JP2000178579A - Oil and fat for medical preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To decrease the endotoxin content to below a specific level by subjecting raw oil and fat to a non-heating treatment for removing endotoxin. SOLUTION: The content of endotoxin in oil and fat is decreased to not more than 20 EU/g. The non-heating treatment for removing endotoxin is carried out by filtration by means of a filtration support. The filtration support used is preferably one modified with a positive charge. The filtration support modified with a positive charge comprises a filtration support, formed of cellulose, nylon, agarose, polystyrene or the like, subjected to fixation of a positively charged electrolyte such as a compound or the like bearing an amino group, introduction of an amino acid group, fixation of histidine, or the like. As the filtration support modified with a positive charge are exemplified Zetapore, Zetaplus or the like. The shape of the filtration support itself is not particularly limited, but preferably film-like, porous resin-like or fiber-like. The pore size is about 0.2-10 μm, preferably 0.2-0.5 μm.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an oil and fat for pharmaceutical preparations which can be used in the field of pharmaceuticals, and more particularly to an oil and fat for pharmaceutical preparations from which endotoxin has been removed to a certain level or less by non-heat treatment.

[0002]

2. Description of the Related Art Compounds used as active ingredients of pharmaceuticals can be classified into water-soluble compounds and oil-soluble compounds. Of these, for oil-soluble compounds, fats and oils are often used as carriers.

[0003] By the way, general fats and oils sometimes contain a pyrogenic substance called endotoxin.
There is a demand for the removal or reduction of fats and oils used in pharmaceutical production. That is, if a drug applied directly to the body, such as intravenous administration, among parenterally administered drugs contains an endotoxin that is a pyrogenic substance, chills during administration,
It can cause severe fever with severe effects and can have serious effects in patients with reduced physical strength.

Therefore, removal or reduction of endotoxin is an important technical point in a pharmaceutical production line. However, as an endotoxin removal method for oils and fats for pharmaceutical preparations, heating at 250 ° C. for 1 to 2 hours.
Only the inactivation of endotoxin by (dry heat sterilization) is mentioned. The heating at 250 ° C. is considered to cause denaturation of the fats and oils themselves, and is not suitable for treating fats and oils for pharmaceutical preparations.

[0005] Endotoxin may be removed by a filter in a water-based solution. However, in an oil-based solution, there is a problem in that the working efficiency is reduced. Therefore, filtration by a filtration carrier has not been practically used.

[0006]

Accordingly, there is a need for the development of a method capable of removing or reducing endotoxin by a non-heat treatment without a problem of denaturation of fats and oils, and the present invention provides such means. Make it an issue.

[0007]

Means for Solving the Problems The present inventors have studied an endotoxin removal method by non-heating in order to solve the above problems, and as a result, it is possible to efficiently remove endotoxin by using an appropriate filtration material. Thus, the present invention has been completed.

[0008] That is, the present invention provides an oil or fat for a pharmaceutical preparation having an endotoxin content of 20 EU / g or less, which is obtained by subjecting a raw oil or fat to an endotoxin removal treatment without heating. The present invention also provides a method for producing an oil and fat for a pharmaceutical preparation having an endotoxin content of 20 EU / g or less, wherein the raw oil and fat is subjected to filtration with a filtration carrier.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The endotoxin content of the present invention is 2
Fats and oils for pharmaceutical preparations of 0 EU / g or less (hereinafter referred to as "the fats and oils of the present invention") are obtained by subjecting raw fats and oils such as vegetable fats and oils, animal fats and oils, and mineral fats and fats to non-heating endotoxin removal treatment.

[0010] Among the raw oils and fats of the present invention, examples of vegetable oils include olive oil, soybean oil, sesame oil, castor oil, corn oil, safflower oil, rapeseed oil, eucalyptus oil and the like.
Examples of animal oils include liver oil, seal oil, sardine oil, docosahexaenoic acid, eicosapentaenoic acid, and docosapentaenoic acid, and examples of mineral oils include liquid paraffin. It is preferable that these fats and oils have been previously purified by a method such as washing with alcohol or molecular distillation. Among the above oils and fats, more preferred are vegetable oils.

[0011] The unheated endotoxin removal treatment is carried out by filtering the raw material fats and oils. The carrier used for this filtration is preferably a positively-charged filtration carrier.

[0012] The filtration support having been subjected to the positive charge modification includes:
Cellulose, nylon, agarose, a filtration carrier formed of polystyrene, etc., for example, immobilization of a positively charged electrolyte such as a compound having an amino group, introduction of an amino acid group,
It has been subjected to treatment such as immobilization of histidine. Specific examples of the filtration carrier subjected to the positive charge modification include Zedapore, Zedapras and the like.

The shape of the filtration carrier itself is not particularly limited, but is preferably a membrane, a porous resin, or a fiber. Further, the pore size is about 0.2 to 10 μm,
Preferably it is 0.2 to 0.5 μm.

