GB2253787A - Hypercholesterolemia treating compositions - Google Patents
Hypercholesterolemia treating compositions Download PDFInfo
- Publication number
- GB2253787A GB2253787A GB9201521A GB9201521A GB2253787A GB 2253787 A GB2253787 A GB 2253787A GB 9201521 A GB9201521 A GB 9201521A GB 9201521 A GB9201521 A GB 9201521A GB 2253787 A GB2253787 A GB 2253787A
- Authority
- GB
- United Kingdom
- Prior art keywords
- chromium
- hmg
- iii
- coa reductase
- reductase inhibitor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
Abstract
Compositions useful for treating hypercholesterolemia comprise LDL-cholesterol lowering amounts of HMG-CoA reductase inhibitor and HDL-cholesterol raising amounts of a biologically effective form of Chromium (III). Inhibitors are typically lovastatin, simvastatin, pravastatin or fluvastatin.
Description
TITLE OF THE INVENTION
HMG-CoA REDUCTASE INHIBITORS AND CHROMIUM (III)
COMBINATIONS
BACKGROUND OF THE INVENTION
Hypercholesterolemia, i.e. elevated cholesterol levels, is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Cholesterol and other lipids are transported in body fluids by lipoproteins of varying density. The two lipoproteins carrying the majority of cholesterol in the blood are low-density lipoproteins (LDL) and high-density lipoproteins (HDL). The role of LDL is to transport cholesterol to peripheral cells outside the liver.
LDL-receptors on a cell plasma membrane bind the LDL and allow for the entry of cholesterol into the cell. HDL may scavenge cholesterol in the tissues for transport to the liver and eventual catabolism.
Thus HDL functions to lower tissue cholesterol which would otherwise be available for plaque formation.
LDL levels are positively correlated with the risk of coronary artery disease while HDL levels are negatively related.
HMG-CoA reductase inhibitors represent a new class of cholesterol-lowering drugs. Lovastatin, a member of this class, has been available in the
United States since September 1987 and has been highly effective in treating elevated cholesterol levels. Administering 40 mg of lovastatin twice daily leads to a mean reduction (from a dietary therapy baseline) in total plasma cholesterol of -33%, in LDL-cholesterol of -41% and an increase in
HDL-cholesterol of +5 to 10%.
The ratio of LDL-cholesterol to
HDL-cholesterol has been reported to be the best predictor of coronary artery disease. Although
HMG-CoA reductase inhibitors are highly beneficial based on their reduction in LDL-cholesterol, the use of these compounds would even further reduce the atherogenic risk if a mechanism was available for augmenting the rise in HDL-cholesterol and thus favorably affecting the LDL/HDL ratio in a broad spectrum of individuals suffering from hypercholesterolemia.
Chromium (III) is considered an essential nutrient for humans and is included among the 1980
RDA's in the United States. However,. dietary deficiencies of this nutrient may be widespread particularly among populations consuming large amounts of refined and processed foods as part of their diet. There is some evidence, in a few noncontrolled studies of small sample size and in one controlled study employing healthly male subjects, that chromium supplementation in the diet may increase HDL-cholesterol. Some medications such as beta-blockers have been found to lower HDLcholesterol by as yet unclear mechanisms. However, in a recent study, patients receiving beta-blockers and a biologically active form of chromium, (Glucose-Tolerance Factor-Chromium (GTF-Chromium)) were found to have higher levels of HDL-cholesterol than those receiving beta blockers and a placebo.
However, there has been no suggestion in the art to combine an HMG-CoA reductase inhibitor with
Chromium (III) to treat hypercholesterolemia more effectively by combining a significant reduction in
LDL-cholesterol with a more consistent increase in
HDL-cholesterol, the increase in HDL-cholesterol being greater than that observed with HMG-CoA inhibitors alone.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to pharmaceutical compositions and a method for treating hypercholesterolemia, in a subject in need thereof, which comprises the adjunct administration of an effective LDL-cholesterol lowering amount of an
HMG-CoA reductase inhibitor and an effective
HDL-cholesterol raising amount of a biologically effective form of Chromium (III).
The compositions disclosed herein provide a favorable effect on both the LDL and HDL levels, and thus the present invention provides a greater effect on hypercholesterolemia over that found from the administration of an HMG-CoA reductase inhibitor alone. This effect is both surprising and unexpected in light of our current understanding of cholesterol biochemistry and metabolism and the art of hypercholesterolemic therapy. The present invention also provides an anti-atheromatous effect and thus a method of counteracting atherosclerosis which comprises the adjunct administration of an effective
LDL-cholesterol lowering amount of an HMG-CoA reductase inhibitor and an effective HDL-cholesterol raising amount of a biologically effective form of
Chromium (III).The present invention is to be understood as providing for the avoidance of atherosclerosis or a slowing of atherosclerosis where this may occur as well as the amelioration of present atherosclerosis. The term counteracting is accordingly to be understood as a precautionary or prophylactic as well as a curative or treatmental effect with respect to atherosclerosis.
The HMG-CoA reductase inhibitor employed may be lovastatin, simvastatin, pravastatin, fluvastatin or any other member of the class of compounds that inhibit HMG-COA reductase. The preparation of lovastatin (U.S. Pat. No 4,231,938) simvastatin, (U.S. Pat. No. 4,444,784) and pravastatin (U.S. Pat.
