Oral drug delivery system

Abstract

An oral drug delivery system comprising a coated tablet having one or more surfaces. The coated tablet further comprises a core and a coating surrounding the core. The core comprises an active ingredient composition comprising at least one active ingredient and a pharmaceutically acceptable excipient and a swellable composition located in an immediate vicinity of one or more preselected surfaces. The coating comprises a defect wherein said defect is not a passageway through the preselected portion of the coating and operable to be reliably removed fully from the one or more of the preselected surfaces of the tablet upon contact with an aqueous environment, but not removed from at least one of the surfaces.

Claims

1. An orally administerable drug delivery system in the form of a coated tablet, having one or more surfaces, the coated tablet further comprising: (1) a core comprising one or more active ingredient composition layers and one or more separate swellable composition layers wherein; (i) the one or more active ingredient composition layers comprising a therapeutically active ingredient and at least one pharmaceutically acceptable excipient, wherein in at least one active ingredient composition layer, at least one pharmaceutically acceptable excipient is a rate controlling excipient and (ii) the swellable composition layer comprising a swellable composition; and (2) a water insoluble polymer coating surrounding the core wherein at least one preselected portion of the coating comprises a defect, and wherein said defect is not a passageway through the preselected portion of the coating wherein one or more of the swellable composition layers is located in an immediate vicinity of one or more preselected portions of the containing the defect in order to be in communication with said preselected portions of the coating, and the one or more therapeutically active ingredient composition layers are in the vicinity of another portion of the coating; and wherein the at least one or more preselected portion of the coating containing the defect that is in immediate vicinity of the swellable composition layer is removed after contact with an aqueous environment and wherein the remaining portion of the coating is not removed.

2. The orally administerable drug delivery system as claimed in claim 1, wherein the coating is impermeable to the pharmaceutically active ingredient.

3. The orally administerable drug delivery system as claimed in claim 1, wherein the therapeutically active ingredient in any one of the therapeutically active ingredient composition layers may be the same or different from the therapeutically active ingredient in any of the other active ingredient composition layers.

4. The orally administerable drug delivery system as claimed in claim 1, wherein the swellable composition comprises a swelling agent.

5. The orally administerable drug delivery system as claimed in claim 4, wherein the swelling agent is selected from a swellable excipient, a gas generating agent, or mixtures thereof.

6. The orally administerable drug delivery system as claimed in claim 1, wherein the swellable composition comprises one or more wicking agents.

7. The orally administerable drug delivery system as claimed in claim 1, wherein the swellable composition comprises one or more osmogents.

8. The orally administerable drug delivery system as claimed in claim 1, wherein the therapeutically active ingredient is released without a substantial delay after the tablet contacts the aqueous environment.

9. The orally administerable drug delivery system as claimed in claim 1, further comprising an outer coating including a pH-dependent polymer.

10. The orally administerable drug delivery system of claim 1, wherein the swellable composition layer is in the form of an in-lay.

11. The orally administerable drug delivery system of claim 1, wherein the defect is in the form of an indent, a tear, a cut, or an etching.

12. The orally administerable drug delivery system of claim 1, wherein the defect is in the form of a brittle portion, a thin portion, or a porous portion of the coating.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1 is a diagrammatic representation of an embodiment of the oral drug delivery system of the present invention wherein the coating has a passageway.

(2) FIG. 1(a) is a diagrammatic representation of an embodiment of the oral drug delivery system of the present invention comprising a core (1) comprising an active ingredient composition, which is surrounded by a coating (2) having a passageway (3) therein.

(3) FIG. 1(b) is a diagrammatic representation of the present invention comprising a core comprising an active ingredient composition (4) and a swellable composition (5), the core being surrounded by a coating (2) having a passageway (3) therein.

(4) FIG. 1(c) is a diagrammatic representation of the present invention comprising a core comprising an active ingredient composition (4) and two swellable compositions (5 & 6) on either side of the active ingredient composition, so as to form a trilayered core, the core being surrounded by a coating (2) having a passageway (3) therein. The swellable compositions may or may not comprise an active ingredient.

(5) FIG. 2 is a diagrammatic representation of an embodiment of the present invention wherein the coating does not have a passageway.

(6) FIG. 2(a) is a diagrammatic representation of one embodiment of the present invention comprising a core comprising an active ingredient composition (1) surrounded by a coating (2).

(7) FIG. 2(b) is a diagrammatic representation of one embodiment of the present invention comprising a core comprising an active ingredient composition (4) and a swellable composition (5), the core being surrounded by a coating (2).

(8) FIG. 2(c) is a diagrammatic representation of one embodiment of the present invention comprising a core comprising an active ingredient composition (4) and two swellable compositions (5 & 6) on either side of the active ingredient composition, so as to form a trilayered core, the core being surrounded by a coating (2). The swellable compositions may or may not comprise an active ingredient.

(9) Further embodiments of the oral drug delivery systems of the present invention are not all illustrated herein. For example, further embodiments wherein any of the systems illustrated in FIGS. 1 and 2 may be further surrounded by an outer coating of a pH-dependent polymer, are not represented herein.

(10) FIG. 3 is a graph showing percent drug (metoprolol) released versus time from formulations of Formulae I, II, III and IV of Example 1.

(11) FIG. 4 is a graph showing percent drug (bupropion) released versus time from formulation of Example 2.

(12) FIG. 5 is a graph showing percent drug (oxybutynin) released versus time from formulations of Examples 3 and 4.

(13) FIG. 6 is a diagrammatic representation of one embodiment of the present invention as described in Example 15,

(14) FIG. 6(a) shows the core indented with three break lines (3).

(15) FIG. 6(b) shows the coated core. The core has an active ingredient composition layer (1) and a swellable composition layer (2) and is surrounded by a coating (4).

(16) FIG. 6(c) shows the progressive rupturing of the coated tablet.

(17) FIG. 7 is a diagrammatic representation of one embodiment of the present invention as described in Example 16,

(18) FIG. 7(a) shows the core indented with a circular centrally placed indent (3).

(19) FIG. 7(b) shows the coated core. The core has an active ingredient composition layer (1) and a swellable composition layer (2) and is surrounded by a coating (4).

(20) FIG. 7(c) shows the progressive rupturing of the coated tablet.

(21) FIG. 8 is a diagrammatic representation of one embodiment of the present invention as described in Example 17.

(22) FIG. 8(a) shows the core with active ingredient composition layer (1) and swellable composition layer (2) with coating (4),

(23) FIG. 8(b) shows the coated core. The indent (3) is created on coating in the form of a partial cut with sharp blade.

(24) FIG. 8(c) shows the progressive rupturing of the coated tablet.

(25) FIG. 9 shows one embodiment of the present invention as described in Example 15.

(26) FIG. 9(a) is a copy of a photograph showing the coated core indented with three break lines, the progressive rupture of the coating upon contact with water is shown in FIG. 9 (b) at 4 min 58 seconds; figure (c) at 5 min 08 seconds; figure (d) at 5 min 15 seconds.

(27) FIG. 10 is a copy of a photograph showing one embodiment of the present invention as described in Example 16,

(28) FIG. 10 (a) shows the coated core indented with a circular centrally placed indent, the progressive rupture of the coating upon contact with water is shown in figure (b) at 15 seconds; figure (c) at 21 seconds; figure (d) at 29 seconds.

(29) FIG. 11 is a copy of a photograph showing one embodiment of the present invention as described in Example 17,

(30) FIG. 11 (a) shows the coated core having an indent in the form of a partial cut, the progressive rupture of the coating upon contact with water is shown in figure (b) at 2 min 22 seconds; figure (c) at 2 min 27 seconds; figure (d) at 2 min 38 seconds.

(31) FIG. 12 is a diagrammatic representation of one embodiment of the present invention as described in Example 18.

(32) FIG. 12(a) shows the coated core. The core has an active ingredient composition layer (1) and reactive composition layer (2) and is surrounded by a coating (3).

(33) FIG. 12(b) and FIG. 12(c) shows the progressive rupturing of the coated tablet.

(34) FIG. 13 is a diagrammatic representation of one embodiment of the present invention as described in Example 19.

(35) FIG. 13(a) shows the coated core. The core has an active ingredient composition layer (1) and reactive composition layer (2) and is surrounded by a coating (3).

(36) FIGS. 13(b) and 13(c) show the progressive rupturing of the coated tablet.

(37) FIG. 14 is a copy of a photograph showing one embodiment of the present invention as described in Example 18.

(38) FIG. 14(a) shows the coated core, the progressive rupture of the coating upon contact with the 0.01N HCl is shown in figure (b) at 20 min 04 seconds; figure (c) at 20 min 11 seconds; figure (d) at 23 min 46 seconds.

(39) FIG. 15 is a copy of a photograph showing one embodiment of the present invention as described in Example 19.

(40) FIG. 15(a) shows the coated core, the progressive rupture of the coating upon contact with the 0.01N HCl is shown in figure (b) at 32 min 41 seconds; figure (c) at 32 min 53 seconds; figure (d) at 34 min 24 seconds,

(41) Any of the embodiments illustrated herein are provided for the purpose of illustration only and are by no means meant to narrow the scope of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

(42) The present invention provides an oral drug delivery system comprising

(43) (a) a core comprising an active ingredient composition comprising at least one active ingredient and a pharmaceutically acceptable excipient, and

(44) (b) a coating surrounding the core,

(45) wherein the drug delivery system is designed in a manner such that the coating is reliably removed fully or partially from one or more preselected surfaces of the system upon contact with an aqueous environment, provided further that the coating is not removed from at least one of the surfaces.

