KR20160133292A - A sustained-release formulation comprising a fluoroquinolone antibiotics and a method for manufacturing the same - Google Patents
A sustained-release formulation comprising a fluoroquinolone antibiotics and a method for manufacturing the same Download PDFInfo
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- KR20160133292A KR20160133292A KR1020150066213A KR20150066213A KR20160133292A KR 20160133292 A KR20160133292 A KR 20160133292A KR 1020150066213 A KR1020150066213 A KR 1020150066213A KR 20150066213 A KR20150066213 A KR 20150066213A KR 20160133292 A KR20160133292 A KR 20160133292A
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
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Abstract
Description
The present invention relates to a sustained-release preparation containing a drug and a method for producing the same. More particularly, the sustained-release formulation is based on an oxidized oil complex in which a fluoride-quinolone antibiotic is supported in a high content, which maximizes drug concentration in the oil, suppresses initial overexpression, Release) and a method for producing the same.
Marbofloxacin is a 9-fluoro-2,3-dihydro-3-methyl-10- (4-methylpiperazin-1-yl) -7-oxo-7H-pyrido [ 3-ij] [1,2,4] forms the benz-oxadiazine-6-carboxylic acid], a material having a structure of (C 17 H 19 FN 4 O 4), carbonyl group and carboxyl group and the quinoline ring plane . Marbophloxacin is a third-generation fluorogenic quinolone antimicrobial and antibiotic developed for animals. It is a DNA-gyrase (an enzyme that supercoils a double helix of topoisomerase II DNA) and topoisomerase IV , Phagosomal enzymes) and exhibits an antibiotic effect. This broad spectrum antibiotics affects various Gram-negative and Gram-positive bacteria and has excellent efficacy for skin, respiratory and urinary tract infections. It is administered by intramuscular injection at a dose of 2 mg of furoxacin per 1 kg of body weight to livestock such as pigs or cattle, and the administration period is 3 to 5 days. The release period before shipment is 2 to 6 days depending on the species. Fluorinated quinolone antibiotics are bactericides and exhibit concentration-dependent bactericidal action. If the plasma concentration of the drug is increased to about 30 times the minimum inhibitory concentration (MIC), the bactericidal action becomes stronger. However, excessive use of antibiotics indefinitely or long-term use of livestock resistant bacteria appeared to reduce the effectiveness of livestock disease treatment. In addition, antibiotic resistant bacteria produced in livestock can be transmitted to humans through livestock food and animal husbandry environments, making it difficult to treat. More specifically, in the case of fluoroquinolone antibiotics, resistance to MRSA, Pseudomonas, coagulase-negative Staphylococcus aureus and E. coli appeared due to chromosomal mutation. Fluorinated quinolone antibiotics are excellent antibiotics with a wide range of antimicrobial properties and good pharmacokinetic properties. However, when the resistant bacteria are generated due to overuse of the drug, the clinical usefulness of the drug may be limited.
A sustained-release injection formulation refers to an injection formulation that is formulated so that the drug can be sustained and uniformly released (sustained release) while maintaining the biological activity in the body during injection. Conventionally, such conventional methods of producing the sustained-release formulations are known as the coacervation method, the melt injection method, the spray drying method, and the solvent evaporation method. Among these methods, the solvent evaporation method is classified into the dual emulsion evaporation method (W / O / W emulsion) and the single emulsion evaporation method (O / W emulsion). However, such microemulsions using multiple emulsions have a disadvantage of high initial overdischarge, and when they dissolve a drug as an active ingredient in an organic solvent or water, they form disadvantages such as changes in physical properties of the drug, loss of stability, see.
