KR101548622B1 - Sustained-release preparations of quinolone antibiotic and Sustained-release antibiotic pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention relates to a sustained-release preparation of a quinolone antibiotic, a sustained-release antibiotic pharmaceutical composition comprising the same, and a method for producing the sustained-release preparation. The suspension injections containing the sustained release formulations of the quinolone antibiotics of the present invention exhibit the efficacy continuously even with a single administration, so that the inconvenience of the conventional agents administered consecutively for 3 consecutive days can be solved, and even if left standing for a long time High stability. 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 quinolone antibiotic and sustained-release antibiotic pharmaceutical composition comprising the same,

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

Quinolone antibiotics are widely used for Gram-positive and Gram-negative bacteria. In particular, it is a drug that works effectively against Gram-negative bacteria.

(9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo- (4,2,1) benzo-adiazine-6-carboxylic acid) is the most recently developed third-generation fluoroquinolone antibiotic and has a broad spectrum. It has a spectrum of gram-positive and gram- It works extensively. In particular, it acts effectively against Gram-negative bacteria and acts on two target protein DNAs of bacteria, gyrase and topoisomerase IV, to slow the production of the strain. In particular, Marbophloxacin has excellent therapeutic effects against diarrhea, pneumonia, infectious gastroenteritis or mastitis of domestic animals or poultry such as pigs and cows caused by Actino Bacillus, Salmonella, Passelella, Streptococcus, Mycoplasma or Hemophilus . Therefore, it is recommended as an antimicrobial agent to be selected as a primary choice in case of illness on the farm.

However, marbophloxacin is poorly soluble and is usually formulated in the form of hydrochloride or sodium salt, but it is a limiting factor in the development of suspension injections due to instability due to moisture.

Quinolone drugs are prepared in colloidal form and injected into the animal. In general, the suspending agent should have properties such as therapeutic efficacy, physical and chemical stability of the drug substance, durability of the drug product, and apparent beautification. However, quinolone drug formulations currently available have a short duration of drug efficacy, There is a problem that the sedimentation speed of the particles is so fast that it is difficult to reproduce the particles.

Prior art relating to a suspension injecting agent is a medicine containing fluoroquinolones using an ammonium compound (International Patent Publication No. WO 2008-025380) or an aqueous composition using a nicotinamide as a solubilizing agent (Korean Patent Registration No. 10-0106603) . There is also stabilization of oily suspensions containing hydrophobic silica (International Patent Publication No. WO 2009-065514) and there is a persistent formulation technology (WO 94/20505) in which the active ingredient is dispersed in vegetable oil as a non-aqueous suspension injectable.

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. In addition, commercially available magofuroxacin preparations have disadvantages in that they are dissolved in water when they are used as a powder-formulated preparation by freeze-drying in an aseptic state for stabilizing the active ingredient, and the manufacturing process is complicated. In addition, commercially available injections are formulated in the form of sodium salt, but they are rapidly distributed in the blood plasma and have a short half-life of the drug, and short duration of the drug can cause side effects such as cartilage abnormalities, vomiting, diarrhea and central nervous system disorders.

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 found that quinolone-based antibiotics can be easily decomposed in the body or delayed rapid release through the kidneys, thereby providing a convenience of administration by sustaining the drug efficacy and developing a sustained-release formulation of a quinolone drug with excellent redispersibility and bioavailability Research efforts. As a result, it was found that a polymer-drug complex in which a quinolone drug and a biodegradable polymer were ionically interposed was developed, and that the formulation containing the same was a sustained release formulation capable of continuously releasing a quinolone antibiotic. .

Accordingly, an object of the present invention is to provide a sustained-release preparation of a quinolone antibiotic.

Another object of the present invention is to provide a sustained-release antibiotic pharmaceutical composition.

