`
`(19) i+ Canadian
`Intellectual Property
`Office
`
`Office de la Propriété
`Intellectuelle
`du Canada
`
`An Agency of
`Industry Canada
`
`Un organisme
`d'Industrie Canada
`
`(11) CA 2 448 997
`(40) 05.12.2002
`(43) 05.12.2002
`
`(13) A
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`
`
`(12)
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`(21) 2448 997
`
`(22)
`
`22.05.2002
`
`(51)
`
`Int. CL:
`
`A61K 9/48
`
`(85)
`
`28.11.2003
`
`(86)
`
`PCT/US02/016185
`
`
`(87) WO002/096347
`(72)
`
`60/294,786 US 31.05.2001
`
`(30)
`
`(71)
`
`MICRODOSE TECHNOLOGIES, INC.,
`4262 U.S.Route 1, MONMOUTH JUNCTION, XX (US).
`(74)
`GOWLING LAFLEUR HENDERSON LLP
`
`
`GUMASTE, ANAND V.(US).
`ABRAMS, ANDREW L. (US).
`
`DOSAGE ET CONDITIONNEMENT DE MEDICAMENTS A LIBERATION CONTROLEE
`METERING AND PACKAGING OF CONTROLLED RELEASE MEDICATION
`
`(54)
`(54)
`
`(57)
`
`Controlled quantities of powdered medication are
`formed in
`controlled
`release
`packages
`using
`electrostating metering. Also provided are combination
`medication therapy delivery packages comprising two or
`more active
`pharmaceuticals segregated from one
`another in a single delivery package.
`
`

`

`iv Office de la Propriété
`Intellectuell
`duCanada
`dindustieCanada
`
`Canadian
`Intellectual P
`Office
`industryCanada
`
`CA 2448997 A1 2002/12/05
`e1) 2 448 997
`a2) DEMANDE DE BREVET CANADIEN
`CANADIAN PATENT APPLICATION
`(13) A1
`
`(86) Date de dépé6t PCT/PCTFiling Date: 2002/05/22
`(87) Date publication PCT/PCT Publication Date: 2002/12/05]
`(85) Entrée phase nationale/National Entry: 2003/11/28
`(86) N° demande PCT/PCTApplication No.: US 2002/016185|
`(87) N° publication PCT/PCT Publication No.: 2002/096347
`(30) Priorité/Priority: 2001/05/31 (60/294 ,786) US
`
`(51) Cl.Int.7Ant.cl.? A61K 9/48
`(71) Demandeur/Applicant:
`MICRODOSE TECHNOLOGIES,INC., US
`(72) Inventeurs/Inventors:
`ABRAMS, ANDREWL., US;
`GUMASTE, ANAND V., US
`(74) Agent: GOWLING LAFLEUR HENDERSON LLP
`
`
`
`(54) Titre : DOSAGE ET CONDITIONNEMENTDE MEDICAMENTSA LIBERATION CONTROLEE
`(54) Title) METERING AND PACKAGING OF CONTROLLED RELEASE MEDICATION
`
`(57) Abrégé/Abstract:
`Controlled quantities of powdered medication are formed in controlled release packages using electrostating metering. Also
`provided are combination medication therapy delivery packages comprising two or more active pharmaceuticals segregated
`from one another in a single delivery package.
`
`OPIC - CIPO 191
`( ‘anada Attp:/opic.gc.ca > Ottawa-Hull KLA 0C9> Aap-“eipo.ge.ca
`OPIc
`
`

`

`CA 02448997 2003-11-28
`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`5 December 2002 (05.12.2002)
`
`
`
`(10) International Publication Number
`WO 02/096347 A3
`
`(51)
`
`International Patent Classification’:
`
`AGLK 9/48
`
`(21)
`
`International Application Number:
`
`=PCT/US02/16185
`
`(22)
`
`International Filing Date:
`
`22 May 2002 (22.05.2002)
`
`(25)
`
`Filing Language:
`
`English
`
`(81) Designated States (national): AK, AG, AL, AM, AI, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
`GM,HR, HU,ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
`MX, MZ, NO, NZ, OM, PH,PL, Pl, RO, RU, SD, SE, SG,
`SILSK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ,
`VN, YU, ZA, ZM, ZW.
