JP2516322B2 - Ionic beads useful for controlled release and adsorption - Google Patents

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates generally to topical and oral compositions. More particularly, the present invention is directed to substantivites on keratinous materials such as hair and skin.
It relates to formulations of ionic polymer delivery systems which prolong the activity of various topical active ingredients by improving y) and oral delivery polymers which release the active substance via ion exchange.

The adhesive properties of substances applied topically to the hair and skin affect initial adsorption and persistence, especially when exposed to water after application. The combined characteristic of adsorption and persistence constitutes a property called "substantivity" which is defined as the ability of a substance to be adsorbed onto keratin and to resist rinsing with water.

An ideal topical substance has an adsorptive affinity for keratinous substances, retains activity for a long time, resists sweating and wash-off by contact with other water, and is the reverse of other components whose uptake is desired. It does not interact with.
No topical substance has yet been found that adequately meets all of these goals.

The most popular topical active preparations available on the market today are, for example, fragrances; cosmetics such as lipsticks, make-ups and foundation powders;
Insect repellents; antibacterial agents; acne treatment compounds; hair treatment compounds such as conditioners and hair growth promoters;
And skin protection formulations such as anti-aging agents; and UV absorbers (sunscreens). These ingredients, substances or formulations may be used alone or in combination with one another and may be applied in pure form or diluted with suitable solvents or carriers.

A frequent problem with such topical actives is their rapid loss of activity after application to the skin. Under normal conditions of heavy sweating and / or contact with water, the concentration of the above substances in the respective topical composition either dilutes to reduce its effect or is washed off to lose its total effect. Is one of. One way to extend activity is to increase the concentration of active ingredient in their respective formulations. However, as the concentration increases, the risk of toxicity and allergic reaction to the user increases. These reactions often occur at higher concentrations, even when exposed to the product for a relatively short period of time.

A second drawback unrelated to the safety of administration of such compositions is the increased cost of using such compositions which are easily washed off. For example, in order to maintain a suitable level of protection from the sun, sunbathing persons will have to wear sunscreen again after entering the water and frequently after sweating.

Therefore, in order to reduce the possibility of toxic and / or allergic reaction to the user, at the same time to increase the adsorption affinity of the topically active composition for keratinous substances, and to prolong the activity of such composition. Providing an approach is highly desirable.

Compositions and methods of releasing an active substance, such as a drug, from a recipient over time are known, and there are numerous specific approaches to achieve such controlled release. Two widely practiced approaches are of particular interest to the present invention. In the first of these approaches, the drug or other active substance is encapsulated or coated with a substance that dissolves or decomposes in response to changing environmental conditions. For example, a pH-responsive coating (referred to as an enteric coating) can be applied to a drug to protect it in the low pH environment of the stomach but to dissolve it as it passes through the intestine and the pH increases. Such coatings include cellulose acetate, polyvinyl phthalate phthalate, hydroxypropyl cellulose phthalate, methyl cellulose phthalate and the like. While these coatings are very effective in protecting the drug in the stomach, they generally do not control the release rate of the drug once it reaches the intestine.

A less widely used delivery approach is one that utilizes porous polymer particles to adsorb and release controlled doses of drugs and other active agents at a controlled rate. For example, U.S. Pat.
See 692,462. In such systems, the rate of diffusion of the drug or other active agent through the pores determines the rate of release. Of course, the diffusion rate depends on the pore size, chemical viscosity, temperature and the like. In the case of drug delivery, the drug absorbed within the porous polymer particles is usually incorporated into an adhesive or other matrix material as part of a transdermal drug delivery system. In another example, the drug adsorbed onto the porous resin beads is then coated with a membrane diffusion barrier layer, such as ethyl cellulose, to produce sustained release. See European Patent Application No. 171528, discussed below.

A difficulty with these systems is that a coating or blocking agent must be incorporated for each active agent to obtain the desired release rate. viscosity,
The properties of drugs and other active agents, including charge characteristics, molecular weight, etc., vary widely, and the release rate of any delivery system varies widely depending on the nature of the agent being delivered. This problem is especially apparent when employing a porous particle delivery system that can only change the properties of the pores within a limited range. Ion exchangers based on synthetic resins can be conveniently prepared by post-polymerization modification of preformed crosslinked beads. For example, the anion exchange resin is
Made from crosslinked polystyrene by halogen-alkylation followed by amination. Cation exchange resins can be made by carboxylating or sulfonylating preformed crosslinked beads. Such ion exchange resins are typically poorly colored, have an ion exchange capacity of less than 2 meq / g, and can require lengthy steps for regeneration. Naturally occurring ion exchangers, such as cellulose-based gels or dextran gels, made by introducing functional groups onto cross-linked natural polymers, shrink or collapse the gel matrix when the active agent is removed. It has only a gel structure that is not mechanically strong enough to prevent Materials based on natural polymers are unstable in the presence of oxidants or strong acids at high temperatures (eg, 120 ° C. for 30 minutes), and because of their biological origin, they are of bacterial and microbial growth. To help.

Thus, it would be desirable to provide improved compositions and methods for the delivery of drugs and other active agents. It would be particularly desirable if the composition could be readily modified to obtain the desired release rate for active agents with a wide range of physical and chemical properties. It would be further desirable to be able to modify a composition to control the release rate of such various active agents under a variety of different external conditions such as pH, temperature, ionic strength, and the like. It would also be desirable if the composition could be readily modified to predictably absorb bile salts in a controlled manner.

2. Description of the Background Art US Pat. No. 4,690,825 discloses an uncharged polymeric bead delivery system suitable for topical application. U.S. Pat.No. 4,30
No. 4,563 discloses cationic polymers (and methods of making them) useful as gels for the treatment of keratin materials such as hair. European Patent Application No. 225615 discloses the use of cationic beads formed from polystyrene sulfonate-divinylbenzene copolymers for controlled oral delivery of negatively charged drugs. South African Patent Application No. 872554 and U.S. Patent No. 4,221,778 disclose sulfonate cation ion exchange resin particles impregnated with certain substances to enhance their stability for oral drug delivery. U.S. Patent No. 3,
691,270 discloses a dermatological cosmetic composition comprising microcapsules formed from a vesicular polymer containing polyvinyl pyridine. However, the microcapsules are uncharged. US Pat. No. 3,880,990 discloses orally administrable compositions containing a drug encapsulated within an anionic polymer. U.S. Pat.No. 4,198,39
No. 5 discloses charged polymeric resin materials useful for treating hypercholesterolemia by oral administration. US Pat. No. 4,552,812 discloses fluorescent and magnetic anionic beads useful for performing assays. European Patent Application No. 060138 discloses the preparation of porous copolymer blocks that can absorb and act as a receptor for liquids such as perfumes. European Patent Application No. 143608 discloses polymeric bead compositions having releasable lipophilic compounds retained therein. British Patent No. 1,48
No. 2,663 describes polymeric bead compositions capable of retaining water soluble drugs. Cationic polymer ion exchange resins containing styrene-divinylbenzene copolymers are sold by suppliers such as Interaction Chemicals, Inc., Mountain View 94043, CA and Rayleigh Tar & Chemicals, Inc., 46204 Indianapolis, IN. There is. The ability of cationic substances to adsorb to the skin and hair has been reported by Goddard (1987) Cosmetics & Toiletries 102: 71.
-80.

