JPH06322253A - Slowly dissolving vehicle - Google Patents

Abstract

PURPOSE:To obtain a slowly dissolving vehicle which contains a drug component, can be molded into a desired shape, exhibits a suitably low dissolution rate in water, allows the drug component to slowly dissolve out, and thus maintain the action of the drug component for a long term. CONSTITUTION:Polyethyleneimine having 10-200 active hydrogen atoms, a number average mol.wt. of 400-10,000, and a branched structure including primary, secondary, and tertiary amino groups or a deriv. of the polyethyleneimine having 10-200 active hydrogen atoms is subjected to addition reaction with a 3-40C epoxide compd. (A) and ethylene oxide (B) in a wt. ratio of A to B of (0:100)-(50:50), giving a polyether compd. having a number average mol.wt. of 5,000-600,000. The polyether compd. is subjected to addition reaction with an 8-40C epoxide compd. in an amt. of 0.4-10 molar equivalents based on the hydroxyl groups of the polyether compd., giving the title material.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a slowly dissolving excipient. More specifically, it can be molded into a certain shape by containing various drug components inside, and when this molded product is placed in water or near the jet outlet of water, it gradually dissolves and contains the drug. The present invention relates to a slow-dissolving excipient capable of steadily and gradually eluting components into water.

[0002]

2. Description of the Related Art Conventional slow-dissolving excipients have, for example, a molecular weight of 1,000 to 1
There are 10,000 polyethylene glycols or their various derivatives. However, when these are used as excipients, they have good water-solubility, so if a product containing a drug inside and shaped into a certain shape is put into water, a certain concentration of the drug component will remain in the water for a long time. Not only could it not be eluted, it also had a short life.

Further, Japanese Patent Publication No. 52-37053 discloses a sustained-dissolving biocide preparation comprising fats and oils and a water-soluble polymer compound. However, since fats and oils are insoluble in water, insoluble matters float on the water surface. And there is a problem that the water becomes cloudy.

Further, in Japanese Patent Laid-Open No. 59-230081,
Polyoxyethylene diester compounds are disclosed as water-soluble excipients. However, such a compound has a drawback that the effect of sustained dissolution is not sufficient, a drug component having a constant concentration cannot be eluted in water for a long time, and the life of the water-soluble excipient itself is short. is there.

The present invention solves the above-mentioned drawbacks of conventional excipients, and when it is placed in water or placed near a water jet outlet, it is excessive in drug even if it is in contact with water for a long period of time. It is possible to elute a drug with a constant concentration in water at all times, and to maintain the action of the drug component in a constant state for a long period of time, and to stabilize various drug components inside arbitrarily. As a result of intensive studies to provide a long-life sustained-dissolving excipient which can be contained in, the present invention finally found a slow-dissolving excipient excellent in such properties, and completed the present invention.

[0006]

The slowly dissolving excipient of the present invention has 10 to 200 active hydrogen atoms and has a number average molecular weight of 4 or less.
A polyethyleneimine having a branched structure of 0 to 10,000 and containing a primary, secondary, and tertiary amino nitrogen or a polyethyleneimine derivative having 10 to 200 active hydrogens, and an epoxide of 3 to 40 carbon atoms ( (A) and ethylene oxide (B) in a weight ratio of (A) / (B) = 0/100 to
Number average molecular weight 5, which is formed by addition reaction at a ratio of 50/50
000 to 600,000 polyether compound and 0.4 to 10 molar equivalents of the hydroxyl group of the polyether compound (that is, 0.4 to 10 moles per hydroxyl group) having 8 to 40 carbon atoms of epoxide ( It comprises a polyether compound formed by addition reaction of C).

The polyethyleneimine or polyethyleneimine derivative used in the present invention has 10 to 200 active hydrogen atoms in the molecule and a number average molecular weight of 400 to 1
20,000, preferably 12 to 100 active hydrogen
And the number average molecular weight is 500 to 5,000.

