CA2426811A1 - Novel formulations of carvedilol - Google Patents
Novel formulations of carvedilol Download PDFInfo
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- CA2426811A1 CA2426811A1 CA002426811A CA2426811A CA2426811A1 CA 2426811 A1 CA2426811 A1 CA 2426811A1 CA 002426811 A CA002426811 A CA 002426811A CA 2426811 A CA2426811 A CA 2426811A CA 2426811 A1 CA2426811 A1 CA 2426811A1
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- carvedilol
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- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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Abstract
This invention relates to a novel formulations comprising carvedilol and methods of using these formulations to treat hypertension, congestive heart failure and angina.
Description
NOVEL FORMULATIONS OF CARVEDILOL
Field of the Invention This invention relates to novel formulations of carvedilol and to the use of such formulations in the treatment of hypertension, congestive heart failure and angina.
Background of the Invention The compound, 1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol, is known by the name " carvedilol" and is the subject of U.S. Patent No. 4,503,067 (the '067 patent), issued March 5, 1985. This compound has the following structure:
O~N~'O
OH H I /
I
/ /
N
H
Carvedilol is useful in the treatment of hypertension, congestive heart failure and angina.
The current commercial formulation for carvedilol is immediate release, and it is administered twice daily. The immediate release formulation of carvedilol is rapidly and extensively absorbed following oral administration, with the terminal elimination half life ranging between 7-10 hours. A once-daily dosing formulation for carvedilol is commercially desirable, would simplify a patient's dosing regimen and may improve compliance rates.
Field of the Invention This invention relates to novel formulations of carvedilol and to the use of such formulations in the treatment of hypertension, congestive heart failure and angina.
Background of the Invention The compound, 1-(carbazol-4-yloxy-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol, is known by the name " carvedilol" and is the subject of U.S. Patent No. 4,503,067 (the '067 patent), issued March 5, 1985. This compound has the following structure:
O~N~'O
OH H I /
I
/ /
N
H
Carvedilol is useful in the treatment of hypertension, congestive heart failure and angina.
The current commercial formulation for carvedilol is immediate release, and it is administered twice daily. The immediate release formulation of carvedilol is rapidly and extensively absorbed following oral administration, with the terminal elimination half life ranging between 7-10 hours. A once-daily dosing formulation for carvedilol is commercially desirable, would simplify a patient's dosing regimen and may improve compliance rates.
2 o Thus, it is an object of the instant invention to develop a once-daily dosing formulation for carvedilol.
According to the instant invention, it has been found that carvedilol can be formulated in novel formulations for once-daily dosing.
Summary of the Invention The present invention provides for the use of a pharmaceutically acceptable organic acid in formulations comprising carvedilol.
'This invention also provides for the use of such formulations for the treatment of hypertension, congestive heart failure and angina.
Description of the Invention According to the present invention, compositions of carvedilol are provided in spray-dried powder form or standard drug substance form. The spray-dried powder compositions are prepared using a process that involves wet milling. The suspension, thus produced, is spray dried using a spray dryer or granulated using a fluid bed granulator. The composition may then be formulated, for example, in the form of tablets or capsules. Orally administrated formulations are preferred.
Importantly, the present invention provides for a formulation comprising carvedilol, which further comprises of a pharmaceutically acceptable organic acid.
1 o As used herein, the term "pharmaceutically acceptable organic acid" refers to organic acids which are without pharmacological effect per se, have acceptable organoleptic properties, have acceptable density, do not have an extreme pH and are preferably solid.
Examples include mono-carboxylic acids and poly-carboxylic acids having from 2 to 25, preferably from 2 to 10, carbon atoms; monocyclic and polycyclic aryl acids, such as benzoic 15 acid; as well as monohydrogen, dihydrogen and metal salts of mufti-valent acids. A single pharmaceutically acceptable organic acid may be used, or two or more of such may be used in combination. Preferably, the organic acid is a C(2_lp)alkyl- or alkenyl-carboxylic acid having from one, two or three carboxylic acid groups, and optionally with one or more hydroxy substituents or an additional CO group in the carbon chain, for instance malonic acid, succinic 2 o acid, fumaric acid, malefic acid, adipic acid, lactic acid, levulinic acid, sorbic acid, glutamic acid, aspartic acid, oleic acid, glutaric acid, glycine, arginine or a fruit acid, such as tartaric acid, malic acid, ascorbic acid or citric acid, most preferably citric acid.