SUMMARY OF THE INVENTION The present invention provides methods of incorporating active and inactive agents within ionic polymer bead delivery systems to form novel compositions. It has been found that imparting cationic functionality to the surface of polymeric beads enhances the substantiveness of the topical active agent when the beads are applied to the skin or hair. The cationic topical polymeric bead delivery system according to the present invention is a keratophilic composition that exhibits an affinity for skin, hair, and other biomolecules,
When delivered orally, it can be used to adsorb bile salts. Anionic delivery systems can deliver basic drugs orally. Anionic polymer bead delivery systems rely on ionic functionalities on the bead surface, ie, normally positively charged pyridine and quaternary ammonium groups in cationic beads, and negatively charged sulfonates and carboxyls in anionic beads. Includes cross-linked polymer beads characterized by a rate. The beads form a porous network that can hold large amounts of inert and active substances. The beads are non-disintegrating, small in diameter, have relatively large pores and a relatively high ratio of pore volume to bead volume.

The cationic polymeric bead delivery system with the topical active ingredient incorporated therein may be used by itself as a topical product or incorporated into a carrier composition or other cosmetic product. When used alone, the cationic polymer delivery system with entrapped topical active ingredient is a dry, free-flowing product that can be rubbed directly onto the skin, resulting in prolonged topical active ingredient release. Provides controlled release. In the normal situation where the cationic polymer delivery system is incorporated into other carriers, vehicles, solvents, or cosmetic formulations, the active ingredient and other ingredients in the topical formulation are used when using the delivery system. Avoid incompatibilities, typically chemical or physical interactions, that may exist between, or between the inert material and the carrier, vehicle, or solvent.

Various physiologically acceptable solvents or media can be used as carriers. However, in order to preserve the cationic functionality on the surface of the pyridine-based polymer beads in the topical formulation, the carrier should be at least slightly acidic, preferably less than about 5, most preferably about 3-4. is there. For carboxylate-based beads, the carrier should have a pH above about 5. It will often be desirable to include a physiologically acceptable buffer in the carrier to maintain the pH within the desired range.

The ionic polymer bead delivery system can be formed by suspension or inverse suspension polymerization of suitable monomers, at least some of which are (for suspension polymerization of non-aqueous monomers). Porogen
In the immiscible phase (comprising n), it either carries a positive charge or a negative charge, or a functionality that can hold either a positive charge or a negative charge under the conditions of use. Generally, the monomers (and porogen, if used) are first suspended together and then the resulting mixture is suspended in the immiscible phase. The immiscible phase is then agitated to form droplets of the monomer mixture and the polymerization of the monomer mixture is initiated to form the desired beads.

Cation number (ie, cationic functionality) is the surface in beads formed or using a preformed cationic monomer, such as a quaternary amine monomer (which retains a substantially permanent charge under the conditions of use). It can be obtained by protonating (or quaternizing) the functionality, for example by protonating the quaternary nitrogen in pyridine with an acid medium. Such protonation may be carried out before or after the uptake of the ingredient, depending on the conditions and the chemistry of the individual active ingredient to be incorporated.

Anion valency (ie, anionic functionality) is, for example,
It can be obtained by suspending sulfonated styrenic beads in a basic solution.

The material may be used as a porogen in a one-step process, provided that there is no substantial degradation of the topically active material under the conditions of polymerization and the material is otherwise suitable. In the more usual case, for more labile components, especially those that are heat or radiation labile, a two-step process can be used to form the compositions of the invention. In this method, substituted porogens, such as alkanes, cycloalkanes, or aromatic solvents may be used to preform the polymer beads. The beads are formed by suspension or inverse suspension polymerization and the porogen is extracted from the resulting bead product. The active substance of interest is then introduced into the beads, typically by catalytic absorption, to produce the desired product. As already mentioned, the polymer beads may be cationic or anionic either before or after incorporating the active substance into the delivery system, or by using charged monomers. In addition to allowing the incorporation of labile substances, such a two-step manufacturing method allows greater control of the bead structure based on the wide selection of porogen materials in the reaction conditions, thus making it less labile. It can be said that it is a desirable manufacturing method even for substances that are not

In addition to enhanced substanceity, the active agent incorporated within the topically applied cationic polymeric bead delivery system of the present invention is enhanced when compared to similar concentrations of components in the non-cationic polymeric bead delivery system. It was found to provide the desired effect. For example, a sunscreen formulation incorporated into a system containing cationic polymer beads has an increased SRF (sun protection factor (Sun protection factor) when comparing non-cationic polymer beads to another identical formulation containing a delivery system. Protection Factor)).

Orally deliverable polymer particles according to the present invention are composed of ionic monoethylenically unsaturated monomers and highly water-soluble polyethylenically unsaturated crosslinking monomers, each of which forms an internal pore network. Comprising hydrophilic polymer hydrogel particles. An oppositely charged counterion is included to render the hydrogel neutral. The hydrogel has a swelling degree r _SW determined as a ratio of swollen particle size (water) to unswollen particle size (dioxane),
It is unique in that it has the surprising result of not being linearly proportional to the amount of crosslinking monomer used during the polymerization of the particles. Furthermore, the equilibrium water fraction (EWF) of the particles with respect to equilibrium with water is linearly proportional to the amount of water used during the polymerization. These properties allow the ionic hydrogel to function as a sustained release ion exchanger whose diffusion pathway can be tailored to suit the particular environment and drug delivered. They also allow "blank" hydrogels to adsorb bile acids.

The oral composition according to the present invention comprises an ionic hydrogel and a counterion. In that case, the counterion is either inert or pharmaceutically active, such as a drug, and is held ionicly bound within the internal pore network. The counterions are exchanged with solute ions in a predetermined aqueous environment such as the digestive tract of animals or humans. In certain embodiments, the counterion is a weakly basic, positively charged drug that is delivered to the gastrointestinal tract based on changes in pH and / or ionic strength of the gastrointestinal tract.

According to the method of making hydrogel particles of the present invention, ionic hydrogels are formed by inverse suspension radical polymerization of suitable ionic monomers cross-linked with monomers soluble in aqueous solution in all proportions. Generally, the ionic monomer is mixed with its counterion and the resulting mixture is mixed with a water soluble crosslinking monomer to form the aqueous phase. An initiator is added to the aqueous phase and the resulting mixture is suspended in the organic phase.
The organic phase is then agitated to form droplets of the aqueous monomer phase and the polymerization of the monomers is initiated to form the desired beads from the droplets. The exact size and properties of the beads are controlled by varying the process parameters such as the amount of water used during the polymerization, the stirring rate, and by varying the amount and type of monomer selected. Once the ionic hydrogel beads are formed, the beads may be used as such (if an inert or stable active ingredient is used as the counterion) by repeated exposure to the drug in the chromatographic column or A suitable labile active counterion may be loaded by contacting the hydrogel beads with the drug solution for an extended period of time.

BRIEF DESCRIPTION OF THE FIGURES FIG. 1 shows the effect of the crosslink density of poly (trimethylammoniumethylmethacrylate chloride-co-N, N'-methylenebisacrylamide) hydrogels on their degree of water swelling. ●,% (v / v) swelling degree in 83% water;
◆,% swelling in 70% water; ▲, EWF (equilibrium water ratio) in 83% water.

FIG. 2 shows D & C Red No. 2 from various beads including cationic hydrogel (■); cationic hydrogel in anionic surfactant (▲); and uncharged beads (●).
8 shows the release profile of 8.

Figure 3 shows how the equilibrium water content of a hydrogel increases linearly with water during polymerization and is essentially crosslink density dependent.