Polyethyleneimine is obtained by addition-polymerizing ethyleneimine to a polymer of ethyleneimine or a substance having active hydrogen such as alcohols, phenols, amines, carboxylic acids and the like. It has one. As these polyethyleneimines, those having not a completely linear structure but a branched structure containing primary, secondary, and tertiary amino nitrogens are used, and primary, secondary, and tertiary amino groups are used. The nitrogen ratio is 1: 1 to 1: 2.
5: 1 is preferable.

Further, the polyethyleneimine has various chemical reactivities, and the remaining active hydrogen has 1
Within the range of 0 to 200, preferably 12 to 100, the derivative can be used as the starting material of the polyether compound related to the slowly dissolving excipient of the present invention.

Typical examples of the derivatives are shown below. (A) Reaction products with aldehydes and ketones (b) Reaction products with alkyl halides (c) Reaction products with isocyanates and thioisocyanates (d) Reactions with active double bonds Products (e) Reaction products with epoxy compounds and epihalohydrins (f) Reaction products with cyanamides, guanidines, urea, etc. (g) Reaction products with carboxylic acids, acid anhydrides, acyl halides, etc.

If the active hydrogen of the polyethyleneimine or polyethyleneimine derivative is less than 10, the sustained solubilization performance is insufficient and the effect of eluting a fixed concentration of the drug component in water over a long period of time is poor. On the other hand, active hydrogen is 20
When it exceeds 0, the viscosity of polyethyleneimine or a polyethyleneimine derivative becomes high, and the addition reaction of epoxide becomes difficult.

As the epoxide (A) having 3 to 40 carbon atoms, which is added to the polyethyleneimine or the polyethyleneimine derivative, compounds having a wide range of epoxy rings can be mentioned, for example, propylene oxide, butylene oxide, styrene oxide, 1,2- Epoxy octane,
One selected from alkylene oxides such as 1,2-epoxydodecane, 1,2-epoxydocosane, and 1,2-epoxyoctacosane, glycidyl ethers such as phenylglycidyl ether, n-hexylglycidyl ether, and n-octylglycidyl ether. Alternatively, two or more kinds are used. However, the present invention is not limited to this example.

An epoxide (A) having 3 to 40 carbon atoms is added to the polyethyleneimine or the polyethyleneimine derivative.
And ethylene oxide (B) are subjected to an addition reaction by a usual method to give a number average molecular weight of 5,000 to 600,000.
Can be produced.

That is, a polyethyleneimine or a polyethyleneimine derivative as a starting material was added with a basic catalyst,
A predetermined amount of the epoxide is added and reacted at 100 to 180 ° C.

The ratio of the epoxide (A) having 3 to 40 carbon atoms and the ethylene oxide (B) which undergoes addition polymerization is (A) /
(B) = 0/100 to 50/50 (weight ratio). When the polymerization ratio of ethylene oxide is less than 50% by weight, the melting point of the finally obtained polyether compound according to the present invention becomes too low, resulting in poor moldability of the excipient.

In the case of addition-polymerizing an epoxide having 3 to 40 carbon atoms with ethylene oxide, it may be block copolymer, random copolymer, or any of them may be added first. Block copolymerization is preferable in terms of moldability.

The number of moles of epoxide and ethylene oxide added to polyethyleneimine or a polyethyleneimine derivative may be appropriately adjusted according to the performance of the intended excipient. One active hydrogen of the polyethyleneimine or polyethyleneimine derivative is used. 10-30 per hit
It is 0 mol, preferably 20 to 200 mol. The resulting polyether compound has a number average molecular weight of 5,000 to 6
0,000, preferably 5,000 to 400,000
Are valid. If an attempt is made to add a number of moles such that the number average molecular weight exceeds 600,000, the reactivity of the epoxide will be poor and production will be difficult.

The slow-dissolving excipient of the present invention generally employs an epoxide (C) having 8 to 40 carbon atoms in addition to the hydroxyl group of the polyether compound having the number average molecular weight of 5,000 to 600,000 obtained above. It can be obtained by an addition reaction according to the above method.