It is still another object of the present invention to provide a method for producing a sustained release formulation of a quinolone 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, there is provided a sustained-release preparation of a quinolone antibiotic comprising a polymer-drug complex formed by ion-binding a quinolone antibiotic with polyacrylic acid or chitosan as a biodegradable polymer, Ml, 37 ° C, and a rotation rate of 95 rpm in a shaking incubator, the dissolution rate of the drug at 24 hours was 5-40% or 45-85%, or 200 ml of a phosphate buffer solution at pH 7.4 , A 37 ° C temperature, and a rotation rate of 95 rpm in a shaking incubator, the dissolution rate of the drug at 24 hours is 20-55% or 70-80%, the sustained release form of the quinolone antibiotic The formulation is provided.

The present inventors have found that quinolone-based antibiotics can be easily decomposed in the body or delayed rapid release through the kidneys, thereby providing a convenience of administration by sustaining the drug efficacy and developing a sustained-release formulation of a quinolone drug with excellent redispersibility and bioavailability Research efforts. As a result, we have developed a polymer-drug complex in which a quinolone drug and a biodegradable polymer are ionically bound, and confirmed that the formulation containing the quinolone antibiotic is a sustained release formulation capable of continuously releasing a quinolone antibiotic.

The above-mentioned quinolone antibiotic is an active ingredient showing pharmacological activity, and forms a polymer-drug complex by ion-binding with a biodegradable polymer such as polyacrylic acid or chitosan. In the present invention, any quinolone antibiotic having a functional group capable of forming a bond (ionic bond) with a functional group (for example, a carboxyl group or an amine group) of the biodegradable polymer (for example, an amine group or a carboxyl group) can be used without limitation.

According to one embodiment of the present invention, the quinolone antibiotic is selected from the group consisting of marbofloxacin, trovafloxacin, gatifloxacin, prulifloxacin, gemifloxacin, , Sitafloxacin, and clinafloxacin. ≪ Desc / Clms Page number 2 >

In one specific example, the quinolone antibiotic is marbloxacin. As shown in the following figure, the marbloxacin has an amphoteric property and can be ion-bonded to the biodegradable polymer.

In another specific example, the quinolone antibiotic is selected from the group consisting of marbloxacin, trovafloxacin, gatifloxacin, prulifloxacin, gemifloxacin, sitafloxacin, ) And clinafloxacin. ≪ / RTI >

The biodegradable polymer functions as a release modifier of the active ingredient quinolone antibiotic. According to the present invention, when polyacrylic acid or chitosan is administered into the body, the pH increases due to buffering action in the body, so that crosslinking of the polymer is formed and viscosity is increased. Therefore, as the PH is higher, the quinolone antibiotic rapidly dissolves and the diffusion accelerating property can be controlled by the biodegradable polymer (see FIG. 1).

According to one embodiment of the present invention, the quinolone antibiotic has an average diameter of 10-100 mu m.

The content of the biodegradable polymer as the release modifier may be different depending on the kind. According to one embodiment of the present invention, the weight ratio of the quinolone antibiotic and the biodegradable polymer is 1: 0.1-10. If the content of the biodegradable polymer is less than 0.1, the dispersibility of the main component may be a problem. If the content of the biodegradable polymer exceeds 10, dilution of the concentration may cause inconvenience in use.

In one specific example, the weight ratio of the quinolone antibiotic to the biodegradable polymer is 1: 0.5-4.

According to an embodiment of the present invention, the sustained-release preparation of the quinolone antibiotic includes a polymer-drug complex formed by ion-bonding an amine group of a quinolone antibiotic to a carboxyl group of a polyacrylic acid, wherein 200 ml of a KOH solution having a pH of 11, 37 When the dissolution rate of the drug was measured at a temperature of 0 ° C and a rotation speed of 95 rpm in a shaking incubator, the drug dissolution rate at 24 hours was 5-40%, or 200 ml of phosphate buffer solution at pH 7.4, 37 ° C, At a rotation speed of 95 rpm, the drug elution rate at 24 hours is 20-55%.

In one particular example, the drug elution rate at 24 hours measured in the KOH solution is 10-40% and the drug elution rate at 24 hours measured in the phosphate buffer solution is 25-55%.