`
`(26)
`
`Publication Language:
`
`English
`
`(84)
`
`(30)
`
`Priority Data:
`60/294,786
`
`31 May 2001 (31.05.2001)
`
`US
`
`(71)
`
`Applicant (for all designated States except US): MICRO-
`DOSE TECHNOLOGIES, INC. [US/US]; 4262 U.S.
`Route 1, Monmouth Junction, NJ 08852 (US).
`
`(72)
`(75)
`
`Inventors; and
`Inventors/Applicants (for US only): ABRAMS,Andrew,
`L. [US/US]; 26 Imperial Avenuc, Westport, CT 06880
`(US). GUMASTE,Anand, V. [US/US]; 7 Ardsley Court,
`Robbinsville, , NJ 08691 (US).
`
`Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Turasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BE, CH, CY, DE, DK, ES, FI, FR,
`GB, GR,IE, IT, LU, MC, NL, PT, SE, TR), OAPI patent
`(BE, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR,
`NE, SN, TD, TG).
`
`Published:
`with international search report
`
`(88)
`
`Date of publication of the international search report:
`27 March 2003
`
`(74)
`
`Agents: SOLOWAY, Norman, P. et al.; Hayes Soloway
`PC., 130 W. Cushing Strect, Tucson, AZ 85701 (US).
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes and Abbreviations" appearing at the hegin-
`ning ofeach regularissue ofthe PCT Gazette.
`
`02/096347A3
`
`(54) Title: METERING AND PACKAGING OF CONTROLLED RELEASE MEDICATION
`
`© (57) Abstract; Controlled quantitics of powdered medication are formed in controlled release packages using clectrostating mcter-
`WwW ing. Also provided are combination medication therapy delivery packages comprising two or more active pharmaceuticals segregated
`
`from one anctherin a single delivery package.
`
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`METERING AND PACKAGING OF CONTROLLED
`
`RELEASE MEDICATION
`
`The present invention relates to the metering and packaging of precise
`quantities of pharmaceuticals and drugs for medical uses. The invention has
`particular utility in the metering and packaging of combinations of two or
`more pharmaceuticals and drugs for the same or co-morbid therapy, and will
`be described in connection with such utility, although otherutilities are _
`
`contemplated.
`The convenience of administering a single dose of a medication which
`releases multiple active ingredients in a controlled fashion and in a chosen
`location over an extended period of time, as opposed to the administration of
`a number of single doses at regular intervals, has long been recognized in the
`pharmaceutical arts. The advantage to the patient and clinician in having
`consistent and uniform blood levels of medication over an extended period of
`
`time are likewise recognized. The advantages of a variety of controlled-
`release dosage forms are well known. Among the most important advantages
`- are: (1) increased contacttime for the drug to allow forlocalactivity in the
`stomach, small intestine, colon, or other locus of activity; (2) increased and.
`
`more efficient absorption for drugs which have specific absorption sites; (3)
`the ability to reduce the number of dosages per period of time; (4)
`employmentof less total drug; (5) minimization or elimination of local and/or
`systemic side effects; (6) minimization of drug accumulation associated with
`chronic dosing; (7) improved efficiency and safety of treatment; (8) reduced
`fluctuation of druglevel; and (9) better patient compliance with overall
`
`disease management.
`' In accordance with the present invention there is provided a
`pharmaceutical delivery package comprising fixed unit dose quantities of
`fixed quantities of two or more different active pharmaceutical ingredients (a)
`‘combined ina single delivery package,-and (b) segregated from one another
`within the package.
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`Additionally, many experts believe controlled release drug delivery
`has many important non-therapeutic ramifications as well, including a
`financial saving to the patient in terms of fewer lost work days, reduced
`
`hospitalization and fewer visits to the physician.
`
`It is knownthat certain design parameters are critical to proper drug
`delivery. Typically, they are: (1) delivering the drugto the targettissue; (2)
`supplying the drug for a predetermined period of time; and (3) fabricating a
`
`delivery system that provides drug in the desired spatial and temporal
`
`pattern. Controlled release drug delivery systems are interided to utilize
`
`these parameters to achieve the aforementioned advantages as compared to
`
`conventional pharmaceutical dosing.
`Previously direct placement of medication onto asubstrate generally
`waslimited to medical placement of large doses or required technology
`where the active pharmaceutical was mixed with the substrate or matrix to
`provide differential delivery, or coated with a material with desired release
`
`characteristics.
`As used herein “controlled-release” is used to describe a system,i.e.
