WO2005025673A1

WO2005025673A1 - Multi-system therapy for diabetes, the metabolic syndrome and obesity comprising a hypoglycemic agent

Info

Publication number: WO2005025673A1
Application number: PCT/US2004/027689
Authority: WO
Inventors: Franco Folli; Paolo Manfredi; Gilbert Gonzales
Original assignee: Individual
Current assignee: Individual
Priority date: 2003-09-08
Filing date: 2004-08-26
Publication date: 2005-03-24
Anticipated expiration: 2006-03-08
Also published as: IL174033A0; CA2538333A1; EP1663395A1; EP1663395B1; DE602004022176D1; ES2328821T3; US20050054731A1

Abstract

A multi-system therapy which is adapted to treat diabetes, metabolic syndrome and obesity includes a hypoglycemic agent, a lipid lowering agent, a blood pressure lowering agent and, preferably, an anti-platelet agent. The composition can further include various vitamins and supplements such as vitamin B6, vitamin B12, arginin, a folate and other vitamins and minerals. Preferably, the hypoglycemic agent is a biguanide hypoglycemic agent without any additional hypoglycemic agent, making the composition suitable for treatment of individuals who are not hyperglycemic as well as those who are hyperglycemic.

Description

_MULTI-_{SYSTEM THER}A_PY FO_R DIABETES, THE METABOLIC SYNDROME AND OBESITY C_OMPRISING A HYPOGLYCEMIC AGENT

RELATED APPLICATION

This application is related to Provisional U.S. Patent Application Serial No. 60/501 ,226, filed on September 9, 2003, the disclosure of which is incorporated herein in its entirety by reference. 5 BACKGROUND OF THE INVENTION

Obesity, the Metabolic Syndrome (also referred to as Syndrome X), and Type II Diabetes Mellitus, are very much interrelated. Type II Diabetes Mellitus is caused by a combination of defective insulin secretion and insulin resistance. This results in elevated blood sugar,

10 elevated blood pressure, increased blood lipids and obesity. This determines micro and macro vascular disease with cardiovascular accidents, renal insufficiencies, neuropathy, blindness and higher incidences of infections. Over 120 million people worldwide suffer from diabetes, and 90% of these are Type II Diabetes. Eighty percent of those 15 with diabetes are obese. This has an enormous economic impact in addition to the obvious personal impact on those suffering from this

disease.

The Metabolic Syndrome is characterized by individuals

having abdominal obesity, high triglycerides, low HDL cholesterol, high

blood pressure and high fasting glucose levels. A diagnosis of Metabolic

Syndrome is made when three or more of these factors are established.

It is believed that as many as 25% of the general population in the United

States suffer from Metabolic Syndrome. In addition to being a direct

cause of death, those suffering from Metabolic Syndrome have a

significantly increased risk of developing Type II Diabetes with all of its

complications, as well as other serious cardiovascular complications.

Finally, in the United States, over 61 % of the population is

obese or overweight. Fifty-eight million people are overweight, forty

million are characterized as obese, and three million are considered

morbidly obese.

A somewhat related malady is polycystic ovary syndrome.

Polycystic ovary syndrome is characterized by anovulation (irregular or

absent menstrual periods) and hyperandrogenism (elevated serum

testosterone and androstenedione). Patients with this syndrome may

complain of abnormal bleeding, infertility, obesity, excess hair growth,

hair loss and acne. Insulin resistance, high blood pressure, high serum

lipids, increased risk for cardiovascular disease and increased risk of

developing Type II Diabetes are also important features. Polycystic ovary syndrome is estimated to affect about half

as many or approximately 10% of women.

One of the major biochemical features of polycystic ovary

syndrome is insulin resistance accompanied by compensatory

hyperinsulinemia (elevated fasting blood insulin levels). Hyperinsulinemia

has also been associated with high blood pressure and increased clot

formation and appears to be a major risk factor for the development of

heart disease, stroke and Type II Diabetes.

The medical literature suggests that the endocrinopathy in

most patients with polycystic ovary syndrome can be resolved with

insulin lowering therapy.

Those people suffering from diabetes generally are treated

with a number of different agents, in particular hypoglycemic agents,

blood pressure medication, as well as cholesterol-lowering drugs. It is

common to use multiple different drugs to treat Type II Diabetes. Several

drug combinations have been produced.

