WO2003028718A1 - Novel formulations of carvedilol - Google Patents

Novel formulations of carvedilol Download PDF

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Publication number
WO2003028718A1
WO2003028718A1 PCT/US2002/031297 US0231297W WO03028718A1 WO 2003028718 A1 WO2003028718 A1 WO 2003028718A1 US 0231297 W US0231297 W US 0231297W WO 03028718 A1 WO03028718 A1 WO 03028718A1
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WIPO (PCT)
Prior art keywords
carvedilol
oral
formulations
captisol
encapsin
Prior art date
Application number
PCT/US2002/031297
Other languages
French (fr)
Inventor
Choon K. Oh
Chen Wei
Ignatious Francis
Original Assignee
Smithkline Beecham Corporation
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Publication of WO2003028718A1 publication Critical patent/WO2003028718A1/en

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin

Definitions

  • 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.
  • 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.
  • carvedilol can be formulated in novel formulations for once-daily dosing.
  • the present invention provides for the use of cyclodextrin complexes in formulations comprising carvedilol.
  • This invention also provides for the use of such formulations for the treatment of hypertension, congestive heart failure and angina.
  • the mean plasma concentrations versus time profiles of carvedilol following bolus oral and intracolonic administration of the instant formulations at 5mg/Kg in dogs are presented in Figure 1.
  • Figures 2 shows the plasma concentration of carvedilol following administration of an oral suspension at 5mg/Kg.
  • Figures 3 shows the plasma concentration of carvedilol following intracolonic administration of the captisol complex at 5mg/Kg.
  • Figures 4 shows the plasma concentration of carvedilol following intracolonic administration of the encapsin complex at 5mg/Kg.
  • compositions of carvedilol comprising carvedilol-cyclodextrin complexes.
  • the composition may then be formulated, for example, in the form of tablets or capsules. Orally administrable formulations are preferred.
  • the present invention provides for a formulation comprising carvedilol- cyclodextrin complexes.
  • carvedilol-cyclodextrin complexes refers to Carvedilol- Captisol®, sulfobutylether beta-cyclodextrin, or Carvedilol-Encapsin, hydroxypropyl beta- cyclodextrin complexes.
  • compositions containing the carvedilol-cyclodextrin complexes, thus produced, are then used in tablets for oral administration 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 release of the active compound, for example by the inclusion of gel forming polymers or matrix forming waxes.
  • Tablets 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.
  • 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.
  • oral formulations may be prepared by conventional methods of blending, filling, 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.
  • 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 or twice daily, preferably once daily.
  • the preferred unit dosage forms include tablets comprising beween about 25-50 mg of carvedilol. No unacceptable toxicological effects are expected when carvedilol is administered in accordance with the present invention.
  • Carvedilol-Captisol®, sulfobutylether beta-cyclodextrin, or Carvedilol-Encapsin, hydroxypropyl beta-cyclodextrin,complexes in pH 6.0 phosphate buffer results in the enhanced absorption of carvedilol in the lower GI tract.
  • Carvedilol is a novel, multiple-action cardiovascular agent that is being developed jointly by SmthKline Beecham and Boehringer Mannheim GmbH. Carvedilol is rapidly absorbed following oral administration in the rat and dog. Due to substantial first pass metabolism, the absolute bioavailability of Carvedilol in the rat and dog is low (20-25% and 10-30%, respectively).
  • Carvedilol was dosed at 5 mg/kg.
  • Intracolonic A solution of Carvedilol-Captisol® complex in water, containing 6% Captisol; Carvedilol concentration, 4.16 mg/mL.
  • Oral suspension A suspension of Carvedilol in 1 % methocel at a concentration of 4.16mg/mL.
  • Dogs Five male beagle dogs surgically prepared with duodenal and colonic vascular access ports were used. Dogs were dosed at 5 mg/kg at a dose volume of 1.2mL/kg. Vascular access ports were x-rayed for placement and patency prior to and post experiment. Dogs were fasted at least 18 hours prior to dosing. On the day of study, the dogs were placed in a sling (Alice King, Chatham Medical Arts, CA) for the first two hours, and fitted with an indwelling catheters in the forelegs to facilitate blood sampling. After two hours post dosing, the dogs were put back in their cages with free access to water and blood samples taken as appropriate. Food was returned to each dog 8 hours post dosing.
  • a sling Alice King, Chatham Medical Arts, CA
  • a 9 mm stomach tubing (20-25 cm) was employed and the dosing solution was followed with 100ml of MilliQ water.
  • Dog plasma samples were assayed by levels of carvedilol. Quantitation was performed by LC MS/MS employing positive-ion electrospray ionisation. A 200microliter aliquot of the sample was used. The LLQ (lower limit of quantification) was 0.5ng/mL and HLQ (high limit of quantification) was 150ng/mL.
  • Captisol and Encapsin complexes of Carvedilol administered intracolonically This is inspite of the fact that Captisol complex is given as a clear liquid, due to its higher aqueous solubility, compared to Encapsin complex being a suspension. It might be speculated that there is not enough fluid in the dog colon to bring about the complete dissociation of the Carvedilol- Captisol complex. The scenario might be different in the human lower GI tract.
  • Encapsin-IC/ Oral 20 64 23 62 31 40 ⁇ 10

