CA1310583C - Polymeric carrier compositions and methods for their preparation and use - Google Patents

Abstract

POLYMERIC CARRIER COMPOSITIONS AND METHODS
FOR THEIR PREPARATION AND USE
ABSTRACT OF THE DISCLOSURE
Polymeric delivery systems for active substances are prepared by suspension polymerization of a porogen and monomer mixture in an immiscible phase, typically an aqueous immiscible phase. By properly controlling the polymerization conditions and percentage of cross-linking, relatively rigid beads are formed having a non-collapsible pore network containing the porogen. The porogen is then extracted from the pore network, and an active substance, such as a UV
absorbant, and insect repellant, a steroid, an emollient, or the like, is introduced into the beads.

Description

"~
~ 3~g3 POLYMERIC CARRIER COMPOSITIONS ~ND ~ETHODS
FOR THEIR PP~EPARATION AND USE

The present ~n~ention relates generally ~o the preparation of compositions and 6yst~ms for the topical delivery of active ~ubstances to the ækin.
More particularly, the invention relates ts the preparation of a rigid polymer bead delivery system for active ~ubstances such as infrared absorbants, insect repellants, 6teroids, emollients, and the like.
It is frequently desirable to topically deliver active ingredients to the human ~kin. In many cases, th2 active ingredients can be applied directly to the skin, either in a substantially pure form or in combination with a liquid vehicle. Such direct application, however, is li~ited in a number of rsspects. First, direct application allows rapid evaporation of volatil2 active substances, uch as those list~d above. SeGond~ application o~ the active ~ub~tanae~ in substantially pure form C~ll o~t~n cause ~oxic and~or allergic re~ctions, particularly in the case of infrared ab~orbant~, insect repellant~ and ~;teroids. While ~uch adverse reactions can often b~
minimized by dilution ~ ~he activ~ substance in a uitable liquid carrier, t~e con~aguent decrease in concentration ~requently limit~ the ef~ectiveness o~
the resulting combina~ion for the intended purpose.
Finally~ many topically applied active substances have undesirable characteristics, such as an oily feel or a strong odor. While dilution of the pure active substance in a suitable liquid carrier can minimize such aesthetic objections, the resulting dilution will also reduce the effectiveness of the final product.
For these reasons, it would be desirable to provide delivery compositions or systems capable of providing controlled and prolonged delivery of active ~k substances af-ter -they have been applied -to -the skin.
Desirably, such clelivery systems should also control any oclor or toxici-ty which may be associated with the active substance, and should be suitable both ior direct applica-tion to the skin and for combination in conventional liquid carriers.
Polymeric beads have been proposed Eor incorpora-ting various active substanees. European Patent No . 61, 701 describes -the preparation of rela-tively non-riyid polymeric beads for incorporating active substances, exemplified by emollien-ts. Al-though such polymer delivery sys-tem will likely resul-t in prolonged release of an active substance, the non-rigid beads allow the internal pore network incorporating the active subs-tance to collapse as -the subs-tanee is released, usually resulting in -the entrap~en-t and was-te oE residual active substanee. Also, the European patent teaehes a preparation proeedure whieh requires the presenee o~ the aetive substanee during the polymeriza-tion of the bead material. Sueh a preparation proeedure is unsuitable ~or hea-t and/or radiation labile aetive subs-tanees whieh will be inactivated under -the polymerization eonditions.
It would therefore be desirable -to provide ~or polymerie : 25 bead delivery sys-tems comprising rela-tively rigicl polymeric beads which allow for substantially complete release of the active in~redient from -the pore network of the beads. It would be partieularly desirable if sueh bead delivery systems could be prepared prior to the introduetion oE -the aet:ive subs-tanee so that the ae-tive substanee is not exposed to relatively harsh polymerization eonditions.
The present invention provides a delivery system eapable of retaining an aetive substanee, said delivery system comprisiny a plurality o~ cross-linked polymer beads eharaeterized by a ri~id, substantially non-collapsible pore network open to the exterior of said beads and whih is substantially free from re-tainecl subs-tances.
The present inven-tion also provides a sunscreen ~-~"J~

composi-tion comprising substantially rigid polymeric beads each defini~g a network of substantially non-collapsible pores open -to -the exterior of said beacls and having a UV
absorptive subs-tance absorbed within said network of pores, wherein said beads have a cross-linking density in the range from about 20% to 80% and an average diameter in -the range from about 10 ~ m to 40 ~m.
The present invention further provides an insect repellent composition comprising substantially rigid polymeric beads each defining a network of substantially non-collapsible pores open to the exterior of saicl beads ancl having an insec-t repellent substance absorbed within said network of pores, wherein said beads have a cross-linking density in the range from abou-t 20% to 80% ancl an average diameter in the range from about 10 ~m to 40 ~m.
The present invention provicles for a polymeric delivery system for a variety of active substances, such as i.nfrared absorbents (sunscreens), insect repellants/ steroids, emollients, and the like, which delivery system may be used alone or may incorporated into a secondary carrier or vehicle composition, or o-ther cosmetic produc-t. The polymeric delivery system with an incorporated ac-tive substance is a dry, free-flowing product which can be rubbed directly on -the skin, providing for the controlled release of -the suhstance over time. In the more usual situation where the polymeric delivery system is incorporated in another carrier, vehi.cle, or cosmetic product, use of the delivery system avoids incompa-tibili-ties, typically chemical. or physical interactions, which might otherwise exist between -the substance ancl o-ther active ingredient(s) in the cos~etic preparation, or be-tween the active subs-tance ancl the carrier or vehicle itself.
The controlled release of the ac-tive subs-tance provided by the polymeric delivery sys-tem of -the presen-t invention affords a prolonged ac-tivi-ty of -the subs-tance on the skin.
such prolonged activity recluces the need to frequently reapply the active substance. Acldi-tionally, controlled release both reduces any odor which may be associated wi-th .~ 3 ' ~`1' ' v ~

~31~8 ~
3a the actlve substanee and lessens the possibility of toxicity and allergic reaction resulting from con-tac-t of the active substance wlth the skin.
In a fur-ther aspect, -the present invention provides a me-thod for preparing a dellvery system for an active substance, said method characterized by introducing the active subs-tance in liquid form to a pluralit-y of preformecl rigid cross-linked polymer beads each defining an in-ternal ne-twork of pores capable of :retaining the active substance.
Accorcling to the present inven-tion, the polymeric delivery system is formed by suspension polymerization of suitable monomers in an immiscible phase including a porogen.
Generally, the monomers and the porogen are first mixed -together and the resulting mixture then suspended i.n the immiscible phase, usually an aqueous phase. The immiscible phase is then agitated to ~orm droplets of the monomer mix-ture, and polymerization of the monomer mix-ture is initia-ted to form the desired beads from -the droplets.
Relatively ri.gid beads having a substantially non-collapsible pore network are formed by providing a cross-linking density .~ ~

