CA2359812C - Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures - Google Patents
Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures Download PDFInfo
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- CA2359812C CA2359812C CA002359812A CA2359812A CA2359812C CA 2359812 C CA2359812 C CA 2359812C CA 002359812 A CA002359812 A CA 002359812A CA 2359812 A CA2359812 A CA 2359812A CA 2359812 C CA2359812 C CA 2359812C
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- poly
- methacrylic acid
- coating layer
- methyl methacrylate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4891—Coated capsules; Multilayered drug free capsule shells
Abstract
The present invention relates to a pharmaceutical composition in a solid unit dosage form for oral administration in a human or lower animal comprising: a. a safe and effective amount of a therapeutically active agent; b. an inner coating layer selected from the group consisting of poly(methacrylic acid, methyl methacrylate) 1:2, poly(methacrylic acid, methyl methacrylate) 1:1, and mixtures thereof; and c. an outer coating layer comprising an enteric polymer or film coating material; wherein the inner coating layer is not the same as the outer coating layer; wherein if the inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:1 then the outer coating layer is not poly(methacrylic acid, methyl methacrylate) 1:2 or is not a mixture of poly(methacrylic acid, methyl methacrylate) 1:1 and poly(methacrylic acid, methyl methacrylate) 1:2; and wherein the inner coating layer and the outer coating layer do not contain any therapeutically active agent. This invention further relates to a method of maintaining the desired site of delivery of a therapeutic agent in the gastrointestinal tract by administering the above compositions to a human or lower animal.
Description
PHARMACEUTICAL DOSAGE FORM WITH
MULTIPLE COATINGS FOR REDUCED IMPACT OF
COATING FRACTURES
TECHNICAL FIELD
The present invention relates to novel unit dosage forms comprising therapeutic agents with improved resistance to coating fractures during processing, manufacturing or packaging.
BACKGROUND OF THE INVENTION
A number of prior art references teaches the advantages of delivery of therapeutic agents to the lower part of the gastrointestinal tract, especially the large intestine or the colon. These reference illustrate the difficulty of formulating dosage forms that will achieve this delivery benefit. For example, US Patent No. 5,541,170 and 5,541,171, Rhodes et al., both issued July 30, 1996, discuss the delivery of pharmacologically active agents, especially 5-aminosalicylic acid, to the large intestine for the treatment of colonic or rectal disorders. US
Patent No. 5,686,105,Kelm . et al., issued November 11, 1997, teaches colonic delivery of therapeutic agents wherein the dosage form comprises a coating system with at least one inner coating layer and one outer coating layer. The inner coating layer is an enteric polymer that begins to dissolve in an aqueous media at a pH between about 5 to about 6.3, and the outer coating layer is an enteric polymer that begins to dissolve in an aqueous media at a pH of between about 6.8 to 7.2. US
Patent No.
5,171,580, Iamartino et al., issued Dec. 15, 1992, teaches pharmaceutical preparations containing an active ingredient to be released in the lower part of the gastrointestinal tract, the large intestine and especially the colon, consisting of a core with the active, the core being coated with three protective layers at different solubilities. This reference focuses on providing more specific and reliable release of a therapeutic active agent to the lower part of the gastrointestinal tract, especially the colon, achieved with the three protection layers, as well as the benefits of having a selective effect in the colon. Other prior art references also focus on the benefits of delivering therapeutic agents to the colon. These references include US Patent Nos.
5,686,106, Kelm et al., issued Nov. 11, 1997; 5,914,132, Kelm et al, issued June 22, 1999; 4,910,021, Davis et al, issued March 20, 1990; 4,432,966, Zeitoun et al., issued Feb. 21, 1984; 5,654,004, Okayama et al., issued August 5, 1997; 5,900,252, Calcanchi et al., issued May 4, 1999;
5,482,718, Shah et al, issued Jan. 9, 1996; 5,316,772, Jurgens et al., issued May 31, 1994; EP
225,189, Davies, et al, la published June 10, 1987; and Khan et al., Drug Development and Industrial Pharmacy, 26(5), 549-554 (2000).
None of the above prior art references, however, discusses the problem or possibility of coating fractures that may occur during processing, manufacturing, or packaging of the oral unit dosage form. Coating fractures may cause unreliable or inconsistent delivery or release of the therapeutic agent to the desired region of the gastrointestinal tract. These fractures may be associated with premature rupture or release of the unit dosage forms. Indeed, coating fractures may especially be problematic for larger than average size unit dosage forms or heavier unit dosage forms resulting from using larger dosages/levels of the therapeutic active.
The present invention, therefore, relates to solid unit dosage forms for oral administration in humans or lower animals which minimizes the impact or negative effects of coating fractures, especially for larger or heavier unit dosage forms. By reducing these negative effects, these compositions maintain the desired site of delivery of the therapeutic agents in the gastrointestinal tract.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition in a solid unit dosage form for oral administration in a human or lower animal comprising:
a. a safe and effective amount of a therapeutically active agent;
b. an inner coating layer selected from the group consisting of poly(methacrylic acid, methyl methacrylate) 1:2, poly(methacrylic acid, methyl methacrylate) 1:1, and mixtures thereof; and c. an outer coating layer comprising an enteric polymer or film coating material;
wherein the inner coating layer is not the same as the outer coating layer;
wherein if the inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:1 then the outer coating layer is not poly(methacrylic acid, methyl methacrylate) 1:2 or is not a mixture of poly(methacrylic acid, methyl methacrylate) 1:1 and poly(methacrylic acid, methyl methacrylate) 1:2;
and wherein the inner coating layer and the outer coating layer contain no therapeutically active agent.
In another embodiment the present invention relates to a pharmaceutical composition in a solid unit dosage form for oral administration in a human or lower animal comprising:
a. a safe and effective amount of a therapeutically active agent;
b. an inner coating layer comprising poly(methacrylic acid, methyl methacrylate) 1:2;
and
MULTIPLE COATINGS FOR REDUCED IMPACT OF
COATING FRACTURES
TECHNICAL FIELD
The present invention relates to novel unit dosage forms comprising therapeutic agents with improved resistance to coating fractures during processing, manufacturing or packaging.
BACKGROUND OF THE INVENTION
A number of prior art references teaches the advantages of delivery of therapeutic agents to the lower part of the gastrointestinal tract, especially the large intestine or the colon. These reference illustrate the difficulty of formulating dosage forms that will achieve this delivery benefit. For example, US Patent No. 5,541,170 and 5,541,171, Rhodes et al., both issued July 30, 1996, discuss the delivery of pharmacologically active agents, especially 5-aminosalicylic acid, to the large intestine for the treatment of colonic or rectal disorders. US
Patent No. 5,686,105,Kelm . et al., issued November 11, 1997, teaches colonic delivery of therapeutic agents wherein the dosage form comprises a coating system with at least one inner coating layer and one outer coating layer. The inner coating layer is an enteric polymer that begins to dissolve in an aqueous media at a pH between about 5 to about 6.3, and the outer coating layer is an enteric polymer that begins to dissolve in an aqueous media at a pH of between about 6.8 to 7.2. US
Patent No.
5,171,580, Iamartino et al., issued Dec. 15, 1992, teaches pharmaceutical preparations containing an active ingredient to be released in the lower part of the gastrointestinal tract, the large intestine and especially the colon, consisting of a core with the active, the core being coated with three protective layers at different solubilities. This reference focuses on providing more specific and reliable release of a therapeutic active agent to the lower part of the gastrointestinal tract, especially the colon, achieved with the three protection layers, as well as the benefits of having a selective effect in the colon. Other prior art references also focus on the benefits of delivering therapeutic agents to the colon. These references include US Patent Nos.
5,686,106, Kelm et al., issued Nov. 11, 1997; 5,914,132, Kelm et al, issued June 22, 1999; 4,910,021, Davis et al, issued March 20, 1990; 4,432,966, Zeitoun et al., issued Feb. 21, 1984; 5,654,004, Okayama et al., issued August 5, 1997; 5,900,252, Calcanchi et al., issued May 4, 1999;
5,482,718, Shah et al, issued Jan. 9, 1996; 5,316,772, Jurgens et al., issued May 31, 1994; EP
225,189, Davies, et al, la published June 10, 1987; and Khan et al., Drug Development and Industrial Pharmacy, 26(5), 549-554 (2000).
None of the above prior art references, however, discusses the problem or possibility of coating fractures that may occur during processing, manufacturing, or packaging of the oral unit dosage form. Coating fractures may cause unreliable or inconsistent delivery or release of the therapeutic agent to the desired region of the gastrointestinal tract. These fractures may be associated with premature rupture or release of the unit dosage forms. Indeed, coating fractures may especially be problematic for larger than average size unit dosage forms or heavier unit dosage forms resulting from using larger dosages/levels of the therapeutic active.
The present invention, therefore, relates to solid unit dosage forms for oral administration in humans or lower animals which minimizes the impact or negative effects of coating fractures, especially for larger or heavier unit dosage forms. By reducing these negative effects, these compositions maintain the desired site of delivery of the therapeutic agents in the gastrointestinal tract.
SUMMARY OF THE INVENTION
The present invention relates to a pharmaceutical composition in a solid unit dosage form for oral administration in a human or lower animal comprising:
a. a safe and effective amount of a therapeutically active agent;
b. an inner coating layer selected from the group consisting of poly(methacrylic acid, methyl methacrylate) 1:2, poly(methacrylic acid, methyl methacrylate) 1:1, and mixtures thereof; and c. an outer coating layer comprising an enteric polymer or film coating material;
wherein the inner coating layer is not the same as the outer coating layer;
wherein if the inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:1 then the outer coating layer is not poly(methacrylic acid, methyl methacrylate) 1:2 or is not a mixture of poly(methacrylic acid, methyl methacrylate) 1:1 and poly(methacrylic acid, methyl methacrylate) 1:2;
and wherein the inner coating layer and the outer coating layer contain no therapeutically active agent.
In another embodiment the present invention relates to a pharmaceutical composition in a solid unit dosage form for oral administration in a human or lower animal comprising:
a. a safe and effective amount of a therapeutically active agent;
b. an inner coating layer comprising poly(methacrylic acid, methyl methacrylate) 1:2;
and
2 c. an outer coating layer comprising an enteric polymer or film coating material;
wherein the inner coating layer is not the same as the outer layer coating.
This invention further relates to a method of maintaining the desired site of delivery of a therapeutic agent in the gastrointestinal tract by reducing the impact of coating fractures, through administering the above compositions to a human or lower animal.
DETAILED DESCRIPTION OF THE INVENTION
'Ille phrase "safe and effective amount", as used herein, means an amount of therapeutically active agent or other component of the present compositions, high enough to provide a significant positive modification of the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. A safe and effective amount of therapeutically active agent or other component of the present compositions, will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the agent selected and like factors.
Therapeutically Active Ageilt The methods and compositions of the present invention comprise a safe and effective amount of the therapeutically active agent. In one embodiment the therapeutic agents suitable for incorporation into dosage forms of the present invention are those for which treatment of the colon is therapeutically advantageous. These include therapeutic agents useful for the treatment of diseases of the colon such as constipation, diarrhea, irritable bowel syndrome (IBS), Crohn's disease, colitis, ulcerative colitis, carcinomas, idiopathic protitis, infection in which systemic absorption of the therapeutic agent is neither required or desired, and other diseases or disorders of the colon or rectum. These include actives for constipation and laxatives such as picosulfate and sennasides, anti-diarrheals such as loperamide, nonsteroidal anti-inflan unatory drugs such as salicylates, indomethacin, ibuprofen, flurbiprofen, naproxen, piroxicam, 5-aminosalicyclic acid (abbreviated as 5-ASA) or pharmaceutically acceptable salts or esters thereof, balsalazide as well as agents disclosed in US
4,412,992, Chan, issued Nov. 1, 1983, as well as NSAIDS disclosed in US 4,552,899, Sunshine et al., issued Nov. 12, 1985, steroids such as hydrocortisone, prednisone, prednisolone, prednisolone phosphate, prednisolone metasulpho-benzoate sodium, prednisolone sodium phosphate, beclomethasone dipropionate and beclomethasone valerate, glucocorticoids such as dextramethazone, antimicrobials or antiparasitic agents, (especially those effective against anaerobic microbes such as methotrexate), 5-aminosalicylic compounds, 4-aminosalicylic
wherein the inner coating layer is not the same as the outer layer coating.
This invention further relates to a method of maintaining the desired site of delivery of a therapeutic agent in the gastrointestinal tract by reducing the impact of coating fractures, through administering the above compositions to a human or lower animal.
DETAILED DESCRIPTION OF THE INVENTION
'Ille phrase "safe and effective amount", as used herein, means an amount of therapeutically active agent or other component of the present compositions, high enough to provide a significant positive modification of the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. A safe and effective amount of therapeutically active agent or other component of the present compositions, will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the agent selected and like factors.
Therapeutically Active Ageilt The methods and compositions of the present invention comprise a safe and effective amount of the therapeutically active agent. In one embodiment the therapeutic agents suitable for incorporation into dosage forms of the present invention are those for which treatment of the colon is therapeutically advantageous. These include therapeutic agents useful for the treatment of diseases of the colon such as constipation, diarrhea, irritable bowel syndrome (IBS), Crohn's disease, colitis, ulcerative colitis, carcinomas, idiopathic protitis, infection in which systemic absorption of the therapeutic agent is neither required or desired, and other diseases or disorders of the colon or rectum. These include actives for constipation and laxatives such as picosulfate and sennasides, anti-diarrheals such as loperamide, nonsteroidal anti-inflan unatory drugs such as salicylates, indomethacin, ibuprofen, flurbiprofen, naproxen, piroxicam, 5-aminosalicyclic acid (abbreviated as 5-ASA) or pharmaceutically acceptable salts or esters thereof, balsalazide as well as agents disclosed in US
4,412,992, Chan, issued Nov. 1, 1983, as well as NSAIDS disclosed in US 4,552,899, Sunshine et al., issued Nov. 12, 1985, steroids such as hydrocortisone, prednisone, prednisolone, prednisolone phosphate, prednisolone metasulpho-benzoate sodium, prednisolone sodium phosphate, beclomethasone dipropionate and beclomethasone valerate, glucocorticoids such as dextramethazone, antimicrobials or antiparasitic agents, (especially those effective against anaerobic microbes such as methotrexate), 5-aminosalicylic compounds, 4-aminosalicylic
3 compounds, sulfasalazine, benzalazine, erythromycin, chloroguine, iodochlorhydroxyquin, disodohydroxyquin, neomycin and tetracyclines, immunosupressants such as cyclosporine A, chemotherapeutics for treatment of carcinomas, gastointestinal stimulants and prokinetic agents such as cisapride, peppermint oil and other carminative essential oils, actives for the removal of excess bile acids such as cholestyramine.