(46) Accordingly, the coating is partially removed from the system but may be fully or partially removed from one or more preselected surfaces. Hereafter, unless it is specified that the coating is removed from a surface the use of the term partial removal of coating will refer to partial removal from the system.

(47) The term reliably as used herein means that the coating is removed from the preselected surfaces and does not rupture from any other non-selected weak point in the coating. In contrast, the prior art system of PCT publication no. WO 02/080887 teaches a system where the opening of the system occurs reliably in time i.e. at a predetermined time but the surface that would rupture is unpredictable; in the present invention the term reliably refers to the removal of coating from any one or more of a preselected surface. Further in contrast, the prior art system disclosed in U.S. Pat. Nos. 6,720,005 and 6,733,784 rupture mostly around the belly-band area only and do not allow pre-selection of any other surface.

(48) More particularly, the present invention provides an oral drug delivery system comprising (a) a core comprising an active ingredient composition comprising at least one active ingredient and a pharmaceutically acceptable excipient, and (b) a coating surrounding the core,
wherein the oral drug delivery system is in the form of a coated tablet and includes a feature such that the coating is removed partially or fully from one or more of the tablet surfaces upon contact with an aqueous environment, further wherein the feature is such that it enables the selection of any of the tablet surface or surfaces from which the coating is desired to be partially or fully removed, provided further that the coating is not removed from at least one of the surfaces.

(49) The oral drug delivery system of the present invention is designed such that the coating is removed fully or partially from a preselected surface or surfaces upon contact with an aqueous environment and not removed from at least one of the surfaces. The partial removal of the coating may be affected by several means and the features enabling the same may be features of the coating or the core, or both, operating cooperatively. For example, the system may be designed such that the coating is soluble or dissolved from one surface of the system, but not dissolved from the other surfaces of the system, thus becoming partially removed from the system. Alternatively, the oral drug delivery system may be designed such that the coating is ruptured and removed fully or partially from one or more preselected surfaces of the system upon contact with an aqueous environment. As used herein the term defective coating refers to coatings that are susceptible to rupture due to a weakness. The defective coating on the preselected surface may be made by creating a weakness in the coating by mechanical, chemical or electrical means, or by radiation, or by designing a brittle coating, or a thin coating, or a brittle and thin coating or a porous coating on the preselected surface or surfaces.

(50) The defect may also be instantly created on the preselected surface by leaching of components of the coating upon contact with the aqueous environment. The leachable components may be selected by a person of skill in the art from known water soluble substances and suitable amounts ordinarily determined by routine optimization. Accordingly in one preferred embodiment of the present invention, the coating comprises one or more water insoluble polymers, leachable components and other conventional coating additives such as plasticizers, colour and mixtures thereof and the like.

(51) Examples of leachable components that may be used include water soluble inorganic compounds and water soluble organic compounds. More specifically inorganic leachable compounds include, for example, sodium chloride, sodium bromide, sodium carbonate, potassium chloride, potassium sulfate, potassium phosphate, potassium nitrate, calcium phosphate, calcium nitrate, calcium chloride, and the like. More specifically, leachable organic compounds include, water soluble polymers such as water soluble cellulose polymers, polyols, for example polyhydric alcohol, polyalkylene polyglycol and the like. Organic compounds that may be used as leachable components also include glucose, sucrose, sorbitol, mannitol, lactitol, lactose, sodium benzoate, sodium acetate, sodium citrate, and the like.

(52) The defect may be in the form of an apparent fault such as an indent or a tear or a cut or an etching, which beginning from the outer surface of the coating may penetrate only partially through the coating or may penetrate completely to the inner surface of the coating so as to form a passageway.

(53) In other words, a skilled artisan would understand that no limitation should be read in the coating, and that the present invention includes cases where the coating may be defective or without any defect or a combination

(54) The core may be designed with a swellable or a reactive composition in the vicinity of the preselected surface. In preferred embodiments of the present invention, the core is swellable, and the coating is impermeable to the active ingredient and has a passageway therein. Upon contact with an aqueous environment, water permeates through the passageway, the core swells and the coating ruptures from the selected surface or surfaces that have one or more passageways. The reactive composition is reactive with the coating in that in the presence of ingredients released from the reactive composition, the coat in the vicinity dissolves, disintegrates, or is weakened. For example a reactive composition comprising ethanol microencapsulated with a water soluble coat will release ethanol on imbibing of water into the core by the system and the ethanol in turn will dissolve ethylcellulose containing not less than 46.5% of ethoxy groups present as component of the coating thereby weakening and removing the coating.

(55) The coating surrounding the core of the oral drug delivery system of the present invention is preferably impermeable to the active ingredient, and has a passageway therein. In one preferred embodiment of the coating with a passageway, the coating is made up of water-insoluble polymers that may be selected from ethyl cellulose, hydrophobic methacrylic acid derivatives and the like, and mixtures thereof. Preselected one or more surfaces of the coating are then provided with a mechanically or laser-drilled passageway, and cause the core to partially remove the coating, thereby exposing a portion of the core for the release of the active ingredient contained therein. In more preferred embodiments of the present invention wherein the coating has a passageway, the oral drug delivery system is in the form of a tablet. The passageways in the coating may be provided on one or more preselected surfaces of the tablet, such that when water from the surrounding environment enters the tablet through the passageway, the core causes partial removal of the coating from the preselected surfaces, thereby exposing a defined surface area for release of the active ingredient. In preferred embodiments the core has components that are swellable or reactive to the coating.

(56) Embodiments of the present invention provide an oral drug delivery system comprising

(57) a. a core comprising an active ingredient composition comprising at least one active ingredient and pharmaceutically acceptable excipients, and

(58) b. a coating surrounding the core,

(59) wherein the oral drug delivery system has at least two surfaces and is designed in a manner such that the coating is removed fully or partially from one of the surfaces when the oral drug delivery system contacts an aqueous environment and further wherein the coating is removed from the surface different from the one having the least surface area. The oral drug delivery systems of the present invention provide benefit over prior art systems which do not provide a flexibility in choice of the surface from which the coating can be removed, and generally expose the surface with the lower surface area.

(60) Specific embodiments of the present invention also provide aforesaid oral drug delivery system, which release the drug without a substantial delay after the oral drug delivery system contacts an aqueous environment. The term without a substantial delay as used herein means that the active ingredient release is initiated from the controlled drug delivery system of the present invention within 0 to 60 minutes from the time the core contacts an aqueous environment, preferably within 0 to 20 minutes, and most preferably within 0 to 5 minutes.

(61) In one embodiment of the present invention, the active ingredient composition is a swellable composition comprising at least one active ingredient and a swelling agent. In another embodiment of the present invention, the core comprises active ingredient composition and swellable composition, which may be present as one or more layers. The active ingredient present in these layers may be the same or different.

(62) in one embodiment of the present invention the active ingredient is isolated from its environment by providing an oral drug delivery system comprising

(63) a. a core comprising the active ingredient and pharmaceutically acceptable excipients, and

(64) b. a coating surrounding the core,

(65) wherein the system has a feature such that upon contact with an aqueous environment the coating ruptures to provide instant and rapid release of the active ingredient. Such systems are useful for active ingredients that are bitter in taste, or active ingredients that irritate the mucosal surface. Also, the system is useful for active ingredients that need to be protected from being degraded by contact with fluids from the surrounding environment.

(66) The partial removal of the coating may also be affected by including a composition comprising gas generating agents in the core, such that when the coating contacts an aqueous environment, the gas generating agents release gas, generating pressure that causes the coating to be removed partially. Preferably, the swellable composition may comprise a mixture of swellable excipients and gas generating agents, the mixture being designed with types and amounts of components selected so as to cause the removal of the coating and initiation of release without a substantial delay or to cause a predetermined period of delay.

(67) The swellable composition used in oral drug delivery system of the present invention comprises a swellable agent that may be selected from a group comprising a swellable excipient, a gas generating agent, and mixtures thereof. The swelling agent is generally used in an amount ranging from about 0.5% to about 95% by weight of the swellable composition. The swellable excipient that may be used may be a highly swellable excipient selected from vinylpyrrolidone polymers such as crospovidone; cellulose and cellulose derivatives such as carboxyalkyl celluloses, crosslinked carboxyalkylcelluloses and their alkali salts; sodium starch glycolate, starch and starch derivatives, resins and mixtures thereof. The highly swellable excipient is preferably used in an amount ranging from about 2% to about 35% by weight of the swellable composition. The swellable excipient that may be used may be a moderately swellable excipient and may be used in an amount ranging from about 5% to about 70% by weight of the swellable composition, preferably about 50% to about 70% by weight of the swellable composition. Gas generating agents that may be used in the present invention include carbonates such as calcium carbonate, bicarbonates such as sodium or potassium bicarbonate, sulfites such as sodium sulfite, sodium bisulfite, or sodium metabisulfite, and the like. These salts may be used alone or in combination with an acid source as a gas generating couple. The acid source may be an edible organic acid, a salt of an edible organic acid, acidic components such as acrylate polymers, or mixtures thereof. Examples of organic acids that may be used include citric acid, malic acid, succinic acid, tartaric acid, fumaric acid, maleic acid, ascorbic acid, glutamic acid, and their salts, and mixtures thereof.