of a~ least about 10%~ u~ually being in the range from about ~0~ ~o 80~%, mor~ u~ually being in the range ~rom 2~% ~o 60~ cross-linking, ~nd typically being in the range from about 45% to 55% cross-linking. ~he bead diameter i~ normally ~aintained in the ran~ from about 5 microns to 100 microns, usually being about 10 microns to 50 microns, and the total pore v~lume is in the range from about 0.1 to 2.0 cc/g, usually being ir.
the range from about 0.3 to 1.0 cc~g. The sur~ace area of the beads will range ~rom about 1 to 500 m2/g, usually being in the range ~rom about 20 to 200 m2/g.
The precise dimensions and characteristics of the beads are controlled by varying process parameters such as agitation speed and natUre of the porogen.
Once ~he beads are formed, porogen is ex~rac~ed from the bead product, typically using ~olvent extraction or evaporation. The desired active substance may ~hen be introduced into thP beads, typically by contact ~bsorption, to create the desired ~, final product. In addition to allowing the incorporation of labile active subst~nces, such a two-step preparation process ~llows greater control over the structure of the bead resulting from a wider choice of porogens and reaction conditions.
Compositions for topical application are ~ormed by incorporating an active substance, such as a W absorbant, an insect repellant substance, a steroid, an emollient, or the like, inside a polymer delivery system comprising cross-linked polymer particles defining an extensive internal pore network capable o*
retaining the substances. The pore network is open to the external surface of the bead, allowing controlled release of the active substance over time after ~he particles are applied to the skin. The particles, usually spherical beads, are formed by suspension polymeriæation of a monomer (or monomers) and poroyen ~3~0583 mixture suspended in an immiscible phase, typically an aqueous immiscible phase. The suspension is agitated, causing small droplets of the monomer and porogen mixture to form within the immiscible phase.
Polymerization and cross-linking of the monomer(s) creates a non-collapsible bead having an internal pore network defined by the entrapped porogen. The porogen is then extracted from the beads, leaving the open pore network substantially empty and capable of receiving the active substance. The active substance may be introduced to the beads, typically by contact absorption, immediately following extraction of the porogen~ Alternatively, the extracted beads may be stored for some time prior to introduction of the active substance, allowing shipment of the beads to another location for final preparation of the dèsired product.
The polymer delivery system of the present invention comprises rigid polymeric beads having a non-collapsible pore structure. That is, the beads will substantially retain their internal pore structure even after the porogen and/or the active substance has been extracted and the pores are empty. such beads are mechanically stable compared with non-rigid matsrials, allowing manufacturing, processing, and handling of the beads under relatively rigorous conditions which might result in the rupture or damage of less stable materials. More importantly, the non-collapsible pores allow substantially complete utilization of the active substance and facilitate introduction of the active substance into the bead after the porogen has been extracted.
The rigid polymeric bead of the present invention is formed by polymerization and cross-linking of one or more preselected monomers to form a molecular structure having a substantially non-collapsible network o~ pores re~ulting from the presence of the p~rogen during polymerization. At least one monomer will be polyethylenically unsaturated, and usually the p~lymer will include a monoethylenically unsaturated co-monomer. The degree of cross-linking may then be controlled by adjusting the ratio of monoethylenically unsaturated monomer to polyethylenically unsaturated monomer, as discussed in more detail hereinbelow. The active substance is held by capillary action within the network of pores and remains there until an external force or energy draws the substance from the beads.
The rigid structure of the bead prevents significant shrinkage or collapse of the bead as the active substance is removed from the network of pores. This is an advantage as it helps attain substantially complete removal and utilization of the w absorptive material. This is contrast to non-rigid beads where the pore structure will collapse as the active substance is extracted, rendering it difficult or impossible for the substance which is entrapped deep within the pore structure to be removed and utilized.
The primary difference between the formation of non-rigid beads and rigid beads o~ the present invention is the degree of cross-linking imparted to the polymer. The rigid polymer beads of the present invention will have greater than 10% cro6s-linking, usually having in the range from about 20% t~ 80%
cross-linking, more usually having in the range ~rom about 25% to 60% cross-linking, and typically being in the range from about 45% to 55% cross-linking. The calculated or theoretical percentage of cross-linking is defined as the weight of polyethylenically unsaturated monomer (or monomers) divided by the total weight of monomer, including both polyethylenically unsaturated and monoethylenically unsaturated monomers.
The beads of the polymer are conveniently formed by suspension polymerization in a liquid-liquid system. In general, a solution containing monomers, a 5 8 ~

polymerization catalyst (if used), and an inert but fully miscible liquid porogen is formed which is immiscible with water. The solution is then suspended in an a~leous solution, which generally contains additives such as surfactants and dispersants to promote the suspension. Once the suspension is established with discrete droplets of the desired size, polymerization is effected (typically by activating the reactants by either increased temperature or irradiation). Once polymerization is complete, the resulting rigid beads are recovered from the suspension. The beads at this point are solid porous structures, the polymer having formed around the inert, water-immiscible liquid, thereby forming the pore network. The liquid porogen has accordingly served as a "pore-forming agent" and occupies the pores of the formed beads.
Materials suitable as porogens will be liquid substances which meet the following criteria:
l. They are either fully miscible with the monomer mixture or capable of being made fully miscible by the addition of a minor amount of non-water-miscible solvent;
2. They are immiscible with water, or at most only slightly soluble;

3. They are inert with respect to the monomers, and stable when in contact with any polymerization catalyst used and when su~jected to any conditions needed to induce polymerization (such as temperature and radiation); and 4. They are readily extracted from the pore network of the beads once polymerization is complete.
Suitable porogens include a wide range of substances, notably inert, non-polar organic solvents.
Some of the most convenient examples are alkanes, cycloalkanes, and aromatics. Specific examples of such `"` 131~58~

solvents are alkanes of from 5 to 12 carbon atoms, straight or branched chain cycloalkanes of from 5 to 8 carbon atoms, benzene, and alkyl-substituted benzenes, such as toluene and the xylenes. Extraction of the porogen may be effected by solvent extraction, evaporation, or similar conventional operations. The porogen extraction step accomplishes the removal of unwanted species from the polymerized structures prior to impregnation with the desired active substance.
Such unwanted species include unreacted monomers, residual catalysts~ and surface active agents and/or dispersants remaining on the bead surfaces.
Extraction of the porogen and its replacement with (i.e., impregnation of the dry bead with) the above substance in the above-described procedure may be effected in a variety of ways, depending on the chemical nature of the porogen and its behavior in combination with that of the other species present.
For example, the beads may be recovered from the suspension by filtration, preferably using vacuum apparatus (such as a Beuchner funnel). The beads are then washed with an appropriate solvent to remove organic species not bound to the polymer, including surfactants having deposited on the bead surfaces from the aqueous phase, unreacted monomers and residual catalysts, and the porogen itself. An example of such a solvent is isopropanol, either alone or in aqueous solution. Once washing is complete, the solvent itself is removed by drying, preferably in a vacuum.
In certain cases, an alternative method of extraction may be used - i.e., where the porogen, unreacted monomer and water will form an azeotrope. In these cases, steam distillation i5 an effective way of extracting porogen from the beads. This again may be followed by drying under vacuum.
Once the beads are rendered dry and free of the porogen and any unwanted organic materials~ they ~ 31~8~

are impregnated with the active substance according to conventional techniques. The most convenient such technique is contact absorption, aided by solvents if necessary to enhance the absorption rate.
The polymerization process used in preparing the beads of the polymer delivery system can be modified to control both the porosity and the particle diameter of the beads. Controlling the porosity, in turn, controls the rate at which the active material will be absorbed and/or released from the beads.
Particle diameter is controlled primarily by the degree of agitation, with more rigorous agitation causing smaller droplets and hence smaller polymeriz~d beads.
The pore diameter and pore volume, in contrast, are controlled primarily by the cross-linking density.
Porosity is increased by increasing the amount of cross-linking monomer used, or by increasing the porogen concentration in the monomer mixture, or both.
An increase in porosity increases the surface area of the bead and hence the weight percent of the active substance which may be held within the bead. Bead diametex is also affected by the concentration of dispersing agent in the immiscibla phase.
The bead diameter in the polymer delivery ~5 system should be in the range from about 5 to lO0 microns. Beads having an average diameter in the range from about 5 microns to no more than about 70 microns are preferred, with a bead diamete~r in the range from about lo microns to about 40 microns being particularly preferred. Beads with a diameter from 10 to 40 microns have been found to be aesthetically pleasing when topically applied to the skin.
The pore dimensions within the beads may vary widely, with optimum dimensions depending on the chemical characteristics of the polymers used as well as the diffusive characteristics of the active substance. Different systems will thus call for `` ~31~8~

