KR101473979B1 - Pharmaceutical composition comprising marbofloxacin - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising magofloxacin, comprising magofloxacin, and a solubilizer, wherein the solubilizer is meglumine. The magabo flocasin preparation of the present invention has an effect of exhibiting high storage stability, particularly high temperature storage stability, while being a preparation in a basic range.

Description

[0001] PHARMACEUTICAL COMPOSITION COMPRISING MARBOFLOXACIN [0002]

The present invention relates to a pharmaceutical composition comprising magok flocasin.

Marbophloxacin is a third-generation fluoroquinolone antibiotic and its IUPAC name is 9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-7H-pyridol 3,2,1-ij) (4,2,1) benzoxadiazin-6 carboxylic acid, and has a structure represented by the following formula (1).

Mabrofloxacin acts to inhibit bacterial DNA replication and exhibits an antibiotic effect. It has a shorter duration of abstinence than conventional antibiotics, and has antimicrobial effects against major respiratory pathogens such as Pasteurella and Bordetella. Other fluroquinolone compounds It is known to be superior to antibiotics.

Marbophylline is mainly used as an antibiotic for veterinary purposes in livestock such as cats, dogs, horses, cattle, pigs, etc. It is currently marketed under the trade name Marbocyl ^TM or Zeniquin ^TM .

Marbophloxacin is prescribed for veterinary purposes for the prevention and treatment of bacterial infections in animals such as livestock, and is administered mainly in the form of injections.

However, the fluoroquinolone antibiotic preparations including marbophocosaccharide have a problem that they do not have good tolerance according to various kinds of animals.

For example, resistance measured in calves can not be expected in pigs, dogs or cats, and vice versa (ie, injectable solutions resistant to dogs are not necessarily resistant to cats or calves).

In particular, local tolerance is very important for pets such as dogs and cats, as opposed to livestock such as cattle and pigs.

Because pet owners can be very sensitive to local intolerance such as swelling, pain and the like, varietal variants frequently performed in pet parts often respond much more sensitively to subcutaneous injections compared to livestock .

Thus, it is not surprising that most fluoroquinolone injections, including maglofocarcin, can not be used in other species as a result of lack of tolerance.

There are a variety of factors that affect tolerance, but pH range is one of the main factors affecting tolerance.

In order to show the most tolerance, it is recommended to keep the pH of the solution as neutral as possible (about pH 7.4), but magofloxacin shows poor solubility at neutral pH. That is, marbloxacin has somewhat low solubility in neutral water (pH 7.0 to 7.52 mg / l).

Such a low solubility of marbloxacin may also be a problem in the production of low-concentration preparations, but it may become a big problem especially when high-concentration injections of 10 wt% or more are manufactured. This is because, due to low solubility, it causes particle formation and the like in the injection, often failing to exhibit storage stability.

Because of this, most of the currently available magabo flocasin preparations have an acid range of about 2.0 to 6.0 in order to improve the solubility and the stability of the preparation.

Conventional techniques for a marbophloxacin preparation having an acidic pH range can be understood with reference to Patent Documents 1 to 2 below. As a result, all of the contents of the following patent documents 1 to 2 are cited as contents of the present invention relating to the prior art.

Patent Literature 1 discloses a formulation for a marbophoscar injected agent, wherein the pH of the injection solution is in the range of 2 to 8, preferably in the range of 2.8 to 5. [

Patent Document 2 discloses an example of a pharmacological preparation that has been adjusted to a pH of about 2.11 with phosphoric acid as a phloroquinolone-based preparation containing Marbophloxacin.

WO 2007/085760 A2 WO 2007/097888 A2

As can be understood with reference to Patent Documents 1 to 2, a conventional marbophloxacin injection preparation having tolerance is mostly in the acidic range. As described above, if the pH range of the preparation is different, It would be highly desirable to provide a magabloxacin basic formulation that can be applied to animals that are intrinsic to acidic magok flocasin by formulating them in a pH range that is different from that of the prior art, as animals may be different.

However, the inventors of the present invention have found that, in the case of basic preparations, stability of the composition is somewhat weak, such as browning during storage, rather than in the case of acidic preparations.

