■uropaisches Patentamt
`•uropean Patent Office
`)ffice europeen des brevets
`
`n) Publication number:
`
`3 0 9 0 5 6 0
`
`3 1
`
`EUROPEAN PATENT SPECIFICATION
`
`D
`
`D
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`g) Date of publication of patent specification: 03.05.89
`Jj) Application number: 83301527.4
`(3) Date of filing: 18.03.83
`
`© Int. CI.4: A 61 K 9/20, A 61 K 9/22
`
`(73) Proprietor: MINNESOTA MINING ANU
`MANUFACTURING COMPANY
`3M Center, P.O. Box 33427
`St. Paul, Minnesota 55133-3427 (US)
`
`Inventor: Mitra, bumiia a. c/o mmnesuuj
`Mining
`Manufact. Co. 2501 Hudson Road P.O. Box 33427
`St. Paul Minnesota 55133 (US)
`
`(74) Representative: Baillie, lain Cameron et al
`c/o Ladas 8i Parry Isartorplatz 5
`D-8000 Munchen 2 (DE)
`
`Sustained release oral medicinal delivery device.
`
`(§) Priority: 26.03.82 US 362116
`
`(§) Date of publication of application:
`05.10.83 Bulletin 83/40
`
`® Publication of the grant of the patent:
`03.05.89 Bulletin 89/18
`
`(0) Designated Contracting States:
`CHDEFRGBITLISE
`
`(JS) References cited:
`FR-A-2263 744
`FR-A-2 382 234
`US-A-4055178
`US-A-4136 145
`US-A-4167 558
`US-A-4252 786
`CHEMICAL ABSTRACTS, vol. 93, no. 20, 17
`november 1980, page 357, abstract no.
`191993d, Columbus, Ohio, US; M. DONBROW
`et al.:"Zero order drug delivery from double-
`layered porous films: release rate profiles from
`ethyl cellulose, hydroxypropyl cellulose, and
`polyethylene glycol mixtures", & J. PHARM.
`PHARMACOL 1980 32(7), 463-70
`
`Note: Within nine months trom the publication ot tne mention or me gram or ine curupecm paiem, any y^,^,, ...cy
`give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall
`be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been
`paid. (Art. 99(1 ) European patent convention).
`Courier Kress, Leamington bpa, tngiana.
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`TEVA EXHIBIT 1023
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
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`Description
`The present invention relates to a multilayered medicament delivery device of the sustained release
`type for orally administering a predetermined selective dose of a medicament. In another aspect, it relates
`to a method of preparing the medicament delivery device of the present invention. In a further aspect, it
`relates to an apparatus for preparing said delivery device.
`The convenience of administering a single dose of medication which releases an active medicament
`over an extended period of time so as to achieve a constant rate of release of medicament has long been
`recognized in the pharmaceutical field. Since oral administration of single dose medicinals is simple and
`10 desirable, considerable interest has been expressed in increasing the residence time of medicaments in the
`stomach.
`One way to retain medication in the stomach is to close off the pylorus, the opening from the stomach
`into the first part of the small intestine, before or during the adminstration of a drug. Tablets or other drug
`dispensing devices which swell, inflate, or unfold when in contact with gastric juices and thus become too
`large to enter the pylorus are known in the art.
`Sustained release devices which are buoyant in gastric juices have been disclosed. U.S. Patent Nos.
`4,140,755 and 4,167,558 relate to a sustained release, hydrodynamically balanced hydrocolloid-
`medicament tablet having a bulk density of less than 1.0 which is capable of floating in gastric fluid. U.S.
`2Q Patent No. 3,976,764 teaches a solid therapeutic preparation for gastric diseases, in which an empty
`globular shell, granular lump, or oval shaped nucleus of polystyrol foam of high buoyancy is coated on the
`external surface with a medicament and additives. Alternatively the medicament may be within the hard
`capsule as a disc shaped tablet.
`Drug administering vehicles that are divisible into unit dosage forms are taught in U.S. Patent Nos.
`25 3,444,858, 4,126,503, and 4,136,145.
`The present invention provides a flexible, sustained release medicament device for oral administration
`which: (1) releases medication approaching a zero order release rate, (2) releases medication for a
`prolonged period of time, (3) remains buoyant in the stomach for an extended period of time during release
`of medicament, (4) comprises a multilayered polymer film which both controls the rate of release and aids
`in the buoyancy of the medicament, (5) is in a linear form suitably marked for facile measurement of
`prescribed medical dosage according to length and capable of being easily cut to the desired length and (6)
`can be dispensed and administered in a compact form which extends in the stomach to remain buoyant.
