JPH0317025A - Sustained release agent for active component - Google Patents

Abstract

PURPOSE:To provide a sustained release agent for active component composed of an ester of an oxyalkylene derivative such as polyhydric alcohol having carboxyl group and an active component having hydroxyl group, soluble in water as well as organic solvents and usable in the form of solid as well as liquid. CONSTITUTION:The objective sustained release agent is composed of an ester of (A) an oxyalkylene derivative of a polyhydric alcohol or polybasic carboxylic acid having carboxyl group (e.g. the compound of formula I to V) and (B) an active component having hydroxyl group such as perfumery (e.g. phenetyl alcohol or geraniol). The active component is slowly released by the hydrolysis of the agent to keep the activity over a long period. Since the agent has polyoxyalkylene ether skeleton, it can be prepared in the form of solid or liquid and the solubility to various solvents can be controlled.

Description

[Detailed Description of the Invention] [Industrial Field of Application] The present invention prevents the premature deactivation of hydroxyl group-bearing activity. Concerning release agents for slow and sustained release.

[Conventional technology]

Controls deactivation of active ingredients. Attempts to make it a sustained release drug have already been made.
1 I am. for example. Regarding highly volatile precepts such as fragrances. Adsorb onto porous material. Methods such as inclusion in cyclodextrin or confinement in gel have been used.

[The problem that the invention attempts to solve]

However, the above method has the following drawbacks. When it is adsorbed to a porous material, desorption occurs at once when it comes into contact with water, and when it is used as an clathrate compound, a compound that can be included must be observed. In addition, since clathrate f-hide compounds are easily displaceable by water, if water is present, they will be released all at once as in the case of adsorption, and in both cases it is desirable to be able to control the release of a certain amount of activity.

Also, when confining it in a gel, it can be used as a solid substance, but it cannot be used as a liquid.

The properties of sustained-release active ingredient release agents include that they can be dissolved in both water and lossy solvents, and can also be dissolved in either solid or liquid forms. Can be used in a very wide range of applications
Ru.

[Means to solve problems]

The inventors. In order to solve these problems, we will seriously consider f. : Benefits. An ester of (a) an oxyalkylene derivative of a 'j-hydric alcohol or polyhydric carboxylic acid having a carboxyl group and (b) an active ingredient having a hydroxyl group. What's more, it releases the active ingredients gradually. The present invention was achieved by discovering that it is compatible with both water and other solvents, and can be made into either solid or liquid forms.

The present invention comprises (a) an oxyalkylene derivative of a polyhydric alcohol or polyhydric carboxylic acid having a carboxyl group;
It is a sustained-release active ingredient release agent consisting of an ester with an active ingredient having a hydroxyl group.

Examples of active compounds with hydroxyl groups include linal.
Geraniol. Shitoμneμ-le. benzyl alcohol.
Finetyl alcohol. Flavoring agents such as cinnamon alcohol; n
-f canol. P-menthane-3,8-diol. :)
Pererins. Cytokinins. Growth regulators such as indole-3-ethyl/-ol; 9-tetradecen-1-ol. 6-/nen-1-ol, Otsu 6-dimethyl-5-hepden-1-ol. Fruits such as bombycol; estradiol. Testosderon. Hydroxytestosterone. Hormones such as cortisone; vitamin A. Vitamin Be. Examples include vitamins such as vitamin C; glycosides such as saponin and 7thocyanin.

An example of an oxyalkylene derivative of a polyhydric alcohol having a carboxyl group is a compound represented by the following formula (1).

(However, 2 is a compound 2 having 2 to 8 hydroxyl groups (OH
) a+b ten. Residues of. AIO. k20 and A3
0 is an oxyalkylene group having 2 to 18 carbon atoms, or two or more. When it is 2al or more, it may be bonded in a block shape or in a random manner, and X is an acyl group of a polybasic acid having an ester bond and a free carboxyl group or one R' COOH.
R' is an alkylene group having 1 to 3 carbon atoms. R has 1 to 2 carbon atoms
4 hydrocarbon group. aat, b≧0. Coo and a+b+
c=2~8. 1ao. m20. n 2 0
and aIt+bm+cn=1 to 1500. ) In equation (1). When X is an acyl group of a summerizable unsaturated polybasic dispersion. A lid polymer or copolymer of the compound of formula <<1>>. Those with carboxyl and oxyalkylene groups are also used.

