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WO1993007862A1 - Billes ioniques permettant la liberation regulee et l'adsorption - Google Patents

Billes ioniques permettant la liberation regulee et l'adsorption Download PDF

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Publication number
WO1993007862A1
WO1993007862A1 PCT/US1992/008907 US9208907W WO9307862A1 WO 1993007862 A1 WO1993007862 A1 WO 1993007862A1 US 9208907 W US9208907 W US 9208907W WO 9307862 A1 WO9307862 A1 WO 9307862A1
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WIPO (PCT)
Prior art keywords
hydrogel
ionic
group
water
accordance
Prior art date
Application number
PCT/US1992/008907
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English (en)
Inventor
Sergio Nacht
Richard Won
Martin A. Katz
Tai Cheng
Christine J. Y. Liau
Robert P. Eury
Michael Froix
Original Assignee
Advanced Polymer Systems, Inc.
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Filing date
Publication date
Application filed by Advanced Polymer Systems, Inc. filed Critical Advanced Polymer Systems, Inc.
Priority to JP5507855A priority Critical patent/JP2516322B2/ja
Priority to KR1019940701299A priority patent/KR100295333B1/ko
Priority to AU28815/92A priority patent/AU662181B2/en
Priority to EP92922201A priority patent/EP0612241A4/en
Publication of WO1993007862A1 publication Critical patent/WO1993007862A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • A61K8/817—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by a single or double bond to nitrogen or by a heterocyclic ring containing nitrogen; Compositions or derivatives of such polymers, e.g. vinylimidazol, vinylcaprolactame, allylamines (Polyquaternium 6)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A61K47/585—Ion exchange resins, e.g. polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0241—Containing particulates characterized by their shape and/or structure
    • A61K8/0279—Porous; Hollow
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/81—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
    • A61K8/8141—Compositions of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides or nitriles thereof; Compositions of derivatives of such polymers
    • A61K8/8152—Homopolymers or copolymers of esters, e.g. (meth)acrylic acid esters; Compositions of derivatives of such polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/54—Polymers characterized by specific structures/properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/54—Polymers characterized by specific structures/properties
    • A61K2800/546—Swellable particulate polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/56—Compounds, absorbed onto or entrapped into a solid carrier, e.g. encapsulated perfumes, inclusion compounds, sustained release forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/60—Particulates further characterized by their structure or composition
    • A61K2800/65—Characterized by the composition of the particulate/core
    • A61K2800/654—The particulate/core comprising macromolecular material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
    • A61Q17/04—Topical preparations for affording protection against sunlight or other radiation; Topical sun tanning preparations