According to another embodiment of the present invention, the polymer-drug complex comprises a polymer-drug complex formed by ion-bonding a carboxyl group of a quinolone antibiotic to an amine group of a chitosan, wherein 200 ml of a KOH solution having a pH of 11, , A drug elution rate of 45-85% at 24 hours, or 200 ml of a phosphate buffer solution at pH 7.4, at 37 ° C, in a shaking incubator at a rotation rate of 95 rpm in a shaking incubator, When the drug dissolution rate is measured at a rate of 95 rpm, the drug dissolution rate at 24 hours is 70-80%.

In one particular example, the drug elution rate at 24 hours measured in the KOH solution is 50-80% and the drug elution rate at 24 hours measured in the phosphate buffer solution is 75-80%.

According to one embodiment of the present invention, the dissolution rate is a value measured at 295 nm in a spectrophotometer by diluting the sample 100 times.

According to one embodiment of the present invention, the sustained-release preparation comprises 0.2 to 20% by weight of a quinolone antibiotic.

As confirmed in the Examples below, the sustained release formulations of the present invention can extend the duration of the quinolone antibiotic to 96 hours (see Figures 2 and 5). 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 present invention, the present invention provides a pharmaceutical composition comprising (i) a pharmaceutically effective amount of a sustained release formulation of said quinolone antibiotic; And (ii) a pharmaceutically acceptable carrier.

The pharmaceutical composition of the present invention comprises a pharmaceutically effective amount of a sustained release formulation of a quinolone antibiotic. 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.

In one particular example, the pharmaceutical composition may be administered intramuscularly or subcutaneously into an animal, such as cattle, pigs, etc., or poultry.

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 present invention, the pharmaceutical composition is an injection.

According to one embodiment of the invention, the pharmaceutical composition is a suspension.

According to one embodiment of the present invention, the pharmaceutical composition is an antibiotic composition and is used as an antibiotic composition for the prevention or treatment of 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 for producing a biodegradable polymer, comprising the steps of: (a) adding a quinolone antibiotic and a biodegradable polymer, such as polyacrylic acid or chitosan, And (b) stirring the mixed solution of step (a) to form a polymer-drug complex in which a quinolone antibiotic is ionically bound to a biodegradable polymer, wherein the quinolone antibiotic is ion- to provide.

According to one embodiment of the present invention, the solvent is distilled water or HCl solution.

According to one embodiment of the present invention, the concentration ratio of the quinolone antibiotic and the biodegradable polymer is 1: 0.1-10. In one specific example, the concentration ratio of the quinolone antibiotic to the biodegradable polymer is 1: 0.5-4.

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

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

(b) The present invention maximizes efficacy with relatively small drug doses to reduce the frequency of dosing.

(c) The suspension injections containing the sustained release formulations of the quinolone antibiotics of the present invention exhibit the efficacy continuously only by single administration, so that the inconvenience of the conventional agents administered consecutively for 3 consecutive days can be resolved, Even if left untreated, stability is high.

(d) Therefore, the present invention can be usefully used as a therapeutic agent for antibiotics and respiratory diseases of animals.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the action of the polymer-drug complex of the present invention. FIG.
FIG. 2 is a graph showing the dissolution rate of polyacrylic acid-magfloxacin sustained-release suspension at pH 11. FIG.
3 is a graph showing the dissolution rate of chitosan-marbophloxacin sustained-release suspension at pH 11.
4 is a graph showing the dissolution rate at pH 7.4 of the polyacrylic acid-magfloxacin sustained-release suspension.
FIG. 5 is a graph showing the dissolution rate of chitosan-mabofloxacin sustained-release suspension at pH 7.4. FIG.

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 1-7. Manufacture of sustained release formulations of quinolone antibiotics

≪ Example 1 >

To prepare a sustained-release suspension, 100 mg of Marbofloxacin (10 mg / ml) was granulated to a particle size of 100 쨉 m or less by a granulator mill. 50 mg of polyacrylic acid (PAA) and 100 mg of marbloxacin (10 mg / ml) (concentration ratio 0.5: 1) were dissolved in 10 ml of tertiary distilled water (Waters Milli-Q) using a homogenizer And uniformly mixed to form a complex.