No. 4,346,227) have been described in the patent literature. The preparation of fluvastatin is described in WIPO Pub. No. W084/02131, published
June 7, 1984. These methods of preparation are hereby incorporated by reference.
Chromium (III) is available in a biologically effective form as GTF-chromium, a source of which is brewers yeast. A particularly concentrated source is brewers yeast grown in chromium-rich soil. However, in general, any biologically effective source of Chromium (III) may be employed and is included within this invention.
In accordance with a method of the present invention, an HMG-CoA reductase inhibitor and
Chromium (III) can be administered separately at different times during the course of therapy or concomitantly in divided or single combination forms. Thus, treatment with Chromium (III) can commence prior to, subsequent to or concurrent with the commencement of HMG-CoA reductase treatment. The present invention is to be understood as embracing all such regimes of treatment and the term "adjunct administration" is to be interpreted accordingly.
The compositions of the instant invention may be administered orally in the form of a capsule, tablet, elixir, or the like. The dosage forms may also include any necessary carrier material, excipient, lubricant, bulking agent, anti-oxidant or the like. The present compositions may be administered in an immediate release or a controlled release form. The general amounts of HMG-CoA reductase inhibitor will be of the same or similar order to that employed in HMG-CoA reductase therapy.
In general, satisfactory results are obtained by administration of 1 to 80 mg/day of the HMG-CoA reductase inhibitor in a single or divided dose.
Doses of Chromium (III) may vary from 50 Fg to 2400 Fg per day measured as the amount of Chromium (III) ion in a biologically available form of chromium.
Tablets or capsules may also be administered which contain both compounds in the dosage ranges indicated.
The following Examples illustrate the preparation of compositions of the present invention and as such are not to be considered as limiting the invention set forth in the claims appendix hereto.
EXAMPLE 1
As a specific embodiment of a composition of this invention, 20 mg of lovastatin and 600 Fg of
Chromium (III) are formulated with sufficient finely-divided lactose to provide a total amount of 580 to 590 mg to fill a size 0 hard-gelatin capsule.
Optionally added are an excipient such as finely divided cellulose, a disintegrant such as Explotab (sodium starch glycollate) and a lubricant such as magnesium stearate.
EXAMPLE 2
The composition of Example 1 is repeated but substituting 10 mg of simvastatin for the lovastatin.
EXAMPLE 3
The composition of Example 1 is repeated but substituting 20 mg of pravastatin for the lovastatin.
EXAMPLE 4
Controlled Release Composition
Lovastatin 40 mg
Chromium 1200 Fg Methocel E5 20 mg
Methocel Kl5M 60 mg
Lactose 95 mg
Claims (10)
1. A pharmaceutical composition for
treating hypercholesterolemia which comprises a
pharmaceutically acceptable carrier and an effective
LDL-cholesterol lowering amount of an HMG-CoA
reductase inhibitor and an effective HDL-cholesterol
raising amount of a biologically effective form of
Chromium (III).
2. A composition of Claim 1 wherein the
HMG-CoA reductase inhibitor is selected from the
group consisting of: lovastatin, simvastatin,
pravastatin and fluvastatin.
3. A composition of Claim 2 wherein the
Chromium (III) is present as GTF-chromium.
4. The use of an HMG-CoA reductase inhibitor in conjunction with a biologically effective form of
Chromium (III) for the manufacture of a medicament for treating hypercholesterolemia.
5. The use as claimed in Claim 4 wherein the
HMG-CoA reductase inhibitor is selected from the group consisting of: lovastatin, simvastatin, pravastatin and fluvastatin.
6. The use as claimed in Claim 5 wherein the
Chromium (III) is present as GTF-Chromium.
7. The use of an HMG-CoA reductase inhibitor in conjunction with a biologically effective form of
Chromium (III) for the manufacture of a medicament for counteracting atherosclerosis.
8. The use as claimed in Claim 7 wherein the
HMG-CoA reductase inhibitor is selected from the group consisting of: lovastatin, simvastatin, pravastatin and fluvastatin.
9. The use as claimed in Claim 8 wherein the
Chromium (III) is present as GTF-Chromium.
10. A product containing an HMG-CoA reductase inhibitor and a biologically effective form of chromium (III) as a combined preparation for simultaneous, separate or sequential use in the treatment of hypercholesterolemia and/or for counteracting atherosclerosis.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US64655891A | 1991-01-28 | 1991-01-28 |
Publications (2)
Publication Number | Publication Date |
---|---|
GB9201521D0 GB9201521D0 (en) | 1992-03-11 |
GB2253787A true GB2253787A (en) | 1992-09-23 |
Family
ID=24593520
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB9201521A Withdrawn GB2253787A (en) | 1991-01-28 | 1992-01-24 | Hypercholesterolemia treating compositions |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB2253787A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002067911A1 (en) * | 2001-02-27 | 2002-09-06 | Bristol-Myers Squibb Company | Pharmaceutical compositions comprising pravastatin for reducing ldl cholesterol levels |
-
1992
- 1992-01-24 GB GB9201521A patent/GB2253787A/en not_active Withdrawn
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002067911A1 (en) * | 2001-02-27 | 2002-09-06 | Bristol-Myers Squibb Company | Pharmaceutical compositions comprising pravastatin for reducing ldl cholesterol levels |
Also Published As
Publication number | Publication date |
---|---|
GB9201521D0 (en) | 1992-03-11 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |