`Khan et al.
`
`[191
`
`[541 DUALC
`DRUG DELIVERY SYSTEMS AND
`METHODS FOR PREPARING SAME
`
`Inventors: Sadath U. Khan, Randolph; Phyllis
`Ying. Mornstown; Russell U. Nesfiitt.
`Somerville; Mahdi B. Fawzi, Flanders;
`Jay Weiss. East Brunswick, all of N.J.
`
`Assignee: Warner-Lambert Company, Morris
`Plains. N.J.
`
`App]. No.:
`Filed:
`
`476,490
`
`Jun. 7, 1995
`
`Related U.S. Application Data
`
`Continuation of Ser. No. 275,198, Jul. 14, 1994, abandoned,
`which is a continuation of Ser. No. 875,846, Apr. 29, 1992,
`abandoned.
`
`Int. Cl.‘ ....................................................... A61K 9/24
`U.S. Cl. .......................... 424/473; 424/472; 424/474;
`424/481; 424/432; 424/440
`Field of Search ...................................._ 424/473, 472,
`424/474. 431, 432, 440
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`USOO5656296A
`
`[11] Patent Number:
`
`5,656,296
`
`[45] Date of Patent:
`
`Aug. 12, 1997
`
`1‘Z'T988IChan .......................................4241480
`
`$789549
`4,797,288
`4,816,264
`4,851,233
`4,892,742
`1-/—l—99—lEiehez.
`4983401
`.
`7/1991 Dansereau.
`5:032:406
`5,063,110 ll/1991 Fawzi
`...................................... 424/461
`
`Primary Exam/‘ner—D. Gabrielle Phelan
`Attamey, Agent, or Firm—Michael J. Atkins
`[57]
`ABSTRACT
`
`The present invention pertains to a dual control sustained
`release drug delivery system which comprises a core and a
`porous coating layer over the core. wherein the coated core
`comprises (A) a core comprising inpercentages by weight of
`the core composition (a) a medicament present in an amount
`from about 60% to about 90%; (b) an edible material having
`amelting point from about 25° C. to about 100° C. selected
`from the group consisting of (i) fatty acids having an iodine
`value from about 1 to about 10, (ii) natural waxes, (iii)
`synthetic waxes, and (iv) mixtures thereof, present in an
`amount from about 5% to about 40%; and (B) a porous
`coating layer over the core comprising in percentages by
`weight of the coating layer composition (a) a
`pH-independent water-insoluble polymer present
`in an
`amount from about 40% to about 80%; and (b) a water-
`soluble film forming polymer present in an amount from
`about 20% to about 60%.
`
`4,756,911
`
`7/1988 Drost ....................................... 424/468
`
`15 Claims, 1 Drawing Sheet
`
`—+—— 500mg
`
`—.A— 750mg
`
`—o— 1000mg
`
`100
`
`90
`
`80
`
`70
`
`60
`
`PERCENT
`DRUG
`DISSOLVED
`
`5
`
`6
`
`7
`
`B910
`
`TIME (HOURS)
`
`TEVA EXHIBIT 1046
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`RBP_TEVA05019004
`
`TEVA EXHIBIT 1046
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`U.S. Patent
`
`Aug. 12, 1997
`
`5,656,296
`
`r'\
`(/3
`(I
`
`DOIx
`
`x
`
`LL]
`
`2I
`
`-
`
`PERCENT DRUGDISSOLVED
`
`TEVA EXHIBIT 1046
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`RBP_TEVA05019005
`
`TEVA EXHIBIT 1046
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`1
`DUAL CONTROL SUSTAINED RELEASE
`DRUG DELIVERY SYSTEMS AND
`w
`1
`vi‘
`.._,
`,I.c|.
