JPH07500596A - Ionic beads useful for controlled release and adsorption - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] FIELD OF THE INVENTION This invention relates generally to topical and oral compositions. More specifically, the present invention is a substance that acts on keratinous substances such as hair and skin. prolongs the activity of various topical active ingredients by improving their Formulation of ionic polymer delivery systems that allow for the release of active substances via ion exchange. The present invention relates to orally delivered polymers.

The adhesion properties of substances applied topically to hair and skin are determined by initial adsorption and persistence. particularly when exposed to water after application. Combining adsorption and sustainability The combined features are the ability of the substance to be adsorbed onto the keratin and the ease with which it can be rinsed off with water. It constitutes a characteristic called “substantivity,” defined as the ability to resist. do.

The ideal topical substance would have adsorption affinity for keratinous substances and maintain its activity over a long period of time. It retains water for a long time, withstands washing off due to perspiration and contact with other water, and is It does not interact adversely with the components of the pond that are desired to be included. All of these goals A topical substance that adequately satisfies these requirements has not yet been found.

Most povicolar topical active formulations available on the market today include, e.g. Makeup such as makeup, lipstick, make-up, etc.) Insect repellents: Antibacterial agents, Acne treatment formulations: Conday/Yonar and hair growth promoters. Hair treatment formulations such as, and skin protection formulations such as anti-aging agents: and Contains UV-absorbing substances (prevents sunburn). These ingredients, substances or combinations are They may be used alone or in combination with each other and may be applied in pure form or in a suitable solution. It may be diluted with an agent or carrier.

A frequent problem with such topical actives is that they rapidly become active after application to the skin. It's about losing. Under normal conditions of heavy sweating and/or contact with water, each The concentration of the substance in the topical composition may be diluted, making it less effective, or Either it is washed away and loses its full effect. One way to increase activity is , to increase the concentration of active ingredients within their respective formulations. deer However, as the concentration increases, toxicity and allergic reactions to the user The risk of Even if the exposure to the product is relatively brief, this reactions often occur at higher concentrations.

A second drawback, unrelated to the safety of administration of such compositions, is that they are easily washed away. The cost of using such compositions is increased. For example, from the sun To maintain a suitable level of protection, sunbathers should re-apply after each entry into the water. And you will have to avoid sunburn frequently after sweating.

thus reducing the possibility of toxicity and/or allergic reactions to the user At the same time, it is possible to increase the adsorption affinity of topical active compositions to keratinous substances. It is very important to provide an approach to prolong the activity of such compositions. desirable.

Compositions and methods for releasing active substances, such as drugs, from their recipients over time A number of specific approaches are known to achieve such controlled release. exists. Two approaches that are widely used in practice are of particular interest to the present invention. Interesting. The first of these approaches involves adjusting the solution in response to changing environmental conditions. Encapsulating or coating a drug or other active substance with a substance that decomposes or decomposes ing. For example, the low pH environment of the stomach protects drugs but prevents them from passing through the intestines. pH-responsive coating (enteric coated) to dissolve when the pH increases. (referred to as tinging) can be applied to chemicals. Such coatings include acetic acid solution. Lulose, polyvinyl acetate phthalate, hydroxypropylcell Includes loin fucrate, methylcellulose phthalate, etc. These coatings Although they are very effective in protecting drugs in the stomach, they generally prevent drugs from entering the intestines. Once this is reached, the release rate cannot be controlled.

A less widely used delivery approach for drugs and other active substances. Utilizes porous polymer particles for adsorption and release at controlled release rates There is an approach. For example, U.S. Patent No. 4.692.462, discussed below. See. In such systems, the rate of diffusion of drugs or other active substances through the pores determines the release rate. Of course, the diffusion rate depends on pore size, drug viscosity, temperature, etc. Exists. In the case of drug delivery, drugs absorbed within porous polymer particles are typically , incorporated within an adhesive or other matrix material as part of a transdermal drug delivery system. Ru.

In other examples, the material is adsorbed onto porous resin beads to provide sustained release properties. The drug is then coated with a membrane diffusion barrier layer, e.g. ethyl cellulose. Ru. See European Patent Application No. 171528, discussed below.

The difficulty with these systems is that the individual actives must be combined in order to obtain the desired release rate. For quality reasons, a coating agent or blocking agent must be introduced.

The physical properties of drugs and other active substances, including viscosity, charge characteristics, molecular weight, etc., vary widely; Additionally, the release rate of any delivery system varies widely depending on the nature of the substance being delivered. do. The problem is that the pore properties can only be changed within a certain limited range. This is particularly evident when employing highly porous particle delivery systems. Based on synthetic resin Ion exchangers are conveniently produced by post-polymerization modification of preformed cross-linked beads. can do. For example, anion exchange resins can be used for halogen-alkylated and It is made from cross-linked polystyrene by subsequent amination. cation exchange resin can be made by carboxylation or sulfonylation of preformed cross-linked beads. I can do it. Such ion-exchange resins typically have poor color and are less than 2 meq/g. It has only a full ion exchange capacity and can require long regeneration steps. crosslinked natural poly Cellulose-based gels made by introducing functional groups onto polymers Alternatively, naturally occurring ion exchangers such as dextran gels can be used to remove active substances. Mechanically strong enough to prevent the gel matrix from shrinking or collapsing when It has no gel structure. Materials based on natural polymers can be used at high temperatures (e.g. (e.g., 120°C for 30 minutes) is unstable in the presence of oxidants or strong acids, and Because of their biological origin, they support the growth of bacteria and microorganisms.

Thus, improved compositions and methods for the delivery of drugs and active agents are provided. It is desirable to provide for active substances with a wide range of physical and chemical properties. It would be particularly desirable if the composition could be easily modified to obtain the desired release rate. . Under a variety of different external conditions such as pl-(, temperature, ionic strength, etc.) It would be further desirable if the composition could be modified to control the rate of release of active agents such as . The composition can also be formulated to predictably absorb bile salts in a controlled manner. It is also desirable if it can be easily denatured.

Description of background technology U.S. Pat. No. 4,690,825 describes the delivery of uncharged polymer beads suitable for topical application. The system is disclosed. U.S. Patent No. 4,304,563 discloses keratin like hair. Cationic polymers useful as gels for the treatment of substances (and manufacturing method). European Patent Application No. 225615 is a negative Polystyrene sulfonate-divy for controlled oral delivery of charged drugs Discloses the use of cationic beads formed from nylbenzene copolymers.

South African Patent Application No. 872554 and U.S. Patent No. 4,221.778 are Sulfones impregnated with certain substances to increase their stability for oral drug delivery Acid-cationic ion exchange resin particles are disclosed. U.S. Patent No. 3.691.27 No. 0 is a microcapsule formed from a cellular polymer containing polyvinylpyridine. Discloses a dermatological cosmetic composition comprising: However, the microcapsules Le is not charged. U.S. Pat. No. 3,880,990 describes anionic polymers Orally administrable compositions containing a drug encapsulated therein are disclosed. US Patent No. 4.198.395 discloses a method for treating hypercholesterolemia by oral administration. Discloses a charged polymeric resin material useful for U.S. Patent No. 4.552 , 812 discloses fluorescent and magnetic anionic beads useful for performing analyses. are doing. European Patent Application No. 060138 describes Discloses the preparation of porous copolymer blocks that can be absorbed and acted upon. Yo Loppa Patent Application No. 143,608 discloses a releasable lipophilic compound retained therein. Discloses a polymer bead composition having: British Patent No. 1.482,663 No. describes polymer bead compositions capable of holding water-soluble drugs. . Cationic polymer ion exchange containing styrene-divinylbenzene copolymers Resin Interaction, Mountain View, CA 94043 - Chemicals Inc. and Rayli, Indianapolis, Indiana 46204 It is sold by suppliers such as Tar & Chemical Company. cationic The ability of substances to adsorb to the skin and hair has been described by Goddard (198 7) Cosmetics & Toiletries 102 Near 1-80 It is being discussed.

Summary of the invention The present invention incorporates active and inert substances within an ionic polymer bead delivery system. A method of forming a novel composition is provided. Cationic functionality When al1ty) is applied to the surface of polymer beads, the beads become suitable for skin or hair. It has been found that the substantivity of topical active substances is increased when used.

The cationic topical polymer bead delivery system according to the present invention can be applied to the skin, hair, and other tissues. It is a keratinophilic composition that exhibits an affinity for body molecules and, when delivered orally, It can be used to adsorb sulfates. Anionic delivery systems deliver basic drugs Can be delivered orally. The anionic polymer bead delivery system ionic functionality on the surface, i.e. the normally positively charged pyridium within the cationic beads. zine and quaternary ammonium groups, and negatively charged sulfones within the anionic beads. It contains cross-linked polymer beads characterized by carbonate and carboxylate. Applicable The beads form a porous network that can hold large amounts of inert and active substances.

The beads are non-disintegrating, have a small diameter, and have relatively large pores and bead volumes. It has a relatively high proportion of pore volume.