`method and materials for making an active ingredient available to the patient
`
`in accordance with a preselected condition,i.e. time, site, etc.. Controlled-
`release includes the use of instantaneous release, delayed release and
`sustained release. “Instantaneous release” refers to immediate release to the
`patient. “Delayed release” meansthe active ingredient is not made available
`until some time delay after administration. Typically, dosages are
`
`administered by oral ingestion, although other forms of administration are
`
`contemplated in accordance with the present invention. “Sustained release”
`refers to release of active ingredient whereby the level of active ingredient
`
`available to the patient is maintained at some level over a period of time. The
`
`methodof effecting each type of release can be varied. For example, the
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`active-ingredient can be placed on asemi-permeable membrane having
`predetermined diffusion, dissolution, erosion or breakdown characteristics.
`Alternatively, the active ingredient can be masked by a coating, a
`laminate, etc. Regardless of the method of providing the desired release
`pattern, the present invention contemplates delivery of a controlled-release
`system which utilizes one or more of the “release” methods and materials.
`Moreover, the present invention advantageously can be employed in the
`development of multiple different release system(s).
`The patent and scientific literature is replete with various sustained
`release (SR) methods and materials. For common methods of obtaining SR
`systems, see “Sustained and Controlled Release Drug Delivery Systems,”
`Robinson, Joseph R., Ed., PP 138-171, 1978, Marcel Dekker, Inc. New York,
`NY, For example it is knownto fill polymeric capsules with a solid, liquid,
`suspension or gel containing a therapeutic agent which is slowly released by
`diffusion through the capsule walls. Heterogeneous matrices, for example,
`compressed tablets, control the release of their therapeutic agents cither by
`_ diffusion, erosion of the mattix or a comibination of both. Other SR systems
`focus onthe fabrication of laminates of polymeric material and therapeutic
`agent which are then formed into a sandwich, relying on different diffusion or
`erosion rates to control release of the therapeutic agent. Liquid-liquid
`encapsulation in a viscous syrup-like solution of polymeralso has been
`knownto be useful in controlling release of the therapeutic agent.
`Additionally, it is generally known that heterogeneous dispersions or
`solutions of therapeutic agents in water-swellable hydrogen matricesare
`useful in controlling the release of the agent by slow surface-to-center
`swelling of the matrix and subsequent diffusion of the agent from the water-
`swollen part of the matrix.
`
`During dissolution of a controlled-release matrix tablet, the dosage
`form generally remainsas a non-disintegrating, slowly eroding entity from
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`which the therapeutic agent leaches out, through a diffusion controlled
`process. Conventional SR formulations are generally designedto release their
`active ingredients over an extended period of time, usually 8-24 hours.
`Conventional SR formulations use waxes or hydrophilic gumsas the primary
`drug carriers to prolong the release of the active ingredients.
`Starch USP (potato or corn) is commonly used as a componentin
`conventional tablet or hard shell capsule formulations.
`.
`The existing sustained release technologies generally involve relatively
`complicated formulations and manufacturing processes which often are
`difficult and expensive to precisely control.For example, one well known SR
`delivery system, OROS, marketed by the Alza Corporation, involves laser
`drilling througha tablet to create passages for the release of the drug from the
`tablet core. In controlled release technologies, it is desirable to be able to
`incorporate the active ingredientin its controlled-release pattern in a single
`dosage unit without deteriorating the active ingredient. Moreover, the dosage
`unit should be able to deliver the system without interfering with-its release
`pattern.
`Various methods have been devised to enable controlled-release
`systemsto be delivered to a patient without destruction of the delivery
`system during manufacturing, handling and distribution. For example,
`controlled-release systems have been provided in the form of beads or
`particles which are packaged in a gelatin capsule for oral dosage. This
`method of delivery of the controlled-release system prevents damageto the
`coating on the beads.
`Furthermore, when controlled-release active ingredients are
`incorporated in compressiontablets, it may be difficult for many people to
`swallow such tablets.Moreover, dissolution of high compression tablets often
`initially is slow and exratic and mayresult in localized hot spots of alimentary
`tract irritation where disintegration and release of the active ingredientfinally
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`occurs. And, present systems do not allow for the accurate deposition of
`doses of powdered medication onto different substrates either in single
`packets, layered packet, or multipackets on the same planeof the base
`substrate, The present invention overcomes the disadvantages of the priorart
`by offeringa simple andinexpensive means of incorporating active ingredient
`(the drug) with a multitude of controlled-release systems.