`
`2
`the above compositions are entirely satisfactory. All of "the
`above sustained release compositions have a tendency to
`
`5,656,296
`
`This is a continuation of Prior application sen No,
`08/275,198 as originally filed on Jul. 14. 1994. now aban-
`doned which was a continuation of U.S. Ser. No. 07/875,846
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`
`This invention pertains to dual control sustained release
`drug delivery systems. The novel drug delivery systems
`contain a core comprising a medicament and a waxy mate-
`rial and a coating layer over the core comprising a
`pH-independent water-insoluble polymer and a water-
`soluble polymer. Therapeutically eliective amounts of the
`drug delivery systems may be utilized in a wide variety of
`pharmaceutically acceptable carriers to prepare medicated
`sustained release compositions. This invention also relates
`to methods for preparing these drug delivery systems and the
`medicated sustained release compositions in which they may
`be used.
`
`2. Description of the Background
`Sustained release compositions for the sequential or timed
`release of medicaments are well known in the art. Generally
`such compositions contain medicament particles, normally
`administered in divided doses two or more times daily,
`mixed with or covered by a coating material which is
`resistant to degradation or disintegration in the stomach
`andlor in the intestine for a selected period of time. Release
`of the medicament may occur by leaching, erosion. rupture,
`diffusion or similar actions, depending upon the nature and
`thiclmess of the coating material.
`A frequently encountered problem in the field of sustained
`release compositions is that many water-miscible drugs have
`a tendency to be dumped or surged into the body during the
`first hour or two after an oral dosage form is ingested. This
`problem is particularly acute when the sustained release
`compositions are administered with food.
`U.S. Pat. No. 4,789,549.
`issued to Khan et al. and
`assigned to Warner-Lambert Company, discloses a sustained
`release composition comprising a medicament in a water-
`soluble polymer matrix coated with a semi-permeable mem-
`brane coating layer consisting of hydroxypropyl cellulose
`and cellulose acetate phthalate with polyoxypropylene poly-
`oxyethylene block copolymer and acetylated monog1yccr—
`ides. The water-soluble polymer matrix is preferably
`hydroxypropyl methylcellulose.
`U.S. Pat. No. 4.816.264, issued to Phillips et al. and
`assigned to Warner-Lambert Company. discloses a sustained
`release drug delivery system containing a core comprising a
`medicament and a cellulosic gelling polymer such as
`hydroxyethyl cellulose coated with a semi-permeable mem-
`brane coating layer comprising a water-soluble cellulosic
`polymer such as hydroxypropyl cellulose and a water-
`insoluble acrylic polymer such as Eudragit E30D.
`U.S. Pat. No. 4.851.233,
`issued to Khan et al. and
`assigned to Warner-Lambert Company. discloses a com-
`pressed table binder system consisting essentially of
`procainamide hydrochloride or sodium meclofenarnate. type
`“H” hydroxyethyl cellulose. and microcrystalline cellulose
`coated with hydroxyethyl cellulose.
`While the above sustained release compositions provide
`some degree of improved sustained release activity. none of
`
`sustained release compositions are administered with food.
`5 Thus itwonldbeadvantageoustc prepareasustainedrelease
`composition having release properties which are unaifected
`by the consumption of food. The present invention provides
`mmwmmmw
`without
`the disadvantages characteristic of previously
`known products. The present invention also provides meth-
`ods for preparing these improved sustained release drug
`delivery systems and the medicated sustained release com-
`positions in which they may be employed
`SUMMARY OF THE INVENTION
`
`The present invention pertains to a dual control sustained
`release drug delivery system which comprises a core and a
`porous coating layer over the core, wherein the coated core
`comprises:
`(A) a core comprising in percentages by weight of the
`core composition:
`(a) a medicament present in an amount from about 60%
`to about 90%;
`(b) an edible material having a melting point from about
`25° C.
`to about 100° C. selected from the group
`consisting of (i) fatty acids having an iodine value from
`about 1 to about 10, (ii) natural waxes, (iii) synthetic
`waxes, and (iv) mixtures thereof, present in an amount
`from about 5% to about 40%; and
`(B) a porous coating layer over the core comprising in
`percentages by weight of the coating layer composition:
`(a) a pH-independent water-insoluble polymer present in
`an amount from about 40% to about 80%; and
`(b) a water-soluble film forming polymer present in an
`amount from about 20% to about 60%.
