1/1955 Halpem et al.
`2,698,822
`3/1961 Goyan et al.
`2,975,099
`6/1962 Goldman ..
`3,039,933
`3,429,308 2/1969 Russell
`..
`3,444,858
`5/1969 Russell
`..
`3,511,914 5/1970 Wolkoff
`3,536,809 10/1970 Applezweig .
`3,598,122
`8/1971 Zaffaroni ..
`3,634,584
`1/1972 Poole ............
`.
`3,670,065
`6/1972 Eriksson et al.
`3,764,703 10/1973 Bergstrom et al.
`3,767,789 10/ 1973 Rankin ........... ..
`3,832,460 8/1974 Kosti ...... ..
`3,870,790
`3/1975 Lowey et al.
`3,881,011
`4/1975 Amann .............
`3,911,099 10/1975 DeFoney et al.
`3,972,995
`8/1976 Tsuk .................
`4,039,653
`8/1977 DeFoney et al.
`4,059,686 11/1977 Tanaka ........... ..
`4,104,190
`8/1978
`4,139,627 2/ 1979
`4,151,273 4/1979
`4,222,956 7/1980
`4,226,848 10/1980
`4,250,163
`2/1981
`4,250,169
`2/1981
`4,264,573 4/ 1981
`4,280,936
`7/1981
`4,292,299 9/ 1981
`4,318,742
`3/1982
`4,333,919
`6/1982
`4,474,902 10/1984
`4,514,528
`4/1985
`
`.......
`Lane et al.
`Riegelman et al
`Dhabhar et al.
`Nagai et al.
`..
`Nagai et al.
`..
`Hosoi et al.
`..
`Powell et al.
`Dhabhar et a1.
`Suzuki et al.
`Lokken ............
`Kleber et al.
`Dhabhar et al.
`Dhabhar et al.
`
`.
`
`252/187 R
`424/267
`...... 424/78
`523/120
`424/435
`.... ,. 424/14
`424/181
`...... 424/19
`.... .. 260/13
`.. 424/435
`106/35
`424/15
`523/ 120
`.
`.................... 523/120
`
`.
`
`United States Patent
`
`[191
`
`Keith et al.
`
`[11]
`
`[45]
`
`Patent Number:
`
`4,764,378
`
`Date of Patent:
`
`Aug. 16, 1988
`
`[54]
`
`[75]
`
`[73]
`
`[21]
`
`[22]
`
`[5 1]
`
`[52]
`
`[5 8]
`
`[56]
`
`BUCCAL DRUG DOSAGE FORM
`Inventors:
`
`Alec D. Keith, Boalsburg; Wallace C.
`Snipes, Pine Grove Mills, both of Pa.
`
`Assignee:
`
`Zetachron, Inc., State College, Pa.
`
`Appl. No.2 827,615
`Filed:
`Feb. 10, 1986
`
`Int. Cl.4 ....................... .. A61K 9/20; A61K 9/26;
`A61K 31/74; A61K 31/79
`U.S. C1. . ................................... .. 424/435; 424/78;
`424/80; 424/81; 424/464; 424/486; 424/487
`Field of Search ..................... 424/78, 80, 81, 435,
`424/464, 486, 487
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`............ ..
`
`.. 167/65
`.. 167/64
`.. 167/82
`424/464
`424/464
`424/263
`.. 424/28
`128/268
`...... 424/21
`264/131
`424/319
`.. 424/78
`.. 424/S4
`424/488
`.. 424/270
`
`5/1985
`4,517,173
`5/1985
`4,518,721
`4,521,551
`6/1985
`7/1985
`4,529,589
`7/1985
`4,530,942
`9/1985
`4,542,168
`2/1986
`4,569,955
`2/1986
`4,572,832
`11/1986
`4,624,849
`4,629,621 12/1986
`4,713,239 12/1987
`
`Kizawa et al.
`Dhabhar et a1.
`
`.................... .. 424/435
`..
`
`..
`
`.
`
`Davydov et al.
`Dhabhar et al.
`Chang et al.
`Dhabhar ........
`Kigasawa et al.
`Toogood ........
`Snipes .........
`Babaian et al.
`
`FOREIGN PATENT DOCUMENTS
`
`59-181218 10/1984 Japan ................................. .. 424/435
`8600802
`2/1986 World Int. Prop. 0.
`.
`1063185
`3/1967 United Kingdom .