A cationic polymer bead delivery system with an open active ingredient incorporated therein is It can also be used alone as a topical product (5) or as a carrier composition or other cosmetic product. You can also incorporate it into the . When used alone, with incorporated topical active ingredients The cationic polymer delivery system is a dry, free-flowing product that can be applied onto the skin. Can be rubbed directly on, resulting in long-term control of topical active ingredients. Provides controlled emissions. The cationic polymer delivery system is compatible with other carriers, vehicles. In the more common situation where this delivery is incorporated into cosmetic preparations, solvents, or When using a system, there may be a gap between the active ingredient and other ingredients in the topical formulation, or Incompatibilities that may exist between carriers, vehicles, or solvents, typically avoid chemical or physical interactions.

A variety of physiologically acceptable solvents or media can be used as carriers. Ru. However, pyridine-based polymer bead surface treatment in topical formulations ) The carrier is at least slightly acidic, in order to preserve the thionic functionality of Preferably it is less than about 5, most preferably about 3 to 4. carboxyle For bead-based beads, the carrier should have a pH above about 5. be. Physiologically acceptable ingredients in the carrier to maintain the pH within the desired range. It will often be desirable to include a buffering agent that can

The ionic polymer bead delivery system can be prepared by suspending or inversely suspending (inv) suitable monomers. can be formed by polymerization of monomers At least some of them are porogens (porogens for suspension polymerization of non-aqueous monomers). currently carrying either a positive or negative charge in the immiscible phase (including or contain a functionality that can retain either a positive or negative charge under the conditions of use. . Generally, the monomers (and porogen, if used) are first suspended together; The resulting mixture is then suspended in the immiscible phase. The immiscible phase is then stirred to form a monomer. forming droplets of the monomer mixture 1 and initiating polymerization of the monomer mixture as desired. form beautiful beads.

The cationic value (i.e., cationic functionality) refers to the preformed cationic monomer, For example, a quaternary amine monomer (which retains a substantially permanent charge under the conditions of use) protonation (or quaternization) of the surface functionality in the beads used or generated. For example, the quaternary nitrogen in pyridine is protonated in an acid medium. It can be obtained by converting Such protonation also depends on the conditions and incorporation. Depending on the chemical nature of the particular active ingredient to be incorporated, You can also go later.

The anionic value (i.e., the anionic functionality) is, for example, sulfonated styrenic It can be obtained by suspending beads in a basic solution.

There is no substantial degradation of the topical active material under the polymerization conditions and the material is otherwise suitable. In some cases, the material may be used as a porogen in the l-step process. more common Generally speaking, the more unstable components are those that are unstable to heat or radiation. In some cases, a two-step process can be used to form the compositions of the present invention. This person In the method, substituted porogens, such as alkanes, cycloalkanes, or aromatic A solvent may be used to preform the polymer beads. Beads can be polymerized by suspension polymerization or reverse polymerization. The porogen is extracted from the resulting bead product formed by suspension polymerization.

The active substance of interest is then introduced into the beads, typically by catalytic absorption. , create the desired product. As already mentioned, before or after incorporating the active substance into the delivery system. In either case, the polymer beads may be cationic or anionic, or they may be electrically charged. This may be done by using monomers. Capable of incorporating unstable substances In addition to enabling Allowing greater control over bead structure based on a wide selection of materials Therefore, it is desirable for substances that are not unstable (it can be said that it is the best manufacturing method). .

In addition to enhanced susceptibility, the topical cationic polymers of the present invention – The active substance incorporated within the bead delivery system is delivered by non-cationic polymer beads. Providing enhanced efficacy when compared to similar concentrations of components in the system I understand. For example, solar radiation incorporated into a system containing cationic polymer beads. The stop formulation was compared to an identical formulation containing a non-cationic polymeric bead delivery system. , the increased SRF (Sun Protection Rate) n Factor)) is considered to have a grade.

Orally deliverable polymer particles according to the present invention have an ionic, monoethylenically unsaturated phase. Comprised of 7-mer and highly water-soluble polyethylenically unsaturated crosslinking monomers. , each containing ionic polymer hydrogel particles defining a network of internal pores. include. Oppositely charged counterions are included to make the hydrogel neutral.

The hydrogel has a swollen particle size (water ) is determined as the ratio of swelling r5. However, the crosslinking monomer used during the polymerization of the particles The unexpected result that is not linearly proportional to the amount of mer is unique. Ru.

Furthermore, the particle's equilibrium water content (equiiibrium wat) with respect to equilibrium with water is er fraction (E WF) is linearly proportional to the amount of water used during polymerization. Proportional. These properties make the diffusion route suitable for the individual environment and drug being delivered. The ionic hydrogel functions as a sustained release ion exchanger that can be regulated to make it possible. They show that the “blank” hydrogel adsorbs bile-11 acids. also possible.

Oral compositions according to the invention include an ionic hydrogel and a counterion. In that case , the counterion is either inert or pharmaceutically active, such as a drug. and is held by ionic bonds within the internal pore network. The counterion is an animal or P is exchanged with solute ions in a defined aqueous environment such as the human gastrointestinal tract.

In certain embodiments, the counterion is at pH and/or ionic strength of the gastrointestinal tract. It is a weakly basic, positively charged drug that is delivered to the gastrointestinal tract upon change.

According to the method of making hydrogel particles of the present invention, ionic hydrogels can be An inverse suspension of suitable ionic monomers cross-linked with monomers soluble in aqueous solution in Formed by radical polymerization. Generally, the ionic monomer is mixed with its counterion. and the resulting mixture is mixed with a water-soluble crosslinking monomer to form an aqueous phase. the water An initiator is added to the phase and the resulting mixture is suspended in the organic phase. Then organic The phases are agitated to form droplets of aqueous monomer phase and initiate polymerization of the monomer. to form desired beads from the droplets. The exact dimensions and properties of the beads are determined by By varying process parameters such as the amount of water used in the and by varying the amount and type of monomers selected.

Once the ionic hydrogel beads are formed, they can be used as is. Chromatograph (if an inert or stable active ingredient is used as counterion) or by repeatedly exposing the hydrogel beads to chemicals in a rough column. Loading with suitable labile active counterions by prolonged contact with chemical solutions FIG. 1 shows poly(trimethylammonium ethyl methacrylic acid chloride-co-N).

crosslinking density of (z-methylenebisacrylamide) hydrogels, their degree of water swelling It shows the effect on -C.・, % (V/V) swelling degree in 83% water; ◆, 70% water % swelling degree, mu, E, W, F at 83% water (equilibrium water percentage).

Figure 2 shows cationic hydrogels (■) and cationic hydrogen in anionic surfactants. D&CR from various beads including drogel (mu) and uncharged beads (・), ed No. 28 is shown.

Figure 3 shows how the equilibrium water content of a hydrogel is linearly proportional to the water content during polymerization. increases, showing that it is substantially crosslinking density dependent.

Figure 4 shows that until anionic surfactant (sodium dodecyl sulfate) is present, D&CRed No. 28 (from cationic hydrogel loaded microporous carrier) This indicates that no anionic dye was released.

Figure 5 shows the results from anionic hydrogels when cationic surfactants are added. Figure 2 shows the release profile of tracycline.)-I CI.

Figure 6 shows the swelling behavior of the hydrogel as a function of pH.

Detailed explanation of specific aspects Beads or microspheres as used in connection with this specification may be rigid or non-rigid. and a positive or negative charge imparted on the surface and capillary or ionic forces. chemically and biologically more open pores with impregnated substances retained inside the pores They are inert particles. In this case, the impregnated substance is a topically or orally active substance or It is an inert counterion. In topical compositions, the charge (positive) is is sufficient to promote the adhesion of the particles to keratinous materials such as. stomata are mutual Because they are connected and open to the particle surface, there is virtually no space between the internal pore space and the outside of the particle. in full contact with the user's skin or hair, thereby allowing the beads to be applied to the user's skin or hair. , or in the case of orally delivered drugs, after application to the gastrointestinal tract, the impregnating material is can be released.

When using cationic beads, the cationic value of the polymer beads of the present invention is small. Derived from the presence of a functionality that can be protonated on at least some of the monomers that are polymerized do. For oral delivery systems, the beads have a yielding a binding affinity for the counterion of at least about 1.0XIO'ml/g. It will have sufficient charge density. (1, ange’s tlandbook of Chemistry, 13th edition, pages 5-119 to 5-122. and. ) The ionic hydrogel contains at least 45% by weight of the total hydrogel of counter ions. It will also have sufficient porosity and charge density to provide capacity. For the present invention Cationic functionalities of particular interest include pyridine, which carries tertiary nitrogen, and quaternary nitrogen. and ammonium, each of which uses topical compositions. It can retain a positive charge under certain conditions. Particularly interesting anionic functionalities include sulfone This includes carboxylate and carboxylate. The beads according to the invention can Approximately 0.1 to 10 milligram equivalents/g (meq/g) capacity for ions (commonly used (measured by acid-base titration), usually about 0.2-10 meq/g, more usually 0.2-10 meq/g. 5-l　Omeq/g, preferably 5.0-IOmeQ/g (again, conventional acid- will have a surface charge density of (determined by base titration).