FIG. 4 shows that D & C Red No. 28 (anionic dye) was not released from the cationic hydrogel loaded microporous carrier until the presence of the anionic surfactant (sodium dodecyl sulfate).

FIG. 5 shows the release profile of tetracycline.HCl from anionic hydrogel upon addition of cationic surfactant.

FIG. 6 shows the swelling behavior of hydrogels as a function of pH.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS The beads or microspheres used in connection with the present specification may be rigid or non-rigid, and have a positive or negative charge imparted on the surface and capillary force. Or, it is an open-pore chemically and biologically inert particle having an impregnating substance retained inside the pores by ionic forces. In this case, the impregnating substance is a topical or orally active substance or an inert counterion. In topical compositions, the charge (positive) is sufficient to promote attachment of the particles to keratinous materials such as human skin and capillaries. Since the pores are interconnected and open to the surface of the particle, there is substantially complete communication between the internal pore space and the exterior of the particle, thereby allowing the beads to contact the skin or hair of the user or the oral delivery agent. In the case of, the impregnating substance can be released over time after application to the gastrointestinal tract.

When using cationic beads, the cation value of the polymeric beads of the present invention results from the presence of a protonatable functionality on at least some of the polymerized monomers. For oral delivery systems, the beads will have a charge density sufficient to produce a binding affinity for the counterion of at least about 1.0 × 10 ⁶ ml / g as measured by the weight distribution coefficient method. (Lange's Handbook of Chemistry, No. 13
Eds., Pp. 5-119-5-122. 3.) The ionic hydrogel will also have sufficient porosity and charge density to provide a counterion capacity of at least 45% by weight of the total hydrogel. Cationic functionalities of particular interest to the present invention include both pyridine with a tertiary nitrogen and ammonium with a quaternary nitrogen, each of which can carry a positive charge under the conditions of using the topical composition. Anionic functionalities of particular interest include sulfonates and carboxylates. The beads according to the invention are about 0.1-10 milligram equivalents of hydrogen ions in water /
g (meq / g) volume (measured by conventional acid-base titration), usually about 0.2-10 meq / g, more usually 0.5-10 meq / g, preferably 5.0-10 meq / g (also conventional acid- (Measured by base titration).

In their most convenient form, the shape of the particles is generally spherical because of using suspension or inverse suspension polymerization as the preferred manufacturing method. Such microspheres vary widely in size, but those with diameters in the range of about 5 to about 100 microns, preferably about 10 to about 40 microns will provide the best results. Microspheres within these size ranges
It gives a smooth feel when applied topically, which is attractive from an aesthetic point of view and is easily excreted in the case of oral delivery.

The pore size of the spheres may also vary widely, with the optimum size depending on the chemistry of the polymer used as well as the diffusivity of the impregnating material. Thus, different systems will require different optimal ranges of pore volume distribution to obtain the most desirable properties for the overall formulation. However, in general,
Total pore volume of about 0.01 to about 4.0 cc / g, preferably about 0.1 to about 2.00 cc / g, about 1 to about 500 m ² / g, preferably about 20 to about 200 m ^2.
Best results are obtained with a surface area of / g and an average pore diameter of from about 0.001 to about 3.0 microns, preferably from about 0.003 to about 1.0 micron. According to the conventional method of measuring and expressing pore size, the pore diameter is measured by BET nitrogen analysis (Brunae
r) et al., (1938) J. Am. Chem. Soc. 60: 309-316) and the mercury intrusion method.
calculated from the measured pore volume by the ion method).

The particles are conveniently formed as microspheres by suspension polymerization in a liquid-liquid system. Generally, a solution containing the desired monomer, polymerization initiator (if used), and inert fluid (porogen) is formed as the first liquid phase. in this case,
The porogen is miscible with the first liquid phase but immiscible with the second liquid phase. The solution is then suspended in a second liquid phase that is immiscible with the first liquid phase. Oil-soluble monomer,
For example, in the case of vinyl pyridine and its derivatives, the first liquid phase will usually be an organic solvent which is immiscible with water but immiscible with water and the second liquid phase will be water. In the case of water-soluble monomers, such as quaternary acrylate and methacrylate derivatives, the first liquid phase will be aqueous (with water as porogen) while the second phase will be a hydrophobic organic solvent.

Polymerization is initiated when a suspension of discrete droplets of the desired size is obtained (typically by activating the reactants by elevated temperature or irradiation). After the polymerization is complete, the beads produced are recovered from the suspension. The beads are, at this point, a polymer of substantially porous structure that is formed around the fluid inside, thereby forming a network of pores. Thus, the fluid serves as a porogen or pore former and occupies the pores of the beads produced. Suitable porogen fluids are described in more detail below. If the organic phase serves as a porogen, the process will be known as suspension polymerization. If water serves as the porogen (in the case of water-soluble monomers), the process will be known as inverse suspension polymerization.

Certain impregnating substances can serve as porogens,
As mentioned above, it may be incorporated into the porous network of the present invention before or after the above charge generation step. An important factor in choosing an impregnating material for topical application is its charge. That is, the impregnating material must be substantially neutral in order to preserve the ionic functionality of the beads when applied to the skin or hair. Slightly negative or positive materials can also be used, but their uptake should not neutralize or affect the surface charge of the beads.

If the impregnating material is selected to serve as a porogen, the porous beads recovered from the suspension immediately after polymerization will be substantially free of surface moisture after any further processing steps including ionization. Can be used immediately. In these cases, microsphere formation and uptake of the impregnating material is done in one step. Therefore, this can be referred to as the one-step method. Impregnating substances that can serve as porogens are liquid impregnating substances that meet the following criteria.

1) They are either completely miscible with the monomer mixture or can be made sufficiently miscible by the addition of a small amount of solvent immiscible with the second liquid phase; 2) they Are immiscible with the second liquid phase (or at best only slightly soluble); 3) they are inert with respect to the monomers, and when contacted with any polymerization catalyst used and the polymerization. They are stable when subjected to some conditions (such as temperature and radiation) necessary to cause the formation of 4; they are normally liquids or have melting points below the polymerization temperature. Solids are often converted to liquids by dissolving in solvents or by forming eutectic mixtures; and 5) they are neutral (or at most slightly negative or positive with respect to their charge). There is only).

When using this method, the process must be carried out under an inert atmosphere such as a stream of nitrogen. With a polymerization catalyst, if the impregnating material is susceptible to oxidation, it should not oxidize the impregnating material. An example of such a catalyst is an azo catalyst. Further, the polymerization temperature is maintained within a mild range.

As an alternative to the one-step method, a substantially neutral impregnating material may be placed inside the pores of the preformed dry porous polymer beads. Thus, the product is manufactured in two successive steps. In this case, the polymerization is first carried out with a substituted porogen, which is then removed and replaced with the active ingredient of interest. Therefore, the porogen and the active ingredient are completely different ingredients in this two-step method. Suitable materials for the substituted porogen would be materials that meet the five criteria listed above for porogen impregnated materials.

Preferred among the substances suitable as substituted porogens when using hydrophobic monomers are hydrocarbons, especially inert, non-polar organic solvents. Some of the most convenient examples are alkanes, cycloalkanes, and aromatic hydrocarbons. Examples of such solvents are straight or branched chain alkanes of 5 to 12 carbon atoms, cycloalkanes of 5 to 8 carbon atoms, benzene, and alkyl-substituted benzenes such as toluene and xylene. Other types of porogen include C _{4 to} C ₂₀
Includes alcohols, perfluoropolyethers, and oils. Removal of porogen can be accomplished by solvent extraction, evaporation, or similar conventional procedure. As noted above, water serves as the porogen in the case of water soluble monomers.

