherein the sustained-release preparation of cephalosporin antibiotics is characterized in that the carboxy group of the alginate in which the particles are formed is hydrogen-bonded or ion-bonded.

The present inventors have conducted studies to develop a sustained-release preparation of cephalosporin antibiotics which maintains the drug efficacy of cephalosporin antibiotics and provides ease of administration and has excellent redispersibility and bioavailability. As a result, it has been found that a complex of alginate and cephalosporin antibiotics is prepared, and each of the alginates of the complex is ion-crosslinked with each other to develop a preparation, and then the preparation is sustained release of cephalosporin antibiotic .

The sustained-release preparation of the present invention is characterized in that the particles formed by gelation of the alginate exhibit (i) a complex formation between the cephalosporin antibiotic and the alginate through hydrogen bonding or ionic bonding between the cephalosporin antibiotic and the carboxy group of the alginate, and ii) ionic crosslinking through divalent cations between the alginates in each complex and the formation of particles therefrom.

The cephalosporin antibiotic is an active ingredient exhibiting pharmacological activity, which binds to the carboxy group of the alginate to form a cephalosporin antibiotic-alginate complex. The cephalosporins are classified as "generation" by their antimicrobial properties, with the first cephalosporin being defined as the first generation, and later an extended range of the cephalosporins being the second generation cephalosporins Respectively. At present, third generation cephalosporins have been recognized, and the fourth generation has been proposed. In the present invention, any cephalosporin antibiotic having a functional group (for example, an amine group) capable of forming a bond (hydrogen bond or ionic bond) with the carboxy group of alginate can be used without limitation.

According to one embodiment of the present invention, the cephalosporin antibiotic is selected from the group consisting of ceftiofur sodium, cell pyramid, cell ferazone, simalactam, ceftriaxone, cytotoxic, cefsoludin, cefditoren, , Omnisep, cefdinir, cefpodoxime, procetyl, ceftazidime, ceftazidime, ceftioxime, cetamenoside, cephimizole, promosole, cellferazone, sepiem, ceftibuten, ≪ / RTI > terram, Septia, and salts thereof. In one particular example, the cephalosporin antibiotic is septiopa sodium.

The cephalosporin antibiotic-alginate complex forms sustained particles by forming an ionic bridge with the alginate in the other complex. That is, the alginate functions as a release modifier of the cephalosporin antibiotic, which is an active ingredient, and is gelled by cross-linking with other alginate through divalent cations (for example, Ca2 ⁺ , Ba2 ⁺ ). Specifically, the carboxy group of the alginate (for example, the carboxyl group of L-glutaric acid) forms an ionic bond with the divalent cation, and the polymer structure of the alginate forms an egg-box structure in which the divalent cation is surrounded .

The alginate forms a gel film at a low pH such as gastric acid to inhibit the diffusion of the active substance. When the pH is increased as in the small intestine, the alginate is rapidly dissolved and diffusion is accelerated. Therefore, by dissolving the cephalosporin antibiotic-alginate complex by crosslinking and reducing the material by using calcium chloride or the like, the dissolution rate can be decreased and the sustained release effect of the slower active substance can be obtained.

According to one embodiment of the present invention, the divalent cation is Ca ²⁺ .

According to one embodiment of the present invention, the gelled and formed particles are beads.

According to one embodiment of the present invention, the particles have a diameter of 10-100 mu m. In one particular example, the particle diameter is 20-70 [mu] m.

According to one embodiment of the invention, the sustained release formulation comprises alginate in a ratio of 1: 0.1-10 relative to the weight of the cephalosporin antibiotic. In one particular example, the sustained release formulation comprises alginate in a ratio of 1: 0.5-4 relative to the weight of the cephalosporin antibiotic.

According to one embodiment of the invention, the sustained release formulation comprises 0.2 to 20% by weight cephalosporin antibiotic.

As confirmed in the following examples, the sustained release formulations of the present invention may prolong the duration of the cephalosporin antibiotic (see Figures 2 and 3). Thus, the sustained release formulation of the present invention can maintain the release persistence in the body of the administered animal.