`|
`In our earlier U.S. Patent 5,699,649, granted December23, 1997, we
`describe a method and apparatus for packaging microgram quantities of fine
`powders such as pharmaceuticals using electrostatic phototechnology
`techniques. More particularly, as described in our aforesaid U.S. Patent
`5,699,649, the ability of powders to acquire an electrical charge
`advantageously is utilized for precisely measuring exact microgram
`quantities of the powder, whereupon these exact microgram quantities are
`then placed in individual containers, and the containers sealed.
`Electrostatic charge has been employed toattract a given quantity of
`powderto a surface. An exampleof this is the laser printer or the electrostatic
`. copy device where a drum is charged and toner particles are attracted and
`held in position by the charge. The charge on the drum is neutralized by the
`attracted toner powder, thus limiting the amount of toner in accordance with
`the charge image on the drum. The charged powderon the printer drum is
`_ then transferred to a sheet of paper orothercarrier to give a final image. In
`our U.S, Patent 5,699,649, electrostatic charge technology is employed for
`transferring a predetermined amountof afinely powdered pharmaceutical or
`drug to a‘carrier or an intermediate such as a drum, carrying a charge of
`predetermined intensity and area, rotating the charged drum surface,
`carrying the predetermined amount of powdered pharmaceutical or drug on
`its surface, to a transfer station where the charge is overcome and the dry
`powderis transferred to a package whichis then sealed. In lieu of a drum, a
`belt, or other movable surface is charged to a given potential in a localized
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`area. Alternatively, a predetermined amount of powdered pharmaceutical or
`drug may be deposited directly in a package using electrostatic charge
`technology.
`When a given amount of a powdered pharmaceutical or drug is to be
`packaged, the charge and area of charge can be determined experimentally for
`each dose of pharmaceutical or drug and each particle size distribution. This
`can be done by controlling either the charged area for a given charge density
`ot the total electrostatic charge on any individual charged area. These
`conditions can be adjusted to provide essentially the exact desired amount of
`the particular pharmaceutical or drug to be transferred at the transfer station.
`
`In our U.S. Application Serial No. 09/097,104, we describe another
`electrostatic charge technology which may be adopted to be used. for
`measuring and packaging unit doses of a pharmaceutical or drug in a readily
`ingestible form, i.e. as a tablet or capsule. The technology thus described also
`permits reproducible precise measurement and packaging of a
`pharmaceutical or drug, and which may be scaled from laboratory to pilot
`. plant to full scale production withoutthe needfor recertification.
`In accordance with one aspect of the present invention, controlled
`quantities of powdered medication are formed in controlled release packages
`using electrostatic metering technology. The present invention also provides,
`in another aspect, combination medication delivery systems in which the
`active ingredients are segregated from one another
`Further features and objects of the present invention will becomeclear
`from the following detailed description taken in conjunction with the
`accompanying drawings, wherein like numerals depict like parts, and
`wherein:
`
`Fig. 1 is a schematic flow diagram showingthe various steps involved
`in practicing the present invention;
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`Fig. 2 is an enlarged cross-sectional view of one embodiment of a
`controlled release tablet made in accordance ‘with the present invention;
`Fig. 3 is a view, similar to Fig. 1, and showing alternative steps
`involved in practicing the present invention;
`Fig. 4 is a view, similar to Fig. 2, and showing an alternative form of a
`controlled release tablet made in accordance with the present invention;
`Fig. 5 is a view similar to Fig. 2, and showing yet another alternative
`embodiment of the present invention;
`Fig. 6 is a view, similar to Fig. 2, and showing yet another embodiment
`of the invention; and
`
`Figs. 7 - 9 are viewssimilar to Fig. 2, and showing yet other
`embodiments of the present invention.
