(12) United States Patent
`McGinity et al.
`
`111111
`
`1111111111111111111111111111111111111111111111111111111111111
`US006488963Bl
`US 6,488,963 Bl
`(10) Patent No.:
`(45) Date of Patent:
`Dec. 3, 2002
`
`(54) HOT-MELT EXTRUDABLE
`PHARMACEUTICAL FORMULATION
`
`(75)
`
`Inventors: James W. McGinity; Feng Zhang,
`both of Austin, TX (US)
`
`(73) Assignee: The University of Texas System,
`Austin, TX (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.: 09/260,694
`(22) Filed:
`Mar. 2, 1999
`
`Related U.S. Application Data
`( 60) Provisional application No. 60/020,623, filed on Jun. 26,
`1996.
`Int. Cl? ........................... A61K 9/10; A61K 47/34
`(51)
`(52) U.S. Cl. ........................................ 424/486; 514/953
`(58) Field of Search ................................. 424/484, 486,
`424/468, 457, 500, 422; 514/953, 964,
`772.7
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`4/1974 Gaunt et a!. ................ 424/364
`3,806,603 A
`4,629,621 A
`12/1986 Snipes
`4,744,976 A
`5/1988 Snipes
`8/1988 Keith et a!. ................. 424/435
`4,764,378 A
`9/1988 Snipes
`4,774,074 A
`2/1989 Snipes
`4,806,337 A
`* 10/1989 Schiraldi
`RE330,943
`4/1991 Snipes
`5,004,601 A
`FOREIGN PATENT DOCUMENTS
`EP0177893
`4/1986
`
`EP
`
`EP
`wo
`wo
`wo
`wo
`
`0598606 A1
`W093/10758
`W093!11749
`W094/08567
`W095/22319
`
`5/1994
`6/1993
`6/1993
`4/1994
`8/1995
`
`OTHER PUBLICATIONS
`El-Egakey et al., Pharm. Acta. Helv. (1971), 46, 31-52.
`Rippie et al., J. Pharm. Sci. (1969), 428-431.
`Mank et al., Pharmazie (1989), 44, 773-776.
`Mank et al., Pharmazie (1990), 45 592-593.
`Follonier, et al., Drug Develop. and Indust. Pharm., (1994),
`20(8), 1323-1339.
`Remington's Pharmaceutical Sciences, 17'h ed. (Mack Pub-
`lishing Co., Easton, PA, 18042, 1985).
`Thoma, Von K. et al., Pharm. Ind. 51, Nr. 6 (1989).
`Janicki, Stanislaw et al.,Acta Pharm. Tecnol. 33(3) 154--155
`(1987).
`Mesiha, Mounir et al., Drug Development and Industrial
`Pharmacy, 19(8), 943-959 (1993).
`* cited by examiner
`
`Primary Examiner-Edward J. Webman
`(74) Attorney, Agent, or Firm---Gardere Wynne Sewell
`LLP; Sanford E. Warren, Jr.; Edwin S. Flores
`ABSTRACT
`(57)
`The present invention relates to pharmaceutical formula-
`tions comprising a hot-melt extrudable mixture of a thera-
`peutic compound and a high molecular weight poly( ethylene
`oxide) in an essentially non-film like preparation. In some
`embodiments, the formulation further comprises poly
`(ethylene glycol). The present invention also includes effi-
`cient methods for hot-melt extruding pharmaceutical formu-
`lations in essentially non-film preparations.