In their most convenient form, the shape of the particles is as follows: Generally spherical in shape due to the use of turbidity or inverse suspension polymerization. Such microspheres have a size of Although it varies widely, the diameter is preferably about 5 to about 00 microns (about 10 to about 40 microns). Anything in the micron range will give the best results. These size ranges From an aesthetic point of view, the microspheres within impart a smooth feel when applied topically. It is attractive from the outside and is easily excreted when delivered orally.

The pore size of the spheres also depends on the chemical nature of the polymer used and the diffusivity of the impregnating substance. The optimum dimensions for this purpose may vary widely. Thus, different systems can be applied throughout the formulation. requires different optimal ranges of pore volume distribution to obtain the most desirable properties. It will be. However, generally about 0.01 to about 4.0 cc/g, preferably About 0.1 to about 2. Total pore volume of OOc c/g, about 1 to about 500 m2/g, preferred Preferably, a surface area of about 20 to about 200 m'/g, and about 0.001 to about 3.0 m'/g. lon, preferably from about 0.003 to about 1. Best results with an average pore diameter of O microns You can get results. According to the conventional method of measuring and expressing pore size, the pore diameter is 8.　 E, T, Nitrogen analysis method (Brunaer et al., (193B) J , AffLCheu Soc, 60:309-316). From the value and mercury intrusion method calculated from measurements of pore volume according to od).

The particles are conveniently formed as microspheres by suspension polymerization in a liquid-liquid system. General the desired monomer, polymerization initiator (if used), and inert fluid (borogen). ) is formed as the first liquid phase. In this case, borogen is the first liquid It is miscible with the second liquid phase but immiscible with the second liquid phase. Then, the first liquid phase and the The solution is suspended in a second liquid phase that is miscible. Oil-soluble monomers, e.g. In the case of lupyridine and its derivatives, the first liquid phase is usually incapable of dissolving the monomer. The liquid phase will be an organic solvent that is immiscible with water, and the second liquid phase will be water. water soluble things For example, in the case of quaternary acrylate and methacrylate derivatives, the first liquid While the body phase is aqueous (with water as the porogen), the second phase is a hydrophobic organic solvent. Dew.

Polymerization begins once a suspension of discrete droplets of the desired size is obtained (typically by activating the reactants by high temperature or irradiation). After polymerization is complete, raw The formed beads are recovered from the suspension. This bead has a fluid inside it at this point. a substantially porous structure formed around the pores thereby forming a pore network. It is a synthetic polymer. Therefore, the fluid serves as a porogen or pore former. and occupy the pores of the beads produced. Suitable porogen fluids are listed below. This will be explained in more detail below. If the organic phase serves as a porogen, the method You will find that it is the same. When water serves as a porogen (for water-soluble monomers) The process would be known as inverse suspension polymerization.

Certain impregnating substances can serve as porogens, as mentioned above. Whether incorporated into the porous network structure of the present invention before or after the charge generation step, good. An important factor in choosing an impregnating substance for topical application is its charge. That is, To preserve the ionic functionality of the beads when applied to the skin or hair, the inclusion of The immersion material must be substantially neutral. Slightly negative or positive substances can also be used However, their incorporation must not neutralize or affect the surface charge of the beads. stomach.

If the impregnating material is chosen to serve as a porogen, the suspension is The porous beads collected from the After further processing steps, it is essentially ready for use. In these cases, Microsphere formation and incorporation of the impregnated substance are performed in one step. Therefore, this is 1 step. It can be called the Tsupu method. Impregnated materials that can serve as porogens are based on the following criteria: It is a liquid impregnated material that is compatible with

l) They are completely miscible with the monomer mixture or immiscible with the second liquid phase. Either can be made sufficiently miscible by the addition of a small amount of a compatible solvent It is.

2) They are immiscible (or at most only slightly soluble) with the second liquid phase ), 3) They are inert with respect to the monomers and any polymerization used upon contact with the catalyst and any conditions necessary for polymerization to occur (temperature and radiation). 4) They are usually liquid or has a melting point below the polymerization temperature. Solids can be made eutectic or by dissolving them in a solvent. frequently converted to a liquid state by forming a mixture; and 5) They are neutral (or at most slightly negative) with respect to their charge or positive).

When using this method, the process must be carried out under an inert atmosphere such as a nitrogen stream. f (No. If a polymerization catalyst is used, if the impregnating material is susceptible to oxidation, it is It must not oxidize the impregnating material. An example of an azo catalyst that burns be. Also, the polymerization temperature is maintained within a mild range.

As an alternative to the one-step method, the pores of preformed dry porous polymer beads are A substantially neutral impregnating material may be disposed in the portion. Thus, the product can be It is manufactured in two steps. In this case, polymerization is first carried out using a substituted porogen. , then removed and replaced with the desired active ingredient. This means that bologen and and the active ingredients are completely different ingredients in this two-step method. As a substituted porogen Suitable materials are those that meet the five criteria listed above for porogen-impregnated materials. Let's become.

Among these substances suitable as substituted porogens when hydrophobic monomers are used, preferred are Preferred are hydrocarbons, especially inert, non-polar organic solvents. some of the most convenient Useful examples are alkanes, monochloroalkanes, and aromatic hydrocarbons. Such melting Examples of media are straight-chain or branched alkanes of 5 to 12 carbon atoms, silanes of 5 to 8 carbon atoms. Chloalkanes, benzene, and alkyl-substituted benzenes such as toluene and quinolene It is. Other types of borogens include C,~C2° alcohols, perfluorinated Contains polyether and oil. Removal of porogens can be accomplished by solvent extraction, evaporation, or can be performed by similar conventional operations. As mentioned above (7), water-soluble In the case of nomers, water serves as the porogen.

A further advantage of using this two-step method is that prior to uptake of the impregnating material, It is possible to remove unnecessary species formed within the composite structure. Examples of unwanted species include Due to the reaction, Zimmer 1 residual catalyst, surfactant and/or cleaning agent remaining on the sphere surface included. A further advantage of this method is that it serves as a means of controlling the pore characteristics of the finished beads. The advantage is that the amount and type of borogen can be selected. Thus, the structure of the beads themselves no longer constrained by the limitations of impregnated substances that arise in order to influence the There isn't. This allows for partial, rather than complete, filling of the pores with impregnated material. and by selecting between swellable and non-swellable porogens, the pore size and Allows for further control of distribution.

Extraction of porogen and replacement with impregnating material in a two-step process (e.g. dry beads) Impregnation with other impregnating substances) is a combination of the chemical properties of the borogen and the behavior of other species present. Depending on the behavior of the combined borogens, this can be done in different ways. first , by filtration, preferably using a vacuum filtration device (such as a Buchner funnel). Collect the beads from the solution. The beads are then washed with a suitable solvent to remove them from the aqueous phase. Surfactant, unreacted monomer and residual catalyst, and porogen deposited on the bead surface Removes organic species not bound to the polymer, including the polymer itself. Examples of such solvents are , isopropanol, alone or in aqueous solution. After washing, drying The solvent itself is removed, preferably by vacuum drying.

In certain cases, i.e. when porogen, unreacted monomer and water form an azeotrope, If so, other extraction methods may be used. In such cases, steam distillation is This is an effective method for extracting borogen from water. After all, vacuum drying was then carried out. Good too.

If the beads are already ionic or (as explained in more detail below) Assuming protonation takes place after incorporation, the beads are dried to form a substituted porogen. Once all unwanted organic substances are removed, they can be used orally to remove the oppositely charged species. It may be absorbed or otherwise impregnated with an impregnating substance according to conventional methods. most convenient One such method is catalytic absorption. The solid active substance is first dissolved in a solvent to form Let the beads absorb the solution. Even if the solvent remains in the finished product, it may evaporate or further remove the solvent. It may be removed by conventional means such as extraction. Limited solubility in certain solvents For solid components that only have By this, high contents in the finished beads can be achieved.

In the case of oral delivery systems, the impregnating substance may be, for example, a basic, positively charged drug. chromatographic methods such as ion-exchange chromatography. and then packed into a matrix of anionic (negatively charged) beads. the spot In this case, the positively charged counterion is exchanged with a drug molecule.

The polymerization process and various parameters and process conditions involved in the polymerization are optimized selection and as a means of controlling the pore properties and, consequently, the capacity and release characteristics of Can be adjusted. For example, the crosslinking means, the amount and type of crosslinking agent, and the Appropriate selection of the amount and type of liquid is a means of achieving such control. temperature , the degree of radiation used, the degree of agitation and any other effects that affect the rate of polymerization reaction. Certain polymerization conditions, including factors, can also be varied towards such effects. .