Various attempts have been made to increase the rate of drug encapsulation of such sustained-release formulations or to produce microparticles which are easy to manufacture and have relatively low initial over-release, but are still unsatisfactory. (1983) 62-74), microspheres were prepared by double emulsion evaporation method, and then the active ingredient, vaccine antigen, was loaded through micropores of microspheres (Tg) of the biodegradable polymer to prevent the initial release by blocking the micropores. However, such a manufacturing method has a serious disadvantage that the drug can be denatured by heat. In addition, the addition of protein trapping agent significantly increased the drug loading efficiency (~97%), but the total loading of active material (1.4 ~ 1.8%) was significantly lower. This method has a disadvantage in that the physiologically active substance can be denatured by heat, and it is also disadvantageous in that it can not be applied to the encapsulation of a high dose drug. Also, it is difficult to produce by a complicated manufacturing process.
Therefore, in order to maximize the amount of the drug to be injected and the efficiency of encapsulation in order to improve the productivity, the drug is continuously maintained at a minimum effective concentration for a certain period of time in order to suppress the initial release and minimize the number of administrations It is an object of the present invention to provide a sustained-release preparation which is uniformly released. It is still another object of the present invention to provide a method for producing the sustained-release preparation. It is also to be easily understood that other objects and advantages of the present invention can be realized by the means or method described in the claims, and combinations thereof.
The present invention relates to a sustained-release preparation containing a fluoride-quinolone antibiotic component to solve the above technical problem.
According to a specific embodiment of the present invention, the sustained-release preparation comprises a fluorinated quinolone antibiotic component, peroxide oil, and saturated oil, wherein the fluorinated quinolone antibiotic component and the peroxide oil are chemically And the peroxide oil has an peroxide value (unsaturation degree) of 800 mEq / kg or more, and is made from an unsaturated oil containing a polyunsaturated fatty acid as a starting material.
In the present invention, the polyunsaturated fatty acid may contain two or more double bonds in the molecule.
In the present invention, the unsaturated oil may contain flaxseed oil.
Here, the unsaturated oil may have a content of a polyunsaturated fatty acid containing two or more unsaturated double bonds of 50% by weight or more based on 100% by weight of an unsaturated oil.
Here, the fluorinated quinolone antibiotic component can comprise a flocked mabo reaper (C 17 H 19 FN 4 O 4).
The present invention also relates to a sustained-release pharmaceutical composition comprising a pharmaceutically effective amount of a sustained-release preparation having the aforementioned characteristics and a pharmaceutically acceptable carrier.
The present invention also relates to a method for producing the sustained release preparation. The method comprises the steps of S1) mixing an unsaturated oil with oxygen to produce a peroxide oil; S2) adding a saturated oil to the peroxidized oil obtained in S1) to prepare a first mixed solution; and S3) adding a fluoroquinolone antibiotic component to the mixed solution of S2) Thereby preparing a mixed solution.
In the above method, the unsaturated oil in the step (S1) may include an oil containing a polyunsaturated fatty acid containing two or more unsaturated double bonds.
In the above method, the content of the polyunsaturated fatty acid having two or more unsaturated double bonds may be 50% by weight or more based on 100% by weight of the unsaturated oil.
In the present invention, the unsaturated oil may contain linolenic acid (? -3) as a polyunsaturated fatty acid.
The sustained-release preparation of the present invention exhibits a high drug loading amount and a high filling efficiency, and exhibits sustained drug release behavior for a certain period of time. Accordingly, when the sustained-release preparation of the present invention is used as an injection preparation, the administration frequency and dosage of the drug can be minimized and the drug efficacy can be maximized with respect to the dosage. In addition, since the sustained-release preparation according to the present invention can be used as a drug delivery vehicle for a quinolone antibiotic, it is expected that the administration of a quinolone antibiotic minimizes the occurrence of live resistant bacteria, reduces labor, and increases productivity have.
1 schematically shows a process for producing an oil-based sustained-release preparation according to the present invention.
FIG. 2 is a graphical representation of the process of increasing the degree of peroxidation by reacting polyunsaturated fatty acids with oxygen in step (S2).
Fig. 3 shows the comparison of the peroxide value of linseed oil and olive oil cottonseed oil.