Further advantages of using this two-step method are:
It is possible to remove unnecessary species formed in the polymerized structure before the impregnation substance is taken in. Examples of unwanted species include unreacted monomer, residual catalyst, and surfactants and / or detergents remaining on the sphere surface. A further advantage of this method is that the amount and type of porogen can be selected as a means of controlling the porosity properties of the finished beads. Thus,
It is no longer constrained by the limitations of the impregnating material that occur because it affects the structure of the beads themselves. This allows the pores to be partially filled rather than completely filled with pores, and the choice between swelling and non-swelling porogens allows further control of pore size and distribution.

Extraction of the porogen and replacement with impregnating material in a two-step process (eg impregnation of dry beads with impregnating material)
It can be done in different ways, depending on the chemistry of the porogen and the behavior of the porogen in combination with the behavior of other species present. First, the beads are recovered from the suspension by filtration, preferably using a vacuum filtration device (such as a Buchner funnel). The beads are then washed with a suitable solvent,
The aqueous phase removes non-polymer bound organic species, including surfactants, unreacted monomer and residual catalyst deposited on the bead surface, and the porogen itself. An example of such a solvent is isopropanol, alone or in aqueous solution. After washing, the solvent itself is removed by drying, preferably by vacuum drying.

In certain cases, i.e. when the porogen, unreacted monomer and water form an azeotrope, another extraction method may be used. In such cases, steam distillation is an effective method to extract the porogen from the beads. After all, vacuum drying may be performed subsequently.

Once the beads have been dried to remove the substituted porogens and any unwanted organics, assuming that the beads are already ionic or undergo protonation after incorporation (as described in more detail below), they are taken orally. It may be used to absorb oppositely charged species, or otherwise impregnated with the impregnating material according to conventional methods. The most convenient such method is contact absorption. The solid active substance is first dissolved in the solvent and the resulting solution is absorbed by the beads. The solvent may remain in the finished product or may be removed by conventional means such as evaporation or further extraction with solvent. For solid components that have only limited solubility in certain solvents, high content in the finished beads can be achieved by repeated absorption and removal of the solvent each time.

In the case of an oral delivery system, the impregnating substance may be, for example, a basic positively charged drug, which may be passed through chromatographic methods such as ion exchange chromatography,
It is packed within a matrix of anionic (negatively charged) beads. In that case, the positively charged counterion is exchanged with the drug molecule.

The polymerization process and various parameters and process conditions involved in the polymerization can be selected and adjusted as a means of controlling the optimum product porosity properties, and consequently the volume and release properties. For example, a suitable choice of crosslinking means, amount and type of crosslinking agent, and amount and type of porogen,
It is a means of achieving such control. Certain polymerization conditions, including temperature, degree of radiation used, degree of agitation, and any other factors that affect the polymerization reaction rate can also be varied for such effects.

Crosslinking in polymer formation is the primary means of controlling pore size. Monomers that can be polymerized to produce the crosslinked polymer beads according to the present invention include polyethylenically unsaturated monomers, ie those having at least two sites of unsaturation, and one or more polyvalent ethylenic monomers. Included are monoethylenically unsaturated monomers in combination with unsaturated monomers. In the latter case, the percentage of cross-links can be controlled by balancing the relative amounts of monoethylenically unsaturated monomer and polyethylenically unsaturated monomer. Usually such a system will contain one monoethylenically saturated monomer and one polyethylenically unsaturated monomer. However, if desired, it would be possible to add additional monomers of each type compatible with the system. For articles on the production of such copolymer systems, see Guyot and Bartlin (Barth).
olin), Desigh and Properties of Polymers as Materi
als for Fine Chemistry, Prog.Polym.Ed. (1982) Vol.
See 8 pp.303-307.

Monoethylenically unsaturated monomers that can be used as part of the monoethylenically unsaturated monomer content of the polymer delivery system include ethylene, propylene, isobutylene, diisobutylene, styrene, sodium styrene sulfonate, ethyl vinyl benzene, vinyl. Benzene chloride, vinyl pyridine and its derivatives, vinyl toluene, and dicyclopentadiene; methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, amyl, hexyl, octyl, ethylhexyl,
Of acrylic and methacrylic acid including decyl, dodecyl, cyclohexyl, isobornyl, phenyl, benzyl, alkylphenyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, ethoxyphenyl, ethoxybenzyl, and ethoxycyclohexyl. Esters; Vinyl esters including vinyl acetate, vinyl propionate, vinyl butyrate and vinyl laurate; Vinyl ketones including vinyl methyl ketone, vinyl ethyl ketone, vinyl isopropyl ketone, and methyl isopropenyl ketone; vinyl methyl ether, vinyl ethyl Vinyl ethers, including ethers, vinyl propyl ether, and vinyl isobutyl ether; silicon and other metals such as vinyl siloxanes Vinyl compounds containing contains. In addition, polyvalent ethylenically unsaturated monomers, such as isopropene, butadiene and chloroprene, which normally act as if they have only one unsaturated group, should also be used as part of the monoethylenically unsaturated monomer content. You can

Suitable polyethylenically unsaturated crosslinking monomers for producing such polymer beads include diallyl phthalate,
Ethylene glycol diacrylate, ethylene glycol dimethacrylate, trimethylolpropane trimethacrylate, divinyl sulfone; ethylene glycol, glycerol, pentaerythritol, diethylene glycol, glycol monothio and dithio derivatives,
And polyvinyl and polyallyl ethers of resorcinol; divinyl ketone, divinyl sulfide, allyl acrylate, diallyl maleate, diallyl fumarate, diallyl succinate, diallyl carbonate, diallyl malonate, diallyl oxalate, diallyl adipate, divinyl sebacate, Diallyl tartrate, diallyl silicate, triallyl tricarballylate, triallyl aconitate, triallyl citrate, triallyl phosphate, divinylnaphthalene, divinylbenzene, trivinylbenzene; 1 to 2 carbon atom alkyl substituents on the benzene nucleus Alkyldivinylbenzenes having 4; alkyltrivinylbenzenes having 1 to 3 alkyl substituents of 1 to 2 carbon atoms on the benzene nucleus; trivinylnaphthalene, polyvinylanthracene, and water-soluble alkyl groups. Examples include acrylate and methacrylate (specifically, those described below) and the like.

At least a portion of the monomer content contains protonated functionality that can retain a positive charge under the conditions of use. This protonated functionality is present in monoethylenically unsaturated monomers, polyethylene unsaturated monomers, or both, and suitable functionalities include pyridine and ammonium. Specific monomers include vinyl pyridine, for example, 2-vinyl pyridine, 4-vinyl pyridine, 3-methyl-2-vinyl pyridine, 4-methyl-2.
-Vinyl pyridine, 6-methyl-2-vinyl pyridine,
3-ethyl-2-vinylpyridine, 5-ethyl-2-vinylpyridine, 2-methyl-4-vinylpyridine, 2-
Methyl-5-vinyl pyridine and 2-ethyl-5-vinyl pyridine and water-soluble acrylates and methacrylates, such as methacrylamidopropyl hydroxyethyldimethylammonium acetate, methacrylamidopropaltrimethylammonium chloride and dimethylaminoethyl methacrylate and dimethylsulfate,
Quaternized products of diethylaminoethyl acrylate and dimethyl sulfate, vinylbenzyl chloride and divinylbenzene and vinylbenzyl and ethylene glycol dimethacrylate. With quaternized ^{monomers, C1 -, F -, Br} -, I - or CH ₃ OSO ₃ ^- counterions such as is taken into its structure.

