WO2008053340A1

WO2008053340A1 - A combination product comprising at least one lipid substituted in the alpha position and at least one hypoglycemic agent

Info

Publication number: WO2008053340A1
Application number: PCT/IB2007/003330
Authority: WO
Inventors: Morten Bryhn; Jan Kopecky
Original assignee: Pronova Biopharma Norge AS
Current assignee: Pronova Biopharma Norge AS
Priority date: 2006-11-03
Filing date: 2007-11-02
Publication date: 2008-05-08
Anticipated expiration: 2009-05-03

Abstract

A combination product comprising: • at least one lipid in the form of a carboxylic acid, or a derivative thereof, a carboxylic ester, a carboxylic anhydride, an alcohol or an amide, which lipid is substituted at carbon 2, counted from the functional group, with at least one substituent, or any pharmaceuticlly acceptable complex, salt, solvate or pro-drug thereof; and • at least one hypoglycemic agent, or any pharmaceuticlly acceptable complex, solvate or pro-drug thereof, is disclosed. Also disclosed is the use of such a combination product for the treatment of diabetic conditions.

Description

A combination product comprising at least one lipid substituted in the alpha position and at least one hypoglycemic agent.

Technical field

The present invention relates to a combination product comprising a substituted lipid and a hypoglycemic agent. It also relates to the use of such a combination product in the treatment of diabetic conditions.

Background of the invention

The prevalence of Type 2 diabetes mellitus is growing in the developed and the developing countries as a function of excess food intake and too little physical exercise. Currently almost one in 20 adults worldwide has type 2 diabetes and 333 million cases are projected by 2025 (Ref BMJ 2006). The trend of reduced cardiovascular mortality in the US which has been achieved by national programs to reduce cholesterol, hypertension and smoking has been halted and the mortality curve in women is moving slowly upwards probably as a function of overweight and subsequently type 2 diabetes. The physiologic consequence of a high calory intake and too little physical exercise is increasing adipose tissue volume. When the storing capacity of triglycerides into the adipocytes is stretched, spill-over of triglycerides to other tissues like the liver and muscle is increasing. These complex events lead to reduced sensitivity of insulin in liver, muscle and fat tissue, a phenomenon called insulin resistance. Insulin resistance occurs long before the clinical onset of diabetes.The exact mechanism taking place at the cellular level is still not fully understood. However, the consequence is reduced effect of insulin on peripheral tissues. In order to retain glucose for production of metabolic energy and hence keeping the organism in a state of normoglycemia, increased production and release of insulin is initiated. The complex clinical situation related to insulin resistance is called the metabolic syndrome.

Patients with the metabolic syndrome have a complex of pathophysiologic mechanisms promoting development of atherosclerosis. Hypertension, coagulopathia, abnormal blood lipids, and type 2 diabetes. Usually they will end up with a combination of different pharmaceuticals addressing these individual risk factors. However, the main objective is to restore normal handling of glucose and lipids by means of weight reduction and physical exercise. However, national programs such as The Diabetes Prevention Program Research Group, has not proven to be very efficient. Therefore several pharmaceuticals are used for treatment of patients with insulin resistance. Metformin, the oldest of the type 2 diabetes pharmaceuticals, has been on the market for nearly 40 years and is still the mostly used pharmaceutical for treatment of these patients. Metformin reduces insulin resistance by mechanisms which have not been full elucidated. Metformin may even be used together with insulin in patients with declining insulin production. A new class of pharmaceuticals for reducing insulin resistance, the thiazolidinediones or glitazones, were introduced during the last 10 years. Glitazones are ligands to the nuclear receptor class PPAR which are a family of ligand-activated transcription factors that modulate multiple aspects of lipid and carbohydrate metabolism. PPARα is primarily implicated in regulation of lipid metabolism, lipoprotein synthesis and metabolism, in liver and other tissue. PPARy plays a pivotal role in adipocyte differentiation and lipid storage in addition to the regulation of glucose metabolism. Many glitazones, like rosiglitazone and pioglitazone, are selective PPARy ligands. Some of the new glitazones also have affinity to the PPARα receptor. Since different anti-diabetics used for treatment of type 2 diabetics have different mode-of-action they are frequently used in combination. A product containing metformin and pioglitazone in fixed formulation was recently launched on the market for treatment of diabetes (Deeks and Scott LJ, Drugs 2006;66: 1863-1877). Polyunsaturated fatty acids are natural ligands to the PPAR receptors mainly PPARα but also PPARy. Effects are rather weak but effects are consistent (Nettleton JA and Katz R, J Am Dietetic Ass 2005; 105:428-440). In particular docosahexaenoic acid (DHA) has demonstrated interesting effects in animal models of obesity and diabetes.

