US005273758A
`_
`5,273,758
`[11] Patent Number:
`[19]
`United States Patent
`
`Royce
`[45] Date of Patent:
`Dec. 28, 1993
`
`[54] DIRECTLY COMPRESSIBLE
`
`FORMS
`
`Inventor: Alli! E. Royce, Effort, Pa.
`[75]
`[73] Assignee:
`Sandoz Ltd., Basel, Switzerland
`[2]] App]. No_; 358,073
`[22] Filed:
`Apr. 13, 1992
`
`[63]
`
`Remed U'S' APP“°‘fi°“ mt‘
`Continuation of Ser. No. 672,503, Mar. 18, 1991, aban-
`d0n¢d-
`Int. c1.s ................................................ A6lK 9/20
`[51]
`[52] U.S. Cl. .................................... 424/455; 424/464;
`424/436; 424/459
`[58] Field of Search ............. .. 424/464, 465, 469, 486,
`424/470
`
`[56]
`
`References Cited
`Pm vocwms
`8/1982 Kawata etnl. ...................... 424/497
`4,343,789
`4,996,047 2/1991 Kelleher et a1.
`.................... 424/483
`Ex
`_
`Th
`K P
`P”
`S'pc:f°
`AS333,
`Attorney, Agent, or Firm—Robert S. Honor; Richard E.
`W3‘ D'““° E‘ Fm”
`[57]
`'
`ABSTRACI‘
`Polyethylene oxide polymer is employed as 41 directly
`compressible binder matrix for therapeutically active
`dosage forms. Advantageously, the polyethylene oxide
`has 3“ 3di“5‘3b1° fa“ °°“"°1 °ff°°‘ 0“ *1“ T°1°”¢ °‘
`mcdicament from the d°Sa8e f°m: enabling in Pmicw
`lar the preparation of sustained release dosage forms.
`
`26 Claims, 1 Drawing Sheet
`
`% Dissolved Clemastine Fumarate
`
` 2
`
`10
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`12
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`14
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`16
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`18
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`4
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`6
`
`8
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`Time, hours
`
`+ POLYOX N80 + POLYOX 303
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`U.S. Patent
`
`Dec. 28, 1993
`
`5,273,758
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`DIRECTLY COMPRESSIBLE POLYETHYLENE
`OXIDE VEHICLE FOR PREPARING
`THERAPEUTIC DOSAGE FORMS
`
`This is a continuation of application Ser. No.
`07/672,503, field Mar. 18, 1991, now abandoned.
`
`FIELD OF THE INVENTION
`
`This invention relates to compositions to be com-
`bined with a therapeutically active medicament and
`formed into solid, shaped unit dosage forms. More par-
`ticularly, the present invention relates to compositions
`comprising a free-flowing directly compressible vehicle
`which can be blended with a medicament, and to di-
`rectly compressed dosage forms prepared therefrom.
`BACKGROUND OF THE INVENTION
`
`In order to prepare solid, shaped dosage forms from
`fine particles or powders comprising therapeutic agents,
`it has generally been necessary to process the powders
`in a manner to improve their flowability, cohesiveness
`and other characteristics which will enable the resulting
`material to be fabricated by conventional processes
`such as tableting, encapsulation, molding, etc. into a
`satisfactory unit form that can suitably deliver an agent
`into the environment of use.
`
`Various processes have therefore been developed for
`modifying starting powders or other particulate materi-
`als, in which typically the powders are gathered to-
`gether with a binder material into larger permanent
`free-flowing agglomerates or granules referred to col-
`lectively as a “granulation.” For example, solvent-
`assisted “we ” granulation processes are generally char-
`acterized in that the powders are combined with a
`binder material and moistened with water or an organic
`solvent under conditions to result in formation of a wet
`granulated mass from which the solvent must then be
`evaporated. Such processes, while widely employed,
`have certain recognized limitations arising from the use
`when necessary of non-aqueous solvents which may be
`environmentally deleterious, and furthermore may not
`be readily adaptable in connection with moisture or
`‘heat sensitive medicaments. Alternatively, the known
`“dry granulation” processes, which can depend on
`fairly complicated milling schemes to produce a suitable
`granulation, also have acknowledged disadvantages.