`
`6 Claims, 1 Drawing Sheet
`
`100
`
`75
`
`50
`
`25
`
`PERCENT
`CPM RELEASED
`
`0
`
`2
`
`8
`6
`4
`RELEASE TIME (h)
`
`10
`
`12
`
`KASHIV1025
`IPR of Patent No. 9,492,393
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`

`U.S. Patent
`
`Dec. 3, 2002
`
`US 6,488,963 Bl
`
`FIG. 1
`
`PERCENT
`CPM RELEASED
`
`FIG. 2
`
`PERCENT
`CPM RELEASED
`
`100
`
`75
`
`50
`
`25
`
`0
`
`0
`
`100
`
`75
`
`50
`
`25
`
`2
`
`8
`6
`4
`RELEASE TIME (h)
`
`10
`
`12
`
`0
`
`0
`
`2
`
`6
`8
`4
`RELEASE TIME (h)
`
`10
`
`12
`
`100
`
`75
`
`50
`
`FIG. 3
`
`PERCENT
`CPM RELEASED
`
`a----~~--~--~--~~
`0
`2
`6
`8
`10
`12
`4
`RELEASE TIME (h)
`
`KASHIV1025
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`US 6,488,963 Bl
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`1
`HOT-MELT EXTRUDABLE
`PHARMACEUTICAL FORMULATION
`
`BACKGROUND OF THE INVENTION
`Hot-melt extrusion as a method for producing polymer-
`based sustained-release pharmaceutical formulations, such
`as with derivatized cellulose, poly( methacrylate) derivative,
`poly( ethylene-co-vinyl acetate), poly( ethylene), poly( vinyl
`acetate-co-methacrylic acid), epoxy resins and caprolac-
`tones is known. These methods do not teach the use of
`poly(ethylene oxide). Hot-melt extrusion as a method for
`producing poly(ethylene glycol) based pharmaceutical for-
`mulations comprising an "erosion rate modifier" has been
`disclosed. These particular compositions have, been
`described as further containing trace amounts of high
`molecular weight PEO, and the hot-melt extrusion process
`used to prepare them requires several steps. These particular
`compositions are also based upon a low melting matrix drug
`delivery system, and are predominantly for transdermal
`rather than oral administration.
`Alderman et al. (EP 0177893 A2) relates to a thermo-
`formable sustained release matrix for the prolonged release
`of an active organic material of a thermoplastic water-
`soluble gel having a water-soluble hydroxypropylmethyl-
`cellulose a plasticizer and an active organic material dis-
`persed in said gel. The plasticizer may be a low molecular
`weight poly( ethylene glycol).
`Mooney et al. (EP 0598606 A1) relates to compositions of
`a thermoplastic water-soluble polymer; a water-soluble
`polymer derived from a carboxylic acid or a pharmaceuti-
`cally acceptable salt thereof; and a plasticizer. The thermo-
`plastic water-soluble polymer may be poly( ethylene oxide),
`and the compositions can be prepared as hot-melts.
`These various methods require several components to
`achieve a desired controlled release profile. Various techni-
`cal disadvantages exist for each of them that creates a
`significant potential for loss in pharmacological activity of
`the included therapeutic agent.
`Hot-melt extrusion processes in the art have generally
`required elevated temperatures. Elevated temperatures in
`processing have been recognized by those in the pharma-
`ceutical formulation arts to cause decomposition of the
`therapeutic agent or polymer matrix. The process of hot-melt
`extrusion of a therapeutic agent and a high molecular weight
`polymer PEO has been primarily confined to the preparation
`of film-like preparations.
`Although various hot-melt extrusion pharmaceutical for-
`mulations and methods for making them are known, devel-
`opment of simple formulations for drug delivery and meth-
`
`The present application claims the benefit of PCT/US
`97/11206, filed Jun. 24, 1997 which claims the benefit of of
`U.S. Pat. No. 60/202,623, filed Jun. 26, 1996.
`
`5
`
`FIELD OF THE INVENTION
`The present invention relates to the field of poly( ethylene
`oxide) (PEO) based hot-melt extrudable pharmaceutical
`formulations that are not film-like preparations. The inven-
`tion relates more specifically to non-film formulations which
`have been prepared by hot-melt extrusion of mixtures con-
`taining high molecular weight PEO and a therapeutic com- 15
`pound. The present formulations cited relate to the field of
`non-film controlled-release drug delivery preparations, as
`they provide preparations useful for providing controlled
`drug delivery.
`
`30
`
`2
`ods for producing them remams a problem in the
`pharmaceutical industry.
`There continues to exist a need in the art to develop
`controlled-release pharmaceutical formulations, as well as
`improved, more efficient methods for their preparation.