different optimum ranges of pore volume distribution to obtain the most desirable properties for the overall formulation. In general, however, best results are obtained with total pore volumes ranging ~rom about 0.1 to about 2.0 cc/g, preferably ~rom about 0.3 to about l.o cc/g; pore surface areas ranging from about 1 to about 500 m2/g, preferably from about 20 to about 200 m /g; and average pore diameters ranging from about 0.001 to about 3.0 microns, preferably from about 0.003 to about 1.0 micron. Following conventional methods of measuring and expressing pore sizes, the pore diameters are measured by techniques such as nitrogen or mercury porosimetry and are based on the model of a pore of cylindrical shape.
In order to form the cross-linked polymer beads of the present invention, it is necessary to polymerize either polyethylenically unsaturated monomers, i.e., those having at least two sites of unsa~uration, or to polymerize monoethylenically unsaturated monomers in the presence of one or more polyethylenically unsaturated monomers. In the latter case, the percentage of cross-linking may be controlled by balancing the relative amounts of monoethylenically unsaturated monomer and polyethylenically unsaturated monomer.
Monoethylenically unsaturated monomers suitable for preparing polymer beads for the polymer delivery system include ethylene, propylene, isobuty-lene, diisobutylene, styrene, ethyl~inylbenzene, vinyltoluene, and dicyclopentadienei esters of acrylic and methacrylic acid, including the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, amyl, hexyl, octyl, ethylhexyl, decyl, dodeyl, cyclohexyl, isobornyl, phenyl, benzyl, alkylphenyl, ethoxymethyl, ethoxyethyl~ ethoxypropyl, propoxymethyl, propoxyethyl, propoxypropyl, ethoxyphenyl, ethoxybenzyl, and ethoxy-cyclohexyl esters; vinyl esters, including vinyl ~3~83 acetate, vinyl propionate, vinyl butyrate and vinyl laurate; vinyl ketones, including vinyl methyl ketone, vinyl ethyl detone, vinyl isopropyl ketone, and methyl isopropenyl ketone; vinyl ethers, including vinyl methyl ether, vinyl ethyl ether, vinyl propyl ether, and vinyl isobutyl ether; and the like.
Polyethylenically unsaturated monomers which ordinarily act as though they have only one unsaturated group, such as isopropene, butadiene and chloroprene, may be used as part of the monoethylenically unsaturated monomer content.
Polyethylenically unsaturated cross-linking monomers suitable for preparing such polymer beads include diallyl phthalate, ethylene glycol diacrylate, ethylene glycol dimethacrylate, trimethylolpropanetri-methacrylate, divinylsulfone; polyvinyl and polyallyl ethers of ethylene glycol, of glycerol, of pentaery-thritol, of diethyleneglycol, of monothio- and dithio-derivatives of glycols, and of resorcinol; divinylke-tone, divinylsulfide, allyl acrylate, diallyl maleate, diallyl fumarate, diallyl succinate, diallyl carbonate, diallyl malonate, diallyl oxalate, diallyl adipate, diallyl sebacate, divinyl sebacate, diallyl tartrate, diallyl silicate, triallyl tricarballylate, triallyl aconitate, triallyl citrate, triallyl phosphate, divinyl naphthalene, divinylbenzene, trivinylbenzene;
alkyldivinylbenzenes having from 1 to 4 alkyl groups of 1 to 2 carbon atoms substituted on the benzene nucleus;
alkyltrivinylbenzenes having 1 to 3 alkyl groups of 1 to 2 carbon atoms substituted on the benzene nucleus;
trivinylnaphthalenes, and polyvinylanthracenes.
The preferred polymer bead of the present invention will be free from reactive groups which will interact with the porogen and/or the active substance which is ultimately incorporated in the composition.
In particular, the beads should be free from reactive amino, hydroxyl, carboxylic, and other reactive ~3~ ~83 1~
functionalities. Such beads will not readily undergo unwanted reactions, will be stable over a wide pH
range, will resist moderate oxidation and reduction, will be stable at higher temperatures, will resist attack by moisture, and will have a relatively long shelf life.
The particularly preferred polymer delivery system of the present invention is formed by the copolymerization of styrene and divinylbenzene, vinyl stearate and divinylbenzene, or methylmethacrylate and ethylene glycol dimethylmethacrylate. Usually, the monoethylenically unsaturated monomer will be present at from about 10 to 80 percent of the monomer mixture, more usually at about 20 to 60 percent of the monomer mixture, typically being in the range from about 45 to 55 percent of the monomer mixture, with the polyethylenically unsaturated monomer forming the remainder of the mixture. Particularly preferred is the styrene-divinylbenzene polymeric bead which consists essentially of a hydrocarbon backbone with benzene rings and which is substantially completely free from reactive groups.
Exemplary active substances which may ba introduced to the polymer bead delivery system of the present invention include ultraviolet (UV) absorptive materials which ~orm a sunscreen product, insect repellant substances, steroids, emollients, and the like.
W absorptive materials suitable for the present invention will be solids or liquids capable in pure form of absorbing at least 95% of the ultraviolet radiation at wavelengths in the range from about 290 to 320 nm, the radiation primarily responsible for causing sunburn. The materials may transmit some or all UV
radiation above 320 nm, particularly if tanning is desired. The presently known UV absorptive materials ~31~583 which are accepted as safe for human use may be clas-sified into five groups, as set forth in Table 1.

Group Exemplary Compounds Absorbance Aminobenzoates _-Aminobenzoic acid (PABA) 260-313 nm Ethyl 4-[bis(hydroxypropyl)]
aminobenzoate 280-330 nm Octyl dimethyl PABA ----------PABA propoxylate ---~
Glyceral PABA 264-315 nm 2-Ethylhexyl PABA
(Padimate O) ----------Pentyl PABA (Padimate A) ----------Cinnamates Cinoxa~e 270-328 nm Diethanolamine ~-methoxy cinnamate 280-310 nm 2-Ethylhexyl ~-methoxycinnamate 290-320 nm Benzones Dioxybenzone 260-320 nm Sulisobenzone ----------Oxybenzone 270-350 nm 2-Ethylhexyl 2-cyano-3,3-diphenylacrylate -----------Salicylates 2-Ethylhexyl salicy].ate 280-320 nm Triethanol amine salicylate 260-320 nm Homosalate 295-315 nm 11 3~83 Miscellaneous Red petrolatum Titanium dioxide ----------Digalloyl trioleate 270-320 nm Lawsone with dihydroxyacetone 290-400 nm 2-Phenylbenzi~idazole-5-sulfonic acid 290-320 nm The W absorptive substances listed in Table 1 may be used alone or in mixtures of two or more when it is desired to increase the range of W absorp-tion over that offered by any one substance. When combining W absorptive substances, care should be taken to avoid undesirable interactions between the substances.
Surprisingly, it has been found that sunscreen compositions prepared by introducing a W
absorptive substance into polymeric beads prepared by the method of the present invention results in a composition capable of adsorbing infrared radiation as well as ultraviolet radiation. As the dangers of exposure to infrared radiation become more apparent, the utility of a sunscreen which is able to absorb both infrared and ultraviolet radiation becomes increasingly clear.
Insect repellant substances suitable for incorporation into the compositions of the present invention will function through volatilization and formation of a thin protective barrier or layer as the repellant is released ~rom the polymèr delivery system.
The repellant substances will usually be liquids, although solids which are dissolved or dispersed in a li~uid carrier may also find use. The substances should be generally non-toxic, at least when incorporated in the polymer delivery system, and should be effective against a wide variety of insects. Insect repellant substances which are presently accepted as .