(68) The swellable composition may further comprise a wicking agent in an amount ranging from about 0.5% to about 10% by weight of the swellable composition. Examples of wicking agents that may be used include, but are not limited to, colloidal silicon dioxide, kaolin, titanium dioxide, fumed silicon dioxide, alumina, niacinamide, sodium lauryl sulfate, low molecular weight polyvinylpyrrolidone, m-pyrol, bentonite, magnesium aluminum silicate, polyester, polyethylene. Preferably, the wicking agents used in the pharmaceutical composition of the present invention include cellulose and cellulose derivatives, colloidal silicon dioxide, and mixtures thereof.

(69) The swellable composition may also comprise osmogents in an amount ranging from about 0.5% to about 10% by weight of the swellable composition. Examples of osmogents that may be used include, but are not limited to, inorganic salts such as magnesium chloride or magnesium sulfate, lithium, sodium or potassium chloride, lithium, sodium or potassium hydrogen phosphate, lithium, sodium or potassium dihydrogen phosphate, salts of organic acids such as sodium or potassium acetate, magnesium succinate, sodium benzoate, sodium citrate or sodium ascorbate; carbohydrates such as mannitol, sorbitol, arabinose, ribose, xylose, glucose, fructose, mannose, galactose, sucrose, maltose, lactose, raffinose; water-soluble amino acids such as glycine, leucine, alanine, or methionine; urea and the like; osmopolymers selected from the group consisting of poly(hydroxyalkyl methacrylate) having a molecular weight of 20,000 to 5,000,000; poly (vinylpyrrolidone) having a molecular weight of about 10,000 to 360,000; poly(vinyl alcohol) having a low acetate content and lightly crosslinked with glyoxal, formaldehyde, glutaraldehyde and having a degree of polymerization from 2,000 to 30,000; poly(ethylene oxide) having a molecular weight from 10,000 to 7,8000,000; acidic carboxy polymers known as carboxypolymethylene or as carboxyvinyl polymers, a polymer consisting of acrylic acid lightly cross-linked with polyallylsucrose and sold under the trademark Carbopol, acidic carboxy polymer having a molecular weight of 200,000 to 6,000,000, including sodium acidic carboxyvinyl hydrogel and potassium acidic carboxyvinyl hydrogel; Cyanamer polyacrylamide; and the like, and mixtures thereof.

(70) In one embodiment of the present invention, the coating surrounding the core is semipermeable in nature and may be obtained by using water-insoluble agents like cellulose derivatives such as cellulose acetate, ethyl cellulose and the like, in admixture with a sufficient amount of one or more water-soluble polymers selected from methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone and mixtures thereof, such that the properties of the semipermeable coating are modified, thereby allowing the coating to be removed partially upon contact with an aqueous environment. The coating does not have any passageway therein. The term semipermeable as used herein to describe a coating refers to a coating which is permeable to water or ions but not permeable to an active ingredient. The coating being semipermeable in nature allows water from the surrounding environment to enter the system, thereby causing the core to remove the coating partially so as to expose a defined surface area for release of the active ingredient. In a preferred embodiment of the present invention, a mixture of a water-soluble polymer and a water-insoluble polymer is used to obtain the coating. For example, a mixture of ethyl cellulose and hydroxypropyl methylcellulose, or a mixture of ethyl cellulose and polyvinylpyrrolidone, may be used to obtain the coating. In embodiments where the coating does not have a passageway, the oral drug delivery system may be coated to a weight gain in the range of about 2% to about 6.5% by weight of the core, such that the active ingredient is released without a substantial delay or may be coated to higher percentage for designing a programmed delay of release into the system. When release without a substantial delay is desired it is preferable that the coating have a passageway. In these embodiments, the release without a substantial delay is obtained more easily and a wide range of coating weights may be used.

(71) The water soluble polymer in the semipermeable coating of this embodiment may alternatively be replaced by other leachable components or alternatively a mixture of water soluble polymer and other leachable components may be present.

(72) The dry weight ratio of the water insoluble polymer to the leachable component ranges from about 10:90 to about 90:10; more preferably from about 60:40 to about 40:60 and most preferably from about 70:30 to about 95:5. Examples of water insoluble polymers are known to a person of skill in the art and are available commercially. For example, water insoluble polymers that may be used include, but are not limited to, ethyl cellulose, cellulose acetate, polyvinyl acetate, nitrocellulose, butadiene styrene copolymers, and water insoluble methacrylate copolymers. Preferably, the water insoluble polymer is selected from the group consisting of ethyl cellulose, poly(ethyl acrylate, methyl rnethacrylate, triethylammonioethyl methacrylate chloride) such as, for example, those commercially available under the trade names Eudragit RS100, Eudragit RS PO, Eudragit RS 30D and Eudragit RS 12.5 and poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride such as those commercially available under the trade names Eudragit RL100, Eudragit RL PO, Eudragit RL 30D and Eudragit RL 12.5. Examples of water insoluble polymers that are insoluble below a pH of about 4.0 but soluble at pH above 7.0 include poly(methacrylic acid, methyl methacrylate such as for example, those commercially available under the tradenames Eudragit L 100, Eudragit 12.5, Eudragit 12.5 P), Poly(methacrylic acid, ethyl acrylate) such as those commercially available under the trade names Eudragit L 30 D-55, Eudragit L 100-55, Eastacryl 30 D, Kollicoat MAE 30 D and Kollicoat MAE 30 DP) and poly(methacrylic acid, methyl methacrylate) such as those commercially available under the trade names Eudragit S 100, Eudragit S 12.5, Eudragit S 12.5 P), cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate and the like and mixture thereof.

(73) According to this embodiment of the present invention with a leachable component in the coating, the coating is applied to the core of the tablet to a weight gain of about 5% to about 20% by weight of the core, preferably from about 8% to about 18% by weight of the core tablet.

(74) According to the present invention, the coating comprises one or more plasticizers. The plasticizers may be those that are conventionally used in the pharmaceutical art. These may be hydrophilic or hydrophobic in nature. Examples of hydrophilic plasticizer that may be used in the coating, include, but are not limited to, triethyl citrate, triethyl acetyl citrate, triacetin, tributyl citrate, polyethylene glycol 6000, polysorbate 80, glycerol and the like and mixtures thereof. Examples of hydrophobic plasticizer that may be used in the coating include, but are not limited to, dibutyl sebacate, diethyl sebacate, diethyl phthalate, vegetable and mineral oil, glyceryl tributyrate and the like and mixtures thereof. More preferably, the plasticizer is a mixture of hydrophobic and hydrophilic plasticizers. In a particular embodiment wherein the coating comprises ethyl cellulose as the water insoluble polymer, the hydrophobic plasticizer is dibutyl sebacate and the hydrophilic plasticizer is triethyl citrate, preferably in the ratio of about 5:1. More particularly, the percent of dibutyl sebacate by weight of ethyl cellulose is about 5% and the percent of triethyl citrate is about 25% by weight of ethyl cellulose.

(75) According to this embodiment of the present invention with a leachable component in the coating, upon contact with the aqueous environment, the leachable component(s) in the coating of the oral drug delivery system dissolves to form a micro porous coating. Water permeates through the coating and interacts with the swellable or reactive composition. Upon imbibing water, the swellable composition or the reactive composition swells or reacts causing the coating on the surface in its immediate vicinity to be removed. The active ingredient composition layer is exposed to the aqueous environment. A control on the release of the active ingredient may be obtained by designing into the system an exposure to aqueous environment by removal of the coating from only a very limited surface area. The coating is removed only from the preselected surface or surfaces without a substantial delay.

(76) In one embodiment of the present invention, the core comprises an active ingredient composition comprising at least one active ingredient and pharmaceutically acceptable excipients. In another embodiment of the present invention, the active ingredient composition is a swellable composition comprising at least one active ingredient, and a swelling agent. In yet another embodiment of the present invention, the core comprises an active ingredient composition and swellable composition, which may both be present as one or more layers. The active ingredient present in these layers may be the same or different. Each of these embodiments comprises a coating surrounding the core, which is semipermeable in nature, and does not have any passageway.

(77) The oral drug delivery system of the present invention may be designed to release the active ingredient contained therein in a controlled manner, or it may be designed to provide instant and rapid release of the active ingredient similar to uncoated conventional dosage forms while providing the desirable protection of the coating. Accordingly, the core of the oral drug delivery system comprises pharmaceutically acceptable excipients that govern the rate of release of the active ingredient from the core. The pharmaceutical excipients are selected so as to provide a conventional release, or controlled release, preferably zero-order release of the active ingredient.