Certain therapeutic: agents, particularly peptides and proteins, are subject to lumenal degradation in the stomach and small intestine. The colon may be a preferable site of absorption for such compounds since lumenal enzymatic activity is less in the colon (M.
Mackay and E.
Tomlinson, in Colonic Drug Absorption and Metabolism, P. R. Bieck, ed., Marcel Dekker, Inc., New York, Basel, Hong Kong, I37-IS8 (1993)). Peptides and proteins that may exhibit improved systemic bioavailability benefit when released in the colon include calcitonin, insulin, and human growth hormone. In certain cases, the peptide or protein may be formulated with a system than enhances the absorption of the macromolecule (M. Mackay and E.
Tomlinson, in Colonic Drug Absorption and Metabolism, P. R. Biec:k, ed., Marc:el Dekker, Ine., New York, Basel, Hong Kong, 137-1S8 (1993)).
The therapeutically active agents are present in the solid dosage forms in suitable unit dosage amounts. These amounts will be known by those skilled in the art. In one embodiment the active agent is S-amino salicylic acid or pharmaceutically acceptable salts or esters thereof at a dosage range of from about 400mg to about 1.5 grams per tablet, in another embodiment is from about 700mg to about 900mg per tablet.
The therapeutically active agent may be incorporated into one of the several substrates described herein in a manner consistent with the physical chemical properties of the drug and its pharmacodynamics, using techniques known to those skilled in the art.
The Inner and Outer Coating Layers In one embodiment the coating layers of the present invention do not contain any therapeutically active agent of the present invention. In addition, the "coating layers" described herein refer to completely encasing or coating all of the solid unit dosage form (does not include coated microcrystal spheres, coated pellets, coated beads, coated microparticles or particles, or coated granules, of the therapeutically active agent).
Certain therapeutic: agents, particularly peptides and proteins, are subject to lumenal degradation in the stomach and small intestine. The colon may be a preferable site of absorption for such compounds since lumenal enzymatic activity is less in the colon (M.
Mackay and E.
Tomlinson, in Colonic Drug Absorption and Metabolism, P. R. Bieck, ed., Marcel Dekker, Inc., New York, Basel, Hong Kong, I37-IS8 (1993)). Peptides and proteins that may exhibit improved systemic bioavailability benefit when released in the colon include calcitonin, insulin, and human growth hormone. In certain cases, the peptide or protein may be formulated with a system than enhances the absorption of the macromolecule (M. Mackay and E.
Tomlinson, in Colonic Drug Absorption and Metabolism, P. R. Biec:k, ed., Marc:el Dekker, Ine., New York, Basel, Hong Kong, 137-1S8 (1993)).
The therapeutically active agents are present in the solid dosage forms in suitable unit dosage amounts. These amounts will be known by those skilled in the art. In one embodiment the active agent is S-amino salicylic acid or pharmaceutically acceptable salts or esters thereof at a dosage range of from about 400mg to about 1.5 grams per tablet, in another embodiment is from about 700mg to about 900mg per tablet.
The therapeutically active agent may be incorporated into one of the several substrates described herein in a manner consistent with the physical chemical properties of the drug and its pharmacodynamics, using techniques known to those skilled in the art.
The Inner and Outer Coating Layers In one embodiment the coating layers of the present invention do not contain any therapeutically active agent of the present invention. In addition, the "coating layers" described herein refer to completely encasing or coating all of the solid unit dosage form (does not include coated microcrystal spheres, coated pellets, coated beads, coated microparticles or particles, or coated granules, of the therapeutically active agent).
4 Inner Coating Layer The inner coating layer is selected from the group consisting of poly(methacrylic acid, methyl methacrylate) 1:2, poly(methacrylic acid, methyl methacrylate) 1:1, and mixtures thereof.
Generally the inner coating layer is selected based on the preferred delivery site desired and is applied to the core of the unit dosage form to achieve a minimum coating thickness from about 20 pm to about 120 p.m. The coating thickness depends on the actual size of the unit dosage form, but in one embodiment the minimum coating thickness of the inner coating layer is from about 20 Eun to about 50 Eun.
In one embodiment the inner coating layer comprises poly (methacrylic acid, methyl methacrylate) 1:2 (Eudragit~ S), or other enteric polymer material which has the same pH release characteristics in aqueous media as Eudragit~ S. Eudragit~ S, an anionic copolymer derived from methacrylic acid and methyl methacrylate, with a ratio of free carboxyl groups to the ester groups of approximately 1:2, and a mean molecular weight of approximately 135,000, from Rohm Tech. In one embodiment the inner coating layer is any other polymer with the same aqueous pH release charcteristics as Eudragit~ S.
Outer Coating Layer The outer coating layer comprises an enteric polymer or film coating material, wherein the inner coating layer is not the same as the outer coating layer. Generally, if the inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:1 (Eudragit~ L) then the outer coating layer is not poly(methacrylic acid, methyl methacrylate) 1:2 (Eudragit~ S) or is not a mixture of poly(methacrylic acid, methyl methacrylate) 1:1 and poly(methacrylic acid, methyl methacrylate) 1:2. The outer coating material can be any coating material that protects the inner coating layer from fractures during handling and that dissolves or is removed in the gastrointestinal tract prior to the inner coating layer. The outer coating layer is either a single coating or multiple coatings of either an enteric polymer material or film coating material. In another embodiment the unit dosage form has a single outer coating layer. In another embodiment the outer coating layer is an anionic copolymer. In one embodiment the outer coating cannot comprise an enteric polymer or mixtures thereof with the same pH of release in aqueous media as Eudragit~ S.
If the inner coating is poly(methacrylic acid, methyl methacrylate 1:2, then the outer coating layer can only comprise poly(methacrylic acid, methyl methacrylate 1:2 (Eudragit~ S) if it is mixed with another enteric polymer or film coating material such that the pH of release, in aqueous media,
Generally the inner coating layer is selected based on the preferred delivery site desired and is applied to the core of the unit dosage form to achieve a minimum coating thickness from about 20 pm to about 120 p.m. The coating thickness depends on the actual size of the unit dosage form, but in one embodiment the minimum coating thickness of the inner coating layer is from about 20 Eun to about 50 Eun.
In one embodiment the inner coating layer comprises poly (methacrylic acid, methyl methacrylate) 1:2 (Eudragit~ S), or other enteric polymer material which has the same pH release characteristics in aqueous media as Eudragit~ S. Eudragit~ S, an anionic copolymer derived from methacrylic acid and methyl methacrylate, with a ratio of free carboxyl groups to the ester groups of approximately 1:2, and a mean molecular weight of approximately 135,000, from Rohm Tech. In one embodiment the inner coating layer is any other polymer with the same aqueous pH release charcteristics as Eudragit~ S.
Outer Coating Layer The outer coating layer comprises an enteric polymer or film coating material, wherein the inner coating layer is not the same as the outer coating layer. Generally, if the inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:1 (Eudragit~ L) then the outer coating layer is not poly(methacrylic acid, methyl methacrylate) 1:2 (Eudragit~ S) or is not a mixture of poly(methacrylic acid, methyl methacrylate) 1:1 and poly(methacrylic acid, methyl methacrylate) 1:2. The outer coating material can be any coating material that protects the inner coating layer from fractures during handling and that dissolves or is removed in the gastrointestinal tract prior to the inner coating layer. The outer coating layer is either a single coating or multiple coatings of either an enteric polymer material or film coating material. In another embodiment the unit dosage form has a single outer coating layer. In another embodiment the outer coating layer is an anionic copolymer. In one embodiment the outer coating cannot comprise an enteric polymer or mixtures thereof with the same pH of release in aqueous media as Eudragit~ S.
If the inner coating is poly(methacrylic acid, methyl methacrylate 1:2, then the outer coating layer can only comprise poly(methacrylic acid, methyl methacrylate 1:2 (Eudragit~ S) if it is mixed with another enteric polymer or film coating material such that the pH of release, in aqueous media,
5 for the mixture is less than the pH of release (aqueous media) for poly(methacrylic acid, methyl methacrylate 1:2 (Eudragit~ S) alone.
In another embodiment the outer coating layer is an enteric polymer material that begins to dissolve in an aqueous media at a pH of less than about 7, in another embodiment at a pH of less than about 6.8. Generally the outer coating layer is applied to the core of the unit dosage form to achieve a minimum thickness of from about 10 pm to about 200 Vim, in another embodiment is from about 30 p,m to about 150 p,m.
In one embodiment the outer coating layer is selected from the group consisting of film coatings, cellulose derivatives, cellulose ethers, methyl cellulose, ethylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low viscosity hydroxypropyl cellulose, low viscosity hydroxypropyl methylcellulose, wax or wax like substance, such as carnauba wax, fatty alcohols, hydrogenated vegetable oils, zein, shellac, sucrose, Arabic gum, polyethylene.
glycol, polyvinylpyrolidone, gelatin, sodium alginate, dextrin, psyllium husk powder, polymethacrylates, anionic polymethacrylates, poly(methacrylic acid, methyl methacrylate) 1:1, mixtures of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1, cellulose acetate phthalate, cellulose acetate trimelliate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate phthalate, poly(methacrylic acid, ethyl acrylate) 1:1, and compatible mixtures thereof.
In another embodiment the outer coating layer is selected from the group consisting of cellulose derivatives, cellulose ethers, methyl cellulose, ethylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low viscosity hydroxypropyl cellulose, low viscosity hydroxypropyl methylcellulose, fatty alcohols, hydrogenated vegetable oils, zein, shellac, sucrose, Arabic gum, polyethylene glycol, polyvinylpyrolidone, gelatin, sodium alginate, dextrin, psyllium husk powder, polymethacrylates, anionic polymethacrylates, poly(methacrylic acid, methyl methacrylate) 1:l, mixtures of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1, cellulose acetate phthalate, cellulose acetate trimelliate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate
In another embodiment the outer coating layer is an enteric polymer material that begins to dissolve in an aqueous media at a pH of less than about 7, in another embodiment at a pH of less than about 6.8. Generally the outer coating layer is applied to the core of the unit dosage form to achieve a minimum thickness of from about 10 pm to about 200 Vim, in another embodiment is from about 30 p,m to about 150 p,m.
In one embodiment the outer coating layer is selected from the group consisting of film coatings, cellulose derivatives, cellulose ethers, methyl cellulose, ethylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low viscosity hydroxypropyl cellulose, low viscosity hydroxypropyl methylcellulose, wax or wax like substance, such as carnauba wax, fatty alcohols, hydrogenated vegetable oils, zein, shellac, sucrose, Arabic gum, polyethylene.
glycol, polyvinylpyrolidone, gelatin, sodium alginate, dextrin, psyllium husk powder, polymethacrylates, anionic polymethacrylates, poly(methacrylic acid, methyl methacrylate) 1:1, mixtures of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1, cellulose acetate phthalate, cellulose acetate trimelliate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate phthalate, poly(methacrylic acid, ethyl acrylate) 1:1, and compatible mixtures thereof.
In another embodiment the outer coating layer is selected from the group consisting of cellulose derivatives, cellulose ethers, methyl cellulose, ethylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low viscosity hydroxypropyl cellulose, low viscosity hydroxypropyl methylcellulose, fatty alcohols, hydrogenated vegetable oils, zein, shellac, sucrose, Arabic gum, polyethylene glycol, polyvinylpyrolidone, gelatin, sodium alginate, dextrin, psyllium husk powder, polymethacrylates, anionic polymethacrylates, poly(methacrylic acid, methyl methacrylate) 1:l, mixtures of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1, cellulose acetate phthalate, cellulose acetate trimelliate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate
6 succinate (HPMCAS), hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate phthalate, poly(methacrylic acid, ethyl acryiate) 1:1, and compatible mixtures thereof.
In another embodiment the outer coating layer is selected from the group consisting of anionic polymethacrylates, poly(methacrylic acid, methyl methacrylate) 1:1, mixtures of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1, cellulose acetate phthalate, cellulose acetate trimelliate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate phthalate, poly(methacrylic acid, ethyl acrylate) 1:1, and compatible mixtures thereof.
In another embodiment the outer coating layer is a single layer of a mixture of poly(methacrylic acid, methyl rnethacrylate) 1:1 (Eudragit~ L) and poly(methacrylic acid, methyl methacrylate) 1:2 (Eudragit~ S) in a ratio of about 1:10 to about :1:10, preferably about 1:5 to about 1:3 more preferably about 2:3. The coating thickness depends on the actual size of the unit dosage form, but in one embodiment the minimum coating thickness of the outer coating layer is from about lOp.m to about 50pm, in another embodiment is from about 20Eun to about 40pm.
In another embodiment the outer coating layer is a single coating of an enteric polymer that begins to dissolve in aqueous media at a pH between about 5 to about 6.3, in another embodiment at a pH between about 5 to about 6, in even another embodiment at a pH between about 5 to about 5.5.
In one embodiment, the function of the outer coating layer is to prevent or minimize fractures of the inner coating layer during formulation processing, manufacturing, and packaging, and the function of the inner coating layer is to maintain the desired point of release of the therapeutic active agent in the gastrointestinal Tract. For example if the inner coating is poly(methacrylic acid, methyl ntethacrylate) 1:2 (Eudragit~ Sj, the present invention maintains the desired point of release, as described, for example, in US Patent Nos.