Crosslinking in polymer formation is the primary means of pore size control. According to the present invention Monomers that can be polymerized to produce crosslinked polymer beads include polyvalent ethylenically unsaturated monomers, i.e. those having at least two sites of unsaturation; and monoethylene in combination with one or more polyethylenically unsaturated monomers. Contains sexually unsaturated monomers. In the latter case, the percentage of crosslinking is Balance the relative amounts of ethylenically unsaturated and polyethylenically unsaturated monomers It can be controlled by Typically, such systems consist of one monoethylenyl It will contain a saturated monomer and one polyethylenically unsaturated monomer. Although , optionally adding additional monomers of the respective type compatible with the system. would also be possible. For a paper on the production of such copolymer systems, see Gyo ( Guyot) and Bartholin, Design and Properties of Polymersas Materials for Fine Chemistry, Prog, Polym, Ed, (1982) Vol. 8. @pp, 303- See 307.

For use as part of the monoethylenically unsaturated monomer content of polymer delivery systems Monoethylenically unsaturated monomers that can be used include ethylene, propylene, and isobutylene. Ren, diisobutylene, styrene, sodium styrene sulfonate, ethyl vinyl Rubenzene, vinylbenzene chloride, vinylpyridine and its derivatives, vinyl Toluene and dicyclopentadiene; methyl, ethyl, propyl, isopropylene butyl, 5ec-butyl, tert-butyl, amyl, hexyl, octyl ethylhexyl, decyl, dodecyl, cyclohexyl, isobornyl, phenylene Nyl, benzyl, alkylphenyl, ethoxymethyl, ethoxyethyl, ethoxy Propyl, Propoquine Methyl, Propoxyethyl, Propoquinepropyl, Etho Acrylics containing xyphenyl, ethoxybenzyl, and ethoxycyclohexyl Acids and esters of methacrylic acid; vinyl acetate, vinyl propionate, vinyl butyrate Vinyl esters, including vinyl and vinyl laurate; vinyl methyl ketone, vinyl Ethyl ketone, vinyl isopropyl ketone, and methyl isopropenyl ketone Containing vinyl ketones; vinyl methyl ether, vinyl ethyl ether, vinyl Vinyl ethers, including propyl ether and vinyl isobutyl ether; Includes vinyl compounds containing silicon and other metals such as luciloxanes. . Furthermore, compounds such as isopropene, butadiene and chloroprene, which are usually Polyethylenically unsaturated monomers that behave as if they had only one unsaturated group , can be used as part of the monoethylenically unsaturated monomer content.

Polyethylenically unsaturated crosslinking monomers suitable for producing such polymer beads - contains diallyl phthalate, ethylene glycol acrylate, and dimethacrylate. Ethylene glycol, trimethylolpropane trimethacrylate, divinyl sulfate Hon, ethylene glycol, glycerol, pentaerythritol, diene of tyrene glycol, of monothio and dithio derivatives of glycol, and of resorcinol polyvinyl and polyallyl ether of alcohol; divinyl ketone, divinyl sulfate Allyl acrylate, Diallyl maleate, Diallyl fumarate, Co/S phosphoric acid Sialyl, diallyl carbonate, diallyl malonate, diallyl oxalate, diadipate Allyl, divinyl sebacate, diallyl tartrate, diallyl silicate, tricarbali triallyl phosphate, triallyl aconitate, triallyl citrate, triallyl phosphate Lyle, novinylnaphthalene, divinylbenzene, trivinylbenzene, 1-2 carbons Alkyldivinylben having 1 to 4 elementary alkyl substituents on the benzene nucleus Zenes, alkaline compounds having 1 to 3 alkyl substituents of 1 to 2 carbon atoms on the benzene nucleus; Quiltrivinylbenzenes nitrivinylnaphthalene, polyvinylanthracene, and water-soluble acrylates and methacrylates (specifically those listed below) ) etc. are included.

At least a portion of the monomer content is capable of retaining a positive charge under the conditions of use Contains protonated functionality. This protonated functionality is monoethylenically unsaturated. present in the polyethylenically unsaturated monomer, polyethylenically unsaturated monomer, or both, with appropriate functionality. Values include pyridine and ammonium. As a specific monomer, vinyl Lupyridine, such as 2-vinylpyridine, 4-vinylpyridine, 3-methyl- 2-vinylpyridine, 4-methyl-2-vinylpyridine, 6-methyl-2-vinylpyridine Lupyridine, 3-ethyl-2-vinylpyridine, 5-ethyl-2-vinylpyridine 2-methyl-4-vinylpyridine, 2-methyl-5-vinylpyridine and 2-methyl-5-vinylpyridine -Ethyl-5-vinylpyridine and water-soluble acrylate and methacrylate examples For example, methacrylamide propyl hydroxyethyl dimethyl ammonium acetate methacrylamide propyltrimethylammonium chloride and dimethyl Aminoethyl methacrylate and dimethyl sulfate, diethylaminoethyl acetate Acrylate and dimethyl sulfate Vinylbenzyl chloride and Divinylbenzene and the quaternization product of vinylbenzyl and ethylene glycol dimethacrylate. Can be mentioned. With quaternized monomers, CM, F-1Br-1■- or CHI A counterion such as 08O1- is incorporated into the structure.

When using water-soluble acrylate and methacrylate monomers, the seven It is necessary that all substances be water soluble. Suitable polyethylene unsaturated resin The polymer (required for crosslinking) is N, N'-methylenebisacrylamide; N, N'-nonamethylenebisacrylamide; and alkoxylated water soluble Examples include polyfunctional acrylates. For water-soluble quaternized monomers, the above inverse suspension A polymerization protocol is used. Microspheres made from water-soluble quaternized monomers are , usually non-rigid hydrogels, containing polar (water and alcohol) soluble substances, e.g. , Hydroquinone, Methyl Salicylate, Insect Repellent (in Alcohol), UV Protection It is effective for adsorbing substances (in alcohol), etc., and is a hydrocarbon with a negative charge. Gels are effective in adsorbing basic drugs, such as alkaloids and steroids. be.

Preferred polymeric beads of the present invention are suitable for ionic interactions such as those found in ion exchange techniques. Reactions with porogens and/or active ingredients that are eventually incorporated into the composition other than action (1 contains no interacting reactive groups. Such beads may cause undesired reactions. It is not easily processed, is stable over the expected pH range of use, and is a common oxidation-reduction agent. It is stable over the expected range of use and has a relatively long potash shelf life. Must be.

Preferred topical cationic polymer delivery systems of the invention include substantially unsoaked beads. 4-vinylpyridine and ethylene glycol dimethacrylate, 4-vinylpyridine and divinylbenzene, 2-vinylpyridine and divinylbenzene 2-vinylpyridine and ethylene glycol dimethacrylate, ethyl methyl Formed by copolymerization of vinyl pyridine and ethylene glycol dimethacrylate Ru. Among these systems, 4-vinylpyridine and divinylbenzene are particularly preferred. , a copolymer of 4-vinylpyridine and ethylene glycol dimethacrylate preferred.

The ionic hydrogel polymeric material of the present invention is soluble in all proportions in aqueous solution. ionic monoethylenically unsaturated monomer and polyethylenically unsaturated crosslinking monomer Contains a copolymerization product of

Preferred cationic polymers for oral delivery systems have the following formula: (where R', R'- R' and R' are the same or different and are saturated alkyl groups having 1 to 6 carbon atoms; , n=1-4, and X is CL F, Br, ■, and CH.

OSO, selected from the group consisting of. ) selected from the group consisting of produced from saturated quaternary ammonium cationic monomers, the water-soluble polyethylene-based Unsaturated crosslinking monomers include N,N'-methylenebisacrylamide, N,N'-nona Methylenebisacrylamide and alkoxylated water-soluble multifunctional acrylate selected from the group consisting of Particularly preferred cationic polymers include trimethyl ammonium edyl methacrylic acid chloride and N,N'-methylene bisacrylate There is a copolymerization product of Ruamide (poly(PTMAEMCI-co-MBA)).

Preferred anionic polymers for oral delivery systems have the following formula 2 (wherein R', R2, R ', R' and R1 are the same or different and H-saturated with 1-4 carbon atoms Y is selected from the group consisting of alkyl, and Y is selected from the group consisting of Na and K. )mosquito A copolymerization product of a monoethylenically unsaturated anionic monomer selected from the group consisting of The water-soluble polyethylenically unsaturated crosslinking monomer is N,N'-methylene Bisacrylamide, N,N'-nonamethylenebisacrylamide and alkoxy Selected from the group consisting of silated water-soluble polyfunctional acrylates. particularly preferred Anionic hydrogel beads are made of methacrylic acid and N,N'-methylene bisacrylate. copolymerization product ((poly)MA-co-MBA) and styrene sulfone Copolymerization product of sodium chloride acid and N,N'-methylenebisacrylamide (poly( SS S-co-MBA)).

Polymer beads of the present invention have greater than 10% crosslinking, preferably from about 7 to about 80 % crosslinking, most preferably from about 20% to about 60% crosslinking. Crosslinking % is polyester The weight of the tyrenic unsaturated monomer is calculated from the weight of the polyethylenically unsaturated monomer and monoethylene. It is determined by those skilled in the art as the amount divided by the total amount of monomers, including both system unsaturated monomers. is justified. Typically, the monoethylenically unsaturated monomer is about 20% of the monomer mixture. -80%, preferably 40%, of the polyethylenically unsaturated monomer; This is the rest of the mixture.