. .

1 31 0~83 safe and which are suitable for use in the present invention are set forth in Table 2.

Group Exemplary Compounds Terpenoids Citronellal Geraniol Terpentine Pennyroyal Cedarwood Eucalyptus Wintergreen Benzoquinones Benzquinone and its homologs, methyl ether derivatives and homologs Aromatics Cresols Benzaldehyde Benzoic acids Synthetics N,N-diethyl-_-toluamide (deet) Ethyl hexanediol Dimethyl phthalate Dimethyl ethyl hexanediol carbate Butopyronoxyl Di-n-propyl isocinchonmeronate N-Octyl bicycloheptene dicarboximi.de 2,3,~,5-bis(2 butylene)tetra-hydro-2-furaldehyde The insect repellant substances listed in Table 2 may be used alone, or more desirably, in combinations tailored to be effective against a greater variety of insects than a single repellant alone.

13~83 Generally, it will be easier to combine different insect repellant substances inside the polymer delivery system of the present invention than it would be combining them by themselves or in liquid vehicles or carriers. Insect repellant substances which would tend to separate because of physical differences, e.g., immiscibility, may be held within the polymer delivery system in a dispersion or mixture which helps assure that they will be released at substantially the same rate over time.
Suitable emollients include mineral oil, isopropyl myristate, isopropyl palmitate, propoxypropylene myristyl ether propionate, C12-C15 alcohol benzoates, vegetable oils, e.g., safflower oil, peanut oil or corn oil, silicone oils such as polydimethylcyclosiloxane, hexamethyldisiloxane, dimethicone, amodimethicone, trimethylsilylamodimethicone, stearyl dimethicone, cetyl dimethicone, stearoxy dimethicone, polysiloxane/polyalkyl copolymers, dialkoxydimethylpolysiloXaneS~ dimethicone copolymers, cetyl dimethicone copolymers and dimethicone propyl PG-betaine, perfluoropolyethers, marine oils, such as shark liver and fish liver oils, linolin, glycerol, sorbitol, bath oils, etc.
Suitable steroids will ba adrenocortical steroids, such as fluocinolone, fluocinolone acetonide, triamcinolone acetonide, beta-methasone valerate, timobesone acetate, hydrocortisone, hydrocortisone acetate, triamcinolone, prednisolone, pr~dnisolone acetate, dexamethasone, beclomethasone dipropionate, betamethasone dipropionate, betamethasone benzoate, clocorolone pivalate, halcinonide, flumethasone pivalate, and desonide. A number of anti-inflammatory steroids suitable for use in the present invention have been disclosed in U.S. Patent Nos. 4,017,615;

~ 3 ~ 8 ~

3,365,446: 3,067,194, 3,364,203; 3,053,833, and 3,513,162.
The polymer delivery composition of the presenk invention may be incorporated in a suitable carrier or vehicle, or into cosmetic preparations, such as face creams, lipsticks, lip balms, baby creams, lotions, shampoos, after shave lotions, hair grooming preparations, and the like. Alternatively, the compositions, which are dry, free-flowing powders, may be utilized by themselves without further incorporation in a carrier of any kind. Usually, the active substance will comprise from about 5% to 65% o~ the polymeric composition by weight, more usually comprising from about 20% to 60% by weight, and most often being in the range from about 40~ to 55~ by weight.
The polymeric beads prepared as jUst described function as a reservoir for controlled delivery of the active substancPs providing a wide range of advantages over the conventional formulations~
Release of the active substance5 from the pores occurs in sustained manner, providing a continuous fresh supply of active substance to the epidermal area to which the preparation has been applied. The active substances diffuse out of the pores into either the vehiclP if one is used or the natural bodily secretions present on one~s skin at the applied area, in accordance with known principles of the diffusion of one liquid through another. The activity-time curve of the active substances are thus extended and flattened out. The magnitude of the release rate is controlled by the pore volume distribution in the bead itself, notably the total pore volume and the average pore diameter. Selection of the values of these parameters according to predetermined standard provides control of the release rate to desired levels.

1~
The ~ollowing examples are offered by way of illustration, not by way of lim~tation.
EXPERIMEMTAL

~Preparation of Beads) A two-liter four-necked reactisn flask equipped with a stirrer driven by a ~ari~ble speed motor, reflux condenser~ thermometer, and nitrogen-inlet tube was set Up. A slow flow o~
nitrogen was maintained throuyh tha reaction flask at all times. An aqueoUs phase made up at 350 parts of deionized Water, 1. 8 parts of gum arabic, and 1~8 parts sodium lignosulfate (NarasperseT~-22, available from Reed Lignin, Inc.) was added to the flask, and an organic solution made up 39.65 parts of styrene, 47.60 parts o~ commercial divinylbenzen~ (55.~%
divinylbenzene, 42.3~ ethylvinylbenzene), 71.35 parts of heptane, and 2.2 parts benzoyl peroxide ~70~ acti~e ~ngredient and 30~ water) was dispersed in the aqueou~
phase with rapid agitation (~tirrer ~peed approximately 950 rpm) to obtain a plurality o~ droplets having an average droplet diameter o~ below about 60 ~icrons as determined by visual observation o~ a ~ampl~ of th~
droplets with an optical microscope.
; 25 The reaction mixture was th~n heated to about 75 c and maintained at that temp~rature for 10 hours to : form porous beads of cross-linked ~tyrene/divinylbenzen~ copolymar having heptane ~ntrapped within the pores. ~he reaction mixture was then cooled to room temperature and the resulting polymeric beads collected by filtration, washed three times with looo parts of deionized water, and three times with lOoO parts of acetone, then dried in a vacuum oven at 80~C for 24 hours.
3~ The calculated or theoretical cross-link density of the purified beads is 30.3%. This density is calculated by multiplying the weight of ` ` 131~3 divinylbenzene (47 . 6 g) by the purity of the divinylbenzene (0.556) to get the actual weight o~ puxe divinylbenzene which is then divided by the total weight of monomer (87.25 g).
The surface area of a sample of the purified beads was 14 6 .2m2/g as measured by B.E.T. nitrogen multipoint analysis and the pore volume was 0.99 ml/g as measured by Mercury porosimetry.

Example II
(Preparation of Beads) A two-liter-necked reaction flask equipped as described in Example I was evacuated and purged with nitrogen. An aqueous phase made up of 450 parts of deionized water, 4 parts of gum arabic, and 4 parts of sodium lignosulfate was added to the flask, and an organic solution made up 52 parts of methylmethacrylate, 78 parts ethyleneglycol dimethacrylate, 1.5 parts of benzoyl peroxide ~70% in ~0 water), and 150 parts of toluene was dispersed in the aqueous phase with rapid ~stirrer speed approximately 9oO rpm) to obtain a plurality of droplets having an average droplet of below about 60 microns, as determined by visual observation of a sample of the droplets being stabilized by the dispersants.
The reaction mixture was heated to 65C for 1 hour, then 75Oc and allowed to remain at this temperature for approximately 7 hours while maintaining a nitrogen flow of 2 ml/minute to form poroUs beads o~
cross-linked methacrylate/ethyleneglycoldimethaCrylate copolymer having toluene entrapped within the pores.
The reaction mixture was then cooled and the beads collected by ~iltration, washed three times with 1000 parts of deionized water, and three time6 with 1000 parts of acetone, then dried in a vacuum oven at 80c for about 2~ hours.