(78) In one embodiment of the present invention, the oral drug delivery system is designed to release the active ingredient in a controlled manner. The active ingredient composition therefore comprises rate controlling excipients that may be selected from hydrophilic polymers such as methyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl methylcellulose, carboxymethylcellulose and sodium carboxymethylcellulose; hydrophobic compounds such as ethyl cellulose, glycerol palmitostearate, beeswax, glycowax, castor wax, carnauba wax, glycerol monostearate, stearyl alcohol, glycerol behenic acid ester, cetyl alcohol, natural and synthetic glycerides, waxes, fatty acids, hydrophobic polyacrylamide derivatives, hydrophobic methacrylic acid derivatives; vinyl pyrrolidone polymers such as polyvinylpyrrolidone and copolymers of vinyl pyrrolidone and vinyl acetate; alkylene oxide homopolymers; gums of plant, animal, mineral or synthetic origin; and mixtures thereof. The active ingredient composition may comprise one or more of the rate controlling excipients mentioned above in an amount ranging from about 2% to about 90% by weight of the core; the specific amounts and type may be selected to either not cause a substantial delay in the initiation of release or to provide a programmed delay in the initiation of release.

(79) The active ingredient composition used in the core of the controlled drug delivery system of the present invention comprises one or more active ingredient, rate controlling excipients and other pharmaceutically acceptable excipients. Drugs that may be used in the pharmaceutical composition of the present invention may be selected from the following, viz. alcohol abuse preparations, drugs used for Alzheimer's disease, anesthetics, acromegaly agents, analgesics, antiasthmatics, anticancer agents, anticoagulants and antithrombotic agents, anticonvulsants, antidiabetics antiemetics, antiglaucoma, antihistamines, anti-infective agents, antiparkinsons, antiplatelet agents, antirheumatic agents, antispasmodics and anticholinergic agents, antitussives, carbonic anhydrase inhibitors, cardiovascular agents, cholinesterase inhibitors, treatment of CNS disorders, CNS stimulants, contraceptives, cystic fibrosis management, dopamine receptor agonists, endometriosis management, erectile dysfunction therapy, fertility agents, gastrointestinal agents, immunomodulators and immunosuppressives, memory enhancers, migraine preparations, muscle relaxants, nucleoside analogues, osteoporosis management, parasympathomimetics, prostaglandins, psychotherapeutic agents, sedatives, hypnotics and tranquilizers, drugs used for skin ailments, steroids and hormones.

(80) In one embodiment of the present invention, the core comprises

(81) a. a first layer of active ingredient composition

(82) b. a second layer of active ingredient composition, and

(83) c. a third layer of a swellable composition,

(84) wherein the active ingredient compositions of the first and second layer may comprise active ingredients that are same or different, and the swellable composition comprises a swelling agent, and may or may not comprise an active ingredient.

(85) In one embodiment of the present invention, the swellable composition is present as an in-lay tablet in a core comprising the active ingredient composition. The term in-lay tablet is well known in the art, see for example, Lieberman H. A. et al., Pharmaceutical Dosage Forms: Tablets, Volume 1, Second Edition revised and expanded, Marcel Dekker, Page 273, 1989. The core with the in-lay tablet is coated with an impermeable coating having a passageway on the surface immediately above the swellable composition. The swellable composition ruptures the coat upon contact with aqueous environment, thereby exposing a defined surface area. The active ingredient is then released from the exposed surface.

(86) In another embodiment of the present invention, the core is compressed into a bilayer tablet; the first layer comprising the active ingredient composition having uninterrupted plain surfaces surrounded by coating or the second layer; and the second layer comprising the swellable composition having at least one surface interrupted by at least one depression or cavity. The coating used in this embodiment is semipermeable in nature and the water entering the system causes the coating to be removed from the surface having the depression or cavity.

(87) In some embodiments of the present invention, any of the aforesaid oral drug delivery systems may be further coated with an outer pH-dependent coating that partially or completely covers the inner coating, which immediately surrounds the core. An intermediate seal coating may be provided between the inner coating and the outer pH-dependent coating. pH-dependent polymers commonly used in the art may be used to provide the outer coating.

(88) The examples that follow do not limit the scope of the invention and are merely used as illustrations.

EXAMPLES

Example 1

(89) Oral drug delivery systems comprising metoprolol succinate were obtained as per the present invention, as detailed in Table 1 below.

(90) TABLE-US-00001 TABLE 1 Quantity (mg/tablet) Ingredients I II III IV First layer Metoprolol succinate 35.625 47.5 47.5 47.5 Hydroxypropyl methylcellulose 15.0 20.0 (HPMC K15M) Hydroxypropyl methylcellulose 20.0 (HPMC K100M) Polyvinylpyrrolidone (PVP K30) 7.5 10.0 10.0 10.4 Lactitol monohydrate 15.0 20.0 20.0 Microcrystalline cellulose 44.5 Hydroxypropyl methylcellulose 10.0 (HPMC E50LV) Sodium starch glycolate 15.0 20.0 20.0 Colloidal silicon dioxide 0.375 0.5 0.5 1.2 Talc 1.125 1.5 1.5 1.7 Magnesium stearate 1.125 1.5 1.5 1.7 Aquacoat ECD 30 (solids) 18.0 Second layer Metoprolol succinate 11.875 Silicified microcrystalline 20.0 34.32 34.32 34.32 cellulose (Prosolv SMCC 90) Crospovidone 12.18 12.18 12.18 Colloidal silicon dioxide 0.75 1.22 1.22 1.22 Sodium bicarbonate 4.0 Eudragit L-100-55 12.0 Mannitol SD 200 20.0 Sodium lauryl sulphate 0.375 0.48 0.48 0.48 Magnesium stearate 2.0 0.5 0.5 0.5 Talc 2.0 0.12 0.12 0.12 Colour q.s. q.s. q.s. q.s. Coating Ethyl cellulose (as aqueous Coated Coated Coated Coated dispersion Aquacoat ECD 30) to a to a to a to a Dibutyl sebacate weight weight weight weight Triethyl citrate gain of gain of gain of gain of 8% by 15% by 15% by 15% by weight weight weight weight of the of the of the of the core core core core

(91) The oral drug delivery systems of Formulae I, II, III, and IV were made as follows: Metoprolol succinate, lactitol monohydrate and povidone K-30 were passed through ASTM (American Society for Testing and Materials) sieve 40 and mixed suitably. The mixture thus obtained was granulated with purified water to a suitable end-point, and the granules obtained were dried to a moisture content of about 1-2%. The dried granules were milled suitably and lubricated with a mixture of sodium starch glycolate, colloidal silicon dioxide, talc, and magnesium stearate, to obtain the blend for the first layer.

(92) Silicified microcrystalline cellulose, crospovidone, sodium lauryl sulfate and a suitable colour were passed through ASTM sieve #40 and mixed suitably. The blend so obtained was lubricated with a mixture of colloidal silicon dioxide and magnesium stearate (previously passed through ASTM sieve #60). In case of the system of Formula I, the blend also included metoprolol succinate, Eudragit L-100-55, sodium bicarbonate, and Mannitol in amounts mentioned above.

(93) The above two preparations were compressed to obtain bilayer tablets, which were coated with an aqueous dispersion of ethyl cellulose to a suitable weight gain. An orifice was then drilled on one side of the tablet.

(94) The tablets thus obtained were subjected to dissolution testing. Tablets of Formula I were tested using United States Pharmacopoeia dissolution apparatus, type II, using 500 ml of 0.01N HCl as the dissolution medium, at 100 rpm. Tablets of Formulae II, III and IV were tested using United States Pharmacopoeia dissolution apparatus, type II, using 500 ml of pH 6.8 buffer as the dissolution medium, at 50 rpm. The results of the dissolution test are recorded in Table 2 below.

(95) TABLE-US-00002 TABLE 2 Percent Drug Released Time (hours) Formula I Formula II Formula III Formula IV 0.25 18 0.5 21 1.0 24 6 5 8 2.0 31 12 11 13 4.0 51 24 21 23 8.0 84 46 39 37 12.0 96 64 55 49 16.0 84 71 58 20.0 99 85 67

(96) The release from the controlled release layer of all the four systems was zero-order, i.e. linear over time (regression co-efficient r.sup.2 being 0.9697, 0.9959, 0.9966 and 0.9816 for Formula I, II III and IV, respectively).

Example 2

(97) A control led release pharmaceutical composition of bupropion hydrochloride was obtained as per the present invention, as detailed in Table 3 below.

(98) TABLE-US-00003 TABLE 3 Quantity Percent by Ingredients (mg/tab) weight First Layer Bupropion hydrochloride 150.0 37.5 Hydroxypropyl methylcellulose (HPMC 20.00 5.0 K100M Premium) Lactose anhydrous (DCL 21) 177.0 44.25 Polyvinylpyrrolidone (PVP K-30) 13.0 3.25 Colloidal silicon dioxide 4.0 1.00 Stearic acid 12.0 3.00 Talc 4.00 1.00 Sodium starch glycolate 20.00 5.0 Second layer Silicified microcrystalline cellulose (Prosolv 205.0 70.7 SMCC 90) Crospovidone 72.5 25.0 Colloidal silicon dioxide 7.2 2.5 Sodium lauryl sulphate 2.90 1.0 Magnesium stearate 2.4 0.83 Colour q.s. Coating Ethyl cellulose (as aqueous dispersion Coated to 14% by weight of Aquacoat) the core tablet Dibutyl sebacate

(99) Bupropion hydrochloride, HPMC K100M lactose anhydrous, PYP K-30 and colloidal silicon dioxide were passed through ASTM sieve #40 and mixed thoroughly. Stearic acid and talc were passed through ASTM sieve #60 and mixed with the blend, to obtain the composition of the first layer.