`1083896
`9/1967 United Kingdom ................ 424/435
`1171691 11/1969 United Kingdom .............. .. 424/435
`2021610A 12/1979 United Kingdom .
`2l08841A 5/1983 United Kingdom .............. .. 424/435
`
`OTHER PUBLICATIONS
`
`Brochure describing Polyox® poly(ethylene oxide),
`Union Carbide Corp., 1981.
`“Carbowax”® polyethylene glycol brochure, Union
`Carbide Chemicals Co., 1960.
`
`Primary Examiner—Shep K. Rose
`Attorney, Agent, or F1'rm—Vorys, Sater, Seymour &
`Pease
`
`[57]
`
`ABSTRACI‘
`
`Buccal dosage forms for transmucosal administration of
`drugs comprise a pharmaceutical compound dispersed
`in an erodible matrix comprising
`from about 20 to about 75 percent by weight of a low
`molecular weight polyethylene glycol component,
`from about 2 to about 65 percent by weight of a medium
`or high molecular weight polyethylene glycol com-
`‘ ponent,
`from about 1% to about 40% percent by weight of an
`auxiliary high molecular weight polymer.
`Preferred auxiliary high molecular weight polymers are
`polyethylene oxide and polyvinylpyrrolidone which
`improve the molding properties of the matrix and pro-
`vide water-activated adhesive properties to the compo-
`sitions to provide a buccal dosage form.
`
`45 Claims, No Drawings
`
`TEVA EXHIBIT 1043
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05018995
`
`TEVA EXHIBIT 1043
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`1
`
`BUCCAL DRUG DOSAGE FORM
`
`4,764,378
`
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`This invention relates to dosage forms for adrninistra-
`tion of drugs and more particularly to buccal dosage
`forms having a polymeric matrix for controlled release
`of a drug.
`2. Description of the Prior Art
`Administration of drugs by absorption through the
`oral mucosa has been found to be an efficient and con-
`venient method of supplying to the body a drug which
`is not well adapted to administration via the intestinal
`route. Some drugs are poorly absorbed from the gastro-
`intestinal tract; others are rapidly metabolized in the
`liver and do not reach the target organ. Transmucosal
`administration, which introduces the drug directly into
`the bloodstream, avoids the problems of poor absorp-
`tion or rapid metabolism.
`However, because the continuous secretion of saliva
`rapidly washes dissolved drugs out of the oral cavity,
`sublingual and buccal administration of drugs have been
`most useful for drugs, such as nitroglycerin, which are
`very rapidly absorbed through the oral mucosa. In
`order to keep a drug in contact with the oral mucosa for
`a longer period of time, sustained release dosage forms
`especially adapted for transmucosal administration of
`drugs have been developed. These have generally com-
`prised a drug dispersed in a matrix which slowly re-
`leases the drug by diffusion from the matrix or by slow
`dissolution or erosion of the matrix. In order to retain
`the dosage form within the mouth, it may be bonded to
`an adhesive patch or the dosage form itself may be
`provided with an adhesive layer which adheres to the
`mucosa. Alternatively, the dosage form itself may ad-
`here to the mucosa and slowly dissolve, releasing the
`drug contained therein.
`For example, Zaffaroni, U.S. Pat. No. 3,598,122, dis-
`closes an adhesive buccal device having an imperme-
`able backing layer and a drug-containing adhesive ma-
`trix layer which adheres to the oral mucosa, allowing
`the drug to diffuse through the mucosa over a period of
`time. This device has the drawback that it must be re-
`moved from the mouth after the drug has been dis-
`pensed.
`Another adherent dosage form comprising an imper-
`vious backing material coated with an adhesive which
`adheres to the mucosa and having a drug reservoir
`matrix comprised of a mixture of low molecular weight
`polyethylene glycol and polyvinylpyrrolidone is dis-
`closed in Tsuk, U.S. Pat. No. 3,972,995. Evidently this
`dosage form suffers from the same problems as that of
`Zaffaroni.
`Another approach is exemplified by Nagai, U.S. Pat.
`No. 4,250,163, who discloses a totally soluble adhesive
`buccal dosage form which adheres to the oral mucosa
`and releases the medication over a period of 10-40 min-
`utes. The dosage form is a lamella having the drug
`dispersed in a matrix comprised of 50-95% of a cellu-
`lose ether and 5-50% of an acrylic polymer. These
`dosage forms are prepared by compression molding of a
`mixture of ingredients in powder form, which some-
`times presents problems in obtaining uniform distribu-
`tion of the drug in the matrix.
