United States Patent [i9j
`Durrani
`
`US006159491A
`[ii] Patent Number:
`[45] Date of Patent:
`
`6,159,491
`Dec. 12, 2000
`
`[54] PROLONGED RELEASE BIOADHESIVE
`VAGINAL GEL DOSAGE FORM
`
`[75] Inventor: Manzer J. Durrani, Waltham, Mass.
`
`[73] Assignee: Biovector Technologies, Inc., New
`York, N.Y.
`
`[21] Appl. No.: 09/250,123
`Feb. 12, 1999
`[22] Filed:
`Int. Cl.7
`[51]
`[52] U.S. Cl
`[58] Field of Search
`
` A61F 6/06; A61F 13/02
` 424/430; 424/434
` 424/430, 434
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`2/1975 Hartop
`3,865,108
`4,226,848 10/1980 Nagai et al
`2/1981 Nagai et al
`4,250,163
`4,615,697 10/1986 Robinson
`4,707,362 11/1987 Nuwayser
`4,708,834 11/1987 Cohen et al
`4,755,378
`7/1988 Buxton et al
`4,795,436
`1/1989 Robinson
`4.983.392
`1/1991 Robinson
`1/1991 Cohen et al
`4.983.393
`4/1991 Calanchi et al
`5,008,117
`5,069,906 12/1991 Cohen et al
`7/1993 Robinson
`5,225,196
`7/1994 Baichwal
`5,330,761
`5,455,046 10/1995 Baichwal
`5,472,704 12/1995 Santus et al
`5,474,768 12/1995 Robinson
`
` 128/260
` 424/19
` 424/14
` 604/890
` 424/433
` 264/4.3
` 424/80
` 424/422
` 424/427
` 424/430
` 424/494
` 424/430
` 424/427
` 424/469
` 424/457
` 424/435
` 424/78.31
`
`5,478,574 12/1995 Baichwal et al
`5,587,175 12/1996 Viegas et al
`4/1997 Kelly
`5,624,675
`7/1997 Britton et al
`5,650,192
`9/1997 Bologna et al
`5,667,492
`5,672,356
`9/1997 Rault et al
`5,700,486 12/1997 Canal et al
`2/1998 Shalaby
`5,714,159
`6/1998 Sachetto
`5,759,520
`7/1998 Fassihi et al
`5,783,212
`5.817.343 10/1998 Burke
`5.824.343 10/1998 Ng et al
`
` 424/485
` 424/427
` 424/405
` 427/2.19
` 604/57
` 424/468
` 424/501
` 424/426
` 424/45
` 424/472
` 424/489
` 424/486
`
`Primary Examiner—Carlos A. Azpuru
`Attorney, Agent, or Firm—Pennie & Edmonds LLP
`ABSTRACT
`[57]
`The present invention relates to a bioadhesive, prolonged
`release vaginal gel dosage form comprising a synergistic
`formulation of carrageenan, acrylic acid containing
`polymers, agarose and an effective amount of a therapeutic
`agent, whereby the therapeutic agent is released from this
`composition initially at a first relatively high rate, to provide
`a loading dose of the therapeutic agent, followed by a
`second, lower rate of release that provides a constant,
`maintenance dose of the therapeutic agent for up to 24 hours.
`More specifically, the present invention includes composi­
`tions within which the agarose is ultra low gelling tempera­
`ture agarose and the acrylic acid containing polymer may be
`carbophil, a copolymer of acrylic acid and divinyl alcohol,
`a copolymer of acrylic acid and C10 to C30 alkyl acrylic acid
`or a polyacrylic acid homopolymer.
`
`27 Claims, No Drawings
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`6,159,491
`
`1
`PROLONGED RELEASE BIOADHESIVE
`VAGINAL GEL DOSAGE FORM
`FIELD OF THE INVENTION
`The present invention relates to bioadhesive compositions
`for the controlled release of therapeutic agents. This inven­
`tion also relates to a process for making the bioadhesive
`compositions and a method of treatment, comprising intra-
`vaginal administration of the bioadhesive composition com­
`prising the therapeutic agent. The present invention is fur­
`ther directed toward a bioadhesive composition providing
`both an initial loading dose of the therapeutic agent through
`an initially higher rate of release as well as providing a
`second, sustained dose, by means of an additional, lower rate
`of release of the therapeutic agent.