(100) Prosolv SMCC 90, colloidal silicon dioxide, sodium lauryl sulfate, crospovidone, and colour were passed through ASTM sieve #40 and mixed thoroughly to obtain a blend. This blend was lubricated with magnesium stearate, to obtain the composition of the second layer.

(101) The two compositions were compressed using standard concave punches to obtain bilayer tablets. The compressed tablets were coated with the coating composition to a weight gain of about 14% by weight of the core. An orifice was drilled on the side of the tablet that contained the second layer, i.e. the layer without bupropion hydrochloride.

(102) The tablets thus obtained were subjected to dissolution testing using United States Pharmacopoeia dissolution apparatus, type II, using 900 ml of water as the dissolution medium, at 50 rpm. The results of the dissolution test are tabulated in Table 4 below. The release was zero-order. i.e. linear over time (regression co-efficient r.sup.2=0.97).

(103) TABLE-US-00004 TABLE 4 Time (hours) % Drug Released 1 6 2 13 3 18 4 22 6 31 8 37 10 43 12 49 16 56 20 67 24 74

Example 3

(104) A controlled release pharmaceutical composition of oxybutynin chloride was obtained as per the present invention, as detailed in Table 5 below.

(105) TABLE-US-00005 TABLE 5 Quantity Percent by Ingredients (mg/tab) weight First Layer Oxybutynin chloride 3.75 5.36 Silicified microcrystalline cellulose (Prosolv 46.64 66.62 SMCC 90) Colloidal silicon dioxide 1.65 2.35 Crospovidone 16.56 23.65 Sodium lauryl sulphate 0.66 0.94 Colour 0.198 0.28 Magnesium stearate 0.53 0.76 Second layer Oxybutynin chloride 7.50 6.0 Hydroxypropyl methylcellulose (HPMC 20.0 16.0 K4M) Lactitol monohydrate 40.0 32.0 Citric acid, anhydrous 2.50 2.0 Microcrystalline cellulose (Avicel PH 102) 33.0 26.4 Sodium starch glycolate 20.0 16.0 Talc 1.00 0.8 Magnesium stearate 1.00 0.8 Coating Ethyl cellulose (as aqueous dispersion Coated to about 14% by Aquacoat) weight of the core tablet Dibutyl sebacate Triethyl citrate

(106) The bilayered tablet was made as follows. Oxybutynin chloride was mixed with Prosolv SMCC 90, colloidal silicon dioxide, crospovidone, sodium lauryl sulfate, colour and magnesium stearate to obtain a first layer composition. The second layer composition was obtained by blending together a mixture of oxybutynin chloride, HPMC K4M, lactitol monohydrate and citric acid. The mixture was granulated using purified water and the granules so obtained were lubricated with a mixture of microcrystalline cellulose, sodium starch glycolate, talc, and magnesium stearate. The first and second layer compositions were then compressed to obtain the bilayered tablets, which were then coated with a coating composition comprising aquacoat, dibutyl sebacate and triethyl citrate to a weight gain of about 14% by weight of the core tablet.

(107) The tablets thus obtained were subjected to dissolution testing using United States Pharmacopoeia dissolution apparatus, type II, using 900 ml of pH 4.5 buffer as the dissolution medium, at 100 rpm. The results of the dissolution test are recorded in Table 6 below. The release from the controlled release layer was zero-order, i.e. linear over time (regression co-efficient r.sup.2=0.9904).

(108) TABLE-US-00006 TABLE 6 Time (hours) % Drug Released 0.5 25 1 30 2 34 4 41 6 46 8 51 12 61 16 69 20 77 24 83

Example 4

(109) A trilayered oral drug delivery system comprising oxybutynin chloride was obtained as per Table 7 below.

(110) TABLE-US-00007 TABLE 7 Quantity Percent by Ingredients (mg/tablet) weight First layer Oxybutynin chloride 3.75 5.36 Silicified microcrystalline cellulose (Prosolv 46.64 66.62 SMCC 90) Colloidal silicon dioxide 1.65 2.35 Crospovidone 16.56 23.65 Sodium lauryl sulphate 0.66 0.94 Colour 0.198 0.28 Magnesium stearate 0.53 0.76 Second layer Oxybutynin chloride 7.50 6.0 Hydroxypropyl methylcellulose (HPMC K4M) 20.0 16.0 Lactitol monohydrate 40.0 32.0 Citric acid, anhydrous 2.50 2.0 Microcrystalline cellulose (Avicel PH 102) 33.0 26.4 Sodium starch glycolate 20.0 16.0 Talc 1.00 0.8 Magnesium stearate 1.0 0.8 Third layer Oxybutynin chloride 3.75 5.36 Silicified microcrystalline cellulose (Prosolv 46.64 66.62 SMCC 90) Colloidal silicon dioxide 1.65 2.35 Crospovidone 16.56 23.65 Sodium lauryl sulphate 0.66 0.94 Colour 0.198 0.28 Magnesium stearate 0.53 0.76 Coating Ethyl cellulose (as aqueous dispersion Coated to about 14% by Aquacoat) weight of the core tablet Dibutyl sebacate Triethyl citrate

(111) The three layers were obtained as mentioned in examples above and compressed to obtain the core, which was then coated with the coating solution to a weight gain of about 14% by weight of the core. An orifice of size 400 microns was drilled on one planar surface of the tablet.

(112) The trilayered tablets thus obtained were subjected to dissolution testing using United States Pharmacopoeia dissolution apparatus, type II, using 900 ml of pH 4.5 buffer as the dissolution medium, at a speed of 100 rpm. The results of the dissolution testing are recorded in Table 8 below.

(113) TABLE-US-00008 TABLE 8 Time (hours) % Drug Released 0.5 28 1 36 2 51 4 63 6 70 8 73 12 78 16 82 20 86 24 88

Example 510

(114) The ingredients of the active ingredient composition and the swellable composition are tabulated in Table 9. The bilayer core having active ingredient composition layer and the swellable composition layer was made according to the process as described in Example 1.

(115) TABLE-US-00009 TABLE 9 % by weight of the mg per active ingredient Ingredients tablet composition Active ingredient composition layer Metoprolor Succinate 11.875 20.47 Hydroxypropyl methyl cellulose K100M 20.0 34.481 Hydroxypropyl methyl cellulose K4M 7.0 12.06 Lactose 76.125 79.52 Povidone 10.0 17.24 Methacrylic acid copolymer type C 10.0 17.24 Colloidal Silicon Dioxide 2.0 3.44 Talc 2.5 4.31 Magnesium Stearate 2.5 4.31 Total 58 mg % by weight of Mg per the swellable Ingredients tablet composition Swellable Composition Layer Silicified microcrystalline cellulose 46.4 32.67 Colloidal silicon dioxide 1.45 1.02 Crospovidone 8.7 6.126 Sodium lauryl sulphate 0.58 0.40 Red Oxide of Iron 0.116 0.08 Magnesium stearate 0.609 0.428 Talc 0.145 0.102 Total 142

(116) The bilayer core prepared according to composition of table 9 was coated with the coating compositions tabulated in Table 10 to give coated tablets of Examples 5-10. The coating compositions include leachable components such as mannitol, lactitol monohydrate, lactose, polyvinyl pyrrolidone, sodium lauryl sulphate, triethyl citrate, and polysorbate 20.

(117) TABLE-US-00010 TABLE 10 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Ingredients mg per tablet Bilayer core As in table 9 As in table 9 As in table 9 As in table 9 As in table 9 As in table 9 Coating composition *Ethyl cellulose 8.51 9.40 10.25 11.078 10.44 10.449 *Cetyl alcohol 0.3154 0.3487 0.3799 0.4103 0.348 0.348 *Sodium lauryl 0.63 0.69 0.7532 0.8206 0.696 0.696 sulphate mannitol 3.04 1.88 0.91 lactose 1.88 Lactol 1.88 monohydrate Polyvinyl 0.61 0.47 0.23 0.47 0.47 pyrrolidone Polysorbate 20 0.05 0.05 0.05 0.05 0.05 Triethyl citrate 0.47 0.52 0.57 0.62 0.52 0.52 Dibutyl Sebacate 2.37 2.62 2.85 3.08 2.62 2.62 Ratio of Water 63.8:36.2 74.52:25.5 80.31:19.69 94.69:5.3 74.39:26.60 insoluble:Water soluble % weight gain 8% Orifice Drilled no yes Opening time in 3-6 5-6 60 1 12-27 4-8 dissolution bath (pH 6.8 buffer in minutes) *applied in the form of Aquacoat ECD 30 which is an aqueous dispersion containing ethyl cellulose (27% w/v), sodium lauryl sulphate 1% w/w and cetyl alcohol 2% w/v in water

Example 11-13

(118) The bilayer core comprising an active ingredient composition layer and the swellable composition layer having the ingredients as given in table 11, are prepared according to the process as described in Example 1.

