(12) United States Patent
`Verma et al.
`
`111111111111111111111111111111111111111111111111111111111111111111111111111
`US006322811Bl
`US 6,322,811 B1
`Nov. 27, 2001
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) ALKYLENE OXIDE POLYMER
`COMPOSITIONS
`
`(75)
`
`Inventors: Surendra Kumar Verma, Charleston;
`Michael Scott Jarrell, South
`Charleston, both of WV (US)
`
`(73) Assignee: Union Carbide Chemicals & Plastics
`Technology Corporation, Danbury, CT
`(US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.:
`
`09/601,633
`
`(22) PCT Filed:
`
`Feb.5, 1999
`
`(86) PCT No.:
`
`PCT/US99/02526
`
`§ 371 Date:
`
`Sep.25,2000
`
`§ 102(e) Date: Sep. 25, 2000
`
`(87) PCT Pub. No.: W099/40156
`
`PCT Pub. Date: Aug. 12, 1999
`
`Related U.S. Application Data
`( 60) Provisional application No. 60/073,872, filed on Feb. 6,
`1998.
`Int. Cl? .............................. A61K 9/48; B32B 15/02
`(51)
`(52) U.S. Cl. .................... 424/451; 428/402; 428/402.21;
`424/464; 424/485; 424/486; 424/488; 424/489
`(58) Field of Search ............................... 428/402, 402.21;
`424/451, 464, 485, 486, 488, 489
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,164,560
`3,328,916
`3,561,187
`3,683,583
`3,772,849
`3,893,258
`3,941,865
`3,991,517
`3,999,358
`4,001,211
`
`1!1965 Suter .. ... ... ... .... ... ... ... ... ... .... ... ... 260/6
`7/1967 Okita eta!. .............................. 47/56
`2/1971 Rohnert et a!. .......................... 53/28
`8/1972 Cochran et a!. ......................... 53/28
`11/1973 Tobin, Jr. et a!.
`..................... 53/180
`7/1975 Compton eta!. ........................ 47/58
`3/1976 Miller et a!. ........................... 264/95
`11/1976 Lewis .................................... 47/57.6
`12/1976 Lewis ....................................... 53/28
`1!1977 Sarkar .................................... 536/84
`
`4,026,986
`4,028,024
`4,609,403
`4,738,724
`4,774,092
`4,851,394
`4,883,660
`5,342,626
`5,405,564
`5,431,917
`5,614,578
`5,660,859
`5,756,036
`5,965,150
`
`5/1977 Christen et a!.
`.. .... ... ... ... ... ... 264/301
`6/1977 Moreland .......................... 425/133.1
`9/1986 Wittwer et a!. ...................... 106/122
`4/1988 Wittwer et a!. ...................... 106/213
`9/1988 Hamilton ............................. 424/453
`7/1989 Kubodera ............................... 514/54
`11/1989 Blackman et a!. ..................... 424/78
`..................... 424/461
`8/1994 Winston et a!.
`4/1995 Stepto et a!. ......................... 264/115
`7/1995 Yamamoto eta!. ................. 424/451
`3/1997 Dong et a!. .......................... 524/377
`8/1997 Cody .................................... 424/451
`5/1998 Grosswald eta!. .................. 264/304
`10/1999 Wada et a!. .......................... 424/408
`
`FOREIGN PATENT DOCUMENTS
`
`9209274
`wo 9613248
`9735537
`wo 9827151
`wo 9907347
`
`11/1991 (WO) .
`10/1995 (WO) .
`3/1997 (WO) .
`12/1997 (WO) .
`5/1998 (WO) .
`
`OTHER PUBLICATIONS
`
`Scientific Status Summary, Edible and Biodegradable Poly(cid:173)
`mer Films: Challenges and Opportunities, vol. 51, No. 2,
`Feb., 1997, Krochta et al. pp. 61-74.
`International Journal of Food Science and Technology
`(1990) 28, 527-537, Preparation of transparent pea protein
`gels: a comparison of isolation procedures, Bacon et al.
`Technology News Degradables, Moldable, Water-Soluble
`Starch-Based Resin Arrives, Plas. Tech. 37, No. 10, Sep.