Such drug combinations are disclosed in Ikeda U.S. patent

5,952,356, Adjei U.S. patent 6,524,621 , Chaudhari U.S. pending

application 2003/0219482 A1 , Jaen et al U.S. application

2002/0037928 A1 ; Fine et al U.S. patent 6,376,594, Pierson U.S.

patent 6,693,094, Whitcomb U.S. patent 6,01 1 ,049, Saho et al U.S.

patent 6,645,997; Chungi U.S. patent 6,669,955; and Luskey U.S.

patent 6,646,004. Further, Liang et al U.S. patent 6,576,256 discloses a combination of a cholesterol-lowering agent, a renin-angiotensin system

inhibitor and aspirin. Sethi et al U.S. patent 6,489,345 discloses a

combination of E vitamins and hypoglycemic drug, and Doebbner et al

U.S. patent 5,847,008 discloses a variety of combinations with acetyl

phenols. Other pending applications include 2003/01491 1 1 ;

2003/01 14469; 2003/01491 1 1 ; and 2003/0158090.

Many of these combinations do not include a hypoglycemic

agent. Further, others will include hypoglycemic agents which are

unsuitable for treatment of Metabolic Syndrome or obesity. The

biguanides are used to treat diabetes, and can also be useful in treating

obesity and Syndrome X. However, other hypoglycemic agent such as

the sulfonylureas, the alpha glucosidase inhibitors, the glitazones, and the

meglitinides will actually induce hypoglycemia in patients who are not

suffering from Type II Diabetes. Biguanides have been combined with

these other hypoglycemic agents for treatment of Type II Diabetes. Other

combination therapies fail to adequately address all of the comorbidities

associated with Type II Diabetes with one medicine. Compliance is a

critical problem for proper treatment of diabetes. Only a fraction of

patients with diabetes is compliant with prescribed regiments. Individuals

required to take five or six different pills, either at once or at different

times of the day, are less likely to do so. Thus, reducing the number of

pills, or, in other words, combining drugs into a single dosage will greatly

improve compliance. SUMMARY OF THE INVENTION

The present invention is premised on the realization that a

combination therapy, that is, a metabolic pill, effective for treatment of

diabetes, the Metabolic Syndrome and obesity as well as their

complications, is provided by utilizing a combination of a biguanide

hypoglycemic agent with a lipid lowering agent, a blood pressure lowering

agent, optionally an anti-platelet agent, and optionally a combination of

vitamins and supplements which have been shown to prevent

atherosclerosis and infections. In order to provide a single pharmaceutical

that can treat all three of these maladies, the hypoglycemic agent cannot

be used in combination with other types of hypoglycemic agents, such

as the alpha-glucosidase inhibitors, and the like, because of the risk of

inducing hypoglycemia. However, when the pharmaceutical is designed

to treat only Type II Diabetes, additional hypoglycemic agents can be

employed.

A preferred form of the present invention includes metformin

as the hypoglycemic agent, simvastatin as the cholesterol lowering agent,

and a renin-angiotensin system inhibitor such as lisinopril as the blood

pressure lowering agent. The preferred anti-platelet agent is aspirin.

These may be combined with one or more of the following: a folate,

vitamin B6, B12 and other supplements such as asparginin, beta-

carotene, vitamins A, C, D, E, K, and polyunsaturated fatty acids. The metabolic pill of the present invention can also improve

the symptoms of polycystic ovary syndrome, reduce blood pressure,

reduce blood lipids and reduce the incidence of developing Type II

Diabetes and cardiovascular complications. The objects and advantages of the present invention will be

further appreciated in light of the following detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is a therapeutic composition, a

metabolic pill or medicine intended to be administered in a single dose

application, i.e., all of the pharmaceuticals combined in a single pill,

capsule or liquid formulation, which includes a biguanide hypoglycemic

agent in combination with additional pharmaceuticals including a

cholesterol lowering agent, a blood pressure lowering agent and,

optionally, an anti-platelet agent, vitamins and supplements. This

composition can be used whenever clinically appropriate to treat Type II

Diabetes and, when appropriate, the Metabolic Syndrome and obesity.

The primary component of the pharmaceutical of the present

invention is a hypoglycemic drug and, in particular, a biguanide.