As the epoxide (C) having 8 to 40 carbon atoms, a wide variety of compounds having an epoxy ring can be mentioned.
Styrene oxide, 1,2-epoxyalkane, n-hexyl glycidyl ether, phenyl glycidyl ether, 2-ethylhexyl glycidyl ether, having 8 to 22 carbon atoms, which are listed as the epoxide (A) having an epoxy group at the terminal of long-chain alkyl One or more selected from glycidyl ethers of higher alcohols and the like are used. However, the present invention is not limited to this example.

The reaction ratio of the epoxide (C) should be 0.4 to 10 molar equivalents with respect to the hydroxyl group of the polyether compound. If it is less than 0.4 molar equivalent, the performance of sustained solution is poor and the sustainability in water is insufficient. 10
If it exceeds the molar equivalent, the tendency to insolubilize with water increases, it is disintegrated in water and the shape cannot be maintained, and on the contrary, elution of the drug component is accelerated or a water-insoluble component is generated, which is not preferable.

When the slow-dissolving excipient of the present invention is used, for example, the above polyether compound is heated and melted,
Depending on the purpose, the necessary drug components may be added, and if necessary, inorganic excipients, fillers, auxiliary components (for example, penetrants, surfactants as detergents, antioxidants, organic solvents) Add and blend, eutectic or uniformly disperse them, and cool and solidify this uniform mixture, or in the middle to shape and solidify in any shape, or pour the uniform mixture into a suitable container Mold by cooling and solidifying.

Further, it is possible to control the apparent specific gravity and to impart a floating property in water by containing arbitrary bubbles in the molten state and cooling and solidifying them.

It is also possible to manufacture by a compression molding method other than the melt molding method.

The ratio of each component in the composition using the slow-dissolving excipient of the present invention depends on the application, the duration of slow-solubilizing drug components, etc.
Although it can be arbitrarily changed according to the purpose, it is usually within the following range. Polyether compound 1-80% by weight Pharmaceutical component 1-80% by weight Auxiliary agent 0-20% by weight Filler / inorganic excipient Remainder

The slow-dissolving excipient of the present invention contains various drug components inside and can be made into a certain shape. It is put in water or installed near the jet outlet of water. In this case, it has a function as a carrier for gradually eluting the internal drug component over a long period of time. Therefore, it can be used in many fields by appropriately selecting a drug component suitable for the purpose. Specific examples of application include the following.

Solid pesticides and solid fertilizers used for paddy fields It is desirable that pesticides and fertilizers for paddy fields be uniformly provided at a constant concentration over a long period of time. Such pesticides and fertilizers are melted and solidified together with the slowly-dissolving excipient of the present invention into granules of an appropriate size, and then sprayed on the paddy field, whereby the pesticides and fertilizers are gradually eluted, and they are used for a long period of time. It can exert its effect across. In other words, the slow-solubilizing effect makes it possible to adjust the effective amount of drug components such as pesticides and fertilizers, and ensure effective spraying, as well as sustaining the drug effect for a long time and enabling labor-saving spraying. Become. Furthermore,
Environmental protection such as prevention of chemical damage due to excessive spraying and suppression of pollution will be achieved.

Solid Water Treatment Agent for Cooling Water and Waste Water of Air Conditioning Device For treating various kinds of water such as industrial cooling water, cooling water for consumer use, waste water of air conditioning device for vehicles, buildings, etc. Water treatment agents such as agents, scale dispersants and rust preventives are used, but it is desirable that these water treatment agents be maintained at a constant effective concentration for a long period of time. A known algicidal agent, a scale dispersant, a water treatment agent such as a rust preventive agent is melted or uniformly dispersed together with the slowly-dissolving excipient of the present invention, and then solidified by cooling to obtain a solid molded article having a suitable shape. By throwing in water, these drug components gradually elute,
For a long period of time, it is possible to prevent the generation of scales and harmful algae, the generation of rust in the circulation route, and the adhesion of scale.

Solid bactericide for pools It is preferable that the bactericidal effect of the solid bactericide for pools lasts for a long period of time. If the bactericide is added as it is at a time, the bactericidal effect at the time of addition cannot be maintained for a long time, but if the eutectic of the present invention and the bactericide are eutectic and solidified by cooling, they are added to water. Thus, the same bactericidal effect can be obtained over a long period of time.