For topically applied neutral impregnating agents, protonation of the polymer beads results in the desired impregnating agent. may occur before or after entanglement within the porous network. Cations of the invention The method for obtaining the beads is, for example, by placing the beads thus recovered from the suspension in an acidic medium. It is protonated in the body. In particular, in order to obtain a positive charge on the surface of the beads of the present invention, For this purpose, after the beads are recovered from the polymerization process, they are washed with an acid such as a 3% aqueous hydrochloride solution. It will be done. Excess acid increases the pH to about 1 to about 4, preferably the second having a pI-(3). Removed with hydrochloride solution.

Moreover, the beads of the present invention have a 0.1. N potassium hydrogen phthalate, O,1NHC1 and and protonated with a pH 3 buffered wash containing deionized water. This buffered wash solution There is no need to remove excess acid, and beads treated in this way can be used immediately. It is wet filtered and dried.

Once the microspheres are formed and dried, they are impregnated with a J-type impregnant for contact adsorption (this step before protonation or unless ion exchange is the method of introducing the active ingredient. (will be done later). In some cases, impregnating agents reduce viscosity and promote adsorption, It is used as a solution dissolved in an appropriate organic solvent to reduce its efficacy.

Examples of such solvents are liquid paraffin, ether, petroleum ether, methanol. , alcohols such as ethanol and higher alcohols, benzene and toluene. Aromatics such as pentane, alkanes such as hexane and heptane, acetone and and ketones such as methyl ethyl ketone, chloroform, carbon tetrachloride, and methylene chloride. Chlorinated hydrocarbons such as carbon and ethylene dichloride, acetates such as ethyl acetate and Oils such as isopropyl myristate, diisopropyl adipate and mineral oil It's fat. After this solution has been adsorbed, the solvent can be evaporated or the pores can be filled with an impregnating agent. It can be kept inside. Other formulation materials typically used in topical formulations, For example, carriers or adjuvants such as fragrances, preservatives, and antioxidants may be mixed. Other softeners may also be present, along with impregnating agents and other materials present. Incorporated into and out of beads.

The substances incorporated into the ionic polymer bead delivery system of the present invention can be used individually or in combination. However, the desired effect can be obtained. Pure active substance, mixture of active substances or active substance The impregnating agent, which is a solution of the substance, typically contains about 5% to about 65% of the total amount of impregnated beads. I'm reading. If the active substance is particularly strong, a dilute solution is usually used to reduce the weight of the active ingredient itself. The amount % can be as low as 0.01% based on the total amount of impregnated beads. can.

Active impregnating agents suitable for topical use include topical applications including cosmetic, therapeutic and other uses. A variety of active substances are contemplated. Specific substances include ultraviolet absorbing substances. (ultraviolet protection), steroids, insect repellents, retinoic acid, fragrances, mino Examples include kinjiru, softening agent, and the like. Incorporating such substances into a polymer bead delivery system The specific method is described in co-pending applications No. 091.647 and No. 112.971. the disclosures of which are incorporated herein by reference.

Once the topical composition is prepared by the one-step or two-step method described above, it can be used alone or further If it is not possible to neutralize the surface charge on the carrier or excipient or bead surface, , at least slightly acidic pH 1 preferably below about pH 6, more preferably p It is mixed into most types of products with H about 3-4. This composition is a dry bundle The composition is used alone by simply applying it to the skin.

The impregnated beads useful for topical application of the present invention may be liquid or solid compositions or gels, creams, etc. such as creams, lotions, ointments, sprays, powders, oils, sticks, etc. It is also incorporated into formulations of the type commonly used for skin treatments. Specific application aspects or Suitable excipients for the method will be readily apparent to those skilled in the art. For example, the composition of the invention Products, especially UV-absorbing compositions, can be used with other products to impart cosmetic and UV protection properties. mixed with The UV-absorbing composition of the present invention provides a highly absorbing and water-repellent final product. Products such as makeup gap foundation and tanning products are being explored. Ideally, it should be suitable for

The method of the present invention used by applying to keratin materials, especially human skin and hair. In topical compositions and formulations, the cationic surface charges of individual polymer particles are Increases the persistence of the active substance being applied by promoting the adhesion of the composition to the skin and hair. Melt.

The ionic hydrogel composition of the present invention can be used for therapeutic, hygiene, analgesic, cosmetic, etc. purposes. Used for delivery to humans or other animals. For such purposes, this composition The products can be delivered orally, intravascularly, intraocularly, intraperitoneally and for similar in vivo uses.

The main in-vivo use of the hydrogel composition of the present invention is for drug use in human and veterinary applications. and for the delivery of other pharmaceutical agents. Specifics delivered by the system of the invention Drugs include analgesics, anesthetics, anthelmintics, antibacterial agents, antipyretics, antiseptics, and antituberculous drugs. drugs, antitussives, antivirals, cardiac agents, laxatives, chemotherapeutics, corticoids ( steroids), antidepressants, diagnostic aids, diuretics, enzymes, expectorants, hormones, Hypnotic agents, mineral supplements, nutritional supplements, parasympathomimetic stimulants, potassium supplements, sedatives. Static agents, sulfa drugs, stimulants, sympathomimetic agents, tranquilizers, urinary anti-infectives, blood Examples include duct constrictors, vasodilators, vitamins, xanthine inducers, and the like.

The anionic hydrogels of the present invention provide cationic drugs that are to be released in the intestine rather than the stomach. is particularly effective for oral delivery of Such drugs include antibiotics, vitamins, and Examples include steroidal anti-inflammatory substances. During storage and while the composition passes through the stomach The negative surface charge causes the drug to ionically bind to the hydrogel. However, intestinal high 1) When exposed to an H environment, sodium and and positively charged ions such as potassium. The drug is then added to the hydrogel. It is released from the network inside the pores of the particles.

For anionic drugs, cationic hydrogels are used for oral delivery. the spot When the bile salts present in the intestine exchange with the positive surface charge of the beads, the drug is released. .

For oral drug delivery, polymeric hydrogel particles carrying the drug are e.g. mington's Pharmaceutical 5 Sciences, M ack Publishing Co, Mr. Easto B Described in Penn 5ylvania, 16th Ed, 1982 as incorporated by reference in its various known forms, the disclosure of which is incorporated herein by reference. . The composition or formulation to be administered includes a drug contained within the ionic hydrogel particles. containing a preselected amount of the agent. Typically, pharmaceutically acceptable non-toxic forms are Mannitol, lactose, starch, magnesium stearate, saccharide sodium, talc, cellulose, glucose, sucrose, magnesium carbonate °C using conventional excipients such as silica. Such compositions can be prepared as solutions, suspensions, , tablets, gunpowder, capsules, powders, etc.

For parenteral administration, including both intravascular and intramuscular administration, the ionic human Drogel polymer particles are typically suspended in a water for injection or saline carrier. It takes Formulations are well known in the art.

Below are specific considerations and preparation and application examples for various specific impregnating agents. be. These examples are provided for illustrative purposes only and are not indicative of the invention in their own right. It is not limited to. Unless otherwise specified, parts and percentages are by weight. .

This example shows the 4-vinylpyridine/ethylene glycol dimethacrylate of the present invention. 2 shows the preparation of topopolymer beads. Steps are shown below: Electric stirrer , 10100O four-neck reaction equipped with reflux condenser, thermometer and nitrogen inlet The flask was evaluated and purged with nitrogen. 300 parts deionized water, 2.5 parts ara beer gum and 2.5 parts of the trademark Marasperse N-22 (Reed Li gnin) glue sulfonate was added to the reaction flask. Dispersion medium (Arabiago This mixture is poured into an oil until the The mixture was heated with stirring at a bath width of about 50°C.

Add 40 parts of 4-vinylpyridine and 60 parts of ethylene glycol dimeta to this mixture. acrylate, 0.8 parts benzoyl peroxide (70% active and 30% water) and A solution of 50 parts of toluene (porogen) was added. Adjusted speed (approximately 900 rp When the aqueous phase and organic solution are stirred at a+), the droplet sample is examined visually using an optical microscope When observed, a large number of droplets with a droplet diameter of 5 to 100 microns was obtained; was stabilized by the dispersion medium.

The reaction mixture was then heated at 60-65°C for 20 minutes and at 74-76°C for an additional 8 hours. Cross-linked 4-vinyl with toluene entangled within a network of pores upon continued heating for Porous beads of pyridine/ethylene glycol dimethacrylate were formed.

The reaction mixture was then cooled to room temperature (7) and the porous polymer beads were removed by filtration. and removed from the reaction flask. First, add the filtered beads to 1 liter of deionized water. Remove the dispersion medium by washing twice with water, then twice with 1 liter of isopropanol. The unreacted residual monomer and toluene were removed. The beads are then heated to 80-90°C. It was dried in an oven for about 8 hours.

Yield: 87.7% opaque beads. It was there. The average particle size of these beads is S edimentation Micromeritics tnstrumen In the case of the measurement by Company L, it was 25 microns. The particle size measurement method is attached to the device. Crostzer 5300 Particle 5ize＾nalyz er In5truction Manual, (1984). It is.