The wet milling process of the present invention is well known to those skilled in the art and is described in:
2 5 J. A. Herbst and J. L. Sepulveda "Fundamentals of Fine and Ultrafine Grinding in a Stirred Ball Mill" International Powder and Bulk Solids Handling and Processing, 452, May 1978 and L. Y. Sadler III, D. A. Stanley, and D. R. Brooks "Attrition Mill Operational Characteristics" Powder Technology 12 (1975) 19-28.
According to the instant invention, it has been found that carvedilol can be formulated in novel formulations for once-daily dosing.
Summary of the Invention The present invention provides for the use of a pharmaceutically acceptable organic acid in formulations comprising carvedilol.
'This invention also provides for the use of such formulations for the treatment of hypertension, congestive heart failure and angina.
Description of the Invention According to the present invention, compositions of carvedilol are provided in spray-dried powder form or standard drug substance form. The spray-dried powder compositions are prepared using a process that involves wet milling. The suspension, thus produced, is spray dried using a spray dryer or granulated using a fluid bed granulator. The composition may then be formulated, for example, in the form of tablets or capsules. Orally administrated formulations are preferred.
Importantly, the present invention provides for a formulation comprising carvedilol, which further comprises of a pharmaceutically acceptable organic acid.
1 o As used herein, the term "pharmaceutically acceptable organic acid" refers to organic acids which are without pharmacological effect per se, have acceptable organoleptic properties, have acceptable density, do not have an extreme pH and are preferably solid.
Examples include mono-carboxylic acids and poly-carboxylic acids having from 2 to 25, preferably from 2 to 10, carbon atoms; monocyclic and polycyclic aryl acids, such as benzoic 15 acid; as well as monohydrogen, dihydrogen and metal salts of mufti-valent acids. A single pharmaceutically acceptable organic acid may be used, or two or more of such may be used in combination. Preferably, the organic acid is a C(2_lp)alkyl- or alkenyl-carboxylic acid having from one, two or three carboxylic acid groups, and optionally with one or more hydroxy substituents or an additional CO group in the carbon chain, for instance malonic acid, succinic 2 o acid, fumaric acid, malefic acid, adipic acid, lactic acid, levulinic acid, sorbic acid, glutamic acid, aspartic acid, oleic acid, glutaric acid, glycine, arginine or a fruit acid, such as tartaric acid, malic acid, ascorbic acid or citric acid, most preferably citric acid.
The wet milling process of the present invention is well known to those skilled in the art and is described in:
2 5 J. A. Herbst and J. L. Sepulveda "Fundamentals of Fine and Ultrafine Grinding in a Stirred Ball Mill" International Powder and Bulk Solids Handling and Processing, 452, May 1978 and L. Y. Sadler III, D. A. Stanley, and D. R. Brooks "Attrition Mill Operational Characteristics" Powder Technology 12 (1975) 19-28.
3 0 Spray drying of milled compositions is carried out most suitably using a spray dryer, such as Yamato GA-32 Spray Dryer [Yamato Scientific America Inc., Orangeburg, NY].
Alternately, granulation of milled compositions is carried out most suitably using a fluid bed granulator, such as Glatt fluid bed granulator, or a high shear granulator.
The spray-dried powder, thus produced, is then used in tablets for oral administration 3 5 in a unit dose. These oral tablets comprise conventional controlled release formulations, such as tablets, having a sustained release or an enteric coating, or otherwise modified to control the _2_ release of the active compound, for example by the inclusion of gel forming polymers or matrix forming waxes.
Additionally, carvedilol drug substance is mixed with an organic acid in either solution or suspension to form a drug medium to subsequently layer onto pellets or granules. The drug layered pellets or granules are then coated to consist of a standard seal coat, enteric coat or a sustained release coat permeable to gastrointestinal juices. The controlled release formulations are prepared, for example, as described in U. S. Patent No. 4,524,060, issued June 18, 1985, and U. S. Patent No. 4,983,401, issued January 8, 1991. ~ther controlled release formulations are described in U. S. Patent No. 4,880,830, issued November 14, 1989, and U.