`
`BACKGROUND OF THE INVENTION
`Prolonged release formulations of therapeutic agents pro­
`vide patients with more uniform levels of the active agent
`over extended periods of time. Consequently sustained
`release formulations allow the therapeutic agent to be
`administered less frequently providing improved conve­
`nience to the patient as well as enhanced compliance over
`alternative, more cumbersome dosage regimens. Sustained
`release of a therapeutic agent is particularly important in
`order to avoid substantially fluctuating concentration of the
`drug in the patient, particularly for active agents having
`relatively short half-lives.
`Uniform dispersion of an active agent within an erodible
`matrix has been employed as one approach to the formula­
`tion of sustained release materials. U.S. Pat. No. 5,817,343
`discloses a method for forming micro particles containing
`therapeutic agents. The process comprises dissolving a poly­
`mer in an organic solvent along with a co-dissolved or
`suspended drug. The solvent is removed, leaving a solid
`drug-polymer matrix that is cooled to a temperature below
`the glass transition temperature for the matrix and then
`fragmented to provide asymmetric micro particles. Suitable
`polymers for use in this method include poly(lactic acid) and
`poly(lactic acid-co-glycolic acid). Sustained release of the
`active agent results from the hydrolysis of these polymers in
`vivo, which gradually erodes the matrix, thereby allowing
`the therapeutic compound or compounds to diffuse into the
`body.
`A further example of a biocompatible, erodible polymer
`useful in the formation of prolonged-release matrices com­
`prising therapeutic agents is provided by U.S. Pat. No.
`5,834,343. This patent discloses the formation of polymeric
`ortho ester matrix component materials by reacting mono­
`meric ortho esters with suitable triols in an appropriate
`solvent. Polymers formed by this method are dissolved in an
`organic solvent providing a viscous solution into which a
`therapeutic agent may be mixed. Removal of the solvent
`yielded a matrix comprising the active agent in a form that
`can be shaped into a bioerodible implant. Sustained release
`of the drug is afforded by the acid lability of the ortho ester
`linkage of the polymer comprising the matrix. The rate of
`hydrolysis of these linkages can be manipulated by the
`inclusion of acidic or basic excipients in formulations com­
`prising the ortho ester polymers, thereby varying the rate of
`release of the active agent from the matrix.
`More complex and sophisticated compositions and sys­
`tems for the controlled, sustained release of therapeutic
`agents within the body have been developed and formulated
`as pills, capsules and microcapsules. U. S. Pat. No. 5,783,
`212 discloses a controlled release pharmaceutical tablet
`
`2
`fabricated with at least three layers, each of which comprises
`swellable, erodible biocompatible polymers. Controlled
`release is obtained by formulating exterior barrier layers that
`erode more rapidly than the internal, drug-containing layer,
`permitting the active agent to diffuse into the local environ­
`ment as the barrier layers degrade. As the barrier layers
`erode, water diffuses to the drug-containing layer allowing
`the active agent to diffuse through the swollen barrier layer.
`Appropriate formulation of the barrier layers, both with
`respect to their composition and relative thickness as com­
`pared with the drug-containing layer, provides a tablet
`yielding a constant rate of release of the drug within the
`body. The tablets disclosed, therefore, display “zero-order”
`release of the therapeutic agent, that is, the amount of drug
`released remains constant with respect to time. Representa­
`tive swellable polymers used in the formulation of the
`individual layers of the tablet disclosed in this patent include
`polyethylene oxide, hydroxypropylmethylcellulose and car­
`boxymethylcellulose.
`An alternative mechanism of controlled drug release
`within the body is disclosed in U.S. Pat. No. 5,069,906 and
`U.S. Pat. No. 4,983,393. These patents disclose an intra-
`vaginal device constructed as a semisolid gel composition,
`comprising a therapeutic agent, capable of dissolution or
`disintegration in the presence of vaginal fluids. The solid gel
`matrix including the biologically active material consists of
`an aqueous solution containing a gelling agent dispersed or
`dissolved therein. Suitable gelling agents include agarose or
`agar, glycosaminonglycans, collagen, carageen or
`carrageenan, locust bean gum, fibrin and glycerine. Erosion
`of the matrix, facilitating the diffusion of the therapeutic
`agent, is effected in part by the inclusion within the formu­
`lation of degradative enzymes selected from the group
`consisting of protease, agarase, collagenase and sacchari-
`dase that hydrolyze the constituent polymers, thereby lead­
`ing to controlled disintegration and dissolution of the intrau­
`terine device.