`Referring now to Fig. 1, there is a schematic flow diagram of the
`various pieces of equipment neededto perform in the total process from
`powder supply to packaged pharmaceutical or drug,i.e. in controlled release
`tablet form, containing a specified amount of pharmaceutical or drug powder
`.in the tablet or package. At 16 is indicated the pharmaceuticalor drug
`powder supply which is fed into a device 18 for creating an aerosolof the
`powder. Next the powderparticles are ionized at 20. As will be indicated
`later, a numberof these steps and pieces of equipment can be combined. At
`24 is indicated a carrier surface capable of maintaining a space charge on its
`surface. This can be a plastic belt, for example, or a selenium drum of the
`type used in Xerox ™ photocopiers. This carrier surface 24 is passed through
`a charging station 25 where a predetermined electrostatic charge 25A (an
`electrostatic “image”) is created on a predetermined area ofthe transfer
`surface. This charged surface 25A then passes through a step 26 wherein
`powderis deposited on the carrier surface in a sufficient amount 26A to
`neutralize the charge carried by the carrier surface. Thereafter, the carrier
`surface, carrying the predetermined amount 26A of powderonits surface, is
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`passed to a powder discharging device 30 which discharges the powder 264
`from the surface 24 onto a membrane 29. Alternatively, the powder may be
`placed directly onto the membrane 29. The membrane 29 containing its
`charge of powder 26A, then passes throughasealing step 32 wherein a
`second membrane 34 which may be porous, permeable or semi-permeable
`covers and seals the discharged powder 26A on the membrane 29. Thereis
`thus produced an aliquot of powdered medicine 26A sandwiched between
`
`semi-permeable or permeable membranes 29 and 34.
`This sandwiched material is thenpassed to a cutting station 38 wherein
`the sandwichis cut into individual tablets or wafers 36.
`
`As mentioned previously in discussing Fig. 1, the carrier surface with
`the electrostatic charge carries a known amountof charge on its surface and
`the polarity of this charge is opposite to that of the powderparticles
`suspended in the chamber. The charged particles migrate to the charged
`surface because of the attraction by the opposite natureof the charges. This
`migration of the particles continues until the charge on the carrier surface is
`neutralized.
`The actual amount of powder mass transferred to the carrier surface is
`a function of the mass-to-charge ratio of the chargedparticles. Althoughit is
`difficult to achieve a linear relationship between the mass and the actual
`charge, it is possible to establish a fixed relationship between the surface area
`of the powderparticles and the charge the powderparticle is carryingat
`charge saturation. However, the surface area of a mixed group of powder
`particles of different sizes and shapes can be extremely difficult to calculate
`mathematically, particularly when the shapesareirregular, (e.g. non-
`spherical, microcrystalline, etc.) As mentioned earlier, the simplest method
`of determining the amount and area of chargeto attract a given weightof
`particles is to estimate the correct area and charge and then apply the
`estimated charge to the estimated area on the carrier surface 24 and expose
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`this selectively charged area to a mass of powder which has been ionized in
`the ionizing step. The amount of powder deposited can then be readily
`measured at the discharge step. Thereafter, either the size of the charged area
`or the amount of charge applied to the area at the chargingstation 25 can be
`adjusted upwardly or downwardly to provide the correct amount of charge,
`both in area and chargeintensity, for picking up a desired weight of
`oppositelycharged powder. Likewise, using the technology of our co-
`pending application Serial No. 09/097,104, larger quantities of medication
`may be deposited.
`A feature and advantageof the present inventionis to produce
`carefully controlled doses of controlled release medication. Electrostatic
`metering and packaging as above described permits exact dosing. And, by
`employing selected porous, permeable or semi-permeable membranesfor
`encapsulating the powdered medicine aliquots, drug release rate and also site
`of drug release can be determined by adjusting membrane material and/or
`membranethickness.
`
`©
`
`The membranes should be formed of ingestible materials having a
`selected permeability porosity to fluids at a selectedsite or sites within the
`alimentary canal, so as to permit controlled release of the medication. By way
`of example, one or both membranes 29, 34 may compriseacid-dissolvable
`materials whenit is desired to release the medication into the stomach or the
`membranes 29, 34 may be alkaline-dissolvable materials at differing pH’s to
`release into chosen locations within the intestine. Porosity, membrane
`thickness, ete., may be selected to provide desired rate of dissolution at the
`site of interest.
`
`The invention is susceptible to modification. For example, referring to
`Figs. 3 and 4 by adding a second powdered medicine supply and discharge
`station (shown generally at 40), a two-component controlled release tablet 48
`may be formed (see Fig, 4) incorporating two different powdered medicines
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`50, 52, encapsulated between membranes 29 and 34 for simultaneous
`controlied release.
