JPH10273451A - Gel having ph responsive function - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject gel useful as a base for releasing a medicine to a specific organ site by including a specific saturated fatty acid, etc., in a gel substance prepared by polymerizing a specified compound. SOLUTION: This gel is obtained by mutually polymerizing the same or different segmental compounds represented by the formula [X is H or methyl; R is H, a lower alkyl, mercapto, etc.; R1 is a lower alkyl; (m) and (n) are each an integer of 0-15] (acryloyl-L-proline, etc.) in the presence of an organic solvent, etc., according to a catalytic or an ionizing radiation polymerization method, adding the resultant polymer into an aqueous solution of a saturated fatty acid (lauric acid, etc.), stirring the prepared solution at 5-40 deg.C for 1-7 days and freeze-drying the resultant solution. A medicine can be contained in the gel to afford a small intestinal delivery system without decomposing and releasing the medicine in the stomach.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for preparing a pH-sensitive gel by incorporating a saturated fatty acid salt into a gel having a temperature response.
The present invention relates to a gel having a pH-responsive function characterized by having a system that responds to a drug, and is useful as a base for releasing a drug at a specific organ site.

[0002]

2. Description of the Related Art In drug treatment, a system that selectively releases a drug to a specific organ site is a very important system in terms of the efficiency of drug efficacy and the reduction of side effects.
Conventionally, in order to selectively release a drug at a specific organ site, the drug is released from the gel body by utilizing a volume phase transition in which the gel body contracts and swells in response to the pH of the digestive tract. There is a report aimed at. As a gel base that responds to pH, it is known to blend an ionic compound into a constituent segment compound. As the ionic compound, acrylic acid (Dong ct al.,
1992) and methacrylic acid (Bell et al., 1).
995, Motor et al. , 1995) are known. However, a gel body containing a saturated fatty acid or a salt thereof in a gel is not known.

[0003]

The polymer or gel prepared from acrylic acid and methacrylic acid used as the above-mentioned ionic compound has a long transition time to the swollen state, which is a driving force for drug release. There are drawbacks and improvements are desired.

[0004]

SUMMARY OF THE INVENTION The present invention provides a gel prepared by polymerizing the compound represented by the formula (1) as a segment or the same or different, into a saturated fatty acid having 10 to 18 carbon atoms or a saturated fatty acid thereof. Provided is a gel having a pH-responsive function, characterized by having a function of responding to pH by incorporating a salt.

[0005]

Embedded image Wherein X is a hydrogen atom or methyl, R is a hydrogen atom, lower alkyl, amino lower alkyl, carboxy lower alkyl, mercapto, benzyl or indolemethyl, R ₁ is lower alkyl, and m and n are Represents 0 or an integer of 1 to 15, provided that m and n are simultaneously 0
is not. In addition, the present invention provides a drug-containing gel in which a drug is included in the above-described pH-responsive gel.

The gel body prepared by polymerizing the segment compound of the formula (1) is in a contracted state in water at 37 ° C. or lower and has a low critical solution temperature (LCST). A gel obtained by incorporating a saturated fatty acid having 10 to 18 carbon atoms or a salt thereof into the gel has a function of responding to pH.

[0007] The lower alkyl in the formula (1) is a group having 1 carbon atom.
To 4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like.

The gel obtained by polymerization of the compound of formula (1) is in a contracted state at 37 ° C. in water.
By incorporating this saturated fatty acid or a salt thereof,
It becomes a gel body having a response function.

The gel of the present invention shrinks in an acidic region and swells by absorbing moisture in a neutral or alkaline region (pH
Due to its response function) properties, when a drug is included, the drug is not released in the stomach but is released only to the small intestine. In addition, since the speed of reaching the saturated swelling is high, a rapid effect of the drug can be expected.

[0010] As described above, the gel of the present invention can be used for small intestine delivery of a drug which is expected to be effective without decomposing and releasing in the stomach a drug which is decomposed by stomach acids and enzymes and a drug which causes gastric disorders. Useful as a base for the system.

[0011]

DETAILED DESCRIPTION OF THE INVENTION Conventional pH-sensitive polymers or gels incorporate a pH-responsive segment in their constituent segments, whereas the gels of the present invention are saturated with temperature-sensitive gels. It is characterized by the inclusion of a fatty acid salt to achieve a pH responsive system.

