JPS6341369B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to an antibacterial agent in which a compound having a β-lactam ring exhibiting antibacterial activity is stabilized with a colloidal solution of hydrophobic silicon dioxide, and a method for producing the same. [Prior art] Penicillin compounds and cefem compounds with 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. It is being However, penicillin compounds, cefem compounds, or their non-toxic salts that have a β-lactam ring are unstable compounds and degrade significantly in the presence of polar substances such as water, amines, alcohols, acids, aldehydes, and glycols. However, during storage, the efficacy decreases and the color changes from yellow to reddish-yellow, to the point where it is no longer useful as a product. Therefore, conventionally, oil-based bases have been frequently used in the preparation of these formulations. As an oil-based base, the number of carbon atoms is 12 or more.
Glycerides of 18 saturated fatty acids such as isopropyl myristate, isopropyl palmitate, animal and vegetable oils and waxes, petrolatum, liquid paraffin, etc. are used as basic raw materials, and oily substances with a relatively high melting point and oily substances with a low melting point are usually combined. Mixing has been used to adjust the base consistency, or 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, increasing their viscosity at low temperatures and decreasing their viscosity at high temperatures, resulting in separation, and are often disadvantageous in practical use. In the case of aluminum stearate, the thickening effect takes advantage of the interaction between food oil and high-temperature heat treatment. There were disadvantages such as being limited to oil and requiring special processes such as high-temperature heat treatment to thicken the viscosity. On the other hand, colloidal silicon dioxide is widely used for the purpose of preventing sedimentation of the active ingredient in a low-viscosity base material in a molten state during the manufacture of rectal preparations, and as a general dispersant for the purpose of preventing sedimentation separation. The colloidal silicon dioxide can easily increase its viscosity through a hydrogen bridge structure between the hydrogen of a hydrophilic silanol group (SiOH) and the hydrogen of a dispersion medium such as water or alcohol by a simple preparation method, and has high thixotropy. It is an excellent dispersant that can be used with a wide range of bases, from polar bases to non-polar bases. 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 being less persistent, 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 a β-lactam ring, but when colloidal silicon dioxide is used as a dispersant for a β-lactam ring compound, the oily group It has been found that penicillin compounds and cefem compounds having a β-lactam ring in the drug are significantly degraded. This is due to the affinity between the silanol hydrophilic groups of colloidal silicon dioxide and traces of polar substances in the base material.
It is speculated that this is a catalytic effect on the decomposition of a compound having a β-lactam ring. [Objective of the Invention] The present invention provides an antibacterial agent that stabilizes a compound having a β-lactam ring that is easily decomposed, reduces efficacy, and is prone to discoloration, and more specifically, an ointment for topical application, and an antibacterial agent for use in animals. The object of the present invention is to provide a mastitis injection, a rectal injection, a vaginal or uterine injection, and a method for producing the same. [Structure of the Invention] The present inventor has conducted various studies to produce stable ointments and rectal administration preparations of penicillin compounds, cefem compounds, or non-toxic salts thereof having a β-lactam ring. By using an oily colloidal liquid of hydrophobic silicon dioxide obtained by replacing the silanol hydrophilic group of silicon with an organosilicon halogen compound or alcohol, the characteristics of colloidal silicon dioxide as an excellent dispersant are slightly diminished. It has now become possible to stabilize formulations of penicillin compounds, cephem compounds, and non-toxic salts thereof having a β-lactam ring. The present invention was completed based on this new knowledge, and consists of compounds having a β-lactam ring of 1.0 to 30.0.
(w/w)%, an oily colloidal liquid of hydrophobic silicon dioxide 0.5-10.0% (w/w), and an oleaginous base. It is characterized by mixing an antibacterial agent and an oily colloidal liquid of hydrophobic silicon dioxide in which an alkyl group is reacted with a compound having a β-lactam ring and a silanol hydrophilic group on at least the surface of silicon dioxide into an oily base. The present invention relates to a method for producing a stable antibacterial agent containing a compound having a β-lactam ring. Here, as a compound having a β-lactam ring, the general formula () Penicillin compounds represented by, specifically propicillin, phenoxymethylpenicillin, cloxacillin, ampicillin, amoxicillin, benzylpenicillin, sulbenicillin, carbenicillin, benzylpenicillin procaine, etc. and their non-toxic salts, or general formula () Cefem compounds represented by the above, specifically cephalexin, cephalothin, cefazoline, cephaloridine, cefapirin, cefoxytin, cefmetazole, latamoxef, cefotetan, etc., and non-toxic salts thereof can be mentioned. The proportion of these compounds having a β-lactam ring in the antibacterial agent is suitably 1.0 to 30.0 (w/w)%. Oil-based colloidal liquid of hydrophobic silicon dioxide (hereinafter referred to as
As the hydrophobic colloidal silicon dioxide), the hydrophilic silanol group on at least the surface of gas-phase colloidal silicon dioxide, light silicic anhydride, etc., is replaced with an organosilicon halide compound such as dimethyldichlorosilane, trimethylchlorosilane, etc. A substance made hydrophobic by substitution with an alcohol, preferably having a primary particle size in the range of 10 to 20 millimicrons and a BET surface area of about 100 to 300 ^{m 2} /g, is suspended in animal or vegetable oil or mineral oil. A colloidal liquid is used, and its proportion in the antibacterial agent is
0.5-10.0 (w/w)% is suitable. Commonly used oil bases include saturated fatty acid glycerides, liquid paraffin, polyoxyethylene hydrogenated castor oil, isopropyl myristate, ethyl oleate, corn oil, cottonseed oil, olive oil, soybean oil, peanut oil, and cocoa butter. An oleaginous base is 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, in the case of ointments and injections, hydrophobic colloidal silicon dioxide is contained in an amount of 1 to 10 (w/w)%;
Concentrations may range from 2% to 8% (w/w) for rectal formulations and from 0.5% to 8% (w/w) for vaginal and uterine injections, and if necessary, other antibacterial substances such as dihydro sulfate. Stabilizers, preservatives and other suitable additives may be added, such as streptomycin, fradiomycin sulfate and kanamycin. Examples of representative examples of stable antibacterial agents containing compounds having a β-lactam ring obtained by the present invention as described above and their stability are as follows. In addition, the residual rate of the antibacterial substance in the examples was extracted with 1% phosphate buffer (PH6.0) and measured by the cylindrical plate method according to the Japanese Antibiotic Testing Standards. Example 1, Ointment for Topical Application 4 g of hydrophobic colloidal silicon dioxide are added to 91 g of isopropyl myristate with good stirring. Next, 5 g of cephalexin was added and homogeneous dispersion was performed using high-speed rotation to obtain a stable antibacterial agent. Table 1 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 in this antibacterial agent at 40°C. Shown below.