`A buccal dosage form comprising a strip of gauze or
`paper impregnated with a drug in a matrix of a mixture
`of polyethylene glycols is disclosed in Applezweig,
`
`2
`U.S. Pat. No. 3,536,809. This dosage form also has the
`drawback that the supporting gauze or paper must be
`removed from the mouth after the medicine has been
`' exhausted.
`DeFoney, in U.S. Pat. Nos. 3,911,099 and 4,039,653,
`discloses a dosage form comprising a tablet or similar
`article formed of a sustained release matrix of polyvi-
`nylpyrrolidone containing an odor masking substance
`which is retained in the oral cavity by means of an
`adhesive layer on one side of the tablet.
`Hence a need has continued to exist for a buccal
`dosage form which adheres to the oral mucosa, pro-
`vides for administration of medication over a controlled
`period of time, has a very uniform distribution of the
`drug in the matrix, and which completely dissolves in
`the mouth.
`
`SUMMARY OF THE INVENTION
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`In accordance with the present invention a matrix
`composition is provided into which a drug can be mixed
`while the matrix is in the molten state and which can
`then be injection molded into unit doses suitable for
`buccal administration. The composition comprises three
`essential ingredients in defined proportions as follows:
`from about 20% to about 75% by weight of a low
`molecular weight polyethylene glycol component,
`from about 2% to about 65% by weight of a medium
`or high molecular weight polyethylene glycol compo-
`nent, and
`from about 1% to about 40% by weight of an auxil-
`iary high molecular weight polymer.
`A dosage form of the invention, particularly a buccal
`dosage form, comprises an effective amount of a trans-
`mucosally administered drug dispersed in the molded
`erodible matrix.
`The dosage forms of the invention may include disks,
`wafers, tablets, lozenges, lamellae and the like.
`Accordingly, it is an object of the invention to pro-
`vide a buccal drug dosage form.
`A further object is to provide a buccal dosage form
`. having controlled release properties.
`A further object is to provide an erodible matrix for
`a buccal dosage form which completely dissolves in the
`oral cavity.
`A further object is to provide a buccal dosage form
`which adheres to the oral mucosa.
`A further object is to provide a buccal dosage form
`which is easily manufactured.
`A further object is to provide a buccal dosage form
`which can be manufactured by injection molding.
`Further objects of the invention will become appar-
`ent from the description of the invention which follows.
`DETAILED DESCRIPTION OF THE
`INVENTION AND PREFERRED
`EMBODIMENTS
`
`The buccal dosage form of this invention is a blend of
`ingredients chosen to provide the proper physical prop-
`erties in manufacture and use. The injection moldable
`matrix should have a melting point which is high
`enough to prevent fusion of packaged dosage forms
`during storage in a reasonably temperate environment,
`yet low enough to permit mixing of the active pharma-
`ceutical
`ingredient with the molten matrix without
`causing significant decomposition of the pharmaceuti-
`cal compound. The molten matrix should also have a
`viscosity suitable for mixing the active ingredient and
`
`TEVA EXHIBIT 1043
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05018996
`
`TEVA EXHIBIT 1043
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`4,764,378
`
`3
`for injection molding to form buccal dosage forms. The
`solidified buccal dosage form may also require special
`properties. For example, in some cases, it may be desir-
`able for the buccal dosage form to adhere to the oral
`mucosa, so that it is retained in the oral cavity for a
`period of time while slowly releasing the active ingredi-
`ent. While the compositions of the invention are spe-
`cially adapted for use as buccal dosage forms, they may
`also be used as conventional oral dosage forms which
`are swallowed and deliver their medication via the
`gastrointestinal tract.
`The desired combination of properties in the buccal
`dosage form of this invention is achieved by proper
`choice of the proportions of the three basic components
`of the matrix.
`The first component of the buccal matrix of the in-
`vention is a low molecular weight polyethylene glycol
`(PEG) component which may be a single PEG or a
`mixture of low molecular weight PEG’s. For purposes
`' of this invention,
`low molecular weight PEG’s are
`those having a molecular weight not greater than about
`4000 daltons. The proportion of low molecular weight
`PEG component may range from about 20% to about
`75% by weight of the matrix. The proportion of low
`molecular weight PEG component affects the rate at
`which the matrix is eroded by saliva and therefore the
`rate of release of the drug and the duration of its action.