`
`BRIEF DESCRIPTION OF THE FIGURE
`
`FIG. 1 is a graph showing the in vitro dissolution profile
`of a procainamide hydrochloride prolonged release tablet
`over a 12 hour period prepared according to the present
`invention.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`The present invention pertains to a sustained release drug
`delivery systems having a dual control mechanism. The drug
`delivery system contains a core comprising a medicament
`and a waxy material and a porous coating layer over the core
`comprising a pH-independent water-insoluble polymer and
`a water-soluble film forming polymer. Applicants have
`found that conventional sustained release compositions con-
`taining a water-soluble polymer matrix in the core have a
`tendency to either dump or delay the release of a medica-
`ment when administered with a high fat meal. Applicants
`have discovered that sustained release compositions con-
`taining the combination of a core having a medicament and
`a waxy material and a semi-permeable coating layer are
`essentially unaffected by food consumption. The dual con-
`trol mechanism is achieved by employing a fatty acid or
`waxy material in the core and a specific combination of
`polymeric materials in the porous coating layer. The
`improved dual control sustained release drug delivery sys-
`tems prolong the release of medieaments for up to 12 hours
`or more.
`
`50
`
`60
`
`65
`
`The dual control sustained release drug delivery systems
`may be utilized in a wide variety of pharmaceutically
`
`TEVA EXHIBIT 1046
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`RBP_TEVA05019006
`
`TEVA EXHIBIT 1046
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`5,656,296
`
`3
`acceptable carriers and confectionery bulking agents to
`prepare medicated sustained release compositions. This
`invention also relates to methods for preparing these dual
`control sustained release drug delivery systems and the
`medicated sustained release compositions in which they may
`be employed.
`As set out above, the dual control susmined release drug
`
`and an edible material having a me] ' g point from about 25°
`C. to about 100° C. selected from the group consisting of (i)
`fatty acids having an iodine value from about 1 to about 10,
`(ii) natural waxes. (iii) synthetic waxes, and (iv) mixtures
`thereof.
`
`The medicarnents (drugs, pharmaceuticals) present in the
`core of the drug delivery system of the present invention
`may be selected from a wide variety of water—soluble and
`water-insoluble drugs and their acid addition or metallic
`salts. Both organic and inorganic salts may be used provided
`the drug maintains its medicament value. Exemplary acid
`addition salts include hydrochloride. hydrobromide,
`orthophosphate. benzoate, maleate,
`tartrate, succinate,
`citrate. salicylate, sulfate and acetate. Exemplary metallic
`salts include sodium, potassium, calcium, and magnesium.
`The medicament may be selected from a wide range of
`therapeutic agents and mixtures of therapeutic agents which
`may be administered in sustained release or prolonged
`action form. Nonlimiting illustrative categories and specific
`examples of such rnedicaments include:
`(a) Analgesics, such as acetylsalicylic acid,
`acetaminophen,
`ibuprofen. phenacetin, phenylbutazone.