`1991, pp 19-23.
`
`Primary Examiner-Samuel A. Acquah
`
`(57)
`
`ABSTRACT
`
`Alkylene oxide polymer compositions having particular
`molecular weight distributions are disclosed. As a result of
`the molecular weight distributions, the disclosed alkylene
`oxide polymer compositions are suitable, among other
`things, for the manufacture of films, e.g., for use in manu(cid:173)
`facturing soft gel capsules. Capsules made from the dis(cid:173)
`closed alkylene oxide polymer compositions can provide
`enhanced resistance to crosslinking often caused by liquid
`filling materials, e.g., polyethylene glycol, used in gelatin
`capsule manufacture.
`
`16 Claims, No Drawings
`
`RBP_TEVA05018007
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 6,322,811 Bl
`
`1
`ALKYLENE OXIDE POLYMER
`COMPOSITIONS
`
`This appln is a 371 of PCT/US99/02526 filed Feb. 5,
`1999 which claim benefit of provisional No. 60/073,872
`filed Feb. 6, 1998.
`
`FIELD OF THE INVENTION
`
`The present invention relates to alkylene oxide polymer
`compositions. More specifically, the present invention
`relates to alkylene oxide polymer compositions having
`molecular weight distributions suitable for the manufacture
`of films, e.g., water soluble, flexible films for use as soft gel
`capsules.
`
`BACKGROUND OF THE INVENTION
`
`10
`
`2
`present invention, enhancements in the concentration of the
`active ingredients in the fill can often be up to 30 percent or
`more as compared to a comparable gelatin capsule.
`DETAILED DESCRIPTION OF THE
`INVENTION
`The alkylene oxide polymers of the present invention are
`prepared from alkylene oxide monomers containing from
`about 1 to 5 carbon atoms per molecule, e.g., ethylene oxide
`or propylene oxide, as well as copolymers and derivatives
`thereof. Alkylene oxide monomers suitable for use as start(cid:173)
`ing materials are commercially available.
`Preferably, the alkylene oxide polymers of the present
`invention comprise ethylene oxide polymers. The ethylene
`15 oxide polymers include, for example, homopolymers of
`ethylene oxide and copolymers of ethylene oxide with one
`or more polymerizable comonomers. The particular
`comonomer is not critical to the present invention and may
`contain hydrocarbon substituents, such as, for example,
`20 alkyl, cycloalkyl, aromatic, alkene (also referred to as
`alkylene) or branched alkyl or alkene groups; provided,
`however, that the water solubility or water-dispersibility is
`maintained. Further details concerning the preparation of
`ethylene oxide polymers is known in the art. See for
`25 example, U.S. Pat. No. 2,969,403 issued to Helmut et al.,
`U.S. Pat. No. 3,037,943 issued to Bailey et al., U.S. Pat. No.
`3,167,519 issued to Bailey et al., U.S. Pat. No. 4,193,892,
`issued to Goeke et al. and U.S. Pat. No. 4,267,309 issued to
`Goeke et al.
`The desired molecular weight distribution of the alkylene
`oxide polymers of the present invention can be obtained by
`polymerizing the alkylene oxide monomers directly or by
`blending alkylene oxide polymers having different molecu(cid:173)
`lar weight ranges. For polymers having a molecular weight
`of less than 50,000 grams per gram mole ("g/gmol"), as used
`herein, the term "molecular weight" means number average
`molecular weight (sometimes referred to herein as "Mn").
`For polymers having a molecular weight of 50,000 g/grnol
`or higher, as used herein, the term "molecular weight"
`means weight average molecular weight (sometimes
`referred to as "Mw"). Techniques for determining the aver(cid:173)
`age molecular weight are known to those skilled in the art.
`A suitable technique to determine number average molecular
`weight is by end group titration and a suitable technique to
`determine the weight average molecular weight is by light
`scattering.