In equation (1), zs-! Examples of compounds having 2 to 8 hydroxyl groups as Ax include catechol. Resorcinol. Hydroquinone. Polyvalent compounds such as μ μ glucine; ethylene glycol. Propylene glycol. Butylene glycol, dodecylene glycol. Octadecylene glycol, neopentyl glycol. Styrene glycol.
Glycerin, diglycerin. Polyglycerin. Trimethylolethane. Trimethylol bread. l. 3.5-
Pentanetriol, erythritol. Pentaerythritol. Diventaerythritol. Sorbitol. Sorbitan. Solbide. Rubitol-glycerin condensate. Adonitol. Arabitol. Xylitol. Polyhydric alcohols such as mannitol; Arabinose. Repose, Rhamnose. glucose. Fructose. Galactose. Mannose. Solport. Cellobiose. Maltose in maltose. Trehalose. Shoe 9 9-S. Rahuinose, Genchi 7 North.
Melezitose K Other sugars: There are partially etherified products and partially esterified products thereof.

A'0. Carbon PJZ2 denoted by A20 and Ago
The oxyalkylene group of 18 is an oxyethylene group. Oxypoopyrene group. Oxybutylene group. Oxytetramethylene group. Oxystyrene group. Oxidedecylene group. Oxytetradecylene group. Oxyhexadecylene group.
Oxyoctadecylene. ! & etc.

As a polybasic acid in which X is an acyl group. Oxalic acid. Mahn's acid: I-succinic acid. Glutaric acid. 7 Dipic acid. Bimelic acid, suberic acid. Azelaic acid. Sebacic acid. Dodeka/
Diacid. Brassiphosphoric acid. Tetradecanonic acid. Saturated dicarboxylic acids such as octadecannivinegar and icosanniic acid; maleic acid, fumaric acid, and itaco 711! ．． Citraconic acid. Mesaconic acid. Cisglutaconic acid. Transglutaconic acid. α
-Unsaturated dicarboxylic acids such as hydromufunic acid, II-hydromucone aI; tricarboxylic acids such as trivallyric acid;
Malic acid. Hydroxycarboxylic acids such as tartaric acid and citric acid; phthalic acid. Isophthal Mausoleum. Terephthalic acid. 3-Methyl phthalic acid. 4-Methylphthalic acid. 2-methylisophthalic acid, 4-methylinphthalic acid, methylterephthalic acid, hemimelitic acid. Trimellitic acid. Examples include aromatic carboxylic acids such as trimesic acid.

1 as a 7-rukylene group having 1 to 3 carbon atoms represented by R'. Methylene group. Ethylene group. Ethylidene group, propylene group. Imp p-bilene group. There are isoprop-pylidene groups, etc.

The hydrocarbon group having 1 to 24 carbon atoms represented by R is a methyl group. Ethyl group. P-pyl group. Imp p-bil group. Butyl group. Inf-thyl group. Tertiary decyl group, amyl group. Inamyl group, hexyl group, hegtyl group, 2-ethylhexyl group, octyl group, /nyl group, decyl group. Kundecyl group. Dodecyl group. Intridecyl group. Tetradecyl group, hexadecyl group. Inhexadecyl group. Octadecyl group. inoctadecyl group, allyl group. Methallyl group. Oleyl group.
Octyldodecyl group, docodecyl group. Decyltetradecyl group, benzyl group, cresyl group, gtylphenyl group, digtylphenyl group. Octyl 7enyl group, nonylphenyl group. Dodecylphenyl group. Dioctylphenyl group. Examples include dinonylphenyl group and styrene/phenyl group.

The compound of formula (1) is. A polyoxyalkylene ether derived from a compound having 2 to 8 hydroxyl groups and a polybasic acid or polybasic acid anhydride are subjected to an esterification reaction, or a polyoxyalkylene ether and quaa acetic acid. Puq
Moacetic acid, 2-prop-bionic acid. 3-pμ pbionic acid. 2-KRR-2-methylpudibionic acid, 2-KI
: It can be obtained by a quarry synthesis reaction with a halogenated alkyl carboxylic acid such as lμ butyric acid and 2-7'μ butyric acid.