`salicylamide, sodium salicylate, and meclofenarnic acid;
`(b) Anthelmintics, such as dithiazanine iodide and gar-
`dona;
`(c) Antiasmatics, such as aminophylline, metaproterenol,
`epinephrine, theophylline. and oxtriphylline;
`(d) Antiarrhythrnics, such as procainamide hydrochloride
`and pinninol;
`(e) Anticholesterolemic and antilipid agents, such as
`gemflbrozil, HMG reductase inhibitors, and ACAT inhibi-
`tors;
`
`(f) Antiemetics, such as prochloroperazine dimaleate;
`(g) Antiepileptic drugs. such as sodium phenytoin;
`(h) Antihistamines, such as chlorphenirarnine maleate,
`brompheniramine maleate, phenindamine tartrate, pyril-
`arnine maleate, methapyrilene fumarate, doxylarnine
`succinate, phenyltoloxamine citrate, diphenylhydramine
`hydrochloride, promethazine, terfenedine and triprolidine;
`(i) Antihypertensives, such as methyldopa;
`(i) Anti-inflammatory agents, such as isoxicam, meclofe-
`namic acid, sodium meclofenamate, and naproxen;
`(lr) Antinauseants. such as dimenhydrinatc and meclizine;
`(1) Antipyretics, such as N-acetyl-p-aminophenol;
`(rn) Antitussives. such as dextromethorphan. dex-
`tromethorphan hydrobromide. noscapine, carbetapentane
`citrate, chlophedianol hydrochloride, codeine and diphen-
`hydrarnine hydrochloride;
`(n) Anxiety agents, such as buspirone hydrochloride and
`N-methylglucamine;
`(0) Appetite suppressants, such as phenylpropanolamine‘
`hydrochloride and caffeine;
`(p) Cathartics. such as castor oil;
`(q) Central nervous system stimulants, such as nicotine
`and caffeine;
`
`4
`(r) Cardiovascular preparations. such as angiotensin con-
`verting enzyme inhibitors (ACE inhibitors). including enala-
`pril maleate and catopril; calcium channel blockers, includ-
`ing verapamil hydrochloride;
`(5) Cognition activators such as tactine;
`(t) Decongestants, such as phenylephrine hydrochloride,
`
`doephedrine
`(u) Expectorants, such as guaifenesin and glycerol guai-
`acolate;
`(V) Laxatives. such as phenolphthalein. danthron, pam-
`abrom and bisocadyl;
`including vitamins and
`(W) Nutritional supplements.
`minerals. such as ascorbic acid. niacin, pantothenic acid,
`vitamin B6. thiamine hydrochloride. riboflavin. potassium
`iodide, potassium chloride, cupric sulfate and ferrous sul-
`fate; and
`(X) Various alkaloids. such as codeine phosphate, codeine
`sulfate and morphine.
`Preferred drugs to be employed include sparingly soluble
`drugs such as sodium meclofenarnate, meclofenarnic acid,
`methyldopa, sodium phenytoin, and the like, and freely
`soluble drugs such as diphenhydramine hydrochloride, pseu-
`doephedrine hydrochloride, procainamide hydrochloride,
`and oxtriphylline. In a preferred embodiment, the medica-
`ment
`is selected from the group consisting of sodium
`meclofenamate and procainarnide hydrochloride. In a more
`preferred embodiment, the medicament
`is procainamide
`hydrochloride.
`The medicament of the present invention may be used in
`many distinct physical forms well known in the pharmaceu-
`tical art to provide an initial dosage of the medicament
`and/or a further time-release form of the medicament. With-
`out being limited thereto, such physical forms include free
`forms and encapsulated forms, and mixtures thereof.
`The amount of medicament drug or its acid addition salt
`used in the present invention may vary depending upon the
`therapeutic dosage recommended or permitted for the par-
`ticular medicament. In general, the amount of medicament
`present is the ordinary dosage required to obtain the desired
`result. Such dosages are known to the skilled practitioner in
`the medical arts and are not a part of the present invention.
` ,meme&cmemmmecme&
`the drug delivery system is present in an amount from about
`60% to about 90%, preferably from about 70% to about
`90%, and more preferably from about 75% to about 85%, by
`Weight of the core composition.
`The edible material present in the core of the drug
`delivery system of the present invention is a material which
`has a melting point in the range from about 25° C. to about
`100° C., preferably from about 35° C. to about 100° C., and
`more preferably from about 45° C. to about 100° C. The
`melting point of the edible material should be within the
`recited range because the sustained release properties of the
`final drug delivery system will be greatly affected by the fat
`or wax constituent.
`The edible materials useful in the core are selected from
`the group consisting of fatty acids, natural waxes, synthetic
`waxes, and the like, and mixtures thereof. Fatty acids are
`carboxylic acids derived from or contained in an animal or
`vegetable fat or oil. Fatty acids are composed of a chain of
`alkyl groups containing from 4 to 22 carbon atoms and are
`characterized by a terminal carboxyl group. Waxes are
`low-melting organic mixtures or compounds having a high
`
`TEVA EXHIBIT 1046
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`RBP_TEVA05019007
`
`TEVA EXHIBIT 1046
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`5,656,296
`
`5
`molecular weight. are solid at room temperature and gen-
`
`both classified as lipids.