`The orally administered, sustained release, flexible medicament device of multilayer composite
`construction is comprised of at least one carrier film and at least one barrier film, the carrier film(s)
`35 containing medicament and the barrier fiim(s) comprising at least one water-insoluble and permeable
`polymer and additives to control release of medicament. The barrier film(s) is sealed or affixed to the
`carrier film(s) along its periphery in such a way as to entrap air onto one or more surfaces of the carrier
`film(s) and render the sustained release medicament device buoyant in the gastric juices of the stomach
`during release of medication.
`Since the ratio of effective dose to toxic dose for some medicinals is very small, e.g. dicoumarin, the
`sustained release medicament delivery device of the present invention has the desirable property of being
`capable of fine adjustment to the needs of the recipient. It is capable of being administered in a
`predetermined selective dose that is not necessarily a unit dose but one that can be accurately measured
`and dispensed according to linear measurement.
`Release of medicament through the barrier and carrier films appears to be achieved by a combination
`of leaching, diffusion (permeability), and erosion. Initial erosion of the films and subsequent leaching of
`medicament occurs when the excipient or water soluble plasticizer dissolves in the gastric juices.
`Permeability depends upon the reservoir concentration (cone, of medicament in the device), membrane
`thickness, polymer stiffner, co-diffusants, molecular weight of diffusants, and chemical functionality of the
`transport of active ingredients. For example, varying the thickness and stiffness of the barrier film enables
`incorporation therein of tailor-made properties for a specific controlled release application. It is desirable
`that the device maintain its integrity for a period up to several weeks, preferably 4 to 24 hours, before
`exiting the stomach or degrading.
`In the accompanying drawing:
`Fig. 1 is a top plan view of a medicament containing device in strip form showing entrapped air
`pockets;
`Fig. 2 is an enlarged cross-sectional view of the device of Fig. 1 taken along lines 2 — 2;
`Fig. 3 is an enlarged cross-sectional view of a device similar to that shown in Fig. 2 showing another
`embodiment of the present invention;
`Fig. 4 is an enlarged perspective view of an open gelatin capsule having the device of the invention in
`pleated strip form contained therein;
`Fig. 5 is a top plan view of a modified embodiment of the invention showing perforations for division
`into unit dosages;
`Fig. 6 is a perspective view of an apparatus for forming devices of the present invention.
`The present invention provides a flexible, sheet-like, sustained release medicament device for orally
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`administering a predetermined selective dose of a medicament, which device is of a multilayer composite
`construction comprising
`(a) at least one carrier film comprising at least one water-insoluble polymer and containing
`medicament, and
`(b) at least one barrier film overlaying said carrier film on at least one surface thereof and sealed to said
`carrier film along its periphery and in such a way as to entrap small quantities of air between said carrier
`and barrier films, said barrier film comprising at least one water-insoluble and water- and medicament-
`permeable polymer or copolymer and optionally additives to control the release of medicament, said
`multilayer composite construction having a bulk density of less than 1.0 g/cc and being facilely divisible
`into any desired length.
`As used in this application:
`"flexible" means pliant or conforming under stress to a new shape, yet still maintaining its integrity;
`"sustained release" means a technique or method in which active chemicals are made available to a
`specified target at a rate and duration designed to accomplish an intended effect;
`"film" means a sheet-like material having a thickness up to 0.05 cm;
`"permeable polymer" means one that allows migration or transport of substances, such as water,
`medicament, excipient, or water-soluble plasticizer therethrough;
`"zero order" release rate means a rate of release that is constant;
`"medicament" means any composition or substance which will produce a pharmacologic response;
`20 and
`"facilely divisible" means readily and easily subdivided, as for example by cutting with a scissors, into
`any dosage which is not necessarily a unit dose.
`Referring to the accompanying drawing, Fig. 1 shows one embodiment of the multilayered sustained
`release medicament containing device 10 with outer barrier film 12 enclosing pockets of air 14. Fig. 2 is an
`enlarged cross-sectional view of device 10 taken along line 2—2 of Fig. 1. Barrier films 12 are shown
`overlying air pockets 14 and carrier film 16 which has medicament therein. Films 12 and 16sealably adhere
`at surfaces 13.
