JP2001058994A - Stabilized amoxicillin inclusion complex - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an amoxicillin preparation which is stabilized, namely controls decomposition at a low pH and maintains antimicrobial activity by using an inclusion complex of amoxicillin with a cyclodextrin (derivative). SOLUTION: An inclusion complex of amoxicillin with a cyclodextrin, preferably β-cyclodextrin, γ-cyclodextrin or a cyclodextrin derivative, preferably dimethyl-β-cyclodextrin is used. The inclusion complex is obtained by formulating an aqueous solution containing a fixed amount of a cyclodextrin (derivative) with amoxicillin in an amount of corresponding molar ratio directly as powder or as a solution dissolved in an organic solvent such as ethanol, acetone, etc., stirring and, if required, removing impurities. In the case of obtaining as a solid substance, a small amount of water is added to the mixture and may be lyophilized. The formulating molar ratio of amoxicillin to the cyclodextrin (derivative) is preferably 1:0.3-3.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a stable inclusion complex of amoxicillin with cyclodextrin or a cyclodextrin derivative.

[0002]

2. Description of the Related Art Amoxicillin is a synthetic penicillin antibiotic listed in the Japanese Pharmacopoeia, Escherichia coli, deformed bacteria (especially Proteus mirabilis), influenza bacteria, hay fungi, hemolytic streptococci, enterococci, pneumococci. It is known to be effective against various infectious diseases caused by staphylococci and T. pallidum. Recently, amoxicillin has been found to have a considerable effect in combination with clarithromycin on eradication of Helicobacter pylori, which is one of the causes of gastric ulcer and gastric cancer. Furthermore, as a typical example of prescription, a combination use of amoxicillin, clarithromycin and a proton pump inhibitor (omeprazole, rabeprazole, lansoprazole, pantoprazole, etc.) has been attempted, and it has been revealed that the composition has a high therapeutic effect. Amoxicillin is a drug that is relatively resistant to acids, however, it is susceptible to chemical degradation under low pH conditions, especially around pH 1 which is the pH of stomach acid, and when taken as an oral formulation, It is said that its therapeutic effect is not enough because it is partially decomposed by stomach acid. On the other hand, it is well known that cyclodextrin generally improves its stability and / or solubility by forming an inclusion complex with a drug in a pharmaceutical formulation.

[0003]

An object of the present invention is to further stabilize a solid preparation for internal use containing amoxicillin, that is, to provide an amoxicillin preparation which suppresses degradation at a low pH and maintains an antibacterial activity. Things.

[0004]

SUMMARY OF THE INVENTION The present invention is an inclusion complex of amoxicillin with cyclodextrin or a cyclodextrin derivative.

In the present invention, cyclodextrin means “unmodified α-, β-, γ- or δ-cyclodextrin”, and the cyclodextrin derivative is
"Modified cyclodextrin (CyD) in which various organic compounds are bonded to cyclodextrin" means, for example, "modified with 1 to 3 alkyl groups having 1 to 4 carbon atoms which may be substituted with a hydroxyl group." Cyclodextrin [Example: dimethyl-β-CyD, trimethyl-β-CyD
Alkylated cyclodextrin, such as hydroxyethyl-β-CyD, 2-hydroxypropyl-β-Cy
D, 3-hydroxypropyl-β-CyD and other hydroxyalkylated cyclodextrins], cyclodextrins modified with 1 to 6 glycosyl groups among sugar residues [eg, glycosyl-β-CyD, maltosyl-β-CyD, And other branched cyclodextrins such as dimaltosyl-β-CyD].

[0006] The cyclodextrin or cyclodextrin derivative in the present invention may be any as long as it can include amoxicillin, and as the cyclodextrin, β-cyclodextrin (β-CyD) or γ is particularly preferred.
-Cyclodextrin (γ-CyD) is desirable, and as the cyclodextrin derivative, dimethyl-β-cyclodextrin (DM-β-CyD) is particularly desirable.

[0007] The present invention is also an antibacterial composition for oral administration comprising amoxicillin and one or more substances selected from dimethyl-β-cyclodextrin, β-cyclodextrin and γ-cyclodextrin.

[0008] Amoxicillin in the present invention is listed in the Japanese Pharmacopoeia and can be easily obtained commercially. Among cyclodextrins, α-cyclodextrin and β
-Cyclodextrin is listed in the excipient specification and is readily available. In addition, various cyclodextrins and cyclodextrin derivatives can be obtained from, for example, Japan Food Processing Co., Ltd.

In the present invention, the molar ratio of amoxicillin to one or more substances selected from various cyclodextrins and cyclodextrin derivatives is preferably 0.3 to 3 for amoxicillin and 1 for cyclodextrin or cyclodextrin derivative. Is 0.5 to 2.
In the present invention, the various cyclodextrins and cyclodextrin derivatives described above can be used alone, or two or more of them can be used in combination. Among them, it is more effective to add β-cyclodextrin, γ-cyclodextrin and / or dimethyl-β-cyclodextrin to amoxicillin.