`SUMMARY OF THE INVENTION
`In one aspect of the present invention comprises a hot-
`melt extrudable controlled-release pharmaceutical formula-
`10 tion. This formulation in some embodiments is further
`described as comprising an effective amount of a therapeutic
`compound and a high molecular weight poly( ethylene
`oxide) homopolymer.
`It is an object of the present invention to provide a
`hot-melt extrudable controlled-release pharmaceutical for-
`mulation comprising high molecular weight poly(ethylene
`oxide) and an effective amount of a therapeutic compound.
`It is another object of the present invention to provide a
`hot-melt extrudable controlled-release pharmaceutical for-
`20 mulation comprising high molecular weight poly(ethylene
`oxide), an effective amount of a therapeutic compound and
`a plasticizer. By way of example, the plasticizer may com-
`prise poly( ethylene glycol).
`It is contemplated and within the scope of the present
`25 invention that the pharmaceutical formulation may be
`administered to a subject by any of a variety of methods
`known to the artisan. In some embodiments, the formula-
`tions are designed to be particularly well suited for oral
`delivery.
`It is also contemplated and within the scope of the present
`invention that the pharmaceutical formulation may comprise
`other components.
`The methods provided on some aspects of the present
`35 invention may comprise a single step or multiple steps for
`preparing the pharmaceutical formulation.
`It is also contemplated that the particular combinations of
`therapeutic compound and PEO (of given molecular weight)
`will result in various formulations, each possessing a par-
`40 ticular combination of properties. Some combinations may
`be better suited for particular types or classes of therapeutic
`compounds while another combination may be better suited
`for other types or classes of therapeutic compounds. Meth-
`ods for the selection of a particular therapeutic compound/
`45 PEO (of a given molecular weight) combination are also
`provided as part of the present invention.
`Some embodiments of the invention comprise a plasti-
`cizer. The particular combinations of therapeutic compound/
`plasticizer/PEG (of given molecular weight) may be selected
`50 to provide a desired combination of physical properties.
`Some particular combination of these ingredients may
`accordingly be better suited for a particular therapeutic
`compound while another combination may be better suited
`for a different therapeutic compound. Methods for the selec-
`55 tion of a particular therapeutic compound/plasticizer/ PEO
`(of a given molecular weight) combination are also dis-
`closed as part of the present invention.
`Another aspect of the invention provides a process for
`preparing a controlled-release pharmaceutical formulation
`60 comprising a therapeutic compound and a high molecular
`weight poly(ethylene oxide) homopolymer. The process in
`some embodiments comprises hot-melt extruding a pharma-
`ceutical formulation. The pharmaceutical formulation com-
`prises a therapeutic compound and a high molecular weight
`65 poly(ethylene oxide) homopolymer.
`Other embodiments of the present controlled-release
`pharmaceutical formulations comprise a therapeutic com-
`
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`5
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`40
`
`US 6,488,963 Bl
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`3
`pound and a high molecular weight poly(ethylene oxide)
`homopolymer, where the formulation is prepared by hot-
`melt extruding a mixture of its components.
`In some embodiments, the pharmaceutical formulations
`of the invention may contain more than one therapeutic
`compound, as well as other non-therapeutic compound
`components. The pharmaceutical formulations may be for-
`mulated to provide sustained, extended, controlled, timed or
`other equivalent release dosage forms.
`Other features, advantages and embodiments of the inven-
`tion will be apparent to those skilled in the art from the
`following description, accompanying data and appended
`claims.
`As used in the description of the present invention, the
`term "effective amount" is defined as an amount or dose
`sufficient to elicit a physiological response in vitro or in vivo
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 Influence of molecular weight of polyethylene
`oxide on the release of chlorpheniramine maleate from
`matrix tablets using USP method II at 37° C. and 100 rpm
`in 900 ml purified water.
`1A=e 6% CPM, 20% PEG (3,350), PEO (7.0 m)
`lB=D 6% CPM, 20% PEG (3,350), PEO (1.0 m)
`FIG. 2 Influence of polyethylene glycol (3,350) on the
`release of chlorpheniramine maleate from matrix tablets
`using USP method II at 37° C. and 100 rpm in 900 ml
`purified water.