`Fig. 3 is an enlarged cross-sectional view of another embodiment of the present invention 10 showing
`barrier films 12, air pockets 14, and a plurality of carrier films 16, each of which can carry therein the same
`30 medicament, different medicaments, or, when desired, no medicament at all. Films 12 and 16 sealabiy
`adhere at surfaces 13 and and films 16 adhere to each other at surfaces 15.
`Fig. 4 shows open gelatin capsule 20 having the device 10 of the present invention in pleated form
`contained therein.
`Fig. 5 shows another embodiment of the device 10 having barrier film 12, air pockets 14, and
`35 perforations 22 which are located at intervals so as to provide unit dosages.
`Fig. 6 shows an apparatus 30 for forming the devices of the present invention. Piston 32 moves heater
`block 34 which has an embossing die of suitable pattern on its undersurface. Carrier film 16 unwinds from
`spool 36 and is overlaid on both surfaces by barrier films 12 which unwind from spools 38 and 42. Device
`10, which has been embossed by the die on the lower surface of block 34 so as to provide air pockets 14 in
`some areas and sealing of the films in other areas, is shown moving in the direction of the arrow. Device 10
`has perforations 22 therein.
`The device of the present invention is an orally administered sustained release drug delivery device
`which is suitable for facile measurement and divisibility for prescribed medical dosage according to length
`and has a bulk density of less than 1 .0 g/cm3 so as to remain buoyant in the stomach for an extended period
`45 of time during which substantially all of the medicament is released therefrom. The device of the invention
`can be prepared with a known amount of medicament per linear measurement. Perforations may be
`provided at regular intervals to provide unit dosages. When it is desirable to very accurately dispense
`medicament, the device of the present invention may be cut, as with a scissors for example, to the precisely
`predetermined length according to the prescribed dosage. The medicament device may be dispensed and
`administered in a compact form which extends in the stomach. For example, the device, in flexible,
`preferably strip form, may be rolled or folded as by pleating so as to easily fit in a gelatin capsule for oral
`administration. The gelatin capsule dissolves in gastric juices at physiological temperatures in a short time
`to allow the constrained medicament device to unroll or unfold.
`The overall dimensions of the drug delivery device are 0.004 to 0.08 cm thick with a preferred thickness
`55 between 0.02 — 0.03 cm, with a length dispensed according to prescribed medical dosage; a length of 14 cm
`is preferred. The width of the device can be from 0.5 cm to 7.5 cm, with a preferred width of 2.1 to 6.1 cm.
`For veterinary use, for example, the size of the sustained release medicament device can be much larger,
`depending on medical and physical requirements of the animals.
`The medicament delivery device of the present invention is a laminated multilayered structure
`comprising two polymeric films having different functions. One film is a carrier film and a second is a
`barrier film. The carrier film is overlaid on at least one surface thereof by an outside barrier film but is not
`limited to this number or arrangement of films. Polymers forming carrier and barrier films are, and remain,
`physiologically inert during the time of complete drug delivery.
`The carrier film, of which there is at least one, is comprised of a film-forming polymer or matrix
`65 containing a medicament or active agent or drug dispersed or dissolved therein or applied thereon. By
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`incorporating multiple carrier films in the device it is possible to vary the number and kind of medicaments
`released and their rates of release. Other additives such as fillers, colorants, excipients, and plasticizers
`may be added to the polymer by simple mixing. The polymeric material or matrix is water insoluble and
`capable of forming a flexible, self-supporting film when containing medicament in the concentration of up
`to 65 percent by weight. The matrix does not swell to any appreciable degree in water and has a softening
`point above 37°C, the normal physiological temperature.
`Examples of polymers that may be used in the carrier film, which may comprise a plurality of layers,
`are ethyl cellulose, poly(v-benzyl glutamate), polyvinyl acetate, cellulose acetate phthalate, a copolymer of
`methyl vinyl ether with maleic anhydride, and the above polymers to which polyvinylpyrrolidone may be
`w added. Other useful polymers and a discussion of controlled release systems in general is given in
`Controlled Release Technologies; Methods, Theory, and Applications, Vol. I, editor A. F. Kydonieus, CRC
`Press Inc., Boca Raton, Florida, pp. 1 — 14, (1980).