That is, a gel obtained by polymerizing the compound represented by the formula (1) shows a state of contracting in water at a temperature of 37 ° C. or less. This gel is a polymer that has a low critical solution temperature (LCST) in water and shrinks at temperatures below 37 ° C.

In the present invention, a saturated fatty acid or a salt thereof which is insoluble in the acidic region and soluble in the neutral and alkaline regions was introduced into the gel. That is, when the gel of the present invention containing a saturated fatty acid or a salt thereof was immersed in the neutral and alkaline regions, it swelled and exhibited pH responsiveness, and the swelling speed was high. Further, the drug contained in the gel of the present invention is not released at pH 3.0,
Released at H6.5.

For this reason, the gel of the present invention is useful as a base for a drug release system that responds to pH. As an application of this method, a drug that is decomposed by an acid or an enzyme in the stomach is included in the gel. It became possible to swell and release the drug.

The gel of the present invention can be produced as follows.

An organic solvent comprising the segment compound of the formula (1)
In the presence or absence of water or the like, a desired gel is obtained by appropriately selecting and employing a catalyst polymerization method, a photopolymerization method, an ionizing radiation polymerization method such as an electron beam or a γ-ray.

Examples of the segment compound of the formula (1) include acryloyl-L-proline methyl ester, acryloyl-L-proline ethyl ester, acryloyl-L-proline propyl ester, methacryloyl-L-proline methyl ester, and methacryloyl-methyl ester.
L-alanine ethyl ester, methacryloyl-L-alanine propyl ester, acryloyl-L-prolyl-L-alanine methyl ester, acryloyl-L-prolyl-L-alanine ethyl ester, methacryloylu L-prolyl L-glycine methyl ester and the like. No.

Next, the gel obtained above is added to an aqueous solution of a saturated fatty acid or a salt thereof, and the solution is added at 5 to 40 ° C. for 1 to 4 hours.
After stirring or standing for 7 days, the mixture is freeze-dried to obtain the gel of the present invention.

The saturated fatty acid or a salt thereof may be any one as long as it is insoluble in water in the acidic region and soluble in the neutral and alkaline regions. For example, lauric acid, myristic acid, palmitic acid, stearic acid or their salts Salts such as sodium and potassium are preferred.

Now, the present invention will be described in detail with reference to Examples, but it should not be construed that the invention is limited thereto. Examples show production examples of the gel body of the present invention and the gel body containing the drug.

[0021]

Example 1 0.02 mol of acryloyl-L-proline methyl ester was added to a mixed solvent of 14 ml of water and 6 ml of acetone and stirred for 10 minutes. This solution was degassed with nitrogen gas and 25 ° C. using γ-rays emitted from a cobalt 60 radiation source.
At 30 kGy to obtain a gel. Gel ratio: 65%.

The gel body was cut into a column having a diameter of 5 mm and a height of 10 mm (weight: about 50 mg), added to an aqueous solution of sodium laurate, left at 5 ° C. for 24 hours, and freeze-dried. A gel containing sodium laurate was obtained. The content of sodium laurate was 0.1 mmol.

[0023]

Example 2 0.02 mol of acryloyl-L-proline ethyl ester was added to a mixed solvent of 14 ml of water and 6 ml of acetone and stirred for 10 minutes. This solution was degassed with nitrogen gas, and the solution was degassed using gamma rays emitted from a cobalt 60 source.
Irradiation at 30 ° C. for 30 kGy gave a gel. Gel ratio: 70%.

This gel body was cut into a column having a diameter of 5 mm and a height of 10 mm (weight: about 50 mg), added to an aqueous solution of sodium laurate, left at 5 ° C. for 24 hours, and freeze-dried. A gel containing sodium laurate was obtained. The content of sodium laurate is 0.15
Mmol.

[0025]

Example 3 0.02 mol of methacryloyl-L-alanine ethyl ester was added to a mixed solvent of 14 ml of water and 6 ml of acetone and stirred for 10 minutes. This solution is degassed with nitrogen gas and subjected to 25 gamma rays emitted from a cobalt 60 radiation source.
Irradiation at 30 ° C. for 30 kGy gave a gel. Gel ratio: 60%.

The gel body was cut into a column having a diameter of 5 mm and a height of 10 mm (weight: about 50 mg), added to an aqueous solution of sodium laurate, left at 5 ° C. for 24 hours, and freeze-dried. A gel containing sodium laurate was obtained. The content of sodium laurate was 0.1 mmol.

