Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-02-16
2001-06-19
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S464000, C424S465000, C424S499000, C424S502000
Reexamination Certificate
active
06248361
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention concerns water-soluble compositions comprising folic acid and/or folic acid analogs, and at least one carbonate or bicarbonate material, methods for making such compositions, and methods for making pharmaceutical dosage forms thereof.
Folic acid has the empirical formula C
19
H
19
N
7
O
6
and the structural formula shown below. It is a B vitamin that is found in liver, kidney, mushrooms, spinach, yeast, green leaves, and grasses. Pure folic acid crystals are yellowish-orange and only very slightly soluble in cold water (0.0016 mg/ml at 25° C.).
Absorption of folic acid by the body is facilitated by enzymes associated with the mucosal cell membrane. More specifically, absorption primarily occurs in the mucosae of the upper intestine, known as the jejunum and duodenum. Insufficient folic acid in the diet and the inability to absorb folic acid can cause anemia and/or birth defects, namely, anecephaly and spina bifida, the latter resulting in brain development abnormalities and even death.
Anecephaly and spina bifida are caused by neural tube defects and the frequency of these defects can be greatly decreased by supplementing the diets of pregnant women with folic acid. The discovery of the importance of folic acid stemmed from a finding that women from lower socioeconomic backgrounds gave birth to infants with neural tube defects at a higher rate than women who were well off and presumably had a well-rounded diet. Researches also found that babies that were conceived during the fall and winter were at an increased risk of neural tube defects, presumably because of the lack of fresh vegetables during the pregnancy. This information lead to the U.S. Public Health Service recommendation in September 1992 that all women of childbearing age consume 400 &mgr;g of folic acid daily.
In February 1996, the Food and Drug Administration recommended that certain foods that are regularly consumed by the public be fortified with folic acid. This action was taken as a preventative measure since most neural tube defects occur in the first 18-30 days of pregnancy, when most women are unaware of the pregnancy.
More recently, epidemiological studies have implicated folic acid in atherosclerosis. Researchers have found elevated levels of homocysteine, an amino acid in the blood, in people suffering from atherosclerosis. Folic acid and other B vitamins contribute to the breakdown of homocysteine and therefore may be useful for controlling atherosclerosis.
While much is known about the benefits derived from folic acid, its very low aqueous solubility have made it difficult to use and administer. Recent studies indicate that dietary supplements containing folic acid generally have failed to meet the United States Pharmacopeia (USP) Convention for dissolution, which is that 75% of the folic acid content in the supplement dissolve in an aqueous medium within one hour, the time regarded to be necessary for folic acid to pass through the stomach and into the intestine where absorption occurs. See 37
J. Am. Pharm. Assoc.
397 (1997) Therefore, compositions and methods for increasing the aqueous solubility of folic acid are needed so that folic acid utilization can be optimized.
BRIEF SUMMARY OF THE INVENTION
The invention provides a folic acid composition that is instantly soluble in even cold water, making possible the fabrication of pharmaceutical dosage forms that easily exceed the USP solubility standard.
One embodiment of the present invention comprises a method for making a substantially dry pharmaceutical trituration composition comprising a first compound selected from the group consisting of folic acid, folic acid analogs, and mixtures thereof; and a second compound selected from the group consisting of carbonate and bicarbonate salts, particularly Group IA metal carbonates, bicarbonates, and mixtures thereof. The second compound preferably is selected from the group consisting of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate, and its concentration generally exceeds that of the first compound. More specifically, the relative concentrations of folic acid compound and the carbonate compound is such that the folic acid compound is not less than 1% and not more than 50% of the total of the two compounds on a dry weight basis. Other components, such as other vitamins, minerals, herbs, and other nutritional products, may be added to this trituration composition to form various other pharmaceutical and dietary supplement compositions.
The present invention also provides a method for making an aqueous-soluble folic acid-containing dosage form. The method comprises forming or obtaining the aforesaid trituration composition and adding to it one or more excipients such as binders, lubricants, diluents, humectants, disintegrants, and mixtures thereof. Tablets or other dosage forms are formed from the resulting mixture according to conventional methods. A preferred dosage form is a tablet comprising a lactose diluent, a magnesium stearate lubricant, a microcrystalline cellulose binder, a silicon dioxide desiccant, and a sodium croscarmellose disintegrant. Dosage forms may also be formulated into controlled release forms by conventional methods.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
As used herein, “folic acid” includes the basic folic acid moiety having the structure shown above and its analogs, preferably those analogs which are capable of being absorbed and utilized by the body. For example, and without limitation, utilization by the body may mean that the folic acid analog can be utilized as a starting point for the synthesis of methionine and certain other amino acids.
In addition to folic acid and/or folic acid analogs, the composition contains one or more carbonate or bicarbonate salts. Preferred materials are the Group 1A metal carbonates or bicarbonates, particularly sodium and potassium carbonates or bicarbonates. Examples of other carbonates that can be used include ammonium carbonate, sodium sesquicarbonate, potassium sesquicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate, and arginine carbonate.
By a “substantially dry” pharmaceutical composition is meant that, following mixing the folic acid component and the carbonate/bicarbonate component the resulting mixture contains not more than about 10 wt % water content.
The folic acid composition is made as follows. Components preferably having a purity suitable for ingestion may be screened to produce material having the desired size of granulation. Highly water-soluble compositions have been made using screens having a mesh size of not more than US #30 (600 &mgr;m). Dry compositions are then formed by mixing the components in the desired ratio, for example, where the relative concentrations of folic acid and carbonate and/or bicarbonate is such that the folic acid compound is not less than 1% and not more than 50% of the total of the folic acid and carbonate on a dry weight basis.
This basic pharmaceutical trituration composition is useful as a raw material in the fabrication of other forms of the aqueous-soluble folic acid composition. For example, it can be incorporated into a sprayable aqueous solution and so applied to processed foodstuffs such as cereals or snacks or it can be combined with other ingredients and formed into pharmaceutical dosage forms such as tablets.
As used herein, the phrase “pharmaceutical dosage form” generally means those forms described in Vol. 24 USP, p. 2107 (2000). One of ordinary skill in the art will appreciate that there are numerous dosage forms which can be used to deliver the folic acid composition to the body. The most preferred forms are tablets, capsules, multiparticulates, sachets and powders.
A tablet of the folic acid-containing composition of the present invention may be formed by conventional tableting methods, e.g., with a tablet press. This process requires that the material to be tableted be compressible and sufficiently lubricated so that it can be ejected from the tablet press witho
Johnson Bruce
Kuna Vladimir
Chernoff Vilhauer McClung & Stenzel LLP
Integ, Ltd.
Page Thurman K.
Tran S.
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