`Often in the art, alkylene oxide polymers having molecu(cid:173)
`lar weights of about 50,000 and higher are referred to as
`polyalkylene oxides, e.g., polyethylene oxide, and alkylene
`50 oxide polymers having molecular weights of less than about
`50,000 are referred to as polyalkylene glycols, e.g., poly(cid:173)
`ethylene glycol. Polyalkylene oxides and polyalkylene gly(cid:173)
`cols are commercially available, for example, from Union
`Carbide Corporation, Danbury, Conn., under the tradenarnes
`55 POLYOX® Water Soluble Resins and CARBOWAX®
`polyethylene glycols (PEG), respectively. Preferably, vari(cid:173)
`ous polyalkylene glycols and polyalkylene oxides are
`blended in appropriate proportions to achieve the desired
`molecular weight distribution of the alkylene oxide polymer
`60 compositions of the present invention.
`In accordance with the present invention, the alkylene
`oxide polymer compositions typically comprise from 1 to
`about 25 wt. %, more typically from 1 to about 19 wt. %,
`preferably from about 2 to 19 wt. %, and more preferably
`65 from about 3 to 18 wt. % of alkylene oxide polymer having
`a molecular weight of about 100 to 2,000 g/gmol, typically
`100 to 1,000 g/gmol.
`
`Gelatin is a protein material produced by hydrolysis of
`collagen from animal bones and connective tissues. Gelatin
`has served as an encapsulating material, a coating for pills,
`an emulsifying agent, a coating for photographic materials,
`a bacterial culture medium, a component of printers' rollers
`and hectograph plates, an ingredient of popular desserts, and
`for many other widely varied uses.
`One common use for gelatin is in the manufacture of soft
`gel capsules for the delivery of active ingredients. Although
`gelatin is generally strong and tough, its extensibility and
`flexibility are generally low. In addition, since gelatin is
`derived from animal sources, there are often inconsistencies
`in product quality from batch to batch. The physical and 30
`chemical properties of gelatin are a function of the source of
`the collagen, method of manufacturing, conditions during
`extraction and concentration, thermal history, pH and the
`chemical nature of impurities and additives. Moreover,
`during storage, gelatin often undergoes a crosslinking reac- 35
`tion which in turn changes the dissolution character and the
`drug bio-availability characteristics. This shortens the useful
`life of the gelatin. Thus, mechanical failures of gelatin soft
`gel capsules are often encountered. Additionally, the use of
`animal derived materials, such as gelatin, has come under 40
`regulatory review due to concerns regarding the transmis(cid:173)
`sion of animal based illness.
`Accordingly, new materials are desired which can func(cid:173)
`tion as replacements for gelatin, particularly gelatin based
`films useful for manufacturing soft gel capsules and the like.
`
`45
`
`SUMMARY OF THE INVENTION
`
`By the present invention, problems commonly associated
`with the use of gelatin in manufacturing films, used for
`example in manufacturing soft gel capsules, have been
`solved. More specifically, films manufactured using the
`polymer compositions of the present invention can have
`enhanced stability, processability and physical and chemical
`properties as compared to films made from gelatin.
`In accordance with the present invention, alkylene oxide
`polymer compositions having certain molecular weight dis(cid:173)
`tributions are provided. Advantageously, the polymer com(cid:173)
`positions of the present invention are water soluble.
`However, quite surprisingly, films made from the composi(cid:173)
`tions of the present invention are substantially insoluble in
`aqueous polyethylene glycol solutions, a liquid often used as
`a physiologically acceptable carrier, when such solutions
`contain about 25 wt. % water or less. As a result of the high
`water tolerance of the films, capsules made from these films
`can accommodate increased amounts of active ingredients,
`e.g., acetaminophen, in the capsule. In accordance with the
`
`RBP_TEVA05018008
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 6,322,811 Bl
`
`15
`
`20
`
`3
`The alkylene oxide polymer compositions further typi(cid:173)
`cally comprise from about 10 to 60 wt. %, more typically
`from about 10 to 50 wt. %, preferably from about 20 to 45
`wt. % and more preferably from about 25 to 35 wt. % of
`alkylene oxide polymer having a molecular weight of from
`about 1,000 to 50,000 g/gmol, typically about 2000 to
`50,000 g/gmol and preferably from about 1,000 to 25,000
`g/gmol.