`Table I, below, summarizes some mechanical properties and sources for polymers and polymer films
`that are used in the examples of this invention.
`The medicament or therapeutic agent or drug can be dispersed homogeneously into the matrix, or it
`may be desirable to increase the concentration of the medicament from the outer wall to the interior of the
`carrier film to approach a zero order release behavior. Any medicament which can be given orally, and for
`which a sustained release action is beneficial or desirable, can be incorporated into the carrier film. The
`medicament can be any substance which is at least partially water-soluble and may comprise acidic, basic,
`20 neutral, or amphoteric substances. Concentration of medicament in the carrier layer may typically vary
`from 0.05 to 65 percent. The carrier may comprise a plurality of layers, generally each having at least one
`medicament incorporated therein, although designated carrier layers may contain no medicament.
`Suitable medicaments used with the device of this invention are those mentioned in, for example, U.S.
`Patent Nos. 3,625,214, 4,248,857 and 4,167,558 and in British Patent No. 1,428,426. Some of these
`25 medicaments are, for example: acetazolamide; antacids such as calcium carbonate and aluminum
`hydroxide; aspirin; belladonna alkaloids; benztropine; bromocriptine; cephalothin; chloropromazine;
`isosorbide dinitrate; ephedrine; estrogens;
`cimetidine; dipyridamole; disopyramide;
`isoephedrine;
`lithium carbonate; methadone; naloxone; nitroglycerin; papavarine; penicillin; phenylpropanolamine;
`potassium chloride; probucol; prochlorperazine; progesterone; quinidine; terbutaline; tetracycline;
`theophylline; tolazoline; and trihexyphenidyl.
`Plasticizers suitable for use in the carrier film of the sustained release formulations of the invention
`include those well known in the art of preparing coatings used in the pharmaceutical industry. Examples
`are acetylated monoglycerides; esters of phthalic acid such as dimethyl phthalate, dibutyl phthalate, and
`dioctyl phthalate; propyleneglycol; glycerol; castor oil; D-sorbitol; diacetin; triacetin; dibutyl tartarate; and
`the like. The preferred percentage of plasticizer varies up to 30 percent by weight with desired percentages
`from 1 — 15% of the carrier film.
`An excipient is usually incorporated into the matrix of the carrier film. The excipient is a water-soluble
`material which gradually dissolves in the gastric juices. This gradual dissolution creates regions of porosity
`within the matrix. Penetration of gastric juices or water into these porous regions results in the controlled
`release of medicament. Excipients generally comprise from 1 .0 to 30 percent by weight of the carrier film.
`Typical excipients are those used in the pharmaceutical industry and some examples are salt, sugar,
`polyvinylpyrrolidone, and polyethylene glycol (molecular weight of these latter two polymers ranges from
`300—20,000).
`The thickness of the carrier film is in the range of 0.001 to 0.05 cm, and preferably it is 0.015 to 0.02 cm
`thick.
`As mentioned above, the barrier film overlays the carrier film on at least one surface. Obviously, if the
`medicament is dispersed homogeneously in a single carrier film, the barrier film will overlay both surfaces
`of the carrier film, unless it is desired to have more rapid release of medicament from one surface of the
`device than from the other. The purpose of the barrier film is to control the rate of release of medicament
`that is present in the carrier film. Another purpose of the barrier film is to control the rate of release of
`medicament such that the control rate profile approaches that of a zero order release profile or any other
`desired release rate profile, in addition, the barrier film provides buoyancy of the medicament release
`device in the stomach by entrapping air in small pockets between it and the carrier film.
`The barrier film is comprised of at least one water-insoluble, permeable, film-forming polymer or
`55 copolymer, and optionally a water-soluble polymer or copolymer, or a mixture thereof, a plasticizer, and
`generally an excipient. In certain instances, the barrier film may also contain medicament. Useful
`water-insoluble, permeable, film-forming polymers, after leaching of the excipient or water-soluble
`plasticizer therefrom have a pore size, as determined by scanning electron microscopy, in the range of 0.1
`to 10 microns, and preferably 0.5 to 5 microns. Portions of the surface of the outermost barrier film of the
`60 drug delivery device are fixed, sealed, or laminated onto the carrier film in such a manner that a pocket, or
`pockets, of air or "bubbles" are entrapped between this external film and the remainder of the drug
`delivery device to provide the device with buoyancy sufficient to float in the stomach (i.e., apparent specific
`gravity of the device is less than that of the gastric juices, which have a specific gravity of between 1.004
`and 1.01) for an extended period of time during which substantially all of the medicament is released. The
`65 bulk density of the device is less than 1.0 g/cc. The barrier film has suitable flexibility and mechanical
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`strength to allow pleating and sealing or affixing of said turn onto tne arug aeuvery aevice in sucn a manner
`as to become the air-entrapped or "bubble" polymer film. The barrier film comprises in the range of 17 to
`60 percent by weight, and preferably 25 to 45 percent by weight, of the sustained release device.
