JP2003267891A - W / O / W emulsion formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a W / O / W type emulsion preparation of a drug which is susceptible to pH and suitable for use as an oral preparation or an injection, which can reduce side effects by controlled release control. I will provide a. A W / O / W type emulsion preparation comprising the following (a) to (c). (A) pH-adjusted inner aqueous phase containing a drug in the range of pH 1 to 8. (B) carbon number 16 to 30% by weight or more containing unsaturated fatty acids
An oil phase containing a lipophilic emulsifier comprising an ester of a fatty acid of 22 and a polyhydric alcohol having 4 or more carbon atoms. (C) External water phase.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a W / O / W type emulsion preparation, and more particularly to a W / O / W type emulsion preparation suitable for use as an oral preparation or an injection, which is suitable for a drug susceptible to pH. The present invention relates to an O / W type complex emulsion preparation.

[0002]

2. Description of the Related Art W / O / W (water-in-oil-in-water) type emulsions are used not only in the fields of food and cosmetics but also in the medical field, such as external preparations, internal preparations, high calorie infusions and It has been used as an injection for artificial blood since ancient times. Examples of the oral agent and the injectable agent include a lymph node-preferring anticancer agent consisting of a carcinostatic agent, an oil and fat, and a nonionic surfactant (JP-A-48-88220), and an oil and fat coexisting with an insulin secretion-enhancing active substance. Oral formulation (JP-A-55
No. 129218), a W / O / W type emulsion preparation has been proposed.

On the other hand, in recent years, the usefulness of W / O / W type emulsion preparations as carriers for realizing sustained release or targeting of drugs has been reconfirmed, and various W / O /
W-type emulsion preparations have been proposed (for example, JP-A-9-316008, JP-A-10-7587, JP-A-10-158152, and JP-A-10-2).
No. 03962, JP 2001-131087 A, JP 2000-507610 A, etc.).

Further, by adding a surfactant to the inner water phase, the uptake rate of the drug is increased and the inflow of water from the outer water phase to the inner water phase is decreased, which is a stable W / O / W type. A wide range of methods for producing an emulsion (Japanese Patent Laid-Open No. 5-97660) or a method in which a hydrophilic emulsifier having an HLB of 7 or more is added to the inner aqueous phase and a lipophilic emulsifier composed of a polyhydric alcohol ester of unsaturated fatty acid is blended in the oil phase. A W / O / W type emulsion (Japanese Unexamined Patent Publication No. 2001-25360), which has good emulsion stability and high safety, has been proposed.

[0005]

SUMMARY OF THE INVENTION The present invention has been made in view of the above circumstances, and its purpose is to be suitable for use as an oral preparation or an injectable preparation in which side effects can be reduced by controlled release. Also, the W /
An object is to provide an O / W emulsion formulation.

[0006]

That is, the gist of the present invention is W / characterized by comprising the following (a) to (c):
It exists in an O / W emulsion formulation. (A) An internal aqueous phase containing a drug, the pH of which is adjusted in the range of 1 to 8. (B) 16 to 16 carbon atoms containing 50% by weight or more of unsaturated fatty acid
An oil phase containing a lipophilic emulsifier comprising an ester of 22 fatty acid and a polyhydric alcohol having 4 or more carbon atoms. (C) External water phase.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention is described in detail below.

<Inner Water Phase> The inner water phase contains a drug which is easily influenced by pH. Such drugs include cisplatin,
Examples include low molecular weight compounds such as salicylic acid and valinomycin, and protein preparations such as insulin and interferon. Among them, irinotecaine hydrochloride (CPT-1
Camptothecin derivatives such as 1) are suitable. Irinotecaine hydrochloride is a prodrug of 7-ethyl 10-hydroxycamptothecin (SN-38), which is a hydrophobic substance, and is hydrolyzed by esterase in vivo to active SN-38, which is an excellent anti-DNA inhibitor. It shows a cancer effect.

The internal aqueous phase has a pH of 1 to 8, preferably pH 2
It is kept constant in the range of ~ 6. pH adjustment is usually
Use buffer. The buffer solution is appropriately selected according to the desired pH, and for example, glycine-HCl buffer solution (pH 1 to
5), phosphate buffer (pH 2-8), Tris buffer (p
H3-8) and the like are used. Camptothecin derivatives are
Since the lactone ring is opened and deactivated at pH above neutral,
Keeping the inner aqueous phase acidic is one key point. In addition, in the internal water phase, usually for the purpose of adjusting the osmotic pressure,
Add 10-500 mM NaCl. Usually, a physiological saline concentration (154 mM) is preferably used. Furthermore, a hydrophilic emulsifier or the like can be added if necessary.

<Oil Phase> The oily component used in the oily phase is not particularly limited, but as the oily component which is normally liquid at room temperature, soybean oil, corn oil, peanut oil, olive oil, sunflower oil, safflower are used. Examples thereof include oils, vegetable oils such as jojoba oil, fish oils, and animal oils such as orange luffy oil. Hydrocarbons such as light liquid paraffin, squalene and squalane, medium chain saturated fatty acids such as caprylic acid and capric acid, long chain unsaturated fatty acids such as oleic acid, linoleic acid and linolenic acid, medium or long chain fats Group alcohols, silicone oils and the like can also be used.