S. Patent No.
Alternately, granulation of milled compositions is carried out most suitably using a fluid bed granulator, such as Glatt fluid bed granulator, or a high shear granulator.
The spray-dried powder, thus produced, is then used in tablets for oral administration 3 5 in a unit dose. These oral tablets comprise conventional controlled release formulations, such as tablets, having a sustained release or an enteric coating, or otherwise modified to control the _2_ release of the active compound, for example by the inclusion of gel forming polymers or matrix forming waxes.
Additionally, carvedilol drug substance is mixed with an organic acid in either solution or suspension to form a drug medium to subsequently layer onto pellets or granules. The drug layered pellets or granules are then coated to consist of a standard seal coat, enteric coat or a sustained release coat permeable to gastrointestinal juices. The controlled release formulations are prepared, for example, as described in U. S. Patent No. 4,524,060, issued June 18, 1985, and U. S. Patent No. 4,983,401, issued January 8, 1991. ~ther controlled release formulations are described in U. S. Patent No. 4,880,830, issued November 14, 1989, and U.
S. Patent No.
5,068,112, issued November 26, 1991.
The controlled release formulations containing carvedilol and organic acid may also be in the form of a non-compressed drug layered pellet loaded into a standard capsule. This capsule is then enteric coated for delayed release and then subsequently coated with an immediate release portion of Carvedilol for a two burst system.
Tablets or capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers and diluents (tableting or compression aids), lubricants, disintegrants, colorants, flavourings, and wetting agents. The tablets may be coated according to techniques well known in the art.
These oral formulations may be prepared by conventional methods of blending, filling, 2 o tableting, or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, well known in the art.
Thus, the present invention provides for the use of a pharmaceutically acceptable organic acid in the formulations comprising carvedilol. The formulation is adapted for oral administration. The formulation is presented as a unit dose. Such a formulation is taken once daily. The preferred unit dosage forms include tablets or capsules comprising 25 mg or 50 mg of carvedilol; however, the present invention also includes doses from 6.25 mg to 100 mg.
No unacceptable toxicological effects are expected when carvedilol is administered in accordance with the present invention.
3 o The following examples are illustrative of the instant invention. These examples are not intended to limit the scope of this invention as defined herein above and as claimed herein below.
Examples 1 & 2 - Carvedilol 50 m~ Controlled Release Aqueous Film Coated Tablets 3 5 The carvedilol 50 mg controlled release (CR) aqueous film coated (AFC) tablets were prepared from a carvedilol spray-dried powder which was blended with external excipients and a lubricant, compressed, and finally coated with a clear aqueous film coat followed by a Eudragit~-based coat. Product CE tablets Were made with fumaric acid, whereas Product CF
tablets are made with citric acid.
Table 1 Unit Formulas for Carvedilol 50 mg CR AFC Tablet, Products CE and CF
Quantity Ingredients (mg/Tablet) "Carvedilol Spray-Dried Powder" consisting of: (~g.061) Carvedilol 52.071 Poloxamer 407 10.381 Povidone 5.231 Hydroxyethyl Cellulose 10.381 Purified Water q.s.2 Fumaric Acid for Product CE 120.00 or Citric Acid (monohydrate) for Product CF
Dibasic Calcium Phosphate Dihydrate155.941 Microcrystalline Cellulose 174.00 Crospovidone 60.00 Silicon Dioxide Colloidal 6.00 Magnesium Stearate 6.00 __.
Total Weight Tablet Core 600.00 Clear Opadry YS-1-19025-A 12.00 Aqueous Dispersion of Methacrylic45.58 Acid Copolymer, Type C (Eudragit~ L30 D-55) Triethyl Citrate 5.83 Sodium Lauryl Sulfate 1.06 Glyceryl Stearate (Imwitor 900 0.53 Powder) Purified Water n ~ 3 Total Weight Coated Tablet 665.00 lBased on 96% label claim for the "Carvedilol Spray-Dried Powder."
These levels will change based upon the % label claim achieved during the spray drying 1 o process and are adjusted during the blending step.
2Removed during spray drying process.
3Removed during drying.