Definitions

  • the present invention relates generally to the preparation of topical and oral compositions. More particularly, it relates to the preparation of ionic polymer delivery systems which prolong the activity of various topically active ingredients by increasing the substantivity on keratinic materials, such as hair and skin, and to orally delivered polymers which release active substances via ion-exchange.
  • the adherent properties of topically-applied substances on hair and skin affects both initial adsorption and retention, particularly on subsequent exposure to water.
  • the combined characteristics of adsorption and retention constitute the property referred to as "substantivity,” which can be defined as the ability of a substance to be adsorbed onto keratin and to resist removal by water rinse-off.
  • An ideal topical substance would have adsorptive affinity for keratinic materials, retain activity for long periods of time, resist being washed away by perspiration and other contact with water, and be free of adverse interactions with other ingredients of which incorporation is desirous. No topical substance has yet been discovered which adequately satisfies all of these objectives.
  • topically active preparations available in the market today include, for example, fragrance substances; cosmetic substances, such as lipsticks, make-up and foundation powders; insect repellents; anti-bacterials; acne treatment formulations; hair treatment formulations, such as conditioners and hair growth promoting agents; and skin protection formulations, such as age-prevention agents; and ultraviolet absorbing substances (sunscreens) .
  • fragrance substances such as lipsticks, make-up and foundation powders
  • insect repellents such as insect repellents
  • anti-bacterials such as acne treatment formulations
  • hair treatment formulations such as conditioners and hair growth promoting agents
  • skin protection formulations such as age-prevention agents
  • ultraviolet absorbing substances unsunscreens
  • a frequently observed problem with such topically active substances is the rapid loss of activity after application to the skin.
  • concentration of the above substances in their respective topical compositions is either diluted, thereby reducing effectiveness, or washed away, thereby losing all effectiveness.
  • One way to extend activity is by increasing the concentrations of the active ingredient in their respective formulations. However, as concentrations are increased, so too are the risks of toxic and allergic reactions to the user. These reactions often occur with the higher concentrations, even if exposure to the product is relatively short.
  • a second drawback, unrelated to the safety of administration of such compositions, is the increased expense of using such compositions which are so easily washed away. For instance, to maintain an adequate level of protection from the sun, a sunbather would have to reapply sunscreen each time after entering the water and frequently after perspiring. It would therefore be highly desirable to provide an approach for increasing the adsorptive affinity of topically active compositions to keratinic materials, and for prolonging the activity of such compositions, while simultaneously reducing the likelihood of toxic and/or allergic reaction to the user.
  • compositions and methods for the release of an active substance, such as a drug, from a reservoir over time are known, and numerous specific approaches exist to achieve such controlled release.
  • Two widely practiced approaches are of particular interest to the present invention.
  • drugs or other active substances are encapsulated or coated with a material which dissolves or degrades in response to a change in environmental conditions.
  • pH- response coatings referred to as enteric coatings
  • enteric coatings may be provided on drugs to protect the drug in the low pH environment of the stomach but dissolve when the pH rises as the drug passes to the intestines.
  • Such coatings include cellulose acetate, phthalate-polyvinyl acetate phthalate, hydroxypropylcellulose phthalate, methyl cellulose phthalate, and the like.
  • a less widely employed delivery approach utilizes porous polymeric particles for absorbing and releasing drugs and other active substances at a controlled release rate. See, e.g., U.S. Patent No. 4,692,462, discussed below.
  • the diffusion rate of the drug or other active substance through the pores determines the release rate.
  • the diffusion rate depends on pore size, drug viscosity, temperature, and the like.
  • drugs absorbed in porous polymeric particles are usually combined in an adhesive or other matrix material as part of a transdermal drug delivery system.
  • drugs have been adsorbed onto porous resin beads which are then coated with a membrane diffusion barrier, e.g., ethylcellulose, in order to effect sustained release.
  • a membrane diffusion barrier e.g., ethylcellulose
  • drugs have been adsorbed onto porous resin beads which are then coated with a membrane diffusion barrier, e.g., ethylcellulose, in order to effect sustained release.
  • a membrane diffusion barrier e.g., ethylcellulose
  • Synthetic resin-based ion exchangers are conventionally produced by post-polymerization modification of preformed, cross-linked beads.
  • anion exchange resins are made from cross-linked polystyrene by halogen-alkylation and subsequent amination.
  • Cation exchange resins can be made by either carboxylation or sulfonylation of the preformed, cross ⁇ linked beads.
  • Such ion exchange resins are typically discolored, have capacities for the exchange of ion less than 2meq/gm, and regeneration can be a lengthy process.
  • Naturally occurring ion exchangers such as cellulose- based or dextran gels which are made by introducing functional groups onto the cross-linked natural polymers, have gel structures which are not mechanically strong enough to prevent the gel matrix from shrinking or collapsing as the active ingredient is removed.
  • the natural polymer-based materials are unstable in the presence of oxidants or strong acids, at elevated temperatures (e.g., 120°C for 30 minutes), and because of their biological origins, they will support bacterial and microbial growth.
  • compositions and methods for the delivery of drugs and other active substances It would be particularly desirable if the compositions could be readily modified to achieve a desired release rate for active substances having a wide range of physical and chemical characteristics. It would be further desirable if the compositions could be modified to control the release rate of such diverse active substances under a variety of different external conditions, such as pH, temperature, ionic strength, and the like. It would also be desirable if compositions could be readily modified to allow absorption of bile salts in a controlled and predictable manner.
  • U.S. Patent No. 4,690,825 discloses an uncharged polymer bead delivery system suitable for topical application.
  • U.S. Patent No. 4,304,563 discloses cationic polymers (and methods for their preparation) useful as gels for treatment .of keratinic materials, such as hair.
  • European patent application 225615 discloses the use of cationic beads formed from a polystyrene sulfonate-divinyl benzene copolymer for the controlled oral delivery of negatively-charged drugs.
  • South African patent application no. 872554 and U.S. 4,221,778 discloses sulfonic acid cationic ion exchange resin particles which have been impregnated with certain agents to enhance their suitability for oral drug delivery.
  • U.S. Patent No. 3,691,270 discloses cosmetic compositions for the skin comprising microcapsules formed from an alveolar polymer, including polyvinylpyridine. The microcapsules, however, are uncharged.
  • U.S. Patent No. 3,880,990 discloses orally-administratable compositions comprising drugs encapsulated in an anionic polymer.
  • U.S. Patent No. 4,198,395, discloses a charged polymeric resin material which is useful for the treatment of hypercholesterolemia by oral administration.
  • U.S. Patent No. 4,552,812 discloses the preparation of fluorescent and magnetic anionic beads useful in performing assays.
  • European patent application 060 138 discloses the preparation of porous copolymeric blocks capable of absorbing and acting as a reservoir for liquids, such as perfume.
  • European patent application 143 608 discloses a polymeric bead composition having a releasable lipophilic compound retained therein.
  • British patent 1,482,663 describe polymeric bead compositions capable of holding water-soluble drugs.
  • Cationic polymeric ion exchange resins, including styrene-divinylbenzene copolymers, are commercially available from suppliers such as Interaction Chemicals, Inc., Mountain View, California 94043; and Reilly Tar & Chemical Corp., Indianapolis, Indiana 46204.
  • the ability of cationic materials to adsorb to the skin and hair is discussed in Goddard (1987) Cosmetics & Toiletries 102:71-80.
  • the present invention provides for the incorporation of active and inert substances in an ionic polymer bead delivery system to form novel compositions. It has been found that when a cationic functionality is imparted on the surface of. the polymeric bead surface, the substantivity of the topically active substances when the beads are applied to the skin or hair is enhanced.
  • Cationic topical polymeric delivery systems according to the present invention are keratinophilic compositions which exhibit an affinity for skin, hair, and other biological molecules and can be used to adsorb bile salts when delivered orally.
  • the anionic delivery systems can deliver basic drugs orally.
  • the ionic polymer bead delivery system comprises crosslinked polymer beads characterized by ionic functionalities on the bead surface, usually positively charged pyridine and quaternary ammonium groups in the cationic beads, and negatively charged sulfonates and carboxylates in the anionic beads.
  • the beads form a porous network capable of retaining large amounts of inert and active substances.
  • the beads are non-collapsible, small diameter, having relatively large pores and a relatively high ratio of pore volume to bead volume.
  • the cationic polymer bead delivery system having topically active ingredients incorporated therein may be used as a topical product by itself or may be further incorporated into a carrier composition' or other cosmetic product.
  • the cationic polymeric delivery system with incorporated topically active ingredient is a dry, free-flowing product which can be rubbed directly onto the skin, providing controlled release of the topically active ingredient over a prolonged period of time.
  • the cationic polymeric delivery system is incorporated in other carriers, vehicles, solvents, or cosmetic preparations, use of this delivery system avoids incompatibilities, typically chemical or physical interactions, which might otherwise exist between the active ingredient and other ingredients in the topical preparation, or between the active substance and the carrier, vehicle, or solvent.