According to another aspect of the invention, the present invention provides a pharmaceutical effective amount of the cephalosporin antibiotic-sustained release formulation; And a pharmaceutically acceptable carrier. ≪ Desc / Clms Page number 2 >

The pharmaceutical compositions of the present invention comprise a cephalosporin antibiotic-sustained release formulation in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" refers to the amount of active ingredient or pharmaceutical composition that elicits a biological or medical response in a tissue system, animal or human, as contemplated by a researcher, veterinarian, physician or other clinician, This includes an amount that induces relief of the symptoms of the disease or disorder being treated. Effective dose levels include factors such as disease type and severity of the patient (animal), age, sex, type of animal, activity of the drug, sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, And other factors well known in the medical arts.

The pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not.

The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).

The pharmaceutical composition of the present invention can be administered orally or parenterally, and parenteral administration is preferred. In the case of parenteral administration, it can be administered by intramuscular injection, intravenous injection, subcutaneous injection, intraperitoneal injection, transdermal administration, and the like.

Suitable dosages of the pharmaceutical compositions of the present invention will vary depending upon factors such as the formulation method, the mode of administration, the age, weight, sex, pathology, food, time of administration, route of administration, excretion rate and responsiveness of the patient (animal) It can be prescribed variously.

The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. Here, the formulations may be in the form of solutions, suspensions, syrups or emulsions in an oil or aqueous medium, or in the form of excipients, powders, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.

According to one embodiment of the invention, the pharmaceutical composition is a suspension. In one particular example, the suspension is in the form of an aqueous or oil-dispersed suspension of cephalosporin antibiotic. The oil in the form of oil dispersion is at least one oil selected from the group consisting of vegetable oil, soybean oil, cottonseed oil, sesame oil, corn oil, olive oil, peanut oil and palm oil.

According to one embodiment of the present invention, the pharmaceutical composition is an injection.

According to one embodiment of the invention, the pharmaceutical composition is an antibiotic composition.

According to one embodiment of the present invention, the pharmaceutical composition is a composition for preventing or treating diarrhea, pneumonia (pleural pneumonia, bronchopneumonia, pustularela pneumonia, mycoplasma pneumonia, etc.), infectious gastroenteritis or mastitis.

According to one embodiment of the present invention, the pharmaceutical composition is for administration of livestock such as pig, cattle, horse, sheep, or poultry.

According to another aspect of the present invention, there is provided a method of preparing a cephalosporin antibiotic-alginate complex, comprising the steps of: (a) hydrogenating or ion-binding a cephalosporin antibiotic to a carboxyl group of an alginate to form a cephalosporin antibiotic- And (b) treating the complex obtained in step (a) with a solution containing a salt of a divalent cation to induce ionic crosslinking by divalent cations between the alginates of the respective complexes. The present invention also provides a method for producing a pharmaceutical composition.

In step (a), the cephalosporin antibiotic and the alginate are placed in a solvent (for example, distilled water) and stirred to form a cephalosporin antibiotic-alginate complex. At this time, homogenizer can be used for stirring.

In step (b), the cephalosporin antibiotic-alginate complex obtained in step (a) is slowly dropped from the solution containing the divalent cation salt to induce ionic crosslinking by divalent cations between the alginates of the respective complexes do. As a result, the complex dropped to the solution instantaneously gels to form particles.

According to one embodiment of the present invention, the salt of the divalent cation is calcium chloride.

The formed particles can be separated from the solvent by means such as filter paper or the like, and the separated particles can be dried and powdered.

The features and advantages of the present invention are summarized as follows:

(a) The sustained-release formulation of the cephalosporin antibiotic of the present invention has a longer half-life than conventional drugs.

(b) The present invention can maximize efficacy with relatively small drug doses, thereby reducing the frequency of dosing.

(c) Suspension injections containing a sustained-release formulation of cephalosporin antibiotic of the present invention exhibit a sustained effect even when administered only once, so that the inconvenience of the existing formulation administered consecutively for 3 consecutive days can be solved, Stability is high even if left for a long time. Therefore, the present invention can be usefully used as a therapeutic agent for antibiotics and respiratory diseases of animals.