As an example of an oxyalkylene derivative of a polycarboxylic acid having a carboxyl group. There is a compound represented by formula (2).

(Just L. Z'l!2 ~41i11i no polyvalent carbonelRzl(C00H)d+e+ff)'AM. A'
O and A501-1 are oxyalkylene groups having carbons a2 to l8, Rl is a hydrocarbon group having carbons at to 24. d≧0, e2
0, f-≧1 and d+s+f=2-4. P,! 0. q
20 and pd+qe=1-1500. ) The polyhydric carboxylic acid with z1 as a residue is. In the formula (l), the ester bond is the same as a polyhydric carboxylic acid in which X is a 7-syl group, and the oxyalkylene groups of A40 and A50 are AIO. A20. It is the same as A30, and the hydrocarbon group of R1 is the same as R.

Also. A polymer of a polyoxyalkylene derivative of an unsaturated monocarboxylic acid or an unsaturated polycarboxylic acid represented by the following formula (3). Or a co-merger of this with an unsaturated monocarboxylic acid or an unsaturated polycarboxylic acid. It can be used as an oxyalkylene derivative of a polycarboxylic acid having a carboxyl group.

(However, Z2 is mono- to tetravalent unsaturated carboxylic acid Z2 (C
OOH) g+h+1 residue 60 and A70 oxyalkylene group having 2 to 18 carbon atoms. R2 has 1 to 24 carbon atoms
hydrocarbon group. g≧O. h20. l20, and g+h+
1=1~4. r20,ago and rg+Ih=1 ~1
It is 500. ) As a mono- to tetravalent unsaturated carboxylic acid with z2 as a residue. Acrylic acid. Methacrylic rice. Cuptonic acid, maleic acid. Fumaric acid. Itaconic acid, citraconic acid. Mesaconic acid.
Cis or trans-glutaconic acid. Examples include α- or β-hydromuconic acid.

A60 and A70 G-! ．． ．． This is the same as A'0 − Aso in equations (1) and (2).

The unsaturated monocarboxylic acid or unsaturated phase polycarpo/acid copolymerized with the compound of formula (3) is. It is the same as the unsaturated phase carbon drum of 1 to lff in which 22 in formula (3) is a residue.

In the sustained release active ingredient release agent of the present invention. The active moiety esterified with the carboxyl group is gradually released by hydrolysis. The polyoxyalkylene ether skeleton and hydrocarbon group determine properties such as sustained release activity, freezing point, and solubility in solvents.

In this polyoxyalkylene ether skeleton, the higher the content of oxyethylene groups, the easier it is to dissolve in water.
If it is too small, it will be difficult to dissolve. Furthermore, oxyalkylene groups and hydrocarbon groups having 3 or more carbon atoms increase affinity with less polar organic solvents.

In the sustained release active ingredient release agent of the present invention. General formula {1}
Or the ester of the compound represented by (2) is. (It is easier to adjust the freezing point and fI!i inertia to the solvent than the monomer or copolymer ester of the compound of formula 31.

〔Effect of the invention〕

The sustained-release active ingredient release agent of the present invention is hydrolyzed to gradually release an active ingredient. It can maintain activity for a long period of time. Also. Because it has a polyoxyalkylene ether skeleton. It can produce solid and liquid products. Furthermore, the solubility in various solvents can be adjusted to a certain degree.

〔Example〕

Next, it will be explained by manufacturing examples and examples.

Production Example 1 Each component of the manure was placed in a sieve and subjected to a polymerization reaction at 80±5°C for 7 hours in a nitrogen gas atmosphere.

CH3 J CH2=CC00(C2H40)s(C3HsO)ls
cH31 1 9 0 , P (1 mol) CI{2=CHCOOTI
7 2 Jl(l mo/lene penzoyl peroxide 12J'(
0. 0 5 mol) Toluene 10007' then. Torue/10-30swHJ'. 100 soil 10゜0
Distilled away. A co-integration compound (compound vI Taka1) of 1050/ was obtained. Compound hawk is a viscous deceiver. Acid value 43.8. Saponification value 85, 2. The weight average molecular weight was 1t62,000.

Production Example 2 Put each of the ingredients below into a four-mouthed 7-rasp. *The reaction was carried out for 3 hours at 100±5°0 in an atmosphere of elementary gas. Then,
Triethylamine and succinic anhydride from 2 to 5111HJ
2350P polyalkylene glycol difusuccinate (Compound Waterfall 2) by distillation at 120±5'O
I got it.