`A “direct compression” process has in limited cases
`provided a simpler and more economical means of pre-
`paring compressed dosage forms.
`In such a process, the therapeutically active ingredi-
`ent is combined with a binder-diluent or vehicle which
`itself is characterized in having the requisite properties
`for tableting, such as flowability, appropriate particle
`size distribution, binding ability, acceptable bulk and tap
`density and dissolution properties, and the resulting
`blend can therefore be.“directly” provided to a die
`cavity or mold for compaction, without prior granula-
`tion. See Shangraw, “Compressed Tablets by Direct
`Compression,” in Phannaceutical Dosage Forms, 2d Ed.,
`1989, Vol. 1, pp. 195-246. The resulting compressed
`dosage form often provides improved stability and dis-
`sociation profiles, as well as batch-to-batch uniformity,
`relative to “wet” or "dry” granulated dosage forms.
`A suitable direct compression vehicle for a given
`application is preferably also tailored, for example, to be
`compatible with the active ingredient, to resist physical
`or chemical change on aging, to be air, moisture and
`
`2
`heat-stable, have sufficient capacity for the active ingre-
`dient in the dosage form, accept colorants uniformly
`when necessary, and not interfere with biological avail-
`ability.
`Materials employed by the art which to varying de-
`grees fulfill the requirements of a direct compression
`vehicle include water soluble materials such as various
`forms of lactose (e.g., spray-dried lactose, Fast Flow ®
`lactose, anhydrous lactose), as well as sucrose, dextrose,
`sorbitol, mannitol and maltodextrin, and relatively in-
`soluble materials such as microcrystalline cellulose
`(e.g., Avicel ®), starch, dicalcium phosphate dihydrate,
`and calcium carbonate.
`
`However, such materials, while often comprising a
`relatively large proportion by weight of the tableted
`formulation in order to impart full advantage of their
`compression properties, nevertheless in themselves are
`generally insufficient to regulate the rate of disintegra-
`tion of the dosage form or release of the medicament,
`and therefore must often be accompanied by various
`additional excipients having such a rate-control effect,
`the latter which (given practical limitations on the size
`of the dosage form) may be confined to low concentra-
`tions at which the rate control effect is not completely
`satisfactory.
`It has therefore been an object to identify a directly
`compressible vehicle which can exert a rate control
`function in the prepared dosage form.
`In particular, it has been an object to prepare both
`immediate and sustained release therapeutically active
`dosage forms comprising such an excipient.
`SUMMARY OF THE INVENTION
`
`It has now been found that directly compressed dos-
`age forms may be prepared from compositions compris-
`ing polyethylene oxide as a binder-matrix.
`The compositions and dosage forms of the invention
`comprise about 5 to about 99.99 wt.% of polyethylene
`oxide polymer, and a therapeutically active medicament
`dispersed therein.
`The therapeutic medicament may comprise from
`about 0.01 to about 95 wt.% of such compositions.
`Advantageously, it has been found that the polyethyl-
`ene oxide can provide an adjustable rate controlling
`effect on the release of medicament from the dosage
`form, and that directly compressed dosage forms may
`therefore be prepared which can dispense medicament
`at varying rates.
`Further advantageously, the direct compression pro-
`cess of the invention provides a therapeutically active
`dosage form wherein the medicament is well dispersed,
`has no loss of activity due to moisture or heat exposure
`such as may occur during a granulation process, and is
`substantially free of solvent residues.
`
`BRIEF DESCRIPTION OF THE DRAWING
`
`FIG 1 is a graph depicting the cumulative amount of
`a medicament dispensed over a prolonged period of
`time from dosage forms prepared according to the in-
`vention.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`65
`
`Polyethylene oxide is a nonionic homopolymer of the
`formula —(——O—CI-I2-CH2—)—,,, wherein n repre-
`sents the average number of oxyethylene groups,
`it
`generally being from about 2,000 to about 100,000. It is
`a water soluble resin which is available as a white pow-
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`5,273,758
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`the therapeutic medicament, as well as other optional
`excipients, and (ii) providing the resulting mixture to a
`compression machine, and applying sufficient pressure
`to the composition to form a unitary dosage form.