`2A=D 6% CPM, 0% PEG, (3,350) and 94% PEO (1.0 m)
`2B=e 6% CPM, 6% PEG, (3,350) and 88% PEO (1.0 m)
`2C=T 6% CPM, 20% PEG, (3,350) and 74% PEO (1.0 m)
`2D=• 6% CPM, 40% PEG, (3,350) and 54% PEO (1.0 m)
`FIG. 3 Influence of drug loading on the release of chlo-
`rpheniramine maleate from matrix tablets using USP method 35
`II at 37° C. and 100 rpm in 900 ml purified water
`3A=e 6% CPM, 94% PEO (1.0 m)
`3B=D CPM, 88% PEO (1.0 m)
`3C=T 6% CPM, 80% PEO (1.0 m)
`DETAILED DESCRIPTION OF THE
`INVENTION
`The use of hot-melt extrudable high molecular weight
`PEO for the preparation of pharmaceutical formulations has
`several advantages. The one-step process presented as part 45
`of the invention also provides therapeutic formulations with
`minimal thermal degradation of either the therapeutic com-
`pound or the PEO.
`Poly( ethylene oxide)
`As used herein, the term "poly( ethylene oxide)" includes 50
`all polymers which are comprised of repeating units of
`ethylene oxide. High molecular weight PEO is generally
`described as having an average molecular weight of from
`about 1,000,000 to about 10,000,000. The poly(ethylene
`oxides) comprising the present formulation are available
`commercially from sources such as Union Carbide Corpo-
`ration. The amount of PEO used in the formulation will
`depend upon its average molecular weight, physical
`properties, interaction with other components of the
`formulation, ability to solubilize the therapeutic compound,
`ease of formulation extrudability, the pharmacological activ-
`ity of the therapeutic compound, the indication being
`treated, the targeted dosing regimen, the projected method of
`administration, the integrity or stability of the final
`formulation, desired release profile or other such reasons.
`Generally, PEO content will not exceed about 99% wt. of the
`formulation.
`
`4
`The average molecular weight of the PEO employed will
`generally affect the processing conditions selected. A very
`high average molecular weight PEO, such as greater than
`about 5,000,000, will generally require higher processing
`temperature, torque and/or pressure than a PEO having an
`average molecular weight less than or equal to about 5,000,
`000. Antioxidants and/or plasticizers may be advantageously
`employed when preparing the formulation of the invention.
`Thus, although not required to obtain a hot-melt extrudable
`10 formulation, addition of one or more plasticizers and/or
`antioxidants to the formulation will generally facilitate the
`preparation process.
`As shown in FIG. 1, PEO average molecular weight also
`affects the release profile of the formulation. Generally,
`increasing average molecular weight decreases the release
`15 rate of the therapeutic compound.
`Plasticizers
`As used herein, the term "plasticizer" includes all com-
`pounds capable of plasticizing high molecular weight PEO.
`The plasticizer should be able to lower the glass transition
`20 temperature or softening point of the PEO in order to allow
`for lower processing temperature, extruder torque and pres-
`sure during the hot-melt extrusion process. Plasticizers, such
`as PEG and low molecular weight PEO, generally broaden
`the average molecular weight of the PEO thereby lowering
`25 its glass transition temperature or softening point. Plasticiz-
`ers also generally reduce the viscosity of a polymer melt
`thereby allowing for lower processing temperature and
`extruder torque during hot-melt extrusion. It is possible the
`plasticizer will impart some particularly advantageous
`30 physical properties to the pharmaceutical formulation of
`PEO.
`As used herein, the term "low molecular weight PEO" is
`intended to mean poly( ethylene oxide) homopolymer having
`an average molecular weight less than about 500,000.
`Plasticizers are not required in order to practice the
`invention. Their addition to the formulation is contemplated
`as being within the scope of the invention. Plasticizers are
`advantageously included when very high molecular weight
`PEO, such as greater than about 5,000,000, is employed.