  • a variety of physiologically-acceptable solvent or medium may be used as a carrier.
  • the carrier should be at least slightly acidic, preferably being below about 5, and most preferably being in the range from about 3 to 4. With carboxylate-based beads, the carrier should have a pH above about 5. It will often be desirable to incorporate a physiologically-acceptable buffer in the carrier to maintain the pH within the range of interest.
  • the ionic polymer bead delivery systems may be formed by suspension or inverse suspension polymerization of suitable monomers, at least some of which include functionalities carrying or capable of carrying either a positive or negative charge under the conditions of use, in an immiscible phase (including a porogen for suspension polymerization of non-aqueous monomers) .
  • an immiscible phase including a porogen for suspension polymerization of non-aqueous monomers
  • the monomers (and the porogen if used) are first mixed together and the resulting mixture is then suspended in the immiscible phase.
  • the immiscible phase is then agitated to form droplets of the monomer mixture, and polymerization of the monomer mixture is initiated to form the desired beads.
  • Cationicity i.e., cationic functionality
  • a preformed cationic monomer e.g., a quaternary amine monomer (which carriers a substantially permanent charge under the conditions of use)
  • protonating (or quaternizing) surface functionalities in the formed bead e.g., protonating a quaternary nitrogen in pyridine with an acid medium.
  • protonation may be performed either before or after entrapping the active ingredient, depending on the conditions and the chemical characteristics of the particular ingredient sought to be incorporated.
  • Anionicity i.e., anionic functionality
  • Anionicity may be obtained by suspending, for example, sulfonated styrenic beads in a basic solution.
  • the topically active substance may be used as a porogen in a one-step process where there will be no substantial degradation of the substance under the conditions of polymerization and the substance is otherwise suitable.
  • the compositions of the present invention may be formed using a two-step process.
  • the polymeric beads may be preformed using a substitute porogen, for example, an alkane, cycloalakane, or aromatic solvent.
  • the beads are formed by suspension polymerization or inverse suspension polymerization and the substitute porogen is extracted from the resulting bead product.
  • the desired active substance may then be introduced into the beads, typically by contact absorption, to create the desired product.
  • the polymeric beads may be rendered cationic or anionic either before or after entrapping the active substance into the delivery system, or by the use of charged monomers.
  • a two-step preparation process allows greater control over the structure of the bead based on a wider choice of porogen substances in reaction conditions, and thus may be the desired preparatory method even for less labile substances.
  • active substances incorporated into the topically applied cationic polymer bead delivery system of the present invention have been found to provide enhanced effectiveness when compared to similar concentrations of the ingredient in non-cationic polymeric bead delivery systems.
  • sunscreen preparations incorporated into systems comprising cationic polymeric beads will be expected to have an enhanced SPF (Sun Protection Factor) rating when compared to otherwise identical preparations comprising a non-cationic polymer bead delivery system.
  • Orally deliverable polymeric particles according to the present invention comprise ionic polymeric hydrogel particles, each defining a network of internal pores, composed of an ionic monoethylenically unsaturated monomer and a highly water-soluble polyethylenically unsaturated cross-linking monomer.
  • An oppositely charged counter ion is included for rendering the hydrogels neutral.
  • the hydrogels are unique in that the swelling ratio, r ⁇ , determined as the ratio of the swollen particle size (water) to the non-swollen particle size (dioxane) is not directly proportional to the amount of cross-linking monomer used during polymerization of the particles, an unexpected result.
  • EWF equilibrium water fraction
  • Oral compositions according to the present invention comprise the ionic hydrogels and counterion, wherein the counterion is either inert or pharmaceutically active, such as a drug, and ionically held within the internal pore network.
  • the counter ion is exchanged for a solute ion in a predetermined aqueous environment, such as an animal or human digestive track.
  • the counter ion is a weakly basic, positively-charged drug which is delivered to the gastrointestinal track upon change in pH and/or ionic strength of the gastrointestinal track.
  • the ionic hydrogels are formed by inverse suspension radical polymerization of suitable ionic monomers cross-linked with a monomer that is soluble in aqueous solutions in all proportions.
  • the ionic monomer is mixed with the counterion and the resulting mixture combined with the water-soluble cross-linking monomer to form an aqueous phase.
  • An initiator is added to the aqueous phase and the resulting mixture suspended in an organic phase.
  • the organic phase is then agitated to form droplets of the aqueous monomer phase, and polymerization of the monomers initiated to form the desired beads from the droplets.
  • the precise dimensions and characteristics of the beads are controlled by varying process parameters such as the amount of water used during polymerization, agitation speed, and varying the amount or type of monomer chosen.
  • the beads can either be used as is (if an inert or stable active ingredient was used as counterion) or loaded with an appropriate labile active counterion by repeated exposure to a drug in a chromatographic column, or by prolonged contact of the hydrogel beads with the drug solution.
  • Fig. 1 shows the effect of cross-link density of poly(trimethylammoniumethylmethacrylic chloride-co- N,N'-methylenebisacrylamide) hydrogels on their aqueous swelling •% swelling v/v; 83% water; ⁇ % swelling, 70% water; ⁇ E.W.F. (equilibrium water fraction) , 83% water.
  • Fig. 2 shows release profiles of D&C Red No. 28 from various beads, including a cationic hydrogel ( ⁇ ) ; a cationic hydrogel in an anionic surfactant (A) ; and an uncharged bead (•) .
  • Fig. 3 shows how the equilibrium water fraction of the hydrogels increases in direct proportion to the water content during polymerization and is substantially independent of the cross-linked density.
  • Fig. 4 shows that no D&C Red No. 28 (an anionic dye) was released from a cationic hydrogel loaded macroporous carrier until an anionic surfactant (sodium dodecyl sulfate) was present.
  • Fig. 5 shows release profiles of tetracycline- HC1 from anionic hydrogels when a cationic surfactant is added.
  • Fig. 6 shows the swelling behavior of hydrogels as a function of pH.
  • the beads or microspheres used in connection with the present invention can be rigid or non-rigid, and are open-pore, chemical and biologically inert particles, with a positive or negative charge imparted on the surfaces and an impregnant held inside the pores by capillary and ionic forces, where the impregnant is a topically or orally active substance or an inert counter ion.
  • the charge (positive) is sufficient to promote adhesion of the particles to keratinic materials, such as human skin and hair.
  • the pores are interconnected and open to the particle surface so that substantially full communication is provided between the internal pore space and the exterior of the particle whereby the impregnant may be released over time after the beads are applied to the user's skin or hair, or, in the case of orally delivered drugs, to the GIT.
  • the cationicity of the polymeric beads of the present invention derives from the presence of a functionality capable of being protonated (or already charged) on at least some of the monomers being polymerized.
  • the beads will have charge density sufficient to produce a binding affinity for a counter ion measured by the weight distribution coefficient method of at least about l.OxlO 6 ml/gm.
  • the ionic hydrogels will also have porosity and charge density sufficient to afford a counter-ion capacity of at least 45% by weight of total hydrogel.
  • the cationic functionalities of particular interest to the present invention include both pyridine which has a tertiary nitrogen and ammonium which has a quaternary nitrogen, each of which is capable of carrying a positive charge under the conditions of use of the topical compositions.
  • the anionic functionalities of particular interest include sulfonates and carboxylates.
  • Beads according to the present invention will have surface charge densities ranging from about 0.1 to 10 milliequivalent/gram (meq/gm) capacity for hydrogen ion in water (determined by conventional acid-base titration) , usually from about 0.2 to 10 meq/gm, more usually from about 0.5 to 10 meq/qm, and preferably from about 5.0 to 10 meq/gm (also determined by conventional acid-base titration) .
  • meq/gm milliequivalent/gram
  • the particles are generally spherical in shape, due to the use of suspension or inverse suspension polymerization as the preferred methods of preparation. While such microspheres vary widely in size, those falling within the range of about 5 to about 100 microns in diameter, preferably from about 10 to about 40 microns, will provide the best results. Microspheres within these size ranges are appealing from an aesthetic point of view by imparting a smooth feel to the touch when applied topically, and are easily expelled when delivered orally.
  • the pore dimensions within the spheres may also vary widely, with optimum dimensions depending on the chemical characteristics of the polymers used, as well as the diffusive characteristics of the impregnant.
  • pore volume distribution ranging from about 0.01 to about 4.0 cc/g, preferably from about 0.1 to about 2.00 cc/g, surface areas ranging from about 1 to about 500 m 2 /g, preferably from about 20 to about 200 m 2 /g, and the average pore diameters ranging from about 0.001 to about 3.0 micron, preferably from about 0.003 to about 1.0 micron.
  • the pore diameters are calculated from the measurement of the surface area by B.E.T. nitrogen analysis (Brunaer et al. (1938) J.
  • the particles are conveniently formed as microspheres by suspension polymerization in a liquid- liquid system.
  • a solution containing the desired monomers, a polymerization catalyst (if used) , and an inert fluid (porogen) is formed in a first liquid phase, where the porogen is miscible with the first fluid phase but immiscible with a second liquid phase.
