United States Patent [191
`Staab
`
`[54] DISSOLVABLE DEVICE FOR
`CONTRACEPTION on DELIVERY OF
`MEDICATION
`[76] Inventor:
`
`Robert J. Staab, 73 Franklin
`Turnpike, Allendale, NJ. 07463
`[21] Appl. 190.; 68,778
`[22] Filed:
`Jun. 1, 1993
`
`[63]
`
`Related US. Application Data
`Continuation-impart of Ser. No. 880,093, May 7, 1992,
`abandoned.
`
`[51] Int. Cl.6 ...................... .. A61F 9/02; A61F 13/15;
`A61F 13/20; AOIN 25/08
`[52] US. Cl. .................................. .. 424/436; 424/409;
`424/430; 424/431; 424/432; 424/433; 424/445;
`424/DIG. 14; 514/7723; 514/777; 514/781;
`514/784; 514/785; 514/841; 514/843; 514/953;
`514/967; 604/358; 604/378; 604/904
`[58] Field of Search ............. .. 424/400, 405, 407, 409,
`424/430, 431, 432, 433, 436, 443, 444, 445, 486,
`488, DIG. 14; 514/7723, 777, 781, 784, 785,
`841, 843, 953, 967; 604/904, 358, 378
`References Cited
`U.S. PATENT DOCUMENTS
`
`[56]
`
`4,304,591 12/1981 Mueller et al. .................... .. 424/433
`4,707,362 11/1987 Nuwayser ......................... .. 424/433
`
`FOREIGN PATENT DOCUMENTS
`
`0050480 4/ 1982 European Pat. Off. .
`2094711 2/1972 France .
`
`US005393528A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,393,528
`Feb. 28, 1995
`
`Primary Examiner——Thurman K. Page
`Assistant Examiner-Carlos Azpuru
`Attorney, Agent, or Firm-Evelyn M. Sommer
`[57]
`ABSTRACT
`A dissolvable element containing an agent material is
`used for local administration of the agent material in an
`internal body area. The dissolvable element is made of
`dissolvable polymer material and/ or complex carbohy
`drate material which are food grade materials and have
`selected dissolving properties, such that it remains in
`substantially solid form before use, and dissolves due to
`human body temperatures and moisture during use to
`release the agent material in a desired timed release and
`dosage. As a contraceptive, the dissolvable element is
`preferably a ?lm made of polyvinyl alcohol, polyethyl
`ene oxide, hydroxypropyl methyl cellulose and/ or car
`boxymethyl cellulose. The dissolvable element may be
`formed as a laminate of different ?lm layers for com
`pound release properties, or it may be ground into parti
`cles and incorporated in a tampon or suppository. The
`dissolvable element may be foamed as a means for in
`creasing its dissolution rate. The agent material can be a
`spermicide, such as Nonoxynol-9, and/or a drug or
`medication. The device of the invention can also be
`applied topically as for example in the treatment of
`wounds, burns and ulcers, as well as to treat, irritations,
`Herpes, and ulcerations and blisters of the oral cavity. It
`is also possible to prepare dressings in which the dis
`solvable element of the invention comprises the bottom
`most layer. This permits painless application of medica
`tion to wounds.
`
`24 Claims, 2 Drawing Sheets
`
`DRL - EXHIBIT 1026
`DRL001
`
`

`
`US. Patent
`
`Feb. 28, 1995
`
`Sheet 1 of 2
`
`5,393,528
`
`FIG.
`
`[3
`
`I5
`
`FIG. 2
`
`(I6)
`
`FIG. 3 s}
`
`22
`
`FIG. 4
`
`/30
`
`2‘)
`
`DRL - EXHIBIT 1026
`DRL002
`
`

`
`US. Patent
`
`Feb. 28, 1995
`
`Sheet 2 of 2
`
`5,393,528
`
`1E1.
`
`FIG. 5
`
`DRL - EXHIBIT 1026
`DRL003
`
`

`
`1
`
`5,393,528
`
`DISSOLVABLE DEVICE FOR CONTRACEPTION
`OR DELIVERY OF MEDICATION
`
`This application is a continuation-in-part of applica
`tion Ser. No. 880,093, ?led May 7, 1992, now aban
`doned.