(119) TABLE-US-00011 TABLE 11 % by weight of the mg per active ingredient Ingredients tablet composition Active ingredient composition layer Venlafaxine hydrochloride 169.710 34.77 Hydroxypropyl methyl cellulose K4M 36.00 7.37 Polyvinyl pyrrolidone 40.00 8.19 Lactose monohydrate 176.290 36.125 Eudragit L100 55 60.0 12.2 Talc 3.0 0.61 Magnesium stearate 3.0 0.61 % by weight of mg per the swellable Ingredients tablet composition Swellable Composition Layer Silicified microcrystalline cellulose 113.116 34.77 Colloidal silicon dioxide 3.550 2.54 Crospovidone 21.3000 15.0 Sodium lauryl sulphate 1.420 1.0 FD & C Blue No. 1 Aluminum lake 0.568 0.4 Magnesium stearate 1.491 1.05 Talc 0.355 0.25

(120) The bilayer core is then coated with the coating composition, details of which are given in table 12. The coating composition comprises a combination of leachable components such as sodium lauryl sulphate, triethyl citrate, and polyvinyl pyrrolidone.

(121) TABLE-US-00012 TABLE 12 Example 11 Example 12 Example 13 Ingredients Mg per tablet Bilayer Core As in As in As in table 11 table 11 table 11 Coating composition *Ethyl cellulose 23.03 20.81 23.03 *Cetyl alcohol 0.85 0.77 0.85 *Sodium lauryl sulphate 1.7 1.54 1.7 Triethyl citrate 1.28 1.16 1.28 Dibutyl sebacate 6.40 5.78 6.40 Polyvinyl pyrrolidone 5.76 mannitol 8.92 Sucrose 5.76 Ratio of insoluble:soluble 74.48:25.51 64.168:35.83 72.48:27.51 % weight gain 8 10 8 Time of opening of the 45-50 20 90 tablet (in minutes) *applied in the form of Aquacoat ECD 30 which is an aqueous dispersion containing ethyl cellulose (27% w/v), sodium lauryl sulphate 1% w/w and cetyl alcohol 2% w/v in water

Example 14

(122) The active ingredient composition layer and the swellable composition layer having the ingredients given in table 13 were prepared by a process as described in the Example 1. The bilayer core was then coated with a coating composition having ethyl cellulose as water insoluble polymer and leachable components which is a mixture of sodium lauryl sulphate, triethyl citrate, hydroxypropyl methyl cellulose low viscosity, polyethylene glycol 400, and polyethylene glycol 8000.

(123) TABLE-US-00013 TABLE 13 % by weight of the mg per active ingredient Ingredients tablet composition Active ingredient composition layer Metoprolol Succinate 47.50 32.53 Hydroxypropyl methyl cellulose K100M 20.0 13.69 Lactose directly compressible 40.50 27.73 Polyvinyl pyrrolidone 10.0 6.85 Eudragit L-100 55 10.0 6.85 Aerosil 0.50 0.34 Talc 1.25 0.85 Magnesium stearate 1.25 0.85 % by weight of Mg per the swellable Ingredients tablet composition Swellable Composition Layer Silicified microcrystalline cellulose 63.042 79.80 Colloidal silicon dioxide 1.975 2.50 Crospovidone 11.85 15.0 Sodium lauryl sulphate 0.79 1.00 FD & C Blue No. 1 Aluminum lake 0.316 0.4 Magnesium stearate 0.9875 1.25 Talc 0.1975 0.25 Coating Composition Mg per tablet *Ethyl Cellulose 10.12 *Cetyl Alcohol 0.37 *Sodium lauryl sulphate 0.74 Triethyl citrate 0.56 Dibutyl sebacate 2.81 Hydroxypropyl methyl cellulose 3.07 Polyethylene glycol 400 0.153 Polyethylene glycol 8000 0.153 % weight gain 8 Ratio of insoluble:soluble 68.39:31.60 Time of opening of the tablet (in mins) 13-25 *applied in the form of Aquacoat ECD 30 which is an aqueous dispersion containing ethyl cellulose (27% w/v), sodium lauryl sulphate 1% w/w and cetyl alcohol 2% w/v in water

Example 15

(124) This example illustrates an embodiment of the present invention wherein the defect is created by applying the coating on a core that is indented with break lines. The defect formed is not a passageway through the preselected portion of the coating.

(125) The ingredients of the active ingredient composition and the swellable composition are given in Table 14. The bilayer core having active ingredient composition layer and the swellable composition layer were made according to the process as described in below.

(126) TABLE-US-00014 TABLE 14 Bilayer Core Composition Percent by weight of Quantity the active ingredient Ingredients (kg/Batch) composition layer Active ingredient composition layer Venlafaxine Hydrochloride 11.05 36.60 Hydroxypropyl methylcellulose 2.15 7.10 Lactose 11.38 37.70 Polyvinyl pyrrolidone 2.60 8.60 Methacrylic acid copolymer/ 2.60 8.60 methacrylic acid-ethyl acrylate copolymer Magnesium Stearate 0.20 0.60 Talc 0.20 0.60 Percent weight of the Quantity Swellable composition Ingredients (kg/Batch) layer Swellable composition layer Microcrystalline cellulose 17.36 78.50 Crospovidone 3.32 15.00 Colloidal Silicon Dioxide 0.55 2.50 FD & C Red No. 40 Aluminum lake 0.02 0.10 Stearic acid 0.43 1.90 Talc 0.43 1.90

(127) Preparation of Active Ingredient Composition Layer:

(128) Venlafaxine hydrochloride, lactose, polyvinyl pyrrolidone, and hydroxypropylmethyl cellulose were geometrically mixed and sifted. This blend was granulated with purified water. The contents were milled through the mill. The granules were dried and blended with methacrylic acid copolymer/methacrylic acid/ethyl acrylate copolymer and further lubricated with a mixture of talc and magnesium stearate.

(129) Preparation of Swellable Composition Layer:

(130) The specified quantities of the microcrystalline cellulose, colloidal silicon dioxide, were mixed and sifted. Crospovidone was also sifted and added to above blend. To this FD & C Red No 40 aluminum lake was added. The blend was lubricated with stearic acid and talc. The blend was slugged using a suitable compression machine. Slugs were milled to form granules. These granules were lubricated with stearic acid and talc.

(131) The granules of the active ingredient composition layer and the granules of the swellable composition layer were loaded into the hoppers of a Bilayer Compression Machine (17 Station) Make: Cadmach Model: Cadmach CMB4D bilayer tablet press. The punches used for compression was of capsule shape having three break lines. Both the lower and upper punch was designed with a three break lines to produce an indent at an equidistance of 4.75 mm. The tablet dies were first filled with the active ingredient composition layer and then above that was filled the swellable composition layer. The capsule shaped bilayer tablet cores were prepared by compressing the above two granules compositions. The bilayer tablet core was then coated with the coating composition having the constituents mentioned in Table 15. Further the coated tablets were film coated with low viscosity hydroxypropyl methylcellulose.

(132) TABLE-US-00015 TABLE 15 Coating Composition Percent by Weight Quantity of the Bilayer Core Ingredients (kg/Batch) Composition Functional coating Ethyl Cellulose 4.62 15.30 Dibutyl Sebacate 0.33 1.10 Triethyl Citrate 0.07 0.20 Polysorbates 0.01 0.02 Talc 0.14 0.50 Film coating Low viscosity hydroxypropyl 1.23 4.10 methylcellulose

(133) The tablets were placed in 900 ml purified water and the coating on the preselected surface i.e., the surface of the core that had a break line and surface which was in the immediate vicinity of the swellable composition layer, was monitored. Water permeated into the core through the coating which was non planar, causing the swellable agent to swell and exert pressure on the coating leading to rupture from the preselected surface.

(134) FIG. 9 is a copy of photographs depicting various stages of the coated core. FIG. 9 (a) shows the coated tablets of Example 15 placed in the purified water at a time point of 2 mins. FIG. 9 (a) depicts the intact coated tablet. At time point of 4 minutes 58 seconds, rupture of the coating begins. This is depicted in FIG. 9 (b). FIG. 9 (c) shows that at 5 min 08 seconds the swellable composition begins to disperse or disintegrate into the aqueous media. FIG. 9 (d), shows that at 5 min 15 seconds, further progress of the disintegration of the contents of the swellable composition from the coating, exposing behind the active ingredient composition layer.

(135) Separately, the tablets were subjected to dissolution testing using United States Pharmacopoeia dissolution apparatus, Type I, using 900 ml of pH 6.8 buffer as the dissolution medium, at a speed of 100 rpm. The results of the dissolution testing are recorded in Table 16 below.

(136) TABLE-US-00016 TABLE 16 Drug Release Profile Time (hours) % Drug Released 1 18 4 52 8 88 20 104

(137) The rupture of the coating from the preselected surface can be correlated with the release of the active ingredient from the active ingredient layer. It can be noted that the release of an active ingredient does not start immediately after rupture of the coating which starts at 4 minutes 58 seconds [FIG. 9 (b)], but the drug release starts only at about 1 hour (see Table 16-18% drug released at 1 hour). This indicates that although the swellable composition layer disintegrates within 5 minutes 15 seconds [See FIG. 9 (d)], the active ingredient composition layer which includes rate controlling excipients, does not allow release to initiate immediately, but rather the release initiates later, at 60 minutes.

Example 16

(138) This example illustrates an embodiment of the present invention wherein the defect is created by applying the coating on a core that has a circular centrally placed indent that forms a well. The defect formed is not a passageway through the preselected portion of the coating.