Fig. 4 shows the fatty acid content distribution of flaxseed oil and olive oil cottonseed oil.
Fig. 5 shows a comparison of the release effect of the example and the comparative example.
DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, preferred embodiments according to the present invention will be described in detail with reference to the accompanying drawings. The terms or words used in the present specification and claims should not be construed to be limited to ordinary or dictionary terms and the inventor shall properly define the concept of the term in order to best explain its invention And therefore should be construed in light of the meanings and concepts consistent with the technical idea of the present invention. In addition, since the embodiments described in the present specification and the configurations shown in the drawings are only the most preferred embodiments of the present invention and do not represent all the technical ideas of the present invention, It is to be understood that equivalents and modifications are possible.
The present invention relates to a sustained-release preparation of fluoroquinolone antibiotics, which maintains the efficacy of fluoroquinolone antibiotics and provides ease of administration and has excellent bioavailability.
The sustained-release preparation according to the present invention is based on an oxidized oil complex formed by combining a fluoride-quinolone antibiotic component and a peroxide oil, and has a high encapsulation efficiency and an excellent sealing efficiency of the drug in the oily phase. In addition, the sustained-release preparation exhibits drug release behavior in which the oxidized oil complex is decomposed by an enzyme in the body after the administration, and the antibiotic component is absorbed into capillary blood vessels to continuously and uniformly release the drug for a predetermined period of time.
In one embodiment of the present invention, the sustained release formulation comprises a fluorinated quinolone antibiotic component, a peroxide oil, and a saturated oil, wherein the fluorinated quinolone antibiotic component is covalently bound to the acid, To form an oxidized oil complex.
The fluorinated quinolone antibiotic is an active ingredient exhibiting pharmacological activity, and is chemically bonded to a peroxide oil to form an oxidized oil complex. The oxidized oil complex is formed by an ester bond and / or an amide bond between an amine group, a hydroxyl group and / or a ketone group in the molecule of the fluoroquinolone antibiotic with a carboxyl group and the like of the peroxide oil.
The fluorinated quinolone antibiotics are excellent antibiotics having a wide range of antimicrobial activity and good pharmacokinetic properties and specifically include Nalidixic acid, Ciprofloxacin, Norfloxacin, Afroxacin Ofloxacin, Gatifloxacin, Levofloxacin, Moxifloxacin,
Moxifloxacin, Sparfloxacin, Trocafloxacin, Marbofloxacin, and the like, preferably marbofloxacin.
Marbophloxacin (C17H19FN4O4) is a compound of the following formula (1), which is a third-generation fluorinated quinolone antimicrobial agent and antibiotic developed for animals, and is a DNA-gyrase and topoisomerase IV Isomerization enzyme) and exhibits an antibiotic effect.
[Chemical Formula 1]
In one specific embodiment of the present invention, the peroxide oil has a peroxide value (unsaturation degree) of 800 mEq / kg or more. In the present invention, the peroxide value (degree of unsaturation) can be measured by referring to American Oil Chemist's Society (AOCS) Official method Cd 8-53, Acetic acid-Chloroform method, expressed as milliequivalents (mEq) of peroxide oxygen per kg of fat .
In the present invention, the peroxide oil is an unsaturated oil containing an unsaturated fatty acid as a starting material. As described later, the peroxide oil can be obtained by reacting an unsaturated oil with oxygen.
In one specific embodiment of the present invention, the unsaturated oil includes an unsaturated fatty acid having a double bond in a molecular chain, preferably a polyunsaturated fatty acid having two or more double bonds in the fatty acid molecular chain or three or more double bonds . Examples of the polyunsaturated fatty acids include oleic acid (? -9), linoleic acid (? -6) and linolenic acid (? -3), but the present invention is not limited thereto.