`The medicament may be employed in powder, crys-
`talline, or other form, and typically need not be com-
`pounded to an amorphous or other type granulated
`form.
`
`3
`der in several grades which vary in viscosity profile
`when dissolved in water, National Formulary XVII, pp.
`1963-1964 (1990) Molecular weights range from about
`l(X),(IX) to about 6,(IX),(XX), corresponding to a viscosity
`range of under about 200 cps for a 5% aqueous solution
`of the lower molecular weight polymers to over about
`6,2!” cps for a 1% solution of the higher molecular
`weight polymers. Polyethylene oxide resins are com-
`mercially available under the tradename Polyox ®
`from Union Carbide Corporation. The Polyox ® WSR
`series corresponds to polymers having a broader distri-
`bution of molecular weight ranges than polymers in the
`WSR N series.
`
`For example, Polyox® WSR N80 has an average
`molecular weight of about 2(X),000, and a 5% aqueous
`solution thereof at 25' C. has a viscosity on a Brookfreld
`RVT, No. l spindle at 50 rpm of about 65 to 115 cps,
`andapl-lof8tol0.
`Polyox ® WSR 303 has an average molecular weight
`of about 5,0(X),000 to 6,000,000, and a 1% aqueous solu-
`tion thereof at 25' C. has a viscosity of 7,200 to 10,000
`cps on a Brookfield RVF, No. 2 spindle at 2 rpm, and a
`pH of 8 to 10.
`Particle size distribution of the above-mentioned Po-
`
`lyox® resins is such that passage through a 10-mesh
`sieve is 100%, and through a 20-mesh sieve is about
`96%. Other particle size distributions may also be useful
`in the invention.
`
`See Union Carbide Corp., POLYOX ® WA TER-
`SOLUBLE RESIN Product Specifications (1988).
`The use of a particular molecular weight polyethyl-
`ene oxide polymer as a binder material will depend on
`the desired disintegration or release rate characteristics
`to be imparted to the prepared dosage form. In general,
`lower molecular weight polyethylene oxide polymers,
`i.e. having MW of up to about 300,000, e.g., Polyox ®
`N80, may be selected to prepare tablets from which the
`medicament is released within a relatively short time
`period, i.e. immediate release tablets. Sustained release
`dosage forms may be prepared from the higher molecu-
`lar weight polymers, i.e. having MW higher than about
`300,000, especially about 5,000,000 (e.g., Polyox ®
`303). It is contemplated that mixtures of varying molec-
`ular weight polymers may also be employed as a matrix
`system to obtain the desired tablet release properties,
`and such mixtures may comprise respective amounts of
`the various polyethylene oxide polymers as shall be
`within the skill of the worker in the art to ascertain to
`provide the appropriate release pattern.
`Other optional components of the compositions of
`the invention include various binders, disintegrants,
`diluents, etc., including cellulose ethers, such as hydrox-
`ypropyl methylcellulose, and waxy substances, 5 well
`as minor amounts of various lubricants such as talc,
`colloidal silicon dioxide, stearic acid or metal stearates,
`etc., and colorants, sweeteners, and the like.
`The compositions of the invention comprise from
`about 5 to 99.99 wt.%, and preferably 20 to 99.99 wt.%,
`of free-flowing, directly compressible polyethylene
`oxide binder material.
`
`In one embodiment, the compositions consist essen-
`tially of the polyethylene oxide binder and the medica-
`merit.
`
`The dosage forms are prepared by a direct compres-
`sion process; that is, the process comprises, and in one
`embodiment, consists essentially of, the steps of (i) dry
`blending particles comprising 5 to 99.99 wt.%, and
`preferably 20 to 99.99 wt.%, of polyethylene oxide with
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`The polyethylene oxide and medicament and other
`optional ingredients are dry blended, i.e. in the absence
`of added solvents or heat, to produce a free-flowing
`material wherein the medicament is well dispersed in
`the polyethylene binder-matrix.
`The mixture is then provided to, for example, a tablet-
`ing machine and a compression force of about 0.5 to 10
`tons is applied.