`As shown in FIG. 2, it is possible that including a
`plasticizer in the present formulation will alter its release
`profile. Generally, increasing the amount of plasticizer
`present will increase the release rate of the therapeutic
`compound.
`It is contemplated and within the scope of the invention,
`that a combination of plasticizers may be used in the present
`formulation. One advantageous combination is that com-
`prised of poly( ethylene glycol) and low molecular weight
`poly( ethylene oxide).
`The plasticizer employed herein may be a solvent for the
`PEO at the temperature where the formulation is prepared.
`Such plasticizer, when mixed with the PEO above a char-
`acteristic temperature at which the PEO becomes soluble
`therein, may dissolve the PEO. Upon cooling, the mixture
`55 forms a matrix having especially useful properties for use in
`a sustained release dosage form.
`Plasticizers useful in the invention include, by way of
`example and without limitation, low molecular weight
`polymners, oligomers, copolymers, oils, small organic
`60 molecules, low molecular weight polyols having aliphatic
`hydroxyls, ester-type plasticizers, glycol ethers, poly
`(propylene glycol), multi-block polymers, single block
`polymers, low molecular weight poly( ethylene oxide)
`(average molecular weight less than about 500,000) and
`65 poly( ethylene glycol).
`Such plasticizers may be ethylene glycol, propylene
`glycol, 1.2-butylene glycol, 2,3-butylene glycol, styrene
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`5
`glycol, diethylene glycol, triethylene glycol, tetraethylene
`glycol and other poly(ethylene glycol) compounds, mono-
`propylene glycol monoisopropyl ether, propylene glycol
`monoethyl ether, ethylene glycol monoethyl ether, diethyl-
`ene glycol monoethyl ether, sorbitol lactate, ethyl lactate, 5
`butyl lactate, ethyl glycolate, triethyl citrate, acetyl triethyl
`citrate, tributyl citrate and allyl glycolate. All such plasti-
`cizers are commercially available from sources such as
`Aldrich or Sigma Chemical Co.
`The PEG based plasticizers are available commercially or 10
`may be made by a variety of methods, such as disclosed in
`Poly (ethylene glycol) Chemistry: Biotechnical and Bio-
`medicalApplications (J. M. Harris, Ed.; Plenum Press, NY)
`the teachings of which are hereby incorporated by reference.
`The amount of plasticizer used in the formulation will 15
`depend upon its composition, physical properties, effect
`upon the PEO, interaction with other components of the
`formulation, ability to solubilize the therapeutic compound
`or other factors to be considered in the preparation of
`pharmaceutical formulations. The amount of plasticizer 20
`present in the formulation affects its properties. By way of
`example, when the plasticizer is PEG, its content will
`generally not exceed about 40% wt. of the formulation.
`When present, the relative amount of plasticizer used may
`be expressed by the ratio high molecular weight PEO % wt.: 25
`plasticizer % wt., and will generally fall in the range of about
`100:0 to about 60:40. The amount of plasticizer will gen-
`erally not exceed the amount of PEO.
`Therapeutic Preparations
`As used herein, the term "therapeutic compound" is taken 30
`to mean an organic chemical substance having desired
`beneficial and therapeutic effects in mammals. Such com-
`pounds are generally classified as pharmaceuticals or bio-
`logicals. As long as the therapeutic compound can diffuse
`from the formulation when exposed to a biological fluid, its 35
`structure is not especially critical.
`The therapeutic compounds contemplated within the
`scope of the invention include hydrophobic, hydrophilic and
`amphiphilic compounds. They may be in their free acid, free
`base, or pharmaceutically acceptable salt forms. They may 40
`be derivatives or prodrugs of a given pharmaceutical.
`It will be appreciated that certain therapeutic compounds
`used in the present invention may contain an asymmetrically
`substituted carbon atom, and may be isolated in optically
`active or racemic forms. It is well known in the art how to 45
`prepare optically active forms, such as by resolution of
`racemic forms or by synthesis, from optically active starting
`materials. Also, it is realized that cis and trans geometric
`isomers of the therapeutic compounds are described and
`may be isolated as a mixture of isomers or as separated 50
`isomeric forms. All chiral, diastereomeric, racemic forms
`and all geometric isomeric forms of a structure are intended,
`unless the specific stereochemistry or isomer form is spe-
`cifically indicated.