`Improved drug delivery systems have been provided by
`the development and application of biocompatible bioadhe­
`sive materials, which, in combination with prolonged release
`formulations, provide sustained release of therapeutic agents
`within particular regions of the body over extended periods
`of time.
`U.S. Pat. No. 4,226,848 discloses a treatment method
`comprising administration of a therapeutic composition
`capable of adhering to the oral or nasal mucosa. The
`composition comprises a water-swellable and mucosa­
`adhesive polymeric matrix made up of a cellulose ether and
`an acrylic acid polymer, in combination with a therapeutic
`agent dispersed within the matrix. The medicament is
`released at a controlled rate and is absorbed through the
`mucosa of the oral or nasal cavity. This patent teaches that
`the individual components are, preferably, mixed as very
`fine powders that may be formed into an appropriate shape.
`U. S. Pat. No. 5,714,159 and U. S. Pat. No. 5,700,486
`disclose bioadhesive sustained release, biodegradable matri­
`ces comprising therapeutic agents, formed from composi­
`tions made up of three components. The first component
`comprises synthetic, block copolymeric chains with self­
`solvating elements to allow its existence as a viscous mate­
`rial at room temperature. The second component is an
`absorbable, microporous low molecular weight polyester
`which is highly crystalline and practically insoluble in the
`first component. The third component, designated a
`plasticizer, is generally a low molecular weight compound
`selected, for example, to aid the dispersion of the second
`component in the first component, to reduce the overall
`
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`6,159,491
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`3
`viscosity of the mixture of the first and the second compo­
`nents or to increase the rate of hydration of the mixture. The
`active agent may be adsorbed carrier materials or mixed
`with the three components forming the matrix. The materials
`of this invention provide hydrogel-forming, self-solvating,
`absorbable polyester copolymers capable of selective, seg­
`mental association into compliant hydrogels upon contact­
`ing an aqueous environment, allowing the controlled release
`of entrained biologically active agents.
`U.S. Pat. Nos. 4,615,697; 4,795,436; 4,983,392; 5,225,
`196 and 5,474,768 issued to Robinson, disclose a bioadhe­
`sive polymer for use in controlled release formulations
`comprising treating agents. The bioadhesive is a water-
`swcllable, but water insoluble, fibrous cross-linked carboxy­
`functional polymer in which at least 80% of the monomeric
`units contain at least one carboxyl functionality. These
`patents define bioadhesives as materials which adhere to
`biological surfaces such as mucus membranes or skin tissue.
`These references quantitate bioadhesion as the force
`required to separate two layers of stomach tissue that are
`adhered together by an adhesive. The active agent may be
`combined with the controlled release, bioadhesive, formu­
`lation either by mixing the corresponding dry solids or by
`swelling the bioadhesive in an aqueous medium containing
`the treating agent, whereby the treating agent is sorbed onto
`or into the swollen particles of bioadhesive material.
`Although the bioadhesive materials may serve as the dose
`rate-controlling medium in these compositions, the rate of
`controlled release is generally provided by a medicinally
`inert matrix. Examples of materials used to form this inert
`matrix include cross-linked human or bovine serum
`albumin, cross-linked gelatin, poly(2-hydroxyethyl
`methacrylate), alkyl cellulose ethers, ethylene vinyl acetate
`copolymers and ethylene propylenediene copolymers, 'lltese
`materials provide controlled release by gradual dissolution
`or erosion of the matrix through a dispersion mechanism,
`thereby providing a fresh supply of the treating agent from
`the matrix in the presence of, for example, gastric or vaginal
`secretions.
`U.S. Pat. No. 5,667,529 discloses a composition compris­
`ing the cross-linked polycarboxylic acid polymer of Robin­
`son formulated with nonoxynol-9, a contraceptive with
`demonstrated activity against human immunodeficiency
`virus and other biological agents responsible for the spread
`of sexually transmitted diseases. Preparation of the compo­
`sitions disclosed includes separate hydration of the
`polymers, mixing of the water-soluble components and
`formulation of the oil soluble ingredients. Once the poly­
`mers have been hydrated, the active agent, nonoxynol-9 is
`added and mixed until a uniform preparation is obtained in
`which the nonoxynol-9 is reversibly associated with the
`polymer. The oil soluble fraction is then added and the two
`phases are mixed thoroughly until a uniform composition is
`obtained. Finally, the pH of the mixture is adjusted to -pH
`4 with sodium hydroxide.