Metformin is the preferred oral hypoglycemic agent. When used to treat Type II Diabetes, the biguanide

hypoglycemic drug can be combined with other hypoglycemic drugs or

replaced altogether by a separate hypoglycemic drug. Other suitable

hypoglycemic drugs include sulfonylureas such as glyburide, alpha glucosidase inhibitors such as acarbose, glitazones such as pioglitazone

and rosiglitazone, and meglitinides such as repaglinide. Preferred

hypoglycemic agents for treatment of Type II Diabetes would include

metformin by itself, pioglitazone by itself, metformin in combination with

glyburide, metformin in combination with acarbose, metformin in

combination with pioglitazone, metformin in combination with

pioglitazone and glyburide, and repaglinide plus pioglitazone.

The minimum effective adult dosage of metformin is about

250 mg, administered daily. The dosage is increased to a maximum

dosage of 3.5 gm daily. The present combination drug is designed to

maintain all of its components within individual drug therapeutic windows

as the dosage is escalated from 1 capsule/pill (5 ml liquid) once a day to

5 capsules/pills (25 ml liquid) 3 times a day. A minimum dose is

established for each of the individual components that is within the

effective dose range for that component for at least a subgroup of

patients. If a higher dosage is required, additional medication (i.e., an

additional pill) is taken. The dosage of the individual component is

established to allow increasing the dosage without exceeding the

maximum dosage of any component. A variety of different blood pressure lowering agents can be

used in the present invention. These include the renin angiotensin system

inhibitors, beta-blockers such as atenolol, diuretics such as hydrochlorothiazide, and calcium channel antagonists, for example,

nifedipine.

The renin angiotensin system inhibitors include ACE

inhibitors which inhibit the conversion of angiotensin I to angiotensin II,

angiotensin II receptor antagonists and renin inhibitors. The ACE

inhibitors are preferred inhibitors of the renin angiotensin systems for use

in the present invention. The ACE inhibitors include sulfhydryl containing

ACE inhibitors including captopril and agents that are structurally related

to captopril such as fentialpril, pivalopril, zofenopril, and alacepril. Other

ACE inhibitors include the dicarboxyl-containing ACE inhibitors including

amalopril, lisinopril, benazapril, quinapril, moexipril, ramipril, spirapril,

perindopril, indolapril, pentopril, and cilazapril. Phosphorus-containing

ACE inhibitors can also be used, such as fosinopril and ACE inhibitors

structurally related thereto. The preferred ACE inhibitors are captopril, silizopril, delapril,

analopril, fentiapril, fosinopril, endolapril, lisinopril, perindopril, pivalopril,

quinapril, ramipril, spirapirl, trandolapril and zofinopril. Particularly

preferred are captopril, enalipril, fosinopril, lisinopril, quinapril, ramipril,

and trandolapril. Most preferred are lisinopril and ramipril. Examples of ACE/NEP inhibitors for use herein include,

without limitation, those disclosed in U.S. patents 5,508,272,

5,362,727, 5,366,973, 5,225,401 , 4,722,810, 5,223,516, 5,552,397,

4,749,688, 5,504,080, 5,612,359 and 5,525,723, the disclosures of which are hereby incorporated by reference in their entirety. Preferred are

those ACE/NEP inhibitors that are designated as preferred in the above

U.S. patents. Particularly preferred are the ACE/NEP inhibitors

omapatrilat and MDL100240, disclosed in U.S. patent 5,430,145. A second type of renin-aηgiotensin system inhibitors are the

angiotensin II receptor antagonists. Examples of angiotensin II receptor

antagonists suitable for use herein are saralasin (including saralasin

acetate), candesartan (including candesartan cilexetil), CGP-63170,

EMD-66397, KT3-671 , LP.B/081 , valsartan, A-81282, BIBR-363,

BIBS-222, BMS-184698, CV1 1 194, EXP-3174, KW-3433, L-161 177,

L-162154, LR-B/057, LY-235656, PD150304, U-96849, U-97018,

UP-275-22, WAY-126227, WK-1492.2K, YM-31472, losartan (including

losartan potassium), E-4177, EMD-73495, eprosartan, HN-65021 ,

irbesartan, L-159282, ME-3221 , SL-91 .0102, tasosartan, telmisartan,

UP-269-6, YM-358, CGP-49870, GA-0056, L-159689, L-162234,

L-1 62441 , L-1 63007, PD-1 231 77, A81 988, BMS-180560,

CGP-38560A, CGP-48369, DA-2079, DE-3489, DuP-1 67, EXP-063,

EXP-6155, EXP-6803, EXP-771 1 , EXP-9270, FK-739, HR-720,

ICI-D6888, ICI-D7155, ICI-D8731 , isoteoline, KRI-1 177, L-158809,

L-158978, L-159874, LR B087, LY-285434, LY-302289, LY-315995,

RG-13647, RWJ-38970, RWJ-46458, S-8307, S-8308, saprisartan,

sarmesin, WK-1360, X-6803, ZD-6888, ZD-7155, ZD-8731 , BIBS39,

CI-996, DMP-81 1 , DuP-532, EXP-929, L163017, LY-301875, XH-148, XR-510, zolasartan, and PD-12331 9. These are disclosed in U.S. patent

6,576,256, the disclosure of which is also incorporated herein by

reference.