`In general, greater amounts of low molecular weight
`PEG component increase the rate of erosion. The rela-
`tive amounts of the low molecular weight PEG compo-
`nent and the medium or high molecular weight compo-
`nent determine the melting point of the buccal matrix of
`the invention. Mixtures of low molecular weight PEG’s
`can be used to attain a desired average molecular
`weight and the desired effect on the properties of the
`matrix. A preferred low molecular weight PEG compo-
`nent comprises a mixture of PEG 1000, PEG 1450 and
`PEG 3350, where the numbers signify the molecular
`weight as is conventional. Another preferred low mo-
`lecular weight PEG component comprises a mixture of
`PEG 1450 and PEG 3350.
`
`The medium to high molecular weight polyethylene
`glycol component has a molecular weight in the range
`from about 6000 daltons to about 20,000 daltons, Its
`proportion in the matrix may range from about 2% to
`about 65% by weight. Greater amounts of the medium
`to high molecular weight component tend to increase
`the melting point of the mixture, and favor the noncrys-
`talline character of the matrix.
`The viscosity of the molten material should be low
`enough to provide for easy mixing of the active ingredi-
`ent into the matrix and also for conforming to the final
`molded shape. This includes the ability to flow freely
`into thin layers when lamellae or disks are to be pre-
`pared by casting, and the ability to flow freely through
`the sprues of a multiple form injection mold.
`The buccal dosage form matrix should also be non-
`hygroscopic for ease in handling the dosage forms and
`should have good mold-release properties to facilitate
`manufacture by injection molding.
`The third ingredient of the buccal dosage matrix of
`the invention is a high molecular weight polymer intro-
`duced to adjust the properties of the matrix, particularly
`the melt viscosity and the molding properties of the
`molten matrix and the adhesion of the dosage form to
`the oral mucosa. The proportion of the third ingredient
`ranges from about 1% to about 40% by weight of the
`matrix. Suitable high molecular weight polymers in-
`
`5
`
`I0
`
`30
`
`35
`
`40
`
`60
`
`4
`clude polyvinylpyrrolidone (PVP), polyethylene oxide
`(PEO), poly(acrylic acid) (PAA), sodium alginate and
`carboxymethyl cellulose. Preferred high molecular
`weight polymers include polyvinylpyrrolidone and
`polyethylene oxide. Both of these polymers provide the
`matrix with water-activated adhesive properties for
`good adhesion to the oral mucosa. They also influence
`the melt viscosity of the molten matrix. The PEO used
`in the matrix may have a molecular weight from about
`100,000 to about 5,000,000 daltons. The PVP may have
`a molecular weight from about 30,000 to about 90,000
`daltons.
`
`In a preferred matrix of the invention the auxiliary
`polymeric ingredient is polyvinylpyrrolidone in a pro-
`portion of about 25% to about 40% by weight of the
`matrix. This dosage form rapidly disintegrates and dis-
`solves after being placed in the buccal pouch, in a per-
`iod of about 60 seconds, leaving no noticeable residue,
`but rather a coating of the matrix ingredients which
`adhere to a relatively large area of the mucosa sur-
`rounding the site where the dosage form was placed.
`The presence of this thin coating is unnoticeable to the
`patient, but it continues to dispense the drug through
`the mucosa until such time as the drug is used up or the
`matrix dissolves in the mouth fluids. Thus, the drug is
`typically dispensed over a period of 10-30 minutes via
`transmucosal absorption directly into the bloodstream.
`Additional ingredients in minor amounts may be in-
`corporated into the buccal matrix of the invention to
`provide desirable physical properties or modify the
`properties of the matrix.‘For example, a plasticizer such
`as propylene glycol, may be added in amounts up to
`about 5% by weight of the matrix.
`The buccal dosage form of the invention is prepared
`by mixing the ingredients at a temperature such that the
`PEG’s are molten and can serve as a solvent for the
`auxiliary high molecular weight polymeric ingredients,
`for any additional auxiliary ingredients and for the ac-
`tive pharmaceutical ingredient. In general, the PEG’s
`are melted and mixed in a vessel equipped with a stirrer
`and a heating device, such as a heating mantle or steam
`jacket. Such melting usually occurs at about 60°—80° C.
`and the viscosity and plasticity adjusting ingredients,
`e.g., polyethylene oxide or polyvinylpyrrolidone, any
`auxiliary ingredients and the pharmaceutically active
`ingredient are added while stirring. After the blending
`is complete, buccal dosage forms are prepared by con-
`ventional procedures, such as casting a thin layer of the
`composition on a flat surface, allowing it to harden and
`cutting the layer so prepared into dosage forms, or by
`injection molding.