`U.S. Pat. No. 5,672,356 discloses bioadhesive pharma­
`ceutical compositions for the controlled release of biologi­
`cally active materials both locally across the buccal cavity as
`well as systemically across a mucus membrane. The com­
`positions described comprise an active agent combined with
`two other compounds. The latter materials are selected from
`two separate groups, the first comprising one or more
`copolymers of methyl vinyl ether and maleic anhydride,
`while the second group includes one or more compounds
`exemplified by polyvinlypyrrolidone, polyvinyl alcohol,
`polyethylene glycol, alginic acid and its derivatives, cellu­
`lose and derivatives thereof, starches, gums, carraghenates.
`
`4
`proteins and cyclodextrins. Bio adhesion is established
`through the binding of one or more of the compounds of the
`pharmaceutical dosage form to functional chemical groups
`at the surface of the biological tissue. The nature of the
`5 interactions involved may be described as physical,
`mechanical or chemical.
`U.S. Pat. No. 5,472,704 also discloses a bioadhesive
`pharmaceutical composition for the controlled release of
`medicinal drugs. The characteristic feature of the composi-
`10 tion is the formation of a plurality of small-size units capable
`of ensuring a gradual release of the active ingredient con­
`tained within each unit coupled with a separate bioadhesive
`polymer layer coating the individual units. Therefore, the
`microunits comprise a core containing the active agent and
`15 a polymer film coating determining the controlled release of
`the active ingredient and a separate, bioadhesive polymeric
`coating that completely envelops the core. Examples of
`bioadhesive polymers useful for this coating include poly­
`acrylic polymers, cellulose derivatives, natural polymers
`20 and mixtures thereof.
`The controlled release microunits include reservoir,
`matrix, osmotic and biodegradable microunits. Reservoir
`units comprise an inert permeable membrane, having spe­
`cific diffusion characteristics, that encases a solution of the
`25 active material. If the solution of the active material is
`saturated, a zero-order drug release profile is obtained; that
`is, there is a constant rate of release of the active agent. If the
`solution is not saturated, then a first-order release profile is
`obtained; that is, there is a decreasing rate of release of the
`30 active agent with time. Matrix units comprise active agents
`dispersed or dissolved uniformly within a rate-controlling
`polymer. These have a “complex” release profile which
`depends upon the amount of the active material embedded,
`the solubility of the active agent in the environment in which
`35 it is placed, the nature of the matrix material and the
`geometry of the device. Osmotic units generally involve
`tablets containing the active agent coated with a membrane
`semipermeable to the active agent. Provided that the solu­
`tion of the active agent within the osmotic unit is saturated,
`40 the release profile will, essentially, be at a constant rate until
`the solution is no longer saturated, after which a first-order
`profile with a decreasing rate of release of the active agent
`would be expected. Biodegradable matrix units comprise an
`active agent dispersed within a polymer matrix, wherein the
`45 active agent is gradually released as the polymer erodes
`through hydrolytic degradation.
`U.S. Pat. No. 5,700,586 discloses biocompatible, con­
`trolled release pharmaceutical compositions in the form of
`particles comprising a biodegradable polymer, a polysac-
`50 charide jellifying and bioadhesive polymer, an amphiphilic
`polymer, an agent modifying the interface properties of the
`particles and a pharmacologically active substance. In one
`application of the process of this disclosure, a biodegradable
`polymer, a polysaccharide, and an agent modifying the
`55 interfacial interactions are solubilized, with or without a
`solvent depending on the materials used, in an amphiphilic
`polymer. The pharmacologically active agent is then dis­
`solved or dispersed within the polymer mixture. The solvent,
`if used, is removed by evaporation and the particle suspen-
`60 sion is centrifuged or filtered, and the collected particles are
`washed. The residue collected is dried to yield the
`biocompatible, controlled release particles of this invention.
`Biodegradable polymers contemplated by this disclosure
`include polylactic acid, polyglycolic acid, polyhydroxybu-
`65 tyric acid, polycaprolacton, polyorthoesters,
`polyanhydrides, chitins, chitosan, hyaluronic acid, and col­
`lagen. Suitable amphiphilic polymers include
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`6,159,491
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`5
`polyethyleneglycols, polyvinylpyrrolidone and polyvinyla­
`lcohols. Suitable jellifying and/or adhesive polysaccharide
`polymers include sclerogulucan, xanthan, chitins, and
`chitosans, cellulose and derivatives, alginates and hyalu­
`ronic acid. Agents able to modify the interface properties of
`the particles comprise surface-active agents including sor-
`bitan esters, polysorbates, lecithins and other phospholipids,
`stearic acid, stearates and derivatives thereof.