In particular, since the injection of marbophoscacin, which is mainly used as a veterinary medicine, is often stored in a farm or a warehouse of a housing facility, the storage environment is generally poor, and a high temperature and high humidity such as a midsummer in East Asia including South Korea or Southeast Asia In view of the fact that products are susceptible to browning under environmental conditions, it is inevitable to develop a magoblocrobicin preparation having high storage stability.

Although Patent Document 1 refers to the formation of precipitate at low temperature of magofloxacin preparation, it has not been disclosed in the case of a country where high temperature environment may be a problem, in the case of a suitable preparation. That is, Patent Document 1 only mentions low-temperature stability and does not disclose a preparation having a high-temperature stability.

Accordingly, the applicant intends to provide a mablofloxacin preparation which is a basic preparation having a different range of resistance applicable to a conventional marbloxacin preparation, and which has high storage stability at a high temperature.

The present invention has been made to solve the problems of the prior art,

Maburofloxacin, and a solubilizing agent,

Wherein the solubilizing agent is meglumine.

In addition, the present invention provides a pharmaceutical composition, wherein the pH of the composition is within a range of 9-12.

Also, the present invention provides a pharmaceutical composition, wherein the marbophloxacin is contained in an amount of 1% by weight to 30% by weight relative to the total composition.

Also, the present invention provides a pharmaceutical composition, wherein the solubilizer is contained in an amount of 3 wt% to 60 wt% with respect to the total composition.

In the present invention, there is also provided a pharmaceutical composition characterized by having a ratio of magofloxacin: solubilizer = 1: 0.9 to 4 molar ratio.

The present invention also provides a pharmaceutical composition, which further comprises dimethyl sulfoxide as a dissolution aid.

Also, in the present invention, the dissolution aids are contained within the range of 0.2 wt% to 20 wt% with respect to the total composition.

In the present invention, there is also provided a pharmaceutical composition, wherein the pharmaceutical composition is in the form of tablets, capsules, powders, granules, emulsions, suspensions, liquids or injections.

The magabo flocasin preparation of the present invention has an effect of exhibiting high storage stability, particularly high temperature storage stability, while being a preparation in a basic range.

1 is a graph showing pH profiles for Example 1 and Comparative Examples 1 to 3 under accelerated test conditions.
2 is a graph showing the pH profiles for Example 1 and Comparative Examples 1 to 3 under long-term storage test conditions.
3 is a photograph showing changes in properties of Example 1 under long-term storage test conditions.
4 is a photograph showing the change in properties of Comparative Example 3 under long-term storage test conditions.
Fig. 5 is a photograph showing changes in properties of Comparative Example 1 under long-term storage test conditions. Fig.
6 is a photograph showing the change in properties of Comparative Example 2 under long-term storage test conditions.
Fig. 7 is a photograph showing changes in properties of Example 1 under accelerated test conditions. Fig.
8 is a photograph showing changes in properties of Comparative Example 3 under accelerated test conditions.
9 is a photograph showing changes in properties of Comparative Example 1 under accelerated test conditions.
10 is a photograph showing the change in properties of Comparative Example 2 under accelerated test conditions.
11 is a photograph showing changes in properties of Example 1 and Comparative Example 1 under accelerated test conditions (Example 1 (Example 1), Comparative Example 1 (right), and 29 days after elapse of 1 day and 13 days (Comparative Example 1) and Example 1 (right)).
Fig. 12 is a photograph comparing changes in properties of Example 1 and Comparative Example 1 under severe test conditions (No. 1: heating property of Example 1, No. 2: properties after heating for 1 hour in Example 1, No. 3, after heating for 2 hours in Example 1, and after heating for 1 hour and 30 minutes in Comparative Example 1).
13 is a graph of transmittance measurement of Example 1 under long-term storage test conditions.
14 is a graph of transmittance measurement of Comparative Example 3 under long term storage test conditions.
15 is a graph of transmittance measurement of Comparative Example 1 under long term storage test conditions.
16 is a graph of transmittance measurement of Comparative Example 2 under long term storage test conditions.
17 is a graph of transmittance measurement of Example 1 under accelerated test conditions.
18 is a graph of transmittance measurement of Comparative Example 3 under accelerated test conditions.
19 is a graph of transmittance measurement of Comparative Example 1 under accelerated test conditions.
20 is a graph of transmittance measurement of Comparative Example 2 under accelerated test conditions.
Fig. 21 is a graph of absorbance measurement of Example 1 under long-term storage test conditions. Fig.
22 is a graph showing the absorbance of Comparative Example 3 under long-term storage test conditions.
23 is a graph showing the absorbance of Comparative Example 1 under long-term storage test conditions.
24 is a graph showing the absorbance of Comparative Example 2 under long-term storage test conditions.
25 is a graph of absorbance measurement of Example 1 under accelerated test conditions.
26 is a graph showing the absorbance of Comparative Example 3 under accelerated test conditions.
Fig. 27 is a graph showing the absorbance of Comparative Example 1 under accelerated test conditions. Fig.
28 is a graph showing the absorbance of Comparative Example 2 under accelerated test conditions.
Fig. 29 is a photograph of changes in properties of Examples 1 to 3 under severe test conditions (numeral% in the circle in Fig. 29 indicates the concentration of dimethylsulfoxide, 1% in Examples 3, 5% for Example 1, and 10% for Example 4).