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, l-(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:
Figure imgf000002_0001
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. 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 cyclodextrin complexes in formulations comprising carvedilol.
This invention also provides for the use of such formulations for the treatment of hypertension, congestive heart failure and angina. Brief Description of the Figures The mean plasma concentrations versus time profiles of carvedilol following bolus oral and intracolonic administration of the instant formulations at 5mg/Kg in dogs are presented in Figure 1. Figures 2 shows the plasma concentration of carvedilol following administration of an oral suspension at 5mg/Kg. Figures 3 shows the plasma concentration of carvedilol following intracolonic administration of the captisol complex at 5mg/Kg. Figures 4 shows the plasma concentration of carvedilol following intracolonic administration of the encapsin complex at 5mg/Kg.
Description of the Invention
According to the present invention, compositions of carvedilol are provided comprising carvedilol-cyclodextrin complexes. The composition may then be formulated, for example, in the form of tablets or capsules. Orally administrable formulations are preferred.
Importantly, the present invention provides for a formulation comprising carvedilol- cyclodextrin complexes.
As used herein, the term "carvedilol-cyclodextrin complexes" refers to Carvedilol- Captisol®, sulfobutylether beta-cyclodextrin, or Carvedilol-Encapsin, hydroxypropyl beta- cyclodextrin complexes.
The compositions containing the carvedilol-cyclodextrin complexes, thus produced, are then used in tablets for oral administration 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 release of the active compound, for example by the inclusion of gel forming polymers or matrix forming waxes.
Tablets 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, 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 or twice daily, preferably once daily. The preferred unit dosage forms include tablets comprising beween about 25-50 mg of carvedilol. No unacceptable toxicological effects are expected when carvedilol is administered in accordance with the present invention.
The following examples are illustrative of the instant invention. These examples are not intended to limit the scope of this invention as defined hereinabove and as claimed hereinbelow.
EXAMPLES
Summary The objective of this study was to determine whether the increased solubility of
Carvedilol-Captisol®, sulfobutylether beta-cyclodextrin, or Carvedilol-Encapsin, hydroxypropyl beta-cyclodextrin,complexes in pH 6.0 phosphate buffer results in the enhanced absorption of carvedilol in the lower GI tract. There is a ten fold increase in the solubility of carvedilol when complexed with Captisol®, compared to Encapsin. These studies were conducted with beagle dogs surgically implanted with colonic ports for dosing. An oral dosing of a suspension of Carvedilol in 1 % methocel was also performed in order to determine the ratio of intracolonic versus oral absorption. Background
Carvedilol is a novel, multiple-action cardiovascular agent that is being developed jointly by SmthKline Beecham and Boehringer Mannheim GmbH. Carvedilol is rapidly absorbed following oral administration in the rat and dog. Due to substantial first pass metabolism, the absolute bioavailability of Carvedilol in the rat and dog is low (20-25% and 10-30%, respectively).
The GI regional absorption study conducted in man with a gelatin suspension (25mg) by Boehringer Mannheim revealed that colonic absorption of Carvedilol is about 7 % of that following oral administration. The relative absorption of Carvedilol in jejunum and ileum were 56 % and 28 %, respectively, compared to oral administration. It is believed that the absorption of Carvedilol in the lower GI tract is limited by its pH dependent solubility rather than the permeability.
Formulations
Carvedilol was dosed at 5 mg/kg.
The following three formulations were prepared for the study: (1) Intracolonic: A solution of Carvedilol-Captisol® complex in water, containing 6% Captisol; Carvedilol concentration, 4.16 mg/mL.
(2) Intracolonic: A suspension of Carvedilol and Encapsin in water, containing 6% Encapsin; Carvedilol concentration, 4.16mg/mL;. (Carvedilol solubility in Encapsin, hydroxypropyl beta- cyclodextrin, is 10 times less compared to Captisol).