`The fatty acids useful in the present invention are acids
`which have an iodine value from about 1 to about 10. The
`10 n '-ue 15 a means 0
`eerrmnrng e egree 0
`unsaturation in a fat or oil. The measurement of iodine
`values is determined by known titrating methods and is
`reported in terms of centigrams of iodine absorbed per gram
`of fat or oil sample titrated. (See “Bailcy’s Industrial Oil and
`Fat Products,” Vol. 2. 4th Ed, Swern, Daniel ed.. pp.
`436-438 (1982)). Hence the fatty acids useful in the present
`invention have an iodine value from about 1 centigrarn to
`about 10 centigrams.
`Fatty acids useful in the present invention are selected
`from the group consisting of hydrogenated palm oil, hydro-
`genated palm kernel oil. hydrogenated peanut oil, hydroge-
`nated rapeseed oil, hydrogenated rice bran oil, hydrogenated
`soybean oil. hydrogenated cottonseed oil. hydrogenated
`sunflower oil. hydrogenated castor oil, and the like, and
`mixtures thereof. Other fatty acids include, for example,
`decenoic acid, docosanoic acid. stearic acid. pa.Imi11'c acid,
`lauric acid. myristic acid. and the like, and mixtures thereof.
`The preferred fatty acids are selected from the group con-
`sisting of hydrogenated palm oil, hydrogenated castor oil,
`hydrogenated cottonseed oil. stearic acid, palmitic acid, and
`mixtures thereof. The most preferred fatty acid is stearic
`acid.
`
`Waxes useful in the present invention include natural
`waxes. such as animal waxes. vegetable waxes, and petro-
`leum waxes (i.e., paratfin waxes, microcrystalline waxes,
`petrolatum waxes, mineral waxes), and synthetic waxes
`which are edible and have a melting point within the range
`from about 25° C. to about 100° C. Specific examples of
`useful waxes are sperrnaceti wax, carnauba wax, Japan wax.
`bayberry wax, flax wax, beeswax, Chinese wax. shellac
`wax, lanolin wax. sugarcane wax, candelilla wax, paraflin
`wax. microcrystalline wax, petrolatum wax. carbowax, and
`the like, and mixtures thereof. Mixtures of these waxes with
`the fatty acids set out above may also be used. The preferred
`waxes are selected from the group consisting of carnauba
`wax. bees Wax, glyceryl tristearate, glyceryl monostearate,
`paraffin wax. rmcrocrystalline wax. glyceryl distearate, and
`mixtures thereof. The most preferred waxes are carnauba
`wax, bees Wax, glyceryl tristearate, glyceryl monostearate,
`and paraflin Wax.
`The wax may also be an ester of a fatty acid having from
`about 12 to about 31 carbon atoms and a fatty alcohol having
`from about 12 to about 31 carbon atoms. the ester having a
`carbon atom content from about 24 to about 62 carbon
`atoms. Examples of such fatty. acid esters are myricyl
`palrnitate. ceryl palrnitate, ceryl cerotate, myricyl melissate,
`stearyl palmitate, stearyl myristate, lauryl laurate, and the
`like, and mixtures thereof. The preferred fatty acid esters are
`selected from the group consisting of stearyl palrnitate,
`stearyl myristate. and mixtures thereof.
`The wax may also be a monoglyceryl ester. diglyceryl
`ester. or triglyceryl ester (glycerides) which is an ester
`formed from a fatty acid having from about 10 to about 22
`carbon atoms and glycerol, wherein one or more of the
`hydroxyl groups of glycerol is substituted by a fatty acid.