Preferred angiotensin II receptor antagonists include losartan

(which is the prototype and best known angiotensin II receptor

antagonist), irbesartan, eprosartan, candesartan, valsartan, telmisartan,

zolasartan, and tasosartan. Particularly preferred is losartan.

A third type of angiotensin system inhibitor are the renin

inhibitors, these are compounds that inhibit renin activity and include

renin antibodies, analogues of prosegment of renin, analogs of pepstatin,

and analogs of the renin substrate angiotensinogin. As most of these

compounds are peptides, they tend to have low oral bioavailability. Non-

peptide renin inhibitors are of the most interest. Preferred inhibitors are

remikiren, A-72517, and A-74273, with remikiren being preferred. The preferred dosage for each of these components

obviously will depend on the particular pharmaceutical. The effective

dosage ranges for these compounds are well known.

The third component of the present invention is a blood lipid

lowering agent. There are many different blood lipid lowering agents.

These include, HMG CoA reductase inhibitors, bile acid sequestrants,

probucol, and fibric acid agents. The HMG CoA reductase inhibitors

include atorvastatin, cerivistatin, fluindostatin, fluvastatin, lovastatin,

mevastatin, pravastatin, simvastatin, and velostatin. The preferred HMG CoA reductase inhibitors are simvastatin pravastatin, lovastatin, and

atorvastatin. The bile acid sequestrants include cholestyramine,

colestipol, and colesevelam. The fibric acid agents include clofibrate,

fenofibrate, and gemfibrozil. Again, the dosage rate for each of these components will be

determined by the particular lipid lowering agent selected. Generally, the

minimum dose will be designed for individuals with normal to slightly

raised lipid levels.

A further component of the present invention is preferably

an anti-platelet drug. The preferred anti-platelet drug is aspirin. Other

salicylates can be used such as magnesium salicylate. Further, there are

other anti-platelet aggregating agents, such as anangrelide, dipyridamole,

clopidogrel, and ticlopidine. Further, cyclooxygenase inhibitors can be

used, including nonstearoidal anti-inflammatory drugs such as ibuprofen,

sulindac, sulindac sulfide, sulindac sulfone, flurbiprofen, indomethacin,

naproxen, meclafenamic acid, and piroxicam. These should be provided

in a dosage effective to inhibit platelet degradation.

The invention further may include various vitamins and

supplements shown to prevent atherosclerosis and to prevent infections.

One preferred vitamin is folic acid, a folate, or folinic acid, commonly

referred to as a folate. Suitable folates include 5-methyl tetrahydrofolic

acid, tetrahydrofolic acid, and 5-formyl tetrahydrofolic acid. Vitamin B components should be included such as

vitamin B6 (pyridoxine), and vitamin B12. Other vitamins and minerals

include beta-carotine and other carotinoids, vitamin A, vitamin C,

vitamin D, vitamin E, vitamin K, zinc, polyunsaturated fatty acids, arginin,

as well as its isomers.

The individual components of the present invention are

preferably combined to form an oral dosage form. This can include

tablets, capsules, caplets, solutions, suspensions and/or syrups, as well

as granules, beads, powders or pellets that may or may not be

encapsulated. Suppository preparations and sublingual preparations, as

well as transdermal patches, may also be used.

A preferred general formulation for the present invention

would include: metformin 50-1500 mg simvastatin 1 -80 mg lisinopril 1 -40 mg

Another preferred general formula includes: metformin 50-1500 mg simvastatin 1 -80 mg lisinopril 1 -40 mg aspirin 5-375 mg folic acid 0.5-1 mg vitamin B6 5-40 mg vitamin B12 0.05-1 mg A preferred specific formula in capsule form includes:

(Specific Formula 1 ) metformin 250 mg aspirin 12.5 mg simvastatin 3.5 mg lisinopril 1 .66 mg folic acid 0.166 mg vitamin B6 8.33 mg vitamin B12 0.166 mg methocel E4M as an excipient (QS in gelatin capsule size 1 )

A liquid formulation would include:

(Specific Formula 2) metformin 250 mg aspirin 12.5 mg simvastatin 3.5 mg lisinopril 1 .66 mg folic acid 0.166 mg vitamin B6 8.33 mg vitamin B12 0.166 mg

in a fixed oil base comprising 200 mg of silica gel, 5 mg butylated

hydroxyteluline, 6.25 mg stevia powder, 0.1 ml of flavor and olive oil

forming 5 ml of medicine.

For the treatment of Diabetes Type II, the composition of the

present invention will preferably include the biguanide hypoglycemic

agent, a lipid lowering agent, blood pressure lowering agent, and,

optionally vitamin B12 compounds, folic acid, vitamin C, arginin, as well

as other supplements. Additional hypoglycemic agents can also be

employed such as the sulfonylureas, alpha-glucosidase inhibitors,

glitazones and meglitinides. For treatment of Syndrome X, polycystic ovary syndrome,

and/or obesity, the composition will include only the biguanide hypoglycemic agent, preferably metformin, and no other type of

hypoglycemic agent. The remainder of the formulation should remain the

same as the above formulation for Type II Diabetes.

Additional examples of formulations encompassing the

present invention are set forth below.

Formula A

Metformin 250 mg, aspirin 1 2.5 mg, simvastatin 3.5 mg,

lisinopril 1 .66 mg, folic acid 0.1 66 mg, vitamin B6 8.33 mg and

vitamin B1 2 0.1 66 mg for each capsule or, in a liquid, for each 5cc.

Formula B

Metformin 50-1 000 mg, simvastatin 1 -40 mg,

lisinopril 1 -1 0 mg, aspirin 5-75 mg, vitamin B6 1 0-50 mg,

vitamin B12 0.2-1 mg, plus folic acid 0.2-1 mg.

Formula C Metformin 1 000-3000 mg, simvastatin 20-40 mg,

ramipril 0.6-1 .25 mg, aspirin 35-75 mg, plus polyunsaturated fatty acids

500-1000 mg.

Formula D

Metformin extended release up to 3500 mg,

repaglinide 2 mg (or glimepiride 2 mg), simvastatin 40 mg,

lisinopril 1 0 mg; aspirin 1 75 mg, vitamin B6 50 mg, vitamin B1 2 1 mg,

plus folic acid 1 mg. Formula E

Metformin 500-3500 mg, repaglinide 0.5 mg,

simvastatin 40 mg, ramipril 2.5 mg, plus aspirin 81 mg.

Formula F Metformin 500-1000 bid or tid, glimepiride 2 mg,

simvastatin 20-80 mg, lisinopril 10-30 mg, aspirin 75 mg,

vitamin B6 50 mg, vitamin B12 1 mg, plus folic acid 2 mg.

Formula G

Metformin ER 1000-3000 mg, simvastatin 40 mg,

lisinopril 5 mg, atenolol 25 mg, hydrochlorothiazide 25 mg,

aspirin 75 mg, vitamin B6 50 mg, vitamin B12 1 mg, plus folic

acid 1 mg.

Formula H I Metformin 1000-3000 mg, repaglinide 0.5 mg,

simvastatin 40 mg, lisinopril 5 mg, atenolol 25 mg,

hydrochlorothiazide 25 mg, aspirin 75 mg, vitamin B6 50 mg,

vitamin B12 1 mg, plus folic acid 1 mg.

Formula I

Metformin ER 1000-3000, simvastatin 40 mg,

lisinopril 5 mg, atenolol 25 mg, hydrochlorothiazide 25 mg;

aspirin 75 mg, vitamin B6 50 mg, vitamin B12 1 mg, plus folic

acid 1 mg. Formula L

Metformin 1000-3000 mg, glimepiride 2 mg,

simvastatin 40 mg, lisinopril 5 mg, atenolol 25 mg,

hydrochlorothiazide 25 mg, aspirin 75 mg, vitamin B6 50 mg,

vitamin B12 1 mg, plus folic acid 1 mg.

Formula M

Metformin ER 3000 mg, simvastatin 40 mg, ramipril 10 mg,

aspirin 75 mg, vitamin B6 25 mg, vitamin B12 1 mg, folic acid 0.8 mg,

plus polyunsaturated fatty acids 1000 mg.