[Example 2, ointment for topical application]

10 g of hydrophobic colloidal silicon dioxide are added to a mixture of 86 g of sulfurized paraffin and 3 g of polyoxyethylene hydrogenated castor oil with good stirring.
Next, 6 g of ampicillin is added and uniformly dispersed by high speed rotation to obtain a stable antibacterial agent. Table 2 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 in this antibacterial agent at 40°C. Shown below.

[Table] The stable antibacterial agent of the present invention had a significantly higher residual rate of ampicillin than the control, and the discoloration was slight. Isopropyl myristate, ethyl oleate, corn oil,
When experiments similar to the above were conducted using cottonseed oil, olive oil, and soybean oil, 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.
Next, benzylpenicillin procaine 3 million units,
Add 3 g of dihydrostreptomycin sulfate and 250 mg of Food Blue No. 1, and perform uniform dispersion by high-speed rotation to obtain a stable antibacterial agent. The stability of benzylpenicillin procaine at 40°C for this antibacterial agent and an antibacterial agent (control) using hydrophilic colloidal silicon dioxide instead of the hydrophobic colloidal silicon dioxide in this antibacterial agent is shown below. It is shown in Table 3.

[Example 4 Rectal administration agent]

Melt 93.5 g of cocoa butter, add 5 g of hydrophobic colloidal silicon dioxide, and mix. Add 6 g of ampicillin and perform uniform dispersion by high-speed rotation to obtain a stable dispersion. The product is then injected into a mold for rectal administration and cooled to solidify. 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 in this antibacterial agent at 30°C are shown in Table 4 below. .

[Example 5, vaginal or uterine injection]

88g of isopropyl palmitate and span
5.2 g of hydrophobic colloidal silicon dioxide are added to 802.8 g of the mixture with good stirring. Further, 4 g of cefoxitin was added, and a stable dispersion was obtained by uniformly dispersing the mixture using high-speed rotation.
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.

[Comparative example]

The present invention and a commonly used sample using colloidal silicon dioxide (ie, hydrophilic) were compared in terms of color tone, degree of separation, and stability of drug efficacy. (1) Test sample Colloidal silicon dioxide base Weighed 3 million units of benzylpenicillin procaine and 2.7 g of hydrophobic colloidal silicon dioxide,
Bring the total weight to 90 g with rapeseed oil, and use high-speed stirring to uniformly disperse the sample solution. Control Weigh out 3 million units of benzylpenicillin procaine, make the total weight 90g with rapeseed oil, and use high-speed stirring to uniformly disperse the solution to obtain a control solution. (2) Observation items and test methods Color tone and degree of separation Fill 9 g each of sample solution and control solution into transparent plastic tubes (inner diameter 14 mm, length 10 cm), seal tightly, and store in a furan container at 40°C. The color tone of the benzylpenicillin procaine particles over time is visually observed, and the degree of separation of the particles is determined by measuring the distance (mm) from the top surface of the filling liquid to the point of sedimentation. Stability of benzylpenicillin procaine Sample solution and control solution were placed in an aluminum tube (inner diameter
14mm, length 10cm) filled with 9g each and sealed tightly.
Store in a furan vessel at 40°C and measure the residual titer of benzylpenicillin procaine over time. (3) Results The results for color tone are shown in Table 6, the results for resolution are shown in Table 7, and the results for residual titer of benzylpenicillin procaine are shown in Table 8.

【table】

【table】

〔Effect of the invention〕

As described above, according to the stable antibacterial agent containing a compound having a β-lactam ring and the method for producing the same of the present invention, it had the effect of decomposing the compound having a β-lactam ring due to its hydrophilic property. Since colloidal silicon dioxide, which has been made hydrophobic by substituting its hydrophilic silanol groups, was used as a dispersant, compounds with β-lactam rings, which are unstable and easily lose their activity and discolor, can be used for a long period of time. It is possible to stably maintain activity and 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.

Claims (1)

[Claims] 1 Compounds having a β-lactam ring 1.0 to 30.0
(w/w)%, an oily colloidal liquid of hydrophobic silicon dioxide 0.5-10.0(w/w)%, and an oily base. Method of manufacturing the agent. 2 A β-lactam characterized in that a compound having a β-lactam ring and an oily colloidal liquid of hydrophobic silicon dioxide in which an alkyl group is reacted with a silanol hydrophilic group on at least the surface of silicon dioxide are mixed into an oily base. A method for producing a stable antibacterial agent containing a ring-containing compound.