`The above-cited references disclose the incremental
`development of controlled release formulations for thera­
`peutic agents. Initial embodiments comprised active agents
`that were dispersed throughout polymeric matrices that
`gradually eroded releasing the therapeutic compounds. This
`degradation of the matrix could be manipulated, for
`example, by the incorporation of acid labile linkages into
`constituent polymers or inclusion of specific hydrolytic
`enzymes that would degrade the device or structure con­
`taining a therapeutic agent. The rate of release of the active
`agent from these compositions would be expected to depend
`primarily on the surface area exposed to the biological
`system being treated. Therefore, first order kinetics would be
`predicted in which the rate of release of the active agent
`would decrease with time.
`In order to provide a constant rate of release of the
`therapeutic agent, compositions were developed as tablets,
`for example, formulated with outer barrier layers that eroded
`more rapidly than the inner, drug-containing layer. Erosion
`of the outer layers allowed more an increasingly more rapid
`diffusion of the drug from the inner layer. Tablets were
`formulated, based upon these principles and materials, that
`provided a compensating balance between the decreasing
`surface area of the tablet and the increasing rate of diffusion,
`thereby effecting a constant rate of release of the active
`agent.
`In parallel, bioadhesive materials were developed and
`applied to controlled release formulations. Cross-linked
`polycarboxylic acid polymers have been used to form matri­
`ces within which therapeutic agents have been dispersed,
`providing controlled release formulations which adhere to
`the biological surface to which they had been applied. These
`compositions, therefore, provide prolonged release of the
`active material at the site of application affording treatment
`benefits over similar compositions lacking the bioadhesive
`components disclosed.
`One application for bioadhesive materials is their formu­
`lation as a separate component used to coat core particles
`which consist of the active agent dispersed within a con­
`trolled release, non-bioadhesive polymer. In this
`embodiment, the bioadhesive and controlled release com­
`ponents are physically separated in the formulation of
`“microunits” providing extended administration of pharma­
`cologically active compounds. In an alternative application,
`a biodegradable polymer is combined with a polysaccharide
`displaying jellifying and/or bioadhesive properties, an
`amphiphilic polymer and a surface active agent to facilitate
`the emulsification of the particles formed by this process.
`The suspended particles were then separated, washed and
`dried to provide an alternative controlled released formula­
`tion with bioadhesive properties.
`In summary, considerable progress has been achieved in
`the development of controlled-release formulations for
`therapeutic agents that have been combined with bioadhe­
`sive materials allowing localized, sustained release of active
`agents. However, the compositions disclosed above provide
`either a constant (zero order kinetics) or a decreasing rate
`(first order kinetics) of release of the therapeutic agent
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`dispersed or dissolved within the controlled release formu­
`lation. Therefore, there remains a need for compositions that
`exhibit both an initial, faster rate of release of the active
`agent thereby providing a loading dose for the therapeutic
`agent, that is followed by a second, slower rate of release
`providing a constant, sustained rate of release of the phar­
`macologically active agent.
`
`SUMMARY OF THE INVENTION
`The present invention relates to a bioadhesive, prolonged
`release drug composition comprising a synergistic formula­
`tion of carrageenan, acrylic acid containing polymers, aga­
`rose and an effective amount of a therapeutic agent. The
`therapeutic agent is released initially at a first relatively high
`rate, to provide a loading dose of the therapeutic agent,
`followed by a second, lower rate of release that provides a
`constant, maintenance dose of the therapeutic agent for up to
`24 hours.
`In one embodiment of the present invention, the agarose
`is ultra low gelling temperature agarose (Fisher Scientific,
`Pittsburgh, PA.). In another embodiment of this invention,
`the acrylic acid containing polymer may be polycarbophil, a
`homopolymer of acrylic acid and divinyl glycol, a copoly­
`mer of acrylic acid and Clo to C30 alkyl acrylate copolymer
`Pemulen™ TRI, TR2, Carbopol® 1342 or 1382 resin.