≪ Example 2 >

In order to prepare a sustained-release suspension, 100 mg of marbloxacin (10 mg / ml) was granularly milled to a particle size of 100 쨉 m or less. 100 mg of polyacrylic acid and 100 mg of magofloxacin (10 mg / ml) (concentration ratio 1: 1) were uniformly mixed in 10 ml of tertiary distilled water (Waters Milli-Q) using a homogenizer to form a complex.

≪ Example 3 >

In order to prepare a sustained-release suspension, 100 mg of marbloxacin (10 mg / ml) was granularly milled to a particle size of 100 쨉 m or less. 200 mg of polyacrylic acid and 100 mg of magofloxacin (10 mg / ml) (concentration ratio 2: 1) were mixed homogeneously in 10 ml of tertiary distilled water (Waters Milli-Q) to form a complex.

<Example 4>

In order to prepare a sustained-release suspension, 100 mg of marbloxacin (10 mg / ml) was granularly milled to a particle size of 100 쨉 m or less. 50 mg of chitosan (intermediate molecular weight) and 100 mg of magofloxacin (10 mg / ml) (concentration ratio 0.5: 1) were homogeneously mixed in 10 ml of HCl (0.1 M) to form a complex by homogenizer. And the mixture was stirred at 60 占 폚 for 30 minutes.

&Lt; Example 5 >

In order to prepare a sustained-release suspension, 100 mg of marbloxacin (10 mg / ml) was granularly milled to a particle size of 100 쨉 m or less. 100 mg of chitosan (intermediate molecular weight) and 100 mg of magofloxacin (10 mg / ml) (concentration ratio 1: 1) were homogeneously mixed in 10 ml of HCl (0.1 M) to form a complex. And the mixture was stirred at 60 占 폚 for 30 minutes.

&Lt; Example 6 >

In order to prepare a sustained-release suspension, 100 mg of marbloxacin (10 mg / ml) was granularly milled to a particle size of 100 쨉 m or less. 200 mg of chitosan (intermediate molecular weight) and 100 mg of magofloxacin (10 mg / mL) (concentration ratio 2: 1) were homogeneously mixed in 10 mL of HCl (0.1 M) to form a complex. And the mixture was stirred at 60 占 폚 for 30 minutes.

&Lt; Example 7 >

In order to prepare a sustained-release suspension, 100 mg of marbloxacin (10 mg / ml) was granularly milled to a particle size of 100 쨉 m or less. 400 mg of chitosan (intermediate molecular weight) and 100 mg of magofloxacin (10 mg / ml) (concentration ratio 4: 1) were homogeneously mixed in 10 ml of HCl (0.1 M) to form a complex. And the mixture was stirred at 60 占 폚 for 30 minutes.

Test example. Measurement of elution of polymer-drug complex

The elution amount of the polymer-drug complex was measured. The amount of elution was tested by preparing a sustained-release suspension according to the compounding ratio of the above-mentioned Examples. The eluate was measured in the PH in which the quinolone antibiotic magofloxacin was dissolved and in the PH, respectively. The pH at which the marbophocosin was dissolved was adjusted to pH 11 using KOH (200 ml). The internal pH was performed at pH 7.4 with phosphate buffer (200 ml). The mixture was placed in a shaking incubator (SI-600R, 95 rpm) at 37 ° C for 24-96 hours and diluted 100-fold and measured at 295 nm using a UV / VIS spectrophotometer (mecasys, optizen 2120UV, Korea).

The sustained-release suspension of the present invention had a large amount of release from the initial release to the 12-hour time but had little change in the cumulative release amount over time and a small amount of release over a certain period of time. Therefore, the sustained-release formulation containing the quinolone antibiotic drug according to the present invention shows prolonged efficacy, and thus it is extended to 96 hours (Figs. 2 to 5).