5,541,170 and .5,541,171, Rhodes et al, In one embodiment the total coating thickness (both the inner and outer coating layers together) is from about 5 mg/cm2 to about 40 mg/crn2, in another embodiment is from about i0 mg/cm2 to about 15 mg/cm2.
Specific examples of the outer coating layer follow.
In another embodiment the outer coating layer is selected from the group consisting of anionic polymethacrylates, poly(methacrylic acid, methyl methacrylate) 1:1, mixtures of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1, cellulose acetate phthalate, cellulose acetate trimelliate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate phthalate, poly(methacrylic acid, ethyl acrylate) 1:1, and compatible mixtures thereof.
In another embodiment the outer coating layer is a single layer of a mixture of poly(methacrylic acid, methyl rnethacrylate) 1:1 (Eudragit~ L) and poly(methacrylic acid, methyl methacrylate) 1:2 (Eudragit~ S) in a ratio of about 1:10 to about :1:10, preferably about 1:5 to about 1:3 more preferably about 2:3. The coating thickness depends on the actual size of the unit dosage form, but in one embodiment the minimum coating thickness of the outer coating layer is from about lOp.m to about 50pm, in another embodiment is from about 20Eun to about 40pm.
In another embodiment the outer coating layer is a single coating of an enteric polymer that begins to dissolve in aqueous media at a pH between about 5 to about 6.3, in another embodiment at a pH between about 5 to about 6, in even another embodiment at a pH between about 5 to about 5.5.
In one embodiment, the function of the outer coating layer is to prevent or minimize fractures of the inner coating layer during formulation processing, manufacturing, and packaging, and the function of the inner coating layer is to maintain the desired point of release of the therapeutic active agent in the gastrointestinal Tract. For example if the inner coating is poly(methacrylic acid, methyl ntethacrylate) 1:2 (Eudragit~ Sj, the present invention maintains the desired point of release, as described, for example, in US Patent Nos.
5,541,170 and .5,541,171, Rhodes et al, In one embodiment the total coating thickness (both the inner and outer coating layers together) is from about 5 mg/cm2 to about 40 mg/crn2, in another embodiment is from about i0 mg/cm2 to about 15 mg/cm2.
Specific examples of the outer coating layer follow.
7 Eudragit~ L, is an anionic copolymer derived from methacrylic acid and methyl methacrylate, with a ratio of free carboxyl groups to the ester groups of approximately 1:1, and a mean molecular weight of approximately 135,000, from Rohm Tech;
Eudragit~ L 30 D, is an aqueous acrylic resin dispersion, an anionic copolymer derived from methacrylic acid and ethyl acrylate with a ratio of free carboxyl groups to the ester groups of approximately 1:1, and a mean molecular weight of approximately 250,000; (it is supplied as an aqueous dispersion containing 30% w/w of dry lacquer substance);
Eudragit~ L 100-55, is an anionic copolymer derived from methacrylic acid and ethyl acrylate, with a ratio of free carboxyl groups to the ester groups of approximately 1:l, and a mean molecular weight greater than about 100,000;
cellulose acetate phthalate or CAP~, available from Eastman Chemical;
cellulose acetate trimelliate, CAT~ available from Eastman Chemical;
hydroxypropyl methylcellulose phthalate (USP/NF type 220824) HPMCP 50~ and (USP/NF type 200731) HPMCP 55~ available from Shin Etsu Chemical;
polyvinyl acetate phthalate, PVAP~, available from Colorcon;
hydroxypropyl methylcellulose acetate succinate, HPMCAS~, available from Shin Etsu Chemical; hydroxypropylcellulose, Klucel ~.
To enhance the elasticity of the coating materials, preferably the coating material of the present invention also comprises a plasticizes. Appropriate plasticizers include polyethylene glycols, propylene glycols, 1, 2-propylene glycol, dibutyl phthalate, diethyl phthalate, tributyl citrate, tributyrin, butyl phthalyl butyl glycolate (Santicizer~ B-16, from Monsanto, St. Louis, Missouri), triacetin, castor oil and citric acid esters; in another embodiment the plasitcizer is dibutyl phthalate, tributyl citrate, or triethyl citrate. These plasticizers are present in an amount to facilitate the coating process and to obtain an even coating film with enhanced physical stability.
Generally the coating material comprises from about 0% to about 50% of aplasticizer, preferably from about 2% to about 25% by weight, more preferably from about 10% to about 20% by weight of the enteric polymer.
In addition, to facilitate the coating process, the coating material may also comprise inert solid particulates. Preferred inert solid particulates include talc and titanium dioxide.
Eudragit~ L 30 D, is an aqueous acrylic resin dispersion, an anionic copolymer derived from methacrylic acid and ethyl acrylate with a ratio of free carboxyl groups to the ester groups of approximately 1:1, and a mean molecular weight of approximately 250,000; (it is supplied as an aqueous dispersion containing 30% w/w of dry lacquer substance);
Eudragit~ L 100-55, is an anionic copolymer derived from methacrylic acid and ethyl acrylate, with a ratio of free carboxyl groups to the ester groups of approximately 1:l, and a mean molecular weight greater than about 100,000;
cellulose acetate phthalate or CAP~, available from Eastman Chemical;
cellulose acetate trimelliate, CAT~ available from Eastman Chemical;
hydroxypropyl methylcellulose phthalate (USP/NF type 220824) HPMCP 50~ and (USP/NF type 200731) HPMCP 55~ available from Shin Etsu Chemical;
polyvinyl acetate phthalate, PVAP~, available from Colorcon;
hydroxypropyl methylcellulose acetate succinate, HPMCAS~, available from Shin Etsu Chemical; hydroxypropylcellulose, Klucel ~.
To enhance the elasticity of the coating materials, preferably the coating material of the present invention also comprises a plasticizes. Appropriate plasticizers include polyethylene glycols, propylene glycols, 1, 2-propylene glycol, dibutyl phthalate, diethyl phthalate, tributyl citrate, tributyrin, butyl phthalyl butyl glycolate (Santicizer~ B-16, from Monsanto, St. Louis, Missouri), triacetin, castor oil and citric acid esters; in another embodiment the plasitcizer is dibutyl phthalate, tributyl citrate, or triethyl citrate. These plasticizers are present in an amount to facilitate the coating process and to obtain an even coating film with enhanced physical stability.
Generally the coating material comprises from about 0% to about 50% of aplasticizer, preferably from about 2% to about 25% by weight, more preferably from about 10% to about 20% by weight of the enteric polymer.
In addition, to facilitate the coating process, the coating material may also comprise inert solid particulates. Preferred inert solid particulates include talc and titanium dioxide.
8 The selections of optional plasticizes, optional inert solid particulate, and levels thereof, coating formulation type (solvent, ammoniated aqueous solution, or aqueous dispersion), and process are based upon the specific enteric polymer or film coatings used and the type of dosage form used according to criteria known to those skilled in the art. The solvent for the coating layers may be organic or aqueous. In one embodiment the coating layer is obtained via the use of an aqueous dispersion of the coating material.
The Dosage Form and Method of Making the Dosage Form A safe and effective amount of therapeutically active agent is incorporated into a solid unit dosage form. The term "solid unit dosage form" means any dosage form, preferably non-liquid, intended to be swallowed and having a sufficiently defined form to be coated. Solid unit dosage forms may be selected from the group consisting of a hard or soft capsule or a compressed tablet. In one embodiment the solid dosage forms of the present invention are selected from the group consisting of soft gelatin capsules; hard gelatin capsules; and compressed tablets of any size or shape. In one embodiment the unit dosage form of the present invention comprises a unit dosage form from about 550 mg to about 1.5 gram total weight, in another embodiment from about 600 mg to about 1.2 grams total weight, and in even another embodiment from about 750 mg to about 1 gram total weight.
In one embodiment the unit dosage form is a spherical or elliptical soft elastic gelatin capsule. The soft elastic gelatin capsule is filled with therapeutically active agent suspended in a suitable vehicle compatible with the soft gelatin capsule.
In still another embodiment the unit dosage form is a hard capsule (i.e.
starch or gelatin hard capsule), for example a starch capsule such as Capill~ from Capsulgel (Greenwood, SC) in which the length of the long axis of the capsule is less than about 10 mm and not more than about 1.5 times greater than the short axis diameter of the capsule. The capsule may be filled with a solid form of therapeutically active agent as described above, or alternatively with therapeutically active agent dissolved or suspended in a suitable vehicle compatible with the capsule wall.
In another embodiment the unit dosage form is a compressed spherical or elliptical tablet.
The tablet is comprised of a solid form of therapeutically active agent and is compressed using conventional equipment and processes.
In addition to the therapeutically active agent the compositions of this invention also generally comprise phan~naceutiacally acceptable excipients. As used herein, "excipient" means one or more compatible solid or liquid filler diluents or encapsulating substances which are
The Dosage Form and Method of Making the Dosage Form A safe and effective amount of therapeutically active agent is incorporated into a solid unit dosage form. The term "solid unit dosage form" means any dosage form, preferably non-liquid, intended to be swallowed and having a sufficiently defined form to be coated. Solid unit dosage forms may be selected from the group consisting of a hard or soft capsule or a compressed tablet. In one embodiment the solid dosage forms of the present invention are selected from the group consisting of soft gelatin capsules; hard gelatin capsules; and compressed tablets of any size or shape. In one embodiment the unit dosage form of the present invention comprises a unit dosage form from about 550 mg to about 1.5 gram total weight, in another embodiment from about 600 mg to about 1.2 grams total weight, and in even another embodiment from about 750 mg to about 1 gram total weight.
In one embodiment the unit dosage form is a spherical or elliptical soft elastic gelatin capsule. The soft elastic gelatin capsule is filled with therapeutically active agent suspended in a suitable vehicle compatible with the soft gelatin capsule.
In still another embodiment the unit dosage form is a hard capsule (i.e.
starch or gelatin hard capsule), for example a starch capsule such as Capill~ from Capsulgel (Greenwood, SC) in which the length of the long axis of the capsule is less than about 10 mm and not more than about 1.5 times greater than the short axis diameter of the capsule. The capsule may be filled with a solid form of therapeutically active agent as described above, or alternatively with therapeutically active agent dissolved or suspended in a suitable vehicle compatible with the capsule wall.
In another embodiment the unit dosage form is a compressed spherical or elliptical tablet.
The tablet is comprised of a solid form of therapeutically active agent and is compressed using conventional equipment and processes.
In addition to the therapeutically active agent the compositions of this invention also generally comprise phan~naceutiacally acceptable excipients. As used herein, "excipient" means one or more compatible solid or liquid filler diluents or encapsulating substances which are
9 suitable for administration to a subject. The term "compatible", as used herein, means that the components of the composition are capable of being commingled with the active agent, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations.
Pharmaceutically-acceptable excipients must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the subject being treated.
Excipients may act to facilitate incorporation of the therapeutically active agent into the dosage form, modify the release of the therapeutically active agent from the dosage form, stabilize the therapeutically active agent, or enhance absorption of the therapeutically active agent. Excipients should be safe for their intended use at the levels employed in the formulation. The formulation of therapeutically active agent and excipients is selected according to criteria well known to those skilled in the art to achieve the desired release rate, stability, absorption, and to facilitate the dosage form manufacture.
Some examples of pharmaceutically-acceptable excipients or components thereof are sugars, such as lactose, glucose, and sucrose; starches, such as cornstarch, potato starch, and sodium starch glycolate at a level of about 1% to about 8% by weight, in another embodiment from about 2% to about 4% by weight; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate; powdered tragacanth; malt; gelatin;
talc; solid lubricants, such as stearic acid, magnesium stearate; or calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid;
emulsifiers, such as the Tweens~; wetting agents such as sodium lauryl sulfate; coloring agents;
flavoring agents; excipients; tableting agents; stabilizers; antioxidants;
preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions. Excipients are described in Remington's Pharmaceutical Sciences, Mack Publishing Co. (19th edit. 1995);
Modern Pharmaceutics, Vol. 7, Chapters 9 & 10, Banker & Rhodes (1979); Lieberman, et al, Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2d (1976). Their selection will depend on secondary considerations like taste, cost, and shelf stability, etc. which are not critical for the purposes of the subject invention, and can be made without difficulty by those skilled in the art.
In one embodiment all of the dosage forms of the present invention are uniform in size prior to coating with the coating layers. The uniform size allows for uniform coating thickness and more uniform dissolution of the coating layers.
Enteric polymers are generally applied onto the unit dosage forms as solutions in organic or aqueous solvents. The solvents commonly employed as vehicles are water, methylene chloride, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate and combinations thereof.
The choice of the solvent is based primarily on the solubility of the polymer, ease of evaporation, and viscosity of the solution.
Some polymers are also available as aqueous systems. These include Eudragit~
(methacrylic acid-ethyl acrylate ester copolymer marketed by Rohm-Haas GmBH, West Germany); Aquateric~ (cellulose acetate phthalate-containing product marketed by FMC
Corporation, Philadelphia, Pa.); and Coateric ~ (a polyvinyl acetate phthalate based product marketed by Colorcon, Inc., West Point, Pa.). Unlike organic solutions, these aqueous-based systems can be prepared at high concentration without encountering high viscosity. Also, these aqueous systems do not have the problems associated with the organic systems such as flammability, toxicity of the residual solvent in the dosage form, etc.
Coating can be achieved by methods known to one skilled in the art such as by using fluidized bed equipment, perforated pans, a regular pharmaceutical pan, compression coating, continuous or short spray methods, or by drenching. For example, a plasticized dispersion of coating polymer may be applied onto the tablet core comprising the therapeutic active agent by spraying using any suitable spray equipment known in the art. In one embodiment the solid unit dosage forms are coated by continuous spray methods. In one embodiment the outer coating layer is applied after the inner coating layer but before the inner coating layer is dried and/or cured. In yet another embodiment the outer coating layer is applied immediately, e.g. within seconds, after the inner coating layer is applied. If a shiny finish coat is desired on the solid dosage forms of the present invention, a small quantity of polyethylene glycol can be applied to the finished dosage form.
The following non-limiting examples provide typical formulations for compositions of the present invention.
Example 1 A wet granulation of 5-ASA (active ingredient), lactose, and povidone is blended with talc, magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide.
The blend is compressed into approximately 1034 mg tablets containing 800 mg of the active ingredient on a standard pharmaceutical rotary tablet press.
An inner layer of an EUDRAGIT ~ S coating of 9.2 mg/cm2 dried coating (i.e.
about 62 microns) is applied to the core tablets first by pouring a portion of the coating formula without pigments and then by spraying coating onto the tablets. The coating suspension sprayed onto the tablets contains approximately 62% by weight on a dry basis of Eudragit ~ S
and is based in isopropyl alcohol and acetone with dibutylphthalate as the acting plasticizes.
An outer coating is either applied immediately following the application of the inner coating or once the inner coating has cured. The outer coating layer is sprayed onto the tablets to achieve of 4.1 mg/cm2 dried coating (i.e. about 28 microns). This coating suspension contains approximately 61% by weight on a dry basis of EUDRAGIT ~ S and L in a ratio of 3:2. It is based in isopropyl alcohol and acetone with dibutylphthalate as the acting plasticizes.
Example 2 A wet granulation of 5-ASA (active ingredient), lactose, and povidone is blended with talc, magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide.
The blend is compressed into approximately 1570 mg tablets containing 1200 mg of the active ingredient on a standard pharmaceutical rotary tablet press.
An inner layer of an EUDRAGIT ~ S and L mixture of 8.8 mg/cm2 dried coating (i.e. about 60 microns) is applied to the core tablets first by pouring a portion of the coating formula without pigments and then by spraying coating onto the tablets. The coating suspension sprayed onto the _ tablets contains approximately 61% by weight on a dry basis of Eudragit ~ S
and L in a ratio of 3:2 and is based in isopropyl alcohol and acetone with dibutylphthalate as the acting plasticizes.
An outer coating is applied immediately following the application of the inner coating or once the inner coating has cured. The outer coating layer is sprayed onto the tablets to achieve of 11.9 mg/cm2 dried coating (i.e. about 80 microns). This coating suspension contains approximately 38% by weight on a dry basis of EUDRAGIT ~ L and is based in isopropyl alcohol and acetone with triethyl citrate as the acting plasticizes.
Example 3 A wet granulation of 5-ASA (active ingredient), lactose" and povidone is blended with talc, magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide.
The blend is compressed into approximately 690 mg tablets containing 500 mg of the active ingredient on a standard pharmaceutical rosary tablet press.
An inner layer of an EUDRAG1T ~ S coating of 15.6 mg/cmZ dried coating (i.e.
about 105 microns) is applied to the core tablets first by pouring a portion of the coating formula without pigments and then by spraying coating onto the tablets. The coating;
suspension sprayed onto the tablets contains approximately 62% by weight on a dry basis of Eudragit C~ S
and is based in isopropyl alcohol and acetone with dibutylphthalate as the acting plasticizer.
An outer coating is applied immediately following the application o:f the inner coating or once the inner coating has cured. The outer Coating layer is a hydroxpropyl rnethylcellulose coating applied to a thickness of about 100 microns of dried coating according to the following formula:
Component Weight per Tablet Dri-Klear 3.7 g White Chroma-Tone2 1 g Water 48 g 'Drs-KIearT"" is a mixture of hydroxypropyl methylcelluiose, polyethylene glycol, hydroxypropyl cellulose, and silicon dioxide, manufactured by CHR Hansen.
2WhiteChroma-ToneT"" is a mixture of titanium dioxide and hydroxypropyl methylcellulose manufactured by CHR Hansen.
Example 4 Core tablets are manufactured to the following formula:
Component Weight per Tablet Ketoprofen 2 mg Lactose 4.96 mg Starch 0.80 mg polyvinylpyrrolidone (PVP) 0.16 mg Magnesium stearate 0.8 mg An inner layer of an EUDRAGIT ~ S coating about 20 microns is applied to the core tablets by spraying coating of the following formula:
Component EUDRAGIT ~ S100 3 g Diethyl phthalate 0.75 ml Silicone fluid 200/20CS 0.75 ml Methanol 25 parts 100 ml Dichloromehtane 75 parts An outer coating layer is applied to the core tablet and inner coating layer.
The outer coating layer is a hydroxpropyl methylcellulose coating applied to a thickness of about 150 microns of dried coating according to the following formula:
Component Dri-Klear 3.7 g White Chroma-Tone4 1 g Water 4g g 3Dri-Klear is a mixture of hyd~oxypropyl methylcellulose, polyethylene glycol, hydroxypropyl cellulose, and silicon dioxide, manufactured by CHR Hansen.
°White Chroma-Tone is a mixture of titanium dioxide and hydroxypropyl methylcellulose, manufactured by CHR Hansen.
Example 5 Applied to the core tablets described in Example 4 is an inner layer of an aqueous EUDRAGIT
L 30 D-55 coating of about 70 microns dried coating of the following formula:
Component EUDRAGIT~ L 30 D-55 26p g Talc 39 g Polyethylene glycol 6000 16 g Water 345 g An outer coating layer is then applied as a hydroxpropyl methylcellulose coating to a thickness of about 50 microns of dried coating according to the following formula:
component Dri-Klear 3.7 g White Chroma-Tone6 1 g Water 48 g Dri-Klear is a mixture of hydroxypropyl methylcellulose, polyethylene glycol, hydroxypropyl cellulose, and silicon dioxide, manufactured by CHR Hansen.
s White Chroma-Tone is a mixture of titanium dioxide and hydroxypropyl methylcellulose, 5 ~ manufactured by CHR Hansen.
Example 6 The following formulation is encapsulated within soft or hard gelatin capsules:
Component Weight per Tablet Insulin 20 i.u. (c.a. 1 mg) Sodium 5-methoxy salicyclate 150.0 mg PEG 4000 3.5 mg PEG 600 187.5 mg Capsule fill wt 342 mg Thereafter, the capsule is coated. An inner layer of an EUDRAGIT ~ S coating is applied to the capsules by spraying coating of the following formula to a thickness of about 100 microns dried coating:
component r UUKAGIT ~ 5100 70 g Triethyl citrate 14 g Acetone 283 g Isopropyl Alcohol 483 g Following the application of the inner coating, an outer coating layer of an EUDRAGIT ~ S and L mixture at a ratio of 2:3 of about 20 microns is applied to the tablets by spraying a coating of the following formula:
component Weight per Tablet EUDRAGIT ~ L100 42 g EUDRAGIT ~ S100 2g g Triethyl citrate 14 g Acetone 283 g Isopropyl Alcohol 483 g While particular embodiments of the present invention have been described, it will be obvious to those skilled in the art that various changes and modifications of the present invention can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention.
Pharmaceutically-acceptable excipients must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the subject being treated.
Excipients may act to facilitate incorporation of the therapeutically active agent into the dosage form, modify the release of the therapeutically active agent from the dosage form, stabilize the therapeutically active agent, or enhance absorption of the therapeutically active agent. Excipients should be safe for their intended use at the levels employed in the formulation. The formulation of therapeutically active agent and excipients is selected according to criteria well known to those skilled in the art to achieve the desired release rate, stability, absorption, and to facilitate the dosage form manufacture.
Some examples of pharmaceutically-acceptable excipients or components thereof are sugars, such as lactose, glucose, and sucrose; starches, such as cornstarch, potato starch, and sodium starch glycolate at a level of about 1% to about 8% by weight, in another embodiment from about 2% to about 4% by weight; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate; powdered tragacanth; malt; gelatin;
talc; solid lubricants, such as stearic acid, magnesium stearate; or calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid;
emulsifiers, such as the Tweens~; wetting agents such as sodium lauryl sulfate; coloring agents;
flavoring agents; excipients; tableting agents; stabilizers; antioxidants;
preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions. Excipients are described in Remington's Pharmaceutical Sciences, Mack Publishing Co. (19th edit. 1995);
Modern Pharmaceutics, Vol. 7, Chapters 9 & 10, Banker & Rhodes (1979); Lieberman, et al, Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2d (1976). Their selection will depend on secondary considerations like taste, cost, and shelf stability, etc. which are not critical for the purposes of the subject invention, and can be made without difficulty by those skilled in the art.
In one embodiment all of the dosage forms of the present invention are uniform in size prior to coating with the coating layers. The uniform size allows for uniform coating thickness and more uniform dissolution of the coating layers.
Enteric polymers are generally applied onto the unit dosage forms as solutions in organic or aqueous solvents. The solvents commonly employed as vehicles are water, methylene chloride, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate and combinations thereof.
The choice of the solvent is based primarily on the solubility of the polymer, ease of evaporation, and viscosity of the solution.
Some polymers are also available as aqueous systems. These include Eudragit~
(methacrylic acid-ethyl acrylate ester copolymer marketed by Rohm-Haas GmBH, West Germany); Aquateric~ (cellulose acetate phthalate-containing product marketed by FMC
Corporation, Philadelphia, Pa.); and Coateric ~ (a polyvinyl acetate phthalate based product marketed by Colorcon, Inc., West Point, Pa.). Unlike organic solutions, these aqueous-based systems can be prepared at high concentration without encountering high viscosity. Also, these aqueous systems do not have the problems associated with the organic systems such as flammability, toxicity of the residual solvent in the dosage form, etc.
Coating can be achieved by methods known to one skilled in the art such as by using fluidized bed equipment, perforated pans, a regular pharmaceutical pan, compression coating, continuous or short spray methods, or by drenching. For example, a plasticized dispersion of coating polymer may be applied onto the tablet core comprising the therapeutic active agent by spraying using any suitable spray equipment known in the art. In one embodiment the solid unit dosage forms are coated by continuous spray methods. In one embodiment the outer coating layer is applied after the inner coating layer but before the inner coating layer is dried and/or cured. In yet another embodiment the outer coating layer is applied immediately, e.g. within seconds, after the inner coating layer is applied. If a shiny finish coat is desired on the solid dosage forms of the present invention, a small quantity of polyethylene glycol can be applied to the finished dosage form.
The following non-limiting examples provide typical formulations for compositions of the present invention.
Example 1 A wet granulation of 5-ASA (active ingredient), lactose, and povidone is blended with talc, magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide.
The blend is compressed into approximately 1034 mg tablets containing 800 mg of the active ingredient on a standard pharmaceutical rotary tablet press.
An inner layer of an EUDRAGIT ~ S coating of 9.2 mg/cm2 dried coating (i.e.
about 62 microns) is applied to the core tablets first by pouring a portion of the coating formula without pigments and then by spraying coating onto the tablets. The coating suspension sprayed onto the tablets contains approximately 62% by weight on a dry basis of Eudragit ~ S
and is based in isopropyl alcohol and acetone with dibutylphthalate as the acting plasticizes.
An outer coating is either applied immediately following the application of the inner coating or once the inner coating has cured. The outer coating layer is sprayed onto the tablets to achieve of 4.1 mg/cm2 dried coating (i.e. about 28 microns). This coating suspension contains approximately 61% by weight on a dry basis of EUDRAGIT ~ S and L in a ratio of 3:2. It is based in isopropyl alcohol and acetone with dibutylphthalate as the acting plasticizes.
Example 2 A wet granulation of 5-ASA (active ingredient), lactose, and povidone is blended with talc, magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide.
The blend is compressed into approximately 1570 mg tablets containing 1200 mg of the active ingredient on a standard pharmaceutical rotary tablet press.
An inner layer of an EUDRAGIT ~ S and L mixture of 8.8 mg/cm2 dried coating (i.e. about 60 microns) is applied to the core tablets first by pouring a portion of the coating formula without pigments and then by spraying coating onto the tablets. The coating suspension sprayed onto the _ tablets contains approximately 61% by weight on a dry basis of Eudragit ~ S
and L in a ratio of 3:2 and is based in isopropyl alcohol and acetone with dibutylphthalate as the acting plasticizes.
An outer coating is applied immediately following the application of the inner coating or once the inner coating has cured. The outer coating layer is sprayed onto the tablets to achieve of 11.9 mg/cm2 dried coating (i.e. about 80 microns). This coating suspension contains approximately 38% by weight on a dry basis of EUDRAGIT ~ L and is based in isopropyl alcohol and acetone with triethyl citrate as the acting plasticizes.
Example 3 A wet granulation of 5-ASA (active ingredient), lactose" and povidone is blended with talc, magnesium stearate, sodium starch glycolate, and colloidal silicon dioxide.
The blend is compressed into approximately 690 mg tablets containing 500 mg of the active ingredient on a standard pharmaceutical rosary tablet press.
An inner layer of an EUDRAG1T ~ S coating of 15.6 mg/cmZ dried coating (i.e.
about 105 microns) is applied to the core tablets first by pouring a portion of the coating formula without pigments and then by spraying coating onto the tablets. The coating;
suspension sprayed onto the tablets contains approximately 62% by weight on a dry basis of Eudragit C~ S
and is based in isopropyl alcohol and acetone with dibutylphthalate as the acting plasticizer.
An outer coating is applied immediately following the application o:f the inner coating or once the inner coating has cured. The outer Coating layer is a hydroxpropyl rnethylcellulose coating applied to a thickness of about 100 microns of dried coating according to the following formula:
Component Weight per Tablet Dri-Klear 3.7 g White Chroma-Tone2 1 g Water 48 g 'Drs-KIearT"" is a mixture of hydroxypropyl methylcelluiose, polyethylene glycol, hydroxypropyl cellulose, and silicon dioxide, manufactured by CHR Hansen.
2WhiteChroma-ToneT"" is a mixture of titanium dioxide and hydroxypropyl methylcellulose manufactured by CHR Hansen.