`Additionally, the alkylene oxide polymer compositions of
`the present invention typically comprise from about 25 to 89
`wt. %, preferably from about 30 to 75 wt. %, more prefer(cid:173)
`ably from about 35 to 70 wt. % and most preferably from
`about 45 to 65 wt. % of alkylene oxide polymer having a
`molecular weight of from about 50,000 to 10,000,000
`g/gmol, preferably from about 100,000 to 4,000,000 g/gmol.
`Unless otherwise indicated, the weight percentages of the
`various molecular weight fractions are based on the total
`weight of the alkylene oxide polymer composition, e.g.,
`including water, other polymers and additives as hereinafter
`described. The alkylene oxide polymer compositions of the
`present invention may comprise one or more alkylene oxide
`polymers within each molecular weight range. For instance,
`in one aspect of the invention, the alkylene oxide polymer
`composition comprises an alkylene oxide polymer having a
`molecular weight of 1,450 g/gmol and an alkylene oxide
`polymer having a molecular weight of about 8,000 g/gmol,
`both of which are within the more broadly stated range of
`about 1,000 to 50,000 g/gmol.
`The alkylene oxide polymer compositions of the present
`invention may comprise additional polymers in order to
`achieve desired properties. Such other polymers include, for
`example, naturally occurring and synthetic neutral, cationic,
`anionic and amphoteric polymers, e.g., polysaccharides and
`derivatives thereof, hyaluronic acid, other polyalkylene
`oxides, linked or cross linked polyalkylene oxides with
`linkers like epoxides, polyvinyl pyrrolidones,
`polycaprolactones, polyvinyl acetates and polycarboxylic
`acids, copolymers of alkylene oxide, acrylic acid and vinyl
`acetate. The polysaccharides include naturally occurring,
`biosynthesized and derivatized carbohydrate polymers and
`mixtures thereof. Such materials encompass high molecular
`weight polymers composed of monosaccharide units joined
`by glycosidic bonds. These materials may include, for
`example, the entire starch and cellulose families; pectin,
`chitosan; chitin; the seaweed products such as agar and
`carrageenan; alginate; the natural gums such as guar, arabic
`and tragacanth; bio-derived gums such as xanthan; and the
`like. Common polysaccharides include cellulosics conven(cid:173)
`tionally employed for the preparation of cellulose ethers, 50
`such as, for example, chemical cotton, cotton linters, wood
`pulp, alkali cellulose and the like. Such materials are com(cid:173)
`mercially available. The molecular weight of the polysac(cid:173)
`charides typically ranges from about 10,000 to 2,000,000
`grams per gram mole. Preferably, the polysaccharides are
`etherified by reacting the polysaccharide with an alkylene
`oxide, e.g., ethylene oxide, propylene oxide or butylene
`oxide or otherwise derivatized by techniques known to those
`skilled in the art.
`When such other polymers are used in the compositions
`of the present invention, they are typically present in
`amounts of from 1 to about 20 wt. %, and more typically
`from about 2 to 15 wt. % based on the total weight of the
`alkylene oxide polymer composition.
`Preferably, the alkylene oxide polymer compositions of
`the present invention comprise water in an amount of from
`1 to about 20 wt. %, more preferably from 1 to about 10 wt.
`
`4
`% and most preferably from about 3 to 8 wt. % based on the
`total weight of the alkylene oxide polymer composition.
`Preferably, water is present in an amount effective to equili(cid:173)
`brate with the amount of moisture in the air or other
`environment in which the compositions are stored, particu(cid:173)
`larly when the compositions are used to manufacture films,
`e.g., gel capsules, as hereinafter described.
`Other additives may be present in the alkylene oxide
`polymer compositions of the present invention in amounts
`10 ir~~tb~u~~t~:r!~~~~ ~~l:~ ~! ;;;e{;s~~ ~f!~:; tt~e a~~~~
`weight of the composition. Typically, other additives com(cid:173)
`prise for example, preservatives, antioxidants, colorants,
`opaquing agents and the like.