`Examples of useful glycerides include glyceryl
`monostearate. glyceryl distearate, glyceryl tristearate. glyc-
`eryl dipalmitate, glyceryl
`tripalmitate. glyceryl
`
`6
`monopalrnitate, glyceryl dilaurate, glyceryl trilaurate, glyc-
`glyceryl
`slaw-ervl
`caproate,
`onocaproate. glceryl dicaproate,
`glyceryl monomyristate, glyceryl dimyristate, glyceryl
`trimyristate, glyceryl monodecenoate, glyceryl didecenoate,
`glyceryl tridecenoate, and the like, and mixtures thereof. The
`
`of glyceryl monostearate, glyceryl distearate, glycery
`tristearate, and mixtures thereof.
`In a preferred embodiment, the edible material is selected
`from the group consisting of carnauba wax, hydrogenated
`vegetable oils, and stearic acid. More preferably, the edible
`material is carnauba wax.
`
`The amount of edible material used in the core may vary
`depending upon the medicament employed and the degree of
`sustained release desired In general, the fatty acid or waxy
`edible material will be present in the core in an amount from
`about 5% to about 40%. preferably from about 5% to about
`30%, and more preferably from about 5% to about 15%, by
`weight of the core composition.
`The core of the drug delivery system of the present
`invention may also contain conventional excipients and
`additives which function to facilitate processing or storage.
`Thus coloring agents. flavoring agents, perfumes, sweeten-
`ing agents, surface active agents,
`lubricants, softeners,
`glidants, stabilizing agents, and the like, and mixtures
`thereof, may be employed
`As set out above, the cores in the drug delivery systems
`are coated with a porous coating layer comprising a
`pH-independent water-insoluble polymer present and a
`water-soluble film forming polymer.
`The pH-independent water-insoluble polymers in the
`coating layer of the drug delivery system of the present
`invention are preferably acrylic polymers. Suitable water-
`insoluble polymers in the present invention include aqueous
`acrylic resin dispersions such as polyacrylamide,
`polyacryldextran, polyalkyl cyanoacrylate, polymethyl
`methacrylate, methacrylic resin copolymer, and the like, and
`mixtures thereof. Preferred resins are the Eudragitsm
`(methacrylic resin copolyrner), made by Rohm Pharma.
`Eudragit NE3ODTM is highly preferred.
`The amount of pH-independent water-insoluble polymer
`used in the present invention may vary depending upon the
`medicament employed and the degree of sustained release
`desired The pH-independent water-insoluble polymer in the
`coating layer is preferably present in an amount from about
`40% to about 80%, more preferably from about 50% to
`about 75%, and most preferably from about 55% to about
`70%, by weight of the coating layer composition.
`The water-soluble fllrn forming polymers in the coating
`layer of the drug delivery system of the present invention
`include
`cellulose
`derivatives
`such
`as
`hydroxypropylcellulose. hydroxypropyl-methylcellulose,
`hydroxypropylmethylcellulose phthalate, sodium
`carboxymethylcellulose, and the like, and mixtures thereof.
`In a preferred embodiment.
`the film forming polymer is
`hydroxypropylcellulose.
`The amount of water-soluble film forming polymer used
`in the present invention may vary depending upon the
`medicament employed and the degree of sustained release
`desired The water-soluble filrn forming polymer in the
`coating layer is preferably present in an amount from about
`20% to about 60%, more preferably from about 25% to
`about 50%, and most preferably from about 30% to about
`45%, by weight of the coating layer composition.
`
`TEVA EXHIBIT 1046
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`RBP_TEVA05019008
`
`TEVA EXHIBIT 1046
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`5,656,296
`
`7
`The coating layer of the drug delivery system of the
`present invention may also contain conventional excipients
`and additives which function to facilitate processing or
`storage. Thus antifoatn agents, fillers. plasticizing agents,
`coloring agents, flavoring agents, perfumes, sweetening
`agents. surface active agents. lubricants, stabilizing agents,
`a.nti—tacking agents, and the like, and mixtures thereof, may
`be employed.
`The weight ratio of core composition to coating layer
`composition is the ratio containing suflicient coating layer to
`prevent potential premature release of the medicament from
`the core without forming a composition so large as to be
`thmapeutically unsuitable for use. In general, the weight
`ratio of core composition to coating layer composition is
`from about 94:6 to about 98:2, preferably from about 95:5
`to about 98:2. and more preferably from about 9624 to about
`98 :2. respectively.