(3) Oral suspension: A suspension of Carvedilol in 1 % methocel at a concentration of 4.16mg/mL.
InVivo Method
Five male beagle dogs surgically prepared with duodenal and colonic vascular access ports were used. Dogs were dosed at 5 mg/kg at a dose volume of 1.2mL/kg. Vascular access ports were x-rayed for placement and patency prior to and post experiment. Dogs were fasted at least 18 hours prior to dosing. On the day of study, the dogs were placed in a sling (Alice King, Chatham Medical Arts, CA) for the first two hours, and fitted with an indwelling catheters in the forelegs to facilitate blood sampling. After two hours post dosing, the dogs were put back in their cages with free access to water and blood samples taken as appropriate. Food was returned to each dog 8 hours post dosing.
For oral dosing, a 9 mm stomach tubing (20-25 cm) was employed and the dosing solution was followed with 100ml of MilliQ water.
Sample Collection
Three mL blood samples were collected into Vacutainer® labelled heparinized tubes at the following intervals: 0, 7, 15, 30, 45, 60, 90, 120, 240, 360, 480, and 1440 min. All blood samples were placed on crushed ice until ready for centrifugation. Once the plasma was removed, it was placed in cryo tubes and quick frozen on dry ice/methanol and stored at -80°C until subsequent analysis.
Sample Analysis
Dog plasma samples were assayed by levels of carvedilol. Quantitation was performed by LC MS/MS employing positive-ion electrospray ionisation. A 200microliter aliquot of the sample was used. The LLQ (lower limit of quantification) was 0.5ng/mL and HLQ (high limit of quantification) was 150ng/mL.
Results and Discussion
The mean plasma concentrations versus time profiles of Carvedilol following bolus oral and intracolonic administration of the various formulations are presented in Figure 1 and Table 1. Figures 2-4 show the plasma concentration of individual dogs following treatment.
As seen from the Table 1, there is no significant difference in the AUC's between the
Captisol and Encapsin complexes of Carvedilol administered intracolonically. This is inspite of the fact that Captisol complex is given as a clear liquid, due to its higher aqueous solubility, compared to Encapsin complex being a suspension. It might be speculated that there is not enough fluid in the dog colon to bring about the complete dissociation of the Carvedilol- Captisol complex. The scenario might be different in the human lower GI tract.
Another interesting comparison is the ratio of AUCs of oral versus intracolonic absorption. A 1995 dog study (DDR #47) concluded that intracolonic absorption of carvedilol is about 19% of oral, when a Carvedilol suspension in methocel was dosed at 3mg/Kg. According to the data presented in Table 2, Captisol and Encapsin complexes show a much higher 60% and 40% respectively, intracolonic absorption compared to oral dosing of a suspension of carvedilol in methocel.
Conclusions • Carvedilol absorption in the colon is enhanced by its complexation with cyclodextrin.
• Carvedilol absorption in the colon is not significantly different for Captisol and
Encapsin complexes.
Table 1
Mean Pharmacokinetic Parameters for Carvedilol Following Oral (PO) and
Intracolonic(IC) Administration of Various Formulations in Dogs at 5mg/Kg
Formulation AUC (ng/mL.min) ± Cmax (ng/mL) Tmax
SEM ± SEM
PO-Unmilled suspension 281754± 64887 537 ± 65 60
IC-Captisol Solution 110436+ 13879 279 ± 31 60
IC-Encapsin Suspension 85159+ 14322 163 + 23 90
Data from DDR#218
IC-Oleic acid Solution 12800± 7880 32 ± 30 36C
IC-Unmilled Suspension 42773± 7368 129 ± 36 90
IC-Milled Suspension 62571+ 28810 115 ± 38 90
Table 2
Comparison of Mean AUC's for Carvedilol Following Intracolonic (IC) and Oral
(PO) Administration in Dogs at 5mg/Kg.
Formulation Dog # Dog # Dog # Dog # Dog # Mean ±
2763036 3339041 2959127 3341941 2960397 SEM
PO- Carvedilol 212064 174501 852956 66173 103078 281754 ±
Suspension 64887
IC-Captisol Solution 100000 210748 145472 42334 53629 110436 1 13879
IC-Encapsin 41375 112130 199478 41129 31683 85159 ±
Suspension 14322
Captisol-IC/Oral % 47 121 17 64 52 60 ± 17
Encapsin-IC/ Oral 20 64 23 62 31 40 ± 10
%
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 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