Hereinafter, the present invention will be described in detail.

The present invention comprises magofloxacin, and a solubilizer, wherein the solubilizer is meglumine.

The above-mentioned meglumine is a known compound having an IUPAC name of 6-methylaminohexane-1,2,3,4,5-pentol and a structure represented by the following general formula (2).

In the present invention, magofuroxacin is poorly soluble at neutral pH, and thus, meglumine is used as a dissolution agent in order to dissolve magofloxacin and formulate it.

Although meglumine is a somewhat weak basic substance as compared with strongly basic compounds sodium hydroxide and potassium hydroxide, it is effective enough to dissolve marbophloxacin and formulate it. In particular, sodium glyphosate and potassium hydroxide are used to formulate meglumine In contrast, when meglumine is used, stability at high temperature storage is greatly improved. The present inventors have discovered the properties of such meglumine and have carried out subsequent studies to complete the present invention. In the present invention, more specific reasons for selecting meglumine as a solubilizer will be understood with reference to Examples and Experimental Examples to be described later.

The pH of the composition is preferably in the range of 9-12. Marbophloxacin can be dissolved in the acidic range, but in the present invention, the application range is expanded to be applicable to animals having an intolerance to conventional acid range preparations (e.g., Marbocyl ^TM ) In particular to the basic range. Even in the basic range, when the pH is less than 9, the solubility of magofloxacin is low and a precipitate may be formed. When the pH is more than 12, it is not preferable because the base resistance may be poor due to strong basicity. More preferably, the pH is within the range of 9 to 10.

The magofuroxacin may be contained in an amount of 1 to 30% by weight, more preferably 5 to 30% by weight, and more preferably 10 to 30% by weight, based on the whole composition. When the concentration is less than 1% by weight, there is an inconvenience that the administration frequency and volume are increased, and when the concentration is higher than 30% by weight, the solubility of the marbled flocosin is difficult to be adjusted and the deposit may be formed.

It is preferable that the solubilizer is contained within a range of 3 to 60% by weight relative to the total composition. If it is less than 3% by weight, it may not be an amount sufficient to uniformly dissolve marbled flocasin, and if it exceeds 60% by weight, the pH may be excessively increased and the local tolerance may be poor.

Particularly, in terms of the solubility of marbophlogasin and the pH of the preparation, it is preferable that the marbophloxacin and the solubilizer are in a ratio of 1: 0.9 to 4 molar ratio of marbophocosaccharin: solubilizer.

In the present invention, it is preferable to further include dimethyl sulfoxide as a dissolution aid in the composition. It is more advantageous in terms of prevention of the formation of insoluble fine particles and prevention of discoloration at high temperatures because the dissolution assistant is added in terms of solubility because the mablofun is melted with meglumine having a slightly weaker basicity than sodium hydroxide or potassium hydroxide.

The dissolution aid is preferably contained in an amount of 0.2 to 20% by weight based on the total composition. When the content is less than 0.2% by weight, the effect of preventing the formation of insoluble fine particles and the effect of preventing high-temperature discoloration may be insufficient. If the content is more than 20% by weight, the effect of preventing high-temperature discoloration may be lowered. A more detailed description thereof will be understood through the following embodiments.

The formulation of the pharmaceutical composition of the present invention is preferably an injection, but is not particularly limited, and may be a tablet, a capsule, a powder, a granule, an oil, a suspension, a liquid or an injection.