  • the solution is then suspended in the second liquid phase which is immiscible with the first liquid phase.
  • the first liquid phase will usually be an organic solvent capable of dissolving the monomers but which is immiscible with water, and the second liquid phase will be water.
  • the first liquid phase will be aqueous (with water as the porogen) while the second phase will be a hydrophobic organic solvent.
  • impregnants may serve as porogen and, as previously mentioned, may be entrapped within the porous network of the present invention before or after the charge producing steps described above.
  • the critical factor in choosing the impregnant for topical applications is its electrical charge. That is, in order to preserve the ionic functionality of the beads when applied to the skin or hair, the impregnant must be substantially neutral. Slightly negative or positive substances may be used; however, their entrapment must not neutralize or otherwise affect the surface charge of the bead.
  • the impregnant so selected serves as the porogen, the porous beads recovered from the suspension immediately after polymerization are substantially ready for use, following removal of surface moisture, and any further processing steps of this nature, including ionization.
  • the steps must be performed under an inert atmosphere such as nitrogen.
  • a polymerization catalyst it must be one which does not oxidize the impregnant, if the latter is susceptible to oxidation.
  • Azo catalysts are examples of such catalysts.
  • polymerization temperatures are being held within a moderate range.
  • the substantially neutral impregnant may be placed inside the pores of preformed dry porous polymer beads.
  • the product is prepared in two steps, performed in sequence, wherein polymerization is performed first with a substitute porogen which is then removed and replaced by the desired active ingredient.
  • the porogen and active ingredients are distinct components in this two-step process.
  • Materials suitable as substitute porogens will be substances which meet the five criteria listed above for porogen impregnants.
  • hydrocarbons particularly inert, non-polar organic solvents.
  • alkanes alkanes, cycloalkanes, and aromatics.
  • solvents alkanes of 5 to 12 carbon atoms, straight or branched chain, cycloalkanes of 5 to 8 carbon atoms, benzene, and alkyl-substituted benzenes such as toluene and the xylenes.
  • Porogens of other types include C 4 - C ⁇ alcohols, perfluoro polyethers, and oils. Removal of the porogen may be effected by solvent extraction, evaporation, or similar conventional operations. As noted above, in the case of water-soluble monomers, water serves as porogen.
  • a further advantage of the use of this two-step process is that it permits the removal of unwanted species formed within the polymerized structures prior to incorporation of the impregnant.
  • unwanted species include unreacted monomers, residual catalysts, and surface active agents and/or dispersants remaining on the sphere surfaces.
  • a further advantage of this technique is that it permits one to select the amount and type of porogen as a means of controlling the pore characteristics of the finished bead. One is thus no longer bound by the limitations of the impregnant as it affects the structure of the bead itself. This permits partial, rather than full, filling of the pores with the impregnant, and further control of the pore size and distribution by selection among swelling and non-swelling porogens.
  • Extraction of the porogen and its replacement with (i.e., impregnation of the dry bead with) the impregnant in the two-step 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.
  • the beads are first recovered from the suspension by filtration, preferably using vacuum filtration apparatus (such as a Buchner 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.
  • an alternative method of extraction may be used — i.e., where the porogen, un ⁇ reacted monomer and water will form an azeotrope.
  • steam distillation is an effective way of extracting porogen from the beads. This again may be followed by drying under vacuum.
  • the beads may be used orally as is to absorb oppositely charged species or are impregnated with the impregnant according to conventional techniques.
  • the most convenient such technique is contact absorption.
  • Solid active ingredients are first dissolved in a solvent, and the resulting solution is absorbed by the beads.
  • the solvent may either be retained in the finished product or removed by conventional means such as evaporation or extraction using a further solvent.
  • high contents in the finished bead can be attained by repeated absorptions each followed by solvent removal.
  • the impregnant may be, for example, a basic positively- charged drug which is loaded into a matrix of anionic (negatively-charged) beads via chromatographic methods, such as ion exchange chromatography. In that case, the positively-charged counter ion is exchanged with the drug molecules.
  • the polymerization process and the various parameters and process conditions involved in the poly ⁇ merization can be selected and adjusted as a means of controlling the pore characteristics and consequently the capacity and release characteristics of the ultimate product.
  • proper selection of the crosslinking means, the amount and type of crosslinking agent, and the amount and type of porogen are means of attaining such control.
  • Certain polymerization conditions may also be varied to such effect, including temperature, degree of radiation where used, degree of agitation and any other factors affecting the rate of the polymerization reaction.
  • Crosslinking in the polymer formation is a major means of pore size control.
  • Monomers which may be polymerized to produce crosslinked polymer beads in accordance with the present invention include polyethy- lenically unsaturated monomers, i.e., those having at least two sites of unsaturation, and monoethylenically unsaturated monomers in combination with one or more polyethylenically unsaturated monomers. In the latter case, the percentage of crosslinking may be controlled by balancing the relative amounts of monoethylenically unsaturated monomer and polyethylenically unsaturated monomer.
  • Such systems will include a single monoethylenically saturated monomer and a single polyethylenically unsaturated monomer, although it will be possible to add additional compatible monomers of each type to the system, if desired.
  • additional compatible monomers of each type for a discussion of the preparation of such copolymer systems, see Guyot and Bartholin, Design and Properties of Polymers as Materials for Fine Chemistry, Prog. Polym. Ed. (1982) Vol. 8, pp 303-307.
  • Monoethylenically unsaturated monomers which may be used as part of the monoethylenically unsaturated monomer content of the polymer delivery system include ethylene, propyiene, isobutylene, diisobutylene, styrene, sodium styrene sulfonate, ethylvinylbenzene, vinylbenzene chloride, vinyl pyridine and its derivatives, vinyltoluene, and dicyclopentadiene; esters of acrylic and methacrylic acid, including the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, amyl, hexyl, octyl, ethylhexyl, decyl, dodecyl, cyclohexyl, isobornyl, phenyl, benzyl, alkylphenyl, ethoxy ethyl,
  • polyethylenically unsaturated monomers which ordinarily act as though they have only one unsaturated group, such as isopropene, butadiene and chloroprene, may also be used as part of the monoethylenically unsaturated monomer content.
  • At least a portion of the monomer content will comprise protonatable functionalities which are capable of retaining a positive charge under the conditions of use.
  • protonable functionalities may be present on the monoethylenically unsaturated monomers, the polyethylenically unsaturated monomers, or both, where suitable functionalities include pyridine and ammonium.
  • Exemplary monomers include vinyl pyridines, such as 2-vinyl pyridine, 4-vinyl pyridine, 3-methyl-2-vinyl pyridine, 4-methy1-2-vinyl pyridine, 6-methyl-2-vinyl pyridine, 3-ethyl-2-vinyl pyridine, 5-ethyl-2-vinyl pyridine, 2-methyl-3-vinyl pyridine, 2-methyl-4-vinyl pyridine, 2-methyl-5-vinyl pyridine, and 2-ethyl-5-vinyl pyridine, as well as water-soluble acrylated and methacrylates, such as methacrylamidopropylhydroxy- ethyldimethylammonium acetate , methacrylamidopropyl- trimethylammonium chloride, and the quaternization products of dimethylaminoethylmethacrylate and dimethyl sulfate, diethylaminoethylacrylate and dimethyl sulfate, vinyl
  • Suitable polyethylenically unsaturated monomers include N,N'-methylenebisacrylamide; N,N•-nonamethylenebis- acrylamide; and alkoxylated water soluble multi ⁇ functional acrylates.
  • the inverse suspension polymerization protocol described above for water-soluble quaternized monomers will be employed.
  • microspheres produced from water soluble quaternized monomers are generally non-rigid hydrogels which are useful for absorbing polar (water and alcohol) soluble materials, such as hydroquinones, methyl salicylate, insect repellents (in alcohols) , sunscreens (in alcohol) , and the like, while negatively charged hydrogels are useful for absorbing basic drugs, such as alkaloids, steroids, etc.
  • polar (water and alcohol) soluble materials such as hydroquinones, methyl salicylate, insect repellents (in alcohols) , sunscreens (in alcohol) , and the like
  • negatively charged hydrogels are useful for absorbing basic drugs, such as alkaloids, steroids, etc.
  • the preferred polymer bead of the present invention will be free from reactive groups which will react or interact with the porogen and/or the active ingredient which is ultimately incorporated in the composition other than through ionic interaction, such as that seen in ion-exchange processes.
  • Such beads should not readily undergo unwanted reactions, should be stable over the expected pH range of use, should resist moderate oxidation and reduction, will be stable at temperatures within the expected range of use, and should have a relatively long shelf life.
  • Preferred cationic topical polymer delivery systems of the present invention comprise substantially non-collapsible beads which are formed by the copolymerization of 4-vinylpyridine and ethylene glycol dimethacrylate, 4-vinylpyridine and divinylbenzene, 2-vinylpyridine and divinylbenzene, 2-vinylpyridine and ethylene glycol dimethacrylate, ethyl methyl vinylpyridine and divinylbenzene, and ethyl methyl vinylpyridine and ethylene glycol dimethacrylate.
  • 4-vinylpyridine and divinylbenzene is particularly preferred, while the copolymer of 4-vinylpyridine and ethylene glycol dimethacrylate is even more particularly preferred.
  • Ionic polymeric hydrogel materials in accordance with the present invention will comprise the copolymerization product of an ionic monoethylenically unsaturated monomer and a polyethylenically unsaturated cross-linking monomer which is soluble in aqueous solutions in all proportions.