The surface area of the purified bead sample is determined by B, E, T, and nitrogen analysis method: l 1.05 IIl"/g, and the pore volume is 0.14 ml/g using the mercury intrusion method. It was g.

Example ■1 This example is based on the 4-vinylpyridine/ethylene glycol dimethacrylate of Example I. This shows the protonation of the polymer beads.

Into an ioooml flask, add 80.0 g of the preformed porous beads of Example I and 300ml of 3% aqueous hydrochloride solution was added.

After stirring this slurry for 3 hours, the porous polymer cation beads were filtered and the salt Excess 3% acid solution was removed from the polymer beads by washing with acid salt dilution, pH 3. . The beads were then dried in an oven at 75°C for 8-IO hours. hydrogen ions in water When the amount of H' was measured, it was 0.78 meq/g.

Example 111 This example describes the preparation and preparation of 4-vinylpyridine/divinylbenzene polymer beads. This shows protonation. The procedure is shown below.・The reaction apparatus is as in Example ■. Prepared. To a reaction flask was added 600 parts of deionized water, 0.6 parts of gum arabic, and 6.0 parts of Marasperse N-22 was added. All solids content of aqueous solution Stir at room temperature until dissolved.

In a flask, 35 parts of 4-vinylpyridine, 65 parts of divinylbenzene (divinyl 55% benzene, 45% ethylhinylbenzene), 100 parts isobutanol and and 1.0 parts of 2.2'-azobis(2- An organic solution of methylbutanenitrile) was added. Droplets were formed as in Example I. The reaction mixture was stirred at approximately 1300 rpm until the temperature reached 800 rpm. Once the rpm was lowered, the reaction mixture was heated to 75°C. 8 hours at this temperature continued to react.

The opaque porous beads were collected by filtration and washed three times with 500 ml of deionized water. Ta. The beads were incubated in 500 ml of O,IN HC] solution by stirring for 30 min. Protonation was performed. The beads were filtered 2 and washed with diluted hydrochloride solution, pH 3. Excess acid was removed. Residual monomer and borogen were removed as in Example I. Bee After drying the rice in an oven at 80-90°C for about 8 hours, dry rice was obtained. Yield is 93 It was hot at g. The average particle size, surface area and pore volume are 36 microns and 2.21 m, respectively. It was 27g and 0.073ml/g.

Example rv This example uses a buffered wash solution to protonate polymer beads of the invention. It shows an alternative method. The procedure is shown below: 1000+nl beaker g of the preformed porous beads of Example I in 250 ml of pH 3.0 buffer (5 00 parts of 0.1N potassium hydrogen phthalate and 223 parts of 0.1N potassium hydrogen phthalate. (including INHc+) and 250 ml of deionized water were added. After stirring this mixture for 30 minutes, filter it. did. The quaternized beads were dried in an oven at 80-90°C for 6-10 hours.

Hitake This example uses 4-vinylpyridine/ethylene resin using xylene as the porogen. 1 shows the preparation of lycosine methacrylate beads. The steps are shown below: A 10100O reaction flask was charged with the aqueous dispersion described in Example I. polo 50 parts of xylene (a mixture of ortho, meta and paraisomers) instead of toluene as the An organic solution was prepared as in Example 1, except that a compound) was used. Droplet size is 10 The reaction was stirred at 130 Orpm until ~60 microns. Then the reaction The material was heated to 65°C and maintained at this temperature for 20 minutes. 800 rpi + l lowering and stirred and heated the reaction to 75°C. The reaction continued at this temperature for 8 hours.

The porous beads were collected by filtration and washed with 500 ml of deionized water. Then, The beads were quaternized in a pH 3, oven bath as described in Example 1. Ta.

Rinsing the beads three times with 500 ml of acetone removes residual monomers. Gen was removed. After drying in an oven at 80-90℃ for about 8 hours, 61g of beans I got z. The average particle size, surface area and pore volume are 22.5 microns and 3.03 microns, respectively. I+'/g and 0.68 ml/g.

Example vr This example shows that in the cationic beads of Example 11, ultraviolet absorber [(ultraviolet protection This indicates that the substance is to be replaced with a substance. The procedure is shown below. Obtained from Example 11 18.0 parts of porous cationic polymer beads and 30 parts of isopropanol were mixed in a glass flask at room temperature using an agitator. Next, the seventh part 12.0 parts of UV protection containing cutyl dimethyl PABA and 2 parts of oxybenzone The substance mixture was added gradually. The resulting suspension was stirred for about 20 minutes.

The solvent was then evaporated to dryness in a fucome hood for 24 hours at room temperature. Approximately 40% purple A mixture of external defense substances was entangled within the pores of the cationic polymer beads.

Great Deaf■J 4-vinylpyridine/ethylene glycol dimethacrylate (4-VP/EGD MA) Copolymer beads adhere to and retain human skin in human subjects. I looked it up. Unprotonated and protonated 4-VP/EGDMA beads as described above Prepared as described in Examples ① and 11, an oil-soluble dye (Oil Red E GN) was mixed. Extract the dye from a small sample of beads and calculate the weight gain (weight of dye/(color) The weight of the particles and beads)×100) was determined using spectrophotometry. Unprotonated Bi It was found that the amount of beads increased by 0.9% and the amount of protonated beads increased by 1.0%.

A measured amount of each bead preparation (one polymer on each hand) was placed in a 6.14 cm It was deposited on the subject's marked forearm covering the face. Then, after soaking your arm in water for 5 seconds , removed. This process was repeated 5 times (this sample did not dry), and the surfactant solution was The polymer retained on the skin was recovered by washing with liquid. Extracted from pigment Then, it was quantified using spectrophotometry, and the amount of extracted dye was correlated with the amount of polymer. The amount of beads retained was increased by The results are shown in Table 1.

artificial Polymer beads Subject Adhesive amount/'cm2 (mg) Retained amount (mg)/cm' Retention x deprotonation! 1.86 0.672 1.89 0.61 34 ．． 26 Protonization! 1.61 0.81 2 1.86 1.25 58.93 These results indicate that highly protonated polymers are more sensitive to skin than unprotonated polymers. It was shown that it was retained in the skin.

B. Ionic hydrogel: This example describes the preparation of PTMAE MCL cationic hydrogel beads using inverse suspension polymerization. Preparation is shown.

Use the following materials: continuous phase Premix the continuous phase with the following ingredients: EMSORB 2500 (sorbitan monooleate) 24g heptane 6 00g The EMSORB 2500 was mixed briefly with the heptane by hand stirring.

Fukure Chair Carrier Premix the discontinuous phase with the following ingredients: 300 ml deionized water Potassium persulfate 1.8g MBA 30g Sipomer (TMAEMCI,) 90 g MBA at a temperature of about 55-60°C Dissolved in water. When the MBA is completely dissolved, combine Sipomer with this solution. Mixed. Then, the initiator (K, SI　O,) was added. Discontinuous phase solution at 64℃ After maintaining the temperature below, it was mixed with the continuous phase solution.

The continuous phase solution was preheated to 60° C. in a 2 liter reaction kettle. Insert the reactor into nitrogen for about 1.5 hours. After purging with water, the monomer was added. Start stirring at 11,000 rpm and mix the monomer. - solution was added to the reaction vessel. The reaction temperature was increased to 75°C. Polymerization occurs gradually at about 64℃ At the beginning, significant exothermic bubbling was observed during the polymerization.

After the hydrogel beads are formed, reduce the stirring speed to 600 rpm; was maintained at 60 Orpm and 75°C for 6 hours.

After cooling the reaction vessel, filter the mixture and wash with deionized water until the filtrate is colorless. Purified.

The hydrogel beads were suspended in 500 ml of methanol and stirred for 1.5 h. and filtered again. This process was repeated twice until the filtrate became colorless. Hydroge The ruby beads were washed again with water to ensure that no residual monomer remained in the filtrate (the filtrate was semi-transparent). If clear, the washing step was repeated until the filtrate was clear). The filtrate becomes colorless. Then, the hydrogel beads were washed with a mixture of methanol and acetone (1:1). , gradually dried the hydrogel beads by increasing the proportion of acetone. hydro The gel beads were left in the exhaust hood to allow the acetone to evaporate.

The hydrogel beads were then dried in a vacuum oven at 50°C for 8 hours. of beads Optical micrographs were taken both before and after swelling. These are shown in FIG.

Characteristics of hydrogel beads Prepared as in Example Vl11 using a crosslinking content of 20-60% according to the above procedure. A cationic hydrogel was prepared. To investigate the amount of water adsorbed by microgels , gel in a square disk (2.5ciX2.5cwiXo, 16cm) It was cast into. Equilibrium water fraction (EWF) between swelling disk and drying disk It was measured as a change in weight.

