Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-10-17
2002-09-17
Pryor, Alton Nathaniel (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S296000, C514S299000
Reexamination Certificate
active
06451808
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention addresses the drug metformin and its possible side effects.
2. Description of the Prior Art
Metformin, or specifically metformin hydrochloride, is an oral antihyperglycemic drug used in the management of non-insulin-dependent (Type II) diabetes. The scientific name of metformin hydrochloride is 1,1-dimethylbiguanide monohydrochloride, and its chemical formula is
An unfortunate side effect associated with metformin is the occurrence of gastrointestinal reactions such as diarrhea, nausea, vomiting, abdominal bloating, flatulence, and anorexia. These reactions occur with approximately 30% greater frequency when compared to placebo-treated subjects, particularly at the initiation stages of metformin administration. The reactions are dose-related, and methods of controlling these reactions include reducing the dose, escalating the dose gradually, or taking the drug with meals. In severe cases, however, dehydration and prerenal azotemia can occur, and many subjects undergoing metformin therapy are forced to discontinue their use of the drug.
SUMMARY OF THE INVENTION
It has now been discovered that emesis and other gastrointestinal side effects of metformin can be reduced or eliminated by administering a 5-hydroxytryptamine-3 (5-HT
3
) receptor antagonist in combination with the metformin. With this co-administration, metformin can be administered at higher dosages for many patients without the need to take the drug with meals. The patient can thus apply greater flexibility in the manner and timing by which the drug is taken without concern about the side effects that are unpleasant to both the patient and to those in the presence of the patient. The use of 5-HT
3
antagonists in accordance with this invention is particularly useful when administered during the first week or first month of metformin therapy, since nausea is most prevalent during this initial period. The administration of 5-HT
3
antagonists improves the ease by which the patient can be “titrated” to an effective level of metformin for controlling blood glucose.
The 5-HT
3
antagonists of particular interest are ondansetron, granisetron, dolasetron, and tropiseton, and others that have molecular structures with a similar 1H-indole or 1H-indazole nucleus. The success achieved with this invention however indicates that 5-HT
3
antagonists in general will serve the common purpose of controlling these side effects.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
Preferred 5-hydroxytryptamine-3 receptor antagonists for use in this invention are substituted 1H-indoles having the generic formula
in which R′ is a member selected from the group consisting of H and lower alkyl, and either:
R
2
and R
3
are combined to form a divalent structure having one of the following formulae:
where * denotes sites of attachment, R
4
is either N or CH, and R
5
, R
6
, and R
7
(two or all of which may be the same or all may be different) are either H, lower alkyl, cycloalkyl, or lower alkenyl, or
R
2
is N or CH,and R
3
is
where * again denotes the site of attachment, R
8
is NH or O, R
9
is N or CH, and either R
10
is lower divalent alkyl and R
11
is H or lower alkyl, or R
10
and R
11
are combined to form either lower trivalent alkyl or oxo-substituted lower trivalent alkyl.
The terms used in defining the formulas appearing in this specification and claims have the same meanings that they have when used in conventional organic nomenclature. Thus, “alkyl” denotes a saturated hydrocarbyl group, including both unbranched and branched groups. Similarly, “alkenyl” denotes a hydrocarbyl group that is unsaturated due to its inclusion of one or more double bonds, again including both unbranched and branched groups. “Lower alkyl” or “lower alkenyl” denotes an alkyl or alkenyl group of relatively few carbon atoms. The term “oxo-substituted” indicates that one or more carbon atoms bears an oxygen atom in the form of a carbonyl group, —C(═O)—.
Within the scope of the generic formula shown above, certain embodiments are preferred, notably those in which R
5
, R
6
, and R
7
(two or all of which may be the same or all may be different) are either H or C
1
-C
3
alkyl, R
9
is N, and either R
10
is divalent C
2
-C
3
alkyl and R
11
is H or R
10
and R
11
are combined to form either C
4
-C
6
trivalent alkyl or oxo-substituted C
4
-C
6
trivalent alkyl. The four specific 5-HT
3
receptor antagonists mentioned above are all within the scope of the generic formula. The molecular structures of these compounds and other 5-HT
3
receptor antagonists within the scope of this invention are as follows:
Ondansetron: 1,2,3 ,9-Tetrahydro-9-methyl-3-[(2-methyl1-H-imidazole-1-yl)methyl]-4H-carbazol-4-one
Granisetron: Endo-1-methyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1H-indazole-3-carboxamide
Tropisetron: Endo-1H-indole-3-carbocylic acid8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester
Dolasetron: 1H-Indole-3 -carboxylic acid (2a, 6a, 8a, 9up)-octahydro-3-oxo-2,6-methano-2H-quinolizin-8-yl Ester
Azasetron: (±)-N-Azabicyclo[2.2.2]oct-3-yl-6-chloro-3,4-dihydro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide
Alosetron: 2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl- 1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one
Ramosetron
Other 5-HT
3
receptor antagonists that can be used in the practice of this invention are hydrodolasetron (an active metabolite of dolasetron), 3-tropanyl-indole-3-carboxylate methiodide, KB-R6933, GK-128, metoclopramide, LY-278,584, and MDL-72222.
The term “metformin” is used herein to include both metformin and metformin hydrochloride, and any other forms of metformin, including therapeutically active salts, that have similar therapeutic activity. Examples of therapeutically active salts of metformin are disclosed in Timmins et al. (Bristol-Myers Squibb Company), U.S. Pat. No. 6,031,004, issued Feb. 29, 2000, the disclosure of which is incorporated herein by reference.
The relative amounts of metformin and 5-HT
3
receptor antagonist to be administered in accordance with this invention are not critical to the invention and may vary, depending on such factors as the past history of the patient, the general condition of the patient, the particular means of administration, and the type of the dosage form. In most cases, best results will be obtained when the weight ratio of metformin to 5-HT
3
receptor antagonist is within the range of from about 1:0.0001 to about 2:1, preferably from about 1:0.0003 to about 0.5:1.
The amount of metformin contained in a single dosage form may likewise vary and is not critical to the invention. The term “pharmaceutically effective amount” as used herein denotes any amount that has a beneficial therapeutic effect on the patient to whom the dosage form is administered. Optimal amounts will vary with the condition of the patient, the type of dosage form, and whether the dosage form is a sustained-release or immediate-release dosage form. In most cases, best results will be achieved with dosage forms that contain from about 100 mg to about 5000 mg of metformin, preferably from about 200 mg to about 2000 mg.
The metformin and 5-HT
3
receptor antagonist combination are administered orally in the practice of this invention, and the dosage form may be any form that is suitable for oral administration. While liquid formulations can be used, the preferred formulations are tablets or capsules. The metformin and 5-HT
3
receptor antagonist may both be included in a single dosage form (i.e., a single solution, tablet or capsule), or separate dosage forms administered simultaneously or in succession.
The metformin and the 5-HT
3
receptor antagonists can be incorporated in the dosage forms in any of various ways. Either or both agents may for example be incorporated in such a manner to cause substantially immediate release into the gastric fluid as soon as the dosage form enters the stomach. Alternatively, either or both agents may be incorporated in such a
DepoMed, Inc.
Pryor Alton Nathaniel
Townsend and Townsend / and Crew LLP
LandOfFree
Inhibition of emetic effect of metformin with 5-HT3 receptor... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Inhibition of emetic effect of metformin with 5-HT3 receptor..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Inhibition of emetic effect of metformin with 5-HT3 receptor... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2899241