Example 4 Core tablets are manufactured to the following formula:
Component Weight per Tablet Ketoprofen 2 mg Lactose 4.96 mg Starch 0.80 mg polyvinylpyrrolidone (PVP) 0.16 mg Magnesium stearate 0.8 mg An inner layer of an EUDRAGIT ~ S coating about 20 microns is applied to the core tablets by spraying coating of the following formula:
Component EUDRAGIT ~ S100 3 g Diethyl phthalate 0.75 ml Silicone fluid 200/20CS 0.75 ml Methanol 25 parts 100 ml Dichloromehtane 75 parts An outer coating layer is applied to the core tablet and inner coating layer.
The outer coating layer is a hydroxpropyl methylcellulose coating applied to a thickness of about 150 microns of dried coating according to the following formula:
Component Dri-Klear 3.7 g White Chroma-Tone4 1 g Water 4g g 3Dri-Klear is a mixture of hyd~oxypropyl methylcellulose, polyethylene glycol, hydroxypropyl cellulose, and silicon dioxide, manufactured by CHR Hansen.
°White Chroma-Tone is a mixture of titanium dioxide and hydroxypropyl methylcellulose, manufactured by CHR Hansen.
Example 5 Applied to the core tablets described in Example 4 is an inner layer of an aqueous EUDRAGIT
L 30 D-55 coating of about 70 microns dried coating of the following formula:
Component EUDRAGIT~ L 30 D-55 26p g Talc 39 g Polyethylene glycol 6000 16 g Water 345 g An outer coating layer is then applied as a hydroxpropyl methylcellulose coating to a thickness of about 50 microns of dried coating according to the following formula:
component Dri-Klear 3.7 g White Chroma-Tone6 1 g Water 48 g Dri-Klear is a mixture of hydroxypropyl methylcellulose, polyethylene glycol, hydroxypropyl cellulose, and silicon dioxide, manufactured by CHR Hansen.
s White Chroma-Tone is a mixture of titanium dioxide and hydroxypropyl methylcellulose, 5 ~ manufactured by CHR Hansen.
Example 6 The following formulation is encapsulated within soft or hard gelatin capsules:
Component Weight per Tablet Insulin 20 i.u. (c.a. 1 mg) Sodium 5-methoxy salicyclate 150.0 mg PEG 4000 3.5 mg PEG 600 187.5 mg Capsule fill wt 342 mg Thereafter, the capsule is coated. An inner layer of an EUDRAGIT ~ S coating is applied to the capsules by spraying coating of the following formula to a thickness of about 100 microns dried coating:
component r UUKAGIT ~ 5100 70 g Triethyl citrate 14 g Acetone 283 g Isopropyl Alcohol 483 g Following the application of the inner coating, an outer coating layer of an EUDRAGIT ~ S and L mixture at a ratio of 2:3 of about 20 microns is applied to the tablets by spraying a coating of the following formula:
component Weight per Tablet EUDRAGIT ~ L100 42 g EUDRAGIT ~ S100 2g g Triethyl citrate 14 g Acetone 283 g Isopropyl Alcohol 483 g While particular embodiments of the present invention have been described, it will be obvious to those skilled in the art that various changes and modifications of the present invention can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of this invention.
Claims (26)
a. a therapeutically active agent;
b. an inner coating layer selected from the group of poly(methacrylic acid, methyl methacrylate) 1:2, poly(methacrylic acid, methyl methacrylate)
1:1, and mixtures thereof; and c. an outer coating layer comprising an enteric polymer or film coating material;
wherein the inner coating layer is not the same as the outer coating layer;
wherein if the inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:1 then the outer coating layer is not poly(methacrylic acid, methyl methacrylate) 1:2 or is not a mixture of poly(methacrylic acid, methyl methacrylate) 1:1 and poly(methacrylic acid, methyl methacrylate) 1:2; and wherein the inner coating layer and the outer coating layer contain no therapeutically active agent.
wherein the inner coating layer is not the same as the outer coating layer;
wherein if the inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:1 then the outer coating layer is not poly(methacrylic acid, methyl methacrylate) 1:2 or is not a mixture of poly(methacrylic acid, methyl methacrylate) 1:1 and poly(methacrylic acid, methyl methacrylate) 1:2; and wherein the inner coating layer and the outer coating layer contain no therapeutically active agent.
2. The composition of claim 1 wherein the inner coating is poly(methacrylic acid, methyl methacrylate) 1:2.
3. The composition of claim 1 wherein the outer coating layer is selected from the group of cellulose derivatives, cellulose ethers, methyl cellulose, ethylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low viscosity hydroxypropyl cellulose, low viscosity hydroxypropyl methylcellulose, wax or wax like substance, carnauba wax, fatty alcohols, hydrogenated vegetable oils, zero, shellac, sucrose, Arabic gum, polyethylene glycol, polyvinylpyrolidone, gelatin, sodium alginate, dextrin, psyllium husk powder, polymethacrylates, anionic polymethacrylates, poly(methacrylic acid, methyl methacrylate) 1:1, mixtures of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1, cellulose acetate phthalate, cellulose acetate trimelliate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate phthalate, poly(methacrylic acid, ethyl acrylate) 1:1, and compatible mixtures thereof.
4. The composition of claim 3 wherein the outer coating layer is selected from the group of anionic polymethacrylates, poly(methacrylic acid, methyl methacrylate) 1:1, mixtures of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1, cellulose acetate phthalate, cellulose acetate trimelliate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate phthalate, poly(methacrylic acid, ethyl acrylate) 1:1, and compatible mixtures thereof.
5. The composition of claim 1 wherein the total coating thickness of the inner and outer coating layers combined is from about 5 mg/cm2 to about 40 mg/cm2.
6. The composition of claim 5 wherein the total coating thickness is from about 10 mg/cm2 to about 15 mg/cm2.
7. The composition of claim 6 wherein the solid dosage form is coated by continuous spray methods wherein the outer coating layer is applied after the inner coating layer but before the inner coating layer is dried or cured.
8. The composition of claim 1 wherein the therapeutically active agent is selected from the group of laxatives, anti-diarrheals, nonsteroidal anti-inflammatory agents, 5-ASA, glucocorticoids, antimicrobials, immunosuppressants, chemotherapeutics or anticancer drugs, peptides, proteins, cardiovascular drugs, psychotropic drugs, H2-blockers, antiasthmatic agents, and antihistamines.
9. The composition of claim 8 wherein the therapeutically active agent is a nonsteroidal anti-inflammatory agent.
10. The composition of claim 9 wherein the therapeutically active agent is 5-ASA.
11. A pharmaceutical composition in a solid unit dosage form for oral administration in a human or lower animal comprising:
a. 5-ASA;
b. an inner coating layer selected from the group of poly(methacrylic acid, methyl methacrylate) 1:2, poly(methacrylic acid, methyl methacrylate) 1:1, and mixtures thereof; and c. an outer coating layer comprising an enteric polymer or film coating material;
wherein the inner coating layer is not the same as the outer coating layer;
wherein if the inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:1 then the outer coating layer is not poly(methacrylic acid, methyl methacrylate) 1:2 or is not a mixture of poly(methacrylic acid, methyl methacrylate) 1:1 and poly(methacrylic acid, methyl methacrylate) 1:2; and wherein the inner coating layer and the outer coating layer contain no 5-ASA.
a. 5-ASA;
b. an inner coating layer selected from the group of poly(methacrylic acid, methyl methacrylate) 1:2, poly(methacrylic acid, methyl methacrylate) 1:1, and mixtures thereof; and c. an outer coating layer comprising an enteric polymer or film coating material;
wherein the inner coating layer is not the same as the outer coating layer;
wherein if the inner coating layer is poly(methacrylic acid, methyl methacrylate) 1:1 then the outer coating layer is not poly(methacrylic acid, methyl methacrylate) 1:2 or is not a mixture of poly(methacrylic acid, methyl methacrylate) 1:1 and poly(methacrylic acid, methyl methacrylate) 1:2; and wherein the inner coating layer and the outer coating layer contain no 5-ASA.
12. A pharmaceutical composition in a solid unit dosage form for oral administration in a human or lower animal comprising:
a. a therapeutically active agent;
b. an inner coating layer comprising poly(methacrylic acid, methyl methacrylate) 1:2; and c. an outer coating layer comprising an enteric polymer or film coating material;
wherein the inner coating layer is not the same as the outer layer coating.
a. a therapeutically active agent;
b. an inner coating layer comprising poly(methacrylic acid, methyl methacrylate) 1:2; and c. an outer coating layer comprising an enteric polymer or film coating material;
wherein the inner coating layer is not the same as the outer layer coating.
13. The composition of claim 12 wherein the outer coating layer is selected from the group of cellulose derivatives, cellulose ethers, methyl cellulose, ethylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, low viscosity hydroxypropyl cellulose, low viscosity hydroxypropyl methylcellulose, wax or wax like substance, carnauba wax, fatty alcohols, hydrogenated vegetable oils, zero, shellac, sucrose, Arabic gum, polyethylene glycol, polyvinylpyrolidone, gelatin, sodium alginate, dextrin, psyllium husk powder, polymethacrylates, anionic polymethacrylates, poly(methacrylic acid, methyl methacrylate) 1:1, mixtures of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1, cellulose acetate phthalate, cellulose acetate trimelliate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate phthalate, poly(methacrylic acid, ethyl acrylate) 1:1, and compatible mixtures thereof.
14. The composition of claim 13 wherein the outer coating layer is selected from the group of anionic polymethacrylates, poly(methacrylic acid, methyl methacrylate) 1:1, mixtures of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1, cellulose acetate phthalate, cellulose acetate trimelliate, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose propionate phthalate, cellulose acetate maleate, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose hexahydrophthalate, polyvinyl acetate phthalate, poly(methacrylic acid, ethyl acrylate) 1:1, and compatible mixtures thereof.
15. The composition of claim 14 wherein the outer coating is selected from the group of poly(methacrylic acid, methyl methacrylate) 1:1 and mixtures of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1.
16. The composition of claim 15 wherein the outer coating is a mixture of poly(methacrylic acid, methyl methacrylate) 1:2 and poly(methacrylic acid, methyl methacrylate) 1:1.
17. The composition of claim 12 wherein the total coating thickness of the inner and outer coating layers combined is from about 5 mg/cm2 to about 40 mg/cm2.
18. The composition of claim 17 wherein the total coating thickness is from about 10 mg/cm2 to about 15 mg/cm2.
19. The composition of claim 18 wherein the solid dosage form is coated by continuous spray methods wherein the outer coating layer is applied after the inner coating layer but before the inner coating layer is dried or cured.
20. The composition of claim 12 wherein the therapeutically active agent is selected from the group of laxatives, anti-diarrheals, nonsteroidal anti-inflammatory agents, 5-ASA, glucocorticoids, antimicrobials, immunosuppressants, chemotherapeutics or anticancer drugs, peptides, proteins, cardiovascular drugs, psychotropic drugs, H2-blockers, antiasthmatic agents, and antihistamines.
21. The composition of claim 20 wherein the therapeutically active agent is a nonsteroidal anti-inflammatory agent.
22. The composition of claim 21 wherein the therapeutically active agent is 5-ASA.
23. The composition of claim 12 wherein the solid dosage form is a compressed tablet.
24. A pharmaceutical composition in a solid unit dosage form for oral administration in a human or lower animal comprising:
a. 5-ASA;
b. an inner coating layer comprising poly(methacrylic acid, methyl methacrylate) 1:2; and c. an outer coating layer comprising an enteric polymer or film coating material;
wherein the inner coating layer is not the same as the outer layer coating.
a. 5-ASA;
b. an inner coating layer comprising poly(methacrylic acid, methyl methacrylate) 1:2; and c. an outer coating layer comprising an enteric polymer or film coating material;
wherein the inner coating layer is not the same as the outer layer coating.
25. Use of the composition of any one of claims 1-24, to maintain a therapeutically active agent at a desired site of delivery.
26. The use to claim 25, wherein the desired site of delivery is the gastrointestinal tract.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002444814A CA2444814C (en) | 2001-10-24 | 2001-10-24 | Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US25212200P | 2000-11-20 | 2000-11-20 | |
| US60/252,122 | 2000-11-20 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002444814A Division CA2444814C (en) | 2001-10-24 | 2001-10-24 | Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2359812A1 CA2359812A1 (en) | 2002-05-20 |
| CA2359812C true CA2359812C (en) | 2004-02-10 |
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ID=22954700
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002359812A Expired - Lifetime CA2359812C (en) | 2000-11-20 | 2001-10-24 | Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures |
Country Status (3)
| Country | Link |
|---|---|
| US (4) | US6893662B2 (en) |
| CA (1) | CA2359812C (en) |
| PE (1) | PE20020529A1 (en) |
Families Citing this family (65)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020035071A1 (en) * | 1997-07-08 | 2002-03-21 | Josef Pitha | Mimicking the metabolic effects of caloric restriction by administration of glucose antimetabolites |
| US20060116330A1 (en) * | 1997-07-08 | 2006-06-01 | The Iams Company | Methods of mimicking the metabolic effects of caloric restriction by administration of mannoheptulose |
| US8563522B2 (en) * | 1997-07-08 | 2013-10-22 | The Iams Company | Method of maintaining and/or attenuating a decline in quality of life |
| CA2359812C (en) * | 2000-11-20 | 2004-02-10 | The Procter & Gamble Company | Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures |
| US8168170B2 (en) * | 2002-10-03 | 2012-05-01 | The Procter And Gamble Company | Compositions having an inner core and at least three surrounding layers |
| WO2004087113A1 (en) * | 2003-04-04 | 2004-10-14 | Ranbaxy Laboratories Limited | Pharmaceutical compositions for colon specific delivery |
| US7825106B2 (en) | 2003-09-03 | 2010-11-02 | Agi Therapeutics Ltd. | Modified release formulations and methods of treating inflammatory bowel disease |
| US7737133B2 (en) | 2003-09-03 | 2010-06-15 | Agi Therapeutics Ltd. | Formulations and methods of treating inflammatory bowel disease |
| MY147202A (en) * | 2003-11-26 | 2012-11-14 | Novartis Ag | Compositions comprising organic compounds |
| US20050158294A1 (en) * | 2003-12-19 | 2005-07-21 | The Procter & Gamble Company | Canine probiotic Bifidobacteria pseudolongum |
| US8894991B2 (en) * | 2003-12-19 | 2014-11-25 | The Iams Company | Canine probiotic Lactobacilli |
| US7785635B1 (en) | 2003-12-19 | 2010-08-31 | The Procter & Gamble Company | Methods of use of probiotic lactobacilli for companion animals |
| US20050152884A1 (en) * | 2003-12-19 | 2005-07-14 | The Procter & Gamble Company | Canine probiotic Bifidobacteria globosum |
| US8877178B2 (en) | 2003-12-19 | 2014-11-04 | The Iams Company | Methods of use of probiotic bifidobacteria for companion animals |
| EP2361620B1 (en) | 2004-02-06 | 2016-04-06 | PHARMATEL (R&D) PTY LIMITED as Trustee for the PHARMATEL (R & D) TRUST | Use of aminosalicylates in diarrhoea-predominant irritable bowel syndrome |
| CN1938006B (en) | 2004-03-31 | 2010-11-10 | Bpsi控股公司 | Enteric coatings for orally ingestible substrates |
| JP5009152B2 (en) * | 2004-05-28 | 2012-08-22 | サリックス ファーマシューティカルズ， インコーポレイテッド | Prevention, treatment, and recovery of radiation-induced enteritis |
| US20090208579A1 (en) * | 2004-12-27 | 2009-08-20 | Eisai R & D Management Co., Ltd. | Matrix Type Sustained-Release Preparation Containing Basic Drug or Salt Thereof, and Method for Manufacturing the Same |
| WO2006070930A1 (en) * | 2004-12-27 | 2006-07-06 | Eisai R & D Management Co., Ltd. | Method for stabilizing anti-dementia drug |
| US20060280789A1 (en) * | 2004-12-27 | 2006-12-14 | Eisai Research Institute | Sustained release formulations |
| US20060246003A1 (en) * | 2004-12-27 | 2006-11-02 | Eisai Co. Ltd. | Composition containing anti-dementia drug |
| US20070129402A1 (en) * | 2004-12-27 | 2007-06-07 | Eisai Research Institute | Sustained release formulations |
| ES2607988T3 (en) * | 2005-05-31 | 2017-04-05 | Iams Europe B.V. | Feline probiotic bifidobacteria |
| EP1880001B1 (en) * | 2005-05-31 | 2011-06-08 | The Iams Company | Feline probiotic lactobacilli |
| US20100154146A1 (en) | 2008-07-02 | 2010-06-24 | S.C. Johnson & Son, Inc. | Carpet decor and setting solution compositions |
| US8557758B2 (en) | 2005-06-07 | 2013-10-15 | S.C. Johnson & Son, Inc. | Devices for applying a colorant to a surface |
| US8061269B2 (en) | 2008-05-14 | 2011-11-22 | S.C. Johnson & Son, Inc. | Multilayer stencils for applying a design to a surface |
| US7776108B2 (en) | 2005-06-07 | 2010-08-17 | S.C. Johnson & Son, Inc. | Composition for application to a surface |
| US20070277849A1 (en) * | 2006-06-06 | 2007-12-06 | Shah Ketan N | Method of neutralizing a stain on a surface |
| US8846154B2 (en) | 2005-06-07 | 2014-09-30 | S.C. Johnson & Son, Inc. | Carpet décor and setting solution compositions |
| US7727289B2 (en) | 2005-06-07 | 2010-06-01 | S.C. Johnson & Son, Inc. | Composition for application to a surface |
| EP1901853A1 (en) | 2005-06-07 | 2008-03-26 | S.C. Johnson & Son, Inc. | Design devices for applying a design to a surface |
| US7452872B2 (en) | 2005-08-24 | 2008-11-18 | Salix Pharmaceuticals, Inc. | Formulations and uses of 2-hydroxy-5-phenylazobenzoic acid derivatives |
| NZ565974A (en) * | 2005-08-24 | 2012-07-27 | Salix Pharmaceuticals Ltd | Balsalazide formulations and manufacture and use thereof |
| US8921344B2 (en) * | 2006-11-03 | 2014-12-30 | Salix Pharmaceuticals, Inc. | Formulations and uses of 2-hydroxy-5-phenylazobenzoic acid derivatives |
| US7964215B1 (en) | 2006-01-24 | 2011-06-21 | Emet Pharmaceuticals, LLC | Delayed release dosage form |
| US20070184111A1 (en) * | 2006-02-03 | 2007-08-09 | Pharmavite Llc | Hybrid tablet |
| US20070253927A1 (en) * | 2006-04-13 | 2007-11-01 | Gwenaelle Jegou | Cosmetic compositions comprising at least one dielectrophile monomer and at least one radical initiator |
| JP5052051B2 (en) * | 2006-06-16 | 2012-10-17 | トーアエイヨー株式会社 | Enteric granules and method for producing the same |
| JP5171626B2 (en) * | 2006-08-11 | 2013-03-27 | 旭化成ケミカルズ株式会社 | Method for producing poorly water-soluble drug-containing spheroid granules |
| BRPI0622007A2 (en) * | 2006-09-13 | 2011-12-20 | Procter & Gamble | use of aminosalicylate to treat ulcerative colitis |
| AU2006348180A1 (en) * | 2006-09-13 | 2008-03-20 | Warner Chilcott Company, Llc | Methods of treatment for ulcerative colitis |
| US8394415B2 (en) * | 2006-11-21 | 2013-03-12 | Mcneil-Ppc, Inc | Modified release analgesic suspensions |
| EP2124966B1 (en) | 2007-02-01 | 2015-09-09 | IAMS Europe B.V. | Method for decreasing inflammation and stress in a mammal using glucose antimetabolites, avocado or avocado extracts |
| CN103316326B (en) | 2007-04-04 | 2016-06-15 | 希格默伊德药业有限公司 | Pharmaceutical cyclosporin compositions |
| SI2152250T1 (en) * | 2007-05-07 | 2020-06-30 | Evonik Operations Gmbh | Solid dosage forms comprising an enteric coating with accelerated drug release |
| US9833510B2 (en) * | 2007-06-12 | 2017-12-05 | Johnson & Johnson Consumer Inc. | Modified release solid or semi-solid dosage forms |
| US20090028944A1 (en) * | 2007-07-16 | 2009-01-29 | Balaji Sathurappan | Pharmaceutical compositions comprising mesalamine |
| US20090036414A1 (en) * | 2007-08-02 | 2009-02-05 | Mutual Pharmaceutical Company, Inc. | Mesalamine Formulations |
| US9771199B2 (en) | 2008-07-07 | 2017-09-26 | Mars, Incorporated | Probiotic supplement, process for making, and packaging |
| WO2010080730A2 (en) * | 2009-01-09 | 2010-07-15 | Mayo Foundation For Medical Education And Research | Methods and materials for delivering bile acids |
| US10104903B2 (en) | 2009-07-31 | 2018-10-23 | Mars, Incorporated | Animal food and its appearance |
| JP5795585B2 (en) * | 2009-08-28 | 2015-10-14 | ハーキュリーズ・インコーポレーテッドＨｅｒｃｕｌｅｓ Ｉｎｃｏｒｐｏｒａｔｅｄ | Film coating composition from solid powder compound |
| US20140066837A1 (en) | 2012-07-26 | 2014-03-06 | Ronald L. Moy | Skin care compositions and methods |
| US20140141075A1 (en) | 2012-11-21 | 2014-05-22 | Warner Chilcott Company, Llc | 5-aminosalicylic acid capsule formulation |
| US8859005B2 (en) | 2012-12-03 | 2014-10-14 | Intercontinental Great Brands Llc | Enteric delivery of functional ingredients suitable for hot comestible applications |
| US9539265B2 (en) | 2013-03-15 | 2017-01-10 | Aihol Corporation | Pharmaceutical formulation containing glycosaminoglycan |
| WO2014152450A1 (en) | 2013-03-15 | 2014-09-25 | Warner Chilcott Company, Llc | Mesalamine pharmaceutical composition with multiple dosage elements for reduced delivery variability |
| US20160331689A1 (en) | 2015-05-12 | 2016-11-17 | SE Tylose USA, Inc. | Aqueous enteric coating composition |
| EP3365180B1 (en) * | 2015-10-21 | 2019-12-18 | Capsugel Belgium NV | Printing process for oral dosage forms |
| US10874617B2 (en) * | 2016-04-19 | 2020-12-29 | Ferring B.V. | Oral pharmaceutical compositions of mesalazine |
| GB2571696B (en) | 2017-10-09 | 2020-05-27 | Compass Pathways Ltd | Large scale method for the preparation of Psilocybin and formulations of Psilocybin so produced |
| US10098898B1 (en) | 2017-12-04 | 2018-10-16 | Handa Pharmaceuticals, Llc | Release stable mesalamine dosage forms |
| CA3138100A1 (en) | 2019-04-17 | 2020-10-22 | Compass Pathfinder Limited | Treatment of depression and other various disorders with psilocybin |
| WO2022254456A1 (en) * | 2021-06-01 | 2022-12-08 | Nbi Biosciences Pvt Ltd | Microbial-triggered oral intestinal drug delivery formulation and method of preparation thereof |
Family Cites Families (186)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2512247A1 (en) | 1975-03-20 | 1976-10-14 | Thomae Gmbh Dr K | Tablets contg. drying agents - for protection against moisture |
| US4211777A (en) * | 1977-11-25 | 1980-07-08 | Fisons Limited | Compositions comprising a compound having sodium cromoglycate activity and aminosalicylic acid |
| FR2471186A1 (en) | 1979-12-10 | 1981-06-19 | Roussel Uclaf | NEW COLIC DELITESCENCE TABLETS AND THEIR PREPARATION PROCESS |
| JPS57500432A (en) * | 1980-03-20 | 1982-03-11 | ||
| SE8003805L (en) | 1980-05-21 | 1981-11-22 | Haessle Ab | A PHARMACEUTICAL PREPARATION WITH IMPROVED EMISSION PROPERTY |
| US4412992A (en) * | 1980-07-21 | 1983-11-01 | Biorex Laboratories Limited | 2-Hydroxy-5-phenylazobenzoic acid derivatives and method of treating ulcerative colitis therewith |
| NZ198241A (en) * | 1980-09-27 | 1983-12-16 | Beecham Group Ltd | Tablet containing amoxycillin and potassium clavulanate |
| US4312806A (en) | 1981-03-02 | 1982-01-26 | G. D. Searle & Co. | Method and compounds for treating inflammatory bowel disease |
| ZA825384B (en) | 1981-07-31 | 1983-05-25 | Tillott J B Ltd | Orally administrable pharmaceutical compositions |
| JPS58109413A (en) | 1981-12-23 | 1983-06-29 | Eisai Co Ltd | Shock-resistant enteric tablet |
| DE3151196A1 (en) | 1981-12-23 | 1983-06-30 | Kurt Heinz Prof. Dr. 7800 Freiburg Bauer | METHOD FOR PRODUCING EASILY SOLUBLE 5-AMINOSALICYL ACID MEDICAL PREPARATIONS |
| JPS58213073A (en) | 1982-06-07 | 1983-12-10 | Masatoshi Yamada | Solidification of oily substance |
| US4539198A (en) * | 1983-07-07 | 1985-09-03 | Rowell Laboratories, Inc. | Solid pharmaceutical formulations for slow, zero order release via controlled surface erosion: expanded range |
| SE457505B (en) | 1984-01-10 | 1989-01-09 | Lejus Medical Ab | LAMINATED ORAL PHARMACEUTICAL COMPOSITION AND PROCEDURES FOR ITS PREPARATION |
| US4552899A (en) * | 1984-04-09 | 1985-11-12 | Analgesic Associates | Cough/cold mixtures comprising non-steroidal anti-inflammatory drugs |
| US4678516A (en) | 1984-10-09 | 1987-07-07 | The Dow Chemical Company | Sustained release dosage form based on highly plasticized cellulose ether gels |
| DK153412C (en) * | 1984-11-22 | 1988-12-19 | Ferring A S | PROCEDURE FOR THE PREPARATION OF P-AMINOPHENOLS BY ELECTROLYSE |