In one specific embodiment of the present invention, the unsaturated oil includes at least 50% by weight of a polyunsaturated fatty acid having two or more double bonds and / or three or more double bonds in a molecular chain relative to 100% by weight of an unsaturated oil. More preferably, it comprises 65 to 90% by weight of a polyunsaturated fatty acid having 3 or more double bonds in its molecular chain relative to 100% by weight of an unsaturated oil.
In one specific embodiment of the present invention, the peroxide oil may include flaxseed oil. Preferably, the flaxseed oil contains at least 50% by weight of a polyunsaturated fatty acid having three unsaturated double bonds in the molecule.
The unsaturated oil used as the starting material of the peroxide oil may be any unsaturated oil containing a double bond in the molecular chain, but it is preferable that the content of the monounsaturated fatty acid having one unsaturated double bond in the molecular chain is high or the content of the polyunsaturated fatty acid, In the case of unsaturated oils having 3% linolenic acid (ω-3) of 50% or less, the initial release can be controlled to a certain extent, but the release effect is minimal.
3 and 4 show the comparison of the peroxide value of flaxseed oil and olive oil cottonseed oil. In the case of olive oil, the content of polyunsaturated fatty acid is as low as about 30%. In case of cottonseed oil, the content of linolenic acid is low, The effect is small. Flaxseed oil is composed of 56-71% of linolenic acid, and the sustained-release formulation using it as a starting material is excellent in control of initial overdischarge and the effect of sustained release.
Further, the present invention is characterized in that an excessive amount of saturated oil is added to prevent the unsaturated peroxide oil from being deformed. Saturated oil means that all of the carbons in the fatty acid chain are linked by a single bond (C16: 0, C18: 0) and are not oxidized by oxygen. In the present invention, the saturated oil is a medium chain triglyceride (MCT) extracted from milk fat or coconut oil, and includes, for example, those marketed under the trade name Miglyol.
In one specific embodiment of the present invention, the content of the saturated oil is 1: 10 to 90: 99 (v / v%) of peroxide: saturated oil. When the saturated oil is put in an excessive amount within the above range, a sustained-release preparation having an appropriate viscosity as the injection preparation can be obtained.
According to another aspect of the present invention, there is also provided a sustained-release pharmaceutical composition comprising a pharmaceutically effective amount of the fluoroquinoline antibiotic-sustained-release preparation. In addition to the sustained release formulations described above, the compositions may additionally comprise a pharmaceutically acceptable carrier.
The pharmaceutical composition of the present invention comprises a pharmacologically effective amount of a fluoroquinolone antibiotic-sustained-release preparation. 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.
In one specific embodiment of the present invention, the carrier is a carrier commonly used in the manufacture of pharmaceutical products, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, 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).
In the present invention, the sustained-release preparation and / or pharmaceutical composition 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.
The appropriate dosage of the sustained release pharmaceutical composition and / or pharmaceutical composition according to the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration route, And response sensitivities. ≪ / RTI >
The sustained-release preparation and / or the pharmaceutical composition according to the present invention can be prepared by using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by those skilled in the art. Or by formulating it into a unit dose form or by inserting it 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 sustained-release preparation and / or the pharmaceutical composition is an antibiotic composition and is also an injection.
According to one embodiment of the present invention, the sustained-release preparation and the pharmaceutical composition containing the same are for administration of domestic animals such as pigs, cows, horses, sheep, or poultry.
According to another aspect of the present invention, there is provided a method for producing a sustained-release preparation containing the fluorinated quinolone antibiotic component.
FIG. 1 is a flow chart schematically showing a method of manufacturing a sustained-release preparation according to the present invention, and the production method will be described in detail with reference to FIG.
First, peroxide oil is prepared by mixing unsaturated oil and oxygen (S1).
According to a specific embodiment of the present invention, the mixing ratio of oxygen and oxygen to 100 ml of the unsaturated oil is in the range of 95% to 1 L of oxygen. It is vigorously mixed for 1 to 48 hours to prepare peroxide oil. In order to shorten the time required for preparing the peroxide oil, the reaction may be carried out at a temperature of from 40 ° C to 100 ° C.