Solid detergent for drainage pipe In order to maintain the cleaning effect for a long time, the excipient of the present invention and the detergent are eutectic and cooled and solidified to a suitable extent near the drainage pipe outlet. If you put it in a container and suspend it, the cleaning agent will flow out into the wastewater every time the wastewater flows in, and the effect can be maintained for a long time.

Although there are applications as described above, the slowly dissolving excipient of the present invention is not limited to these applications.

[0031]

The present invention will be described in more detail with reference to the following examples.

Production Example 1 (Production of Polyether Compound 1) In a stainless steel autoclave, polyethyleneimine having 28 active hydrogens and a number average molecular weight of 1,200 (ratio of amino nitrogen; primary: secondary: third) (Class = 1: 2: 1)
After adding 10 parts by weight, the inside of the autoclave was replaced with nitrogen. Next, 70 parts by weight of propylene oxide was added at 130 ° C. to carry out an addition reaction. Further, 700 parts by weight of ethylene oxide was added at 130 ° C. to carry out an addition reaction to obtain a polyether compound having a number average molecular weight of 90,000. Furthermore, 167 parts by weight of a mixed 1,2-epoxyalkane having 12 and 14 carbon atoms (average molecular weight 196) (3.5 molar equivalents relative to the hydroxyl groups of the above polyether compound) was added, and 150
Polyether compound 1 that reacts at ℃ and is wax-like at room temperature
Got

Production Example 2 (Production of Polyether Compound 2) In a stainless steel autoclave, polyethyleneimine having 28 active hydrogens and a number average molecular weight of 1,200 (ratio of amino nitrogen; primary: secondary: third) Grade = 1: 1.9:
1) 10 parts by weight and 3.3 parts by weight of lauric acid were added, and a dehydration condensation reaction was performed at 160 ° C. under a nitrogen stream to obtain a partially lauric acid amidated polyethyleneimine. Next, after the inside of the autoclave was replaced with nitrogen, 95 parts by weight of propylene oxide was added at 130 ° C. to carry out an addition reaction.
At 130 ° C., 600 parts by weight of ethylene oxide was added to carry out an addition reaction to obtain a polyether compound having a number average molecular weight of 100,000. Furthermore, mixed 1,2-epoxyalkane (average molecular weight 252) having 16 and 18 carbon atoms was added to 15
0.7 parts by weight (2.5 mol equivalent to the hydroxyl group of the above polyether compound) was added and reacted at 150 ° C. to obtain a waxy polyether compound 2 at room temperature.

Production Examples 3 to 8 (polyether compounds 3 to 8)
Production) Polyethyleneimine and epoxide used in Production Example 1 were changed in type and reaction parts by weight to carry out the same reaction as in Production Example 1 to obtain polyether compounds 3 to 8 shown in Table 1.

[0035]

[Table 1]

Example 1 (pesticide granule) 5 parts by weight of diazinon [(2-isopropyl-4-methylpyrimidyl-6) -diethylthiophosphate],
65 parts by weight of the polyether compounds 1 to 8 of the present invention described in Production Examples 1 and 2 and Table 1 are heated to a temperature of 70 to 80 ° C. to be melt mixed, and the molten mixture is bentonite 20 at 70 to 80 ° C. Parts by weight and 10 parts by weight of talc were added and kneaded, passed through a screen having a diameter of 1 mm, and cooled and solidified to obtain granules containing 5% of diazinon.

The granules (4.0 g) were immersed in an Erlenmeyer flask with a ground stopper containing 2 liters of distilled water and allowed to stand at 25 ° C., and the elution rate of diazinon with time was measured. As a comparative example, the granules were prepared in the same manner by using the compounds 9 to 12 described in Table 1, and the diazinon dissolution rate measurement test was carried out in the same manner. The dissolution rate was calculated by the following formula.

[0038]

[Equation 1]

The results are shown in Table 2.

[0040]

[Table 2]

As is clear from Table 2, the pesticidal granules prepared by the slow-dissolving excipient of the present invention continued to dissolve the pesticidal active ingredient in water for a long period of time and was excellent in slow-dissolving property.