Hereinafter, the present invention will be described in more detail by way of examples. It is to be understood that the following embodiments are for the purpose of illustration only and are not intended to limit the scope of the present invention.

Example

Dimethyl sulfoxide as a solubilizing agent, sodium hydrogen sulfite as an antioxidant, n-butanol as an anhydrous agent, and benzyl alcohol as a preservative were sequentially added to the water for injection (distilled water), and then meglumine as a solubilizer was added thereto to adjust the pH to about 9.5 ± 1.0.

The main component, marbophloxacin, was added to the solution, and the mixture was mixed with water for injection (distilled water) so that the total amount of the liquid composition became 100 ml. Finally, a liquid composition adjusted to a pH within the range of about 9.5 ± 0.5 was prepared.

The above-mentioned steps were sequentially carried out to prepare a liquid composition which can be used for main use. The components of Examples 1 to 3 and Comparative Examples 1 to 3 were as shown in Table 1 below.

Experimental Example - stability experiment

The stability, the pH profile, the property, the transmittance, and the content variation were measured for the Examples 1 to 3 and Comparative Examples 1 to 3 prepared above.

The environmental conditions for each test were as follows.

- Accelerated test: 40 ℃, 75% RH, Glass container for injection (Type 2, USP grade)

- Long term storage test: 25 ℃, 60% RH, Glass container for injection (Type 2, USP grade)

- Severe test: 100 ℃, 1 ~ 2 hours heating

One. pH  profile( pH  profile)

The pH was measured according to the pH measurement method in the General Test Methods for Veterinary Drugs (National Veterinary Research and Quarantine Service) for Example 1 and Comparative Examples 1 to 3, and the results were as shown in FIG. 1 and FIG. FIG. 1 shows the acceleration test, and FIG. 2 shows the long-term storage test according to the environmental conditions.

As shown in FIG. 1 and FIG. 2, the pH profile of the test drug was maintained at an average value of 9.63 within the range of the veterinary drug compliance standard range of 8.5 to 10.5 as a result of preparing the pH profile under the individual stability test conditions for 6 weeks. In other words, the effect of the thermal insulator on the pH change is considered to be insignificant.

2. Appearance

(1) Comparison between Example 1 and Comparative Example 3

With respect to Example 1 and Comparative Examples 1 to 3, changes in properties were visually observed under acceleration test, long-term storage test, and severe test conditions for about 2 months or more. The results were as shown in Figs. 3 to 12. Figs. 3 to 7 are graphs showing the results of the comparison between Examples 1, 4 and 8, Comparative Examples 3, 5, and Fig. 9 is for Comparative Example 1, and FIG. 6 and FIG. 10 are for Comparative Example 2.

On the other hand, FIG. 11 compares the properties of Example 1 and Comparative Example 1 under accelerated test conditions (Example 1, Comparative Example 1, and 29 days after 1 day and 13 days, respectively) (Comparative Example 1) and Example 1 (right)).

As can be seen from Figs. 3 to 6, the stability of the properties of Example 1 and Comparative Example 3 was excellent under long-term storage test conditions.

7 to 11, under the accelerated test conditions, the discoloration patterns of Example 1 and Comparative Example 1 which are basically the same are similar, but the degree of discoloration of Example 1 was better than that of Comparative Example 1, In case of Example 2, discoloration to deep purple color was observed and the stability of the property was not the worst.

Fig. 12 compares the properties of Example 1 and Comparative Example 1 under the severe test conditions. (1) Properties of heating in Example 1, 2) Properties after heating for 1 hour in Example 1, 3) Heating for 2 hours in Example 1 (After heating for 1 hour and 30 minutes in Comparative Example 1).

As can be seen from FIG. 12, the degree of discoloration was severe in the order of (4), (3), (2) and (1), and Example 1 was superior in stability at high temperature as compared with Comparative Example 1.

(2) Comparison of Examples 1 to 3

For Examples 1 to 3, changes in properties were observed under severe test conditions. The results were as shown in Fig. 29 (numeral% in the circle in Fig. 29 represents the concentration of dimethylsulfoxide, 1% , 5% for Example 1, and 10% for Example 4).

