JPS60169431A - Stable antibacterial agent containing compound having beta-lactam ring and its preparation - Google Patents

Abstract

PURPOSE:To provide a stable antibacterial agent composed of a compound having lactam ring, hydrophobic colloidal silicon dioxide, and an oleaginous base. CONSTITUTION:The objective antibacterial agent can be prepared by mixing an oleaginous base (e.g. glyceride of saturated fatty acid, liquid paraffin, polyoxyethylene hardened castor oil, etc.) with (A) 1.0-30.0W/W% compound having beta-lactam ring selected from the penicillin compound of formula I (e.g. propicillin, phenoxymethylpenicillin, etc.) or the cephem compound of formula II (e.g. cephalexin, cephalothin, etc.) and (B) 0.5-10.0W/W% hydrophobic colloidal silicon dioxide. It is applied in the form of ointment for local application, infusion for animal mammitis, agent for rectal infusion, or agent for vaginal or intrauterine infusion.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to an antibacterial agent in which a compound having a β-lactam ring exhibiting antibacterial activity is stabilized with hydrophobic colloidal silicon dibromide, and a method for producing the same. It is.

[Prior art]

Penicillin compounds and cephem compounds having a β-lactam ring are bactericidal antibiotics whose mechanism of action is to disrupt bacterial cell wall synthesis, and many of them are widely recognized to have highly broad-spectrum antibacterial properties.

However, penicillin compounds, cephem compounds, or their non-toxic salts having a β-lactam ring are unstable compounds in the presence of polar substances such as water, amines, alcohols, acids, aldehydes, glycosyl, etc. However, it decomposes significantly and its efficacy decreases during storage, and the color changes from yellow to reddish-yellow, to the point where it is no longer useful as a product.

Therefore, oleaginous bases have conventionally been frequently used in these formulations. As the oily base, glycerides of saturated fatty acids having 12 to 18 carbon atoms, such as isopropyl myristate,
Using animal/vegetable oils and waxes such as isopropyl palmitate, petrolatum, liquid paraffin, etc. as basic raw materials, the consistency of the base is adjusted by mixing oily substances with a relatively high melting point and oily substances with a low melting point. Alternatively, high temperature heat treatment in the presence of a dispersant such as aluminum stearate has been used.

However, these preparations are easily affected by temperature, and their viscosity increases at low temperatures, and their viscosity decreases at high temperatures, resulting in separation and often disadvantages in practical use. . In the case of aluminum stearate, etc., the thickening effect takes advantage of the interaction between food oil and high-temperature heat treatment. It has disadvantages such as being limited to oil and requiring special processes such as high ftA heat treatment for thickening effect.

On the other hand, colloidal silicon dioxide is
Preventing the sedimentation of the active ingredient in a base substance with low viscosity in a molten state,
It is widely used as a general dispersant for the purpose of preventing sedimentation separation.

The viscosity of the colloidal silicon dioxide can be easily increased using simple formulation methods, and it has features such as high thixotropy and is not easily affected by temperature. It is an excellent dispersant that can be used in a wide range of formulations. Furthermore, in recent years, the persistence of antibacterial substances due to base materials and additives has become a problem, but colloidal silicon dioxide bases have the advantage of low persistence, and will become more and more commonly used in the future. It is considered to be a drug.

Therefore, it is conceivable to use this colloidal silicon dioxide as a dispersant for compound preparations having β-lactam rings, but when colloidal silicon dioxide is used as a dispersant for β-lactam ring compounds, oil-based base β in
- It was learned that penicillin-based compounds and cephem-based compounds that have lactam rings are significantly decomposed. The cause of this is presumed to be a catalytic effect on the decomposition of the compound having a β-lactam ring, which is due to the affinity between the silanol hydrophilic groups of colloidal silicon dioxide and traces of polar substances in the base.

[Purpose of the invention]

The present invention provides an antibacterial agent stabilized with a compound having a β-lactam ring, which is easily degraded, resulting in decreased efficacy and discoloration, and more specifically, an ointment for topical application, and a mastitis injection for animals. The present invention aims to provide a rectally administered preparation, a vaginal or uterine injection preparation, and a method for producing the same.

[Structure of the invention]

As a result of various studies aimed at producing stable ointments and rectal administration preparations of penicillin compounds, cephem compounds, or non-toxic salts thereof, which have a β-lactam ring, the present inventor discovered that silanol of colloidal silicon dioxide By using hydrophobic colloidal silicon dioxide obtained by substituting hydrophilic groups with organosilicon halogen compounds or alcohols, β- It has become possible to stabilize formulations of penicillin compounds, cephem compounds, and their nontoxic salts that have lactam rings. The present invention was completed based on this new knowledge, and includes 1.0 to 30-0 (W/W)% of a compound having a β-lactam ring and 0.5 to 10% of hydrophobic colloidal silicon dioxide. 0(W/W
)% and an oleaginous base, and a method for producing the same.

Here, examples of compounds having a β-lactam ring include penicillin compounds represented by the general formula (D), specifically propicillin, phenoxymethylpenicillin, cloxacillin, ampicillin, amoxicillin, benzylpenicillin, sulpenicillin, carbenicillin, and benzylpenicillin procaine. and their non-toxic salts, or cephem compounds represented by the general formula (2), specifically cephalexin, cephalothin, cefazolin, cephaloridine, cephapirin, cefoxitin, cefmetazole, latamoxef, cefotetan, etc., and their non-toxic salts. It will be done.

The appropriate proportion of these compounds having a β-lactam ring in the antibacterial agent is 1.0 to 30.0 (W/W)%.