Figure 1 schematically illustrates the process for the preparation of the cephalosporin antibiotic sustained release formulation of the present invention.
Fig. 2 shows the dissolution rate of the sustained-release suspension injected through Example 1-4.
Fig. 3 shows the dissolution rates of the sustained-release suspension injections prepared in Examples 5-9.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Examples 1-9. Manufacture of a sustained release formulation of cephalosporin antibiotics

≪ Example 1 >

4 g of alginate (40 mg / ml, Sigma-aldrich) was added to 100 ml of tertiary distilled water (Waters Milli-Q) at a ratio of 0.5: 1 in a homogenizer To form a cephalosporin antibiotic-alginate complex. The complex was slowly cured at a height of 10-30 cm at a water surface using a syringe (21 gage) in a 300 mL aqueous solution of 5% (w / w) calcium chloride being stirred at 100 rpm, Thereby forming a bead. After curing time was 5-15 minutes, it was washed with distilled water. Filtered paper (Filter paper, Qualitative circles, 185 mmΦ) was used to filter the beads and dried at 60 ° C for 12 hours or more with a vacuum pump . The dried composite was pulverized using a granulator mill.

< Example  2>

4 g of Sephodium (40 mg / ml) and 4 g of alginate (40 mg / ml, Sigma-aldrich) were added to 100 ml of tertiary distilled water (Waters Milli-Q) at a concentration ratio of 2: 1 using a homogenizer To form a complex. The complex was slowly dropped at a height of 10-30 cm at the surface of the water using a syringe (21 gage) in an aqueous solution of 300 ml of 5% (w / w) calcium chloride at 100 rpm to instantaneously cure to form beads . The beads were washed with distilled water and filtered using filter paper (Qualitative circles, 185 mmΦ). The beads were dried at 60 ° C for 12 hours or more with a vacuum pump. The dried composite was pulverized using a granulator mill.

&Lt; Example 3 >

4 g of alginate (40 mg / ml, sigma-aldrich) was added to 100 ml of tertiary distilled water (Waters Milli-Q) at a concentration ratio of 4: 1 using a homogenizer To form a complex. The complex was slowly dropped at a height of 10-30 cm at the surface of the water using a syringe (21 gage) in an aqueous solution of 300 ml of 5% (w / w) calcium chloride at 100 rpm to instantaneously cure to form beads . The beads were washed with distilled water and filtered using filter paper (Qualitative circles, 185 mmΦ). The beads were dried at 60 ° C for 12 hours or more with a vacuum pump. The dried composite was pulverized using a granulator mill.

< Example  4>

4 g of alginate (40 mg / ml, sigma-aldrich) was dissolved in 100 ml of tertiary distilled water (Waters Milli-Q) at a concentration ratio of 8: 1 using a homogenizer To form a complex. The complex was slowly dropped at a height of 10-30 cm at the surface of the water using a syringe (21 gage) in a 300 ml aqueous solution of 5% (w / w) calcium chloride being stirred at 100 rpm to momentarily cure to form beads Respectively. After curing time was 5 to 15 minutes, it was washed with distilled water. The resulting beads were filtered using filter paper (qualitative circles, 185 mmΦ) and dried at 60 ° C for 12 hours or more with a vacuum pump. The dried composite was pulverized using a granulator mill.

&Lt; Example 5 >

4 g of alginate (40 mg / ml, sigma-aldrich) was dissolved in 100 ml of tertiary distilled water (Waters Milli-Q) at a concentration ratio of 0.5: 1 in homogenizer To form a complex. The composite was slowly cured at a height of 10-30 cm at a water surface using a syringe (21 gage) in an aqueous solution of 300 ml of 5% (w / w) calcium chloride which had been stirred at 100 rpm to instantaneously cure to form beads . After curing time was about 5-15 minutes, it was washed with distilled water. The resulting beads were filtered using filter paper (qualitative circles, 185 mmΦ) and dried at 60 ° C for 12 hours or more by vacuum pump. The dried composite was pulverized using a granulator mill.

&Lt; Example 6 >

4 g of marbophousasin (40 mg / ml) and 4 g of alginate (40 mg / ml, sigma-aldrich) were added to 100 ml of tertiary distilled water (Waters Milli-Q) at a concentration ratio of 1: 1 using a homogenizer To form a complex. The complex was slowly cured at a height of 10-30 cm at a water surface using a syringe (21 gage) in an aqueous solution of 300 ml of 5% (w / w) calcium chloride which was being stirred at 100 rpm to instantaneously cure the beads . After curing time was about 5-15 minutes, it was washed with distilled water. The resulting beads were filtered using filter paper (qualitative circles, 185 mmΦ) and dried at 60 ° C for 12 hours or more by vacuum pump. The dried composite was pulverized using a granulator mill.