As can be seen from Fig. 29, Example 3 containing 5% by weight of Example 3 containing 1% by weight of dimethylsulfoxide showed better discoloration at higher temperature than Example 4 containing 10% by weight of dimethylsulfoxide , Indicating higher stability of the constitution.

3. Transmittance ( Transmission ,% T)

For Example 1 and Comparative Examples 1 to 3, the transmittance was measured using a spectrophotometer (UV-1200, Labentech). The results are shown in Figs. 13 to 20. Figs. 13 to 17 show the results of the comparison between Examples 1, 14 and 18, Comparative Examples 3, 15 and Figs. 19 is for Comparative Example 1, and FIG. 16 and FIG. 20 are for Comparative Example 2.

As can be seen from Figs. 13 to 16, the transmittance was high in the order of Comparative Example 3, Example 1, Comparative Example 1 and Comparative Example 2 under the condition of long-term storage test. As a result, And the stability was excellent. On the other hand, in Comparative Example 2, the color change pattern was different from that of Example 1 or Comparative Example 1 while changing to purple color.

Also, as can be seen from Figs. 17 to 20, under the accelerated test conditions, Example 1 and Comparative Example 3 showed high transmittance and Example 1 showed the highest transmittance among basic products.

4. Absorbance

For Example 1 and Comparative Examples 1 to 3, the absorbance was measured using a spectrophotometer (UV-1200, Labentech). The results are shown in Figs. 13 to 20. Figs. 21 to 24 show the long-term storage test conditions, Figs. 25 to 28 show accelerated test environmental conditions, Figs. 21 and 25 show Examples 1, 22 and 26, Comparative Examples 3, 27 is for Comparative Example 1, and FIGS. 24 and 28 are for Comparative Example 2.

As can be seen from Figs. 21 to 24, under the long-term storage test conditions, the wavelength shift range of the chromophore in Comparative Example 1 was the largest in comparison with other products.

Also, as shown in FIG. 25 to FIG. 28, under the accelerated test conditions, the acidic Comparative Example 3 showed a constant absorbance pattern and showed good discoloration degree. In the case of Basic 1 and Comparative Examples 1 and 2, exhibited Bathochromic shift pattern to move a long wavelength side. The change of chromophore wavelength showed that the marc flocosan showed little change over time at high temperature in the acid range rather than the basic range.

Further, it was confirmed from the analysis of the chromophore wavelength that Example 1 maintained a stable state in the basic product as compared with Comparative Example 1 or Comparative Example 2.

5. Insoluble particle test

Examples 1 to 3 and Comparative Examples 1 to 3 were examined for insoluble microparticles according to the insoluble particulate matter test method in the General Test Methods for Veterinary Drugs (National Veterinary Research Quarantine Service). When tested according to this test method, the number of particles of not less than 10 μm and not more than 25 μm should not be more than 10 μm per injection.

As a result of the test, all of Examples 1 to 3 and Comparative Examples 1 to 3 satisfied the insoluble particulate matter test standard.

In the case of Example 2, about 4 to 5 marbloxacin particles in the range of about 12 to 15 mu m were detected. As a result, it was found that the amount of meglumine having slightly weaker basicity than that of sodium hydroxide or potassium hydroxide It is preferable that the solubilizing agent is added in terms of solubility.

Claims (8)

Maburofloxacin, and a solubilizing agent,
Wherein the solubilizing agent is meglumine,
Wherein the pH of the composition is within the range of 9-12. delete [Claim 2] The pharmaceutical composition according to claim 1, wherein the marbophloxacin is contained in an amount ranging from 1% by weight to 30% by weight relative to the total composition. [Claim 2] The pharmaceutical composition according to claim 1, wherein the solubilizer is contained in an amount of 3% by weight to 60% by weight relative to the total composition. The pharmaceutical composition according to claim 1, wherein the ratio of marbophoscase: solubilizer is 1: 0.9 to 4 molar ratio. The pharmaceutical composition according to claim 1, further comprising dimethylsulfoxide as a dissolution aid. [Claim 6] The pharmaceutical composition according to claim 6, wherein the solubilizing aid is contained in an amount of 0.2 to 20% by weight relative to the total composition. The pharmaceutical composition according to any one of claims 1 to 3 to 7, wherein the pharmaceutical composition is in the form of a tablet, a capsule, a powder, a granule, an emulsion, a suspension, a liquid or an injection.

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