`A judicious selection of the polymers or copolymers having the required degree of permeability for
`forming the barrier film can dictate the rate of release of medicament from the drug delivery system. The
`required degree of permeability of the barrier film can be obtained by starting with a permeable polymer or
`by adding from 0.5 to 30 percent by weight of a water-soluble polymer to the film-forming polymer.
`Examples of water-insoluble, permeable film-forming polymers are ethylcellulose, polyvinyl acetate,
`cellulose acetate phthalate, polyesters laminated with low-density and medium-density polyethylene and
`<o copolymers of polyethylene and polyvinyl acetate. Examples of water-soluble polymers are polyvinyl
`pyrrolidone and hydroxypropylmethyl cellulose. Table I summarizes some mechanical properties and
`sources for some of the polymers and polymeric films that are used as examples in this invention.
`TABLE I
`Data on polymers and polymer films
`Physical properties
`
`ts
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`20
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`25
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`30
`30
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`35
`35
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`Polymer or copolymer
`
`Ethylcellulose
`
`Poly(-benzyl glutamate)d
`
`Copoly(ethylenevinyl-
`acetate)8
`
`Molecular weight3 or viscosity0'
`0.045— 0.11 Pa • S, 45— 110 cP
`0.063—0.085 Pa • S, 63—85 cP
`(preferred for carrier film)
`0.041—0.085 Pa • S, 41—85 cP
`(preferred for barrier film)
`50,000— 100,000°
`
`50,000—100,000
`
`Cellulose acetate phthalate
`Copolymer of methyl vinyl High viscosity type
`ether — maleic anhydride11
`
`50,000—100,000
`
`him tensne strengtn
`
`Pascal (Pa)
`
`Ib.sq. in. (Pbl)
`
`5.87x10'
`—
`
`—
`
`1.65x10'
`
`3.8x1 07
`
`—
`
`—
`
`b,b2u
`—
`
`—
`
`2,400'
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`5,500
`
`—
`
`—
`
`Polyethylene terephthalate
`40 polyester laminated with
`polyethylene'
`
`so
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`20,000 (mol. wt. of polyester)
`5,000—100,000 (mol. wt. of
`laminated polyethylene)
`4.14X107
`6,000k
`10,000—50,000 (preferred)
`a Number average molecular weight; flow rate and pressure limit data for cellulose ester membrane
`45 materials are given in Millipore Corp. Bulletin PB085, incorporated herein by reference
`b Viscosity reported in Pascal-second (Pa • S) and Centipoise (cP)
`c Viscosity of Methocel® E-15 (Dow Chemical Co.) determined as a 2% solution in water at 20°C. Viscosity of
`Ethocel®-45 (Dow Chemical Co.) determined as a 5% solution in toluene-ethanol (80:20, vol/vol) at 25°C.
`Viscosity of Ethocel®-70 (Dow Chemical Co.) determined as a 5% solution in toluene-ethanol (60:40,
`vol/vol) at 25°C.
`d Prepared according to directions of S. B. Mitra, N. K. Patel and J. M. Anderson, Int. J. Biol.
`Macromolecules 1, 55 (1979)
`e Molecular weight determined in dichloroacetic acid, see P. Doty, J. H. Bradbury and A. M. Holtzer, J. Am.
`Chem. Soc. 75, 947 (1956)
`55 f Stress at failure reported by J. M. Anderson et al, J. Biomed. Mater. Res. Symposium, No. 3, 25 (1972)
`9 Scotchpak® laminated copolymer (3M) heat sealable polyester film Nos. 112, 113, 115, 125
`"Gantrez® AN-169 copolymer (GAF)
`' Scotchpak® laminated copolymer (3M) Nos. 5, 6
`' Laminated with low density polyethylene
`60- k Laminated with medium density polyethylene
`Plasticizers suitable for use in barrier films of the invention include those well known in the art for
`preparing coatings used in the pharmaceutical industry and can be those plasticizers that are listed above
`as suitable for use in the carrier film of the invention. The percentage of plasticizer can be in the range of 0.5
`65 to 30 percent, preferably 20 to 25 percent, by weight of the barrier film.
