United States Patent
`
`[193
`
`Khan et al.
`
`[11] Patent Number:
`
`5,656,296
`
`[45] Date of Patent:
`
`Aug. 12, 1997
`
`USOO5656296A
`
`4,789,549 12/1988 Khan ....................................... 424/480
`4,797,288
`1/1989 Shanna
`...... 424/476
`4,816,264
`3/1989 Phillips
`...... 424/468
`4,851,233
`7/1989 Khan . .......
`...... 424/480
`4,892,742
`1/1990 Shah .. ...
`...... 424/480
`4,983,401
`1/1991 Eichez ......
`...... 424/473
`5,032,406
`7/1991 Dansereau
`.. 424/472
`5,068,110 11/1991 Fawzi ...................................... 424/461
`
`
`
`Primary Examirzer—D. Gabrielle Phelan
`Attomey, 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 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%.
`
`[54]
`
`[75]
`
`[73]
`
`[21]
`
`[22]
`
`[63]
`
`[51]
`[52]
`
`[53]
`
`[56]
`
`DUAL CONTROL SUSTAINED RELEASE
`DRUG DELIVERY SYSTEMS AND
`METHODS FOR PREPARING SAME
`
`Inventors: Sadath U. Khan, Randolph; Phyllis
`Ying, Morristown; Russell U. Nesbitt,
`Somerville; Mahdi B. Fawzi, Flanders;
`Jay Weiss, East Brunswick, all of N.J.
`
`Assignee: Warner-Lambert Company. Morris
`Plains. N.J.
`
`Appl. No.:
`Filed:
`
`476,490
`
`Jun. 7, 1995
`
`Related US. 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. C1.° ....................................................... A61K 9/24
`U.S. Cl. .......................... 424/473; 424/472; 424/474;
`424/481; 424/482; 424/440
`Field of Search ..................................... 424/473, 472,
`424/474. 481, 482, 440
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,756,911
`
`7/1988 Drost ....................................... 424/468
`
`15 Claims, 1 Drawing Sheet
`
`-—+—— 500mg
`
`-—A.— 750mg
`—o— 1000m
`
`9
`
`100
`
`90
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`PERCENT
`DRUG
`DISSOLVED
`
`4
`
`5
`
`6
`
`7
`
`89101112
`
`TIME (HOURS)
`
`DRL — EXHIBIT 1046
`
`DRL001
`
`DRL - EXHIBIT 1046
`DRL001
`
`

`
`U.S. Patent
`
`Aug. 12,1997
`
`5,656,296
`
`N_.
`
`: O
`
`F m
`
`m
`
`nmm
`
`e
`
`Ammaozvmzfi
`
`2:
`
`om
`
`on
`
`on
`
`8
`
`om
`
`2.
`
`on
`
`9ON
`
`pzuommm
`
`2:5
`
`S>._omm_o
`
`DRL - EXHIBIT 1046
`
`DRL002
`
`DRL - EXHIBIT 1046
`DRL002
`
`

`
`1
`DUAL CONTROL SUSTAINED RELEASE
`DRUG DELIVERY SYSTEMS AND
`METHODS FOR PREPARING SAME
`
`This is a continuation of prior application Ser. 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
`filed Apr. 29. 1992. now abandoned
`
`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 effective 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
`and/or in the intestine for a selected period of time. Release
`of the medicament may occur by leaching, erosion. rupture.
`dilfusion 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 monoglycer—
`ides. The water-soluble polymer matrix is preferably
`hydroxypropyl methylcellulose.
`U.S. Pat. No. 4.816.264, issued to Phillips et al. and
`as signed 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 meclofenamate. 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
`
`5,656,296
`
`2
`
`the above compositions are entirely satisfactory. All of the
`above sustained release compositions have a tendency to
`rapidly release water-miscible drugs into the body when the
`sustained release compositions are administered with food.
`Thus it would be advantageous to prepare a sustained release
`composition having release properties which are unaflected
`by the consumption of food. The present invention provides
`such improved sustained release drug delivery systems
`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 fonning 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 medicaments for up to 12 hours
`or more.
`
`The dual control sustained release drug delivery systems
`may be utilized in a wide variety of pharmaceutically
`
`5
`
`10
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`65
`
`DRL - EXHIBIT 1046
`
`DRL003
`
`DRL - EXHIBIT 1046
`DRL003
`
`