`In one aspect of the invention, the alkylene oxide com-
`positions of the present invention contain minor amounts,
`e.g., less than about 20 wt. % based on the total weight of
`the composition, of gelatin. More preferably, there is a
`substantial absence, e.g., less than about 5 wt. %, preferably
`less than about 1 wt. % based on the total weight of the
`composition, of gelatin.
`The alkylene oxide compositions of the present invention
`may be provided in any desired form. Typical forms include,
`for example, liquids, small particles, e.g., 0.001 to about 100
`25 microns, large particles or granules, e.g., about 1 to 10
`millimeters ("mm"), extrudates, tablets, films and capsules.
`The alkylene oxide polymer compositions of the present
`invention are particularly suitable for manufacturing films.
`Typically, prior to making the films, polymers having the
`30 desired molecular weights are first uniformly blended along
`with water in a conventional mixer such as a V blender,
`Hobart mixer, or ball mill, e.g., for about 60 minutes. A
`preferred composition is comprised of 5.4 wt. % of CAR(cid:173)
`BOWAX® PEG 300 (Mw=300 g/gmol), 8.1 wt. %of CAR-
`35 BOWAX® PEG 1450 (Mw=1450), 27 wt. % of CARBO(cid:173)
`WAX® PEG 8000 (Mw=8000), 54 wt. % of POLYOX®
`WSR N-750 (Mw=300,000) and 5.5 wt. % water. Details
`concerning the manufacture of films comprising the alkylene
`oxide polymers of the present invention are known to those
`40 skilled in the art.
`Preferably, films made from the alkylene oxide polymer
`compositions of the present invention have thicknesses of
`from about 0.05 to 1.0 mm and preferably from about 0.1 to
`0.5 mm. Typically, the films are flexible, i.e., not rigid, and
`45 are water soluble, disperse or disintegrate rapidly in water.
`As used herein, the term "water soluble" means that at least
`one gram and preferably two grams of the alkylene oxide
`polymer composition are soluble in 100 grams of distilled
`water at 25° C. and one atmosphere.
`Preferably, the films made from the alkylene oxide poly-
`mer compositions of the present invention have desirable
`properties in terms of flexibility, toughness, uniformity and
`clarity. Typically, the mechanical properties of the films
`prepared by the alkylene oxide polymer compositions of the
`55 present invention have the following mechanical properties.
`The tensile strength of extruded and thermal pressed films,
`as measured in accordance with ASTM Method 412-68, is at
`least about 200 psi or more with an elongation of at least
`about 50%. Normally, the air blown films have about 20%
`60 lower tensile strength. Furthermore, the films are preferably
`sealable. That is, the films should be able to seal onto
`themselves with the help of elevated temperature, pressure,
`or both, with or without the help of a dilute aqueous solution
`of one of the ingredients of the film. Further details con-
`65 cerning the sealing of ethylene oxide polymer films are
`known in the art. See for example, U.S. Pat. No. 3,999,358
`issued to Lewis, et al.
`
`RBP_TEVA05018009
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 6,322,811 Bl
`
`5
`Quite surprisingly, the alkylene oxide polymer composi(cid:173)
`tions of the present invention are substantially insoluble in
`polyalkylene glycols and aqueous polyethylene glycol solu(cid:173)
`tions (molecular weight equal to 400 g/gmol) containing up
`to about 25 wt. % water. As used herein, the term "substan(cid:173)
`tially insoluble" means that less than about 5 wt. %, pref(cid:173)
`erably less than about 3 wt. % and more preferably less than
`about 1 wt. % of the polymer dissolves in the solution at 25°
`C. and one atmosphere over a time period of 10 minutes.
`This unexpected property provides a solution to the problem 10
`of mechanical failures associated with gelatin soft gel cap(cid:173)
`sules where the liquids used inside the capsules often
`adversely affect the integrity of the capsule walls. More
`specifically, polyalkylene glycols, e.g., polyethylene glycol,
`are often used as the liquid filling material in soft gel 15
`capsules because they are physiologically acceptable carri(cid:173)
`ers. Polyethylene glycol has a high infinity for the gelatin
`capsules and softeners often used in preparing soft shell
`gelatin capsules. As a result, the gelatin capsules can
`undergo a crosslinking reaction which changes the dissolu- 20
`tion character and drug bio-availability characteristics.