Example 2 (Solid Water Treatment Agent) 10 parts by weight of a triazine algaecide, 10 parts by weight of sodium polyacrylate (average molecular weight 8,000), 20 parts by weight of sodium sulfate, polyether compounds 1 to 5 of the present invention 60 parts by weight of was mixed and heated at 70 to 80 ° C., and 30 g of this mixture was poured into a cylindrical mold having a diameter of 30 mm and solidified to obtain a solid water treatment agent. As comparative examples, compounds 9 to 12 shown in Table 1 were used to obtain solid water treatment agents in the same manner.

Each solid water treatment agent was packed in a saran net bag and immersed in a pit of a cooling tower having a water holding capacity of 200 liters in which a sprinkler shower dropped directly onto the pit until the solid water treatment agent dissolved and disappeared. The number of days was observed. However, the cooling tower was operated continuously and the pit water temperature was adjusted to 20 to 25 ° C. The results are shown in Table 3.

[0044]

[Table 3]

As is clear from Table 3, the solid water treatment agent prepared by the slow-dissolving excipient of the present invention is excellent in slow-dissolving ability, has a long life, and has a long-term algicidal effect. I was able to get it.

Example 3 (solid sterilization for dew condensation drainage from air conditioner )
Agent) 50 parts by weight of benzethonium chloride and 50 parts by weight of the polyether compounds 1 to 8 of the present invention are heated to 80 to 90 ° C. for melt mixing, and cooled and solidified through a 1 mm diameter screen to give a granular solid bactericide. Obtained. As comparative examples, compounds 9 to 12 shown in Table 1 were used to obtain solid bactericides in the same manner.

50 g of benzethonium chloride corresponding to each of the prepared solid bactericides was packed in a cloth bag.
Water droplets were dripped at a rate of 1 liter / hour each time using a metering pump, and water was collected each time. The concentration of benzethonium chloride contained in the dropped water was measured every 10 times.
The results are shown in Table 4.

[0048]

[Table 4]

From Table 4, it is clear that the solid disinfectant for dew condensation drainage of an air conditioner prepared by the slow-dissolving excipient of the present invention gradually elutes the disinfectant component by a fixed amount over a long period of time.

[0050]

EFFECTS OF THE INVENTION The sustained-release excipient of the present invention can contain various drug components inside and can be molded into a fixed shape.
The dissolution rate in water is moderately slow, the drug component is gradually eluted, and the action of the drug component can be maintained for a long period of time, which is extremely useful.

Claims (6)

[Claims] 1. A polyethyleneimine having 10 to 200 active hydrogens, a number average molecular weight of 400 to 10,000, and a branched structure containing primary, secondary, and tertiary amino nitrogen, or active hydrogen 10. To 200 parts by weight of the polyethyleneimine derivative containing 3 to 40 carbon atoms of epoxide (A) and ethylene oxide (B) in a weight ratio of (A) / (B) = 0.
/ 100 to 50/50 in a polyether compound having a number average molecular weight of 5,000 to 600,000, which is obtained by an addition reaction, and 0.4 to 10 molar equivalents of carbon atoms to the hydroxyl group of the polyether compound. A slowly-dissolving excipient composed of a polyether compound obtained by addition reaction of 40 to 40 epoxides (C). 2. The polyethyleneimine is active hydrogen 1
2 to 100, number average molecular weight of 500 to 5,000, and ratio of primary, secondary and tertiary amino nitrogen is 1: 1 to 1: 1:
The slowly dissolving excipient according to claim 1, which is a polyethyleneimine of 2.5: 1. 3. A slow-dissolving excipient for solid agricultural chemicals, which comprises the polyether compound according to claim 1 or 2. 4. A slow-dissolving excipient for solid fertilizer, which comprises the polyether compound according to claim 1 or 2. 5. A slow-dissolving excipient for a solid water treatment agent, which comprises the polyether compound according to claim 1 or 2. 6. A slow-dissolving excipient for a solid bactericide, which comprises the polyether compound according to claim 1 or 2.