`It is not necessary for the therapeutic compound to be 55
`soluble in any given formulation component. The therapeu-
`tic compound may be either dissolved, partially dissolved or
`suspended in the polymer matrix of the formulation. It is
`necessary for the therapeuticcompound to be stable during
`the hot-melt extrusion process conditions used. By stable, it 60
`is meant that a significant portion of the therapeutic com-
`pound will not be significantly degraded or decomposed
`throughout the hot-melt extrusion process.
`The therapeutic compounds which may be hot-melt
`extruded in the formulation of the invention may be used for 65
`treating indications such as, by way of example and without
`limitation, inflammation, gout, hypercholesterolemia,
`
`6
`microbial infection, AIDS, tuberculosis, fungal infection,
`amoebic infection, parasitic infection, cancer, tumor, organ
`rejection, diabetes, heart failure, arthritis, asthma, pain,
`congestion, urinary tract infections, vaginal infection, sei-
`zure related disorder, depression, psychosis, convulsion,
`diabetes, blood coagulation, hypertension and birth control.
`The following therapeutic compounds can be adminis-
`tered by the pharmaceutical formulation of the present
`invention:
`(1) analgesics such as aspirin, acetaminophen, deflunisal
`and the like;
`(2) anesthetics such as lidocaine, procaine, benzocaine,
`xylocaine and the like;
`(3) antiarthritics and anti-inflammatory agents such as
`phenylbutazone, indomethacin, sulindac,
`dexamethasone, ibuprofen, allopurinol, oxyphenbuta-
`zone probenecid, cortisone, hydrocortisone,
`betamethasone, dexamethasone, fluocortolone,
`prednisolone, triamncinolone, indomethacin, sulindac
`and its salts and corresponding sulfide and the like;
`( 4) antiasthma drugs such as theophylline, ephedrine,
`beclomethasone dipropionate, epinephrine and the like;
`( 5) urinary tract disinfectives such as sulfarmethoxazole,
`trimethoprim, nitrofurantoin, norfloxicin and the like;
`( 6) anticoagulants such as heparin, bishydroxy coumarin,
`warfarin and the like;
`(7) anticonvulsants such as diphenylhydantoin, diazepam
`and the like;
`(8) antidepressants such as amitriptyline,
`chlordiazepoxide, perphenazine, protriptyline,
`imipramine, doxepin and the like;
`(9) agents useful in the treatment of diabetics and regu-
`lation of blood sugar, such as insulin, tolbutamide
`tolazamide, somatotropin, acetohexamide, chlorpropa-
`mide and the like;
`(10) antineoplastics such as adriamycin, fluouracil,
`methotrexate, asparaginase and the like;
`(11) antipsychotics such as prochlorperazine, lithium
`carbonate, lithium citrate, thioridazine, molindone,
`fluphenazine, trifluoperazine, perphenazine,
`amitriptyline, triflupromazine and the like;
`(12) antihypertensives such as spironolactone,
`methyldopa, hydralazine, clonidine, chlorothiazide,
`deserpidine, timolol, propranolol, metaprotol, prazosin
`hydrochloride, reserpine and the like;
`(13) muscle relaxants such as mephalan, danbrolene,
`cyclobenzaprine, methocarbarnol, diazepam, succinoyl
`chloride and the like;
`(14) antiprotozoals such as chloramphenicol, chloroquine,
`trimethoprim and sulfamethoxazole;
`(15) spermicidals such as nonoxynol;
`(16) antibacterial substances such as beta-lactam
`antibiotics, tetracyclines, chloramphenicol, neomycin,
`cefoxitin, thienamycin, gramicidin, bacitracin,
`sulfonamides, aminoglycoside antibiotics, tobramycin,
`nitrofurazone, nalidixic acid and analogs and the anti-
`microbial combination of fludalanine/pentizidone;
`(17) antihistamines and decongestants such as perilamine,
`chlorpheniramine, tetrahydrozoline and antazoline;
`(18) antiparasitic compounds such as ivermectin; and
`(19) antiviral compounds such as acyclovir and inter-
`feron.