`in
`A tableted dosage form is therefore prepared,
`which the medicament is generally evenly dispersed
`throughout the polyethylene oxide binder, and which is
`free of solvent residues.
`As used herein, the term “tablet” refers to a com-
`pressed body which is composed of a plurality of dis-
`crete particles, and includes pills,
`lozenges, dragee
`cores, capsule slugs, molded forms, and the like.
`The tableted dosage forms of the invention can pro-
`vide relatively immediate or more sustained release of
`the therapeutic medicament into the environment.
`The expression “therapeutic medicament” or “drug"
`shall include any physiologically or pharmacologically
`active substance that produces a local or systemic ef-
`fect(s) in animals, which include warm-blooded mam-
`mals, humans, primates, etc.
`The term “physiological” as used herein denotes the
`administration of a drug to effect normal levels and
`functions. The term “pharmacological” denotes varia-
`tions in response to the amount of drug administered to
`the host. The devices have found a particular use as
`vehicles for various human and animal drugs, particu-
`larly for the oral administration thereof, although for
`other systems as well, including systems such as buccal,
`implant, nose, artificial gland, rectum, cervical, intrau-
`terine, occular, arterial, venous, ear and the like, may be
`manufactured according to the process of the invention.
`The active drugs that can be delivered include inor-
`ganic and organic drugs, without limitation, drugs that
`act on the central nervous system, cardiovascular drugs,
`endocrine drugs, drugs for metabolic disorders, immu-
`nologic drugs, and drugs for treatment of allergies and
`infectious diseases. More particularly, such drugs may
`comprise depressants, hypnotics, sedatives, psychic
`energizers,
`tranquilizers, anti-hypertensives, antican-
`vulsants, muscle relaxants, antiparkinson agents, analge-
`sics, anti-inflammatory, local anesthetics, muscle con-
`tractants,
`anti-microbials,
`anti-malarials,
`hormonal
`agents, contraceptives, sympathomimetics, diuretics,
`anti-parasitics, neoplastics, hypoglycemics, ophthal-
`mics, electrolytes, diagnostic agents, and the like.
`Compositions according to the invention may be
`prepared which comprise clemastine fumarate in free
`base form, or in a pharmaceutically acceptable acid
`addition salt form. Clemastine fumarate, i.e., (1) Pyrrol-
`idone, 2-[2-[1-(4—chlorophenyl)-l-phenylethoxy]ethyl]-
`1-methyl-,
`[R-(R‘,R')]-,
`(E)-2-butenedioate;
`(2)
`(+)-(2R)-2-[2-[[(R)-p-Chloro-a-methyl-a-phenylben-
`zyl]-oxy]-ethyl]-l-methylpyrrolidone furnarate, is a col-
`orless to faintly yellow, practically odorless, crystalline
`powder. It belongs to the benzhydryl ether group of
`antihistaminic compounds and has activity as an H1-
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`receptor antagonist (CAS 14976-57-9; CAS-l5686-5l-
`8).
`The following examples are merely intended to be
`illustrative of the invention and not limitative thereof’.
`Unless otherwise expressly indicated the chemical sub- 5
`stances usedare in the National Formulary or the U.S.
`Pharmacopeia.
`
`EXAMPLE 1
`
`2.68 mg. clemastine fumarate, available from Sandoz
`Corp. under the tradename Tavist ®, is combined with
`177.32 mg. of polyethylene oxide having a molecular
`weight of (a) 200,000 (Polyox® N80, Union Carbide)
`or (b) 6,000,000 (Polyox® 303, Union Carbide), and
`passed through a 60-mesh screen. The blended powders
`are then compressed into tablets on a hand-operated
`Carver press. A compaction force of 1 ton is applied.
`Two tablets, prepared as in (a) and (b) above, are
`subjected to dissolution studies according to the method
`described in US. Pharmacopoeia (1985) Vol. XXI, pp.
`1243-1244.