`;
~3~Q~3 The calculation of theoretical cross-linking density of the purified beads is 60% and is calculated by dividing the weight of ethyleneglycoldimethacrylate ~78 g) by the weight of monomer (130 g).
The surface area of a sample was 180.59 m2/g and the pore volume was 0.684 ml/g, determined as described in Example I above.

Example III
(Impregnation of Beads of Example I with UV Absorbant) A 25 parts portion of macroporous cross-linked copolymer beads as described in Example I
above was mixed at room temperature with 100 parts of isopropanol in a glass beaker with a stirring bar.
Then 25 parts of octyl dimethyl PABA were added slowly with stirring. The solvent was then allowed to evaporate to dryness in a fume hood at room temperature. The beads containing 49.7% octyl dimethyl PABA entrapped within thair pores axe obtained.

Example IV
(Impregnation of Beads of Example I with W Absorbant) By repeating the procedure of Example III, usiny 25 parts of the styrene/divinylbenzene porous cross-linked polymeric beads prepared in Example I, 25 parts of 2-ethylhexyl-p-methoxycinnate and 100 parts of isopropanol as the solvent, beads containing ~9.0~
2-ethylhexyl-p-methoxycinnanamate entrapped within their pores are obtained.

Example V
(Impregnation of Beads of Example I with UV Absorbant) By again repeating the procedure of Example IV, using 50 parts of the 3~ methylmethacrylate/ethyleneglyCOldimethaCrylate po~ymeric beads prepared by Example II, 50 parts of a mixture o~ octyldimethyl PABA and oxybenzone 3 (7 parts - -`` ~L3~0~3 of octyldimethyl PAB~ and 3 parts o~ oxybenzone-3), and 140 parts of isopropanol as the solvent, beads containing 49.6% octyldimethyl PABA/oxybenzone-3, entrapped within their pores are obtained.
Example VI
(Preparation of Beads) A 2000 ml four-necked reaction flask equipped with a motorized stirrer, reflux condenser, thermometer, and nitrogen inlet was evacuated and purged with nitrogen. 900 Parts of deionized water, 7.Z parts of gum arabic and 7.2 parts of a sodium-based liynosulfonate (Reed lignin) available from the American Can Co. under the trademark Marasperse N-22, were charged to the reaction flask. The mixture was heated, with stirring, in an oil bath at about 50 degrees Celsius until the dispersants (gum arabic and lignosulfate) dissolved to form an aqueous phase.
To this mixture there was then added a freshly prepared solution of 143.3 parts of styrene (99.8% purity), 44.6 parts of commercial divinylbenzene (55.6~ divinyl benzene, 42.3% ethylvinylbenzene), 7.7 ; parts of benzoyl peroxide (70% active ingredient and 30% water), and 144 parts of toluene (porogen). The aqueous phase and organic solution were agitated by stirring at a rate adjusted to give a plurality of droplets having an average droplet diameter o~ about 10-60 microns, as determined by visual observation of a sample of the droplets with an optical microscope (400X) with the droplets being stabilized by the dispersants. The reaction mixture was then heated to about 95 degrees Celsius and maintained at that temperature for about 20 hours, at the previously adjusted stirring rate, to form porous beads of cross-linked styrene/divinylbenzene copolymer having toluene entrapped within the network of pores. The mixture was then cooled and the porous polymeric beads were removed ~rom the reaction flask by filtration.

~3~l0583 The filtered beads were washed initially threa times with one liter portions o~ deionized water ~o remove the dispersants, followed by three washes wit~ one liter portions of isopropanol to remove any residual, unreacted monomer and the toluene used as the porogen during polymerizationO The beads were then dried in an oven at 70C for six hours. The average particle diameter of these beads was 10 microns, as measured by optical microscopy.
The calculated or theoretical cross-linking density o~ the purified beads is 13%. This density is calculated by multiplying the weight of divinylbenzene (44.6 parts) by the purity of the divinylbenzene (0.556) to get the actual weight of pure divinylbenzene which is then divided by the total weight of monomer (144.3 parts + 44.6 parts) and multiplied by 100.
The surface area of a sample of the purified beads was determined by the B.E.T. method to be 1.1 meters2/gram while the pore volume was determined by the mercury intrusion method to be 0.0195 ml./gram.
The B.E.T. method is described in detail in Brunauer, S. Emmet, P.H., and Teller, E., J. Am. Chem Soc., 60, 309-16 (1938).

Example VII
(Preparation of Beads) By repeating the procedure of Example VI in every essential detail, except for the weights of monomers employed, macroporous cross-linked polymer beads having the following characteristics were obtained:
Styrene, parts 85.6 Divinylbenzene, parts 102.3 Porogen, parts Toluene, 188 Calculated Cross-Linking Density, %30 Average Particle Diameter, ~m 2 5 Sur~ace Area, M2~g 1. 8 Pore Volume, ml/g O. 04 ~xample VIII
(Insect Repellant~
A 15 part portion of the macroporous cross linked polymer beads prepared as described in each of Examples VI and VII above was mixed a~ room temperature with a 60 part portion of diethyl-m-toluamide, and the resulting suspensions were stirred at about 100 rpm for 24 hours in a closed container.
~he suspensions were then filtered and the filtrates washed three times with an a~ueous detergent s~lu~ion (Triton~, then three times wi~h deionized water. The wa~hed beads were th~n oven-dried at 70-C
~or 6 hours, and their diethyl-~-toluamide contents 2~ were determin~d by acetone ~xtraction to be 45%.

~xample IX
~Release of In~ect Repellant from ~eads) ~ O.S part sample of the diethyl-~~tolu~mide containing beads o~ Example VIII, on a sheet o~ filter paper, and a ~heet o~ filter paper impregnated with an equivalen~ amount of diethyl-m-toluamide, were heated under a vacuum of 25 inches of mercury at 1~0C ~or 10 : hours, during which time the percentage weight loss of diethyl-m-toluamide was determined each hour by weighing the bead and filter paper samples. The results of these weight loss determinations demonstrate that a high degree of sustained release can be achieved using the polymeric delivery sys~ems of this invention.

:
, , ` ~31~83 Example X
(Steroid) A 2000 ml four-necked reaction flask equipped with a stirrer, condenser, thermometer, and nitrogen inlet was evacuat~d and charged with nitrogen. 800 ml deionized water, 6.4 grams of gum arabic and 6.4 grams of a lignosulfonate available from the American can Co.
under the trademark Marasperse N-22, were charged into the reaction ~lask. The mixture was stirred for about 30 minutes. To this mixture was added a freshly prepared solution of 85.6 grams of styrene (99.8%
purity), 102.3 grams commercial divinylbenzene (55%
divinylbenzene), 5.33 grams benzoyl peroxide (70%
active ingredient and 30% water), and 187.9 grams of toluene to serve as a porogen. The phase and solution were agitated by a mechanical stirrer whose stirring rate of about 900-1200 rpm was adjusted to obtain a plurality of droplets having a droplet diameter smaller than about 50 microns. The gum arabic and lignosulfonate serve to stabilize the plurality of droplets. The reaction mixtur~ was heated to about 78 degrees Celsius while maintaining a constant rate o~
stirring and passing a slow stream of nitrogen through the reaction vessel. After about 2 hours cross-linking became noticeable. The mixture was stirred another 22 hours at 78C and was then allowed to cool to room temperature. The porous polymeric beads were removed from the reaction flask by filtration and washed several times with water to remove gum arabic and lignosulfonate, followed by several washes of isopropanol/acetone mixed solvent (7:3 by volume) and were finally stirred in ~00 ml of isopropanol/acetone mixed solvent (7:3) for 20 hours. The polymer was filtered and dried overnight at 65C in vacuo. The yield was practically quantitative. The residual monomers such as styrene, DVB and naphthalene were smaller than about 0.01%.