(139) The ingredients of the active ingredient composition and the swellable composition are given in Table 17. The bilayer core having active ingredient composition layer and the swellable composition layer was made according to the process as described in Example 15.

(140) TABLE-US-00017 TABLE 17 Bilayer Core Composition Percent by weight of Quantity the active ingredient Ingredients (kg/Batch) composition layer Active ingredient composition layer Venlafaxine Hydrochloride 2.73 36.40 Hydroxypropyl methylcellulose 0.52 6.90 Lactose 2.86 38.10 Polyvinyl pyrrolidone 0.65 8.70 Methacrylic acid copolymer/ 0.65 8.70 methacrylic acid-ethyl acrylate copolymer Magnesium Stearate 0.05 0.65 Talc 0.05 0.65 Percent weight of the Quantity Swellable composition Ingredients (kg/Batch) layer Swellable composition layer Microcrystalline cellulose 4.34 78.40 Crospovidone 0.85 15.20 Colloidal Silicon Dioxide 0.13 2.30 FD & C Red No 40. aluminum lake 0.01 0.12 Stearic acid 0.11 1.90 Talc 0.11 1.90

(141) The granules of the active ingredient composition and the granules of the swellable composition layer were loaded into the hoppers of a Bilayer Compression Machine (17 Station) Make: Cadmach Model: Cadmach CMB4D bilayer tablet press. The lower punch was conventional whereas the upper punch was designed with a punch tip having a diameter of about 3 mm and height of about 1.2 mm to produce an indent on the surface of the swellable composition layer. The tablet dies having a total diameter of 7.0 mm were first filled with the active ingredient composition layer and then above that was filled the swellable composition layer. The circular bilayer tablet cores were compressed. The bilayer tablet core was then coated with the coating composition having the constituents mentioned in Table 18. Further the coated tablets were film coated with low viscosity hydroxypropyl methylcellulose.

(142) TABLE-US-00018 TABLE 18 Coating Composition Percent by weight Quantity of the bilayer core Ingredients (kg/Batch) composition Functional coating Ethyl Cellulose 1.37 13.50 Dibutyl Sebacate 0.10 1.00 Triethyl Citrate 0.02 0.20 Polysorbates 0.001 0.01 Talc 0.05 0.40 Film coating Low viscosity hydroxypropyl 0.36 3.50 methylcellulose

(143) The tablets were placed in 900 ml of purified water and the coating on the preselected surface, i.e., the surface of the core that had a circular centrally placed indent which was in the immediate vicinity of the swellable composition layer, was monitored. Water permeated into the core through the coating which was non planar causing the swellable agent to swell and exert pressure on weak coating, leading to rupture from the preselected surface.

(144) FIG. 10 is a copy of photographs depicting various stages of the coated core. FIG. 10 (a) shows the coated tablets of example 16 placed in the purified water at a time point of 6 seconds. FIG. 10 (a) shows that the coated tablet is intact. At time point of 15 seconds, rupture of the coating begins. This is depicted in FIG. 10 (b). FIG. 10 (c) shows that at 21 seconds the swellable composition begins to disperse or disintegrate the aqueous media. FIG. 10 (d), shows that at 29 seconds, further progress of the disintegration of the contents of the swellable composition from the coating, exposing behind the active ingredient composition layer.

(145) Separately, the tablets were subjected to dissolution testing using United States Pharmacopoeia dissolution apparatus, Type I, using 900 ml of pH 6.8 buffer as the dissolution medium, at a speed of 100 rpm. The results of the dissolution testing are recorded in Table 19 below.

(146) TABLE-US-00019 TABLE 19 Drug Release Profile Time (hours) % Drug Released 1 25 4 59 8 89 20 93

(147) The rupture of the coating from the preselected surface can be correlated with the release of the active ingredient from the active ingredient layer. It can be noted that the release of an active ingredient does not start immediately after rupture of the coating which starts at 15 seconds [FIG. 10 (b)], but the drug release starts only at about 1 hour (see Table 19-25% drug released at 1 hour). This indicates that although the swellable composition layer disintegrates within 29 seconds [See FIG. 10 (d)], the active ingredient composition layer which includes rate controlling excipients, does not allow release to initiate immediately, but rather the release initiates later, at 60 minutes.

Example 17

(148) This example illustrates an embodiment of the present invention where the defect is created in the form of a fault which begins from the outer surface of the coating and penetrates only partially through the coating. Thus, the defect is formed but the defect is not a passageway through the preselected portion of the coating.

(149) The ingredients of the active ingredient composition and the swellable composition are given in Table 20. The bilayer core having active ingredient composition layer and the swellable composition layer was made according to the process as described in Example 15.

(150) TABLE-US-00020 TABLE 20 Bilayer Core Composition Percent by weight of Quantity the active ingredient Ingredients (kg/Batch) composition layer Active ingredient composition layer Venlafaxine Hydrochloride 5.51 36.60 Hydroxypropyl methylcellulose 1.01 6.70 Lactose 5.82 38.60 Polyvinyl pyrrolidone 1.24 8.20 Methacrylic acid copolymer/ 1.30 8.60 methacrylic acid-ethyl acrylate copolymer Magnesium Stearate 0.10 0.60 Talc 0.10 0.60 Percent weight of the Quantity Swellable composition Ingredients (kg/Batch) layer Swellable composition layer Microcrystalline cellulose 4.34 78.50 Crospovidone 0.83 15.00 Colloidal Silicon Dioxide 0.14 2.50 FD & C Red No 40 Aluminum lake 0.01 0.10 Stearic acid 0.11 1.90 Talc 0.11 1.90

(151) The granules of the active ingredient composition and the granules of the swellable composition layer were loaded into the hoppers of a Bilayer Compression Machine (17 Station) Make: Cadmach Model: Cadmach GMB4D bilayer tablet press. The bilayer tablet core was then coated with the coating composition having the constituents mentioned in Table 21. Further the coated tablets were film coated with low viscosity hydroxypropyl methylcellulose. Then the defect in coating was created by partially cutting the coat on the preselected surface of the swellable composition layer using a sharp blade.

(152) TABLE-US-00021 TABLE 21 Coating Composition Percent by Weight Quantity of the Bilayer Core Ingredients (kg/Batch) Composition Functional coating Ethyl Cellulose 1.14 7.6 Methacrylic acid copolymer/ 0.58 3.8 methacrylic acid-ethyl acrylate copolymer Mannitol 0.09 0.6 Polyvinyl pyrrolidone 0.03 0.2 Dibutyl Sebacate 0.08 0.6 Triethyl Citrate 0.03 0.2 Film coating Low viscosity hydroxypropyl 0.73 4.8 methylcellulose

(153) The tablets were placed in 900 ml of purified water and the coating on the preselected surface, i.e., the surface of the core that had a circular indent which was in the immediate vicinity of the swellable composition layer was monitored. Water permeated into the core through the coating which was non planar causing the swellable agent to swell and exert pressure on weak coating causing it to rupture from the preselected surfaces.

(154) FIG. 11 is a copy of photographs depicting depicts various stages of the coated core. FIG. 11 (a) shows the coated tablets of Example 7 placed in the purified water at a time point of 1 min. FIG. 11 (a) shows that the coated tablet intact. At time point of 2 minutes 22 seconds, rupture of the coating begins which is depicted in FIG. 11 (b). FIG. 11 (c) shows that at 2 minutes 27 seconds the swellable composition begins to disperse or disintegrate into the aqueous media. FIG. 11 (d), shows that at 2 minutes 34 seconds, further progress of the disintegration of the contents of the swellable composition from the coating, exposing behind the active ingredient composition layer.

Example 18

(155) This example illustrates an embodiment wherein the core comprises a reactive composition layer comprising reactive ingredient in the vicinity of a preselected surface of a reactive coating.

(156) The ingredients of the active ingredient composition and the reactive composition are given in Table 22. The bilayer core having active ingredient composition layer and the reactive composition layer made according to the process as described below.

(157) TABLE-US-00022 TABLE 22 Bilayer Core Composition Percent by Weight of Quantity the Active Ingredient Ingredients (kg/Batch) Composition Layer Active ingredient composition layer Venlafaxine Hydrochloride 5.51 36.60 Hydroxypropyl methyl cellulose 1.01 6.70 Lactose 5.82 38.60 Polyvinyl pyrrolidone 1.24 8.20 Methacrylic acid copolymer/ 1.30 8.60 methacrylic acid-ethyl acrylate copolymer Magnesium Stearate 0.10 0.60 Talc 0.10 0.60 Percent by Weight of Quantity the Reactive Ingredients (kg/Batch) Composition Layer Reactive composition layer Micro crystalline cellulose 4.69 55.50 Sodium lauryl sulphate 0.07 0.80 Crospovidone 1.09 12.80 FD & C Red No 40 Aluminum lake 0.01 0.10 Talc 0.02 0.20 Magnesium stearate 0.08 0.90 Veegum 0.55 6.50 Sodium bicarbonate 1.95 23.10

(158) Preparation of Active Ingredient Composition Layer:

(159) Venlafaxine hydrochloride, lactose monohydrate, polyvinyl pyrrolidone, and hydroxypropylmethyl cellulose were geometrically mixed and sifted. This blend was granulated with purified water. The contents were milled through the mill. The granules were dried and blended with methacrylic acid copolymer/methacrylic acid/ethyl acrylate copolymer and lubricated with a mixture of talc and magnesium stearate.