If water-soluble acrylate and methacrylate monomers are used, it is necessary that all the monomers used be water-soluble. Suitable polyethylenically unsaturated monomers (necessary for crosslinking) include N, N'-methylenebisacrylamide; N, N'-nonamethylenebisacrylamide; and alkoxylated water-soluble polyfunctional acrylates. For water soluble quaternized monomers, the inverse suspension polymerization protocol described above is used. Microspheres made from water-soluble quaternized monomers are usually non-rigid hydrogels and contain polar (water and alcohol) soluble materials such as
Effective for adsorbing hydroquinone, methyl salicylate, insect repellents (in alcohol), UV protection substances (in alcohol), etc., while negatively charged hydrogels adsorb basic drugs such as alkaloids and steroids. It is effective for

Preferred polymer beads of the present invention do not contain reactive groups that react or interact with the porogen and / or active ingredient that are eventually incorporated into the composition other than ionic interactions as found in ion exchange methods. Such beads do not easily undergo undesired reactions, are stable over the expected use pH range, are resistant to common redox,
It must be stable and have a relatively long shelf life within the expected range of use.

A preferred topical cationic polymer delivery system of the present invention is
Contains substantially uncrushed beads, 4-vinylpyridine and ethylene glycol dimethacrylate, 4-
It is formed by the copolymerization of vinylpyridine and divinylbenzene, 2-vinylpyridine and divinylbenzene, 2-vinylpyridine and ethylene glycol dimethacrylate, and ethylmethylvinylpyridine and ethylene glycol dimethacrylate. Among these systems, 4-vinylpyridine and divinylbenzene are particularly preferable, and a copolymer of 4-vinylpyridine and ethylene glycol dimethacrylate is further preferable.

The ionic hydrogel polymeric material of the present invention comprises a copolymerization product of an ionic monoethylenically unsaturated monomer and a polyethylene-based unsaturated crosslinking monomer that is soluble in all proportions in aqueous solution.

Preferred cationic polymers for oral delivery systems have the formula: (In the formula, R ¹ , R ² , R ³ and R ⁴ are the same or different and are 1 to 6
A saturated alkyl group having 4 carbon atoms, n = 1-
4, X is selected from the group consisting of Cl, F, Br, I and CH ₃ OSO ₃ . ) Produced from a monoethylenically unsaturated quaternary ammonium cation monomer selected from the group consisting of N, N'-methylenebisacrylamide and N, N'-nonamethylenebisacrylic, It is selected from the group consisting of amides and water-soluble polyfunctional acrylates that are alkoxylated. A particularly preferred cationic polymer is a copolymerization product of trimethylammoniumethylmethacrylate chloride and N, N'-methylenebisacrylamide (poly (PTMAEMCl-co-MB
A)).

Preferred anionic polymers for oral delivery systems have the formula: (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same or different, and
-4 selected from the group consisting of H-saturated alkyl having 4 carbon atoms and Y selected from the group consisting of Na and K. )
Which is produced from a copolymerization product of monoethylenically unsaturated anionic monomers selected from the group consisting of N, N'-methylenebisacrylamide and N, N'-nonamethylenebisacrylamide. And an alkoxylated water-soluble polyfunctional acrylate. Particularly preferred anionic hydrogel beads are the copolymerization products of methacrylic acid and N, N'-methylenebisacrylamide ((poly) MA-co-MB).
A) and a copolymerization product of sodium styrenesulfonate and N, N′-methylenebisacrylamide (poly (SSS-co
-MBA)).

The polymer beads of the present invention are greater than 10% crosslinked, preferably about 10 to about 80% crosslinked, and most preferably about 20 to about 60.
% Of crosslinks. Crosslinking% is defined by those skilled in the art as the weight of polyethylene unsaturated monomers divided by the total amount of monomers including both polyethylene unsaturated monomers and monoethylenically unsaturated monomers. Usually, the monoethylenically unsaturated monomer is about 20 to about
It is present at 80%, preferably 40%, the polyethylenically unsaturated monomer being the balance of the mixture.

In the case of a topically applied neutral impregnating agent, protonation of the polymer beads is performed before or after the desired impregnating agent is entangled within the porous network. The method of obtaining the cationic beads of the present invention is, for example, to protonate the beads thus recovered from the suspension in an acidic medium. In particular, in order to obtain a positive charge on the surface of the beads of the present invention, after the beads are recovered from the polymerization step, acid washing such as 3% aqueous solution of hydrochloric acid is carried out. , Preferably with a secondary hydrochloride solution having a pH of 3.

The beads of the present invention are also protonated with a pH 3 buffered wash containing 0.1N potassium hydrogen phthalate, 0.1N HCl and deionized water. The use of this buffered wash does not require the removal of excess acid and the beads thus treated are directly filtered and dried.

Once the microspheres are formed and dried, the impregnant is impregnated by catalytic adsorption (this step is carried out before or after protonation unless ion exchange is the method of introducing the active ingredient). In some cases, the impregnant is used as a solution in a suitable organic solvent to reduce viscosity and promote adsorption, reduce efficacy, and the like. Specific examples of such a solvent include liquid paraffin, ether, petroleum ether,
Alcohols such as methanol, ethanol and higher alcohols, aromatics such as benzene and toluene, alkanes such as pentane, hexane and heptane, ketones such as acetone and methyl ethyl ketone, chloroform, carbon tetrachloride, methylene chloride and ethylene dichloride. Such as chlorinated hydrocarbons, acetates such as ethyl acetate and fats and oils such as isopropyl myristate, diisopropyl adipate and mineral oil. After adsorbing this solution, the solvent can be evaporated or kept with the impregnant inside the pores. Other formulation materials typically used in topical formulations may be mixed, for example carriers or auxiliaries such as fragrances, preservatives, antioxidants, other softeners may be present, impregnation Incorporated into and out of the beads with the agent and other materials present.

The substances incorporated into the ionic polymer bead delivery system of the present invention can be used individually or mixed to achieve the desired effect. The impregnating agent, either the pure active substance, the mixture of active substances or the solution of active substances, usually comprises from about 5 to about 65% of the total amount of the impregnated beads. If the active substance is particularly strong, it is usually a dilute solution and the weight% of active ingredient itself can be as low as 0.01% relative to the total amount of impregnated beads.

Suitable active impregnating agents for topical use include various active substances intended for topical application, including cosmetic, therapeutic and other uses. Examples of the specific substance include an ultraviolet absorbing substance (ultraviolet protective substance), a steroid agent, an insect repellent, retinoic acid, an aromatic, minoxidil, a softening agent and the like. Specific methods of incorporating such materials into polymeric bead delivery systems are taught in co-pending applications 091,647 and 112,971, the disclosures of which are incorporated herein by reference.

When the topical composition is prepared by the one-step or two-step method above,
If used alone or additionally unable to neutralize the surface charge on the surface of the carrier or excipient or beads, at least a slightly acidic pH, preferably about pH 6 or less, more preferably about pH 3-4. It is mixed with most types of products that it has. The composition is used alone by simply applying the dry composition to the skin.