&Lt; Example 7 >

4 g of alginate (40 mg / ml, Sigma-aldrich) was added to 100 ml of tertiary distilled water (Waters Milli-Q) at a concentration ratio of 2: 1 using homogenizer To form a complex. The complex was slowly cured at a height of 10-30 cm at a water surface using a syringe (21 gage) in an aqueous solution of 300 ml of 5% (w / w) calcium chloride which was being stirred at 100 rpm to instantaneously cure the beads . After curing time was about 5-15 minutes, it was washed with distilled water. The resulting beads were filtered using filter paper (qualitative circles, 185 mmΦ) and dried at 60 ° C for 12 hours or more by vacuum pump. The dried composite was pulverized using a granulator mill.

&Lt; Example 8 >

16 g of Marbophousasin (160 mg / ml) and 4 g of alginate (40 mg / ml, sigma-aldrich) were added to 100 ml of tertiary distilled water (Waters Milli-Q) at a concentration ratio of 4: 1 using homogenizer To form a complex. The complex was slowly cured at a height of 10-30 cm at a water surface using a syringe (21 gage) in an aqueous solution of 300 ml of 5% (w / w) calcium chloride which was being stirred at 100 rpm to instantaneously cure the beads . The beads were washed with distilled water and then filtered using filter paper (Qualitative circles, 185 mmΦ). The beads were dried at 60 ° C for 12 hours or more with a vacuum pump. The dried composite was pulverized using a granulator mill.

< Example  9>

4 g of alginate (40 mg / ml, sigma-aldrich) was added to 100 ml of tertiary distilled water (Waters Milli-Q) at a concentration ratio of 8: 1 using homogenizer To form a complex. The complex was slowly cured at a height of 10-30 cm at a water surface using a syringe (21 gage) in an aqueous solution of 300 ml of 5% (w / w) calcium chloride which was being stirred at 100 rpm to instantaneously cure the beads . After curing time was about 5-15 minutes, it was washed with distilled water. The resulting beads were filtered using filter paper (qualitative circles, 185 mmΦ) and dried at 60 ° C for 12 hours or more by vacuum pump. The dried composite was pulverized using a granulator mill.

Test Example 1. The loading rate of cephalosporin antibiotic and the size of the powdered sustained particle of Example 1-4

The loading rate of the complex prepared by crosslinking and reduction of calcium with the cephalosporin antibiotic and alginate complex prepared in Example 1-4 was determined by diluting (10 μl: 1 ml) 1000 times of the aqueous solution filtered through the filter paper after curing the composite, (SI-600R) at 37 ° C after mixing the 20% (w / w) sodium acetate solution with the dissolution-eluting solution at a ratio of 3: 1. After 24-48 hours, (10 [mu] l: 1 ml), and the measurement was carried out using a UV / VIS spectrophotometer at 295 nm. The size of the powdered particles was measured using an electrophoretic light scattering spectrometer (ELS-Z).

In the elution test, a predetermined amount (20 mg / ml) of the sustained-release preparation prepared according to the Example was added to a PBS shaking incubator (SI-600R) stirred at 37 ° C and the time (0, 1, 2, 4, 8, 12, 24, and 48 hours), and quantitative analysis was performed at 295 nm on a UV / VIS spectrophotometer. The size of the powdered particles was determined using a standard testing sieve (nominally 140, 106 μm) and measured using an electrophoretic light scattering spectrophotometer.

The measurement results are shown in Table 1 and Fig.

division Sample ID Loading rate (%) Particle Size (μm) Example 1 Cef 20 96.4 42 Example 2 Cef 40 97.2 35 Example 3 Cef 80 97.8 42 Example 4 Cef 160 97 50

Injection solutions containing cephalosporin antibiotic drugs were prepared according to the components and mixing ratios of the above examples. As a result of the elution test, it was found that the duration of the drug efficacy was superior to the known cephalosporin antibiotic drugs.

The amount of elution was experimented by preparing a sustained-release preparation according to the compounding ratio of the above Example. The sustained-release suspension had a high release rate from the initial release to the 12-hour release, but had little change in the cumulative release over time and a small amount of release over a period of time. Therefore, the sustained-release preparation (suspension composition) containing the cephalosporin antibiotic according to the present invention was found to be extended to 24 hours by continuously showing the efficacy.