EWF increases from o, 85 to 0.7 as the crosslinking content increases from 20% to 80%. 8 (Figure 1). The discrete phase of all samples contained 83% water by weight. . The release profile of D&CRed No. 28 showed a controlled release trigger (Figure 2). Figure 2 shows macroporous beads alone (curve A), anionic surfactant (curve A), and anionic surfactant (curve A). Cationic hydrogel according to the invention (curve B ) and ionic hydrogel (curve C) in neutral surfactant (polyox). In comparison, the ionic hydrogel was mixed with water or water and a nonionic surfactant (0,5 %polyox) produced no detectable release. This shows that. However, the sample was mixed with anionic surfactant (0.5% LA). When added to a release solution containing sodium uryl sulfate), the dye was released. The release rate is slower than the control (curve A) and anionic surfactants (similar to biosalts) The result of an ion exchange mechanism that exchanges with an anionic dye to form a complex with a cationic polymer. Met.

By measuring the weight increase of hydrogel disks swollen in water, The relationship between water equilibrium proportion and crosslink density as a function of water content was determined. Figure 3 shows the The water equilibrium proportion of the logel increases in direct proportion to the water content during polymerization and increases in crosslinking density. This shows that there is no qualitative dependence. This means that the hydrogel is highly swollen. This indicates that the hydration was polymerized in the form of hydration, which subsequently became a limiting factor for hydration.

The ionic hydrogel was poly(TMAEMC]-co-MBA).

Generally the same as made and disclosed in U.S. Patent No. 4.690.825 various materials were polymerized inside the pores of the macroporous material. D&CRed No. 28 Typical release profiles for release containing Polyox or SDS surfactant The exudate is shown in Figure 4. As shown in the case of hydrogel systems, the anionic field Anionic dye from cationic gel-filled sponge until surfactant (SDS) is present did not emit. The release rate of the dye into the SDS release solution was determined by gel-free microspons. It was the same as disubstance. i.e., by ionic hydrogel-filled microsponges. Several mechanisms serve to control the release profile of the active ingredient. hydro Gel swells when exposed to water, so by squeezing out the active ingredients from the pores, The active ingredient can be released, and the hydrogel is resistant to the active ingredient until it is swollen. It can act as a dense coating or plug that is impermeable. In addition, As already proven, Drogel absorbs ionic active components through an ion exchange mechanism. Release can be controlled.

Example ix Entangle the acidic type ingredients and remove the ingredients until exposed to the appropriate anion for exchange. The poly(TMAEMCl-co- MBA) hydrogels contain stable cationic charges (quaternary amine groups). Many Since many pharmaceutically active substances are basic materials, conventional basic hydrogel materials does not bind basic drugs9 and therefore does not bind basic active ingredients, e.g. alkaloids. In order to expand the application possibilities of hydrogels for , N'~methylenebisacrylamide), [poly(MA-co-MBA,) ] A hydrogel was synthesized.

A hydrogel consisting of 10-15% crosslinking (W/'If) was described in Example Vl11. It was prepared by inverse suspension polymerization. Poly(TMAEMCl-co-MBA) Hydroge As seen in the figure, poly(MA, -co-MBA) materials with low crosslinking content are There was a tendency to agglomerate during drying.

Tetracycline-1-ICI as a model basic active ingredient for release rate experiments, This was selected because of its UV detectability and water solubility. swollen gel matrix Release characteristics of tetracycline-HCl into deionized water of 50% cross-linked beads. I followed it. Effect of gel charge density on tetracycline-HCl diffusion coefficient , 0.5% benzalkonium chloride, and a release liquid containing cationic surfactant. Examined. 0.5% benzalconi chloride from poly(MA-co-MBA) polymer system Release profile of tetracycline-HCl into the dissolution medium of water or water (Figure 5 ) was not significantly different from the control.

Figure 6 also shows the swelling behavior of cationic and anionic hydrogels as a function of pH. It is. Poly (TMAEMCI-co-MBA,), 25%TMAEMCL and poly(SSS-co-MBA), the charge density of 30% SSS is dependent on pH. do not have. Therefore, the swelling behavior of these materials is pH independent. Poly (M A - co-M B A), the charge density of 1°% MA is a function of pH, and this material Becomes negatively charged at high pH. That is, as the pl-1 of this material increases, As a result, the degree of swelling increases.

Place 1 g of dry material in a graduated cylinder and add 25 c- Swelling was achieved by adding to the depth. After equilibrating the material and buffer, the volume I read the amount.

For clarity of understanding, the foregoing detailed description and examples of the present invention may be helpful. Although the invention has been described in detail, certain changes and modifications may be made within the scope of the following claims. That is clear.

% crosslinking density FIG.1 SORT (Hr,) FIG, 2゜ -70% water +-83% water +90% water FIG, 3° Time (Hr,) FIG, 4° Time (Hr,) FIG　5゜ pH FIG, 6° Procedural amendment Heisei Year Month Day

Claims (1)