The above-mentioned filtration carrier can be used as it is without depyrogenation treatment.
It is preferable to dry after performing a usual depyrogenation treatment, and to use it for filtration of raw material fats and oils.

On the other hand, as a device for filtering raw fats and oils using the above-mentioned filter carrier, a closed filtration line is used in order to prevent re-contamination of the fats and oils of the present invention, which is the object, by endotoxin and to prevent mixing of other components. Preferably, it is used. This filtration line is more preferably equipped with a filtration tank, a piping tube, and an air filter capable of depyrogenating.

As described above, for example, the endotoxin content of the raw oil / fat of about 100 EU / g is reduced to at least 20 EU / g.
g or less, and can be used as the oil and fat of the present invention for use in medicine. Further, according to the present invention, the amount of endotoxin that is more preferable for pharmaceutical use, for example, 5 EU / g or less, and further 1 EU / g or less can be achieved.

[0017]

EXAMPLES Next, the present invention will be described in detail with reference to examples and test examples, but the present invention is not limited to these examples.

Example 1 Using 250 g of olive oil as a raw material fat and oil, endotoxin-free olive oil was obtained as follows. That is, the endotoxin treatment is performed by adding a positively charged filter (a small capsule filter SCF manufactured by CUNO Corporation; zetapore 0.20 μm) to a filtration line that has been depyrogenated by a conventional method.
m) was mounted and filtration was performed. Filtration is performed by attaching the above filter to a filtration tank, connecting a tube to a receiving container, and using a closed system. At room temperature, pressurize with nitrogen gas through an air filter (1 kg / cm ² ).
It was carried out by doing.

EXAMPLE 2 Olive oil 200 having a different endotoxin content from Example 1
g and filtration with a filter in the same manner as in Example 1 except that the pressure with nitrogen was set to 2 kg / cm ² to obtain endotoxin-free olive oil.

Test Example Measurement of endotoxin content in olive oil: The endotoxin content of the endotoxin-free olive oil obtained in Examples 1 and 2 was measured by the following method. In this measurement, the amount of endotoxin in the raw olive oil before treatment was also measured as a control, and the measurement was performed twice.

(Test Method) An endotoxin extract (Wako Pure Chemical Industries, Ltd.) was prepared by weighing about 50 mg of each oil and fat sample (Olive oil) and diluting it 20-fold with water for injection.
Add 5 ml, shake on a shaker for 60 minutes,
Centrifuged at rpm for 10 minutes. The upper oil layer was removed and centrifuged again. The operation from the removal of the oil layer to the centrifugation was repeated until the lower layer (extract liquid layer) was no longer turbid, and the extract liquid layer after centrifugation was taken as a measurement sample. Endotoxin was measured for the measurement sample (Seikagaku Corporation Toxicolor System), and the endotoxin content contained in the olive oil was measured.

(Results) The results of Examples 1 and 2 are shown in the table. Both Examples 1 and 2 showed that the endotoxin content in the olive oil was significantly reduced by filtration using a positively charged filter.

[0023]

[Table 1]

[0024]

As described above, according to the present invention, it is possible to remove endotoxin from raw material fats to at least 20 EU / g or less, more preferably 5 EU / g or less, more preferably 1 EU / g or less. It is possible to obtain an oil and fat for pharmaceutical preparations having no problem such as heat generation. In particular, since the oils and fats for pharmaceutical preparations obtained in the present invention are not subjected to heat treatment, they have no problem due to the deterioration of the oils and fats, and are highly useful. that's all

Claims (9)

[Claims] 1. An oil or fat for pharmaceutical preparations having an endotoxin content of 20 EU / g or less, obtained by subjecting a raw oil or fat to an endothermic endotoxin removal treatment. 2. The fat or oil for pharmaceutical preparations according to claim 1, wherein the raw fat or oil is a vegetable fat, animal fat or mineral fat. 3. The oil or fat for pharmaceutical preparations according to claim 2, wherein the vegetable oil or fat is olive oil, soybean oil, sesame oil, castor oil, corn oil, safflower oil, rapeseed oil or eucalyptus oil. 4. The fat or oil for pharmaceutical preparations according to claim 1, wherein the unheated endotoxin removal treatment is filtration using a filtration carrier. 5. The fat or oil for pharmaceutical preparations according to claim 4, wherein the filtration carrier used is a filtration carrier subjected to positive charge modification. 6. A method for producing an oil and fat for a pharmaceutical preparation having an endotoxin content of 20 EU / g or less, wherein the raw oil and fat is subjected to filtration with a filter carrier. 7. The method for producing an oil and fat for pharmaceutical preparations according to claim 6, wherein the filtration carrier used is a filtration carrier subjected to positive charge modification. 8. The method according to claim 6, wherein the raw material fat is a vegetable fat, animal fat or mineral fat. 9. The method according to claim 6, wherein the vegetable oil is an olive oil, a soybean oil, a sesame oil, a castor oil, a corn oil, a safflower oil, a rapeseed oil or a eucalyptus oil.