As a method for preparing the amoxicillin clathrate according to the present invention, a precipitate obtained by adding amoxicillin to a saturated solution of cyclodextrin or a cyclodextrin derivative as it is or by dissolving it in a small amount of an appropriate solvent is added. A saturated aqueous solution method, a kneading method in which a small amount of water is added to cyclodextrin or a cyclodextrin derivative to form a slurry, and then amoxicillin or an amoxicillin solution is added and dried, a solvent is distilled off from the cyclodextrin or cyclodextrin derivative and the amoxicillin solution. And a mixed grinding method of grinding a powder mixture of cyclodextrin or a cyclodextrin derivative and amoxicillin, etc., and any of these manufacturing methods may be used. More specifically, the inclusion complex of amoxicillin of the present invention with cyclodextrin or a cyclodextrin derivative can be obtained by directly adding amoxicillin in a corresponding molar ratio as a powder,
It is obtained by adding as a solution dissolved in a suitable organic solvent such as methanol or acetone, stirring, and filtering off insolubles as necessary. When obtained as a solid, for example, this clathrate, or a combination of amoxicillin and cyclodextrin or a mixture of cyclodextrin derivatives having a certain molar ratio shown below, with a small amount of water or the like added thereto, It can be produced by freeze-drying. The stirring is usually performed at 0 ° C. to room temperature, and the required time is sufficient if the added amoxicillin is dissolved, and is usually 1 minute to 24 hours. As a solvent of the aqueous solution containing the cyclodextrin or the cyclodextrin derivative, water is usually used, and a small amount (0.001% to 1% v / v) is added thereto.
(Ethanol, methanol, etc.) and ketones (acetone, methyl ethyl ketone, etc.) can also be used. The concentration of cyclodextrin or cyclodextrin derivative used is 0.001 to 1 M / L.
It is. The molar ratio of the clathrate is such that amoxicillin in a solid state is added to an aqueous solution containing a certain concentration of cyclodextrin or a cyclodextrin derivative until saturation, and after filling and stirring, the mixture is filtered and the amount of amoxicillin in the filtrate is determined by the UV method or H method.
It can also be obtained by quantification by the PLC method.

The composition of the present invention may contain pharmaceutically acceptable binders, excipients, disintegrants, sweeteners, flavors, pigments, lubricants, etc., and may be prepared by known methods. , Tablets, capsules, powders, granules or dry syrups.

Amoxicillin undergoes significant chemical degradation, especially in low pH solutions. Compositions and / or formulations in which additives are added to the various cyclodextrins or cyclodextrin derivatives described above in the present invention,
It has a very remarkable effect of suppressing the degradation of amoxicillin in gastric acid.

[0013]

According to the present invention, amoxicillin which is unstable under acidic conditions can be stabilized. The effect example is shown below.

Experimental Example 1) Interaction between amoxicillin and cyclodextrin or a cyclodextrin derivative (I) A 0.3 mM / L amoxicillin aqueous solution was prepared.
In this aqueous solution at 5 ° C, α-CyD, γ-CyD
Alternatively, after adding and dissolving DM-β-CyD to 0 to 0.6 mM / L and β-CyD to 0 to 0.4 mM / L, the absorbance at a wavelength of 270 nm was measured. The measured values were substituted into Hildebrand's equation, and the stability constant was determined from the slope. The results are shown in Table 1.

[0015]

[Table 1]

The solution to which β-CyD or DM-β-CyD is added has a greater stability constant than other cyclodextrins or cyclodextrin derivatives, and therefore, a solution between amoxicillin and the cyclodextrin or the cyclodextrin derivative is used. It is clear that the interaction is strong, forming a stronger complex. (II) preparing a 4 mM / L amoxicillin aqueous solution,
Equimolar (4 mM / L) α in this aqueous solution at 5 ° C.
-CyD, β-CyD, γ-CyD or DM-β-Cy
After adding and dissolving D, using TMS external standard method
¹ H-NMR (JNM LA500; JEOL) was measured. FIG. 1 shows the structural formula of amoxicillin, which also shows the number of each signal, and the results of the experiments are shown in Table 2 and FIG. 2 (in Table 2, △ indicates the case where amoxicillin was used as a reference for each signal). The shift value of each clathrate was shown).

[0017]

[Table 2] The aqueous solution to which γ-CyD or DM-β-CyD is added,
Since almost all peaks of amoxicillin are shifted to the high magnetic field side, it is clear that amoxicillin is almost completely incorporated into each cyclodextrin ring. Also, in the aqueous solution to which β-CyD is added, amoxicillin is included because the shift of H5 to the high magnetic field side in the structural formula of amoxicillin is large and the shift of H6 to the low magnetic field side is large. It is clear.