[0027]

Embodiments 4 to 8 The same operation as in Embodiment 1 is performed to obtain Embodiment 4.
~ 8 gels were produced.

[0028]

[Table 1]

Measurement Method The gels obtained in Examples 1 to 3 were subjected to pH 3.0 to pH 9.0.
And the equilibrium swelling ratio at 37 ° C. at each pH was determined. The swelling ratio was determined by the following equation. The results are shown in FIG.

[0030]

(Equation 1) W _s: saturated fatty acids or weight W _L at equilibrium swelling of the gel was included its salts: saturated fatty acids or weight W _d of the dry gel was included its salts: gel does not include saturated fatty acid or a salt thereof Dry weight

Next, examples of gels containing a drug in the gel of the present invention and the results of a drug release test thereof will be shown.

[0032]

Example 9 50 mg of the gel obtained by radiation polymerization in Example 1 was added to an aqueous solution of sodium laurate and ketoprofen, left at 5 ° C. for 7 days, freeze-dried to obtain a gel containing ketoprofen. Obtained.

The gel thus obtained is subjected to pH adjustment at 37 ° C.
After 3 hours of incubation in 3.0 buffer, the gel was then removed and placed in pH 6.5 buffer, incubated for 2 hours, and further incubated in pH 3.0 buffer for 2 hours. A cycle test was performed. FIG. 2 shows the release behavior of ketoprofen in the cycle test.

As is clear from FIG. 2, at pH 3.0, the release of ketoprofen from the gel was suppressed,
At 6.5, the release rate is about 8 to 10 times higher than that at pH 3.0, and when the pH is returned to 3.0 again,
The release of ketoprofen was controlled.

[0035]

Example 10 50 mg of the gel obtained by the radiation polymerization shown in Example 2 was added to an aqueous solution of sodium laurate and ketoprofen, left at 5 ° C. for 7 days, lyophilized, and gel containing ketoprofen I got The release property of the drug was examined in the same manner as in Example 9. The results are shown in FIG.

[0036]

Example 11 50 mg of the gel obtained by the radiation polymerization shown in Example 3 was added to an aqueous solution of sodium laurate and ketoprofen, left at 5 ° C. for 7 days, freeze-dried and gel containing ketoprofen I got The release property of the drug was examined in the same manner as in Example 9. The results are shown in FIG.

[0037]

As described above, the drug contained in the gel of the present invention was not released at pH 3.0, but was released at pH 6.5. Therefore, the gel of the present invention is useful as a drug base for directing a pH-dependent drug release system.

[Brief description of the drawings]

FIG. 1 is a graph showing the swelling ratio of a gel containing sodium laurate with respect to pH.

FIG. 2 is a graph showing the release behavior of ketoprofen from an acryloyl L-proline methyl ester gel containing sodium laurate.

FIG. 3 is a graph showing the release behavior of ketoprofen from an acryloylu L-proline ethyl ester gel containing sodium laurate.

FIG. 4 is a graph showing the release behavior of ketoprofen from a methacryloylu L-alanine ethyl ester gel containing sodium laurate.

 ──────────────────────────────────────────────────続 き Continued on front page (72) Inventor Takeshi Suwa 1233 Watanukicho, Takasaki City, Gunma Prefecture Inside the Japan Atomic Energy Research Institute Takasaki Research Institute (72) Inventor Katsuharu Miyajima 2512-1 Oshikiri, Konan-cho, Osato-gun, Saitama Prefecture Zeria Shinyaku Kogyo Co., Ltd. (72) Inventor Munehiro Negishi 2512-1 Oshikiri, Konan-cho, Osato-gun, Saitama Prefecture Zeria Shinyaku Kogyo Co., Ltd.

Claims (2)

[Claims] 1. A gel prepared by polymerizing the same or different types with the compound represented by the formula (1) as a segment, containing a saturated fatty acid having 10 to 18 carbon atoms or a salt thereof to respond to pH. A gel having a pH responsive function, characterized in that the gel has a function of performing pH responsiveness. Embedded image Wherein X is a hydrogen atom or methyl, R is a hydrogen atom, lower alkyl, amino lower alkyl, carboxy lower alkyl, mercapto, benzyl or indolemethyl; R1 is lower alkyl; Or an integer of 1 to 15, provided that m and n are simultaneously 0
is not. ) 2. A drug-containing gel comprising the gel having the pH-responsive function according to claim 1 and a drug.