(160) Preparation of Reactive Composition Layer:

(161) The specified quantities of the microcrystalline cellulose, veegum granules, and sodium lauryl sulphate were mixed and sifted. Crospovidone was sifted and added to above blend. To this FD and C red No 40 aluminum lake was added. The blend was lubricated with magnesium stearate and talc. The blend was slugged using a suitable compression machine. Slugs were milled to form granules. These granules were lubricated with veegum granules, magnesium stearate, talc, and sodium bicarbonate.

(162) The granules of the active ingredient composition and the granules of the reactive composition layer were loaded into the respective hoppers of a Mayer Compression Machine (17 Station) Make: Cadmach Model: Cadmach CMB4D bilayer tablet press. The circular bilayer tablet cores were prepared by compressing the above two granule compositions. The bilayer tablet core was then coated with the coating composition having the constituents mentioned in Table 23. Further the coated tablets were film coated with low viscosity hydroxypropyl methylcellulose.

(163) TABLE-US-00023 TABLE 23 Coating Composition Percent by Weight Quantity of the Bilayer Core Ingredients (kg/Batch) Composition Functional coating Ethyl Cellulose 1.14 7.60 Methacrylic acid copolymer/ 0.58 3.80 methacrylic acid-ethyl acrylate copolymer Mannitol 0.09 0.60 Polyvinyl pyrrolidone 0.03 0.20 Dibutyl Sebacate 0.08 0.60 Triethyl Citrate 0.03 0.20 Film coating Low viscosity hydroxypropyl 0.73 4.80 methylcellulose

(164) The tablets were placed in 900 ml of 0.01N HCl and the coating on the preselected surface i.e., the surface of the reactive composition layer of the core was monitored. Water permeated into the core through the coating. The reactive composition layer containing reactive ingredient, sodium bicarbonate reacts with the acidic coating constituent, methacrylic acid methacrylate copolymer, and a polymer which is soluble in neutral to alkaline pH medium but not soluble in acidic environment.

(165) FIG. 14 is a copy of photographs depicting various stages of the coated core. FIG. 14(a) shows the coated tablets of Example 18 placed in the 0.01N HCl at a time point of 19 minutes 49 seconds. FIG. 14 (a) shows that the coated tablet is intact. At time point of 20 minutes 04 seconds, rupture of the coating begins which is evident from FIG. 14(b), FIG. 14(c) shows that at 20 min 11 seconds the reactive composition begins to disperse or disintegrate into the aqueous media. FIG. 14(d), shows that at 23 min 46 seconds, further progress of the disintegration of the contents of the reactive composition from the coating, exposing behind the active ingredient composition layer.

(166) Separately, the tablets thus obtained were subjected to dissolution testing using United States Pharmacopoeia dissolution apparatus, Type I, using 900 ml of 0.01N HCl as the dissolution medium, at a speed of 100 rpm. The results of the dissolution testing are recorded in Table 24 below.

(167) TABLE-US-00024 TABLE 24 Drug release profile Time (hours) % Drug Released 1 8 4 18 8 35 12 50 16 63 20 74 24 82

(168) The rupture of the coating from the preselected surface can be correlated with the release of the active ingredient from the active ingredient layer. It can be noted that the release of an active ingredient does not start immediately after rupture of the coating which starts at 20 minutes [FIG. 14 (b)], but the drug release starts only at about 1 hour (see Table 24-8% drug released at 1 hour). This indicates that although the reactive composition layer disintegrates within 20 minutes [See FIG. 14(b)], the active ingredient composition layer which includes rate controlling excipients, does not allow release to initiate immediately, but rather the release initiates later, at 60 minutes.

Example 19

(169) This example illustrates an embodiment of the present invention where the core comprises a reactive composition layer comprising reactive ingredient in the vicinity of a preselected surface of a reactive coating.

(170) The ingredients of the active ingredient composition and the reactive composition are given in Table 25. The bilayer core having active ingredient composition layer and the reactive composition layer made according to the process as described below.

(171) TABLE-US-00025 TABLE 25 Bilayer Core composition Percent by Weight of Quantity the Active Ingredient Ingredients (kg/Batch) Composition Layer Active ingredient composition layer Venlafaxine Hydrochloride 5.51 36.60 Hydroxypropyl methyl cellulose 1.01 6.70 Lactose 5.82 38.60 Polyvinyl pyrrolidone 1.24 8.20 Methacrylic acid copolymer/ 1.30 8.60 methacrylic acid-ethyl acrylate copolymer Magnesium Stearate 0.10 0.60 Talc 0.10 0.60 Percent by Weight of Quantity the Reactive Ingredients (kg/Batch) Composition Layer Reactive Composition Layer Micro crystalline Cellulose 13.75 77.20 Sodium lauryl sulphate 0.17 0.10 Crospovidone 2.57 14.40 Colloidal silicon dioxide 0.43 2.40 FD & C Red No 40. Aluminum lake 0.02 0.10 Talc 0.05 0.20 Magnesium stearate 0.18 1.00 Trisodium phosphate 0.65 3.60

(172) Preparation of Active Ingredient Composition Layer:

(173) Venlafaxine hydrochloride, lactose monohydrate, polyvinyl pyrrolidone, and hydroxypropyl-methyl cellulose were geometrically mixed and sifted. This blend was granulated with purified water. The contents were milled through the mill. The granules were dried and blended with methacrylic acid copolymer/methacrylic acid/ethyl acrylate copolymer and lubricated with a mixture of talc and magnesium stearate.

(174) Preparation of Reactive Composition Layer:

(175) The specified quantities of the silicified microcrystalline cellulose, colloidal silicon dioxide, and sodium lauryl sulphate were mixed and sifted. Crospovidone was sifted and added to above blend. To this FD and C red No 40 aluminum lake was added. The blend was lubricated with magnesium stearate and talc. The blend was slugged using a suitable compression machine. Slugs were milled to form granules. These granules were lubricated with magnesium stearate, talc, and trisodium phosphate.

(176) The granules of the active ingredient composition and the granules of the reactive composition layer were loaded into the respective hoppers of a Mayer Compression Machine (17 Station) Make: Cadmach Model: Cadmach CMB4D bilayer tablet press. The circular bilayer tablet cores were prepared by compressing the above two granule compositions. The bilayer tablet core was then coated with the coating composition having the constituents mentioned in Table 26. Further the coated tablets were film coated with of low viscosity hydroxypropyl methylcellulose.

(177) TABLE-US-00026 TABLE 26 Coating Composition Percent by Weight Quantity of the Bilayer Core Ingredients (kg/Batch) Composition Functional coating Ethyl Cellulose 1.14 7.60 Methacrylic acid copolymer/ 0.58 3.80 methacrylic acid-ethyl acrylate copolymer Mannitol 0.09 0.60 Polyvinyl pyrrolidone 0.03 0.20 Dibutyl Sebacate 0.08 0.60 Triethyl Citrate 0.03 0.20 Film coating Low viscosity hydroxypropyl 0.73 4.80 methylcellulose

(178) The tablets were placed in 900 ml of 0.01N HCl and the coating on the preselected surface i.e., the surface of the reactive composition layer of the core was monitored. Water permeated into the core through the coating. The reactive composition layer containing reactive ingredient, sodium bicarbonate reacts with the acidic coating constituent, methacrylic acid methacrylate copolymer, and a polymer which is soluble in neutral to alkaline pH medium but not soluble in acidic environment.

(179) FIG. 15 is a copy of photographs depicting depicts various stages of the coated core. FIG. 15(a) shows the coated tablets of Example 19 placed in the 0.01N HCl at a time point of 19 minutes 49 seconds. FIG. 15(a) shows that the coated tablet is intact. At time point of 32 minutes 41 seconds, rupture of the coating begins which is evident from FIG. 15(b), FIG. 15(c) shows that at 32 min 53 seconds the reactive composition begins to disperse or disintegrate into the aqueous media. FIG. 15(d), shows that at 34 min 24 seconds, further progress of the disintegration of the contents of the reactive composition from the coating, exposing behind the active ingredient composition layer.

(180) Separately, the tablets thus obtained were subjected to dissolution testing using United States Pharmacopoeia dissolution apparatus, Type I, using 900 ml of 0.01N HCl as the dissolution medium, at a speed of 100 rpm. The results of the dissolution testing are recorded in Table 22 below.

(181) TABLE-US-00027 TABLE 27 Drug Release Profile Time (hours) % Drug Released 1 3 4 16 8 35 12 52 16 67 20 77 24 84

(182) The rupture of the coating from the preselected surface can be correlated with the release of the active ingredient from the active ingredient layer. It can be noted that the release of an active ingredient does not start immediately after rupture of the coating which starts at 20 minutes [FIG. 15(b)], but the drug release starts only at about 1 hour (see Table 27-3% drug released at 1 hour). This indicates that although the reactive composition layer disintegrates within 20 minutes [See FIG. 15(b)], the active ingredient composition layer which includes rate controlling excipients, does not allow release to initiate immediately, but rather the release initiates later, at 60 minutes.

(183) While the invention has been described by reference to specific embodiments, this was done for purposes of illustration only and should not be construed to limit the spirit or the scope of the invention,