`Formulation of the compositions of the invention in
`the molten state has a number of advantages over the
`conventional method of formulation by mixing of pow-
`dered or granulated ingredients in the solid state. The
`mixing equipment needed for mixing of liquid ingredi-
`ents is generally simpler than that used for solid materi-
`als. The fact that the ingredients are actually dissolved
`in the matrix makes for more uniform distribution of the
`active ingredients in the composition and a more uni-
`form rate of release as the dosage form dissolves in the
`oral cavity. The use of a molten matrix for formulating
`the composition also permits the use of injection mold-
`ing to prepare the dosage forms themselves.
`Injection molding of pharmaceutical dosage forms
`has a number of advantages over conventional tablet-
`ting.‘ Injection molding allows a greater uniformity in
`size and density, a greater range of shapes for the dos-
`
`TEVA EXHIBIT 1043
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05018997
`
`TEVA EXHIBIT 1043
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`4,764,378
`
`6
`ple a dosage form may be in the form of a lozenge, a
`lamella, a disk, a wafer, a tablet or the like. It should
`have dimensions which fit conveniently into the buccal
`cavity or under the tongue. Suitable dimensions for the
`dosage form are a length of 5 to 10 mm, a width of 2 to
`10 mm and a thickness of 0.2 to 3 mm. A preferred
`thickness is 0.5 to 1.5 mm. The total weight of the dos-
`age form may be from about 10 to about 150 mg, prefer-
`ably 50 to 100 mg.
`The invention will be illustrated by the following
`examples, which are not intended to be limiting. Parts
`and percentages in the examples are by weight unless
`otherwise specified.
`
`5
`age forms, and a greater uniformity of distribution of
`the drug within the matrix. Handling and metering of a
`molten matrix composition is also much simpler than for
`powdered or granulated compositions.
`Any drug suitable for transmucosal administration
`may be incorporated into the buccal dosage form of this
`invention. Such drugs may include locally or systemi-
`cally acting drugs, but in most cases will be systemically
`acting drugs. The drugs may be selected from among
`any group wherein a transmucosal administration of the
`drug over a period ranging from a few minutes to sev-
`eral minutes is desired. The drug may be selected from
`among analgesic, anorexic, antiarthritic, antibacterial,
`antibiotic, anticonvulsant, anti-depressant, antidiabetic,
`antifungal, antihistaminic, anti-hypertensive, anti-in-
`flammatory, anti-neoplastic, antiparkinsonism, antipy-
`retic, anticholinergic, anesthetic, antimicrobial, antivi-
`ral, anti-ulcer, bronchodilator, cardiovascular, contra-
`ceptive, central nervous system affecting,
`inotropic,
`vasodilator, vasoconstrictor, decongestant, diuretic,
`hypoglycemic, hormone, hypnotic, hematinic, electro-
`lyte supplement, germicidal, muscle relaxant, parasym-
`pathetolytic, parasyrnpathetomimetic, tranquilizer, oph-
`thalmic, psychostimulant, vitamin, and the like drugs.
`Preferred drugs for incorporation into the buccal
`dosage form of this invention include estrogens in gen-
`eral, e.g. estradiol and esters thereof such as the valerate
`ester, ethinylestradiol, progestins including norethin-
`drin, gonadotropin releasing hormone (GNRH), human
`growth hormone, insulin, nicotine, phenylephrine, de-
`smopressin (DDAVP), oxytocin, vasopressin, epineph-
`rine, peptides useful in the treatment of patients with
`Paget’s disease or other calcium deficiency syndromes,
`such as calcitonin and the like, nitroglycerin, isosorbide
`dinitrate,
`scopolamine,
`verapamil,
`oxymetazoline,
`tamoxifen and the like.
`The proportion of active ingredient in the buccal
`dosage form of the invention will vary according to the
`potency of the drug and the needs of the patient, as will
`be understood by those skilled in the art. The active
`ingredient will generally comprise from about 0.01 per-
`cent by weight to about 10 percent by weight, typically
`0.1 percent to 1 percent by weight, the remainder of the
`composition being the matrix. The concentration of the
`drug in the composition will also vary with the size of 45
`the dosage form prepared, since as will be understood
`by those skilled in the art, the amount of drug delivered
`in a single dose will depend on both the concentration
`of the drug_ in the matrix and the size of the buccal
`dosage form.