`
`3
`
`4
`
`5,656,296
`
`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 sustained release drug
`delivery systems contain a core comprising a medicament
`and 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.
`
`The medicaments (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 medicaments include:
`(a) Analgesics, such as acetylsalicylic acid,
`acetaminophen,
`ibuprofen, phenacetin, phenylbutazone,
`salicylarnide, sodium salicylate, and meclofenamic acid;
`(b) Anthelmintics, such as dithiazanine iodide and gar-
`dona;
`(c) Antiasmatics, such as aminophylline, metaproterenol,
`epinephrine, theophylline, and oxtriphylline;
`(d) Antiarrhythmics, such as procainamide hydrochloride
`and pirminol;
`(e) Anticholesterolemic and antilipid agents, such as
`gemfibrozil, I-IMG reductase inhibitors, and ACAT inhibi-
`tors;
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`(f) Antiemetics, such as prochloroperazine dimaleate;
`(g) Antiepileptic drugs. such as sodium phenytoin;
`(h) Antihistamines, such as chlorpheniramine maleate,
`brompheniramine maleate, phenindamine tartrate, pyril—
`arnine maleate, methapyrilene fumarate, doxylamine
`succinate, phenyltoloxamine citrate, diphenylhydrarnine
`hydrochloride, promethazine, terfenedine and triprolidine;
`(i) Antihypertensives, such as methyldopa;
`(j) Anti-inflammatory agents, such as isoxicarn, meclofe-
`narnic acid, sodium meclofenamate, and naproxen;
`(k) Antinauseants, such as dimenhydrinate and meclizine;
`(1) Antipyretics, such as N-acetyl-p-aminophenol;
`(m) Antitussives. such as dextromethorphan, dex-
`tromethorphan hydrobromide, noscapine, carbetapentane
`citrate, chlophedianol hydrochloride, codeine and diphen-
`hydramine hydrochloride;
`(n) Anxiety agents, such as buspirone hydrochloride and
`N-methylglucarnine;
`(o) Appetite suppressants, such as phenylpropanolamine‘
`hydrochloride and caffeine;
`(p) Cathartics, such as castor oil;
`(q) Central nervous system stimulants, such as nicotine
`and calfeine;
`
`45
`
`50
`
`55
`
`65
`
`(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,
`phenylpropanolamine hydrochloride, pseudoephedrine
`hydrochloride, pseudoephedrine hydrobromide, pseu-
`doephedrine sulfate and ephedrine;
`(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 meclofenamate, meclofenamic 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 procainamide 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.
`In a preferred embodiment, the medicament in the core of
`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
`
`DRL - EXHIBIT 1046
`
`DRL004
`
`DRL - EXHIBIT 1046
`DRL004
`
`

`
`5
`
`6
`
`5,656,296
`
`molecular weight, are solid at room temperature and gen-
`erally are similar in composition to fats and oils except that
`waxes contain no glycerides. Waxes may be hydrocarbons or
`esters of fatty acids and alcohols. Fatty acids and waxes are
`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
`iodine value is a means of determining the degree of
`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 “Bailey’s Industrial Oil and
`Fat Products,” Vol. 2, 4th Ed., Swem, Daniel ed., pp.
`436-438 (1982)). Hence the fatty acids useful in the present
`invention have an iodine value from about 1 centigram 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 palmitic 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, palrnitic 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., paraffin 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 spermaceti 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 camauba
`wax, bees wax, glyceryl tristearate, glyceryl monostearate,
`paraffin wax. microcrystalline wax, glyceryl distearate, and
`mixtures thereof. The most preferred waxes are camauba
`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
`palmitate. 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 palmitate,
`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
`
`monopalmitate, glyceryl dilaurate, glyceryl trilaurate, glyc-
`eryl monolaurate, glyceryl didocosanoate, glyceryl
`tridocosanoate, glyceryl monodocosanoate, glyceryl
`monocaproate, glyceryl dicaproate, glyceryl
`tricaproate,
`glyceryl monomyristate, glyceryl dimyristate, glyceryl
`trimyrtistate, glyceryl monodecenoate, glyceryl didecenoate,
`glyceryl tridecenoate, and the like, and mixtures thereof. The
`preferred glycerides are selected from the group consisting
`of glyceryl monostearate, glyceryl distearate, glyceryl
`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 Pharrna.
`Eudragit N'E30DTM 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 film 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 film 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.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`65
`
`DRL - EXHIBIT 1046
`
`DRL005
`
`DRL - EXHIBIT 1046
`DRL005
`
`

`
`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 antifoam agents, fillers, plasticizing agents,
`coloring agents, flavoring agents, perfumes, sweetening
`agents, surface active agents. lubricants, stabilizing agents,
`anti-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
`therapeutically 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 96:4 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 antifoaming
`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
`cores and 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
`
`10
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`65
`
`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 (l)(A)(b) and
`admixing the medicament from step (1)(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 pharrnaceutically 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, toffee,
`nougat, 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 “so ” confectionery. The medicated com-
`positions of the present invention can be incorporated into
`confectionery compositions by admixing the inventive com-
`positions into conventional hard and soft confections.
`As used herein, the term confectionery material means a
`product containing a bulking agent selected from 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, toflee, nougat, 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
`fonns: 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
`
`DRL - EXHIBIT 1046
`
`DRL006
`
`DRL - EXHIBIT 1046
`DRL006
`
`

`
`9
`
`10
`
`5,656,296
`
`considered a solid syrup of sugars generally having from
`about 0.5% to about 1.5% moisture. Such materials nor-
`mally contain up to about 92% corn syrup, up to about 55%
`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,
`sweetening agents, acidulants, coloring agents and the like
`may also be added.
`Boiled candy lozenges may also be prepared fiom non-
`ferrnentable 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 9.5:0.5 up to about
`75:25, 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 carbo