  • Preferred cationic polymers for oral delivery systems are formed from cationic monoethylenically unsaturated quaternary ammonium monomers selected from the group consisting of:
  • Particularly preferred cationic polymers include the copolymerization product of trimethylammonium- ethylmethacrylic chloride and N,N , -methylenebisacrylamide (poly(PTMAEMCl-co-MBA) ) .
  • Preferred anionic polymers for oral delivery systems are formed from the copolymerization product of an anionic monoethylenically unsaturated monomer selected from the group consisting of:
  • R 1 , R 2 , R 3 , R 4 , and R 5 are the same or different and are selected from the group consisting of H-saturated alkyls having from 1-4 carbon atoms, wherein Y is selected from the group consisting of Na and K, wherein said water-soluble polyethylenically unsaturated cross ⁇ linking monomer is selected from the group consisting of N,N'-methylenebisacrylamide, N,N'-nonamethylene- bisacrylamide, and alkoxylated water-soluble multi ⁇ functional acrylates.
  • Particularly preferred anionic hydrogel beads are the copolymerization products of methacrylic acid and N,N*-methylenebisacrylamide ( (poly)MA-co-MBA) , and the copolymerization product of sodium styrene sulfonate and N,N'-methylenebisacrylamide (poly(SSS-co-MBA) ) .
  • the polymer beads of the present invention will have greater than 10% crosslinking, preferably from about 10% to about 80% crosslinking, and most preferably from about 20% to about 60% crosslinking.
  • the percentage crosslinking is defined among those skilled in the art 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 monoethylenically unsaturated monomer will be present at from about 20% to 80% of the monomer mixture, preferably 40%, with the polyethylenically unsaturated monomer forming the remainder of the mixture.
  • protonation of the polymeric beads may be performed either before or after entrapping the desired impregnant within the porous network.
  • One way of obtaining the cationic beads of the present invention is, for example, protonating the beads thus recovered from the suspension with an acid medium.
  • an acid wash such as, for example, a 3% aqueous hydrochloride solution, is performed after the beads are recovered from the polymerization step. Excess acid is removed with a second hydrochloride solution having a pH ranging from about 1 to about 4; preferably, however, pH 3.
  • the beads of the present invention may be protonated with a pH 3 buffered rinse, comprising 0.1N potassium hydrogen phthalate, 0.1N HC1 and deionized water.
  • a pH 3 buffered rinse comprising 0.1N potassium hydrogen phthalate, 0.1N HC1 and deionized water.
  • the microspheres may be impregnated with the impregnant by contact absorption (this step may be performed either before or after protonation unless ion-exchange is the method of introducing the active ingredient) .
  • the impregnant may be used in the form of a solution in a suitable organic solvent for purposes of decreasing viscosity and facilitating absorption, decreasing potency, or the like.
  • solvents examples include liquid petrolatum, ether, petroleum ether, alcohols including methanol, ethanol and higher alcohols, aromatics including benzene and toluene, alkanes including pentane, hexane and heptane, ketones including acetone and methyl ethyl ketone, chlorinated hydrocarbons including chloroform, carbon tetrachloride, methylene chloride and ethylene dichloride, acetates including ethyl acetate, and oils including isopropyl myristate, diisopropyl adipate and, mineral oil.
  • the solvent can be evaporated or, if desired, retained inside the pores together with the impregnant.
  • compositions typically used in topical formulations may be incorporated, such as carriers or adjuvants such as fragrances, preservatives, antioxidants, and other emollients can also be present, and will be incorporated into and onto the beads together with the impregnants and any other materials present.
  • Substances incorporated in the ionic polymer bead delivery system of the present invention may be used individually or may be combined to achieve a desired effect.
  • the impregnant whether it be pure active substance, a mixture of active substances or a solution of active substance(s) , will generally comprise between approximately 5% and approximately 65% of the total weight of the impregnated beads. When the active substance is particularly potent, it will generally be in the form of a dilute solution, and the weight percent of the active ingredient itself may range as low as 0.01% based on the total weight of the impregnated beads.
  • Suitable topically active impregnants include a wide variety of active substances intended for topical application, comprising cosmetic, therapeutic, and other uses. Specific substances include ultraviolet absorbing substances (sunscreens) , steroids, insect repellents, retinoic acid, fragrances, minoxidil, emollients, and the like. Specific methods for incorporating such substances in polymer bead delivery systems are taught in copending application serial numbers 091,647 and 112,971, the disclosures of which are incorporated herein by reference.
  • topical compositions may be used alone or further incor ⁇ porated in a carrier or vehicle or in virtually any type of product, provided that they are incapable of neutralizing the surface charge on the bead surface, having at least a slightly acidic pH, preferably being below about pH 6, more preferably having a pH in the range from about 3 to 4.
  • the composition may be used alone by simply applying the composition, which is a dry powder, to the skin.
  • the impregnated beads useful for topical application of the present invention may also be incorporated in fluid or solid compositions or preparations of the type commonly used for skin treatment, including gels, creams, lotions, ointments, sprays, powders, oils, sticks, and the like.
  • Appropriate vehicles for particular areas or methods of application will be readily apparent to those skilled in the art.
  • the compositions of the present invention, particularly the UV absorbing compositions will be incorporated in other products in order to impart cosmetic as well as sunscreen properties.
  • the UV absorbing compositions of the present invention are ideally suited for combining with make-up foundations, suntan preparations, and the like, wherein high adsorption and water-repulsion of the final production is sought.
  • the cationic surface charge on the individual polymeric particles promotes adhesion of the compositions to the skin and hair, enhancing the persistence of the active substance which is being applied.
  • the ionic hydrogel compositions of the present invention will be used to deliver an active ingredient to a human or other animal for purposes of therapy, hygiene, analgesics, cosmetics, or the like.
  • the compositions may be delivered orally intravascularly, intraoccularly, intraperitoneally, and similar in vivo uses.
  • the major in vivo use for the hydrogel compositions of the present invention will be for the delivery of drugs and other pharmaceutical agents in human and veterinary applications.
  • Exemplary drugs which may be delivered by the system of the present invention include analgesics, anesthetics, anthelmintics, antimicrobials, antipyrretics, antiseptics, antituburculotics, antitussives, antivirals, cardioactive drugs, cathartics, chemotherapeutic agents, chorticoids (steroids), depressants, diagnostic aids, diuretics, enzymes, expectorants, hormones, hypnotics, minerals, nutritional supplements, parasympathomimetics, potassium supplements, sedatives, sulfonamids, stimulants, sympathomimetics, tranquilizers, urinary anti-infectives, vasoconstrictors, vasodilators, vitamins, xanthine derivatives, and the like.
  • analgesics anesthetics, anthelmintics, antimicrobials, antipyrretics, antiseptics, antituburculotics, antitussives, antivirals, cardioactive drugs, cathartics
  • the anionic hydrogels of the present invention are particularly useful for the oral delivery of cationic drugs which are to be released in the intestines rather than in the stomach.
  • cationic drugs include antibiotics, vitamins, non-steroidal anti-inflammatory substances, and the like.
  • the negative surface charge will ionically bind the drug to the hydrogel during storage and while the composition passes through the stomach.
  • the drug On exposure to the high pH environment on the intestines, however, the drug will exchange with positively-charged ions such as sodium and potassium in the intestines in a typical ion exchange process. The drug will then be released from the internal pore network of the hydrogel particles.
  • anionic drugs cationic hydrogels will be used for oral delivery.
  • the polymeric hydrogel particles carrying the drug may be incorporated into a variety of known dosage forms, as described in, for example, Remington' s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 16th Ed., 1982, the disclosure of which is incorporated herein by reference.
  • the composition or formulation to be administered will contain a preselected quantity of the drug contained within the ionic hydrogel particles.
  • a pharmaceutically-acceptable non-toxic dosage form is prepared using conventional excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • excipients such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Such compositions may be in the form of solutions, suspensions, tablets, pills, capsules, powders, and the like.
  • the ionic hydrogel polymeric particles of the present invention will normally be suspended in an injectable water or saline carrier.
  • Such formulations are well known in the art.
  • This example illustrates the preparation of 4-vinylpyridine/ethyleneglycoldimethacrylate polymeric beads of the present invention.
  • the procedure is set forth below: A 1000 ml four-necked reaction flask equipped with a motorized stirrer, reflux condenser, thermometer, and nitrogen inlet was evaluated and purged with nitrogen. 300 parts of deionized water, 2.5 parts gum arabic and 2.5 parts lignosulfonate under the trademark Marasperse N-22 (Reed Lignin) , were added to the reaction flask. The mixture was heated, with stirring, in an oil bath at about 50°C until the dispersants (gum arabic and Marasperse N-22) dissolved to form an aqueous phase. To this mixture was added a solution of 40 parts of 4-vinylpyridine, 60 parts ethyleneglycoldimeth- acrylate, 0.80 parts benzoyl peroxide (70% active ingredient and 30% water) , and 50 parts toluene
  • the aqueous phase and organic solution were agitated by stirring at a rate (approx. 900 rpm) adjusted to give a plurality of droplets having a droplet diameter in the range of 5 to 100 microns, as determined by visual observation of a sample of the droplets with an optical microscope with the droplets being stabilized by the dispersants.