The impregnated beads useful for topical application of the present invention are liquid or solid compositions or formulations of the type commonly used in skin treatment such as gels, creams, lotions, ointments, sprays, powders, oils, sticks and the like. Is also mixed. Suitable excipients for a particular application or method will be readily apparent to those skilled in the art. For example, the composition of the present invention, especially
The UV absorbing composition is mixed with other products to impart cosmetic and UV protection properties. The UV absorbing composition of the present invention comprises
Ideally, it should be suitable for mixing with makeup foundations, tanning products, etc., where the end products are highly absorbent and water repellent.

In the topical compositions and formulations of the present invention used by application to keratin materials, especially human skin and hair, the cationic surface charge of the individual polymer particles promotes adhesion of the composition to skin and hair, Increases the persistence of the active substance being applied.

The ionic hydrogel composition of the present invention has therapeutic, hygiene,
It is used for delivery to humans or other animals for the purpose of painkillers, cosmetics, etc. For such purposes, the compositions are delivered orally, intravascularly, intraocularly, intraperitoneally and similar in vivo uses.

The main in vivo use of the hydrogel compositions of the present invention is for the delivery of drugs and other pharmaceutical agents in human and veterinary applications. Specific agents delivered by the system of the present invention include analgesics, anesthetics, antiparasitics, antibacterial agents, antipyretics, antiseptics, antituberculous agents, antitussives, antiviral agents, cardioactive agents, laxatives, chemotherapy. Agents, corticoids (steroids), antidepressants, diagnostic aids, diuretics, enzymes, expectorants,
Hormones, hypnotics, minerals, nutritional supplements, parasympathomimetic stimulants, potassium supplements, sedatives, sulfa drugs, stimulants, sympathomimetics, tranquilizers, urinary antiinfectives, vasoconstrictors, blood vessels Examples include dilators, vitamins, and xanthine inducers.

The anionic hydrogels of the present invention are particularly effective for oral delivery of cationic drugs to be released in the intestine rather than the stomach. Examples of such drugs include antibiotics, vitamins, non-steroidal anti-inflammatory substances and the like. The negative surface charge causes the drug to ionically bind to the hydrogel during storage and during passage of the composition through the stomach. However, when exposed to the high pH environment of the intestine, it exchanges with positively charged ions such as sodium and potassium in the intestine during the typical ion exchange process. The drug is then released from the network within the pores of the hydrogel particles.

In the case of anionic drugs, cationic hydrogels are used for oral delivery. In that case, the bile salts present in the intestine exchange with the positive surface charge of the beads to release the drug.

For oral drug delivery, drug-loaded polymer hydrogel particles are commercially available, for example, from Remington's Pharmaceutical Sci.
ences, Mack Publishing Co., Easton, Pennsylvania, 16th
It is incorporated into a variety of known dosage forms as described in Ed., 1982, the disclosure of which is incorporated herein by reference.
The composition or formulation to be administered comprises a preselected amount of drug contained within the ionic hydrogel particles. Generally, pharmaceutically acceptable non-toxic dosage forms include the pharmaceutical agents mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose,
It is prepared using conventional excipients such as glucose, sucrose, magnesium carbonate and the like. Such a composition is a solution,
It may be a suspension, tablet, pill, capsule, powder or the like.

For parenteral administration, including both intravascular and intramuscular administration, the ionic hydrogel polymer particles of the invention are usually suspended in water for injection or saline carrier. Such formulations are well known in the art.

Following are examples of specific considerations and preparations and applications for various impregnating agents. These examples are provided solely for purposes of illustration and are not limiting of the invention by itself. Unless stated otherwise, parts and%
Is all weight.

Experiment A. Topical Formulation Example I This example demonstrates the preparation of 4-vinylpyridine / ethylene glycol dimethacrylate polymer beads of the present invention. The procedure is shown below: A 1000 ml four-neck reaction flask equipped with an electric stirrer, reflux condenser, thermometer and nitrogen inlet was evaluated,
Purge with nitrogen. 300 parts deionized water, 2.5 parts gum arabic and 2.5 parts trademark Marasperse N-22 (Reed Ligni
The lignosulfonate of n) was added to the reaction flask. This mixture was heated with stirring at about 50 ° C. in an oil bath until the dispersion media (gum arabic and Marasperse) dissolved and formed an aqueous phase.

To this mixture was added a solution of 40 parts 4-vinylpyridine, 60 parts ethylene glycol dimethacrylate, 0.8 parts benzoyl peroxide (70% active ingredient and 30% water) and 50 parts toluene (porogen). Adjusted speed (about 900rp
When the aqueous phase and the organic solution are stirred in m), a large number of droplets having a droplet diameter of 5 to 100 microns are obtained and the droplets are dispersed when the droplet sample is visually examined using an optical microscope. It was stabilized by the medium.

The reaction mixture is then heated at 60-65 ° C for 20 minutes,
Heating at 76 ° C. was continued for an additional 8 hours to form crosslinked 4-vinylpyridine / ethylene glycol dimethacrylate porous beads with toluene entangled within the pore network. Then, the reaction mixture was cooled to room temperature, and the porous polymer beads were taken out from the reaction flask by filtration. The filtered beads were first washed twice with 1 liter of deionized water to remove the dispersion medium and then twice with 1 liter of isopropanol to remove unreacted residual monomer and toluene. The beads were then dried in an oven at 80-90 ° C for about 8 hours.

The yield was 87.0 g of opaque beads. The average particle size of these beads is determined by Sedimentation Micromeritics Inst
It was 25 microns when measured by rument. The particle size measurement method is based on the Microsizer 5300 Particle attached to the device.
It is described in detail in the Size Analyzer Instruction Manual, (1984).

The surface area of the purified bead sample was determined to be 11.05 m ² / g by BET nitrogen analysis, and the pore volume was determined to be 0.14 ml / g by mercury intrusion method.

Example II This example illustrates the protonation of the 4-vinylpyridine / ethylene glycol dimethacrylate polymer beads of Example I.

To a 1000 ml flask was added 80.0 g of the preformed porous beads of Example I and 300 ml of 3% aqueous hydrochloric acid solution.

After stirring this slurry for 3 hours, the porous polymeric cation beads were filtered and washed with a hydrochloric acid diluent, pH 3 to remove excess 3% acid solution from the polymeric beads. The beads were then dried in an oven at 75 ° C for 8-10 hours. The amount of hydrogen ions (H ⁺ ) in the water was measured and found to be 0.78 meq / g.

Example III This example demonstrates the preparation and protonation of 4-vinylpyridine / divinylbenzene polymer beads. The procedure is shown below: The reactor was prepared as in Example I. To the reaction flask was added 600 parts deionized water, 0.6 parts gum arabic and 6.0 parts Marasperse N-22. The aqueous solution was stirred at room temperature until all solids were dissolved.

In a flask 35 parts 4-vinylpyridine, 65 parts divinylbenzene (divinylbenzene 55%, ethylvinylbenzene 45%), 100 parts isobutanol and 1.0 parts DuPont.
An organic solution of the brand name VAZO 67, 2,2'-azobis (2-methylbutanenitrile), was added. The reaction mixture was stirred at about 1300 rpm until the droplets formed as in Example I. The reaction mixture was then heated to 75 ° C. when stirring was reduced to 800 rpm. The reaction was continued at this temperature for 8 hours.