`
`FIELD OF THE INVENTION
`This invention generally relates to a dissolvable de
`vice for use as a contraceptive or for internal delivery of
`medication, and more particularly, to ?lms made of a
`safe, polymer material incorporating a spermicide and
`/ or medication that is released by dissolution of the ?lm
`over time. The ?lms may be adapted for rapid dissolu
`tion (for example in 5-60 seconds) or for dissolution
`over prolonged periods (for example up to 12-24
`hours).
`
`10
`
`2
`“Nonoxynol-9” and glycerine as a plasticizer material.
`However, the VCF ?lm does not dissolve readily, and
`has poor stability in hot, humid environments. The
`texture of the ?lm is relatively hard, and the ?lm has a
`sharp edge. The ?lm also delivers only 65 mg. of sper
`micide, which may be insuf?cient. It is also expensive to
`make and unlike a preferred embodiment of the present
`invention as illustrated in FIG. 3 infra, it has no capacity
`to be used as a barrier contraceptive.
`More importantly, the VCF product suffers from
`de?ciencies of all like prior art products in that it does
`not dissolve readily and in addition is not stable to pro
`longed storage at high temperature and high humidity,
`such as is generally encountered in numerous tropical
`third world countries as well as seasonally in more
`temperate climates. Such products become, under expo
`sure to adverse humidity conditions, sticky and exces
`sively hygroscopic. To resolve this problem, prior art
`devices, as typi?ed by the VCF device, employ expen
`sive protective packaging, such as foil-packs and the
`like. Such packaging greatly increases the cost of the
`product to the end user. The high cost discourages use
`in areas of the world where the product is most needed.
`Moreover, foil packaging increases package compo
`nents and since the foils used are not readily decompos
`able in land?lls, such packages have a disadvantaged
`environmental impact.
`It should be noted that as used herein, high tempera
`ture means up to 140° F., high humidity means up to
`99% relative humidity and prolonged storage means in
`excess of three years.
`
`20
`
`30
`
`BACKGROUND ART
`Due to the growing awareness of medical complica
`tions associated with the use of oral contraceptives and
`intra-uterine devices, interest in other contraceptive
`methods has increased. Other contraceptive methods
`presently in use include diaphragms, sponges, cervical
`25
`caps, spermicidal creams, foams, and suppositories for
`women, and condoms for men. Diaphragms and cervi
`cal caps usually require ?tting by trained medical per
`sonnel, and must be re?tted or replaced on a regular
`basis. Sponges take up a relatively large volume, which
`may result in a feeling of discomfort. Chemical barrier
`contraceptives such as creams, foams, jellies, tablets,
`and suppositories are often inconvenient and messy to
`apply and use, and in some cases cause irritation. Con
`doms are considered inconvenient to use during sexual
`activity and interfere with the sensation of the users,
`Thus, all such contraceptive methods in current use
`cause some inconvenience to users and detract from the
`users spontaneity or feeling of pleasure during sexual
`activity.
`Moreover, it is often desirable to administer medica
`tion in the vagina or other internal areas of the body
`such as the mouth, rectum, nose, ear and eye. In the case
`of the vagina, medication can be administered, either in
`conjunction with use of a contraceptive device or sepa
`rately. In the treatment of vaginal disorders, it is often
`desirable that the medication be applied throughout the
`areas of the vaginal tract and cervix over an extended
`period of time, for example, several hours or days. The
`remoter areas of the vaginal tract might not be readily
`reached by conventional vaginal suppositories due to
`the compact size and shape required for convenience of
`insertion. Also, because of the structure and shape of
`the vagina, inserted suppositories or tablets often do not
`stay in place, or, upon melting, the medication may
`55
`drain out of the vaginal passage, thereby reducing the
`effectiveness of the applied medication. Medicated tam
`pons also do not extend far enough or widely enough
`into the vaginal tract to deliver medication throughout
`the vaginal tract. Other types of rigid applicators have
`similar delivery problems and are uncomfortable to
`insert and use. Thus, under current methods, the desired
`medication may not be applied or maintained effec
`tively in the vaginal tract for a suf?cient period of time.