What is claimed is:
1. A composition comprising a carvedilol-cyclodextrin complex.
2. The composition according to claim 1 wherein the carvedilol-cyclodextrin complex is Carvedilol-Captisol®.
3. The composition according to claim 1 wherein the carvedilol-cyclodextrin complex is Carvedilol-Encapsin.
4. A formulation in tablet form for oral administration comprising any one of the compositions of claims 1-3.
5. 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 claim 4.
6. The use of the composition according to claim 4 in the manufacture of a medicament for the treatment of hypertension, congestive heart failure or angina.
PCT/US2002/031297 2001-10-01 2002-10-01 Novel formulations of carvedilol WO2003028718A1 (en)

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US60/326,368 2001-10-01

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7268156B2 (en) 2002-06-27 2007-09-11 Sb Pharmco Puerto Rico Inc. Carvedilol phosphate salts and/or solvates thereof, corresponding compositions and/or methods of treatment
WO2007124869A2 (en) * 2006-05-02 2007-11-08 Bayer Animal Health Gmbh Liquid pharmaceutical formulation
WO2009079679A3 (en) * 2007-12-21 2009-11-26 Aop Orphan Pharmaceuticals Ag Pharmaceutical composition for the parenteral administration of ultrashort-effective beta-adrenoreceptor antagonists
US7649010B2 (en) 2002-06-27 2010-01-19 SmithKline Beechman Cork Limited Carvedilol hydrobromide
US7750036B2 (en) 2003-11-25 2010-07-06 Sb Pharmco Puerto Rico Inc. Carvedilol salts, corresponding compositions, methods of delivery and/or treatment
US10772869B1 (en) 2019-07-24 2020-09-15 ECI Pharmaceuticals, LLC Pharmaceutical compositions including carvedilol and methods of using the same

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US4503067A (en) * 1978-04-13 1985-03-05 Boehringer Mannheim Gmbh Carbazolyl-(4)-oxypropanolamine compounds and therapeutic compositions
US4727064A (en) * 1984-04-25 1988-02-23 The United States Of America As Represented By The Department Of Health And Human Services Pharmaceutical preparations containing cyclodextrin derivatives
US5874418A (en) * 1997-05-05 1999-02-23 Cydex, Inc. Sulfoalkyl ether cyclodextrin based solid pharmaceutical formulations and their use
US5902821A (en) * 1995-02-08 1999-05-11 Boehringer Mannheim Pharmaceuticals Corporation Smith Kline Corporation Limited Partnership No. 1 Use of carbazole compounds for the treatment of congestive heart failure
US5904929A (en) * 1996-12-25 1999-05-18 Janssen Pharmaceutica, N.V. Acylated cyclodextrin-containing pharmaceutical composition