| IL77186A0 (en) | 1985-11-29 | 1986-04-29 | Touitou Elka | Pharmaceutical insulin composition |
| SE460945B (en) | 1987-01-15 | 1989-12-11 | Lejus Medical Ab | A MULTIPLE-UNIT DOS COMPOSITION OF FUROSEMID |
| US5026560A (en) * | 1987-01-29 | 1991-06-25 | Takeda Chemical Industries, Ltd. | Spherical granules having core and their production |
| US5068110A (en) * | 1987-09-29 | 1991-11-26 | Warner-Lambert Company | Stabilization of enteric coated dosage form |
| JP2514078B2 (en) | 1988-08-22 | 1996-07-10 | エスエス製薬株式会社 | Compressed formulation |
| IT1230576B (en) * | 1988-10-20 | 1991-10-28 | Angeli Inst Spa | ORAL PHARMACEUTICAL FORMULATIONS WITH SELECTIVE LIBERATION IN THE COLON |
| DE3838094A1 (en) | 1988-11-10 | 1990-05-17 | Nordmark Arzneimittel Gmbh | SOLID PHARMACEUTICAL RETARD FORM |
| DE3907973A1 (en) | 1989-03-11 | 1990-09-13 | Merck Patent Gmbh | DRYER TABLET |
| GB8909559D0 (en) * | 1989-04-26 | 1989-06-14 | Smith Kline French Lab | Pharmaceutical compositions |
| US5540945A (en) | 1989-05-11 | 1996-07-30 | Chugai Seiyaku Kabushiki Kaisha | Pharmaceutical preparations for oral administration that are adapted to release the drug at appropriate sites in the intestines |
| JPH0383914A (en) * | 1989-08-18 | 1991-04-09 | W R Grace & Co | Drug carrier |
| US5027797A (en) | 1989-10-12 | 1991-07-02 | Horace Bullard | Apparatus for the movement of blood by external pressure |
| GB8926639D0 (en) * | 1989-11-24 | 1990-01-17 | Agricultural & Food Res | Delayed release formulations |
| US5175003A (en) | 1990-04-06 | 1992-12-29 | Biosytes Usa, Inc. | Dual mechanism controlled release system for drug dosage forms |
| US5018621A (en) * | 1990-04-16 | 1991-05-28 | Connell Jr John J O | Cylindrical container and dispenser for spherical objects |
| IT1246382B (en) | 1990-04-17 | 1994-11-18 | Eurand Int | METHOD FOR THE TARGETED AND CONTROLLED DELIVERY OF DRUGS IN THE INTESTINE AND PARTICULARLY IN THE COLON |
| IT1246383B (en) * | 1990-04-17 | 1994-11-18 | Eurand Int | METHOD FOR MASKING THE TASTE OF DRUGS |
| JP2773959B2 (en) | 1990-07-10 | 1998-07-09 | 信越化学工業株式会社 | Colon release solid preparation |
| GB2253346A (en) * | 1991-02-22 | 1992-09-09 | John Rhodes | Delayed release oral dosage forms for treatment of intestinal disorders |
| SE9003296L (en) | 1990-10-16 | 1992-04-17 | Kabi Pharmacia Ab | PROCEDURE SHOULD FORMULATE MEDICINAL PRODUCTS |
| US5519014A (en) | 1990-10-22 | 1996-05-21 | Borody; Thomas J. | Treatment of non-inflammatory and non-infectious bowel disorders |
| US5316772A (en) | 1990-12-19 | 1994-05-31 | Solvay & Cie, S.A. (Societe Anonyme) | Bilayered oral pharmaceutical composition with pH dependent release |
| US5629012A (en) * | 1991-06-17 | 1997-05-13 | Farmaceutisk Laboratorium Ferring A/S | Process for producing suppositories by compression and suppositories obtained by the process |
| DK0542364T3 (en) | 1991-11-13 | 1996-03-11 | Glaxo Canada | Controlled release device |
| US5580578A (en) | 1992-01-27 | 1996-12-03 | Euro-Celtique, S.A. | Controlled release formulations coated with aqueous dispersions of acrylic polymers |
| US5656296A (en) * | 1992-04-29 | 1997-08-12 | Warner-Lambert Company | Dual control sustained release drug delivery systems and methods for preparing same |
| US5837277A (en) | 1992-06-04 | 1998-11-17 | Smithkline Beecham Corporation | Palatable pharmaceutical compositions |
| US20050090553A1 (en) * | 1992-06-30 | 2005-04-28 | Shapiro Howard K. | Compositions and method for treatment of chronic inflammatory diseases |
| US5654004A (en) | 1992-11-06 | 1997-08-05 | Hisamitsu Pharmaceutical Co., Inc. | Oral pharmaceutical preparation releasable in the lower digestive tract |
| US5914132A (en) * | 1993-02-26 | 1999-06-22 | The Procter & Gamble Company | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery |
| US5656290A (en) | 1993-02-26 | 1997-08-12 | The Procter & Gamble Company | Bisacodyl dosage form with multiple enteric polymer coatings for colonic delivery |
| US5686105A (en) | 1993-10-19 | 1997-11-11 | The Procter & Gamble Company | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery |
| EP0621032B1 (en) * | 1993-04-23 | 2000-08-09 | Novartis AG | Controlled release drug delivery device |
| DK66493D0 (en) | 1993-06-08 | 1993-06-08 | Ferring A S | PREPARATIONS FOR USE IN TREATMENT OF INFLAMMATORY GAS DISORDERS OR TO IMPROVE IMPROVED HEALTH |
| JPH072650A (en) | 1993-06-18 | 1995-01-06 | Tanabe Seiyaku Co Ltd | Release part control type preparation |
| DE4332394A1 (en) * | 1993-09-23 | 1995-03-30 | Falk Pharma Gmbh | Controlled release budesonide pellets and method of making the same |
| US5500227A (en) | 1993-11-23 | 1996-03-19 | Euro-Celtique, S.A. | Immediate release tablet cores of insoluble drugs having sustained-release coating |
| HU213407B (en) * | 1993-12-09 | 1997-06-30 | Egyt Gyogyszervegyeszeti Gyar | Process for producing tablet with diffusive-osmotic release |
| US5482718A (en) * | 1994-03-23 | 1996-01-09 | Hoffmann-La Roche Inc. | Colon-targeted delivery system |
| US5536507A (en) | 1994-06-24 | 1996-07-16 | Bristol-Myers Squibb Company | Colonic drug delivery system |
| DE19511131A1 (en) | 1995-03-27 | 1996-10-02 | Basf Ag | Mechanically stable solid active substance preparation forms |
| DE19680202D2 (en) * | 1995-03-30 | 1997-08-21 | Werner Kreutz | Drugs for the selective control of tumor tissue |
| US5686106A (en) | 1995-05-17 | 1997-11-11 | The Procter & Gamble Company | Pharmaceutical dosage form for colonic delivery |
| US5631245A (en) | 1995-06-06 | 1997-05-20 | Biodynamics Pharmaceuticals, Inc. | Method for medicating the inflammatory controlling system and adverse inflammatory reactions and for making compounds for treating the pathology of adverse inflammatory reactions |
| US5656294A (en) * | 1995-06-07 | 1997-08-12 | Cibus Pharmaceutical, Inc. | Colonic delivery of drugs |
| US5945124A (en) * | 1995-07-05 | 1999-08-31 | Byk Gulden Chemische Fabrik Gmbh | Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole |
| FR2738150B1 (en) * | 1995-09-01 | 1997-10-31 | Synthelabo | USE OF SULPHASALAZINE AND ITS METABOLITES FOR THE MANUFACTURE OF A MEDICAMENT USEFUL IN THE TREATMENT OF VENOUS INSUFFICIENCY AND VENOUS ULCERS |
| IT1277663B1 (en) * | 1995-09-28 | 1997-11-11 | Crinos Industria Farmaco | STABLE AQUEOUS SUSPENSIONS OF MESALAZINE FOR TOPICAL USE |
| US6004581A (en) * | 1995-12-21 | 1999-12-21 | Farmaceutisk Laboratorium Ferring A/S | Modified release oral pharmaceutical composition and method for the treatment of bowel diseases |
| CN1155369C (en) | 1995-12-21 | 2004-06-30 | 药物实验室费林公司 | Modified release oral pharmaceutical composition contg. 5-ASA and method for treatment of bowel diseases |
| US6231888B1 (en) | 1996-01-18 | 2001-05-15 | Perio Products Ltd. | Local delivery of non steroidal anti inflammatory drugs (NSAIDS) to the colon as a treatment for colonic polyps |
| WO1998006385A1 (en) * | 1996-08-15 | 1998-02-19 | Losan Pharma Gmbh | Easy to swallow oral medicament composition |
| CA2279651A1 (en) * | 1996-09-05 | 1998-03-12 | Massachusetts Institute Of Technology | Compositions and methods for treatment of neurological disorders and neurodegenerative diseases |
| CN1239425A (en) | 1996-11-15 | 1999-12-22 | 普罗克特和甘保尔公司 | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery |
| AU5775398A (en) | 1996-12-17 | 1998-07-15 | Poli Industria Chimica S.P.A. | Site-specific controlled release dosage formulation for mesalamine |
| WO1998027967A1 (en) | 1996-12-20 | 1998-07-02 | Dumex-Alpharma A/S | Release-controlled coated tablets |
| US5811121A (en) * | 1997-01-29 | 1998-09-22 | Eastman Chemical Company | PH-sensitive coatings based on cellulose acetoacetate |
| US5788987A (en) | 1997-01-29 | 1998-08-04 | Poli Industria Chimica Spa | Methods for treating early morning pathologies |
| US20020039594A1 (en) * | 1997-05-13 | 2002-04-04 | Evan C. Unger | Solid porous matrices and methods of making and using the same |
| DE19732903A1 (en) * | 1997-07-30 | 1999-02-04 | Falk Pharma Gmbh | Pellet formulation for the treatment of the intestinal tract |
| US5895663A (en) | 1997-07-31 | 1999-04-20 | L. Perrigo Company | Pseudoephedrine hydrochloride extended-release tablets |
| CA2220038A1 (en) | 1998-01-05 | 1999-07-05 | Amina Odidi | Device for the delivery of high dose pharmaceutical, neutraceutical, agricultural, biological, and chemical substances |
| US6365185B1 (en) * | 1998-03-26 | 2002-04-02 | University Of Cincinnati | Self-destructing, controlled release peroral drug delivery system |
| GB9810181D0 (en) | 1998-05-13 | 1998-07-08 | Smithkline Beecham Plc | Novel formulations |
| US6962717B1 (en) | 1999-01-29 | 2005-11-08 | Disphar International B.V. | Pharmaceutical compositions |
| US6326364B1 (en) * | 1999-02-08 | 2001-12-04 | Cedars-Sinai Medical Center | Use of 5-aminosalicylates as antimicrobial agents |
| US6383471B1 (en) * | 1999-04-06 | 2002-05-07 | Lipocine, Inc. | Compositions and methods for improved delivery of ionizable hydrophobic therapeutic agents |
| US6395300B1 (en) * | 1999-05-27 | 2002-05-28 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
| ITMI991316A1 (en) * | 1999-06-14 | 2000-12-14 | Cip Ninety Two 92 S A | ORAL PHARMACEUTICAL COMPOSITIONS WITH MODIFIED RELEASE OF MESALAZINE |
| EP1183014B1 (en) | 1999-06-14 | 2003-10-08 | Cosmo S.p.A. | Controlled release and taste masking oral pharmaceutical compositions |
| IT1318376B1 (en) | 2000-03-07 | 2003-08-25 | Pharmatec Internat S R L | ORAL SOLID FORMS WITH CONTROLLED RELEASE CONTAINING MESALAZINE AS AN ACTIVE PRINCIPLE. |
| DE10013029A1 (en) * | 2000-03-17 | 2001-09-20 | Roehm Gmbh | Multilayer formulation for controlled drug release in colon, comprising drug-containing core having inner and outer coatings of acrylic copolymers with quaternary ammonium and anionic groups respectively |
| DE10013030A1 (en) | 2000-03-17 | 2001-09-20 | Roehm Gmbh | Formulation for treating ulcerative colitis, comprising active agent, e.g. 5-aminosalicylic acid or prednisone, coated with acrylic copolymer to provide delayed release at high pH in the colon |
| SE0001151D0 (en) | 2000-03-31 | 2000-03-31 | Amarin Dev Ab | Method of producing a controlled-release composition |
| WO2001091716A1 (en) | 2000-05-30 | 2001-12-06 | Add Advanced Drug Delivery Technologies Ag | Peroral therapeutic system comprising glipizide |
| US6365209B2 (en) * | 2000-06-06 | 2002-04-02 | Capricorn Pharma, Inc. | Confectionery compositions and methods of making |
| DE10029410A1 (en) * | 2000-06-15 | 2002-01-03 | Bfgoodrich Diamalt Gmbh | Process for the preparation of 5-aminosalicylic acid |
| IT1318625B1 (en) * | 2000-07-14 | 2003-08-27 | Roberto Valducci | ORAL SOLID PHARMACEUTICAL FORMULATIONS WITH MULTI-PHASE RELEASE - EMPLOYEE. |
| JP2004507487A (en) | 2000-08-29 | 2004-03-11 | メファ・アクチェンゲゼルシャフト | Intestinal disease drug |
| CA2359812C (en) * | 2000-11-20 | 2004-02-10 | The Procter & Gamble Company | Pharmaceutical dosage form with multiple coatings for reduced impact of coating fractures |
| US20030175349A1 (en) * | 2001-01-30 | 2003-09-18 | Council Of Scientific And Industrial Research | Pharmaceutical compostion for extended/sustained release of a therapeutically active ingredient |
| HU229291B1 (en) * | 2001-01-31 | 2013-10-28 | Evonik Roehm Gmbh | Multi-particulate form of medicament, comprising at least two differently coated forms of pellet |
| JP2004530676A (en) * | 2001-04-18 | 2004-10-07 | ノストラム・ファーマスーティカルズ・インコーポレイテッド | Novel coatings for sustained release pharmaceutical compositions |
| US20070059368A1 (en) | 2005-05-31 | 2007-03-15 | Cherukuri S R | Modified release formulations of anti-irritability drugs |
| US20030044458A1 (en) | 2001-08-06 | 2003-03-06 | Curtis Wright | Oral dosage form comprising a therapeutic agent and an adverse-effect agent |
| US20030099711A1 (en) * | 2001-08-29 | 2003-05-29 | David Meadows | Sustained release preparations |
| US8101209B2 (en) * | 2001-10-09 | 2012-01-24 | Flamel Technologies | Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles |
| AR036797A1 (en) * | 2001-10-15 | 2004-10-06 | Ferring Bv | A METHOD TO PREPARE A PHARMACEUTICAL COMPOSITION THAT INCLUDES 5-AMINOSALICILIC ACID TO USE IN THE TREATMENT OF ULCEROSE COLITIS AND CROHN DISEASES |