`Thus, a preferred use for the alkylene oxide polymer
`compositions of the present invention is in the manufacture
`of soft gel capsules. Quite advantageously, the alkylene
`oxide compositions of the present invention can replace
`gelatin in the manufacture of soft shell capsules. In general,
`the soft shell capsules can be prepared by a rotary die
`process in which they are formed, filled, and sealed in a
`single operation. They are filled with a solution or suspen(cid:173)
`sion of drug or die in liquids that will not solubilize the shell.
`The compositions of the present invention can also be
`used to manufacture hard shell capsules which are generally
`rigid. The hard shell capsules comprise two, fitted cap and
`body pieces. The rigidity of the capsule can be increased by
`increasing the amount of the high molecular weight polymer
`fractions and/or decreasing the low molecular weight poly(cid:173)
`mer fractions. They can be made by a punch and die
`operation that is carried out at above the softening tempera(cid:173)
`ture of the polymer, e.g., 50 to 80° C.
`In general, the capsules of the present invention, both hard
`shell and soft gel, comprise a continuous, flexible wall
`having an outer surface and an inner surface. The wall is
`comprised of a film made from the alkylene oxide polymer
`compositions of the present invention. The inner surface of
`the capsule at least partially surrounds the inner space of the
`capsule.
`Further details concerning the manufacture of gel cap(cid:173)
`sules and appropriate apparatus useful in manufacturing
`such capsules are known in the art, such as described in U.S.
`Pat. No. 4,028,024 issued to Moreland.
`The size of the capsules can be determined by those
`skilled in the art depending upon the intended use. For
`example, capsules for oral drug delivery for humans will
`typically have a size ranging from about 1 mm to 10 mm. In 55
`contrast, capsules for oral drug delivery for animals may be
`significantly larger, e.g., about 10 mm to 30 mm. Capsules
`used for other purposes, such as, for example, in the manu(cid:173)
`facture of paint balls may be relatively large, whereas
`capsules used to contain ink or other fluids may be extremely 60
`small. Thus, typically the size of the capsules will range
`from about 1 mm to 50 mm. In the case of non-spherical
`capsules, e.g., elliptically shaped capsules, the above men(cid:173)
`tioned diameter is made with reference to the largest dimen(cid:173)
`sion perpendicular to the longitudinal axis.
`The capsules of the present invention may or may not
`contain a filling or material within the inner space of the
`
`6
`capsule. When the capsules contain a filling, such filling can
`be a liquid, gas, semi-solid, solid or gel. The particular form
`of the filling is not critical to the present invention.
`Often, liquid fillings are employed in the capsules of the
`present invention. Preferably, the liquid used as the filling
`material does not adversely affect the integrity of the capsule
`wall. More specifically, it is preferred that the liquid does not
`promote the dissolution of the capsule wall or cause the
`capsule wall to crosslink over time. Typically, the interior
`space of the capsule will be at least 10 percent by volume
`filled with liquid, preferably at least 25 percent, more
`preferably at least 50 percent and most preferably at least 75
`volume percent filled.
`Those skilled in the art will recognize that the capsules of
`the present invention will have a variety of industrial and
`personal care uses. For instance, the capsules can be used for
`the oral delivery of pharmaceutically active agents to
`humans and animals. In addition, the capsules can be used
`in personal care applications, e.g., hair care and skin care
`formulations, to deliver oils, vitamins, proteins, polymers
`and other personal care ingredients. The capsules can also be
`used, for example, to provide bath oil beads, fragrances and
`time released ingredients. Further, the capsules can be used
`in the manufacture of paint balls and other recreational
`25 products. Moreover, the capsules can be employed in a
`variety of industrial uses, such as, for example, in the
`delivery of inks, catalysts, initiators, enzymes, and the like.