  • the reaction mixture was then heated to 60 to 65°C for 20 minutes, and heating was continued for another 8 hours at 74-76°C to form porous beads of crosslinked 4-vinylpyridine/ethyleneglycoldimethacrylate having toluene entrapped within the network of pores.
  • the reaction mixture was then cooled to room temperature and the porous polymeric beads were removed from the reaction flask by filtration.
  • the filtered beads were washed initially twice with one liter portions of deionized water to remove the dispersants, followed by two washes with one liter portions of isopropanol to remove any residual, unreacted monomers and the toluene.
  • the beads were then dried in an oven at 80 to 90°C for about 8 hours.
  • the yield was 87.Og of opaque beads.
  • the average particle diameter of these beads was 25 microns, as measured by Sedimentation Micromeritics Instrument Co.
  • the particle diameter determination method is described in detail in the Microsizer 5300 Particle Size Analyzer Instruction Manual , (1984) associated with the instrument.
  • the surface area of a sample of the purified beads was determined by the B.E.T. Nitrogen Analysis method to be 11.05 m 2 /g, while the pore volume was de ⁇ termined by the mercury intrusion method to be 0.14 ml/g.
  • EXAMPLE II This example illustrates the protonation of the 4-vinylpyridine/ethyleneglycoldimethacrylate polymeric beads of Example I.
  • porous polymeric cationic beads were filtered and washed with a dilute hydrochloride solution, 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 to 10 hours. Hydrogen ion (H + ) capacity in water was measured to be 0.78 meq/g.
  • EXAMPLE III This example illustrates the preparation and protonation of 4-vinylpyridine/divinylbenzene polymeric beads. The procedure is set forth below: The reaction apparatus was prepared as in
  • Example I To the reaction flask was added 600 parts deionized H 2 0, 6.0 parts gum arabic, and 6.0 parts Mar ⁇ asperse N-22. The aqueous solution was stirred at room temperature until all solids were dissolved. To the flask was added an organic solution containing 35 parts 4-vinylpyridine, 65 parts divinyl ⁇ benzene (55% divinylbenzene, 45% ethylvinylbenzene) , 100 parts isobutanol, and 1.0 part 2, 2'-azobis (2- methylbutanenitrile) available from the DuPont Co. under the tradename VAZO 67. The reaction mixture was agitated at approximately 1300 rpm until droplets were formed as in Example I. The reaction mixture was then heated to 75°C at which point agitation was reduced to 800 rpm. The reaction was allowed to continue for 8 hours at this temperature.
  • Opaque porous beads were collected by filtration and washed three times with 500 ml portions of deionized water. Protonation was effected by stirring the beads in 500 ml of 0.1N HC1 solution for 30 minutes. The beads were filtered and washed with a dilute hydrochloride solution, pH 3, to remove excess acid. Residual monomers and porogen were removed as in Example I. A dry powder was obtained after drying the beads in an 80 to 90°C oven for approximately 8 hours. The yield was 93 g. The average particle diameter, surface area, and pore volume were 36 micron, 2.21 m 2 /g, and 0.073 ml/g, respectively.
  • EXAMPLE V This example illustrates the preparation of 4-vinylpyridine/ethyleneglycoldimethacrylate beads using xylene as the porogen. The procedure is set forth below:
  • Example II A 1000 ml reaction flask was charged with an aqueous dispersion solution as described in Example I.
  • An organic solution was prepared as in Example I, with the exception of using 50 parts xylenes (a mixture of ortho, eta and para isomers) as porogen rather than toluene.
  • the reaction was agitated at 1300 rpm until droplet sizes ranged from 10 to 60 microns.
  • the reaction was then heated to 65°C and maintained at this temperature for 20 minutes. Agitation was reduced to 800 rpm, and the reaction was heated to 75°C. The reaction was allowed to continue at this temperature for 8 hours.
  • porous beads were collected by filtration and rinsed with 500 ml deionized H 2 0.
  • the beads were then quaternized with a pH 3.0 buffer as described in Example IV.
  • the residual monomers and porogen were removed by rinsing the beads three times with 500 ml portions of acetone. After drying approximately 8 hours in a 80 to 90°C oven, 61g of beads were obtained.
  • the average particle diameter, surface area, and pore volume were 22.5 microns, 3.03 m 2 /g, and 0.68 ml/g, respectively.
  • This example illustrates the substitution of an ultraviolet absorbing substance (sunscreen) in the cationic beads of Example II.
  • the procedure is set forth below: An 18.0 parts portion of the porous cationic polymeric beads obtained from Example II was mixed at room temperature with 30 parts of isopropanol in a glass flask with an agitator. Then 12.0 parts of a sunscreen mixture containing 7 parts octyldimethyl PABA and 2 parts Oxybenzone were added slowly. The resulting suspension was stirred for about 20 minutes. The solvent was then allowed to evaporate to dryness in a fume hood at room temperature for 24 hours. Approximately 40% of the sunscreen mixture was entrapped within the pores of the cationic polymeric beads.
  • the continuous phase is premixed with the following components:
  • EMSORB 2500 24 g (Sorbitan monooleate)
  • the EMSORB 2500 was easily mixed with heptane by hand stirring.
  • discontinuous phase The discontinuous phase is premixed with the following components:
  • the MBA was dissolved in water at a temperature of about 55°-60°C.
  • the sipomer was then mixed with the solution when the MBA was completely dissolved.
  • An initiator K 2 S 2 O g ) was then added.
  • the discontinuous phase solution was kept at a temperature below 64°C before mixing with the continuous phase.
  • the continuous solution was preheated in a 2 liter reaction kettle at 60°C.
  • the reaction kettle was purged with nitrogen for about one-half hour before the addition of the monomers. Agitation was begun at 1000 rpm and the monomer solution added to the reaction kettle.
  • the reaction temperature was increased to 75°C. Polymerization started gradually at about 64°C, with no significant exothermal foaming observed during polymerization.
  • the agitation speed was reduced to 600 rpm after formation of the hydrogel beads, and the stirring rate was kept at 600 rpm for 6 hours at 75°C.
  • the reaction vessel had cooled, the mixture was filtered and washed with deionized water until the filtrate was colorless.
  • the hydrogel beads were then suspended in 500 ml methanol and stirred for one-half hour and again filtered. This process was repeated twice until the filtrate was colorless.
  • the hydrogel beads were again washed with water to make sure there was no residual monomer left in the filtrate (if the filtrate was hazy, the washing steps were repeated until the filtrate became clean) .
  • the hydrogel beads were washed with a mixture of a solution of methanol and acetone (1:1) and the hydrogel beads gradually dried by increasing the ratio of acetone.
  • the hydrogel beads were set still in the evacuation hood for evaporating out the acetone.
  • the hydrogel beads were then dried in a vacuum oven at 50°C for 8 hours. Photomicrographs of the beads were taken both before and after swelling. These are shown in Figure 1. Characterization of Hvdro el Beads
  • Cationic hydrogels made as in Example VIII were made with 20%-60% cross-linked content according to the procedure described above.
  • the gels were cast into square discs (2.5 cm. x 2.5 cm. x 0.16 cm.) in order to investigate the amount of water that the microgels could absorb.
  • the equilibrium water fractions (EWF) were measured as the weight change between the swollen and dried discs.
  • the EWF decreased from 0.85 to 0.78 as the cross-linked content increased from 20% to 80% ( Figure 1) .
  • the discontinuous phase for all the samples contained 83% water by weight.
  • the release profile of D&C Red No. 28 was indicative of a controlled release trigger ( Figure 2).
  • Figure 2 shows a comparison of a macroporous bead alone (curve A) , a cationic hydrogel in accordance with the present invention (curve B) when mixed with an anionic surfactant (to simulate biosalts) , and a cationic hydrogel (curve C) in a neutral surfactant (polyox) no detectable release occurred when the ionic hydrogels were incubated in either water or water plus non-ionic surfactant (0.5% polyox) .
  • the dye was released when the sample was added to a release fluid containing anionic surfactant (0.5% sodium lauryl sulfate) .
  • the release rate was slower than the control (curve A) and was the result of an ion exchange mechanism wherein the anionic surfactant (simulating biosalts) with exchange for the anionic dye which was complexed to the cationic polymer.
  • EXAMPLE IX The poly(TMAEMCl-co-MBA) hydrogels discussed in Example VIII contain stable cationic charges (quaternary amine groups) which were shown to entrap acidic types of ingredients and not release those ingredients until exposed to an anion suitable for exchange. Many pharmaceutically active substances are basic materials, thus the previous basic hydrogel materials do not bind the basic drugs. Therefore, poly(methacrylic acid-CO-N, N'-methylenebisacrylamide) , [poly(MA-CO-MBA) ] hydrogels were synthesized to broaden the applicability of the hydrogels to basic active ingredients, for example, alkaloids.
  • Hydrogels consisting of 10%-15% cross-linking (W/W) were prepared by the inverse suspension polymerization as discussed in Example VIII. As was seen for the poly(TMAEMCl-co-MBA) hydrogels, poly(MA-co-MBA) materials with a lower cross-linked content tended to clump during drying.
  • Tetracycline-HCl was chosen as the model basic active ingredient for the release rate studies since it was UV detectable and water soluble.
  • the release characteristics of tetracycline-HCl into deionized water from swollen gel matrices was determined for 50% cross ⁇ linked beads.
  • the effect of the gels charge density on the tetracycline-HCl diffusion coefficient was also investigated for release fluids containing 0.5% benzalkonium chloride, a cationic surfactant.
  • the release profile ( Figure 5) of tetracycline-HCl from poly(MA-co-MBA) polymer systems into dissolution mediums of 0.5% benzalkonium chloride or water did not show much difference from that of the control.
  • Figure 6 shows the swelling behavior of cationic and anionic hydrogels as a function of pH.
  • the charge density on poly(TMAEMCl-co-MBA) , 25% TMAEMCL, and poly(SSS-co-MBA) , 30% SSS, are independent of pH. Therefore, the swelling behavior of these materials was independent of pH.
  • the charge density on poly(MA-CO- MBA) , 10% MA is a function of pH with the material becoming more negatively charged at higher pH. Thus, the degree of swelling increases with increasing pH for this material.
  • the swelling was determined by placing one gram of dry material into a graduated cylinder and adding the buffer solution to a depth of 25 cm. The material and buffer were allowed to equilibrate before the volume reading was taken.