`A particularly preferred buccal dosage form of the
`invention incorporates an estrogen, a ‘progestin or pref-
`erably both, to prepare a dosage form useful as an oral
`contraceptive or a post-menopausal estrogen supple-
`ment. An oral contraceptive dosage form according to
`the invention will typically contain a progestin and an
`estrogen in amounts suitable for providing contracep-
`tive activity. A typical contraceptive formulation will
`include 0.02-0.05 percent by weight of ethinylestradiol
`and 1.0-5.0 percent by weight of norethindrone in a
`buccal matrix of the invention. A typical dosage form
`for post-menopausal estrogen supplement will contain
`0.2-0.5 percent by weight of 17-beta-estradiol and
`1.0-5.0 percent by weight of norethindrone in a buccal
`matrix of the invention.
`The buccal dosage forms prepared from the composi-
`tion of this invention may have any of the conventional
`shapes and sizes used for such dosage forms. For exam-
`
`EXAMPLE 1
`
`This example illustrates the preparation of a buccal
`dosage form of the invention.
`A molten mixture was prepared by the procedure
`described above having the following composition
`
`PEG 1000
`PEG 1450
`PEG 3350
`PEG 8000
`Propylene glycol
`Polyvinylpyrrolidone
`
`20%
`38%
`3%
`3%
`3%
`33%
`
`After the ingredients were melted together, the mol-
`ten mixture was cast on a smooth flat surface and al-
`lowed to cool. The film so formed was hard and some-
`what flexible at room temperature. Dosage forms of a
`size to fit comfortably in the buccal pouch were cut
`from the film (about 1 cmX3 cm). These lamellae dis-
`solved rapidly when placed in the buccal pouch or
`sublingually.
`Another dosage form was prepared by the same pro-
`cedure except that a small amount of a dye was incorpo-
`rated into the matrix. When the dosage form was placed
`in the buccal pouch, it dissolved in less than 60 seconds.
`However, it was observed from the dye pattern that the
`matrix adhered to an area of about 10 cm2 on the cheek
`and about 10 cm2 on the adjacent gum, and remained
`there for a period of 10-30 minutes.
`EXAMPLE 2
`
`This example illustrates another formulation of a
`dosage form of this invention.
`.
`A molten mixture was prepared by the procedure
`described above having the following composition
`
`PEG 1000
`PEG 1450
`PEG 3350
`PEG 8000
`Propylene glycol
`Polyvinylpyrrolidone
`
`18%
`38%
`3%
`3%
`5%
`33%
`
`this
`When tested by the procedure of Example 1,
`formulation also was found to dissolve rapidly and to
`form a coating on the mucosa close to the site of appli-
`cation.
`
`EXAMPLE 3
`
`A 10 g batch of the composition of Example 1 was
`prepared incorporating 20 mg of scopolamine. The
`formulation was molded by injection molding to pre-
`pare a buccal dosage form containing 0.2% of scopola-
`mine useful for treating patients having motion sickness.
`
`TEVA EXHIBIT 1043
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05018998
`
`TEVA EXHIBIT 1043
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`7
`EXAMPLE 4
`
`4,764,378
`
`8
`-continued
`A
`B
`29.4%
`28.8%
`2.0%
`3.8%
`
`c
`27.7%
`7.4%
`
`D
`25.9%
`13.8%
`
`PEG 20000
`PEO (MW 100,000)
`
`A 10 g batch of the composition of Example 1 was
`prepared incorporating 5% by weight of verapamil
`hydrochloride to prepare a buccal dosage form useful
`for treating cardiovascular conditions.
`EXAMPLE 5
`
`5
`
`This example illustrates a buccal matrix composition
`of the invention.
`By the general procedure outlined above a number of
`matrix formulations were prepared having the follow-
`ing compositions:
`
`PEG 1000
`PEG 20,000
`PEO (MW 100,000)
`
`A
`71%
`11%
`18%
`
`B
`60%
`15%
`25%
`
`C
`60%
`20%
`20%
`
`D
`61%
`22%
`17%
`
`In general all formulations exhibited satisfactory rates
`of erosion when used as buccal dosage forms.
`A quantity of 20 mg of calcitonin was added to 10 g
`of the molten composition A and a buccal dosage form
`was prepared containing 0.2% of calcitonin which was
`useful in treating patients with Paget’s disease or other
`calcium deficiency syndromes.
`A quantity of 10 mg of scopolamine was added to 10
`g of the molten composition A to form a pharmaceutical
`composition which was formed into a buccal dosage
`forms containing 0.1% scopolamine useful in treating
`patients having motion sickness.