Formula N

Pioglitazone 20 mg metformin 1 000 mg,

repaglinide 1 .25 mg, simvastatin 40 mg, ramipril 10 mg; aspirin 75 mg,

vitamin B6 50 mg, vitamin B12 1 mg, folic acid 1 mg, plus

polyunsaturated fatty acids 1000 mg.

EXPERIMENTAL STUDY

To determine preliminary toxicology, normal mice, with a

starting weight range of 18.4 -24.4 grams, were randomly assigned to

one of four treatment groups, ten mice for each group, and treated once

a day for 7 days by gastric gavage with one of 0.2 ml normal saline,

0.015 ml of a placebo comprising calcium carbonate and a fixed oil base

in combination with 0.185 ml normal saline, or, 0.015 ml of specific

formula 1 , plus 0.185 ml normal saline, or, 0.03 ml of specific formula 1

plus 0.17 ml of normal saline. At the end of the treatment the animals were weighed and sacrificed. Blood was obtained for biochemical and

hormonal tests. Heart, liver and kidney were frozen at -70° C for further

proteomic and enzymatic studies, and the liver was fixed for routine

histological examination. On day 7, all animals appeared to be in good

health. Biochemical tests did not show signs of liver or kidney toxicity.

The weight was lower in both treatment groups 3 and 4 compared to the

placebo groups 1 and 2. Leptin levels were decreased in the treatment

groups compared to placebos. Glucose and triglycerides were lower and

insulin levels were higher in the treatment group. Set forth below are the

starting and ending weights of the respective mice, broken down by

groups.

GROUP 1 : NS

GROUP 2: VEHICLE

GROUP 3: MTDMO 0.1 ml

GROUP 4: MTDMO 0.2 ml

As can be seen, Groups 3 and 4 lost substantially more weight than the

placebo groups. The compositions of the present invention are designed to

significantly improve compliance, and lower costs. Compliance is often

a primary issue, especially as drug regimens become more complex.

Type II Diabetes and the Metabolic Syndrome X and obesity, when not

responsive to diet and exercise, require complex drug regimen for optimal

treatment and prevention of the complications. Improvement of

compliance is the primary goal of all effective treatments, especially

important with complex regimens. A combination pill such as this will

reduce costs and significantly increase the likelihood of compliance. Particularly for patients with Type II Diabetes, multiple drugs

are required. Based on the recommendations of the American Diabetes

Association, the cholesterol lowering agent is indicated even if cholesterol

level is normal, and an inhibitor of a renin angiotensin system is indicated

even if the blood pressure is normal. Aspirin is indicated in patients with

Type II Diabetes, even in the absence of previous cardiovascular events.

One prescription, such as the above, would cover both diabetes control

and prevention of complications improving patients compliance. The

availability of one formulation which contains all of the ingredients

needed by patients with diabetes will help physicians correctly prescribe

for their patients. Furthermore, the cost of a single pill will significantly

lower costs compared to the cost of the different pharmaceuticals taken

separately.

All the above combinations can be used in combination with

insulin. Insulin is frequently required in patients with long standing

diabetes mellitus, and oral hypoglycemic agents may lower the insulin

requirements. Insulin at high doses may have a proatherogenic effect.

The combination drug will, therefore, have multiple benefits compared to

insulin alone. With respect to Metabolic Syndrome, which is not

responsive to diet and exercise, the above formulation can slow the

evolution toward diabetes, particularly utilizing metformin and the ACE

inhibitor. Further,. the composition will decrease body weight, using the metformin, and lower the risk of cardiovascular complications employing

basically all of the components.

Further, with respect to treatment of obesity, the above

composition has been effective to provide weight loss in experimental

work. Obese patients are at high risk for diabetes and cardiovascular

complications. Metformin and the ACE inhibitors can prevent the

development of diabetes. All the above components will help prevent

cardiovascular complications. The biguanide hypoglycemic agents,

particularly metformin, is the hypoglycemic agent of choice. Metformin

does not cause hypoglycemia and is, therefore, the drug of choice for

prevention of diabetes in patients and with Metabolic Syndrome and

obesity not responding to diet and exercise.

The formulation of the present invention, aside from treating

diabetes, Syndrome X and obesity, can be used to treat other maladies

such as polycystic ovary syndrome.