`The coated cores may also be agglomerates of coated
`cores which may contain one or more core gathered into a
`cluster under a single coating layer. The terms “coated
`cores” and “agglomerates of coated cores” are used inter-
`changeably herein.
`The present invention is also directed at methods for
`preparing the dual control sustained release drug delivery
`systems. In general, the drug delivery systems are prepared
`by first melting the fatty acid or waxy edible material and
`then admixing the medicament and traditional additives such
`as softeners into the melted core. The melted core is then
`cooled, congealed, and milled to the desired particle size.
`Additives such as glidants and lubricants may then be
`admixed with the milled mixture. The mixture is then
`compressed into tablet cores and is ready to be coated with
`the porous coating layer.
`A suspension of the porous coating layer is then prepared
`by admixing the pH—independent water-insoluble polymer
`and the water-soluble film forming polymer in water with
`traditional additives such as a softener, an antifoaruing
`agent, and an anti-tacking agent. The coating layer suspen-
`sion is sprayed onto the tablets until the weight increase in
`the tablets is the range from about 4% to about 8%. A color
`coat may optionally be applied to the coated tablets to
`improve the aesthetics of the tablets.
`The drug delivery systems of the present invention may
`be admixed, compressed. and spray coated using standard
`techniques and equipment known to those skilled in the art.
`The exact conditions for forming and compressing tablet
`coresnnd spray coating the cores will vary with the par-
`ticular apparatus selected and are readily determined by
`those skilled in the art without the need for undue experi-
`mentation. Tablet compressing and pan coating are well
`known in the arts and therefore the selection of the specific
`apparatus will be apparent to the artisan.
`In a specific embodiment. the present invention is directed
`at a method for preparing a dual control sustained release
`drug delivery system which comprises a core and a porous
`coating layer over the core, which comprises the steps of:
`(1) providing the following ingredients:
`(A) a core comprising in percentages by weight of the
`core composition:
`(a) a medicament present in an amount from about 60%
`to about 90%;
`(b) an edible material having a melting point from
`about 25° C. to about 100° C. selected from the
`group consisting of (i) fatty acids having an iodine
`value from about 1 to about 10, (ii) natural waxes.
`(iii) synthetic waxes, and (iv) mixtures thereof,
`present in an amount from about 5% to about 40%;
`and
`
`8
`(B) a porous coating layer over the core comprising in
`percentages by weight of the coating layer composi-
`tion:
`(a) a pH-independent water-insoluble polymer present
`in an amount from about 40% to about 80%; and
`(b) a water-soluble film forming polymer present in an
`amount from about 20% to about 60%;
`(2) melting the edible material from step Il)(AI(b1 and
`admixing the medicament from step (l)(A)(a) to form a
`molten mixture;
`(3) cooling and milling the mixture from step (2) and
`compressing milled mixture to form tablet cores;
`(4) admixing the ingredients from step (1)(B) in water to
`form a porous coating layer suspension; and
`(5) coating the tablet cores from step (3) with the coating
`layer suspension from step (4) to form the dual control
`sustained release drug delivery system.
`Once prepared, the coated core compositions may be
`stored for future use or may be formulated with conventional
`additives such as pharmaceutically acceptable carriers and
`confectionery bulking agents to prepare a wide variety of
`medicated sustained release compositions to suit particular
`applications.
`An important aspect of the present invention includes a
`hard or soft confectionery composition incorporating the
`inventive drug delivery systems and a method for preparing
`the hard or soft confections. In this form of the invention. the
`medicated sustained release compositions includes the
`coated cores and a pharmaceutically acceptable carrier such
`as a confectionery bulking agent. and various additives. The
`confectionery may be in the form of a lozenge, tablet, tofl’ee,
`ncugat, suspension, chewy candy. and the like. The phar-
`maceutically acceptable carriers may be prepared from a
`wide range of materials. Without being limited thereto, such
`materials include diluents, binders and adhesives, lubricants,
`disintegrants, coloring agents, bulking agents, flavoring
`agents, sweetening agents and miscellaneous materials such
`as buffers and adsorbents in order to prepare a particular
`medicated confection.
