Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1999-04-16
2001-02-20
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S464000
Reexamination Certificate
active
06190693
ABSTRACT:
Throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.
FIELD OF THE INVENTION
This invention relates to compositions and methods for delivering folic acid to subjects afflicted with, or at an increased risk of becoming afflicted with, a folic acid-treatable disorder. The folic acid is incorporated into a chronically administered pharmaceutical composition intended for treating or preventing a condition different than the folic acid-treatable disorder.
BACKGROUND OF THE INVENTION
Folic Acid Generally
Folic acid is a vitamin. It plays a crucial role in DNA synthesis, and in hematopoiesis (although the details of this role remain undefined). Folic acid is involved, for example, in single carbon transfers (such as those required for purine and pyrimidine metabolism), and in the re-methylation of homocysteine to methionine.
Folic acid is available, primarily as the polyglutamate, from dietary sources such as whole grains, mushrooms, vegetables, red meat, fish and legumes. Supplementation, however, is provided in the form of the monoglutamate (pteroglutamic acid). Folic acid is absorbed primarily in the proximal small bowel, is highly protein-bound, and is stored in the liver. Almost no unchanged folic acid appears in the urine under normal circumstances, unless excess is provided.
Minimum requirements of folic acid are in the range of 50 &mgr;g/day, and increase 3 to 6 times during pregnancy and/or lactation. The U.S. recommended daily allowance for pregnant women is 400 &mgr;g/day, and the average pharmacological replacement dose is between 1 and 5 mg/day. Most prenatal vitamins contain 1 mg of folic acid.
The total body store of folic acid is about 5 mg. When a folic acid-deficient patient is treated, reversal of the deficiency begins rapidly (reticulocytosis within 4 days) and resolves within 2 months. If folic acid is administered at a rate of only 50 &mgr;g day, assuming no dietary or other intake, signs of folic acid deficiency are manifest after an approximately 3 month lag time. In cases of increased bodily folic acid requirements, such as pregnancy or lactation, this time frame is shortened to 2 to 4 weeks. Fortunately, folic acid supplementation in otherwise healthy young women who have such increased folic acid needs is an accepted practice.
Folic acid has not been reported to cause adverse effects when administered in reasonable, pharmacological doses. The only reported adverse reaction for folic acid is a decreased level of plasma zinc in the case of prolonged high-dose administration.
Oral Contraceptives and Folic Acid
In pregnant women, correction of low folic acid levels takes at least two months, and reserves can last as little as a few weeks. According to a public health service recommendation, all women who can become pregnant should consume 400 &mgr;g/day of folic acid to reduce the risk of birth defects (MMWR Morb Mortal Wkly Rep 1992; 41(RR-14):1-7). Supplementation immediately before discontinuing oral contraceptive use or immediately after positive pregnancy test results may be insufficient to optimally protect the developing fetus.
In addition, multiple studies of women taking oral contraceptives show decreased folic acid levels relative to negative controls. Postulated mechanisms reported for this phenomenon include decreased absorption of polyglutamates, increased excretion of folic acids, increased production of folic acid-binding proteins, and induction of folic acid-dependent hepatic microsomal enzymes.
Decreases of folic acid levels among oral contraceptive users pose an additional risk for such users who become pregnant within three to six months following discontinuation of use.
Disorders and Folic Acid
Numerous disorders can result from insufficient intake of folic acid. Enhanced effects of risk factors for cervical dysplasia (e.g. HPV infection) have been linked to decreased folic acid levels. Sub-optimal body stores of folic acid, as measured by red cell folic acid concentrations, may amplify oncogenic risk. Locally diminished folic acid stores, for example, in cervical tissue, may be a result of oral contraceptive use and are responsible for the dysplastic process. Finally, decreased folic acid levels early in pregnancy are associated with increased birth defects, primarily neural tube defects (“NTD's”). Indeed, randomized control trials of vitamin supplements containing folic acid have shown a dramatic reduction of the incidence of spina bifida and anencephaly.
Administering folic acid can reduce the onset of disorders such as cardiovascular disease and cervical dysplasia. For example, most clinical trials show that high folic acid doses (up to 10 mg/day) have a prophylactic, although not therapeutic, effect against cervical dysplasia (Butterworth, C. E., et al., JAMA (1992) 267(4):528-533; Butterworth C. E., et al., Am J Obstet Gynecol (1992) 166:803-809; Potischman, N. and Brinton, L. A., Cancer Causes and Control (1996) 7:113-126).
As for certain cardiovascular disorders, results from numerous studies indicate that doses of folic acid (1-5 mg/day) reduce elevated levels of homocysteine which can cause such disorders (Boushey, C. J., et al., JAMA (1995) 274:1049-1057); Landgren, F., et al., J Intern Med (1995) 237:381-388). A single study by Guttormsen (Guttormsen, A. B., et al., J Clin Invest (1996) 98:2174-2183) demonstrated that low-dose folic acid supplementation (200 &mgr;g/day) reduces elevated plasma homocysteine levels in patients with intermediate hyperhomocysteinemia (>40 &mgr;mol/L). This reduction is influenced, in part, by the initial causes of hyperhomocysteinemia, i.e., genetic mutation, dietary deficiency and concurrent disease.
SUMMARY OF THE INVENTION
This invention provides a pharmaceutical composition comprising (a) an oral contraceptive for preventing pregnancy in a subject, and (b) folic acid in an amount sufficient to treat or prevent a disorder which (i) afflicts subjects for whom the oral contraceptive is indicated at a higher-than-normal incidence, and (ii) is treatable or preventable by folic acid administration.
This invention also provides a pharmaceutical composition comprising (a) a hormonal replacement composition for treating or preventing a menopausal condition in a subject, and (b) folic acid in an amount sufficient to treat or prevent a disorder which (i) afflicts subjects for whom the hormonal replacement composition is indicated at a higher-than-normal incidence, and (ii) is treatable or preventable by folic acid administration.
This invention further provides a pharmaceutical composition comprising (a) a hormonal replacement composition for treating or preventing a hypogonadal condition in a subject, and (b) folic acid in an amount sufficient to treat or prevent a disorder which (i) afflicts subjects for whom the hormonal replacement composition is indicated at a higher-than-normal incidence, and (ii) is treatable or preventable by folic acid administration.
This invention further provides a method of administering folic acid to a subject for whom an oral contraceptive is indicated for preventing pregnancy, which comprises administering to the subject the instant pharmaceutical composition, wherein the subject is from a population whose members are afflicted with, or predisposed to become afflicted with, a disorder at a higher-than-normal incidence, the disorder being treatable or preventable by folic acid administration.
This invention further provides a method of administering folic acid to a subject for whom a hormonal replacement composition is indicated for treating or preventing a menopausal condition, which comprises administering to the subject the instant pharmaceutical composition, wherein the subject is from a population whose members are afflicted with, or predisposed to become afflicted with, a disorder at a higher-than-normal incidence, the disorder being treatable or preventable by folic acid administrati
Kafrissen Michael E.
Oakley Godfrey
Azpuru Carlos A.
Morrison Alan J.
Ortho-McNeil Pharamceutical, Inc.
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