The lipophilic emulsifier used in the oil phase contains 30% by weight or more of unsaturated fatty acids, preferably 50% by weight or more,
More preferably, it comprises an ester of a fatty acid having 16 to 22 carbon atoms and containing 70% by weight or more of a polyhydric alcohol having 4 or more carbon atoms. By using such a lipophilic emulsifier, leakage of the drug from the internal phase can be suppressed. In the lipophilic emulsifier, examples of the unsaturated fatty acid that serves as the hydrophobic portion include palmitooleic acid, oleic acid, erucic acid, etc., and among them, erucic acid is preferable. Examples of the polyhydric alcohol serving as the hydrophilic part include sucrose, lactose, glucose, polyglycerin, sorbitol, sorbitan and the like. As the polyglycerin, polyglycerin having a polymerization degree of 4 to 20 is preferable.

More preferred lipophilic emulsifiers are sucrose fatty acid esters having an HLB of 3 or less, polyglycerin fatty acid esters having an HLB of 10 or less, and sorbitan fatty acid esters having a substitution degree of 1 to 3. These emulsifiers are preferably used because they are easily dissolved in the oily component and the stability of the internal phase W / O type emulsion is excellent. The most preferred lipophilic emulsifiers are sucrose erucic acid esters of HLB1 to 3 or sucrose oleic acid esters, and hexaglycerin erucic acid esters or decaglycerin erucic acid esters having an HLB of 8 or less.

The lipophilic emulsifier is usually contained in the oil phase in an amount of 0.1 to 30% by weight, preferably 1 to 1% by weight based on the total amount of the oil phase components.
Contains 0% by weight. The lipophilic emulsifiers may be used in combination of two or more kinds, and the combination of both may be appropriately selected.

<External Water Phase> The external water phase is not particularly limited, but like the internal water phase, a buffer solution may be appropriately used for the purpose of adjusting to a desired pH. In addition, osmotic pressure may be adjusted by adding NaCl to the external water phase.
A hydrophilic emulsifier can be added to improve the stability of the / O / W type emulsion preparation.

When a hydrophilic emulsifier is added to the outer water phase,
From the viewpoint of preventing leakage of the drug in the inner aqueous phase, hydrophilic polyglycerin stearic acid ester having a degree of polymerization of constituent polyglycerin of 4 to 20, particularly polyglycerin stearic acid ester having HLB of 10 or more is preferable. Examples of commercially available products of such polyglycerin stearic acid ester include “Ryoto Polyglyceride SWA” manufactured by Mitsubishi Chemical Foods Co., Ltd.
-10D "is preferably used.

The amount of hydrophilic polyglycerin stearate used is usually 0.05 to 10% by weight, preferably 0.1 to 5% by weight, based on the total amount of the outer aqueous phase.

<Production Method of Emulsion Formulation> The W / O / W emulsion formulation of the present invention usually has a pH of 1 to 8 containing the above drug in an oily component in which a predetermined amount of the above lipophilic emulsifier is dissolved. The internal water phase component of (1) was added dropwise with stirring to emulsify to prepare a W / O type emulsion, and then the obtained W
The / O type emulsion can be easily produced by dropping it into a predetermined amount of the external aqueous phase liquid and emulsifying and dispersing as an internal phase emulsion.

The stirring can be carried out by a commonly used stirrer such as a propeller mixer and a disper. The number of rotations cannot be generally stated because it depends on the capacity, but usually 5
It is in the range of 0 to 30,000 rpm. The particle size of the dispersed droplets can be adjusted by adjusting the stirring intensity (= power x time).
It can be controlled between 0.1 and 50 μm.

The ratio of each phase of the W / O / W type emulsion is not particularly limited. The volume ratio of the outer water phase to the inner phase O / W emulsion is usually 99: 1 to 50:50, and the volume ratio of the inner water phase to the oil phase in the inner phase emulsion is usually 1:
It is in the range of 99 to 50:50. The content of the drug in the inner aqueous phase is not particularly limited as long as it is an effective amount or more according to the purpose.

[0020]

EXAMPLES The present invention will be described in more detail with reference to examples below, but the present invention is not limited to the following examples as long as the gist thereof is not exceeded. In the following examples, irinotecaine hydrochloride (CPT-11) was used as a drug to prepare W / O / W emulsions, and the leakage rate (%) of the drug to the external water phase is shown in Table 1. The emulsifier was evaluated. The amount of leakage of the drug from the inner water phase to the outer water phase was measured by the following method. Of course, the leak rate is preferably as close to 0 as possible, and at a practical level, it is preferably 5% or less for at least one hour.

<Measuring Method of Leakage Amount of CPT-11> W /
After preparing the O / W type emulsion, 1 mL of a sample was sampled with stirring with a stirrer in a 37 ° C. constant temperature bath and centrifuged for 5 minutes (Tomy Seiko LT-01).
5 type; 2900 rpm), and then diluted 5 times, with a fluorescence spectrophotometer (Perkin Elmer LS50B type; excitation wavelength 365 nm, emission wavelength 430 nm).
The amount of PT-11 was measured.