`The preparation of confectionery formulations is histori-
`cally well known and has changed little through the years.
`Confectionery items have been classified as either “hard”
`confectionery or “soft” confectionery. The medicated com-
`positions of the present invention can be incorporated into
`confectionery compositions by admixing the inventive com-
`pm
`As used herein, the term confectionery material means a
`product containing a bulking agent selected fiom a wide
`variety of materials such as sugar, corn syrup, and the like,
`and in the case of sugarless bulking agents, sugar alcohols
`such as sorbitol and mannitol and the like, and mixtures
`thereof. Confectionery material may include such exemplary
`substances as lozenges, tablets, tollee, ncugat, suspensions,
`chewy candy, chewing gum and the like. The bulking agent
`is present in a quantity suflicient to bring the total amount of
`confectionery composition to 100%.
`Lozenges are flavored medicated dosage forms intended
`to be sucked and held in the mouth. Lozenges may be in the
`form of various shapes such as flat, circular, octagonal and
`biconvex forms. The lozenge bases are generally in two
`forms: hard. boiled candy lozenges and compressed tablet
`lozenges.
`Hard boiled candy lozenges may be processed and for-
`mulated by conventional means. In general, a hard boiled
`candy lozenge has a base composed of a mixture of sugar
`and other carbohydrate bulking agents kept in an amorphous
`or glassy condition. This amorphous or glassy form is
`
`TEVA EXHIBIT 1046
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`RBP_TEVA05019009
`
`TEVA EXHIBIT 1046
`TEVA PHARMACEUTICALS USA, INC. V. MONOSOL RX, LLC
`
`
`
`5,656,296
`
`9
`considered a solid syrup of sugars generally having from
`about 0.5% to about 1.5% moisture. Such materials nor-
`’
`C
`I
`I
`I 0
`mfly
`In sum
`4
`sugar and from about 0.1% to about 5% water, by weight of
`the final composition. The syrup component is generally
`prepared from corn syrups high in fructose, but may include
`other materials. Further ingredients such as flavoring agents,
`sweeteningngents. acidulants coloring a ents and the like
`may also be added
`Boiled candy lozenges may also be prepared from non-
`fermentable sugars such as sorbitol, mannitol. and hydro-
`genated corn syrup. Typical hydrogenated corn syrups are
`Lycasin, a commercially available product manufactured by
`Roquette Corporation, and Hystar. a commercially available
`product manufactured by Lonza. Inc. The candy lozenges
`may contain up to about 95% sorbitol. a mixture of sorbitol
`and mannitol in a ratio from about 9.5:O.5 up to about
`7.525, and hydrogenated corn syrup up to about 55%, by
`weight of the solid syrup component.
`Boiled candy lozenges may be routinely prepared by
`conventional methods such as those involving fire cookers,
`vacuum cookers, and scraped-surface cookers also referred
`to as high speed atmospheric cookers.
`Fire cookers involve the traditional method of making a
`boiled candy lozenge base. In this method.
`the desired
`quantity of carbohydrate bulking agent is dissolved in water
`by heating the agent in a kettle until the bulking agent
`dissolves. Additional bulking agent may then be added and
`the cooking continued until a final temperature of 145° C. to
`156° C. is achieved The batch is then cooled and worked as
`a plastic-like mass to incorporate additives such as flavoring
`agents, coloring agents and the like.
`A high-speed atmospheric cooker uses a heat-exchanger
`surface which involves spreading a film of candy on a heat
`exchange surface, the candy is heated to 165° C. to 170° C.
`in a few minutes. The candy is then rapidly cooled to 100°
`C. to 120° C. and worked as a plastic-like mass enabling
`incorporation of the additives, such as flavor agents, color-
`ing agents and the like.
`In vacuum cookers, the carbohydrate bulking agent is
`boiled at a temperature from about 125° C. to about 132° C.,
`vacuum is applied and additional water is boiled off without
`extra heating. When