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4503067A (en) * 1978-04-13 1985-03-05 Boehringer Mannheim Gmbh Carbazolyl-(4)-oxypropanolamine compounds and therapeutic compositions
US4727064A (en) * 1984-04-25 1988-02-23 The United States Of America As Represented By The Department Of Health And Human Services Pharmaceutical preparations containing cyclodextrin derivatives
US5902821A (en) * 1995-02-08 1999-05-11 Boehringer Mannheim Pharmaceuticals Corporation Smith Kline Corporation Limited Partnership No. 1 Use of carbazole compounds for the treatment of congestive heart failure
US5904929A (en) * 1996-12-25 1999-05-18 Janssen Pharmaceutica, N.V. Acylated cyclodextrin-containing pharmaceutical composition
US5874418A (en) * 1997-05-05 1999-02-23 Cydex, Inc. Sulfoalkyl ether cyclodextrin based solid pharmaceutical formulations and their use

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7268156B2 (en) 2002-06-27 2007-09-11 Sb Pharmco Puerto Rico Inc. Carvedilol phosphate salts and/or solvates thereof, corresponding compositions and/or methods of treatment
US7902378B2 (en) 2002-06-27 2011-03-08 Smithkline Beecham (Cork) Limited Carvedilol phosphate salts and/or solvates thereof, corresponding compositions, and/or methods of treatment
US7893100B2 (en) 2002-06-27 2011-02-22 Sb Pharmco Puerto Rico Inc. Carvedilol phosphate salts and/or solvates thereof, corresponding compositions, and/or methods of treatment
US7759384B2 (en) 2002-06-27 2010-07-20 Smithkline Beecham (Cork) Limited Carvedilol phosphate salts and/or solvates thereof, corresponding compositions, and/or methods of treatment
US7626041B2 (en) 2002-06-27 2009-12-01 Smithkline Beecham (Cork) Ltd Carvedilol phosphate salts and/or solvates thereof, corresponding compositions, and/or methods of treatment
US7649010B2 (en) 2002-06-27 2010-01-19 SmithKline Beechman Cork Limited Carvedilol hydrobromide
US7750036B2 (en) 2003-11-25 2010-07-06 Sb Pharmco Puerto Rico Inc. Carvedilol salts, corresponding compositions, methods of delivery and/or treatment
WO2007124869A3 (en) * 2006-05-02 2008-04-17 Bayer Healthcare Ag Liquid pharmaceutical formulation
WO2007124869A2 (en) * 2006-05-02 2007-11-08 Bayer Animal Health Gmbh Liquid pharmaceutical formulation
WO2009079679A3 (en) * 2007-12-21 2009-11-26 Aop Orphan Pharmaceuticals Ag Pharmaceutical composition for the parenteral administration of ultrashort-effective beta-adrenoreceptor antagonists
US10660964B2 (en) 2007-12-21 2020-05-26 Aop Orphan Pharmaceuticals Ag Pharmaceutical composition for the parenteral administration of ultrashort-effective beta-adrenoreceptor antagonists
US11517624B2 (en) 2007-12-21 2022-12-06 Aop Orphan Pharmaceuticals Gmbh Pharmaceutical composition for the parenteral administration of ultrashort-effective β-adrenoreceptor antagonists
US10772869B1 (en) 2019-07-24 2020-09-15 ECI Pharmaceuticals, LLC Pharmaceutical compositions including carvedilol and methods of using the same
US10959985B1 (en) 2019-07-24 2021-03-30 ECI Pharmaceuticals, LLC Pharmaceutical compositions including carvedilol and methods of using the same

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