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Abstract

Compositions ioniques comportant un ingrédient actif absorbé dans un réseau de pores internes délimités par une pluralité de particules polymères. De préférence, les particules sont des billes polymères réticulées dont le diamètre est compris entre 5 et 100 microns environ, et dont la densité de charge superficielle est comprise entre 0,1 et 10 meq/qm environ de capacité d'ions d'hydrogène. Les ingrédients actifs sont libérés lentement par les billes polymères ioniques lorsqu'on administre celles-ci par voie orale, qu'on les applique sur une matière kératinique, habituellement la peau ou les cheveux, ou qu'on les libère dans un milieu cible. L'emploi d'une charge cationique facilite l'adhésion des billes à la matière kératinique.
PCT/US1992/008907 1991-10-21 1992-10-19 Billes ioniques permettant la liberation regulee et l'adsorption WO1993007862A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP5507855A JP2516322B2 (ja) 1991-10-21 1992-10-19 制御された放出及び吸着に有用なイオン性ビ―ズ
KR1019940701299A KR100295333B1 (ko) 1991-10-21 1992-10-19 제어방출및흡착에유용한이온성비이드
AU28815/92A AU662181B2 (en) 1991-10-21 1992-10-19 Ionic beads useful for controlled release and adsorption
EP92922201A EP0612241A4 (en) 1991-10-21 1992-10-19 Ionic beads useful for controlled release and adsorption.