2) Effect of inclusion of cyclodextrin and cyclodextrin derivative on the stability of amoxicillin Amoxicillin α-CyD, β-CyD, γ-CyD
Alternatively, the inclusion complex of DM-β-CyD was added to and dissolved in a pH 1 buffer, respectively, at 37 ° C., 50 ° C. and 60 ° C.
Was evaluated over time. The stability of amoxicillin was evaluated by HPLC under the following conditions. (HPLC column) Asahipak ODP-50 (mobile phase) Distilled water: methanol: acetic acid = 74: 25:
1 (Detection) Ultraviolet absorption spectrophotometer (wavelength = 273 nm) The amount of amoxicillin remaining in each clathrate in pH 1 buffer solution at 37 ° C, 50 ° C and 60 ° C over time is shown in Figs. 3, 4 and 4, respectively. 5 is shown. Table 3 shows the half-life of amoxicillin in each clathrate in a pH 1 buffer solution at 37 ° C.

[0019]

[Table 3]

By adding α-CyD, β-CyD, γ-CyD or DM-β-CyD, the pH at any temperature can be increased.
Amoxicillin degradation was also suppressed in the buffer solution. In particular, the addition of β-CyD or DM-β-CyD has a great effect of suppressing the decomposition.
The half-life of amoxicillin at the time of addition of yD and DM-β-CyD was prolonged by 6.7-fold and about 8.9-fold, respectively, as compared with the case without the addition, indicating that the stability of amoxicillin was reduced. The effect of β-CyD and DM-β-CyD on the effect is clear.

3) Effect of inclusion by cyclodextrin and cyclodextrin derivative on the antibacterial activity of amoxicillin Antibacterial activity was tested by the cup method according to the Japanese Antibiotic Standards. The method is as follows. (Preparation of test solution): Equimolar amounts of α-CyD, β-CyD, γ-CyD or DM-β-CyD are added to 10 μg of amoxicillin and dissolved in a pH 1 buffer solution, and the total amount is 1
ml. In addition, as a control, 10 μg of amoxicillin was used.
The sample was added to and dissolved in a pH 1 buffer to make a total volume of 1 ml. (Use medium): SCD medium (Digo), normal broth medium (Test bacteria): Escherichia coli NIHJ JC-2 Staphylococcus aureus ATCC 6538
P) The results are shown in Table 4.

[0022]

[Table 4] When pH 1 buffer was used, no expansion of the inhibition circle was observed in the control experiment, but β-C was added to amoxicillin.
By adding yD or DM-β-CyD, the expansion of the inhibition circle was observed. Also, as shown in Table 4,
Amoxicillin β-CyD, γ-C with suppressed degradation
The inclusion complex of yD or DM-β-CyD was able to maintain the antibacterial activity of E. coli and Staphylococcus aureus more strongly than that of amoxicillin alone under the condition of pH1. It is clear that the dextrin derivative suppresses a decrease in the antibacterial activity of amoxicillin at a low pH. Therefore, it is considered that the clathrate is also effective when used for eradication of Helicobacter pylori.

[0023]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto.

EXAMPLE 1 1 to 2 parts by weight of water was added to 1 part by weight of β-CyD, kneaded in advance, an equimolar amount of amoxicillin was added, and the mixture was stirred and kneaded for 1.5 hours, and then dried. Thus, a powder of an inclusion complex of amoxicillin with β-CyD was obtained. The clathrate was obtained even when powdering was performed using any of the commonly used methods of ventilation drying, heating drying, freeze drying and spray drying.

[0025]

Example 2 To 1 part by weight of the clathrate described in Example 1, 8 parts by weight of a usual excipient was added and mixed, followed by dry granulation, and 0.1 part by weight of a lubricant was added. And amoxicillin-containing tablets.

[0027]

[Brief description of the drawings]

[0038]

FIG. 1 is a structural formula of amoxicillin including signal numbers in ¹ H-NMR.

[0039]

FIG. 2: Amoxicillin aqueous solution and equimolar α-Cy
^{1 is} a ¹ H-NMR chart of a solution to which D, β-CyD, γ-CyD, or DM-β-CyD is added.

[0040]

FIG. 3 is a graph showing the change over time in the amount of amoxicillin remaining in each clathrate in a pH 1 buffer at 37 ° C.

[0041]

FIG. 4 is a graph showing the change over time of the amount of amoxicillin remaining in each clathrate in a pH 1 buffer at 50 ° C.

[0042]

FIG. 5 is a graph showing the change over time of the amount of amoxicillin remaining in each clathrate in a pH 1 buffer at 60 ° C.

 ──────────────────────────────────────────────────続 き Continued on the front page F term (reference) 4C086 AA01 AA02 AA03 CC04 GA20 MA02 MA05 MA35 MA52 NA03 NA05 ZA68 ZB32 4C090 AA02 AA09 BA11 CA46 DA09 DA23

Claims (3)

[Claims] 1. An inclusion complex of amoxicillin with cyclodextrin or a cyclodextrin derivative. 2. The clathrate according to claim 1, wherein the cyclodextrin is β-cyclodextrin or γ-cyclodextrin. 3. The clathrate according to claim 1, wherein the cyclodextrin derivative is dimethyl-β-cyclodextrin.