The opaque porous beads were collected by filtration and washed 3 times with 500 ml deionized water. Protonation was performed by stirring the beads in 500 ml of 0.1 N HCl solution for 30 minutes.
The beads were filtered and washed with hydrochloride diluent, pH 3 to remove excess acid. Residual monomer and porogen were removed as in Example I. The beads were dried in an oven at 80 to 90 ° C for about 8 hours to obtain a dried powder. The yield was 93g. The average particle size, surface area and pore volume were 36 microns, 2.21 m ² / g and 0.073 ml / g, respectively.

Example IV This example demonstrates an alternative method of protonating the polymer beads of the invention with a buffered wash. The procedure is shown below: In a 1000 ml beaker, 100 g of the preformed porous beads of Example I, 250 ml pH 3.0 buffer (containing 500 parts 0.1N potassium hydrogen phthalate and 223 parts 0.1N HCl) and 250 ml.
Of deionized water was added. The mixture was stirred for 30 minutes and then filtered. 6) Quaternized beads in an oven at 80-90 ° C
Dried for ~ 10 hours.

Example V This example illustrates the preparation of 4-vinylpyridine / ethylene glycol dimethacrylate beads using xylene as the porogen. The procedure is shown below: A 1000 ml reaction flask was charged with the aqueous dispersion described in Example I. An organic solution was prepared as in Example I except 50 parts xylene (mixture of ortho, meta and para isomers) was used as the porogen instead of toluene. The reaction was stirred at 1300 rpm until the droplet size was 10-60 microns. The reaction was then heated to 65 ° C and maintained at this temperature for 20 minutes. Reduce to 800 rpm and stir to bring the reaction mass to 75
Heated to ° C. The reaction was continued at this temperature for 8 hours.

The porous beads were collected by filtration and washed with 500 ml deionized water. The beads were then quaternized with pH 3.0 buffer as described in Example IV. 500 ml beads
Residual monomer and porogen were removed by rinsing with 3 × acetone. After drying in an oven at 80-90 ° C for about 8 hours, 61 g of beads were obtained. The average particle size, surface area and pore volume were 22.5 microns, 3.03 m ² / g and 0.68 ml / g, respectively.

Example VI This example shows that the cationic beads of Example II are replaced with an ultraviolet absorbing substance (ultraviolet protective substance). The procedure is shown below: of the porous cationic polymer beads obtained in Example II
18.0 parts and 30 parts of isopropanol were mixed in a glass flask at room temperature using an agitator. Then containing 7 parts octyldimethyl PABA and 2 parts oxybenzone 1
2.0 parts of the UV protection substance mixture were gradually added. The resulting suspension was stirred for about 20 minutes. Then the solvent is allowed to stand at room temperature for 24
Evaporated to dryness in a fume hood for hours. About 40% of the UV protectant mixture was entangled within the pores of the cationic polymer beads.

Example VII The adhesion and retention of 4-vinylpyridine / ethylene glycol dimethacrylate (4-VP / EGDMA) copolymer beads to human skin was investigated in human subjects.
Unprotonated and protonated 4-VP-EGDMA beads were prepared as described in Examples I and II above and mixed with an oil soluble dye (Oil Red EGN). Dye was extracted from a small sample of beads and the% increase (weight of dye / (weight of dye and beads) x 100) was quantified using spectrophotometry. 0.9% increase in non-protonated beads and 1.0% in protonated beads
It turned out that the amount was increased.

A measured amount of each bead preparation (1 polymer in each hand) was applied to the subject's marked forearm covering a 6.14 cm ² surface. The arm was then soaked in water for 5 seconds and then removed. This was repeated 5 times (during which the hands were not dried), and the polymer retained on the skin was recovered by washing with a surfactant solution. The amount of beads retained was determined by extracting from the dye, quantifying it using spectrophotometry and correlating the amount of dye extracted with the amount of polymer. The results are shown in Table 1.

These results indicated that higher amounts of protonated polymer were retained on the skin than unprotonated polymer.

B. Ionic Hydrogel: Preparation and Oral Formulation Example VIII This example demonstrates the preparation of PTMA EMCL cationic hydrogel beads using inverse suspension polymerization.

Use the following materials: Continuous Phase Premix the continuous phase with the following ingredients: EMSORB2500 (sorbitan monooleate) 24 g heptane 600 g EMSORB 2500 was mixed briefly with heptane by hand stirring.

Discontinuous Phase The discontinuous phase is premixed with the following components: Deionized water 300 ml Potassium persulfate 1.8 g MBA 30 g Sipomer (TMAEMCL) 90 g MBA was dissolved in water at a temperature of about 55-60 ° C. When MBA was completely dissolved, Sipomer was mixed with this solution. Then the initiator (K ₂ S ₂ O ₈ ) was added. The discontinuous phase solution was maintained at a temperature below 64 ° C and then mixed with the continuous phase solution.

The continuous phase solution was preheated at 60 ° C in a 2 liter reaction kettle.
After purging the reaction kettle with nitrogen for about 1.5 hours, the monomers were added. Stirring was started at 1000 rpm and the monomer solution was added to the reaction kettle. The reaction temperature was raised to 75 ° C. The polymerization gradually started at about 64 ° C, and remarkable exothermic bubbling was observed during the polymerization.

After the hydrogel beads are formed, the stirring speed is 600 rpm
And the stirring speed was maintained at 75 rpm at 600 rpm for 6 hours.

After cooling the reaction vessel, the mixture was filtered and washed with deionized water until the filtrate became colorless.

The hydrogel beads were then suspended in 500 ml of methanol, stirred for 1.5 hours and filtered again. This process was repeated twice until the filtrate became colorless. The hydrogel beads were washed again with water to prevent residual monomer from remaining in the filtrate (if the filtrate was translucent, the washing process was repeated until the filtrate became transparent). When the filtrate became colorless, the hydrogel beads were washed with a mixture of methanol and acetone (1: 1) and the hydrogel beads were gradually dried by increasing the ratio of acetone. The hydrogel beads were left in the exhaust hood for evaporation from acetone. The hydrogel beads were then dried in a vacuum oven at 50 ° C for 8 hours. Light micrographs were taken both before and after the beads were swollen. These are shown in FIG.

Characteristics of Hydrogel Beads Example VI using 20-60% crosslink content according to the above procedure
A cationic hydrogel prepared as in II was prepared. To examine the amount of water adsorbed by the microgel, the gel was cast on a square disk (2.5 cm x 2.5 cm x 0.16 cm). Equilibrium water rate (EWF) was measured as the change in weight between swollen and dry discs. EWF decreased from 0.85 to 0.78 as the crosslink content increased from 20% to 80% (Figure 1). The discontinuous phase of all the samples contained 83% by weight of water. The release profile of D & C Red No. 28 showed a controlled release trigger (Figure 2). FIG. 2 shows macroporous beads alone (curve A), a cationic hydrogel according to the invention (curve B) and a neutral surfactant (polyox) when mixed with anionic surfactants (to mimic biological salts). Compare the ionic hydrogel (curve C) and compare the ionic hydrogel with water or water and a nonionic surfactant (0.5% polyo
It shows that when incubated in x) it did not produce any detectable release. However, the dye was released when the sample was added to a release solution containing anionic surfactant (0.5% sodium lauryl sulfate). The release rate was tolerated by the control (curve A) and was the result of an ion exchange mechanism in which the anionic surfactant (similar to biosalt) exchanges with the anionic dye to complex with the cationic polymer.