The peroxidized oil binds to the double bond of the oil to form a peroxide (peroxide) having active oxygen, which is combined with an amine group, a hydroxyl group, a ketone group, etc. of the antibiotic component, , And the like, and a magofloxacin-oxidized oil complex is obtained.
FIG. 2 is a graphical representation of the process of increasing the degree of peroxidation by reacting polyunsaturated fatty acids with oxygen in step (S2). According to this, oxygen binds to the double bond part of the fatty acid molecular chain, and peroxide having active oxygen is produced.
Next, saturated oil is added to the peroxide oil obtained in step S1 to prepare a first mixed solution (S2). An excess amount of saturated oil is added so as to prevent the unsaturation of the peroxide oil obtained in the step (S1) from being deformed and to exhibit an appropriate viscosity.
Next, a fluorinated quinolone antibiotic component is added to the first mixed solution to prepare a second mixed solution (S3). In this step, an antibiotic component, in particular marbophloxacin and peroxide, is combined by ester bond or the like to form a sustained-release preparation based on an oxidized oil complex. The reaction can be induced by stirring for 2 hours or more using a magnetic stirrer.
The complex obtained in the step (S3) may be used as an injectable preparation in its final form or dispersed in a suitable carrier. The marbella flocassin-oxidized oil complex of the present invention is injected into the body through a muscle-feeding preparation, and the complex is slowly decomposed by enzymes in the body, and the separated drug is absorbed into capillary blood vessels, have. This technique is an example of a prodrug delivery method, which is the first attempt to deliver a sustained delivery of marbled flocasin.
Hereinafter, the present invention will be described more specifically by way of examples. It will be apparent to 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
Example : Magoblocker Bearing Preparation of oxidized oil complex
Peroxide oil was prepared by adding high purity oxygen (95%) at 100 ℃. At this time, 1 liter of oxygen was added to 100 ml of flax seed oil, and the injection time was 8 hours. 9.5 ml of Miglyol (5:95, v / v%) was added to 0.5 ml of each peroxide oil (1277.9 (± 5.4) mEq / kg) obtained above and uniformly stirred to obtain a first mixed solution. Next, 1 g of Mabofroxasin (Zhejiang Guobang Pharmaceutical Co., Ltd .. micronized) was added to the first mixed solution to prepare a second mixed solution having a concentration of 100 mg / ml and stirred for 6 hours by a magnetic stirrer to induce an ester reaction, A sustained-release preparation was obtained.
Comparative Example One
A sustained release preparation for injection was prepared in the same manner as in Example except for the use of flaxseed oil not oxidized.
Comparative Example 2
1 g of Mabo flocasin (Zhejiang Guobang Pharmaceutical Co. Ltd. .. micronized) was added to 10 ml of Miglyol to prepare a mixed solution, which was stirred for 6 hours by a magnetic stirrer to obtain a sustained-release preparation for injection.
Comparative Example 3
A sustained release preparation for injection was obtained by the same method as in Example except for using cottonseed oil instead of flaxseed oil.
The components and the contents used in the above Examples and Comparative Examples are summarized in Table 1 below.
Experiment on oxidation degree measurement by oil
100 ml of flaxseed oil, olive oil, and cottonseed oil were directly injected into the oil at a rate of 1 L at 100 ° C with high purity oxygen (95%) and reacted for 8 hours to prepare oil per peroxide.
Experiments and results
Experimental Example 1: Oxidation measurement by oil
As shown in Fig. 3, the degree of peroxidation of olive oil was not substantially increased even after prolonged oxidation. In the case of flaxseed oil, the degree of oxidation increased rapidly over time. When oxygen was injected under the same conditions, the degree of oxidation was higher than that of cottonseed oil.