`A recent commercial product is a contraceptive ?lm
`65
`sold under the name “VCF” by Apothecus, Inc., of
`Great Neck, New York. The VCF ?lm is made of poly
`vinyl alcohol (PVA) and contains the spermicide called
`
`35
`
`45
`
`SUMMARY OF THE INVENTION
`In accordance with the present invention, a device
`adapted for local administration of an agent material in
`an internal body area such as the vagina, rectum, oral
`cavity, nasal passages and the like, comprises a dissolv
`able element and an agent material carried in said dis
`solvable element, wherein said dissolvable element is
`made of dissolvable polymer material, particularly, a
`mixture of polyvinyl alcohol, polyethylene oxide, and
`/or complex carbohydrate material, which are selected
`such that the dissolvable element remains in solid form
`before use, and dissolves due to human body tempera
`tures and moisture during use to release said agent mate
`rial for local administration in the internal body area.
`The preferred dissolvable element is a ?lm made of
`polyvinyl alcohol, polyethylene oxide, and/or a com
`plex carbohydrate material such as hydroxypropyl
`methyl cellulose which are safe, food-grade materials
`selected to obtain a desired release characteristic for the
`agent material. Two or more ?lm layers may be com
`bined as a laminate for compound release properties.
`Alternatively, a larger ?lm layer or multiple laminates
`may be used as a barrier contraceptive. The dissolvable
`material may also be employed as an applicator tube for
`delivery of a contraceptive or delivery of medication or
`medical device. The dissolvable element dissolves
`within the body area so that it does not have to be
`physically removed after use. It can also dissolve com
`pletely when flushed away, so that no plumbing block
`age or ecologically disturbing solid waste occurs.
`The dissolution properties and texture of the dissolv
`able element may be modi?ed by adding nitrogen or
`other suitable gases in forming the ?lm, as well as the
`use of polyethylene oxide alone or in mixtures with
`polyvinyl alcohol and/or complex carbohydrate mate
`rial. Forming the ?lm in the invention with different
`
`DRL - EXHIBIT 1026
`DRL004
`
`

`
`5,393,528
`3
`?lm layers or polymer materials allows varied dissolu
`tion properties. The polyethylene oxide and complex
`carbohydrate materials add lubricity to the product as
`an added bene?t. The composition of the dissolvable
`element is selected to have an improved heat and hu
`midity stability, feel, texture, and dissolution time (2 to
`3 times quicker) as compared to the conventional VCF
`?lm. The VCF ?lm does not use gases to modify disso
`lution properties, nor does it use polyethylene oxide or
`complex carbohydrate materials either alone or in com
`bination with polyvinyl alcohol to modify dissolution or
`texture. As compared to the invention, the VCF ?lm
`also does not employ a laminate of dissolvable ?lms for
`compound release properties, and cannot be used as a
`barrier contraceptive.
`It should be noted that heretofore, the signi?cance of
`the addition of gases in the formation of the film to alter
`the texture and solubility of the ?lm has not been recog
`nized.
`20
`The active agent(s) may be incorporated into either
`the entire portion of the device i.e., as a homogeneous
`blend or in the case of a laminate, the device may in
`clude a layer of active material, the other layer or layers
`containing different active materials or have been se
`lected with a view to the overall dissolution properties.
`As a contraceptive device, the dissolvable ?lm incor
`porates a spermicide and is inserted by hand or by
`means of an applicator or inserter into the vaginal tract
`adjacent to the cervix. The contraceptive ?lm is safe
`and fully dissolvable. It can be made at substantially
`lower cost and does not have the problems of removal,
`cleaning, reuse, and/or re?tting as compared to conven
`tional diaphragms and sponges. Alternatively, the film
`may be molded with a dissolvable ?exible rim like a
`conventional diaphragm for greater expansion and re
`tention in the area of the cervix.