`Veraparnil hydrochloride was mixed with the molten
`composition C in an amount equal to 5% of the total
`composition, and the molten composition was molded
`into buccal dosage forms useful
`in treating patients
`having cardiac arrythrnia or angina pectoris.
`Verapamil (free base) was mixed with the molten
`composition D in an amount equal to 10% of the total
`composition. The composition was formed into buccal 40
`dosage forms useful for transmucosal administration of
`verapamil for treating cardiovascular conditions.
`EXAMPLES 6-10
`
`The examples illustrate dosage forms according to 45
`the invention incorporating other drugs.
`An excipient composition is prepared having the
`composition of Example 5A. To separate portions of the
`composition are added amounts of the gonadotropin
`releasing hormone (GNRH),
`insulin, phenylephrine,
`desmopressin (DDAVP) and epinephrine to prepare
`pharmaceutical
`compositions
`containing
`effective
`amounts of each drug. Buccal dosage forms are pre-
`pared which are useful in treating patients in need of
`these drugs.
`
`EXAMPLE 1 1
`
`This example illustrates the effect of varying propor-
`tions of polyethylene oxide on the buccal controlled
`release matrices of the invention.
`By the general procedure outlined above a series of
`matrix formulations were prepared having the follow-
`ing compositions
`
`PEG 3350
`PEG 8000
`
`A
`49.0%
`19.6%
`
`B
`48.0%
`19.4%
`
`C
`46.3%
`18.6%
`
`D
`43.1%
`17.2%
`
`Formulations A and B exhibited good viscosity char-
`acteristics for mixing in a pharmaceutical compound;
`formulation C was acceptable; formulation D was diffi-
`cult to use at 80° C. because it exhibited a relatively high
`viscosity and stringiness.
`EXAMPLE 12
`
`This example illustrates another buccal device of the
`invention.
`
`A formulation was prepared by the general proce-
`dure described above having the following composi-
`tion:
`
`PEG 3350
`PEG 8000
`PEG 20000
`PEO (MW 100,000)
`Scopolamine HCl
`
`44.9%
`20.0%
`30.0%
`5.0%
`0.1%
`
`A buccal device was made from this composition
`which was useful in administration of scopolamine to
`patients suffering from motion sickness.
`EXAMPLE 13
`
`This example illustrates another buccal matrix of this
`invention.
`
`A formulation was prepared by the general proce-
`dure described above having the following composi-
`tion:
`
`PEG 1000
`PEG 8000
`PEO (MW 5,000,000)
`PVP (MW 30,000)
`pvp (MW 90,000)
`
`50.0%
`24.9%
`0.1%
`20.0%
`5.0%
`
`This matrix was easy to mold but was somewhat
`hygroscopic.
`
`EXAMPLE 14
`
`This example illustrates another buccal matrix of the
`invention.
`_
`A formulation was prepared by the general proce-
`dure described above having the following composi-
`tion:
`
`PEG 1000
`PEG 1450
`PEG 3350
`PEG 8000
`Propylene glycol
`PVP (MW 30,000)
`
`24%
`20%
`10%
`10%
`3%
`33%
`
`This composition yielded a solid matrix which rap-
`idly dissolved in water but was somewhat hygroscopic.
`EXAMPLE 15
`
`This example illustrates another buccal matrix of the
`invention.
`
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`TEVA EXHIBIT 1043
`
`RBP_TEVA05018999
`
`TEVA EXHIBIT 1043
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`9
`A formulation was prepared by the general proce-
`dure described above having the following composi-
`tion:
`
`4,764,378
`
`PEG 1450
`PEG 3350
`PEG 8000
`PEO (MW 5,000,000)
`
`PEG 1000
`PEG 1450
`PEG 3350
`PEG 8000
`Propylene glycol
`PVP (MW 30,000)
`
`EXAMPLE 16
`
`This example illustrates another buccal matrix of the
`invention.
`A formulation was prepared by the general proce-
`dure described above having the following composi-
`lI10l'l:
`
`PEG 1000
`PEG 1450
`PEG 3350
`PEG 8000
`Propylene glycol
`PEO (MW 5,000,000)
`
`EXAMPLE 17
`
`This example illustrates another buccal dosage form
`of the invention.