Test Example 2. Loading rate of cephalosporin antibiotic and size of powdered sustained particle of Example 5-9

The loading rate of the complex prepared by crosslinking and reducing calcium with the cephalosporin antibiotic prepared in Example 5-9 and the alginate complex was determined by diluting (10 μl: 1 ml) 1000 times of the aqueous solution filtered through the filter paper after curing the composite, Alternatively, 20% (w / w) sodium acetate solution is mixed with the dissolution-eluted solution at a ratio of 3: 1 and then placed in a shaking incubator (SI-600R) at 37 ° C. After 24-48 hours, (10 [mu] l: 1 ml) at a wavelength of 295 nm using a UV / VIS spectrophotometer (mecasys, optizen 2120UV).

In the elution test, a predetermined amount (20 mg / ml) of the sustained-release preparation prepared according to the Example was added to a PBS shaking incubator (SI-600R) stirred at 37 ° C and the time (0, 1, 2, 4, 8, 12, 24, and 48 hours), and quantitative analysis was performed at 295 nm on a UV / VIS spectrophotometer.

The size of the powdered particles was determined using a standard testing sieve (nominally 140, 106 μm) and electrophoretic light scattering spectrophotometer (ELS-Z).

The measurement results are shown in Table 2 and FIG.

division Sample ID Loading rate (%) Particle Size (μm) Example 5 Marbo 20 81.6 45 Example 6 Marbo 40 90.4 47 Example 7 Marbo 80 95.4 45 Example 8 Marbo 160 97.7 33 Example 9 Marbo 320 98.4 35

Injection solutions containing cephalosporin antibiotic drugs were prepared according to the components and mixing ratios of the above examples. As a result of the elution test, it was found that the duration of the drug efficacy was superior to the known cephalosporin antibiotic drugs.

The amount of elution was experimented by preparing a sustained-release preparation according to the compounding ratio of the above Example. The sustained-release suspension had a high release rate from the initial release to the 12-hour release, but had little change in the cumulative release over time and a small amount of release over a period of time. Therefore, the sustained-release formulation containing the cephalosporin antibiotic according to the present invention (present liquid composition) shows prolonged efficacy and is extended to 24 hours.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (10)

Wherein the cephalosporin antibiotic is ceftiofur or ceftiofur sodium, the alginate is cross-linked with each other by divalent cations to form particles, , Wherein the cephalosporin antibiotic is hydrogen bonded or ion-bonded to the carboxyl group of the alginate which is crosslinked to form the particle, and the sustained release preparation of cephalosporin antibiotic.
The sustained-release formulation according to claim 1, wherein the particles have a diameter of 10-100 탆.
The sustained release formulation of claim 1, wherein the sustained release formulation comprises alginate in a ratio of 1: 0.1-10 relative to the weight of the cephalosporin antibiotic.
The sustained release formulation of claim 1, wherein the sustained release formulation comprises 0.2 to 20% by weight cephalosporin antibiotic.
A marbofloxacin antibiotic and an alginate, wherein the alginate is cross-linked with each other by divalent cations to form particles, and the marbophloxacin antibiotic is crosslinked to form a hydrogen bond or an amide bond to the carboxy group of the alginate, Lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt;
(i) a pharmaceutically effective amount of a sustained release formulation of an antibiotic according to any one of claims 1 to 5; And (ii) a pharmaceutically acceptable carrier.
7. The pharmaceutical composition according to claim 6, wherein the sustained-release pharmaceutical composition is an injection.
7. The pharmaceutical composition according to claim 6, wherein the sustained release pharmaceutical composition is a suspension.
(a) hydrogen bonding or ion-binding a cephalosporin antibiotic to the carboxy group of an alginate to form a cephalosporin antibiotic-alginate complex, wherein the cephalosporin antibiotic is ceftiofur or ceftiofur sodium ; And
(b) treating the complex obtained in step (a) with a solution containing a salt of a divalent cation to induce ionic crosslinking by a divalent cation between the alginate of each complex; and a cephalosporin antibiotic &Lt; / RTI &gt;
The process according to claim 9, wherein the salt of the divalent cation is calcium chloride.

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