`In another embodiment, one or more of the therapeutic
`agents dispersed or dissolved within the bioadhesive, pro­
`longed release drug composition of the present invention,
`are selected from the group consisting of a spermicide,
`antiviral, antibacterial, antifungal, antimycotic, antipruritic,
`emollient, humectant, anti-inflammatory,
`immunomodulator, hormonal, antineoplastic or an analgesic
`agent.
`A further embodiment of this invention is directed toward
`a method of administering a therapeutic agent comprising
`providing a bioadhesive, prolonged release drug composi­
`tion comprising carrageenan, an acrylic acid containing
`polymer, agarose and an effective amount of a therapeutic
`agent and applying this composition to the vaginal mucosa
`of the patient. This embodiment further contemplates that
`the therapeutic agent is, or the therapeutic agents are,
`released initially at a first relatively high rate, to provide a
`loading dose of the therapeutic agent, followed by a second,
`lower rate of release that provides a constant, maintenance
`dose of the therapeutic agent for up to 24 hours.
`A still further embodiment of this invention is directed to
`a method for making a bioadhesive, prolonged release drug
`composition. This embodiment contemplates first dissolving
`soluble components, including, but not limited to sodium
`chloride, methylparaben, acetate buffer, and, optionally, a
`therapeutic agent in a suitable amount of purified water. The
`therapeutic agent is added either in the first step or the last
`step of this process depending upon whether or not heating
`would be required for dissolution of this material or upon the
`thermal stability of the specific therapeutic agent employed.
`The gelling agents, low melting temperature agarose and
`carrageenan, are gradually added, with stirring, to this first
`solution until a uniform dispersion is obtained. The acrylic
`acid containing polymer, selected from the group consisting
`of polycarbophil, a homopolymer of acrylic acid crosslinked
`with divinyl glycol, polyacrylic acid homopolymers
`(Carbopol 974P-NF and Carbopol 971P-NF and other
`carbomers), and other copolymers of acrylic acid, ETD
`(easy-to-disperse) resins and copolymers of acrylic acid and
`C10 to C30 alkyl acrylic acid, is added slowly, with stirring
`until dispersed. This mixture, while being stirred, is heated
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`6,159,491
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`7
`to 90° C. for a short period of time and then cooled to 70°
`C. for a second short period of time. The mixture is cooled
`until it reaches room temperature where stirring is continued
`until the mixture is uniform. If heating is not required for
`dissolution of the therapeutic agent, or if it is heat labile, it
`may be stirred into this mixture at room temperature.
`In another embodiment of this process for making the
`bioadhesive, prolonged release drug composition of the
`present invention, the therapeutic agent is selected from the
`group consisting of a spermicide, antiviral, antibacterial,
`antifungal, antimycotic, antipruritic, emollient, humectant,
`anti-inflammatory, immunomodulator, hormonal, antine-
`oplastic or an analgesic agent.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The present invention comprises a bioadhesive, prolonged
`release vaginal gel dosage form designed to incorporate a
`therapeutic agent for local or systemic action when admin­
`istered intravaginally. It is intended for vaginal administra­
`tion and designed to release initially at a more rapid rate to
`provide a “loading” dose of the therapeutic agent and then
`to provide for a prolonged release of the incorporated
`therapeutic agent for up to 24 hours, depending upon the
`exact formulation. The gel comprises two natural gelling
`agents (carrageenan and an agarose derivative) and a third
`agent (carbophil or copolymers of polyacrylic acid contain­
`ing C10-C30 alkyl acrylate groups) that has been incorpo­
`rated into this formulation in order to minimize syneresis, or
`a “squeezing out” of the dispersion medium in the gel
`matrix. Various concentrations of the product can be pre­
`pared. This bioadhesive, prolonged release vaginal gel dos­
`age form is designed to be packaged in disposable tubes or
`vaginal syringes for single-use purposes.
`The bioadhesive, controlled release drug delivery system
`of this invention is based upon the synergistic action of
`carrageenan, polycarbophil/polyacrylic polymer and agar­
`ose polymers, which generates a complex network structure
`that not only promotes bioadhesion but also forms a difiu-
`sional barrier to drug migration, thereby increasing the
`duration of drug action.
`The formulated prolonged-release bioadhesive vaginal
`gel dosage form disclosed herein provides administration of
`therapeutic agents over a period of time of up to 24 hours.