`The amount of the particular active ingredient utilized
`depends on the particular end use. Typically, the amount of
`30 active ingredient will range from about 0.01 to 99 wt. %
`based on the total weight of the filling material, e.g., liquid
`and active. As used herein, the term "active ingredient"
`means the ingredient or ingredients introduced into the
`capsule to achieve the desired effect upon delivery. Whether
`35 such effect is pharmacological, chemical, cosmetic, physical
`or otherwise is not critical to the present invention. Further
`details concerning the selection and amounts of the appro(cid:173)
`priate filling materials and active ingredients can be deter(cid:173)
`mined by those skilled in the art.
`One preferred end use for the capsules of the present
`invention is for the delivery of active ingredients in phar(cid:173)
`maceutical and personal care applications. For such
`applications, the liquid material comprises a physiologically
`acceptable carrier, preferably a polyalkylene glycol, more
`45 preferably polyethylene glycol having a weight average
`molecular weight of about 100 to 500, preferably about 400
`g/gmol. More preferably, the filling material comprises an
`aqueous, polyalkylene glycol solution comprising from
`about 1 to 30 wt. %, typically from about 5 to 25 wt. %,
`50 preferably from about 10 to 25 wt. % and more preferably
`from about 15 to 25 wt. % water, based on the total weight
`of the liquid, e.g., polyalkylene glycol plus water.
`Typical actives for personal care applications, i.e., both
`pharmaceutical and cosmetic, include but are not limited to
`spermicides, virucides, analgesics, anesthetics, antibiotic
`agents, antibacterial agents, antiseptic agents, vitamins,
`corticosteriods, antifungal agents, vasodilators, hormones,
`antihistamines, autacoids, decongestants, bronchodilators
`and other antiasthmatic agents, beta-blockers, anti(cid:173)
`nauseants, antiemetics, anticonvulsants, kerolytic agents,
`anti-diarrhea agents, anti-alopecia agents, anti-inflammatory
`agents, exfoliating agents, sunscreens, anti-oxidants,
`enzymes, anti-infection agents. Typical pharmaceutically
`active ingredients suitable for use in the invention include
`65 acetaminophen, famotidine, chlorpheniramine,
`pseudoephedrine, dectromethorphan, diphenhydramine,
`brompheniramine, phenylpropanolamine, clemastine,
`
`40
`
`RBP_TEVA05018010
`
`TEVA EXHIBIT 1005
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`US 6,322,811 Bl
`
`7
`terfenadine, astemizole, pharmaceutically acceptable salts
`thereof and mixtures thereof.
`Other components of the liquid filling material can be
`determined by those skilled in the art and include materials,
`such as for example, solvents, diluents and adjuvants such
`as, for example, ethyl alcohol, isopropyl alcohol, higher
`alcohols, glycerine, propylene glycol, sorbitol, preserva(cid:173)
`tives, surfactants, menthol, eucalyptus oil, other essential
`oils, fragrances, viscosity adjusters, and the like.
`The concentration of the active ingredient in the capsule
`is, of course, dependent on the particular end use and the
`active agent, which can be determined by those skilled in the
`art. For example, the pharmaceutically active ingredients are
`usually present in the capsule in a therapeutically effective
`amount which produces the desired therapeutic response
`upon administration. In determining such amounts, the par- 15
`ticular compound being administered, the bio-availability
`characteristics of the compound, the dose regiment, the age
`and weight of the patient, and other factors must be con(cid:173)
`sidered.
`The following Examples are provided for illustrative
`purposes and are not intended to limit the scope of the claims
`which follow. The concentrations of ingredients are pro(cid:173)
`vided in weight percent unless otherwise indicated.
`The designations and abbreviations used in the Examples
`are defined as follows:
`
`20
`
`25
`
`10
`
`8
`The tensile strength measurements were conducted on an
`Instron Extensometer employing ASTM Method D 412-68.
`Film dissolution studies were conducted by a visual and a
`gel permeation chromatographic ( GPC) method. A piece of
`the film with known weight (0.05 to 0.5 gram) was added to
`10 grams of water or an aqueous PEG solution. The time it
`took to dissolve the film was recorded. If the film did not
`dissolve in over 42 hours, the observation was stopped. The
`liquid phase was sampled periodically and analyzed by GPC
`to detect the presence of components of the film in the
`solution.