`
`Alternatively, as shown in Fig. 5, two different drugs 60, 62 may be
`layered on one another, separated by a membrane64 so the two medications
`may be delivered sequentially either in the same location, or in different
`locations within the alimentary canal. Another feature and advantage of the
`multi-drug tablet of Fig. 4 and Fig. 5, as will be discussed in detail herein
`below,is that two normally incompatible drugs may be to be safely packaged
`in a single tablet.
`The-invention is susceptible to modification. For example, individual
`doses may be formedby electrostatic deposition in accordance with U.S.
`Patent No. 5,714,007.
`Other possibilities are possible. For example, referring to Fig, 6, the
`tablet 70 may incorporate an adhesive layer 72 such as a mucosal adhesive,
`which in turn is covered by an acid or alkaline dissolvable protective
`membrane 74, which dissolves at a selected site allowing the adhesive to
`-adhere, for example, to the intestinal wall, thereby increasing residence time
`of the medication in a chosen location. Alternatively, an acid or alkaline
`activatable adhesive may be applied to the outer surface of the tablet. In yet
`another possibility, the membrane may be a material which expands on
`contact with the acid or alkaline in the alimentary canal and becomes more
`porous whereby to slowly release medication in a chosen location within the
`alimentary canal.
`As mentioned above,a particular feature and advantage of the present
`invention is that it permits packaging, within a single tablet of two or more
`different drugs normally considered to be incompatible. Certain drugs are
`known to cause undesirable side effects which need to be countered bya
`second drug. For example, Omeprazole! whichfinds substantial utility as an
`oral antiulcer agent, also is known to block the release of B12 from its protein
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`bincling site in food. This can lead to pernicious anemia. The present
`invention permits packaging of time-release Omeprazole with Vitamin B12 in
`an appropriate dosage of, e.g. 251gm-1me. After taking the medication, one
`membrane will dissolve allowing absorption of the B12, while the remaining
`membrane package carrying the Omeprazole will pass into the small intestine
`where the drug is released and absorbed.
`The invention is susceptible to modification. For example, while the
`membranes have been described as being preformed, permeable,
`semipermeable or porous material, one or both membranes could be formed
`
`in place from a gelor liquid.
`The ability to accurately place the dose of medication onto a plurality
`of substrates and seal the dose with other membranesin accordance with the
`present invention, allows for the fabrication of many different dosage forms;
`by altering the substrates and encapsulating material a single unit dose form
`canbe fabricated with a plurality of different drugs in different coverings,
`membranes and barriers. ‘This will provide a single dosage form with
`|
`multiple active ingredients each being delivered to the appropriate site for
`absorption. Alternatively, two or more active medicaments may be combined
`in a single delivery container, Le. pill, capsule or caplet without actually
`mixing the two or more ingredients. For example, referring to Fig. 7, the
`active ingredients are segregated from one another in a compartmentalized
`capsule 100. Alternatively, two or more tablets 102, 104 each containing only
`oneactive ingredient, could be placed in a larger absorbable capsule or
`encased in a larger tablet 106. Or, as shown in Fig. 9, two or more active
`ingredients could each be formulated as encapsulated particles 108A, 108B,
`and the encapsulated mixed particles placed in a capsule 110 where the only
`contact is betweentheparticle inert coatings,etc.
`There are many drugs which could benefit from combinations to
`improve patient benefit. However, with many active ingredients, there is a
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`question of chemical interaction. Thus, several drugs are normally prescribed
`as separate tablets or capsules which presents a problem in terms of patient
`compliance, e.g. TB triple therapy, AIDS multi-drug therapy, anti-infectives,
`etc. Also, delivery of two or more active medicaments could reduce side
`effects, and/or improve therapeutic response which may in turn permit a
`decrease in the required dosage.
`The combination of drugsof the present invention can be groupedinto
`polypharmacy for a therapeutic area, and into polypharmacy for treatmentof
`co-morbid diseases. The invention will now be described with reference to
`the following non-limiting examples.
`(1)
`Omeprazole! and analogs andisomers - As noted above
`Omeprazole is an inhibitor of gastric secretion and also inhibits the absorption
`of certain drugs/compoundsthat require stomach acid such as Vitamin B12,
`the deficit of which results in pernicious anemia. A combination of B12 with
`Omeprazole would eliminate the potential problem.
