Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1994-11-14
2001-10-02
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S893000, C514S894000
Reexamination Certificate
active
06297229
ABSTRACT:
BACKGROUND OF THE INVENTION
Nonalcoholic steatohepatitis (NASH) involves the development of histologic changes in the liver that are comparable to those induced by excessive alcohol intake but in the absence of alcohol abuse. Macrovesicular and/or microvesicular steatosis, lobular and portal inflammation, and occasionally Mallory bodies with fibrosis and cirrhosis characterize NASH. NASH is also commonly associated with hyperlipidemia, obesity, and type II diabetes mellitus. Other clinical conditions characterized by hepatic steatosis and inflammation include excessive fasting, jejunoileal bypass, total parental nutrition, chronic hepatitis C, Wilson's disease, and adverse drug effects such as those from corticosteroids, calcium channel blockers, high dose synthetic estrogens, methotrexate and amiodarone. Thus, the term “nonalcoholic steatohepatitis” can be used to describe those patients who exhibit these biopsy findings, coupled with the absence of (a) significant alcohol consumption, (b) previous surgery for weight loss, (c) history of drug use associated with steatohepatitis, (d) evidence of genetic liver disease or (e) chronic hepatitis C infection. See, J. R. Ludwig et al.,
Mayo Clin. Proc.,
55, 434 (1980) and E. E. Powell et al.,
Hepatol.,
11, 74 (1990).
The pathogenesis of NASH is unknown. A correlation seems to exist between the degree of steatosis and the degree of fibrosis. For example, see I. R. Wanless et al.,
Hepatology,
12, 1106 (1990). Elevated hepatocellular free fatty acids may cause membrane injury with subsequent inflammation, possible cholestasis, and subcellular organelle dysfunction. Cell death and fibrosis follow persistent inflammation, and cirrhosis occurs if the injury continues. Steatohepatitis is now considered an important cause of end-stage liver disease and may be the cause of an unknown number of cases of clyptogenic cirrhosis. See E. E. Powell et al, cited above. Unfortunately, once cirrhosis is established, the only therapeutic modality available is orthotopic liver transplantation. Thus, effective therapy for nonalcoholic steatohepatitis is clearly needed.
SUMMARY OF THE INVENTION
The present invention provides a therapeutic method comprising administering to a human patient afflicted with nonalcoholic steatohepatitis (NASH) an amount of ursodeoxycholic acid (UCDA), a pharmaceutically acceptable ester or a pharmaceutically acceptable salt thereof, which amount is effective to treat said nonalcoholic steatohepatitis. Of the modes of administration, the oral administration of total dosages of about 500-1000 mg/day (adult) of UCDA is preferred. As used herein, the term “treat” is intended to include significant lowering of at least one of the serum enzyme markers, the elevation of which is associated with NASH, or histologic improvement by at least one grade. The clinical condition of the patient treated may be improved, but, as in the case of any progressive pathology, effective treatment also comprises slowing the progression of the condition, as well as halting it completely.
DETAILED DESCRIPTION OF THE INVENTION
Ursodeoxycholic acid (UDCA) has the formula:
and the full chemical name 17&bgr;-(1-methyl-3-carboxypropyl)etiocholane-3&agr;, 7&bgr;diol. No major toxicity is known to be associated with UDCA (W. H. Bachrach et al.,
Dig. Dis. Sci.,
30, 642 (1985)). Thus, pharmaceutically acceptable salts and esters of UDCA include nontoxic esters of the free hydroxyl groups of UDCA with (C
1
-C
4
)alkanoic acids such as formic, acetic or propionic acid, phosphate esters of the OH groups, (C
1
-C
4
)alkyl esters of the free (C
24
) carboxylic acid group and nontoxic alkali metal, ammonium or amine salts of the free carboxylic acid moiety. This ester and salts can be readily prepared from free UCDA by methods well known to the art. At least the diformate and diacetate esters are known compounds. See,
The Merck Index
(11th ed. 1989) at 1556. UDCA is commercially available in 300 mg hard gelatin capsules as Actigall® from Summit Pharmaceuticals, Summit, N.J., and is prescribed for gallbladder stone dissolution.
It will be further appreciated that the amount of UDCA required for use in treatment will vary not only with the particular form of UDCA selected but also with the route of administration, the severity of the symptoms being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian. In general, however, a suitable daily dose will be in the range of from about 5 to about 25 mg/kg, e.g., from about 8-10 mg/kg to about 16-20 mg/kg of bodyweight per day.
Preferably, the amount of ursodeoxycholic acid is administered orally, in single or multiple daily doses, at from about 500-1500 mg total daily doses, i.e., via pharmaceutical unit dosage forms, such as tablets or capsules, which are adapted for oral administration. Prolonged treatment with UDCA is contemplated in accord with the method, involving treatment periods of 1-5 years or longer.
While it is possible that, for use in therapy, a compound of the invention may be administered as the pure acid, it is preferable to present the active ingredient as a pharmaceutical formulation. The invention thus further provides a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof together with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Pharmaceutical formulations include those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The formulations may, where appropriate, be conveniently presented in discrete unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Pharmaceutical formulations suitable for oral administration may conveniently be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a suspension or as an emulsion. The active ingredient may also be presented as a bolus, electuary or paste. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants, or wetting agents. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives.
UDCA and its derivatives may also be formulated for parenteral administration (e.g., by injection, for example, bolus injection or continuous intravenous or enteral infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.
When des
Mayo Foundation for Medical Education and Research
Schwegman Lundberg Woessner & Kluth P.A.
Travers Russell
Wang Shengjun
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