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`An excipient is usually incorporated into the film-forming polymer of the barrier film. The excipient is a
`water-soluble material which gradually dissolves in the gastric juices. The excipient and plasticizer (if
`water-soluble) allow medicament to pass through the barrier film. Typical examples of excipients are salt,
`sugar, and water-soluble polyvinylpyrrolidone and polyethyleneglycol mentioned above. Excipients make
`5 up from 1 to 30 percent by weight of the barrier film, with a preferred range of 20 — 25%.
`Since the barrier film contains an excipient or a water-soluble plasticizer that, in use, dissolves in
`gastric juices, the film is left with opened pores. When the medicament is a solid, the barrier film preferably
`is of such a character as to become wetted by liquid water and thereby allows gastric juices to pass through
`the opened pores and come in contact with the medicament-containing carrier film. The medicament,
`10 which, to be effective has a solubility in water of at least 0.1 mg/l, dissolves in gastric juices and the
`resulting medicament-containing gastric juices can then pass through pores in the barrier film again and
`enter the stomach. Liquid medicament would even more readily enter the stomach.
`The overall dimensions of the barrierfilm are 0.5 cm to 7.5 cm wide, preferably 2.1 to 6.1 cm wide, with
`a length dispensed according to prescribed medical dosage. The most preferred overall dimensions of the
`'5 barrier film are made to the same size as the carrier film, generally 14 cm long by 2.1 cm wide, with a
`preferred thickness between 0.002 and 0.005 cm, but the overall size is not limited to these dimensions. The
`preferred tensile strength of the barrier films ranges from 3.8x107 to 5.9x107 Pa (5,500 to 8,520 PSI).
`The barrier film makes up 15 to 60 percent by weight of the sustained release drug device, with the
`20 preferred range being 25 — 45% by weight.
`The barrier and carrier films may be prepared by any of the common techniques employed for the
`preparation of polymeric films. One method, for example, consists of dissolution of the desired polymer in
`a suitable solvent at ambient temperatures, followed by the addition of other ingredients such as
`plasticizers, excipients, drugs and other additives, to form a homogeneous dispersion or solution of high
`25 viscosity (0.1 — 0.5 Pa • S, 100 — 500 cP) followed by coating (e.g., knife coating) to a suitable thickness.
`Removal of solvent by heat or evaporation or a combination thereof, for example, leaves a self-supporting
`film.
`Another method for film formation involves mixing a solid polymer with the necessary additives, e.g.,
`plasticizers, excipients, medicinals, and extruding this mixture into a film whose thickness and shape is
`30 dictated and controlled by the dimensions of the extruding die.
`The sustained release pharmaceutical delivery device is constructed from the barrier and carrier films
`by sealing or laminating along their edges and between air pockets, while maintaining the same perimeter
`to give an envelope configuration. By "envelope" is meant any complete enclosure formed by one or more
`sheets of the sheet material which have their edges secured together, which enclosures may be of any
`3S shape required to enclose the component. The films may be sealed or laminated together by any suitable
`technique, for example, by the use of heat, pressure or solvent sealing, or combinations thereof.
`An apparatus, one embodiment of which is shown in Fig. 6, is provided for sealing the air entrapped,
`bubble-containing, or "waffle" type barrierfilm onto the resultant composite film of this invention. The die,
`which may have any pattern embossed thereon, is heated by the attached heater block, and it performs two
`functions. The first function is to emboss one or more of resultant sealed air sacs, bubbles or "waffle" type
`patterns between the top barrier film and the film, or films, under this barrier film. The second function of
`the embossed die is to seal together all the edges of the film composite and the areas between the air
`pockets to give an envelope configuration. The die may contain a row of suitably raised dimples or other
`suitable embossed design which leads, on the film composite, to a row of perforations, see Figs. 5 and 6, or
`other marked interval design, suitable for detaching, tearing or cutting the device of this invention.
`A second means for simply sealing films together involves the use of a jaw-type sealer (robot Model
`RTP-F sealer, Pac