`Films were viewed under Scanning Electron Microscope
`(SEM) for their uniformity and microstructure.
`
`EXAMPLE 1
`
`Preparation of Composite
`
`The composites were prepared in batches of 300 grams of
`total material. The blending was carried out in two steps.
`First, solid polymer powders such as POL YO X®, PEG 8000
`and other polymers (as set forth in Examples 4 and 5) for
`desired properties were milled in a one quart ball mill for 30
`minutes. To this blend, a water solution of PEG 300 and PEG
`1450 was added with additional mixing. KITCHEN AID and
`HOBART mixers were used for blending the composites of
`larger size (500 to 5000 grams). The resulting wet granular
`blend was then extruded as described in Examples 2 and 3.
`
`TONE® Polymer P-767
`
`PVAc GB 101
`
`PVP (Polyvinylpyrrolidone)
`
`The following test procedures define the performance
`tests used in the evaluation.
`
`A wet granular mass, as prepared in Example 1, was fed
`to a electrically heated 3" flexible lip ribbon die using a
`
`POLYOX ® WSR N 750
`
`POLYOX ® WSR N 10
`
`CARBOWAX ® PEG
`Compound 20M
`
`CARBOWAX ® PEG 8000
`
`CARBOWAX ® MPEG 5000
`
`CARBOWAX ® PEG 1450
`
`CARBOWAX ® PEG 400
`
`CARBOWAX ® PEG 300
`
`An ethylene oxide polymer having a
`molecular weight of about 300,000
`g/gmol, available from Union Carbide
`Corporation, Danbury, cr.
`An ethylene oxide polymer having a
`molecular weight of about 100,000
`g/gmol, available from Union Carbide
`Corporation, Danbury, cr.
`An epoxide linked polyethylene glycol
`having a molecular weight of about 18,000
`g/gmol, available from Union Carbide
`Corporation, Danbury, cr.
`A polyethylene glycol having a molecular
`weight of about 8,000 g/gmol, available
`from Union Carbide Corporation,
`Danbury, CT.
`A methoxy polyethylene glycol having a
`molecular weight of about 5,000 g/gmol,
`available from Union Carbide
`Corporation, Danbury, cr.
`A polyethylene glycol having a molecular
`weight of about 1450 g/gmol, available
`from Union Carbide Corporation,
`Danbury, CT.
`A polyethylene glycol having a molecular
`weight of about 400 g! gmol, available
`from Union Carbide Corporation,
`Danbury, CT.
`A polyethylene glycol having a molecular
`weight of about 300 g! gmol, available
`from Union Carbide Corporation,
`Danbury, CT.
`CELLOSIZE ® HEC QP-40 Hydroxyethyl cellulose having a
`molecular weight of about 120,000
`g/gmol, available from Union Carbide
`Corporation, Danbury, cr.
`A polycaprolactone resin having a
`molecular weight of about 35,000 to
`55,000 g/gmol, available from Union
`Carbide Corporation, Danbury, cr.
`A vinyl acetate polymer having a
`molecular weight of about 40,000
`g/gmol, available from Union Carbide
`Corporation, Danbury, cr.
`A 1-ethynyl-2-pyrrolidinone polymer
`
`30
`
`EXAMPLE 2
`
`Air Blown Extrusion Process
`
`35
`
`A composite sample, as prepared in Example 1, was fed
`to a heated circular die using a single screw Brabender
`extruder (Model #11505). The extruder chamber was fur(cid:173)
`nished with a three zone electric heating and control system.
`The blend was heated to about 125° C. prior to entering the
`circular die. With the help of air that was blowing from the
`center of the die, the hot extruded film was blown into a
`40 cylindrical shape. After it had cooled, the film was rolled on
`a take-up roller that was located about three feet from the
`die. The film thickness was about 0.2 mm.
`
`EXAMPLE 3
`
`45
`
`Slot Cast Die Extrusion and Pressing Process
`
`A wet granular mass, as prepared in Example 1, was fed
`to a 2" wide slot cast die using a single scr