`For treatment of vaginal and urethral conditions requiring
`antiftungal, amoebicidal, trichomonacidal agents or
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`7
`antiprotozoals, the following agents can be used: polyoxy-
`ethylene nonylphenol, alkylaryl sulfonate, oxyquinoline
`sulfate, miconazole nitrate, sulfanilamide, candicidin,
`sulfisoxazole, nysatitin, clotrimazole, metronidazole and the
`like.
`Loading of the therapeutic compounds into the final
`formulation may be accomplished following the techniques
`below. Generally, the therapeutic compound is loaded by
`premixing it with PEO and any other formulation compo-
`nents and hot-melt extruding the mixture. The mixture may
`be either a solution, slurry, suspension or solid. When solids
`are present in the mixture, they may be, by way of example
`and without limitation, either powdered, crystalline,
`amorphous, pelletized, beaded, spheronized, granular or the
`like.
`It should be understood that the amount of therapeutic
`compound loaded into the formulation may be varied
`according to, for example, the high molecular weight PEO-
`:therapeutic compound or the high molecular weight
`PEO:plasticizer:therapeutic compound ratios used in the
`pre-extruded mixture. Although a given loading method may
`be optimal for a particular high molecular weight PEO-
`:therapeutic compound combination, all of the described
`methods will generally result in compound loading to some
`degree.
`The therapeutic amount of compound loaded into the
`formulation will vary according to the pharmacological
`activity of the compound, the indication being treated, the
`targeted dosing regimen, the projected method of
`administration, the integrity or stability of the final formu-
`lation or other such reasons.
`As shown in FIG. 3, the amount of therapeutic compound
`loaded into the formulation will generally have only a
`marginal effect upon the release profile of therapeutic com-
`pound. In this particular embodiment, a 300 mg tablet
`contained high molecular weight PEO (about 60, or about
`80- to about 90, or about 94% wt., MW 1,000,000) and
`chlorpheniramine maleate (about 5, or about 6- to about
`200% wt.) . The formulation was prepared following the
`procedure described in Example 3, and the release profile
`was determined following the procedure described in
`Example 1. In some embodiments, the compound loading
`into the formulation of the invention will not exceed about
`20% wt. of the final formulation.
`Hot-Melt Extrusion Process
`As used herein, the term "hot-melt extrudable" refers to a 45
`compound or formulation that may be hot-melt extruded. A
`hot-melt extrudable polymer is one that is sufficiently rigid
`at standard ambient temperature and pressure but is capable
`of deformation or forming a semi-liquid state under elevated
`heat or pressure. Although the formulation of the invention
`need not contain a plasticizer to render it hot-melt
`extrudable, plasticizers of the type described herein may be
`included and still remain within the scope of the invention.
`Although the process referred to above has been called a
`hot-melt extrusion, other equivalents processes such as 55
`injection molding, hot dipping, melt casting and compres-
`sion molding may be used. By using any of these methods,
`the formulation may be shaped as needed according to the
`desired mode of administration, e.g. tablets, pills, lozenges,
`suppositories and the like.
`The hot-melt extrusion process employed in some
`embodiments of the invention is conducted at an elevated
`temperature, i.e. the heating zone(s) 20 of the extruder is
`above room temperature (about 20° C.). It is important to
`select an operating temperature range that will minimize the
`degradation or decomposition of the therapeutic compound
`during processing. The operating temperature range is gen-
`
`8
`erally in the range of from about 60° C. to about 160° C. as
`determined by the setting for the extruder heating zone(s).
`In some embodiments of the invention, the hot-melt
`extrusion may be conducted employing a slurry, solid,
`5 suspension, liquid, powdered or other such feed comprising
`PEO and a therapeutic compound. Dry feed is advanta-
`geously employed in the process of the present invention.