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`A multiple position dissolution stirrer such as that
`described at USP p. 1244, Apparatus 2, is employed,
`which is equipped with a Teflon paddle (20 rpm) in
`each of six vessels. A dissolution medium comprising
`900 ml. of deaerated and distilled water is maintained at
`37‘.-L-0.5‘ C. A tablet is sequentially dropped into each
`vessel. Stirring and timing (time zero) is commenced as
`the first tablet hits the bottom of the vessel (under the
`paddle).
`At regular intervals, aliquots of test solution are with-
`drawn from each of the vessels in the order in which the
`tablets were originally dropped, using a stainless steel
`cannula. The aliquots are withdrawn from a point mid-
`way between the surface of the dissolution medium and 35
`the top of the paddle and not less than 1 cm. from each
`vessel wall.
`
`30
`
`The amount of clemastine fumarate present in each of
`the vessels is calculated by reference to standard solu-
`tions using UV spectroscopy.
`the cumulative
`Accompanying FIG.
`1 depicts
`amount of medicament delivered by each tablet over an
`extended period of time.
`It will be seen that the tablets of the invention provide
`a gradual, controlled release of the medicament over an 45
`extended period of time.
`EXAMPLE 2
`
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`Placebo tablets, each 4.9 mg., are prepared in a batch
`by mixing 98.7 mg of polyethylene oxide having a mo- 50
`lecular weight of (a) about 200,0()0 (Polyox ® N80) or
`(b) about 6,000,000 (Polyox® 303), with 11.0 mg. of
`hydroxypropyl methylcellulose (Pharmocoat 606) and
`0.27 mg of magnesium stearate, in a free-fall blender,
`and then compressing the blend on a high speed tablet
`press (Manesty, Betapress).
`For the tablets prepared according to (a) above, i.e.
`comprising polyethylene oxide having a molecular
`weight of about 200,000, a compressive strength (hard-
`ness) and weight variation are obtained which indicate
`that the flowability of the formulation is adequate for
`the direct tableting process. The disintegration times for
`the tablets using the USP method of Example 1 range
`from 30-45 min., indicating that relatively immediate
`release of a medicament can be effected by the tablets.
`For the tablets prepared according to (b) above, i.e.
`comprising polyethylene oxide having a molecular
`weight of about 6,000,000 (Polyox ® 303), the compres-
`
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`6
`sion results are equivalent to those of the tablets pre-
`pared in (a). However, these higher molecular weight
`polyethylene oxide-based tablets do not disintegrate
`under standard testing procedures, indicating suitability
`as a sustained release dosage form.
`What is claimed is:
`1. A direct compression process for preparing a tab-
`leted pharmaceutical dosage form consisting of the
`steps of:
`a. blending a powder for crystalling therapeutic med-
`icament with a direct compression vehicle consist-
`ing essentially of polyethylene oxide, in the absence
`of added solvent or heat, to form a composition in
`which the medicament in dispersed; and
`b. compresseing the resulting composition under suf-
`ficient pressure to form a tablet.
`2. A process according to claim 1 wherein the com-
`position comprises 0.01 to 95 wt.% medicament.
`3. A process according to claim 2 wherein the com-
`position comprises 5 to 99.99 wt.% polyethylene oxide.
`4. A process according to claim 1 wherein the poly-
`ethylene oxide is selected from polymers having an
`average molecular weight of up to about 300,000, poly-
`mers having an average molecular weight of about
`300,000 or greater, and mixtures thereof.
`5. A process according to claim 1 wherein the medi-
`cament comprises from about 0.01 to about 95 wt.% of
`the dosage form.
`6. A direct compression process for preparing a tab-
`leted pharmaceutical dosage form consisting essentially
`of the steps of:
`a. blending the medicament clemastine fumarate in
`free base or pharmaceutically acceptable acid addi-
`tion salt form with a direct compression vehicle
`comprising polyethylene oxide, in the absence of
`added solvent or heat, to form a composition in
`which the medicament is dispersed; and
`b. compressing the resulting composition under suffi-
`cient pressure to form a tablet.
`7. A process according to claim 6 wherein the poly-
`ethylene oxide has the formula —-(O—CH2—CH2),,—
`wherein n represents the average number of oxyethyl-
`ene groups, and n is 2,000 to 100,000.