[Claims] 1. ionic polymer hydrogels comprising copolymerization products of ionic monoethylenically unsaturated monomers and polyethylenically unsaturated crosslinking monomers that are soluble in aqueous solution in any proportion, for use as ion exchangers; a composition of matter suitable for A composition having a degree of swelling that is linearly proportional to volume percent and in which the equilibrium water content of the hydrogel when equilibrated with water is dependent on the amount of water used during polymerization. 2. The hydrogel binds to a counterion having an opposite charge to the hydrogel. 2. The ionic hydrogel of claim 1, having a charge density sufficient to provide binding affinity, as measured by weight distribution coefficient method, of at least about 1.0 x 10 mI/g. 3. The ionic hydrogel has a capacity for counterions having an opposite charge to the hydrogel of at least about 45% by weight of the total weight of the hydrogel and counterions. 2. The ionic hydrogel of claim 1, having a porosity and charge density sufficient to free the ionic hydrogel. 4. 3. The ionic hydrogel of claim 2, wherein the charge density is about 1 to about 10 meq/g hydrogel. 5. 3. The ionic hydrogel of claim 2, wherein the charge density is about 5 to about 10 meq/g hydrogel. 6. The weight percent of the crosslinking monomer used ranges from about 10 to about 80 weight percent of the total hydrogel. % and when the volume percent of water used during polymerization is from about 70 to about 90% of the total volume of the reaction mixture, the ionic hydrogel has a degree of swelling of about 1.0 to about 2.0. The ionic hydrogel of claim 1 exhibiting the following. 7. when the weight percent of crosslinking monomer used is from 20 to about 60 percent by weight of the total hydrogel and when the volume percent of water used during polymerization is from about 75 to about 85 percent of the total volume of the reaction mixture. 2. The ionic hydrogel of claim 1, wherein the ionic hydrogel exhibits a degree of swelling of about 1.2 to about 1.8. 8. The ionic hydrogel is cationic, and the ionic monoethylenically unsaturated monomer is a quaternary ammonium compound selected from the group consisting of compounds of the following formula: and the water-soluble polyethylenically unsaturated crosslinking monomer is N,N'-methylenebisacrylamide, N,N'-nonamethylenebisacrylamide, and and alkoxylated water-soluble polyfunctional arylates. An ionic hydrogel according to claim 1. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R1, R2, R3, and R4 are saturated alkyl groups having 1 to 6 carbon atoms, which may be the same or different, and n = 1 to 4, X is selected from the group consisting of Ce, F, Br, and 1)9. The ionic hydrogel is anionic, and the ionic monoethylenically unsaturated monomer is composed of CH2=C(R)-COOH (R is a saturated alkyl group having 1 to 4 carbon atoms). Selected acrylic acid and alkyl acrylic acid selected from the group consisting of lylic acid, and the water-soluble polyethylenically unsaturated crosslinking module The group consisting of N,N'-methylenebisacrylamide, N,N'-nonamethylenebisacrylamide, and alkoxylated water-soluble triatarylate The ionic hydrogel of claim 1, selected from: 10. The ionic hydrogel is anionic and the ionic monoethylene the water-soluble polyvalent ethylenically unsaturated crosslinking monomer is selected from the group consisting of compounds of the following formula; and an alkoxylated water-soluble polyfunctional arylate. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R1, R2, R3, R4, and R5 may be the same or different and are selected from the group consisting of H and a saturated alkyl group having 1 to 4 carbon atoms. , Y is Na and and K. )11. A composition for controlled ion exchange of a counterion and a solute ion in a preselected environment, the composition comprising a crosslinked ionic polymer hydroxide. A network of internal pores containing gel particles, each having a counterionic bond within it. the hydrogel atomizer includes physical influences selected to alter the rate of exchange of counterions and solute ions from the internal pores in response to changes in environmental conditions. A composition having the following chemical properties: 12. The particles are cationic and are composed of a crosslinked polymer polymerized from a polyethylenically unsaturated monomer selected from the group consisting of compounds of the following formula, and the water-soluble polyethylenically unsaturated crosslinking monomer is N,N'-methylene bisac Lylamide, N,N'-nonamethylenebisacrylamide, and alkoxylate 12. The composition of claim 11, wherein the composition is selected from the group consisting of water-soluble polyfunctional arylates. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, Rl, R2, R3, and R4 are saturated alkyl groups having 1 to 6 carbon atoms, which may be the same or different, and n = 1 to 4, X are Ce, F, Br, 1, and and CH3OSO3. )13. The ionic hydrogel is anionic, and the ionic monoethylenically unsaturated monomer is from the group consisting of CH2=C(R)-COOH, where R is a saturated alkyl group having 1 to 4 carbon atoms. selected from the group consisting of acrylic acid and alkyl acrylic acid, and the water-soluble polyethylenically unsaturated crosslinking monomer is Sacrylamide, N,N'-nonamethylenebisacrylamide, and alkoxy 12. The composition of claim 11 selected from the group consisting of sylated water-soluble multifunctional arylates. 14. The ionic hydrogel is anionic and the ionic monoethylene the water-soluble polyvalent ethylenically unsaturated crosslinking monomer is selected from the group consisting of compounds of the following formula; and an alkoxylated water-soluble polyfunctional arylate. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R1, R2, R3, R4, and R5 may be the same or different and are selected from the group consisting of H and a saturated alkyl group having 1 to 4 carbon atoms. , Y is Na and It is selected from fresh consisting of K and K. )15. The ionic hydrogel is substantially in the form of spheres and has an average diameter of about 1 to about 200 microns, a total pore volume of about 0.01 to about 4.0 cc/g, and an average pore of about 1 to about 200 m2. 12. The composition of claim 11, wherein the composition is a porous bead having a surface area. 16. The ionic hydrogel is substantially in the form of spheres and has an average diameter of about 1 to about 50 microns, a total pore volume of about 0.1 to about 1.0 cc/g, and an average pore of about 1 to about 20 m2. 12. The composition of claim 11, wherein the composition is a porous bead having a surface area. 17. The environment is the gastrointestinal tract of an animal or human, and the counterion is an analgesic, an anesthetic, an anthelmintic, an antidote, an antiemetic, an antihistamine, an antimalarial, an antibacterial, an antipyretic, an antiseptic, an antituberculous agent, an antitussive. , antivirals, cardiac agents, laxatives, chemotherapeutic agents, drugs Lutcoids (steroids), sedatives, diagnostic aids, diuretics, enzymes, expectorants, hormones, hypnotics, minerals, nutritional supplements, parasympathomimetic agents, potassium supplements, sedatives, sulfa drugs a positively charged pharmaceutically active ingredient selected from the group consisting of stimulants, sympathomimetic agents, tranquilizers, urinary antiinfectives, vasoconstrictors, vasodilators, vitamins, and xanthine inducers. , the set of materials of claim 13 A product. 18. The environment is the gastrointestinal tract of an animal or human, and the counterion is an analgesic, an anesthetic, an anthelmintic, an antidote, an antiemetic, an antihistamine, an antimalarial, an antibacterial, an antipyretic, an antiseptic, an antituberculous agent, an antitussive. , antivirals, cardiac agents, laxatives, chemotherapeutic agents, drugs Lutcoids (steroids), sedatives, diagnostic aids, diuretics, enzymes, expectorants, hormones, hypnotics, minerals, nutritional supplements, parasympathomimetic agents, potassium supplements. Fillers, sedatives, sulfa drugs, stimulants, sympathomimetic agents, tranquilizers, urinary antisensitivity 15. The composition of claim 14, wherein the composition is a positively charged pharmaceutically active ingredient selected from the group consisting of dyes, vasoconstrictors, vasodilators, vitamins, and xanthine inducers. 19. the environment is the gastrointestinal tract of an animal or human, said counterion is an inert negatively charged moiety selected from the group consisting of Ce, Br, F-, 1, and CH3OSO3, and said solute ion is said 13. The composition of claim 12, wherein the composition is a negatively charged moiety of a bile salt present in the gastrointestinal tract. 20. 20. The composition of claim 19, wherein said moiety is Ce-. 21. 12. The composition of claim 11, wherein the change in environmental conditions includes a change in environmental pH and ionic strength. 22. further comprising the hydrogel and an inert carrier for the counterion; The rear is styrene divinylbenzene, methacrylate-ethylene glycol dimethacrylate, vinyl-divinylbenzene stearate, 4-vinylpyridine-ethylene glycol dimethacrylate, and 4-vinylpyridine-divinylbenzene. 12. The composition of claim 11, wherein the composition is comprised of microporous copolymer beads selected from the group consisting of: 23. Preparation of an ion exchange composition comprising performing the following steps in a predetermined order: Construction method. (a) A counter ion having a first charge is transferred to an ion having a charge opposite to that of the counter ion. (b) a water-soluble polyvalent ethylenically unsaturated crosslinking monomer and water are mixed together to form a first solution; (b) the crosslinking monomer completely dissolves in the water; (c) mixing the first and cough second solutions together with an initiator to form a discontinuous phase and forming a discontinuous phase; The reaction phase is mixed with an organic continuous phase containing a suspending agent and an inert, non-polar organic solvent. forming a reaction mixture, and stirring the reaction mixture for a time and at a temperature sufficient to form droplets of aqueous phase, and the monomers within the droplets to polymerize and become ionically incorporated therein. Forming porous, ionic polymer hydrogel beads with counterions. 24. the hydrogel is cationic and is selected from the group consisting of compounds of the formula: and the water-soluble polyethylenically unsaturated crosslinking monomer is derived from an ionic monoethylenically unsaturated monomer containing N,N'-methylenebisacrylamide, N,N'-nonamethylenebisacrylamide, and an alkoxylate. 24. The method of claim 23, wherein the method is selected from the group consisting of water-soluble polyfunctional arylates. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R1, R2, R3, and R4 are saturated alkyl groups having 1 to 6 carbon atoms, which may be the same or different, and n = 1 to 4, X is selected from the group consisting of Ce, F, Br, and 1)25. The hydrogel is anionic and contains an acid selected from the group consisting of CH2=C(R)-COOH, where R is a saturated alkyl group having 1 to 4 carbon atoms. is derived from an ionic monoethylenically unsaturated monomer selected from the group consisting of lylic acid and alkyl acrylic acid, and the water-soluble polyethylenically unsaturated crosslinking monomer is N,N'-methylenebisacrylamide, N, N'-nonamethylene bi sacrylamide, and an alkoxylated water-soluble polyfunctional arylate. 24. The method of claim 23, wherein the method is selected from the group consisting of: 26. the hydrogel is anionic and is selected from the group consisting of compounds of the formula: and the water-soluble polyethylenically unsaturated crosslinking monomer is derived from anionic monoethylenically unsaturated monomers such as N,N'-methylenebisacrylamide, N,N'-nonamethylenebisacrylamide, and alkoxylates. 24. The method of claim 23, wherein the method is selected from the group consisting of water-soluble polyfunctional arylates. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R1, R2, R3, R4, and R5 may be the same or different and are selected from the group consisting of H and a saturated alkyl group having 1 to 4 carbon atoms. , Y is Na and and K. )27. The weight percent of water used during polymerization was determined beforehand for water-equilibrated hydrogels. 24. The method of claim 23, having the percentage of total monomer weight adjusted to provide an equilibrium water content. 28. The weight percent of water used during the polymerization is about 20 to about 80 weight percent of the total weight of monomers used during the polymerization, and the water has an equilibrium water percentage at equilibrium. water in an amount of about 20 to about 80 percent by weight of the hydrogel plus water. 24. The method of claim 23, wherein the method provides: 29. 24. The method of claim 23, wherein increasing the weight percent of crosslinking monomer relative to the percent of total monomer increases the degree of swelling of the resulting ionic hydrogel. 30. 30. The method of claim 29, wherein the weight percent of crosslinking monomer used is about 10% to about 80% by weight of total monomer and the degree of swelling is about 1.0 to 2.0. 31. Controlled ionization of counterions and solute ions in a predetermined aqueous environment a porous water-insoluble ionic copolymer hydrogel having an internal network of pores with counterions ionically retained within the internal network of pores. administering copolymer particles to the environment, wherein the ionic hydrogel is linearly proportional to the weight percent of crosslinking monomer in the polymer, in which the crosslinking monomer is soluble in an aqueous solution in any proportion. 32. 32. The method of claim 31, wherein the aqueous environment is an animal or human body. 33. 32. The method of claim 31, wherein the counterion is a pharmaceutically active substance. 34. 32. The method of claim 31, wherein the particles have an average diameter of about 1 to about 200 microns, a pore volume of about 0.01 to about 4.0 cc/g, and an average pore surface area of about 1 to about 200 m2. 35. 32. The method of claim 31, wherein the particles have an average diameter of about 1 to about 50 microns, a total pore volume of about 0.1 to about 1.0 cc/g, and an average pore surface area of about 1 to about 20 m2. 36. the ionic hydrogel has a charge density sufficient to create a binding affinity for a counterion having an opposite charge to the hydrogel, according to the weight distribution coefficient method; 32. The method of claim 31, wherein the method has a charge density of at least about 1.0 x 106 ml/g as measured by chromatography. 37. The ionic hydrogel contains at least about 45% by weight of the total weight of the hydrogel and counterions for free counterions having an opposite charge to the hydrogel. 32. The method of claim 31, having sufficient porosity and charge density to provide a volume. 38. 32. The method of claim 31, wherein the charge density is about 1 to about 10 meq/g hydrogel.