Examples 3 & 4 - Carvedilol 50 m~ Controlled Release Matrix Tablets The carvedilol controlled release (CR) matrix tablets (Products CG and CH) are prepared from a carvedilol granulation containing either a carvedilol spray-dried powder or standard carvedilol drug substance, respectively. A citric acid granulation is prepared separately. The desired carvedilol granulation and the citric acid granulation are blended together along with external excipients and finally a lubricant to produce the mix from which tablets are then compressed.
Table 2 Unit Formulas for Carvedilol 50 mg CR Matrix Tablets, Products CG and CH
Quantity (mg/Tablet) Ingredients CG CH
Carvedilol Gz-anulatiofz "Carvedilol Spray-Dried Powder" (78.214) consisting of:
Carvedilol 52.174 ---Poloxamer 407 10.404 ---Povidone 5.244 ---Hydroxyethyl Cellulose 10.404 -'-Purified Water q.s.5 ---Carvedilol --- 50.00 Hydroxypropyl Methylcellulose77.01 95.96 Carboxymethylcellulose 38.30 47.57 Sodium Povidone 8.07 8.06 Purified Water q.s.5 q,s.5 Citric Acid Grazzulation Citric Acid 104.98 104.98 Hydroxypropyl Methylcellulose54.43 54.43 Carboxymethylcellulose 27.22 27.22 Sodium Povidone 7.78 7.78 Purified Water q.s.5 q.s_5 Final Blefzd Microcrystalline Cellulose192.00 192.00 Silicon Dioxide Colloidal6.00 6.00 Magnesium Stearate 6.00 6.00 Total Tablet Weight 600.00 600.00 4Based on 96% label claim for the "Carvedilol Spray-Dried Powder."
1o These levels will change based upon the % label claim achieved during.the spray drying process and are adjusted during the blending step.
SRemoved during processing.
Example 5 - Carvedilol 25 m~ Controlled Release Capsule The carvedilol controlled release (CR) capsule is prepared from carvedilol drug layered pellets containing standard carvedilol drug substance, aspartic acid and Opadry Clear.
The drug layered pellets are then coated with a sustained release coat, Aquacoat ECD-30, and filled into standard capsule shells for administration.
Ingredients (mg/Capsule) "Carvedilol Drug Layered Pellets" consisting(480.7) of:
Carvedilol 25.0 L-Aspartic Acid 31.2 Opadry Clear 25.0 Purified Water q.s.l Microcrystalline Cellulose Spheres 399.5 Ethylcellulose Aqueous Dispersion (Aquacoat113.9 ECD-30) Dibutyl Sebacate 36.1 Purified Water q.s.l Opadry Clear 1.9 Purified Water q.s.l Size 00 Capsule Shell 118.0 Total Weight Capsule 750.6 lRemoved during drug layering or coating process 1 o Example 6 - Carvedilol 25 m~ Controlled Release Capsule The carvedilol controlled release (CR) capsule is prepared from carvedilol drug layered pellets containing standard carvedilol drug substance, aspartic acid and Opadry Clear.
22.5 mg strength drug layered pellets are filled into standard capsule shells.
The capsules are enteric coated for the delayed release portion and a 2.5 mg strength immediate release top-coat is then applied for the initial burst effect.
Ingredients (mg/Capsule) "Carvedilol Drug Layered Pellets" consisting of: (432.7) Carvedilol 22.5 L-Aspartic Acid 28.1 Opadry Clear 22.5 Purified Water q.s.l Microcrystalline Cellulose Spheres 359.6 Aqueous Dispersion of Methacrylic Acid Copolymer, Type 49.7 C (Eudragit~ L30 D-55) Triethyl Citrate 5.8 Silicon Dioxide Colloidal 4.2 Sodium Lauryl Sulfate 0.4 Purified Water q.s.l Carvedilol 2.5 L-Aspartic Acid 0.2 Opadry Clear 2.5 Purified Water q.s.l Size 1 Capsule Shell '76.0 Total Weight Capsule 574.0 lRemoved during drug layering or coating process i~a vivo Pharmacokinetic evaluation of formulations The bioavailability of the formulations according to the present invention are evaluated in healthy human volunteers. The study is an open-label, single dose, randomized, four-period, incomplete block, crossover study. Each subject receives a single dose of the immediate release formulation in addition to single oral doses of 3 of the 4 controlled-release formulations according to a randomization schedule. The regimens for the study are tabulated below:
Product Description CE 50 m carvedilol in a controlled-release, Enteric I tablet formulation CF 50 m carvedilol in a controlled-release, Enteric II tablet formulation CG 50 m carvedilol in a controlled-release, Matrix I tablet formulation CH 50 m carvedilol in a controlled-release, Matrix II tablet formulation CI 2 x 25 mg carvedilol immediate release tablets, commercial formulation Pharmacokinetic sampling for measurement of plasma carvedilol concentrations is conducted over a 48-hour period following administration of study medication in each study session. There is a washout period of at least 7 days between dosing in sessions. Female subjects return 7-10 days following dosing in the last study session for a follow-up pregnancy test. The total duration (from screening to end of the study) of each subject's participation will be five to eight weeks.
The primary endpoint is the AUC of carvedilol. Secondary endpoints include Cmax, Tmax, and T1/2, as data permit.
It is to be understood that the invention is not limited to the embodiments illustrated hereinabove and the right is reserved to the illustrated embodiments and all modifications 2o coming within the scope of the following claims. The various references to journals, patents and other publications which are cited herein comprise the state of the art and are incorporated herein by reference as though fully set forth.
The controlled release formulations containing carvedilol and organic acid may also be in the form of a non-compressed drug layered pellet loaded into a standard capsule. This capsule is then enteric coated for delayed release and then subsequently coated with an immediate release portion of Carvedilol for a two burst system.
Tablets or capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers and diluents (tableting or compression aids), lubricants, disintegrants, colorants, flavourings, and wetting agents. The tablets may be coated according to techniques well known in the art.
These oral formulations may be prepared by conventional methods of blending, filling, 2 o tableting, or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, well known in the art.
Thus, the present invention provides for the use of a pharmaceutically acceptable organic acid in the formulations comprising carvedilol. The formulation is adapted for oral administration. The formulation is presented as a unit dose. Such a formulation is taken once daily. The preferred unit dosage forms include tablets or capsules comprising 25 mg or 50 mg of carvedilol; however, the present invention also includes doses from 6.25 mg to 100 mg.
No unacceptable toxicological effects are expected when carvedilol is administered in accordance with the present invention.
3 o The following examples are illustrative of the instant invention. These examples are not intended to limit the scope of this invention as defined herein above and as claimed herein below.
Examples 1 & 2 - Carvedilol 50 m~ Controlled Release Aqueous Film Coated Tablets 3 5 The carvedilol 50 mg controlled release (CR) aqueous film coated (AFC) tablets were prepared from a carvedilol spray-dried powder which was blended with external excipients and a lubricant, compressed, and finally coated with a clear aqueous film coat followed by a Eudragit~-based coat. Product CE tablets Were made with fumaric acid, whereas Product CF
tablets are made with citric acid.
Table 1 Unit Formulas for Carvedilol 50 mg CR AFC Tablet, Products CE and CF
Quantity Ingredients (mg/Tablet) "Carvedilol Spray-Dried Powder" consisting of: (~g.061) Carvedilol 52.071 Poloxamer 407 10.381 Povidone 5.231 Hydroxyethyl Cellulose 10.381 Purified Water q.s.2 Fumaric Acid for Product CE 120.00 or Citric Acid (monohydrate) for Product CF
Dibasic Calcium Phosphate Dihydrate155.941 Microcrystalline Cellulose 174.00 Crospovidone 60.00 Silicon Dioxide Colloidal 6.00 Magnesium Stearate 6.00 __.
Total Weight Tablet Core 600.00 Clear Opadry YS-1-19025-A 12.00 Aqueous Dispersion of Methacrylic45.58 Acid Copolymer, Type C (Eudragit~ L30 D-55) Triethyl Citrate 5.83 Sodium Lauryl Sulfate 1.06 Glyceryl Stearate (Imwitor 900 0.53 Powder) Purified Water n ~ 3 Total Weight Coated Tablet 665.00 lBased on 96% label claim for the "Carvedilol Spray-Dried Powder."
These levels will change based upon the % label claim achieved during the spray drying 1 o process and are adjusted during the blending step.
2Removed during spray drying process.
3Removed during drying.
Examples 3 & 4 - Carvedilol 50 m~ Controlled Release Matrix Tablets The carvedilol controlled release (CR) matrix tablets (Products CG and CH) are prepared from a carvedilol granulation containing either a carvedilol spray-dried powder or standard carvedilol drug substance, respectively. A citric acid granulation is prepared separately. The desired carvedilol granulation and the citric acid granulation are blended together along with external excipients and finally a lubricant to produce the mix from which tablets are then compressed.
Table 2 Unit Formulas for Carvedilol 50 mg CR Matrix Tablets, Products CG and CH
Quantity (mg/Tablet) Ingredients CG CH
Carvedilol Gz-anulatiofz "Carvedilol Spray-Dried Powder" (78.214) consisting of:
Carvedilol 52.174 ---Poloxamer 407 10.404 ---Povidone 5.244 ---Hydroxyethyl Cellulose 10.404 -'-Purified Water q.s.5 ---Carvedilol --- 50.00 Hydroxypropyl Methylcellulose77.01 95.96 Carboxymethylcellulose 38.30 47.57 Sodium Povidone 8.07 8.06 Purified Water q.s.5 q,s.5 Citric Acid Grazzulation Citric Acid 104.98 104.98 Hydroxypropyl Methylcellulose54.43 54.43 Carboxymethylcellulose 27.22 27.22 Sodium Povidone 7.78 7.78 Purified Water q.s.5 q.s_5 Final Blefzd Microcrystalline Cellulose192.00 192.00 Silicon Dioxide Colloidal6.00 6.00 Magnesium Stearate 6.00 6.00 Total Tablet Weight 600.00 600.00 4Based on 96% label claim for the "Carvedilol Spray-Dried Powder."
1o These levels will change based upon the % label claim achieved during.the spray drying process and are adjusted during the blending step.
SRemoved during processing.
Example 5 - Carvedilol 25 m~ Controlled Release Capsule The carvedilol controlled release (CR) capsule is prepared from carvedilol drug layered pellets containing standard carvedilol drug substance, aspartic acid and Opadry Clear.
The drug layered pellets are then coated with a sustained release coat, Aquacoat ECD-30, and filled into standard capsule shells for administration.
Ingredients (mg/Capsule) "Carvedilol Drug Layered Pellets" consisting(480.7) of:
Carvedilol 25.0 L-Aspartic Acid 31.2 Opadry Clear 25.0 Purified Water q.s.l Microcrystalline Cellulose Spheres 399.5 Ethylcellulose Aqueous Dispersion (Aquacoat113.9 ECD-30) Dibutyl Sebacate 36.1 Purified Water q.s.l Opadry Clear 1.9 Purified Water q.s.l Size 00 Capsule Shell 118.0 Total Weight Capsule 750.6 lRemoved during drug layering or coating process 1 o Example 6 - Carvedilol 25 m~ Controlled Release Capsule The carvedilol controlled release (CR) capsule is prepared from carvedilol drug layered pellets containing standard carvedilol drug substance, aspartic acid and Opadry Clear.
22.5 mg strength drug layered pellets are filled into standard capsule shells.
The capsules are enteric coated for the delayed release portion and a 2.5 mg strength immediate release top-coat is then applied for the initial burst effect.
Ingredients (mg/Capsule) "Carvedilol Drug Layered Pellets" consisting of: (432.7) Carvedilol 22.5 L-Aspartic Acid 28.1 Opadry Clear 22.5 Purified Water q.s.l Microcrystalline Cellulose Spheres 359.6 Aqueous Dispersion of Methacrylic Acid Copolymer, Type 49.7 C (Eudragit~ L30 D-55) Triethyl Citrate 5.8 Silicon Dioxide Colloidal 4.2 Sodium Lauryl Sulfate 0.4 Purified Water q.s.l Carvedilol 2.5 L-Aspartic Acid 0.2 Opadry Clear 2.5 Purified Water q.s.l Size 1 Capsule Shell '76.0 Total Weight Capsule 574.0 lRemoved during drug layering or coating process i~a vivo Pharmacokinetic evaluation of formulations The bioavailability of the formulations according to the present invention are evaluated in healthy human volunteers. The study is an open-label, single dose, randomized, four-period, incomplete block, crossover study. Each subject receives a single dose of the immediate release formulation in addition to single oral doses of 3 of the 4 controlled-release formulations according to a randomization schedule. The regimens for the study are tabulated below:
Product Description CE 50 m carvedilol in a controlled-release, Enteric I tablet formulation CF 50 m carvedilol in a controlled-release, Enteric II tablet formulation CG 50 m carvedilol in a controlled-release, Matrix I tablet formulation CH 50 m carvedilol in a controlled-release, Matrix II tablet formulation CI 2 x 25 mg carvedilol immediate release tablets, commercial formulation Pharmacokinetic sampling for measurement of plasma carvedilol concentrations is conducted over a 48-hour period following administration of study medication in each study session. There is a washout period of at least 7 days between dosing in sessions. Female subjects return 7-10 days following dosing in the last study session for a follow-up pregnancy test. The total duration (from screening to end of the study) of each subject's participation will be five to eight weeks.
The primary endpoint is the AUC of carvedilol. Secondary endpoints include Cmax, Tmax, and T1/2, as data permit.
It is to be understood that the invention is not limited to the embodiments illustrated hereinabove and the right is reserved to the illustrated embodiments and all modifications 2o coming within the scope of the following claims. The various references to journals, patents and other publications which are cited herein comprise the state of the art and are incorporated herein by reference as though fully set forth.
Claims (7)
1. A matrix formulation comprising carvedilol and a pharmaceutically acceptable organic acid.
2. The formulation according to claim 1 wherein the pharmaceutically acceptable organic acid is citric acid.
3. An enteric coated formulation comprising carvedilol and a pharmaceutically acceptable organic acid.
4. The formulation according to claim 3 wherein the pharmaceutically acceptable organic acid is citric acid.
5. A drug layered formulation comprising carvedilol and a pharmaceutically acceptable organic acid.
6. The formulation according to claim 5 wherein the pharmaceutically acceptable organic acid is aspartic acid.
7. A method of treating hypertension, congestive heart failure or angina which comprises administering to a subject in need thereof an effective amount of the formulation according to any one of claims 1-6.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24291100P | 2000-10-24 | 2000-10-24 | |
| US60/242,911 | 2000-10-24 | ||
| PCT/US2001/050872 WO2002065834A2 (en) | 2000-10-24 | 2001-10-23 | Novel formulations of carvedilol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2426811A1 true CA2426811A1 (en) | 2002-08-29 |
Family
ID=22916614
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002426811A Abandoned CA2426811A1 (en) | 2000-10-24 | 2001-10-23 | Novel formulations of carvedilol |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1335707A4 (en) |
| JP (1) | JP2004518734A (en) |
| AU (1) | AU2001297631A1 (en) |
| CA (1) | CA2426811A1 (en) |
| WO (1) | WO2002065834A2 (en) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2327685C (en) | 1998-04-03 | 2008-11-18 | Bm Research A/S | Controlled release composition |
| IN191028B (en) * | 2001-05-17 | 2003-09-13 | Sun Pharmaceutical Ind Ltd | |
| US20040253310A1 (en) | 2001-09-21 | 2004-12-16 | Gina Fischer | Morphine polymer release system |
| EP2957281A1 (en) | 2001-09-21 | 2015-12-23 | Egalet Ltd. | Polymer release system |
| WO2003024426A1 (en) * | 2001-09-21 | 2003-03-27 | Egalet A/S | Controlled release solid dispersions |
| AU2003275953A1 (en) | 2002-11-08 | 2004-06-07 | Egalet A/S | Controlled release carvedilol compositions |
| EP1610768B1 (en) | 2003-03-26 | 2008-07-02 | Egalet A/S | Matrix compositions for controlled delivery of drug substances |
| EP2301526B1 (en) | 2003-03-26 | 2016-03-23 | Egalet Ltd. | Morphine controlled release system |
| 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 |
| EP1686967A4 (en) * | 2003-11-25 | 2012-08-08 | Smithkline Beecham Cork Ltd | Carvedilol free base, salts, anhydrous forms or solvates thereof, corresponding pharmaceutical compositions, controlled release formulations, and treatment or delivery methods |
| AU2006216420B2 (en) | 2005-02-25 | 2010-07-15 | The Regents Of The University Of Michigan | Compositions and methods for treating and preventing cardiomyopathy and heart disease |
| HU227490B1 (en) * | 2005-08-26 | 2011-07-28 | Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag | Sustained release pharmaceutical preparation containing carvedilol |
| JP5537152B2 (en) | 2006-08-01 | 2014-07-02 | フリクサス ファーマシューティカルズ， インコーポレイテッド | Treatment for chronic progressive heart failure |
| HU227881B1 (en) * | 2007-02-23 | 2012-05-29 | Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag | Sustained release pharmaceutical preparation containing carvedilol |
| WO2008114276A1 (en) * | 2007-03-16 | 2008-09-25 | Lupin Limited | Novel oral controlled release composition of carvedilol |
| JP2010523569A (en) | 2007-04-05 | 2010-07-15 | フリクサス ファーマシューティカルズ， インコーポレイテッド | Compositions and methods for treating heart failure |
| WO2008148798A2 (en) | 2007-06-04 | 2008-12-11 | Egalet A/S | Controlled release pharmaceutical compositions for prolonged effect |
| FR2936709B1 (en) * | 2008-10-02 | 2012-05-11 | Ethypharm Sa | ALCOHOL-RESISTANT TABLETS. |
| WO2010089132A1 (en) | 2009-02-06 | 2010-08-12 | Egalet A/S | Immediate release composition resistant to abuse by intake of alcohol |
| NZ597283A (en) | 2009-06-24 | 2013-07-26 | Egalet Ltd | Controlled release formulations |
| TWI415604B (en) * | 2009-09-29 | 2013-11-21 | Tsh Biopharm Corp Ltd | Controlled release carvediolol formulation |
| US9549899B2 (en) | 2012-07-06 | 2017-01-24 | Egalet Ltd. | Abuse deterrent pharmaceutical compositions for controlled release |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19637082A1 (en) * | 1996-09-12 | 1998-03-19 | Boehringer Mannheim Gmbh | Rapidly disintegrating pellets |
| IL131713A (en) * | 1997-03-11 | 2004-08-31 | Arakis Ltd | Dosage forms comprising separate portions of r- and s-enantiomers |
| DE19816036A1 (en) * | 1998-04-09 | 1999-10-14 | Roche Diagnostics Gmbh | Production of pharmaceutical preparations with high disintegration rate containing difficultly soluble active ingredient, e.g. carvedilol |
| KR100336090B1 (en) * | 1998-06-27 | 2002-05-27 | 윤승원 | Solid dispersed preparation of poorly water-soluble drug containing oil, fatty acid or mixture thereof |
| DE19833119A1 (en) * | 1998-07-23 | 2000-01-27 | Roche Diagnostics Gmbh | Storage-stable injectable solution of vasodilator and beta blocker Carvedilol contains buffer, organic solvent, antioxidant and complexing agent |
| PE20001302A1 (en) * | 1998-11-27 | 2000-11-30 | Hoffmann La Roche | PREPARATIONS OF A PHARMACEUTICAL COMBINATION CONTAINING CARVEDILOL AND HYDROCHLOROTHIAZIDE |
| US6515010B1 (en) * | 1999-11-15 | 2003-02-04 | Smithkline Beecham Corporation | Carvedilol methanesulfonate |
| CA2402336C (en) * | 2000-04-03 | 2008-03-11 | F. Hoffmann-La Roche Ag | Concentrated solutions of carvedilol |
-
2001
- 2001-10-23 AU AU2001297631A patent/AU2001297631A1/en not_active Abandoned
- 2001-10-23 EP EP01273804A patent/EP1335707A4/en not_active Withdrawn
- 2001-10-23 WO PCT/US2001/050872 patent/WO2002065834A2/en not_active Application Discontinuation
- 2001-10-23 CA CA002426811A patent/CA2426811A1/en not_active Abandoned
- 2001-10-23 JP JP2002565411A patent/JP2004518734A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP1335707A4 (en) | 2005-07-06 |
| WO2002065834A3 (en) | 2002-10-03 |
| EP1335707A2 (en) | 2003-08-20 |
| JP2004518734A (en) | 2004-06-24 |
| AU2001297631A1 (en) | 2002-09-04 |
| AU2001297631A8 (en) | 2005-09-15 |
| WO2002065834A2 (en) | 2002-08-29 |
| WO2002065834A8 (en) | 2003-06-26 |
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