Hydrophobic colloidal silicon dioxide includes gas-phase ring colloidal silicon dioxide, light anhydrous silicic acid, etc., made hydrophobic by replacing the silanol group with an organosilicon halogen compound or alcohol, preferably with a primary particle size of 10 ~20 mm range and about 100-300 m
A compound having a BET' surface area of ''/11 is used, and its proportion in the antibacterial agent is suitably 0.5 to 10.0 (W/W)%.

In addition, as the oil-based base, saturated fat-glyceride,
Oil bases used in 6K, such as liquid paraffin, polyoxyethylene hydrogenated castor oil, isopropyl myristate, ethyl oleate, corn oil, cottonseed oil, olive oil, soybean oil, peanut oil, and cocoa butter, are used.

These stable antimicrobial agents can be prepared by incorporating a compound having a β-lactam ring and hydrophobic colloidal silicon dioxide into an oleaginous base.

Specifically, hydrophobic colloidal silicon dioxide is 1 to 10 (W/W)% for ointments and injections, 2 to 8 (W/W)% for rectal preparations, and 2 to 8 (W/W)% for vaginal and uterine injections. 0.5
The concentration may be in the range of ~8 (W/W)%, and if necessary, other antibacterial substances such as dihydrostreptomycin sulfate, fradiomycin sulfate and kanamycin, stabilizers, preservatives and other suitable additives may be added. May be added.
) As described above, the stable antibacterial agent oid silicon dioxide Ios containing the compound having a β-lactam ring obtained according to the present invention is added with thorough stirring. Next, 6 g of ampicillin is added and uniformly dispersed by high speed rotation to obtain a stable antibacterial agent. This antibacterial agent and the antibacterial agent [control] using hydrophilic colloidal silicon dioxide instead of the hydrophobic colloidal silicon dioxide in this antibacterial agent.
The color tone and stability under conditions of 0°C are shown in Table 2 below.

The stable antibacterial agent of the present invention had a significantly higher residual rate of ampicillin than the control, and had only slight discoloration.

Similar experiments were conducted using isopropyl myristate, ethyl oleate, corn oil, cottonseed oil, olive oil, and soybean oil instead of definite paraffin, and similar results were obtained with each. Furthermore, when experiments similar to those described above were conducted using cephalexin and cefoxitin instead of ampicillin, similar results were obtained for each.

Example 3 Injection for mastitis in animals 2 g of hydrophobic colloidal silicon dioxide are added to a mixture of 88.4 g of peanut oil and 2.2 g of polyoxyethylene lauryl ether with good stirring. Then benzylpenicillin procaine 3 million units, dihydrostreptomycin sulfate 38 strength and food blue No. 1 250 mg
A stable antibacterial agent is obtained by adding t-i and performing a uniform dispersion operation by high-speed rotation. Stability of benzylpenicillin procaine at 40°C for this antibacterial agent and an antibacterial agent (control) using hydrophilic colloidal silicon dioxide instead of hydrophobic colloidal silicon dioxide in this antibacterial agent. It is shown in Table 3 below.

The residual rate of beampicillin was extremely high, almost the same as at the time of preparation, and there was almost no discoloration compared to the control.

Experiments similar to those described above were conducted using cephalexin and cefoxitin instead of ampicillin, and similar results were obtained for each.

[Example 5 Its! Or uterine injection] 5.2 g of hydrophobic colloidal silicon dioxide is added to a mixture of 88 g of palmitin-dipped isopropyl and Span 802-yellow with thorough stirring.

Furthermore, cefoxitin 4s titer was added and homogeneous dispersion operation was performed using high speed rotation, and a stable portion W1. Get the liquid. It is then filled into gelatin capsules for vaginal or uterine injection.

Table 5 below shows the color tone and stability of this antibacterial agent and an antibacterial agent (control) using hydrophilic colloidal silicon dioxide instead of hydrophobic colloidal silicon dioxide at 40°C.

Table 5: Stability over time of the antibacterial agent of the present invention The antibacterial agent had a significantly higher residual rate of cefoxitin than the control, and had almost no discoloration compared to the control.

Experiments similar to those described above were conducted using ampicillin, a penicillin compound, and cephalexin, a cephalosporin compound, in place of cefoxitin, a cephamycin compound having a β-lactam ring, and similar results were obtained for each.

〔Effect of the invention〕

As described above, according to the stable antibacterial agent containing a compound having a β-lactam ring of the present invention and its production method, it has the action of decomposing a compound having a β-lactam ring due to its hydrophilic property. Colloidal silicon dioxide, in which the hydrophilic silanol groups of colloidal silicon dioxide are substituted to make it hydrophobic, was used as a dispersant, so that compounds with β-lactam rings, which are unstable and easily lose activity and discolor, can be made longer. It can maintain its activity stably for a long time and can prevent discoloration. Therefore, it can exhibit excellent antibacterial properties even after long-term storage, and has high commercial value without discoloration or separation and sedimentation. In addition, the manufacturing method is relatively simple and can produce a large amount of antibacterial agents, making it an excellent industrial manufacturing method.

patent applicant Nihon Zenyaku Kogyo Co., Ltd.

Claims (1)

[Scope of Claims] 1) Compounds having a β-lactam ring 1.0 to 30.0 (
W/W)% and hydrophobic colloidal silicon diacetate from 0.5 to
1. A stable antibacterial agent containing a compound having a β-lactam ring, characterized by comprising 1 (LO (W/W)%) and an oleaginous base. 2) A compound having a β-lactam ring and a hydrophobic 1. A method for producing a stable antibacterial agent containing a compound having a β-lactam ring, the method comprising mixing colloidal silicon dioxide into an oleaginous base.