~31~8~

The calculated or theoretical cross-linking density of the purified beads iS 30~. This density is calculated by multiplying the weight of divinylbenzene (102.3 g~ by the purity of the divinylbenzene (.55) to get the actual weight of pure divinylbenzene which is then divided by the total weight of monomer t102.3 g +
85.6 g).
The surface area of a sample of the purifi~d beads was determined by the s.E. T . method to be 1.8 meters2/gram. The s.E.T. method is described in detail in srunauer~ s. Emmet, P.H., and Teller, E., J. Am.
Chem. Soc., 60, 309-16 (1938). The surface area of the polymer can be modified by using different porogens such as stable oil compounds which might include, by way of example only, mineral oil, vegetable oils or silicon oils.
The particle size of the beads was determined by an optical microscope to be 60 microns or less with an average approximate particle size diameter of about 10 microns.
The adrenocortical steroid fluocinonide (Syntex) was entrapped in the beads described above by exposing the beads to a 1% solution of fluocinonide in propylene carbonate : propylene glycol (7:3) for a period of time sufficient to allow the beads to absorb the active ingredient solution. The amount of active ingredient solution used relative to the amount of polymer beads was adjusted according to the desired final concentration of active ingredient to be contained within the beads. Where a low final concentration is desired~ the active ingredient solution may be further diluted With a solvent SUCh as acetone, methanol or ethanol prior to combining the solution wikh the beads in order to achieve a sufficient amount of starting solution to form a slurry with the beads. The diluent solvent was later removed by heating under a vacuum.

~ 3:l0~83 To obtain beads with a final active ingredient concentration of 0.05%, 7.6 g of the polymer beads described above were combined with 0.4 g of a 1%
solution of fluocinonide in propylene carbonate : pro-pylene glycol (7:3) and 14.8 g acetone. The initial slurry was stirred approximately every five minutes over a period of approximately thirty minutes, during which period the mixture becomes cake-like and, finally, powder-like in consistency. The resulting powder was then oven-dried for approximately three hours at 40 - 60C and 25 mmHg, at which point the powder reached a constant weight and the acetone was removed~ Similarly, a 0.25% formulation may be achieved by mixing 4.8 g polymer beads, 3.2 g steroid solution and 6.4 g acetone as described above.
It has been found that the therapeutic anti-inflammatory activity of fluocinonide-containing beads in a petrolatum-based delivery medium is comparable, based on final weight concentration of the fluocinonide, to that of commercially-available fluo-cinonide ointments such as Lidex~ (Syntex). Thus, ointments formed using the delivery vehicles of the present invention may employ active ingredient concen-tration parallel to those of typical ointments~ i.e., 0.01% to 1% by weight. It should be noted, however, that therapeutically effective anti-inflammatory compo-sitions may include as little as 0.00001% by weight steroid active inyredient and as much as 5% by weight steroid or higher. A range of 0.01% to 0.2% is parti cularly useful, with 0.01% to 0.05% being preferred for the more active corticosteroids such as the fluocino-nides, and 0.01% to 0.1% being preferred for less active corticosteroids such as the betnovates and the triamcinolones. When polymer beads containing active 3~ ingredient are used topically in powder form, thera-peutic anti-inflammatory activity may be lower than that of commercial ointments, although activity is ~310~83 increased and/or provided over longer time periods if the polymer heads are rubbed occasionally to promote release of the active ingredient.
Suit~ble ointments cont~ining polymer beads with active ingredlent were prepared by combining an appropriate amount of the polymer beads with petrolatum and an emulsifier (Amercho~ CAB). To achieve a 0.05%
fluocinonid~ ointment, 4.6 parts by weight (pbw) Amerchol CAB, 32.2 pbw white pe~rolatum USP (Ul~ima) and 50.7 p~w white petrolatum USP were ~irst combined and mel~ed, and 12.5 pbw 0.4% fluocinonide polymer beads was then mixed with the melted mixture and cooled. A 0.1% ointment was obtained by combining 4.o pbw Amerchol CAB, 28.4 pbw white petrolatum USP
(Ultima) and 42.6 pbw white petrolatum (usP) with 25.0 pbw 0.4~ fluocinonide ~eads. ~ 0~2% ointment was formula~ed by combining 2.6 p~w Amerchol CAB, 19~O pbw white petr~latum (USP) and 28.4 pbw white petrolatum USP wlth 50.0 pbw 0.4~ fluocinonide beads. By starting With polymer b~ad~ containing different amounts of active ingredient, the relative weight proportion o~ 1.
polymer bead delivery vehicle can be modulated.
The efficacy o the polymex bead d~livery vehicle of the present invention was demonstrated ~or both the powder and ointment forms of the beads using a vasoconstriction assay. This method is based on the Stoughton-McKenzie vasocontriction assay for cortico-steroid formulations (McKenzie, A.W., and Stought~n, R.B., "Method for Comparing Percutaneous Absorption of Steroids," Arch. Dermatol., 86, 608-lo (1962)). All test preparations was placad in identical container~, coded and assiqned by random tables to individual test ~ites. The test subjects are normal adult male and female volunteers not receiving any steroids and who have not participated in any studies using steroids for at least four weeXs prior to testing. The ~orearms of the subjects are prepared ~y gentle washing and drying.

~31~5~3 Strips of doubl~-adhesive coated slenderm~ tape (3M) with 7 x 7 mm prepunched squares are applied to each forearm to isolate the application sites. An appropri-ate dose of the test formulation (either 2 mg or 3 mg) was then applied to the skin in each square and was spread and rubbed with consistent pressure using a clean HPLC vial at each application site. In cases where powder-~orm polymer beads containing fluocinonide is used, the forearm was inverted after application and each individual site was gently brushed wit~ a clean square of gauze to remove excess polymer beads. A pro-tective cage was applied over the sites on the forearm designated for "open" application. On the other arm ("occluded") the sites were covered with Saran Wrap~, thP margins sealed With tape and a protective cage placed over the sites. A~ter six hours of exposure Of the skin to the corticosteroid preparations, all the tapes are removed and the forearms are washed.

Scoring in the assay was preformed by two experienced observers who independently scored the presence or absence of vasoconstriction and the degree and blanching at 8, 24 and 32 hours after the time of application of the formulations to the sites.
As evidenced in Table 3, the powder form polymer bead formulations o~ the present invention achleved slgnificant vasoconstriction as compared to commercially-supplied Lidex~ fluocinonide ointment (Syntex) not using a polymer bead delivery vehicle.
Although vasoconstriction due to the powder form polymer beads is somewhat less than that observed With the LidexT~ ointment, this difference may be due to the fact that excess powder formulation is brushed Off after application to the forearms. Table 4 demonstrates that intermittent rubbing of the powder-form formulations acts to promote and prolong vasoconstriction activity. Table 5 demonstrates that the polymer bead delivery vehicle of the present invention, when applied in an ointment form comparable to that of commercially supplied fluocinonide ointment, achieves a level of vasoconstriction approximately equal to that of the commercially-supplied product.
This effect is achieved independent of any rubbing of the polymer bead ointment subsequent to application.
It may be expected that such rubbing will further enhance vasoconstriction activity attributable to the delivery vehicle of the present invention.