[0022]

[Table 1] <Lipophilic emulsifier>"ER-290": sucrose erucic acid ester (manufactured by Mitsubishi Chemical Foods Inc., erucic acid 90% by weight, HLB2) "ER-190": sucrose erucic acid ester (Mitsubishi Chemical Foods Erucic acid 90% by weight, HLB1) "O-170": sucrose oleic acid ester (Mitsubishi Chemical Foods, Inc., 70% by weight oleic acid, HLB1) "POS-135": sucrose mixed fatty acid ester (Mitsubishi Chemical Foods Co., palmitic acid / oleic acid / stearic acid = 30/40/30 (weight ratio), HLB1) “L-195”: sucrose laurate ester (Mitsubishi Chemical Foods Co., Ltd., 95% by weight, HLB1) “ER-60D”: decaglycerin erucic acid ester (manufactured by Mitsubishi Kagaku Foods, 90% by weight erucic acid, HLB
6) "TGCR": condensed ricinoleic acid tetraglycerin ester (average condensation degree 4.4, HLB1) <hydrophilic emulsifier>"Tween20": polyoxyethylene (20) sorbitan monolaurate (HLB16) "S-1570": Sucrose stearate (manufactured by Mitsubishi Kagaku Foods, stearic acid 70% by weight, HLB1
5) “SWA-10D”: decaglycerin stearic acid ester (manufactured by Mitsubishi Chemical Foods Inc., stearic acid 70% by weight,
HLB15) "L-7D": decaglycerin lauric acid ester (manufactured by Mitsubishi Kagaku Foods, 95% by weight lauric acid, HLB1)
6)

Examples 1-5 and Comparative Examples 1-2 W / O / W type emulsions were prepared according to the formulations shown in Table 2. First, while adding 3 mL of the inner aqueous phase to 6 mL of the oil phase, a homogenizer (PT-manufactured by KINEMATICA).
MR2100) was used and stirred at 24,000 rpm to prepare a W / O type emulsion. Next, to the obtained W / O emulsion 5mL, the external water phase 50mL
And add a stirrer (NISSIN
(Manufactured by SW-M60) was used and stirred at 100 rpm to prepare a W / O / W type emulsion. Obtained W
Leaked to the external water phase of the / O / W emulsion
Table 3 shows the results of measuring PT-11 (leakage rate; weight%).

[0024]

[Table 2]

[0025]

[Table 3]

Examples 6 to 7 The procedure of Example 2 was repeated except that the concentration of ER-190 added to the oil phase was changed. The results are shown in Table 4.

[0027]

[Table 4]

Example 8 and Reference Examples 1 to 3 The same procedure as in Example 2 was carried out except that 0.5% by weight of various hydrophilic surfactants were added to the outer water phase. The results are shown in Table 5.

Example 9 Example 9 was repeated except that 0.5% by weight of SWA-10D was added to the outer water phase. The results are shown in Table 5.

[0030]

[Table 5]

[0031]

As described above, according to the present invention, the pH
There is provided a W / O / W type emulsion preparation suitable for use as an oral preparation or an injectable preparation, in which side effects of a drug susceptible to are controlled by controlled release.

   ─────────────────────────────────────────────────── ─── Continued front page    (72) Inventor Eiichi Tohsaka             6-10-1 Hakozaki, Higashi-ku, Fukuoka City, Fukuoka Prefecture Kyushu Univ.             Graduate School of Engineering, Department of Applied Chemistry (72) Inventor Yuko Kamiichi             6-10-1 Hakozaki, Higashi-ku, Fukuoka City, Fukuoka Prefecture Kyushu Univ.             Graduate School of Engineering, Department of Applied Chemistry F term (reference) 4C076 AA18 BB01 BB11 CC27 DD08                       DD22 DD51 EE53 FF31 FF63                       FF67                 4C086 AA01 AA02 CB22 MA03 MA05                       MA09 MA22 NA03 NA06 NA12                       ZB26

Claims (6)

[Claims] 1. A W / O / W type emulsion preparation comprising the following (a) to (c): (A) An internal aqueous phase containing a drug, the pH of which is adjusted in the range of 1 to 8. (B) 16 to 16 carbon atoms containing 30% by weight or more of unsaturated fatty acid
An oil phase containing a lipophilic emulsifier comprising an ester of 22 fatty acid and a polyhydric alcohol having 4 or more carbon atoms. (C) External water phase. 2. The preparation according to claim 1, wherein the pH of the inner aqueous phase is in the range of 2-6. 3. The preparation according to claim 1, wherein the drug is a camptothecin derivative. 4. The preparation according to claim 1, wherein the unsaturated fatty acid constituting the lipophilic emulsifier is selected from the group of palmitooleic acid, oleic acid and erucic acid. 5. The preparation according to any one of claims 1 to 4, wherein the lipophilic emulsifier is selected from the group consisting of sucrose erucic acid ester, sucrose oleic acid ester, and polyglycerin erucic acid ester. 6. The preparation according to claim 1, which contains hydrophilic polyglycerin stearic acid ester in the external water phase.