Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-05-23
2003-02-11
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S451000, C424S457000, C424S464000, C424S468000, C424S470000, C514S341000
Reexamination Certificate
active
06517871
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a phamaceutically active compound, bioenhanced formulations of eprosartan or eprosartan mesylate, processes for manufacturing the compound and these formulations and methods of using the bioenhanced formulations of eprosartan in the treatment of certain disease states in mammals, in particular man. Most specifically, the present invention relates to the use of eprosartan or eprosartan mesylate in the production of bioenhanced immediate and modified (both sustained and targeted) release oral solid dosage forms (tablet or capsule formulations) to block angiotensin II (AII) receptors and to treat hypertension, congestive heart failure and renal failure.
BACKGROUND OF THE INVENTION
The compound (E)-&agr;-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid is known by the name eprosartan and is the subject of U.S. Pat. No. 5,185,351 (the '351 patent), issued Feb. 9, 1993. This patent discloses a process for making the anhydrous form of (E)-&agr;-[2-n-butyl-1-(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid and its methanesulfonate salt (eprosartan mesylate). Additionally, the '351 patent discloses conventional techniques for formulating (E)-&agr;-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid. This compound is claimed to have utility in blocking angiotensin II receptors and to be useful in the treatment of hypertension, congestive heart failure and renal failure.
Because the variable and mean absolute bioavailability of eprosartan is approximately 13%, doses as high as 800 mg per day may be required for an effective treatment of hypertension, congestive heart failure and renal failure. Additionally, since the commercial form of the drug is as its mesylate, which becomes dihydrated during the formulation process, high dose tablets (e.g., 600 mg tablets weigh 1,200.0 mg) may be difficult to swallow. Therefore, there is a need for a formualtion that enhances the bioavailabiltiy of eprosartan.
Surprisingly, it has been found that eprosartan dissolved in ammonium hydroxide in the presence of poly(vinylpyrrolidone) (PVP) does not crystallize when spray dried or spray granulated using a fluid bed granulator. The drug substance in this spray dried or fluid bed granulated material is predominately in the amorphous form and, thus, is significantly more soluble in water, as well as body fluids. Consequently, the formulation containing the drug substance predominately in the amorphous form has been found to exhibit significantly greater bioavailability relative to the tablets of the current commercial formulation. Also, the present invention has resulted in a significant reduction in tablet size and may result in a significant increase in patient compliance. This is particularly important when formulating eprosartan or its mesylate salt for therapeutic use.
SUMMARY OF THE INVENTION
The present invention provides the amorphous ammonium salt of eprosartan. This form of eprosartan is prepared by dissolving eprosartan or eprosartan mesylate in ammonium hydroxide in the presence of a crystallization inhibitor.
Another aspect of the invention provides bioenhanced oral solid dosage forms of eprosartan, (E)-&agr;-[2-n-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid, or its any of its salt forms, in particular the monomethanesulfonate salt form, for the treatment of diseases in which blockade of angiotensin II receptors is indicated, for example, in the treatment of hypertension, congestive heart failure and renal failure. The present invention also provides a process for preparing bioenhanced capsule or tablet formulations of eprosartan or eprosatan mesylate by dissolving the anhydrous form of the drug substance in ammonium hydroxide in the presence of a pharmaceutically acceptable crystallization inhibitor, such as polyvinylpyrrolidone (PVP), and spray drying or granulating in a fluid bed granulator. These spray dried/fluid bed granules are blended with additional pharmaceutically acceptable to produce immediate release or modified (sustained or targeted) release oral solid dosage forms (capsules and tablets).
BRIEF DESCRIPTION OF THE FIGURES
The anhydrous forms of eprosartan and eprosartan mesylate exhibit a single thermal event, a melting endotherm at about 269° C. and 252° C., respectively. No significant weight loss prior to melting is observed in its TGA (thermogravimetric analysis), suggesting that neither of these compounds contains significant quantities of surface adsorbed water and/or residual solvents. The powder X-ray diffraction (XRD) patterns of the anhydrous form of eprosartan, eprosartan mesylate, spray dried eprosartan and spray dried eprosartan mesylate are presented in FIG.
1
. The powder X-ray diffraction pattern of eprosartan exhibits characteristic diffraction lines corresponding to 2&thgr; values of 8.15, 9.74, 14.20, 16.09, 17.09, 19.99, 20.71, 21.81, 22.38, 24.49, 26.84 and 31.39 degrees, while the XRD of eprosartan mesylate exhibits characteristic diffraction lines corresponding to 2&thgr; values of 7.15, 13.90, 14.35, 18.30, 18.90, 20.10, 20.45, 21.00, 22.20, 24.35, 28.95 and 34.20 degrees. The spray dried formulations containing granules of eprosartan or eprosartan mesylate dissolved in ammonium hydroxide in the presence of PVP [Povidone (K-15/18)] exhibit a halo indicating that the formulations contain the drug substance predominately in the amorphous form. The pH-solubility profiles of the drug substances and their formulations are presented in FIG.
2
. It is clear from these profiles that the formulations containing the spray dried granulations of eprosartan or eprosartan mesylate exhibit significantly higher solubilities and faster dissolution in water, as well as in gastrointestinal fluids, than their crystalline counterparts. The relative bioavailability data in dogs for the spray dried eprosartann formulation suggest that the mean AUC
(0-12)
and Cmax values increased 36% and 115%, respectively, when compared to the commercial eprosartan mesylate granules.
DETAILED DESCRIPTION OF THE INVENTION
(E)-&agr;-[2-n-Butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene-2-thiophenepropionic acid (eprosartan) is known to exist in an anhydrous form. The commercial form of eprosartan is as its methanesulfonic acid salt and it has the following structure:
Eprosartan and eprosartan mesylate are claimed in U.S. Pat. No. 5,185,351. Reference should be made to said patent for its full disclosure, the entire disclosure of which is incorporated herein by reference.
The present invention provides a novel form of eprosartan, which is the amorphous ammonium salt form of eprosartan. This form of eprosartan is prepared by dissolving eprosartan or eprosartan mesylate in ammonium hydroxide in the presence of a crystallization inhibitor. Preferably, the crystallization inhibitor used in this process is polyvinylpyrrolidone (PVP).
Suitably, eprosartan or eprosartan mesylate are granulated predominately in amorphous form by dissolving the drug substance in ammonium hydroxide in the presence of a crystallization inhibitor, such as PVP, and optionally one or more pharmaceutically acceptable excipients, and then spray drying said solution or granulating said solution in a fluid bed granulator.
Preferably, a bioenhanced formulation of eprosartan or eprosartan mesylate is prepared by:
(i) dissolving eprosartan or eprosartan mesylate in ammonium hydroxide in the presence of a crystallization inhibitor and optionally one or more pharmaceutically acceptable excipients;
(ii) spray-drying the above solution, or granulating a mixture of pharmaceutical excipients and the above solution followed by drying in a fluid bed granulator; and
(iii) filling into capsules or compressing into tablets the dried granulation, after additional blending with pharmaceutical excipients.
Suitably, the p
Gudipati Manga R.
Venkatesh Gopadi M.
Fubara Blessing
Kinzig Charles M.
McCarthy Mary E.
Page Thurman K.
SmithKline Beecham Corporation
LandOfFree
Bioenhanced formulations comprising eprosartan in oral solid... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Bioenhanced formulations comprising eprosartan in oral solid..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Bioenhanced formulations comprising eprosartan in oral solid... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3116318