`The hot-melt extrusion process is generally described as
`follows. An effective amount of a powdered therapeutic
`10 compound is mixed with a high molecular weight PEO, and
`in some embodiments, with a plasticizer such as PEG. Other
`components may be added in the various embodiments of
`the invention. In some embodiments, the therapeutic com-
`pound: PEO ratio is generally about 0.01: about 99.99 to
`15 about 20: about 80% wt., depending on the desired release
`profile, the pharmacological activity and toxicity of the
`therapeutic compound and other such considerations. The
`mixture is then placed in the extruder hopper and passed
`through the heated area of the extruder at a temperature
`20 which will melt or soften the PEO and/or plasticizer, if
`present, to form a matrix throughout which the therapeutic
`compound is dispersed. The molten or softened mixture then
`exits via a die, or other such element, at which time, the
`mixture (now called the extrudate) begins to harden. Since
`25 the extrudate is still warm or hot upon exiting the die, it may
`be easily shaped, molded, chopped, ground, molded, sphe-
`gonized into beads, cut into strands, tableted or otherwise
`processed to the desired physical form.
`The extruder used to practice the invention may be any
`30 such commercially available model equipped to handle dry
`feed and having a solid conveying zone, one or multiple
`heating zones, and an extrusion die. A two stage single screw
`extruder, such as that manufactured by C.W. Brabender
`Instruments Incorporated (NJ) is one such apparatus. It is
`35 particularly advantageous for the extruder to possess mul-
`tiple separate temperature controllable heating zones.
`Many conditions may be varied during the extrusion
`process to arrive at a particularly advantageous formulation.
`Such conditions include, by way of example, formulation
`40 composition, feed rate, operating temperature, extruder
`screw RPM, residence time, die configuration, heating zone
`length and extruder torque and/or pressure. Methods for the
`optimization of such conditions are known to the skilled
`artisan.
`When very high molecular weight PEO, such as greater
`than about 5,000,000, is employed, the hot-melt extrusion
`may require higher processing temperature, pressure and/or
`torque than when PEO having a molecular weight less than
`or equal to about 5,000,000 is employed. By including a
`50 plasticizer, and, optionally, an antioxidant, in a formulation
`comprising very high molecular weight PEO, processing
`temperature, pressure and/or torque may be reduced.
`Pharmaceutical Compositions and Their
`Administration
`The pharmaceutical formulation of the present invention
`may be administered by a variety of methods. Such methods
`include, by way of example and without limitation: oral,
`nasal, buccal, rectal, ophthalmic, otic, urethral, vaginal, or
`60 sublingual dosage administration. Such methods of admin-
`istration and others contemplated within the scope of the
`present invention are known to the skilled artisan.
`In vivo stability of the present formulation may vary
`according to the physiological environment to which it is
`65 exposed and the specific therapeutic compound, PEO and
`plasticizer used. Therefore, the necessity for or frequency of
`readministration may be different for various formulations.
`
`KASHIV1025
`IPR of Patent No. 9,492,393
`
`

`

`US 6,488,963 Bl
`
`9
`The pharmaceutical formulation of the present invention
`may be provided in a variety of ways. Additional compo-
`nents that would not significantly prohibit the hot-melt
`extrusion process may be added to the formulation prior to
`hot-melt extrusion. The additional components would still
`allow for the high molecular weight PEO: therapeutic com-
`pound mixture to be formulated using a hot-melt extrusion
`process.
`For nasal administration, the pharmaceutical formulation
`may be a paste, cream or ointment containing the appropri-
`ate solvents (such as water, aqueous, nonaqueous, polar,
`nonpolar, hydropic, hydrophilic and/or combinations
`thereof) and optionally other compounds (stabilizers,
`perfumes, antimicrobial agents, antioxidants, pH modifiers,
`surfactants and/or bioavailability modifiers). It is contem-
`plated that bioavailability enhancers such as alcohols or
`other compounds that enhance the penetration of the thera-
`peutic compound from the pharmaceutical formulation into
`the nasal mucosa may be needed to prepare suitable formu-
`lations for nasal administration.
`For oral, buccal, and