Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form
Reexamination Certificate
1999-02-26
2001-06-19
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
C424S667000, C424S668000, C424S669000, C424S670000, C424S671000
Reexamination Certificate
active
06248335
ABSTRACT:
FIELD OF THE INVENTION
This invention describes a stabilize an oral pharmaceutical composition comprised of iodide and iodate as the active agents in the presence of other pharmaceutical excipients and method for preparing these stabilized compositions.
BACKGROUND OF THE INVENTION
U.S. application Ser. No. 08/960,149 filed on Oct. 29, 1997, the disclosure of which is herein incorporated by reference, describes a method of generating molecular iodine in the stomach of a human or animal using an iodine reductant and an iodine oxidant. One reductant/oxidant pair identified as one of the preferred embodiments in this invention is iodide and iodate. One reason that iodide and iodate are preferred is that both of these compounds are used separately as food additives and both have GRAS (generally regarded as safe) status in the U.S. The literature describes the stability of iodide and iodate individually but there are no published reports of the stability of these two compounds in combination. In fact, these two chemicals in an appropriate medium can react rapidly with each other to yield molecular iodine.
This invention describes methods and compositions to stabilize an oral pharmaceutical composition that generates molecular iodine in situ wherein the active agents in said compositions are iodide and iodate. Methods for preparation of said stabilized pharmaceutical compositions are also described. It is a further objective of this invention to set forth the conditions and materials necessary to formulate a stable dosage form of iodide and iodate in the presence of accepted pharmaceutical excipients. It is a further objective of this invention to identify methods and compositions that comply with the strict stability objectives embodied in published regulatory guidelines of the FDA.
Regulatory bodies in different territories around the world have published guidelines that define requirements that must be met to manufacture and distribute a new pharmaceutical agent for human and animal use. In the U.S. the Food and Drug Administration (FDA) regulates drugs. Stability testing is a mandated aspect of the FDA drug development process and is required for manufacture and distribution of drugs.
DETAILED DESCRIPTION OF THE INVENTION
For the purposes of this invention the term iodide is the iodide anion which is commonly represented as I
−
. Iodide salts such as calcium iodide, sodium iodide, potassium iodide, magnesium iodide, zinc iodide, cupric iodide, and manganese iodide are readily available and are representative of the types of compounds that can, individually or in combination, serve as a suitable source of iodide. In fact, for the purpose of this application “a source of iodide” includes any nontoxic chemical entity that releases iodide anion upon dissolution in water.
For the purposes of this application the term iodate is the iodate anion which is commonly represented as IO
3
−
. Iodate salts such as calcium iodate, sodium iodate, potassium iodate, magnesium iodate, zinc iodate, cupric iodate, and manganese iodate are easily obtained and are representative of the types of entities that can, individually or in combination, serve as a suitable source of iodate. In fact, for the purpose of this application “a source of iodate” includes any chemical entity that releases the iodate anion upon dissolution in water.
For the purposes of this invention the term “oral pharmaceutical composition of iodide and iodate” shall mean a composition comprised of pharmaceutically acceptable excipients combined with iodide and iodate. Such a composition is to be administered orally to an animal or human. Suitable excipients include sodium alginate, alginic acid, dicalcium phosphates, tricalcium phosphate, microcellulose, citric acid, fructose, magnesium stearate, &agr;-cyclodextrin, &bgr;-cyclodextri, &ggr;-cyclodextrin, povidone, hydroxypropylmethylcelluiose, hydroxypropylmethylcellulose phthalate, disodium phosphate, sodium stearate, sorbitol, starch, sucrose, sodium acetate, sodium carboxymethylcellulose, ethyl vanillin, mannitol, sodium chloride, calcium sulfate, maltodextrin, dextrose, dextrin, dextrates, myvatex-TL, and saccharin. Other pharmaceutically acceptable excipients known in the art may also be used. The iodide and iodate are preferably uniformly dispersed. For example, in the case of a solid this can be accomplished by means of a granulation or by “slugging” both iodide and iodate with selected excipients. Common solid pharmaceutical dosage formats such as tablets, capsules or powders are suitable for this invention as is a liquid solution.
For the purposes of this application the term “granulation solution pH” is the pH of the solution for granulation that contains at least one of the following two components: iodide and iodate. If such solution for granulation contains only one of the two active components (iodide/iodate) then the second active will be combined during the granulation onto the pharmaceutical excipients. Such solution for granulation is combined with suitable pharmaceutical excipients alone or in combination with either iodide or iodate to prepare a wet granulation of an oral pharmaceutical composition of iodide or iodate. It is highly preferred to combine both iodate and iodide in the granulation solution to insure a homogeneous composition.
For the purposes of this application the term “pH control agents” shall refer to chemicals that control the “effective pH” of the dried granulation. The effective pH is measured by preparing a 10% (w/v) solution of a granulation or tablet in distilled water and determining the pH. Suitable pH control agents include sodium carbonate, calcium carbonate, potassium carbonate, magnesium carbonate, sodium hydroxide, bentonite (Al
2
O
3
.4SiO
2
.H
2
O), dibasic calcium phosphate dihydrate, magnesium oxide, magnesium trisilicate, sodium bicarbonate, dibasic sodium phosphate, tribasic sodium phosphate, dibasic potassium phosphate, and tribasic potassium phosphate.
This invention describes methods and compositions that allow iodide and iodate to be combined to form an oral pharmaceutical composition of iodide and iodate with iodide and iodate stability adequate to meet regulatory requirements. Regulatory requirements mandate that 100±10% of the concentration of a drug be maintained while it is used in general commerce. However, maintaining at least 90% of the initial concentration of two reactive agents that are held in intimate contact with each other is difficult.
Example 1 demonstrates that it is possible to stabilize iodide and iodate on a pharmaceutical excipient. In this example, and every other observation thereafter, it is clear that it is necessary to carefully control the pH of the process of preparing these compositions if adequate stability is to be achieved. At an effective pH above 7.0, solid compositions of iodide and iodate exhibit stability that is adequate for a pharmaceutical product. Neither iodide nor iodate are materially effected by a pH even as high as 12.0.
Every example provided in this invention supports the need to control the pH of iodide and iodate to achieve the stability mandated in a regulated product. The inventors have identified a group of preferred pH control agents to accomplish this objective. These agents include sodium carbonate, calcium carbonate, potassium carbonate, magnesium carbonate, sodium hydroxide, bentonite (Al
2
O
3
.4SiO
2
.H
2
O), dibasic calcium phosphate dihydrate, magnesium oxide, magnesium trisilicate, sodium bicarbonate, dibasic sodium phosphate, tribasic sodium phosphate, dibasic potassium phosphate, tribasic potassium phosphate, dibasic potassium phosphate, and tribasic potassium phosphate. These agents can be used alone or in combination. The amount of one or more pH control agents necessary to provide a beneficial pH will depend upon the particular pH control agents, the manufacturing process, and the other pharmaceutical excipients. For instance, the amount of a pH control agent necessary to achieve a pH of 7.0 with any given excipient will vary. Our observ
Dinehart Kirk
Duan Yongjun
Hickey John
Kessler Jack
Anderson Kill & Olick P.C.
Symbollon Corporation
Travers Russell
Wang Shengjun
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