" ~3~05~3 TABLE ~

Vasoconstrlction As~say Readings--Pol~nner Powder Porsulations ~ours After Application 8 24 32 Total %
_ _ FLUOCINONIDE FORMUI~TION
Polymer Bea ~ .4%) ~9~oe~
Sites Responding (%): 50.0 62.5 50.0 162.5 Intensity of Response (%): 22.9 22.9 16.7 62.5 Polymer Beads ~0.4%~
Open Application:
Sites R~p~nding ~: 62 . 5 56, 3 25. 0 143 . 8 Intensity o~
Responss (%): 25A 0 18.8 8.3 52.1 ~0 Ointment (O. 05%~ :
Occluded AppllcationA.
Sit~s Responding (%): loo. o 87 . 5 ~5 . 0 262 . 5 Intansity of ~esponse (~): 72.9 33.3 27.1 1~3.3 Ointment (0.05%~
open Application:
Sites Responding (~): 93.8 lOo.O 93.8 287.6 Intensity o~
Response (~): 68.3 39.6 31.3 139.7 NOTE: Dosage was 2 mg o~ polymer powder, wi~h entrapped fluocinonide ~0.4%), or 2 mg Lidex 0.05% fluocinonide ointment. Test sites were rubbed at time zero, washed at time 6 hours, and read at the times indicated.

"`` 1 3 ~ 3 E~fect o~ Re-Rubbing on Vasoconstriction Effect of Polymer Powder Formulations Hours After Application 8 24 32 Total %
FLUOCINONIDE FORMULATION
10Polymer Beads (0.5%) Sites Responding (Increase ~) 25.0 12.5 31.3 62.8 Intensity of Response (Increase ~) J8.3 4.1 10.4 22.8 15Polymer Beads (0.25%) Sites Responding (Increase %~ 0 31.3 31.3 62.6 Intensity o~ Response (Increase %) O 10.4 12.5 22.9 Polymer Beads (O.4%) Sites Responding (Inc~ease %) -18.7 12.5 25.0 18~8 Intensity of ResponsP
(Increase %) -10.4 4.1 10.4 4.1 ~
NOTE: Dosage was 2 mg of polymer powder, with entrapped fluocinonide at indicated proportion. All test sites were left open (unoccluded) and were rubbed and brushed off at time zero. Control powder sites were washed at time 6 hours; re-rubbed powder sites were re-rubbed at 6, 8, and 24 hours. Readings were made at times indicated.
Data represents percent readings taken at re-rubbed sites minus percent readings taken at corresponding control sites.

13~83 Vasoconstriction Assay Readin~s--Polymer-in-Ointment Formulations Hours After Application 8 24 32 Total %
FLUOCINONIDE FORMULATION
Polymer Beads (0.05% in Ointment-- Occluded) Sites Responding (%) 87.5 68.8 81.3 237.6 Intensity of Response (%) 75.0 29.2 29.2 133.4 Polymer Beads (0.05% in Ointment--Open) Sites Responding (~) 87.5 62.5 68.8 218.8 Intensity of Response (%) 72.9 20.8 25.0 118.7 Polymer Beads (0.1% in Ointment--Occluded) Sites Responding (%) 87.5 62.5 68.8 218.8 Intensity of Response (%) 66.7 25.0 22.9 114.6 Polymer Beads (0.1% in Ointment--Open) Sites Responding (~) 93.8 75.0 81.3 250.1 Intensity of Response (%) 72.9 27.1 29.2 129.2 Polymer Beads (0.2% in Ointment--Occluded) Sites Respondin~ (%) 75.0 81.3 81.3 237.6 Intensity of Response (%) 58.3 29.2 29.2 116.7 Polymer Beads (0.2% in Ointment--Open) Sites Responding (~) 93.8 62.5 37.5 193.8 Intensity of Response (~) 68.8 25.0 12.5 106.3 Commercial 0intment (0. 05%- -Occluded) Sites Responding (%) 93.8 68.8 68.8 231.4 Intensity o~ Re~ponse (~) 79.2 27.1 22.9 129.2 Commercial Ointment ~ _05%--Open~
Sites Responding (%) 87.5 75.0 87.5 250.0 Intensity of Response (%) 77.1 27.1 33.3 137.5 NOTE: Dosage was 3 mg of petrolatum-based ointment containing poly-mer powder, with entrapped fluocinonlde at indicated proportion, or 3 mg Lidex~ 0.05% fluocinonide ointment. Test sites were rubbed at time zero, washed at time 6 hours, and read at the times indicated.

~31~5~

In an additional study, fluocinonide was dissolved in a 30/70 propylene glycol/propylenP
carbonate system and entrapped in the polymer delivery system of the present invention. The degree of vasoconstriction produced served as an indicator of the release of the corticosteroid solution from the delivery system. Equal amounts o~ the beads were directly applied to human forearms, rubbed gently, and the excess powder brushed off. On one arm, no further application or manipulation was made. On the other arm, the site of initial application was gently rubbed at 7, 23, and 31 hours, but no additional product was added.
Vasoconstriction responses were measured and recorded at 8, 24, and 32 hours and the results are prese~ted in Table 6. The increased and continued vasoconstriction produced in the arm that was rubbed several times is definitive evidence of the demand and sustained release of the corticosteroid solution from the polymer del ivery system .

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5 ~ 3 Example XI
(Preparation of Beads) A 2000 ml four-necked reac~ion flask e~uipped with a motorized stirrer, reflux condenser, thermometer, and nitrogen inlet was evacuated and purged with nitrogen. 1200 parts of deionized water, 9.6 parts of gum arabic and 9.6 parts of a sodium-based lignosulfonate (Reed lignin) available from the American Can Co. under the trademark Marasperse N-22, were charged to the reaction flask. The mixture was heated, with stirring, in an oil bath at about 50 degrees Celsius until the dispersants (gum arabic and lignosulfate) dissolved to form an aqueous phase.
To this mixture there was then added a ~reshly prepared solution of 90.5 parts of styrene (99.8~ purity), 55 parts of commercial divinylbenzene (55.6% divinyl benzene, 42.3% ethylvinylbenzene), 2 parts of benzoyl peroxide (70% active ingredient and 30% water), and 69.4 parts of toluene (porogen). The aqueous phase and organic solution were agitated by stirring at a rate adjusted to give a plurality of droplets having an average droplet diameter of about 10-60 microns, as determined by visual observation of a sample of the droplets with an optical microscope (400X) with the droplets being stabilized by the dispersants. The reaction mixture was then heated to about 85 degrees Celsius and maintained at that temperature for about 12 hours, at the previously adjusted stirring rate, to ~orm porous beads of cross linked styrene/divinylbenzene copolymer having toluene entrapped within the network of pores. The mixture was then cooled and the porous polymeric beads were removed from the reaction flask by filtration.
The filtered beads were washed initially three times ~5 with one liter portions of deionized water to remove the dispersants, followed by three washes with one liter portions of isopropanol to remove any residual, 131~

unreacted monomer and the toluene used as the porogen during polymerization~ The beads were then dried in an oven for eight hours. The average particle diameter of these beads, which were white and opaque in appearance, indicating their macroporosity, was less than 35 microns, as measured by a mercury intrusion porosimeter or by optical microscopy.
The calculated or theoretical cross-linking density of the purified beads is 21.01%. This density is calculated by multiplying the weight of divinylbenzene (55 parts) by the purity of the divinylbenzene (0.556) to get the actual weight of pure divinylbenzene which is then divided by the total weight of monomer (90.5 parts ~ 55 parts) and multiplied by 100.
The surface area of a sample o~ the purified heads was determined by the B.E.T. method to be 36.41 meters /gram while the pore volume was determined by nitrogen adsorption isotherm to be 0.206 ml/gram. The B.E.T. method is described in detail in Brunauer, S.
Emmit, P.H., and Teller, E., J. Am. Chem. Soc., 60:309-16 (1938). The nitrogen adsorption isotherm method is described in detail in Barrett, E.P., Joyner, L.G. and Helenda, P~P., J. Am. Chem. Soc., 73:373-80 (1951).