Fig. 4 shows the constituents of fatty acids by oil type. As can be seen, olive oil has a single unsaturated fatty acid with a single double bond in the molecular chain of 72%, which makes it difficult to increase the degree of peroxidation. The content of linoleic acid (ω-6) with two double bonds in the molecule is 54 % Of cottonseed oil takes too much time to show a certain degree of peroxidation. Flaxseed oil is composed of 56-71% of linolenic acid (ω-3) with three double bonds in the molecule, and this structural difference shows that the oxidation rate increases rapidly compared to other oils.
The degree of peroxidation of the peroxidized oils was varied according to the degree of unsaturation of the oil. This affects the reaction with magok flocasin in the next step and is thus an important factor in determining the release characteristics.
Experimental Example 2: Oil formulation in - vitro Measurement of drug release behavior
In order to measure the release behavior of the drug, 1.4 ml of the sustained-release preparation prepared in Example 4 and Comparative Examples 1 to 3 was added to 30 ml of PBS (phosphate buffer saline, pH 7.4) at a total concentration of 4 mg / ml, The samples were kept in an isothermal period and samples were taken at time intervals. The collected samples were diluted 100-fold and placed in a disposable cuvette, and the absorbance at a wavelength of 335 nm was measured using a UV-vis meter. The absorbance value was converted to the concentration of the released drug, and the cumulative percentage of the released drug in each time zone was calculated by the cumulative percentage of the total drug in each sample. The oil formulation prepared in Comparative Examples 1 to 3 was used as a control for this experiment. The measurement results are shown in Fig.
According to the results, it was confirmed that Comparative Examples 1 to 3 had higher initial release of the drug than the Examples. In the case of the example, it was confirmed that the initial release amount was also effectively controlled and the release of the drug over time was effectively controlled. Based on the degree of peroxidation of the added flaxseed oil, the drug release rate can be controlled and an oil-based sustained-release formulation can be produced which continuously releases the drug over a period of 2 to 3 days. On the other hand, in the case of oils with an unsaturated oil content of less than 50% (ω-3) (olive oil, cottonseed oil, etc.), the drug release over time was controlled to a certain extent, but initial overdischarge was not controlled.
Claims (10)
Wherein the fluorinated quinolone antibiotic component and the peroxide oil are chemically bonded by a covalent bond,
Wherein said peroxide oil has an peroxide value (unsaturation degree) of 800 mEq / kg or more and is an unsaturated oil containing a polyunsaturated fatty acid as a starting material.
Wherein the polyunsaturated fatty acid comprises two or more double bonds in the molecule.
Wherein said unsaturated oil is linseed oil.
Wherein the unsaturated oil has a polyunsaturated fatty acid content of 2 or more unsaturated double bonds of 50 wt% or more based on 100 wt% of unsaturated oil.
Sustained release formulation of the fluorinated quinolone antibiotic component is in mabo floc reaper (C 17 H 19 FN 4 O 4),.
S2) adding a saturated oil to the peroxidized oil obtained in the step S1) to prepare a first mixed solution; and
S3) A method for producing a sustained release preparation according to claim 1, comprising the step of adding a fluoroquinolone antibiotic component to the mixed solution of step S2) to prepare a second mixed solution.
The method of producing a sustained release preparation according to claim 1, wherein the unsaturated oil in step (S1) is an oil containing a polyunsaturated fatty acid containing two or more unsaturated double bonds.
The method for producing a sustained release preparation according to claim 1, wherein the unsaturated oil has a polyunsaturated fatty acid content of at least 2 unsaturated double bonds of at least 50% by weight based on 100% by weight of the unsaturated oil.
The method of producing a sustained release preparation according to claim 1, wherein the unsaturated oil comprises linolenic acid (? -3) as a polyunsaturated fatty acid.
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| CN113662912B (en) * | 2021-08-23 | 2024-05-28 | 山东畜牧兽医职业学院 | Marbofloxacin controlled-release gel for livestock and preparation method thereof |
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