The relationship between water equilibrium ratio and crosslink density as a function of water content during polymerization was determined by measuring the weight gain of hydrogel discs swollen in water. FIG. 3 shows that the water equilibrium percentage of the hydrogel increases in direct proportion to the water content during polymerization and is substantially independent of crosslink density. This indicates that the hydrogel polymerized in a very swollen form and subsequently became a factor limiting water content. Ionic hydrogels are poly (TMAEMC1-co
-MBA).

Generally, the same type of material was polymerized within the pores of macroporous materials, as made and disclosed in US Pat. No. 4,690,825. A typical release profile of D & C Red No. 28 is shown in FIG. 4 as a release solution containing Polyox or SDS surfactant. As shown for the hydrogel system, the anionic dye was not released from the cationic gel-filled sponge until the anionic surfactant (SDS) was present. The release rate of the dye to the SDS release solution was the same as the gel-free microsponge material. Thus, several mechanisms have helped to process the active ingredient release profile by the ionic hydrogel-filled microsponges. The hydrogel swells when exposed to water, so the active ingredient can be released by squeezing out the active ingredient from the pores, and the hydrogel has a dense coating that is impermeable to the active ingredient until swollen. It can act as an object or a stopper. Furthermore, hydrogels can control the release of ionic actives by an ion exchange mechanism as has already been demonstrated.

Example IX The poly (TMAEMCl-co-MBA) hydrogel described in Example VIII, which showed that it entraps acidic type components and does not release components until exposed to the appropriate anion for exchange, has a stable cationic charge. (Quaternary amine group). Since most pharmaceutically active substances are basic materials, conventional basic hydrogel materials do not bind basic drugs. Therefore, poly (methacrylic acid-co-N, N'-methylenebisacrylamide), [poly (MA-co-MBA)] hydrogels have been used in order to extend the applicability of hydrogels to basic active ingredients such as alkaloids. Was synthesized.

A hydrogel consisting of 10-15% cross-linking (w / w) was used in Example V.
Prepared by inverse suspension polymerization as described in III. Poly (TMAEMCl
-Co-MBA) hydrogels, poly (MA-co-MBA) materials with low crosslink content tended to aggregate during drying.

Tetracycline-HCl was selected as a model basic active ingredient for release rate experiments due to its UV detectability and water solubility. The release characteristics of tetracycline-HCl into swollen gel matrix into deionized water were determined for 50% cross-linked beads. The effect of gel charge density on the tetracycline-HCl diffusion coefficient was also investigated for a release solution containing 0.5% benzalkonium chloride, a cationic surfactant. The release profile of tetracycline-HCl from the poly (MA-co-MBA) polymer system into the dissolution media of 0.5% benzalkonium chloride or water (Figure 5) was not significantly different from the control.

FIG. 6 shows the swelling behavior of cationic and anionic hydrogels as a function of pH. Poly (TMAEMCl-co
-MBA), 25% TMAEMCL and poly (SSS-co-MBA), 30% S
The charge density of SS is pH independent. Therefore, the swelling behavior of these materials is pH independent. Poly (MA-co-MB
A), the charge density of 10% MA is a function of pH and this material becomes negatively charged at high pH. That is, the pH of this material
The higher the, the greater the swelling. Place 1g of dry material in a graduated cylinder and add the buffer solution.
Swelling was determined by adding to a depth of 25 cm. Volume was read after equilibration of material and buffer.

For clarity of understanding, the foregoing invention has been described in considerable detail by way of specific description and examples.
Apparently, certain changes and modifications may be made within the scope of the following claims.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical display location C08F 220/34 MMR C08F 220/34 MMR C08L 101/14 LTB C08L 101/14 LTB (72) Inventor Karts Martin A USA California 94025 Menlo Park Whitney Court 5 (72) Inventor Chen Thailand USA California 94040 Mountain View Kenzo Court 3375 (72) Inventor Liou Christine Jay Wai California 94043 Mountain View 163 West Middlefield Road 777 (72) Inventor Yuri Robert Pee United States California 94019 Half Moon Bay 3 Spruce Street 691 (72) Inventor Froix Michael United States California 94040 Mountain View Woodstock Lane 3433

Claims (11)

(57) [Claims] 1. An ionic polymer hydrogel comprising a copolymer of an ionic monoethylenically unsaturated monomer and a polyhydric ethylenically unsaturated crosslinking monomer that is soluble in aqueous solution in all proportions, said method comprising: A hydrogel that has a degree of swelling that is linearly proportional to the weight percent of the crosslinking monomer in the copolymer and that the equilibrium water percentage of the hydrogel when equilibrated with water depends on the amount of water used during polymerization. . 2. The hydrogel of claim 1 used as an ion exchanger. 3. The hydrogel has a charge density sufficient to produce a binding affinity for a counterion having an opposite charge to the hydrogel and is at least 1.0 × 10 ⁶ ml / measured by the weight distribution coefficient method. The hydrogel of claim 1, having a charge density of g. 4. The hydrogel has a porosity and a charge density sufficient to provide a capacity for counterions having an opposite charge to the hydrogel of at least 45% by weight based on the total weight of the hydrogel and counterions. The hydrogel of claim 1. 5. The hydrogel of claim 2, wherein the charge density is 5-10 meq / g hydrogel. 6. The weight percentage of the crosslinking monomer is 20 to 60 wt% of the total hydrogel and the volume percentage of water used during the polymerization is 75 to 85% of the total volume of the reaction mixture.
The hydrogel of claim 1, wherein the hydrogel exhibits a degree of swelling of 1.2 to 1.8 when 7. The hydrogel is cationic, the ionic monoethylenically unsaturated monomer is a quaternary ammonium compound selected from the group consisting of compounds of the following formulas, and the polyvalent ethylenically unsaturated crosslink is Monomer for
The hydrogel of claim 1, selected from the group consisting of N, N'-methylenebisacrylamide, N, N'-nonamethylenebisacrylamide, and alkoxylated water-soluble polyfunctional acrylates. (In the formula, R ¹ , R ² , R ³ , and R ⁴ are the same or different saturated alkyl groups having 1 to 6 carbon atoms, n = 1 to 4, X is Cl, F , Br, and I.) 8. The hydrogel is anionic and the ionic monoethylenically unsaturated monomer is CH ₂ ═C.
(R) -COOH (wherein 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 said polyvalent ethylenic The hydrogel of claim 1, wherein the saturated crosslinking monomer is selected from the group consisting of N, N'-methylenebisacrylamide, N, N'-nonamethylenebisacrylamide, and alkoxylated water-soluble triacrylate. 9. The hydrogel is anionic, the ionic monoethylenically unsaturated monomer is selected from the group consisting of compounds of the formula: and the polyvalent ethylenically unsaturated crosslinking monomer is N, N. The hydrogel of claim 1, selected from the group consisting of'-methylenebisacrylamide, N, N'-nonamethylenebisacrylamide, and alkoxylated water-soluble multifunctional acrylate. (Wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁵ 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 selected from the group consisting of Na and K.) 10. A composition for the controlled ion exchange of counterions and solute ions in a preselected environment, said composition comprising crosslinked ionic polymer hydrogel particles, said hydrogel particles. Form a network of internal pores having a counterionic bond therein such that the hydrogel particles alter the exchange rate of counterions and solute ions from the internal pores in response to changing environmental conditions. A composition having selected physical and chemical properties. 11. Porous material wherein the hydrogel is in substantially spherical form and has an average diameter of 1 to 50 microns, a total pore volume of 0.1 to 1.0 cc / g, and an average pore surface area of 1 to 20 m ^2. 11. The composition of claim 10, which is a bead.