Example XII
(Emollient) A 30 part portion of the macroporous cross-linked polymer beads prepared as described in Example XI above was mixed at room temperature with 100 ml of ethyl acetate. Then 15 parts o~ Carnation White Mineral Oil, U . S . A. Light, were added with stirring, and the resulting suspension was hand-stirred for a few minutes. The solvent was then allowed to evaporate to dryness. The beads contained 33% mineral oil entrapped within their macropores.

~ 3 ~ 3 Example XIII
(Emollient) A 2000 ml four-necked reaction flask equipped with a motorized propeller-type stirrer, reflux condensor, thermometer, and nitogen inlet was evacuated and p~rged with nitrogen. 800 parts of deionized water, 6.4 parts of gum arabic and 6.4 parts of a sodium-based lignosulfonate (Reed lignin) available from the American Can Co. under the trademark Maraspere N-22, were charged to the reaction flask.
The mixture was heated, with stirring, in an oil bath at about 60C until the dispersants (gum arabic and lignosulfate) dissolved to form an aqueous phase.
To this mixture there was then added a freshly prepared solution of 102.3 parts of styrene (99.8% purity), 85.6 parts of commercial divinylbenzene (55.6% divinylbenzene, 42.3% ethylvinylbenzene), 5.3 parts of benzoyl peroxide (70% active ingredient and 30% water), and 190 parts of heptane (porogen). The aqueous phase and organic solution were agitated by stirring at a rate adjusted to obtain a plurality of droplets having an average droplet diameter of below about 60 microns, as determined by visual observation of a sample of the droplets with an optical microscope (400X), with the droplets being stabilized by the dispersants. This rate is approximately 1200 rpm.
The reaction mixture was then heated to about 80-90C and maintained at that temperature for about 20 hours at the previously adjusted stirring rate, while maintaining a nitrogen flow of 1 ml/min, to form porous beads of cross-linked styrene/divinylbenzene copolymer having heptane (porogen) entrapped within the network of pores. The mixture was then cooled, diluted with 200 parts of water, and the porous polymeric beads were removed from the reaction flask by filtration. The filtered beads were washed initially 3 times with 1 liter portions of water to remove the dispersants, - ~3~8~

followed by three washes with 0.6 liter of a mixed solution of isopropyl alcohol and acetone (7:3 by weight) to remove any residual, unreacted monomer and the heptane used as the porogen during polymerization.
The beads were then dried at room temperature for 20 hours and then in an oven at 100C for 20 hours. The average particle diameter of these beads, which were white and opaque in appearance, indicating their macroporosity, was less than approximately 2S microns and they had a pore volume of 0. 68 ml/g and a surface area of 58 m /g.
The calculated or theoretical cross-linking density of the purified beads is 25%. This density is calculated by multiplying the weight of divinylbenzene 85.6 parts by the purity of the divinylbenzene (0.5~6) to get the actual weight of monomer 102.3 parts + 85.6 parts and multiplied by 100.
The surface area of a sample of the purified beads was determined by the B.E.T. (Brunauer, Emmett and Teller) method and the pore volume was determined by mercury intrusion porosimetry.

Examples XIV and XV
(Emollient) By repeating the procedure of Example XIII in every essential detail except for the weights of monomers used and the amount and type of porogen present, the macroporous polymer beads prepared as described in mable 7 below were obtained.

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~ ' ~ 3 ~ 3 Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be obvious that certain changes and modifications may be practiced with.in the scope of the appended claims.

Claims (15)

1. A method for preparing a delivery system for an active substance, said method characterized by introducing the active substance in liquid form to a plurality of preformed rigid cross-linked polymer beads each defining an internal network of pores capable of retaining the active substance, said beads having a total pore volume in the range from about 0.1 to 2.0 cc/g, a surface area in the range from about 1 to 500 m2/g, and an average pore diameter in the range from about 0.001 to 3.0 µm.

2. A method as in claim 1, wherein the preformed beads have a cross linking density of at least about 10% and an average diameter in the range from about 5 µm to 100 µm.

3. A method as in claim 2, wherein the preformed beads have a cross-linking density in the range from about 20% to 80% and a diameter in the range from about 10 µm to 50 µm.

4. A method as in claim 1, wherein the pore volume is in the range from about 0.3 to 1.0 cc/g, the surface area is in the range from about 20 to 200 m2/g, and the average pore diameter is in the range from about 0.003 to 1.0 µm.

5. A method as in claim 1, wherein the preformed rigid polymeric beads are selected from the group consisting of a styrene-divinylbenzene copolymer and a methyl methacrylate-ethylene glycol dimethacrylate copolymer.

6. A method as in claim 1, wherein the active substance is selected from the group consisting of UV absorbants, insect repellant substances, steroids, and emollients.

7. A method as in claim 4, wherein the active substance is a UV absorbant selected from the group consisting of aminobenzoates, cinnamates, benzones, and salicylates.

8. A method as in claim 4, wherein the active substance is an insect repellant substance selected from the group consisting of terpenoids, benzoquinones, aromatics, and synthetics.

9. A method as in claim 4, wherein the active substance is an adrenocortical steroid.

10. A method as in claim 4, wherein the active substance is an emollient.

11. A delivery system capable of retaining an active substance, said delivery system comprising a plurality of cross-linked polymer beads characterized by a rigid, substantially non-collapsible pore network open to the exterior of said beads and which is substantially free from retained substances, said beads having a total pore volume in the range from about 0.1 to 2.0 cc/g, a surface area in the range from about 1 to 500 m2/g, and an average pore diameter in the range from about 0.001 to 3.0 µm.

12. A delivery system as in claim 11, wherein the beads have a cross-linking density of at least about 10% and an average diameter in the range from about 5 µm to 100 µm.

13. A delivery system as in claim 11 or 12, wherein the beads have a cross-linking density in the range from about 20% to 80% and a diameter in the range from about 10 µm to µm.

14. A delivery system as in claim 11, wherein the polymeric beads are selected from the group consisting of a styrene-divinylbenzene copolymer and a methyl methacrylate-ethylene glycol dimethacrylate copolymer.

15. A sunscreen composition comprising substantially rigid polymeric beads each defining a network of substantially non-collapsible pores open to the exterior of said beads and having a UV absorptive substance absorbed within said network of pores, said UV absorptive substance comprises from about 5% to 65% of the sunscreen composition by weight, wherein said beads have a cross-linking density in the range from about 20% to 80%, an average diameter in the range from about 10 µm to 40 µm, a pore volume in the range from about 0.3 to 1.0 cc/g, a surface area in the range from about 20 to 200 m2/g, and an average pore diameter in the range from about 0.003 to 1.0 µm.