Applications Claiming Priority (2)

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US77968191A 1991-10-21 1991-10-21
US07/779,681 1991-10-21

Publications (1)

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WO1993007862A1 true WO1993007862A1 (fr) 1993-04-29

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PCT/US1992/008907 WO1993007862A1 (fr) 1991-10-21 1992-10-19 Billes ioniques permettant la liberation regulee et l'adsorption

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EP (1) EP0612241A4 (fr)
JP (1) JP2516322B2 (fr)
KR (1) KR100295333B1 (fr)
AU (1) AU662181B2 (fr)
CA (1) CA2121687A1 (fr)
WO (1) WO1993007862A1 (fr)

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WO1995030411A1 (fr) * 1994-05-09 1995-11-16 Korea Research Institute Of Chemical Technology Systeme d'administration de medicaments par voie transdermique, possedant des reseaux polymeres ioniques
WO1998017257A1 (fr) * 1996-10-19 1998-04-30 Quadrant Healthcare (Uk) Limited Microcapsules poreuses et leur utilisation en tant que vehicules therapeutiques et diagnostiques
US6946145B2 (en) 2001-11-16 2005-09-20 A.P. Pharma, Inc. Block copolymers based on poly(ortho esters) containing amine groups
US6982298B2 (en) 2003-01-10 2006-01-03 The Cleveland Clinic Foundation Hydroxyphenyl cross-linked macromolecular network and applications thereof
FR2913597A1 (fr) * 2007-03-14 2008-09-19 Chanel Parfums Beaute Soc Par Utilisation cosmetique de resinates organiques
US7438898B1 (en) 1998-07-30 2008-10-21 The Procter & Gamble Company Hair conditioning composition comprising carboxylic acid/carboxylate copolymer, and visible particle
US7465766B2 (en) 2004-01-08 2008-12-16 The Cleveland Clinic Foundation Hydroxyphenyl cross-linked macromolecular network and applications thereof
FR2919183A1 (fr) * 2007-07-26 2009-01-30 Chanel Parfums Beaute Sas Unip Utilisation de resines pour stabiliser des colorants.
US7749487B2 (en) 2006-03-10 2010-07-06 Conopco, Inc. Method to assess surfactant adsorption on skin
US8080260B2 (en) 2008-02-13 2011-12-20 The Cleveland Clinic Foundation Molecular enhancement of extracellular matrix and methods of use
US8138265B2 (en) 2003-01-10 2012-03-20 The Cleveland Clinic Foundation Hydroxyphenyl cross-linked macromolecular network and applications thereof
US8137688B2 (en) 2003-01-10 2012-03-20 The Cleveland Clinic Foundation Hydroxyphenyl cross-linked macromolecular network and applications thereof
US8410180B2 (en) 2008-04-30 2013-04-02 The Cleveland Clinic Foundation Methods to treat urinary incontinence
WO2015163337A1 (fr) 2014-04-24 2015-10-29 L'oreal Composition cosmétique

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AU676971B1 (en) * 1995-08-24 1997-03-27 Dainichiseika Color & Chemicals Mfg. Co. Ltd. Production process of connected microgel particles and articles treated with connected microgel particles
JP4283355B2 (ja) * 1997-11-10 2009-06-24 久光製薬株式会社 薬剤用徐放化剤及びそれを含有した徐放性医薬組成物

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US4256840A (en) * 1958-07-18 1981-03-17 Rohm And Haas Company Macroreticular cation exchange beads and preparation of same
US4351922A (en) * 1979-02-19 1982-09-28 Showa Denko Kabushiki Kaisha Process for the production of highly water-absorbing but less water-soluble hydrogels
US4304563A (en) * 1979-02-27 1981-12-08 Societe Anonyne Dite: L'oreal Composition and process for the treatment of keratinic materials based on fluorine derivatives
US4564644A (en) * 1982-08-02 1986-01-14 The Dow Chemical Company Ion exchange resins prepared by sequential monomer addition
US4690825A (en) * 1985-10-04 1987-09-01 Advanced Polymer Systems, Inc. Method for delivering an active ingredient by controlled time release utilizing a novel delivery vehicle which can be prepared by a process utilizing the active ingredient as a porogen

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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995030411A1 (fr) * 1994-05-09 1995-11-16 Korea Research Institute Of Chemical Technology Systeme d'administration de medicaments par voie transdermique, possedant des reseaux polymeres ioniques
WO1998017257A1 (fr) * 1996-10-19 1998-04-30 Quadrant Healthcare (Uk) Limited Microcapsules poreuses et leur utilisation en tant que vehicules therapeutiques et diagnostiques
US7438898B1 (en) 1998-07-30 2008-10-21 The Procter & Gamble Company Hair conditioning composition comprising carboxylic acid/carboxylate copolymer, and visible particle
US6946145B2 (en) 2001-11-16 2005-09-20 A.P. Pharma, Inc. Block copolymers based on poly(ortho esters) containing amine groups
US8021350B2 (en) 2003-01-10 2011-09-20 The Cleveland Clinic Foundation Hydroxyphenyl cross-linked macromolecular network and applications thereof
US6982298B2 (en) 2003-01-10 2006-01-03 The Cleveland Clinic Foundation Hydroxyphenyl cross-linked macromolecular network and applications thereof
US7368502B2 (en) 2003-01-10 2008-05-06 The Cleveland Clinic Foundation Hydroxyphenyl cross-linked macromolecular network and applications thereof
US8207262B2 (en) 2003-01-10 2012-06-26 The Cleveland Clinic Foundation Hydroxyphenyl cross-linked macromolecular network and applications thereof
US8137688B2 (en) 2003-01-10 2012-03-20 The Cleveland Clinic Foundation Hydroxyphenyl cross-linked macromolecular network and applications thereof
US8138265B2 (en) 2003-01-10 2012-03-20 The Cleveland Clinic Foundation Hydroxyphenyl cross-linked macromolecular network and applications thereof
US7465766B2 (en) 2004-01-08 2008-12-16 The Cleveland Clinic Foundation Hydroxyphenyl cross-linked macromolecular network and applications thereof
US7749487B2 (en) 2006-03-10 2010-07-06 Conopco, Inc. Method to assess surfactant adsorption on skin
FR2913597A1 (fr) * 2007-03-14 2008-09-19 Chanel Parfums Beaute Soc Par Utilisation cosmetique de resinates organiques
WO2008110628A3 (fr) * 2007-03-14 2009-01-22 Chanel Parfums Beaute Utilisation cosmétique de résinates organiques
US9198850B2 (en) 2007-03-14 2015-12-01 Chanel Parfums Beaute Cosmetic use of organic resinates
WO2009016323A3 (fr) * 2007-07-26 2009-03-12 Chanel Parfums Beaute Utilisation de resines echangeuses d'ions pour stabiliser des colorants
FR2919183A1 (fr) * 2007-07-26 2009-01-30 Chanel Parfums Beaute Sas Unip Utilisation de resines pour stabiliser des colorants.
US8080260B2 (en) 2008-02-13 2011-12-20 The Cleveland Clinic Foundation Molecular enhancement of extracellular matrix and methods of use
US8410180B2 (en) 2008-04-30 2013-04-02 The Cleveland Clinic Foundation Methods to treat urinary incontinence
WO2015163337A1 (fr) 2014-04-24 2015-10-29 L'oreal Composition cosmétique

Also Published As

Publication number Publication date
CA2121687A1 (fr) 1993-04-29
AU662181B2 (en) 1995-08-24
KR940702731A (ko) 1994-09-17
KR100295333B1 (ko) 2001-09-17
JP2516322B2 (ja) 1996-07-24
JPH07500596A (ja) 1995-01-19
AU2881592A (en) 1993-05-21
EP0612241A1 (fr) 1994-08-31
EP0612241A4 (en) 1997-03-05

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