`Although alternative methods of vaginal drug administration
`are currently available there is still a need for a drug delivery
`system that can be easily administered, that provides a
`prolonged administration of the active agent, and provides
`an administered dosage form that adheres to the vaginal wall
`and does not fall out, leak out or cause irritation. Examples
`of therapeutic agents that can be formulated within the
`prolonged-release bioadhesive vaginal gel dosage form dis­
`closed herein, include, but are not limited to, spermicides for
`contraception, antibiotics for vaginitis, antipruritics for vagi­
`nal itching, humectants and emollients for vaginal dryness,
`corticosteroids for inflammations, antifungals for fungal
`infections and antimycotics for mold and yeast infections,
`anti-cancer agents, antiviral agents and hormones for pre­
`menstrual syndrome (PMS) and hormone replacement
`therapy (HRT).
`The prolonged-release bioadhesive vaginal gel dosage
`form disclosed herein is particularly effective for the deliv­
`ery of therapeutic levels of spermicides. Although there are
`a number of contraception methods available including oral
`contraceptives, barriers (condoms, diaphragm), intrauterine
`devices, spermicides and others, they possess certain disad-
`
`8
`vantages and/or side effects. They are inconvenient, contain
`irritating agents, or are expensive. A need exists for an
`easy-to-administer, safe, nonirritating, rapidly effective pro­
`longed release gel containing a spermicidal agent. The
`preparation described here consists of naturally derived
`gelling agents (Carrageenan, ULGT agarose) formulated to
`provide a prolonged release of an incorporated spermicidal
`agent (nonoxynol-9) and an agent to prevent syneresis
`(polycarbophil).
`The gel dosage form disclosed herein may readily be
`formulated to contain between 2 pph (parts per hundred) and
`10 pph of nonoxynol-9 in a total volume of approximately
`3 mL of the matrix, providing a dosage range of about 60
`mg. to about 300 mg. of nonoxynol-9 that falls within the
`range utilized by the commercial products described below.
`In vitro studies have shown that about 25% of the
`nonoxynol-9 is released from the gel matrix in the first 1-2
`hours, another 25% is released after 6 hours and the remain­
`der is released continuously for up to 24 hours after admin­
`istration. Therefore, the formulation disclosed provides for a
`more rapid initial release of the therapeutic agent followed
`by a slower, linear rate of release for the remainder of the 24
`hour period, yielding a biphasic zero order release profile.
`Antibiotic agents incorporated into the gel formulations
`disclosed herein would allow convenient once-daily admin­
`istration of these compounds. If the formulation were to be
`administered in the evening, for example, the prolonged
`release of the drug throughout the night and into the fol­
`lowing day would provide a consistently higher drug con­
`centration in the vagina as compared to other modes of drug
`administration including conventional vaginal inserts,
`tablets, suppositories or douches. Antibiotics that could be
`formulated into the gel dosage form disclosed herein would
`include, but not be limited to, bacitracin, clindamycin,
`colistimethate, colistin, lincomycin, metronidazole,
`novobiocin, polymyxin B, spectinomycin, vancomycin,
`amikacin, gentamicin, kanamycin, neomycin, netilmicin,
`streptomycin and tobramycin. Similarly, antifungal agents
`that could be formulated into the gel dosage form disclosed
`herein include, but are also not limited to, amphotericin B,
`fluconazole, flucytosine, griseofulvin, itraconazole,
`ketoconazole, nystatin and terbinafine. Examples of anti-
`neoplastic agents that could be formulated into the gel
`dosage form disclosed herein include, without limitation,
`5-fluorouracil, cisplatin and paclitaxel. Anti-viral agents that
`could be formulated into the gel dosage form disclosed
`herein include, without limitation, anti-HIV and anti-Herpes
`agents.
`The prolonged release bioadhesive vaginal dosage form
`of the present invention provides a gel that consists of
`carrageenan, ultra low gelling temperature agarose, carbo­
`phil or polyacrylic acid polymers, sodium chloride,
`methylparaben, sodium acetate, acetic acid in purified water,
`and an active drug agent. The polycarbophil can be replaced
`by copolymers of polyacrylic acid containing Cj0-C30 alkyl
`acrylate groups. The gel is soft, clear to translucent and
`easily manipulated. Accordingly, this vaginal gel formula­
`tion can be administered, conveniently and easily by means
`of either a vaginal syringe or a suitable applicator. A more
`detailed description of the individual components of the
`compositions of the present invention is presented below.
`Carrageenan (CAS 9000-07-1; Chondrus, Carrageen,
`Ir