`The dissolvable element may also be in tubular form
`as a vaginal tampon, the dissolvable device being in
`serted within the vaginal cavity using an applicator, or
`40
`as a suppository, or ground as timed-release powders
`?lled into other delivery devices. It can also be used to
`deliver medications such as anti-infectives, anti-in?am
`matories, coronary vasodilators, anesthetics, antitus
`sives, expectorants, estrogenic, progestational, or pros
`taglandin agents, and the like. It may include fragrance,
`flavorants, coloring agents, preservatives, etc., to pro
`vide a more acceptable, environmentally sound product
`for consumers, as well as a plasticizer or gas additive for
`better handling, lubricity, and/or release characteris
`tics.
`Other objects, features , and advantages of the pres
`ent invention will become apparent from the following
`detailed description of the best mode of practicing the
`invention when considered in conjunction with the
`drawings as follows:
`
`45
`
`4
`FIG. 5 is a flow sheet showing an embodiment of the
`process of the invention.
`
`DESCRIPTION OF PREFERRED
`EMBODIMENTS
`In the invention, a dissolvable device for contracep
`tion or delivery of medication contains a dissolvable
`element made of a dissolvable polymer material, partic
`ularly, a mixture of polyvinyl alcohol, polyethylene
`oxide, and/ or complex carbohydrate material, used for
`local administration of a spermicide and/or medication
`agent in an internal body area. The dissolvable polymer
`material is preferably a food-grade material safe for
`internal use. The dissolvable element is designed to be
`heat stable (e.g., up to 140° F.), and humidity stable
`(e.g., up to 99% relative humidity) so as to remain in
`substantially solid form and not begin dissolving before
`its intended use. Lubricity is another desirable property
`for use in the vagina and other internal (e.g., rectal)
`areas where sensitive tissues are likely to be encoun
`tered.
`The preferred dissolvable element is in the form of a
`?lm made of the combination of grades of polyvinyl
`alcohol, polyethylene oxide, and/or complex carbohy
`drate material. Polyvinyl alcohol (PVA) is a preferred
`material for the ?lm because it is non-toxic and medi
`cally safe to use internally. PVA comes in different
`grades that can be classi?ed as cold water soluble (dis
`solves from 400 to 212° F.), intermediate dissolving
`(1100 to 212° F.), fully hydrolyzed (1400 to 212° F.),
`and superhydrolyzed (1800 to 212° F.). PVA is com
`mercially available from companies such as Air Prod
`ucts Company, of Allentown, Pennsylvania. The cold
`water soluble and intermediate dissolving grades are the
`most useful for the desired moisture and heat- dissolving
`properties for contraceptive purposes. A particularly
`preferred cold water soluble grade of PVA is an 80%
`hydrolyzed polyvinyl alcohol having a molecular
`weight of 9,000—l0,000; for intermediate solubility, an
`87-89% hydrolyzed polyvinyl alcohol having a molec
`ular weight of l3,000—23,000 for a slow dissolving, a
`98-99% hydrolyzed polyvinyl alcohol having a molec
`ular weight of 31,000—50,000 and for the least dis
`solving, a fully hydrolyzed 99% of polyvinyl alcohol
`having a molecular Weight of 85,000-186,000 being
`preferred. All of the aforementioned polyvinyl alcohol
`preparations are available from Aldrich Chemical,
`Milkwaukee, Wis. However, in the invention, a ?lm of
`the higher temperature or water soluble grade may be
`combined with a ?lm of the lower temperature or water
`soluble grade in order to alter the temperature dissolu
`tion and moisture, solubility and stability properties so
`that the ?lm can be used most suitably in the vaginal
`environment. The PVA material or materials are se
`lected for contraceptive use to dissolve relatively
`quickly, e.g., over several minutes, or in some cases as
`low as several seconds. For use in delivering medica
`tions, the film composition may be selected for a longer
`release time, such as several days. In the case of medica
`tions to be administered via the oral cavity, it is advan
`tageous that dissolution take place fairly rapidly.
`Polyethylene oxide is another good material for the
`?lm because it has very good moisture, particularly
`humidity, stability and further is a food contact grade
`material. It is very compatible with the spermicide
`nonoxynol-9 and many other medications. It also has
`the added bene?t of good lubricity, which makes the
`?lm structure even more comfortable to insert and use
`
`15
`
`25
`
`35
`
`55
`
`DESCRIPTION OF THE DRAWINGS
`FIG. 1 is a schematic diagram of a dissolvable device
`in accordance/ with the present invention in the form of
`60
`a contraceptive ?lm.