| US7815936B2 (en) * | 2001-10-30 | 2010-10-19 | Evonik Degussa Gmbh | Use of granular materials based on pyrogenically produced silicon dioxide in pharmaceutical compositions |
| BRPI0117180B8 (en) | 2001-11-23 | 2021-05-25 | Procter & Gamble | pharmaceutical composition in a solid dosage unit form for oral administration to a human or lower animal |
| DE10208335A1 (en) * | 2002-02-27 | 2003-09-04 | Roehm Gmbh | Pharmaceutical form and process for its preparation |
| FR2837100B1 (en) | 2002-03-18 | 2004-07-23 | Flamel Tech Sa | MODIFIED RELEASE MICROCAPSULE-BASED TABLETS |
| MXPA05000128A (en) | 2002-07-05 | 2005-09-30 | Temrel Inc | Controlled release composition. |
| US8216609B2 (en) * | 2002-08-05 | 2012-07-10 | Torrent Pharmaceuticals Limited | Modified release composition of highly soluble drugs |
| US7985422B2 (en) * | 2002-08-05 | 2011-07-26 | Torrent Pharmaceuticals Limited | Dosage form |
| DE10250543A1 (en) | 2002-10-29 | 2004-05-19 | Röhm GmbH & Co. KG | Multilayer dosage form |
| US20040121003A1 (en) * | 2002-12-19 | 2004-06-24 | Acusphere, Inc. | Methods for making pharmaceutical formulations comprising deagglomerated microparticles |
| DE10304403A1 (en) | 2003-01-28 | 2004-08-05 | Röhm GmbH & Co. KG | Process for the preparation of an oral dosage form with immediate disintegration and drug release |
| US20040185097A1 (en) * | 2003-01-31 | 2004-09-23 | Glenmark Pharmaceuticals Ltd. | Controlled release modifying complex and pharmaceutical compositions thereof |
| MXPA05009886A (en) * | 2003-03-14 | 2006-05-04 | Nirmal Mulye | A process for preparing sustained release tablets. |
| WO2004087113A1 (en) | 2003-04-04 | 2004-10-14 | Ranbaxy Laboratories Limited | Pharmaceutical compositions for colon specific delivery |
| US7825106B2 (en) | 2003-09-03 | 2010-11-02 | Agi Therapeutics Ltd. | Modified release formulations and methods of treating inflammatory bowel disease |
| EP1670442A4 (en) * | 2003-09-19 | 2011-09-14 | Penwest Pharmaceuticals Co | Delayed released dosage forms |
| WO2005027932A1 (en) | 2003-09-22 | 2005-03-31 | Nisshin Kyorin Pharmaceutical Co., Ltd. | 5-aminosalicylic acid solid preparation improved in discoloration and method of storing the same |
| WO2005030173A1 (en) | 2003-09-25 | 2005-04-07 | Ranbaxy Laboratories Limited | Colon-specific drug delivery using interpolymer complexations |
| EP1691789B1 (en) * | 2003-11-25 | 2017-12-20 | SmithKline Beecham (Cork) Limited | Carvedilol free base, salts, anhydrous forms or solvate thereof, corresponding pharmaceutical compositions, controlled release formulations, and treatment or delivery methods |
| EP1547601A1 (en) | 2003-12-23 | 2005-06-29 | Ferring B.V. | Coating method |
| FR2872044B1 (en) | 2004-06-28 | 2007-06-29 | Flamel Technologies Sa | PHARMACEUTICAL FORMULATION BASED ON ANTIBIOTICS IN THE MICROCAPSULAR FORM |
| KR20080085924A (en) | 2004-09-01 | 2008-09-24 | 더 프록터 앤드 갬블 캄파니 | Compositions comprising 5-amino-2-hydroxybenzoic acid and a reducing sugar |
| EP1811975A2 (en) | 2004-10-19 | 2007-08-01 | The State of Oregon Acting by and | Enteric coated compositions that release active ingredient(s) in gastric fluid and intestinal fluid |
| KR100912307B1 (en) | 2004-10-21 | 2009-08-14 | 유니버시티 오브 아이오와 리써치 파운데이션 | In situ controlled release drug delivery system |
| US20060141054A1 (en) | 2004-10-25 | 2006-06-29 | Thomas Piccariello | Metal coordinated compositions |
| CN102631289B (en) | 2004-10-28 | 2016-05-04 | 潘特克股份公司 | Highly porous speed collapses solid dosage forms and comprises the preparation method who produces powder and step of freeze drying |
| FR2878159B1 (en) | 2004-11-24 | 2008-10-17 | Flamel Technologies Sa | ORAL MEDICATION WITH MODIFIED RELEASE OF AT LEAST ONE ACTIVE PRINCIPLE IN MULTIMICROCAPSULAR FORM |
| US7691364B2 (en) | 2005-01-28 | 2010-04-06 | Bezwada Biomedical, Llc | Functionalized drugs and polymers derived therefrom |
| US9149439B2 (en) | 2005-03-21 | 2015-10-06 | Sandoz Ag | Multi-particulate, modified-release composition |
| EP1883614A4 (en) | 2005-05-23 | 2010-04-14 | Nicox Sa | Organic nitric oxide enhancing salts of nonsteroidal antiinflammatory compounds, compositions and methods of use |
| US20090017110A1 (en) | 2005-05-31 | 2009-01-15 | Capricorn Pharma Inc. | Modified release formulations of anti-irritability drugs |
| US20060292225A1 (en) | 2005-06-24 | 2006-12-28 | Felix Arthur M | Water soluble analgesic formulations and methods for production |
| WO2007036952A2 (en) | 2005-07-01 | 2007-04-05 | Rubicon Research Pvt Ltd. | Novel sustained release dosage form |
| US9198862B2 (en) | 2005-07-22 | 2015-12-01 | Rubicon Research Private Limited | Dispersible tablet composition |
| WO2007020508A1 (en) | 2005-08-12 | 2007-02-22 | Ferring International Center S.A. | Method and device for dividing granules |
| WO2007019888A2 (en) | 2005-08-12 | 2007-02-22 | Ctg Pharma S.R.L. | Therapeutic compositions containing mesalamine and a co-agent for treating colon diseases |
| US7452872B2 (en) | 2005-08-24 | 2008-11-18 | Salix Pharmaceuticals, Inc. | Formulations and uses of 2-hydroxy-5-phenylazobenzoic acid derivatives |
| US8921344B2 (en) | 2006-11-03 | 2014-12-30 | Salix Pharmaceuticals, Inc. | Formulations and uses of 2-hydroxy-5-phenylazobenzoic acid derivatives |
| WO2007052299A2 (en) | 2005-08-24 | 2007-05-10 | Rubicon Research Pvt Ltd. | Controlled release formulation |
| US8158152B2 (en) | 2005-11-18 | 2012-04-17 | Scidose Llc | Lyophilization process and products obtained thereby |
| US9603941B2 (en) | 2006-01-24 | 2017-03-28 | Minghui Chai | Method of preparing dendritic drugs |
| EP1976486A1 (en) | 2006-01-27 | 2008-10-08 | The Provost, Fellows And Scholars Of The College Of The Holy And Undivided Trinity Of Queen Elizabeth Near Dublin | A method of producing porous microparticles |
| WO2007127488A1 (en) | 2006-04-27 | 2007-11-08 | Shenoy Narmada R | Compositions and methods for treating or preventing diseases of body passageways |
| WO2007128349A1 (en) | 2006-05-10 | 2007-11-15 | Evonik Degussa Gmbh | Use of roll compacted pyrogenically produced silicon dioxide in pharmaceutical compositions |
| US20080014228A1 (en) | 2006-07-14 | 2008-01-17 | Olivia Darmuzey | Solid form |
| KR20090027734A (en) | 2006-07-27 | 2009-03-17 | (주)아모레퍼시픽 | Process for preparing powder comprising nanoparticles of sparingly soluble drug |
| BRPI0622007A2 (en) | 2006-09-13 | 2011-12-20 | Procter & Gamble | use of aminosalicylate to treat ulcerative colitis |
| AU2006348180A1 (en) | 2006-09-13 | 2008-03-20 | Warner Chilcott Company, Llc | Methods of treatment for ulcerative colitis |
| US20080081070A1 (en) | 2006-09-15 | 2008-04-03 | Auriga Laboratories, Inc. | Pharmaceutical formulation with enhanced solubility for the delivery of corticosteroids |
| WO2008056200A1 (en) | 2006-11-10 | 2008-05-15 | Ranbaxy Laboratories Limited | Oral pharmaceutical compositions of simethicone |
| AU2007321906A1 (en) | 2006-11-17 | 2008-05-29 | Shire Development Inc. | Method of treatment for inflammatory bowel disease |
| US20100179170A1 (en) | 2006-12-05 | 2010-07-15 | Lisa Claire Du Toit | Heterogeneously configured multiparticulate gastrointestinal drug delivery system |
| WO2008085484A2 (en) | 2006-12-28 | 2008-07-17 | Jacobus Pharmaceutical Company, Inc. | Treatment of inflammatory bowel disease with enteric coated formulations comprising 5-aminosalicylic acid or 4-aminosalicylic acid |
| DE102007009243A1 (en) | 2007-02-22 | 2008-09-18 | Evonik Röhm Gmbh | Pellets with a drug matrix and a polymer coating, and a method for producing the pellets |
| DE102007009242A1 (en) | 2007-02-22 | 2008-09-18 | Evonik Röhm Gmbh | Pellets with enteric-coated matix |
| IE20070129A1 (en) | 2007-02-28 | 2008-12-24 | Giuliani Int Ltd | Ppar-gamma agonists stimulate enteric defensin expression |
| WO2008140461A1 (en) | 2007-05-16 | 2008-11-20 | Fmc Corporation | Solid form |
| WO2008140459A1 (en) | 2007-05-16 | 2008-11-20 | Fmc Corporation | Solid form |
| WO2008140460A1 (en) | 2007-05-16 | 2008-11-20 | Fmc Corporation | Solid form |
| US20080286344A1 (en) | 2007-05-16 | 2008-11-20 | Olivia Darmuzey | Solid form |
| US20080311162A1 (en) | 2007-05-16 | 2008-12-18 | Olivia Darmuzey | Solid form |
| US20080286343A1 (en) | 2007-05-16 | 2008-11-20 | Dzenana Cengic | Solid form |
| US7541384B2 (en) | 2007-06-08 | 2009-06-02 | Axcan Pharma Inc. | Mesalamine suppository |
| US8217083B2 (en) | 2007-06-08 | 2012-07-10 | Aptalis Pharma Canada Inc. | Mesalamine suppository |
| US8637080B2 (en) | 2007-06-28 | 2014-01-28 | Osmotica Kereskedelmi és Szolgáltató, KFT | Rupturing controlled release device comprising a subcoat |
| US8974825B2 (en) | 2007-07-06 | 2015-03-10 | Lupin Limited | Pharmaceutical compositions for gastrointestinal drug delivery |
| US20090028944A1 (en) | 2007-07-16 | 2009-01-29 | Balaji Sathurappan | Pharmaceutical compositions comprising mesalamine |
| US20090036414A1 (en) | 2007-08-02 | 2009-02-05 | Mutual Pharmaceutical Company, Inc. | Mesalamine Formulations |
| AU2008303129B2 (en) | 2007-09-25 | 2013-08-01 | Formulex Pharma Innovations Ltd. | Compositions comprising lipophilic active compounds and method for their preparation |
| WO2009047801A1 (en) | 2007-10-10 | 2009-04-16 | Lupin Limited | Therapeutic combinations and compositions for the treatment of gastrointestinal disorders |
| WO2009047802A2 (en) | 2007-10-10 | 2009-04-16 | Lupin Limited | Novel colon targeted modified release bioadhesive formulation of 5-amino salicylic acid or its salts and metabolites thereof |
| WO2009148470A1 (en) | 2007-10-25 | 2009-12-10 | The Board Of Trustees Of Southern Illinois University | Methods for diagnosing bowel disease |
| WO2009078872A1 (en) | 2007-12-18 | 2009-06-25 | Soluprin Pharmaceuticals, Inc. | Orally disintegrating water soluble analgesic formulations and methods for production thereof |
| US20090162434A1 (en) | 2007-12-21 | 2009-06-25 | Disphar International Bv | Mesalazine tablet |
| ITMI20072429A1 (en) | 2007-12-24 | 2009-06-25 | Giuliani Int Ltd | COMPOUNDS FOR THE SELECTIVE TREATMENT OF THE INTESTINAL IMMUNE-INFLAMMATORY COMPONENT OF THE CELIAC DISEASE |
| US20090169622A1 (en) | 2007-12-27 | 2009-07-02 | Roxane Laboratories, Inc. | Delayed-release oral pharmaceutical composition for treatment of colonic disorders |
| AP2010005341A0 (en) | 2008-01-11 | 2010-08-31 | Cipla Ltd | Solid pharmaceutical dosage form |
| EP2133071A1 (en) | 2008-06-09 | 2009-12-16 | Université de la Méditerranée | Process for making gastroretentive dosage forms |
| WO2009150530A2 (en) | 2008-06-11 | 2009-12-17 | Ferring International Center Sa | Novel foam composition |
| EP2135601A1 (en) | 2008-06-20 | 2009-12-23 | Capsulution Nanoscience AG | Stabilization of amorphous drugs using sponge-like carrier matrices |
| WO2009158384A1 (en) | 2008-06-27 | 2009-12-30 | The Procter & Gamble Company | Methods and kits for the treatment inhibition, and maintenance of gastrointestinal disorders |
| US20090326069A1 (en) | 2008-06-30 | 2009-12-31 | Bltn, Llc | Azelaic acid ester compositions and methods for diagnosing and treating tissue conditions using azelaic acid ester compositions and proteinaceous biomarkers |
-
2001
- 2001-10-24 CA CA002359812A patent/CA2359812C/en not_active Expired - Lifetime
- 2001-11-15 US US09/996,555 patent/US6893662B2/en not_active Expired - Lifetime
- 2001-11-16 PE PE2001001148A patent/PE20020529A1/en not_active Application Discontinuation
-
2005
- 2005-03-03 US US11/070,995 patent/US8580302B2/en active Active
- 2005-04-01 US US11/096,457 patent/US20050181053A1/en not_active Abandoned
-
2013
- 2013-10-11 US US14/051,950 patent/US9089492B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2359812A1 (en) | 2002-05-20 |
| US8580302B2 (en) | 2013-11-12 |
| US20050169996A1 (en) | 2005-08-04 |
| US20140093576A1 (en) | 2014-04-03 |
| PE20020529A1 (en) | 2002-07-18 |
| US20020098235A1 (en) | 2002-07-25 |
| US6893662B2 (en) | 2005-05-17 |
| US20050181053A1 (en) | 2005-08-18 |
| US9089492B2 (en) | 2015-07-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20211025 |