`A formulation was prepared by the general proce-
`dure described above having the following composi-
`tion:
`
`PEG 3350
`PEG 8000
`PEO (MW 5,000,000)
`Calcitonin
`
`30.0%
`64.8%
`5.0%
`0.2%
`
`This composition exhibited excellent physical proper-
`ties and could be easily molded into buccal dosage
`forms by injection molding.
`EXAMPLE 18
`
`10
`
`15
`
`20
`
`30
`
`35
`
`40
`
`45
`
`This example illustrates another buccal matrix of the ,
`invention.
`
`EXAMPLE 20
`
`This example illustrates the preparation of dosage
`forms suitable for use as oral contraceptives or post-
`menopausal estrogen supplements.
`A buccal dosage form matrix having the following
`composition is prepared by the procedure of Example 1.
`
`PEG 1000
`PEG 1450
`PEG 3350
`PEG 8000
`Propylene glycol
`PVP (MW 30,000)
`
`20%
`34%
`8%
`5%
`3%
`30%
`
`Into portions of this matrix are incorporated the fol-
`lowing estrogens and progestins in the listed propor-
`tions
`
`l7-beta-estradiol
`A.
`. ethinylestradiol
`. norethindrone
`. ethinylestradiol
`norethindrone
`. 17-beta-estradiol
`norethindrone
`
`0.2% by weight
`0.02% by weight
`2.0% by weight
`0.02% by weight
`2.0% by weight
`0.2% by weight
`2.0% by weight
`
`Formulation A through C are useful as components
`of a dosage regimen for contraception or estrogen sup-
`plement. Formulation D is suitable for use as an oral
`contraceptive. Formulation E is suitable as a post-
`menopausal estrogen supplement.
`EXAMPLE 21
`
`This example illustrates the superior bioavailability
`provided by transmucosal administration using the buc-
`cal dosage forms of this invention as compared with
`oral administration.
`
`A formulation was prepared by the general proce-
`dure described above having the following composi-
`tion:
`
`50
`
`A buccal dosage form matrix having the following
`composition was prepared by the procedure of Example
`1.
`
`PEG 1450
`PEG 3350
`PEG 8000
`PEO (MW 5,000,000)
`
`11.0%
`25.4%
`60.6%
`3.0%
`
`PEG 1000
`PEG 1450
`PEG 3350
`PEG 8000
`Propylene glycol
`PVP (MW 30,000)
`
`20%
`34%
`8%
`5%
`3%
`30%
`
`This formulation was used to prepare buccal dosage
`forms which dissolved slightly faster than those of Ex-
`ample 17.
`
`60
`
`EXAMPLE 19
`
`This example illustrates a highly preferred buccal
`matrix of the invention.
`A formulation was prepared by the general proce-
`dure described above having the following composi-
`tion:
`
`65
`
`Dosage forms were prepared from this matrix in the
`form of lozenges containing 192 micrograms of l7-beta-
`estradiol each. The dosage forms were administered to
`a human volunteer by the buccal route (transmucosal
`absorption) and by the oral route (absorption from the
`gastrointestinal tract). Blood levels were measured at
`various intervals after administration and the results for
`each method of administration are given below.
`
`TEVA PHARMACEUTICALS USA, |NC.iV. MONOSOL RX, LLC
`
`TEVA EXHIBIT 1043
`
`RBP_TEVA05019000
`
`TEVA EXHIBIT 1043
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`

`
`4,764,378
`
`.~
`
`Time after
`administration
`(minutes)
`
`Plasma level
`(micrograms/milliliter)
`Oral administration
`
`0
`30
`90
`240
`360
`
`0
`30
`90
`240
`360
`
`I0
`89
`64
`94
`10
`
`Buccal Administration
`
`I5
`655
`355
`115
`18
`
`Inspection of the data reveals that the blood level
`attained via buccal administration is much greater than
`that attained by oral administration.
`The invention having now been fully described, it 20
`should be understood that it may be embodied in other
`specific forms or variations without departing from its
`spirit or essential characteristics. Accordingly, the em-
`bodiments described above are to be considered in all
`
`12
`6. The dosage form of claim 1 wherein said medium
`or high molecular weight polyethylene glycol com-
`prises PEG 20,000.
`7. The dosage form of claim 1 wherein said medium
`or high molecular weight component is a mixture of
`medium and high molecular weight polyethylene gly-
`cols.
`8. The dosage form of claim 7 wherein said mixture of
`medium and high molecular weight polyethylene gly-
`cols is a mixture of PEG 8000 and PEG 20,000.
`9. The dosage form of claim 1 wherein said polyethy