This has been a description of the present invention along

with the preferred method of practicing the present invention. However,

the invention itself should only be defined by the appended claims,

WHEREIN WE CLAIM:

Claims

1 . A composition for treatment for Type II Diabetes,

Syndrome X and obesity comprising a hypoglycemic agent consisting of

a biguanide; a lipid lowering agent; and a blood pressure reducing agent.

2. The composition claimed in claim 1 wherein said blood

pressure lowering agent is selected from the group consisting of renin,

angiotensin system inhibitors, beta-blockers, diuretics, and calcium

channel antagonists.

3. The composition claimed in claim 2 wherein said blood

pressure lowering agent is a renin angiotensin system inhibitor selected

from the group consisting of ACE inhibitors, angiotensin II receptor

antagonists, and renin inhibitors.

4. The composition claimed in claim 3 wherein said blood

pressure lowering agent is an ACE inhibitor selected from the group

consisting of sulfhydril containing ACE inhibitors, dicarboxyl containing

ACE inhibitors and phosphorus containing ACE inhibitors.

5. The composition claimed in claim 4 wherein said ACE

inhibitor is selected from the group consisting of lisinopril and ramipril.

6. The composition claimed in claim 3 wherein said

angiotensin II receptor antagonist is selected from the group consisting

of losartan, irbesartan, eprosartan, candesartan, valsartan, telmisartan,

zolasartin, and tasosartan.

7. The composition claimed in claim 3 wherein said renin

inhibitor is remikiren.

8. The composition claimed in claim 1 wherein said blood lipid

lowering agent is selected from the group consisting of HMG CoA

reductase inhibitors, bile acid sequestrants, probucol and fibric acid

agents.

9. The composition claimed in claim 8 wherein said HMG CoA

reductase inhibitor is selected from the group consisting of simvastatin

pravastatin, lovastatin, and atorvastatin.

10. The composition claimed in claim 8 wherein said bile acid

sequestrant is selected from the group consisting of cholesteramine,

colestipol, and colesevelam.

1 1 . The composition claimed in claim 8 wherein said fibric acid

agent is selected from the group consisting of clofibrate, fenofibrate and

gemfibrozil.

12. The composition claimed in claim 1 wherein said biguanide

hypoglycemic agent is selected from the group consisting of metformin.

13. The composition claimed in claim 12 further comprising an

anti-platelet drug.

14. The composition claimed in claim 13 wherein said anti-

platelet drug is selected from the group consisting of salicylates, anti-

platelet aggregating agents, and cyclooxygenase inhibitors.

15. The composition claimed in claim 14 wherein said salicylate

is selected from the group consisting of acetyl salicylic acid and

magnesium salicylate.

16. The composition claimed in claim 14 wherein said anti-

platelet aggregating agent is selected from the group consisting of

anangrelide, dipyridamole, clopidogrel, and ticlopidine.

17. The composition claimed in claim 14 wherein said

cyclooxygenase inhibitor is selected from the group consisting of

ibuprofen, sulindac, sulindac sulfide, sulindac sulfone, flurbiprofen,

indomethacin, naproxen, meclafenamic acid, and piroxicam.

18. The composition claimed in claim 1 further comprising at

least one of the following: a folate, vitamin B6, vitamin B12, a

carotinoids, vitamin A, vitamin C, vitamin D, vitamin E, vitamin K, zinc,

polyunsaturated fatty acids, arginin and isomers thereof.

19. The composition claimed in claim 18 wherein said folate is

selected from the group consisting of folic acid, folinic acid,

5-methyltetrahydrofolic acid, tetrahydrofolic acid and

5-formyltetrahydrofolic acid.

20. The composition claimed in claim 1 8 wherein said

composition includes vitamin B6 and vitamin B12.

21 . A composition for treatment of Type II Diabetes comprising

a hypoglycemic agent, a lipid lowering agent, and a blood pressure

lowering agent, and at least one of the following: an anti-platelet drug, a

folate; vitamin B6; vitamin B12; a carotinoids; vitamin A, vitamin C,

vitamin D, vitamin E, vitamin K, zinc, polyunsaturated fatty acid, arginin,

and an arginin isomer.

22. The composition claimed in claim 21 wherein said oral

hypoglycemic agent is selected from the group consisting of a biguanide,

a sulfonylurea, an alpha-glucosidase inhibitor, a glitazone, a meglitinide,

and combinations thereof.