`(2)
`Valacyclovir? and analogs and is used to treat Herpes Zoster. It
`is well knownthat two drugs Cimetidine? and Probenecid‘ both increase the
`AUC (area under curve) and Cmax. A combination drug can be constructed
`with a combination of either one or moreof these components to provide
`more efficacy.
`(3)
`Enalapril? and analogs and isomersis an ACE inhibitor used for
`the treatment of hypertension. This drug has been used with the following
`and analogs and isomers beta adrenegic-blocking agents, methyldopa, nitrate,
`calcium blocking agents, Hydralazine®, Prazosin’ and Digoxin’ without
`clinically significant side effects. One or more ofthese agents may be
`combined with Enalapril to improve the compliance ofpatient with
`hypertension and hypertension and other cardiac diseases.
`(4)
`Ketoconazole? and analogs and isomersis used to treat fungal
`infections. One of the side effects is the reduction of Testosterone. This side
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`effect could be mitigated by the combination of Testosterone or oneofits
`isomers or analogs to overcomethesideeffect.
`(5)
`Omeprazole! and analogs and isomersis also used in
`combination with Clarithoromycin"® for ulcer treatment. These two drugs
`may be combined as a single dose for patient compliance.
`(6)
`Tamoxifen! and analogs and isomers used in treatment of
`breast cancer has a +/- 30% incident of water retention with weight gain >
`5%. This can be a disturbing consequencefor patients with an éven more
`disturbing disease. The addition of a diuretic or combination diuretic
`provides a single dosage form for reduction in side effect and compliance.
`(7)
`Isotretinoin! and analogs and isomers used for the treatment of
`postular acne has a severe danger if taken by a woman whois pregnant. The
`incorporation of oral contraceptive medication eliminates the potential for
`pregnancy while medicated.
`(8) Metformin ICIand analogs and isomers are hypoglycemic
`agents which have been used in combination with Sulfonylurea! and analogs
`. and isomerstotreat Type 2 Diabetes. These two agents act in different ways
`on reducing glucose levels. A combination is helpful for those patients
`requiring more aggressive oral therapy for their diabetes.
`(9)
`This example provides various drug combinations for treating
`hypertension.
`
`Combinations for treating hypertension include:
`Combination # 1 Diuretic + Angiotensin converting enzyme inhibitor
`(ACE inhibitor)
`An example includes the following classes of diuretics:
`1.
`Carbonic anhydrase inhibitors - e.g.
`Dichlorophenamide?®.
`2.
`Loop diuretics, e.g. Furosemide’,
`3.
`Potassium sparing diuretics, e.g. Aldactone!’,
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`Thiazides and related drugs, e.g. Hydrochlorthiazidel®
`4,
`.
`and Chlorthalidonel®.
`5.
`A diuretic which is already formulated as a combination
`diuretic, e.g. Aldactazide, a combination of Spironolactone? (potassium
`sparing diuretic + hydrochlorothiazide), This combination makes use of the
`different methodsof action of two different diuretics separated by a barrier
`from an ACEinhibitor such as Enalapril maleate21, Fosinopril sodium22, or
`Lisinopril?5,
`
`Combination diuretics such as Zestoretic AstraZeneca a combination of
`Lisinopril?” 10 or 20 mg and Hydrochlorthiazide!’ 12.5 or 25 mg, exist in tablet
`form comprising mixed active ingredients in the pill or tablet form. The
`present invention segregates the Lisinopril and Hydrochlorthiazide,
`In accordance with the present invention, we can form e.g. 10 mg and
`20 mg Lisinopril” pills, and 12.5 and 25 mg Hydrochlorthiazide!7 pulls and
`then put them together with a barrier between twoactive ingredients. Pills
`can be in the form of tablets, pills, capsules or other solid oral dosage forms.
`Combination # 2 Diuretic + Angiotensin Il Receptor Antagonist
`Diuretics as described in combination drug #1 plus an angiotensin II
`receptor antagonist such as Losartan potassium” and/or Valsartan25, '
`These combinations also permit administration of two or more drugs
`which,if in direct contact, have an unacceptable reaction.
`Combination # 3 Diuretic + Beta Adrenergic Blocking Agent
`Diuretic as described in combination #1, plus a beta adrenergic
`blocking agent such as Bioprolol fumarateor Metoprolol succinate2’,
`Combination # 4 Diuretic + Calcium chanel block
`Diuretic as described in combination #1, plus a Calcium chanel block
`' suc