HO (C2H40)3 (C3H60)M (
CzI{io)3H2254J' (1 mol) 210/ (2.1 mol) 101P (1 mol) 16.5 cst. Esterification rate of succinic anhydride triethylamine compound/1l! 12 is kinematic viscosity II (4 0'O)
5 Acid value 47,9. The hydroxyl value is 1.2. It was 97.6 excellent.

Manufacturing example 3 Auto each share below Under a gas atmosphere. 100±5 Sodium water bath armpit l5 After all Doatsujin. l30±1 For crepes. nitrogen gas “Heat to 0.9N monohydric acid 〇1 gradually became overwhelming.

Reactions between 5 #s were carried out at 0°0. Then, it was taken out from the autoclave, and 35% hydrochloric acid was added to adjust the pH to 2 or less, and the mixture was treated at 100±10° for 1 hour. Washing was performed three times with IJ saturated saline. After dehydration at 110*10'0.10 to 30mHJ'. Separate the crystals to obtain the product (compound/I63) 1930P
I got it.

CI8H370 (C2H40) 35 (C3H60) 7
H 2 2 1 8 J' (1 mol) CjCH2COOH 1 1
3. 4 J' (1.2 mol) Compound 7% 3 has kinematic viscosity J'Z (4 0 'O) 3
4 5. 3 c s t . Acid value 2 5. 1.
The hydroxyl value is 1.2. The etherification rate was 95 or better.

below. Each compound shown in Table 1 was soaked in the same manner.

Practical Example 1 Put 3.113.7 mmol (0.05 mol) of compound z% and 300 t of toluene into four flasks. Hue half-tyl alcohol 6. 17 (0.05 mol) and valatoluenesulfonoffi 1. 2 Add 7. The esterification reaction was carried out at 10'C in a nitrogen gas atmosphere.

Stop the reaction after water runs out. After washing three times with 500 liters of saturated saline. llO±10'0.10~30w
Dehydration and toluene removal were performed using HJ', and the crystals were separated to obtain phenethyl alcohol ester (saponification number: 23.9).

Thereafter, 7enethyl alcohol esters of each compound in Table 1 were obtained in the same manner.

Formula 50 methanol aqueous solution M containing 1 p of each of the 7 enethyl alcohol esters in Table 1 adjusted to pH 4 with hydrochloric acid.
I did f8WL on 50J'. Place it in a Petri dish with a diameter of 414 and 10α. Leave the petri dish open for 24 hours at a constant temperature of 50°C with ventilation.
The amount of remaining phenethyl alcohol was measured by the following method.

That is, the solution remaining in the petri dish is reduced to 0. 2j
Dissolved in 50P of soN+4 methanol aqueous solution containing sodium hydroxide. After refluxing at 80±10'O for 1 hour, the liberated phenethyl alcohol was extracted using diethyl ether. Phenethyl alcohol was determined by gas chromatography (sample f direct). Using the remaining half of a 50% methanol aqueous solution by weight of phenethyl alcohol ester with a pH of 4 as a control, phenethyl alcohol was determined in the same manner (Contol Co., Ltd.) from the sample value to the control value. Table 2 shows the results of determining the residual rate of phenethyl alcohol in the 7-enethyl alcohol ester.

Also, for comparison, 0. 0.9t of polyoxyethylene (IO mol)/nylphenyl ether added to 1 J' of fethanyl alcohol. The same V. Experiment. The results are also shown in Table 2.

From Table 2. It can be seen that the sustained release agent of the present invention has excellent sustainability.

Table 2 Example 2 Six-geraniol ester was produced in the same manner as in Example 1. Persistence was measured in the same manner as in Example 2. For comparison, a mixture of graniol and rubitan monooleate (20 moles) and a mixture of acrylamide were used. These results are shown in Table 3.

From Table 3. It can be seen that the sustained-release active ingredient release agent of the present invention has excellent sustainability.

Claims (1)

[Claims] 1. A sustained-release active ingredient release agent comprising an ester of (a) an oxyalkylene derivative of a polyhydric alcohol or polycarboxylic acid having a carboxyl group and (b) an active ingredient having a hydroxyl group.