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 (14)

A sustained-release preparation of a quinolone antibiotic comprising a polymer-drug complex formed by ion-binding a quinolone antibiotic with polyacrylic acid or chitosan as a biodegradable polymer,
when the drug elution rate is measured under the conditions of 200 ml of a KOH solution at pH 11, a temperature of 37 ° C, and a rotation speed of 95 rpm in a shaking incubator, the drug elution rate at 24 hours is 5-40% or 45-85%
when the drug elution rate was measured under the conditions of 200 ml of a phosphate buffer solution of pH 7.4 at 37 ° C and a rotation rate of 95 rpm in a shaking incubator, the drug elution rate at 24 hours was 20-55% or 70-80%
The quinoline antibiotic may be selected from the group consisting of marbofloxacin, trovafloxacin, gatifloxacin, prulifloxacin, gemifloxacin, sitafloxacin, Wherein the antibiotic is one or more antibiotics selected from the group consisting of clinafloxacin.
The sustained-release preparation according to claim 1, wherein the quinolone antibiotic has an average diameter of 10-100 [mu] m.
The sustained-release preparation according to claim 1, wherein the weight ratio of the quinolone antibiotic to the biodegradable polymer is 1: 0.1-10.
The sustained-release preparation according to claim 1, wherein the weight ratio of the quinolone antibiotic to the biodegradable polymer is 1: 0.5-4.
The sustained-release preparation according to claim 1, wherein the quinolone antibiotic is marbofloxacin.
6. The method according to claim 5, wherein the quinolone antibiotic is selected from the group consisting of maburofloxacin, trovafloxacin, gatifloxacin, prulifloxacin, gemifloxacin, sitafloxacin) and clinafloxacin. &lt; RTI ID = 0.0 &gt; 8. &lt; / RTI &gt;
The sustained-release preparation of the quinolone antibiotic according to claim 1, wherein the sustained release formulation of the quinolone antibiotic comprises a polymer-drug complex formed by ion-bonding an amine group of a quinolone antibiotic to a carboxyl group of a polyacrylic acid,
when the drug elution rate was measured under the conditions of 200 ml of a KOH solution at pH 11, a temperature of 37 캜, and a rotation speed of 95 rpm in a shaking incubator, the drug elution rate at 24 hours was 5-40%
characterized in that the dissolution rate of the drug at 24 hours is 20 to 55% when the drug dissolution rate is measured at 200 ml of a phosphate buffer solution at pH 7.4, at a temperature of 37 캜, and at a rotation rate of 95 rpm in a shaking incubator. .
The pharmaceutical composition according to claim 1, wherein the polymer-drug complex comprises a polymer-drug complex formed by ion-bonding a carboxyl group of a quinolone antibiotic to an amine group of chitosan,
when the drug elution rate was measured under the conditions of 200 ml of a KOH solution of pH 11, a temperature of 37 ° C, and a rotation speed of 95 rpm in a shaking incubator, the drug elution rate at 24 hours was 45-85%
characterized in that the dissolution rate of the drug at 24 hours is 70 to 80% when the drug dissolution rate is measured at 200 ml of a phosphate buffer solution at pH 7.4, at a temperature of 37 캜, and at a rotation rate of 95 rpm in a shaking incubator. .
(i) a pharmaceutically effective amount of a sustained release formulation of a quinolone antibiotic according to any one of claims 1 to 8; And
(ii) a sustained-release antibiotic pharmaceutical composition comprising a pharmaceutically acceptable carrier.
10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is an injection.
10. The pharmaceutical composition according to claim 9, wherein the pharmaceutical composition is a suspension.
(a) adding a quinolone antibiotic and a biodegradable polymer such as polyacrylic acid or chitosan to a solvent which is distilled water or an HCl solution; And
(b) stirring the mixed solution of step (a) to form a polymer-drug complex in which a quinolone antibiotic is ion-bonded to a biodegradable polymer.
delete 13. The method according to claim 12, wherein the concentration ratio of the quinolone antibiotic to the biodegradable polymer is 1: 0.5-4.

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