23. The composition claimed in claim 22 wherein said

hypoglycemic drug is selected from the group consisting of a biguanide,

a biguanide in combination with a sulfonylurea, a glitazone by itself, a

biguanide in combination with a carbose, a biguanide in combination with

a glitazone, a biguanide in combination with a glitazone in combination

with a sulfonylurea, or a meglitinide in combination with a glitazone.

24. The composition claimed in claim 21 wherein said

hypoglycemic agent is selected from the group consisting of metformin,

pioglitazone, metformin and glyburide, metformin and acarbose,

metformin and pioglitazone, metformin plus pioglitazone plus gliburide,

and repaglinide plus pioglitazone.

25. A method of treating an individual diagnosed with at least

one of Type II Diabetes, Syndrome X, polycystic ovary syndrome, and

obesity comprising administering to said individual a single dose medicine

said medicine including a hypoglycemic agent consisting of a biguanide;

a lipid lowering agent; and a blood pressure reducing agent.

26. The method claimed in claim 25 wherein said blood pressure

lowering agent is selected from the group consisting of renin, angiotensin

system inhibitors, beta-blockers, diuretics, and calcium channel

antagonists.

27. The method claimed in claim 25 wherein said blood pressure

lowering agent is a renin angiotensin system inhibitor selected from the

group consisting of ACE inhibitors, angiotensin II receptor antagonists,

and renin inhibitors.

28. The method claimed in claim 27 wherein said blood pressure

lowering agent is an ACE inhibitor selected from the group consisting of

sulfhydril containing ACE inhibitors, dicarboxyl containing ACE inhibitors

and phosphorus containing ACE inhibitors.

29. The method claimed in claim 28 wherein said ACE inhibitor

is selected from the group consisting of lisinopril and ramipril.

30. The method claimed in claim 27 wherein said angiotensin II

receptor antagonist is selected from the group consisting of losartan,

irbesartan, eprosartan, candesartan, valsartan, telmisartan, zolasartin, and

tasosartan.

31 . The method claimed in claim 27 wherein said renin inhibitor

is selected from the group consisting of remikiren.

32. The method claimed in claim 25 wherein said blood lipid

lowering agent is selected from the group consisting of HMG CoA

reductase inhibitors, bile acid sequestrants, probucol and fibric acid

agents.

33. The method claimed in claim 32 wherein said HMG CoA

reductase inhibitor is selected from the group consisting of simvastatin,

pravastatin, lovastatin and atorvastatin.

34. The method claimed in claim 32 wherein said bile acid

sequestrants is selected from the group consisting of cholesteramine,

colestipol, and colesevelam.

35. The method claimed in claim 32 wherein said fibric acid

agent is selected from the group consisting of clofibrate, fenofibrate and

gemfibrozil.

36. The method claimed in claim 25 wherein said biguanide

hypoglycemic agent is selected from the group consisting of metformin.

37. The method claimed in claim 36 further comprising an anti-

platelet drug.

38. The method claimed in claim 37 wherein said anti-platelet

drug is selected from the group consisting of salicylates, anti-platelet

aggregating agents, and cyclooxygenase inhibitors.

39. The method claimed in claim 38 wherein said salicylate is

selected from the group consisting of acetyl salicylic acid and magnesium

salicylate.

40. The method claimed in claim 38 wherein said anti-platelet

aggregating agent is selected from the group consisting of anagrelide,

dipyridamole, clopidogrel and ticlopidine.

41 . The method claimed in claim 38 wherein said

cyclooxygenated inhibitor is selected from the group consisting of

ibuprofen, sulindac, sulindac sulfide, sulindac sulfone, flurbiprofen,

indomethacin, naproxen, meclafenamic acid, and piroxicam.

42. The method claimed in claim 25 wherein said medicine

further comprises at least one of the following: a folate, vitamin B6,

vitamin B12, a carotinoids, vitamin A, vitamin C, vitamin D, vitamin E,

vitamin K, zinc, polyunsaturated fatty acids, arginin and isomers thereof.

43. The method claimed in claim 42 wherein said folate is

selected from the group consisting of folic acid, folinic acid,

5-methyltetrahydrofolic acid, tetrahydrofolic acid and

5-formyltetrahydrofolic acid.

44. A method of treating an individual diagnosed with at least

one of obesity, Syndrome X, diabetes mellitus and polycystic ovary

syndrome comprising administering to said individual the composition

claimed in claim 1 in a single dosage form.

45. A method of treating an individual with Type II Diabetes

comprising administering to said individual the composition claimed in

claim 20 in a single dosage form.