`FIG. 2 shows a contraceptive device made of a lami
`nate of ?lm layers.
`FIG. 3 shows a variation using the dissolvable ?lm in
`a barrier contraceptive incorporating a dissolvable ?ex
`ible rim for shape retention.
`FIG. 4 shows a contraceptive or medication applica
`tor formed by a roll of dissolvable ?lm.
`
`65
`
`DRL - EXHIBIT 1026
`DRL005
`
`

`
`15
`
`20
`
`5,393,528
`5
`during sexual activity. Preferred polyethylene oxide
`materials are sold by Union Carbide Corp., of Danbury,
`Connecticut, in molecular weights of from 50,000 to
`8,000,000 Daltons. The polyethylene oxide is available
`from Aldrich Chemical, Milwaukee, Wis.
`The use of inert gases such as nitrogen, in forming the
`?lm to modify the dissolution properties of the dissolv
`able element formed from polyethylene oxide has been
`found to be equally favorable in this case as their use in
`connection with the polyvinyl alcohol ?lms. The disso
`lution of the ?lm can be readily adjusted by using differ
`ent viscosities of the hydroxypropyl methyl cellulose
`ranging from less than 80 to more than 4,000 centi
`poises.
`A complex carbohydrate material suitable for use in
`the ?lm is hydroxypropyl methyl cellulose, or carboxy
`methyl cellulose which is sold, for example, under the
`trademark “Methocel” by Van Waters & Rogers, Inc.,
`of Seattle, Washington. This material is also food-grade,
`medically safe‘ to use internally, low cost, and very
`stable in a humid environment. “Methocel” is cellulosic
`in nature being derived from trees. It is dissolvable in
`the same temperature ranges as PVA. Hydroxypropyl
`methyl cellulose is a particularly preferred material for
`use in forming the ?lms of the invention. Its acceptance
`25
`by the FDA as a direct food additive is well known
`(CAS 9004-65-3). The preferred hydroxypropyl methyl
`cellulose has an average molecular weight of about
`86,000.
`The ?lm may be a laminate of two or more layers of 30
`different polymer materials, or may be a single layer
`with two or more polymer ingredients mixed together.
`Further, the ?lm laminate may be a gas foamed ?lm or
`constructed of layers of different gas foamed ?lms or of
`layers of both non-foamed and gas foamed ?lms. The
`35
`exact mixture used will depend upon the intended use
`and combination of qualities desired, which may in
`clude heat-dissolving temperature range, time release
`period, lubricity, shelf life, turgidity, stability in a mois
`ture environment, compatibility with spermicides and
`/or medications etc. In the case of contraception, two
`films may be used which dissolve at varying rates. Such
`a laminate device can offer prompt efficacy upon inser
`tion combined with extended contraceptive protection
`with dissolution taking place over a period of many
`45
`hours. Thus in accordance with the invention, the ?lm
`may be constructed as a laminate composed of gas
`foamed ?lm with non-gas foamed ?lm layers, polyvinyl
`alcohol and polyethylene oxide ?lm layers, polyvinyl
`alcohol and hydroxypropyl methyl cellulose layers, in
`all possible combinations. The laminates can be formed
`in the conventional manner, for example the mixture in
`liquid form will be poured or cast on to a plate or into
`a mold and allowed to begin to set, at which time an
`other liquid mixture of different composition will be
`poured on to the ?rst setting up mixture, and both mix
`tures allowed to set up completely producing a laminate
`or layers of different materials.
`Fully formed ?lms can also be laminated to each
`other through use of an adhesive. A preferred adhesive
`is a dilute aqueous solution of the polymer from which
`the ?lm has been made. Thus, for example, a polyvinyl
`alcohol ?lm could be adhered to another polyvinyl
`alcohol ?lm through use of a dilute solution of polyvi
`nyl alcohol.
`The agent material to be administered locally may be
`spermicide for contraceptive use, and/or drug or medi
`cation. The agent material is evenly distributed
`
`6
`throughout the ?lm, so that as the ?lm slowly dissolves,
`it releases the agent material in the proper dosage to
`perform its spermicidal or medicating function. The
`agent material is selected for compatibility with the
`polymer material and its dissolution characteristics. The
`device of the invention thus is composed of a biologi
`cally compatible material that has been blended homo
`geneously with a spermicide or drug which is released
`into a body cavity at a controlled rate upon contact
`with the body fluid.
`Some'spermicides have good surfactant properties
`which facilitate dissolving and dispersing in vaginal
`fluids. Examples of those suitable for use include nonyl
`phenoxypolyethoxy ethanol (sold under the trademark
`“Nonoxynol-9”) , p-methanyl phenylpolyoxyethylene
`ether (MenfeGol), polyoxyethylene oxypropylene stea
`rate, polyoxethylene laureate, Glycerol ricinolate,
`mono-iso’octyl phenyl ether, polyethylene glycol, me
`thoxy polyoxyethylene Glycol 500 laureate, polyoxy
`ethylene stearylamine, benzalkonium chloride, cetyl
`trimethylammonium bromide, methyl benzethonium
`chloride, sodium dodecylsulfate, nonylphenol polyeth
`ylene sodium sulfate, sodium oleate, zinc phenosulfon
`ate, dodecyl diaminoethyl Glycine, p-diisobutyl
`phenoxy polyethanol (Octoxynol), dodecamethylene
`Glycol monolaureate, sodium lauryl sulfate and the like.
`A suitable dosage of nonoxynol-9 for contraceptive use
`is about 100 to 150 mg. However, the amount of spermi_
`cide may vary in accordance with their rate of release
`from the device and the spermicidal ef?cacy.
`The dissolvable element may be used to deliver a
`medication internally in the vaginal or cervical area in
`combination with a spermicide or alone. Suitable medi
`cations which can be delivered with the ?lm include:
`(1) anti-infectives such as antibiotics, sulfonamides,
`antivirals, antifun gals, antiprotozoan and antibacte
`rials;
`(2) anti-in?ammatories, such as hydrocortisone, dexa
`methasone, triamcinolone, and various predniso~
`lone compounds;
`(3) estrogenic steroids, such as estrone;
`(4) progestational agents, such as progesterone;
`(5) prostaglandins;
`(6) coronary vasodilators;
`(7) antitussives;
`(8) antihistamines;
`(9) anesthetics and
`(10) decongestants.
`Monoclonal antibodies such as those useful against
`cell surface components or against pathogenic organ
`isms such as the human-immunode?ciency (HIV) fam
`ily of viruses may be incorporated into the device of the
`present invention for ultimate intravaginal release.
`Combinations of the various drugs may be used as de
`sired. Typically the range of drug additives may be in
`the amount of 0.000l% to about 50% by weight. The
`medications may be in a variety of chemical forms, such
`as uncharged molecules, molecular complexes, or non
`irritating, pharmacologically acceptable salts. Simple
`derivatives of such medications, such as ethers, esters,
`amides, and the like, can also be used for desirable prop
`erties such as retention, release, and easy hydrolyzation
`by body pH, enzymes, etc. The amount of medication to
`be used varies depending upon the particular drug, the
`desired therapeutic or prophylactic effect, and required
`release times. Other drugs include clotrimazole,
`miconazole, ticonazole, benzalkonium chloride, nysta
`tin, dennally active steroids, hormones, benzocaine,
`
`50
`
`55
`
`65
`
`DRL - EXHIBIT 1026
`DRL006
`
`

`
`8
`-continued
`nitrogen gas added to form foamed web
`‘nonoxynol-9 from Rhone Poulenc, NJ
`III. Clotrimazole Film, 100 mg clotn'mazole
`hydroxpropyl methyl cellulose
`glycerine
`clotrimazole‘
`
`0
`
`nitrogen gas added to form foamed web
`‘clotrimazole from e.g., Flavine, Inc. Closter, NJ
`IV. Vagigal Deodorant Film
`polyethylene oxide
`glycerine
`fragrance
`
`nitrogen gas added to form foamed web
`fragrance from e.g., IFF, Dayton, NI
`V. Vagig Lubricant
`polyethylene oxide
`glycerine
`
`nitrogen gas added to form foamed web
`
`36.0%
`29.0%
`35.0%
`100.0%
`
`55.0%
`35.0%
`‘10.0%
`100.0%
`
`75.0%
`25.0%
`100.0%
`
`5,393,528
`7
`sulfas, biologically prepared actives, decongestants,
`cough/cold remedies, psychotropics, nitroglycerine,
`etc. If the drug can be applied on or in a moist area of
`the body, such as the mouth, skin, vagina, rectum, ear
`canal, eye, etc., then the ?lm can be used to deliver the
`drug effectively with timed release of the proper dos
`age. This should be an ideal way for treating ulcers of
`the mucous membranes and of the skin as well as treat
`ing burn wounds.
`The dissolvable element may also include plasticizer
`material, such as water, Glycols, glycerin, and like
`materials,in order to enhance lubricity and softness.
`While water is suitable as a plasticizer it is not useful in
`all cases, but this factor can be readily ascertained. A
`preferred plasticizer is Glycerin USP, sold by Van Wa
`ters & Rogers, Inc., in either natural or synthetic form.
`Glycerine (Glycerol) CAS 56-81-5 is particularly pre
`ferred. The plasticizer may be added in any desired
`concentration, for example, from 0.1% to 35%, for
`better handling and lubricity. The softness and ?exibil
`ity of the dissolvable ?lm, due to its thin layer structure
`without any rigid elements, and particularly when com
`bined with plasticizer, ensures that the device may be
`worn with complete comfort and will not be felt by the
`sexual partners.
`Various preservatives, antifungal agents, antibacterial
`agents, antiviral agents, antiprotozoal agents, and anti
`oxidants may also be added if desired. Flavors, fra
`grances, and/ or coloring agents may also be added. The
`polymer ?lm may be substantially transparent, or may
`be embossed with indicia or colored with opaquing
`agents. These additives may be present in any desired
`concentration, for example, from 0.001% to 50%. The
`concentrations of these additives will depend upon the
`desired properties, the agent to be released, the potency,
`the desired dosage, dissolution times, etc.
`In preparation, the polymer solids, water, or other
`solvent, contraceptive and/or medicinal, glycerine etc.
`are admixed in the proper concentrations and the mix
`ture heated to the appropriate temperature for dissolu
`tion and formation of a uniform blend to take place. The
`heating can take place, for example, by submerging
`vessels containing the mixture in water or jacketed
`vessels held at constant temperature, for example
`104°-l40° F. The mixture can either be cast directly or
`transferred into another water bath of cooler tempera
`ture, for example 68°-l04° F. and other heat sensitive
`ingredients introduced with stirring. The application of
`heat is, however, not necessary, which is advantageous
`when pharmaceuticals or other agents to be added are
`heat sensitive.
`Several formulations utilizing different polymers as
`well as different active ingredients are listed below:
`
`25
`
`45
`
`50
`
`55
`
`65
`
`I. Benzalkonium Film, 19 mg benzalkonium chloride
`hydroxypropyl methyl cellulose
`glycerine
`BZK‘
`
`52.5%
`37.5%
`10.0%
`100.0%
`< 1.0%
`
`nitrogen gas added to form
`foamed web
`*BZK, e.g. , ETC-50, a 50% aqueous active drug from Stepan
`Company, North?eld, Illinois.
`Chemical, Jersey City, NJ
`11. Nonoxynol-9 Film, 100 mg nonoxynol-9
`hydroxypropyl methyl cellulose
`glycerine
`nonoxynol-9‘
`
`36.0%
`29.0%
`35.0%
`100.0%
`
`The ?lm characteristics may also be altered by add
`ing appropriate amounts of gas, such as air, nitrogen, or
`other inert gases,.which canproduce a more acceptable
`?lm texture and modify the dissolution rates accord
`ingly. For example, it has surprisingly been found that
`the addition of nitrogen or other inert gas to a PVA ?lm
`containing nonoxynol-9 halves the dissolution rate of
`the ?lm. The ?ne tuning of dissolution rates and deliv
`ery of agent material, by the addition of gases and by
`altering the grades or mixtures of polymer materials or
`layers, is an important aspect of the present invention.