`8. A process according to claim 6 wherein the poly-
`ethylene oxide has an average molecular weight of
`100,000 to 6,000,000.
`9. A process according to claim 8 wherein the poly-
`ethylene oxide has a viscosity of under about 200 cps for
`a 5% aqueous solution thereof.
`10. A process according to claim 8 wherein the poly-
`ethylene oxide has a viscosity over about 6,200 cps for
`a 1% aqueous solution thereof.
`11. A process according to claim 8 wherein the poly-
`ethylene oxide has a viscosity of 65 to 115 cps for a 5%
`aqueous solution thereof at 25° C. on a Brookfield RVT,
`No. 1 spindle at 50 rpm.
`12. A process according to claim 8 wherein the poly-
`ethylene oxide has a viscosity of 7,200 to 10,000 cps for
`a 1% aqueous solution thereof at 25° C. on a Brookfield
`RVF, No. 2 spindle at 2 rpm.
`13. A process according to claim 6 wherein the com-
`position comprises 0.0l to 95 wt.% medicament.
`14. A process according to claim 6 wherein the com-
`position comprises 5 to 99.99 wt.% polyethylene oxide.
`15. A process according to claim 1 wherein the poly-
`ethylene oxide has the formula —(O—CH2—-CH2)”-
`wherein n represents the average number of oxyethyl-
`ene groups, and n is 2,000 to 100,000.
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`16. A process according to claim 1 wherein the poly-
`ethylene oxide has an average molecular weight of
`l(X),0(X) to 6,030,000.
`17. A process according to claim 16 wherein the
`polyethylene oxide has a viscosity of under about 200
`cps for a 5% aqueous solution thereof.
`18. A process according to claim 16 wherein the
`polyethylene oxide has a viscosity over about 6,2(X) cps
`for a 1% aqueous solution thereof.
`19. A process according to claim 16 wherein the
`polyethylene oxide has a viscosity of 65 to 115 cps for a
`5% aqueous solution thereof at 25‘ C. on a Brookfield
`RVT, No. l spindle at 50 rpm.
`20. A composition according to claim 16 wherein the
`polyethylene oxide has a viscosity of 7,200 to l0,000 cps
`for a 1% aqueous solution thereof at 25' C. on a Brook-
`field RVF, No. l spindle at 2 rpm.
`
`21. A process according to claim 1 wherein the poly-
`ethylene oxide has an average molecular weight of
`about 200,000.
`22. A process according to claim 1 wherein the poly-
`ethylene oxide has an average molecular weight of
`about 5,000,000 to 6,000,000.
`23. A process according to claim 1 wherein the parti-
`cles comprise about 20 to 99.99 wt.% polyethylene
`oxide.
`
`24. A process according to claim 16 wherein the
`composition comprises 0.01 to 95 wt.% medicament.
`25. A process according to claim 24 wherein the
`composition comprises 5 to 99.99 wt.% polyethylene
`oxide.
`26. A process according to claim 1 wherein the medi-
`cament comprises clemastine fumarate in free base or
`pharmaceutically acceptable acid addition salt form.
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`CERTIFICATE OF CORRECTION
`
`5,273,758
`PATENTW =
`DATED
`: December 28, 1993
`
`|NVENTOR(S): Alan E, Royce
`
`It is certified that enor appears in the above-identified patent and that said ‘Letters Patent is hereby
`tnummasfluwnbdmm
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`Col. 6, l. 10: delete "for" and insert therefor -— or -—.
`
`
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`UNITEDSTATESPATENTANDTRADEMARKOFFICE
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`Col. 6, 1. 10: delete "crystalling" and insert therefor
`—— crystalline -—.
`
`Col. 6, 1. 14: delete "in" and insert therefor —— is -—.
`
`Col. 6, 1. 15: delete "compresseing" and insert therefor
`-— compressing -—.
`
`Signed and Sealed this
`
`Twentieth Day of September, 1994
`
`A““’-'
`
`I
`
`644“ WW9‘
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`E i1
`
`Arresting Officer
`
`Commissioner of Patents and Trademarks‘
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`mumEuummN
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`DRL - EXHIBIT 1044
`DRL007