`On addition of the gas, preferably nitrogen, a web is
`formed of the ?nal formulation and the gas. The resul
`tant structure can be described as a foam with various
`sized air bubbles trapped in the matrix. There is a dual
`bene?t that has been surprisingly observed in this con
`nection, namely that not only can the size of the bubbles
`in the foam alter the dissolution rates and correct what
`is a serious ?aw in standard polymer ?lms, it also offers
`to the user a perceptible softness to the ?lm which ena
`bles the delivery of many types of drugs to tender mu
`cosal tissues. It has been observed that the formation of
`this web of the polymer/drug formulation and the gas
`must be made just prior to casting on the glass or steel
`plates. This offers precise control over the microbub
`bles and resultant control over the dissolution,
`Without this web formation, the quick release of drug
`was heretofore not possible. This frothy foam mixture
`or web can also be added to a mold to provide a formed
`device such as a barrier delivery system which com
`pletely dissolves upon use in a body cavity, e.g. the
`vagina.
`The gases, for example, air or nitrogen are introduced
`near the point of application of the liquid polymer mate
`rial to the stainless steel casting sheet. The gases are
`added in a closed system by mixing with whipping
`blades or a motor driven homogenizer to homogenize
`the mixture of polymer, active material and gas to form
`a frothy foam. The ?nal mixture then sets up or gels as
`a foam. It is also possible to pour the frothy foam mix
`ture into a mold. The mold is then deformed and the
`formed device such as a diaphragm, is removed.
`As a contraceptive, the ?lm can be formed in a dia
`phragm shape or a sponge shape with the spermicide
`incorporated therein. The ?lm can also function as a
`barrier to the cervical os. The user enjoys the bene?t of
`
`DRL - EXHIBIT 1026
`DRL007
`
`

`
`l0
`
`15
`
`25
`
`5,393,528
`9
`not having to remove the device the morning after, and
`can remove the dissolved residue simply by douching or
`bathing. Any residue will dissolve completely when
`?ushed away. Where the user discards a dissolvable
`diaphragm or sponge or an incompletely used ?lm, no
`plumbing blockage or ecologically disturbing solid
`waste occurs.
`Referring to FIG. 1, a preferred form of contracep
`tive and/ or drug delivery device employs a single layer
`dissolvable ?lm 10 having a shape and area of approxi
`mately 4 square inches by 3 mils thick. The agent is
`evenly dispersed throughout the ?lm matrix and can
`dissolve once it is placed in a warm moist body cavity,
`e.g., the vagina. The ?lm is intended to remain in sub
`stantially solid form, for shelf storage or prior to use, at
`temperatures up to 1400° F. Controlled environmental
`storage (temperature and humidity) of the ?lm prior to
`use may be desirable if ambient temperatures and hu
`midity are extreme. Once installed in the vaginal tract,
`the ?lm will dissolve due to the moisture and body
`20
`temperature in the vagina, typically 98.6° F. As the
`spermicide or drug is released from the dissolving ?lm,
`it becomes mixed in the vaginal ?uids and adheres to the
`tissues where it forms an effective matrix for drug ac
`tion, e. g., spermicidal or anti-infective action. After use,
`the residual polymer, drug, and vaginal fluids are re
`moved naturally from the body by washing.
`In FIG. 2, another version of the ?lm device employs
`a laminate 11 of ?lm layers. A ?rst ?lm layer 13 is made
`of, for example, a faster dissolving polymer material for
`30
`release of a drug material 140. A second ?lm layer 15 is
`made of slower dissolving polymer material for release
`of more drug or another drug material 14b in combina
`tion, for example, a spermicide and an anti-infective or
`anti-in?ammatory medication. A third (and additional)
`layer(s) 16 with additional drug can also be employed
`for sustained release of the drug. In place of ?lm layers
`which have not been foamed, it is possible,and often
`preferred to form the laminate of foamed or combina
`tions of foamed with non-foamed layers as a way of 40
`readily controlling th