Summary of the invention

The aim of the present invention is to provide new treatments for diabetic conditions.

This aim is achieved by a combination product comprising: • at least one lipid in the form of a carboxylic acid, or a derivative thereof, a carboxylic ester, a carboxylic anhydride, an alcohol or an amide, which lipid is substituted at carbon 2, counted from the functional group, with at least one substituent, or any pharmaceutically acceptable complex, solvate, salt or pro-drug thereof; and

• at least one hypoglycemic agent, or any pharmaceuticlly acceptable complex, solvate or pro-drug thereof.

The lipid may have a chain length of 16-24 carbon atoms, and suitably contains at least two double bonds with E and/or Z configuration.

For example, the lipid may be an omega-3 lipid compound is selected from the group consisting of: • (all-Z)-4,7,10,13,16,19-docosahexaenoic acid,

• (all-Z)-5,8, 11 ,14,17-eicosapentaenoic acid,

• (all-Z)- 9,12,15-octadecatrienoic acid,

• (all-Z)-6,9, 12,15-octadecatetraenoic acid,

• (all-Z)-7,10,13,16,19-docosapentaenoic acid, • (all-Z)-11 ,14,17-eicosatrienoic acid,

• (all-Z)-6,9, 12, 15,18,21 -tetracosahexaenoic acid,

• (4E, QZ, 11Z, 14Z, 17Z)-4,8,11 ,14,17-eicosapentaenoic acid,

• (5E, 8Z, 11Z, 14Z, 17Z)-5,8,11 ,14,17-eicosapentaenoic acid,

• (all-Z)-8,11 ,14,17-eicosatetraenoic acid, and • (AE, IZ, 10Z, 13Z, 1 QZ, 1 QZ)-AJ, 10,13,16,19-docosahexaenoic acid. Alternatively, the lipid may be an omega-6 lipid compound selected from the group consisting of:

• (all-Z)-9,12-octadecadienoic acid,

• (all-Z)-6,9,12-octadecatrienoic acid, and • (all-Z)-8,11 ,14-eicosatrienoic acid.

The substituent at carbon 2 may be selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, a carboxy group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group, and an alkylamino group.

In particular, the lipid may be (all-Z)-4,7,10,13, 16,19-docosahexaenoic acid (DHA), (all-Z)-5,8,11 ,14,17-eicosapentaenoic acid (EPA) or (all-Z)- 7,10,13,16,19-docosapentaenoic acid, and the substituent may be an alkyl group, e.g. ethyl or propyl, an alkoxy group, e.g. methoxy or ethoxy, and alkylthio group, e.g. thiomethyl or thioethyl, or an aryl group, e.g. a benzyl group or a substituted benzyl group. For example, the lipid is present in the form of a carboxylic acid, or a derivative thereof, or an ethyl or methyl ester. The derivative of a carboxylic acid may be a salt, a phospholipid, or a tri-, di-, or monoglyceride.

Salts of the lipids of the invention may comprise a monovalent cation such as Li⁺, Na⁺, K⁺, NH4⁺, meglumine, tris(hydroxymethyl)aminomethane, diethylamine, arginine; a divalent ion such as Mg²⁺, Ca²⁺, ethylenediamine, piperazine; or a polyvalent cation such as chitosan.

Furthermore, when the lipid is present as a derivative of a carboxylic acid in the form of a phospholipid, such a derivative may be represented by

wherein

, or

and

wherein

, or

and

wherein

or

When the lipid is present as a derivative of a carboxylic acid in the form of a triglyceride, such a derivative may be represented by:

(IV)

In addition, when the lipid is present as a derivative of a carboxylic acid in the form of a 1-monoglyceride, such a derivative may be represented by

(V)

Alternatively, when the lipid is present as a derivative of a carboxylic acid in the form of a 2-monoglyceride, such a derivative may be represented by

The hypoglycemic agent is suitably a PPAR Y agonist, a PPAR y partial agonist, and/or a PPAR y modulator, and suitably lowers the blood glucose level. Examples of hypoglycemic agents are: a thiazolidinedione (TZD) derivative, e.g. rosiglitazone or pioglitazone, or metformin.

The invention also relates to the combination product for use as a medicament and for use in therapy.

Further, the present invention relates to a pharmaceutical composition comprising a combination product according to the above, and the use of such a pharmaceutical composition as a medicament and in therapy. The lipid and the hypoglycemic agent may be formulated in different pharmaceutical compositions or in a common pharmaceutical composition.

The pharmaceutical composition may be formulated to provide a daily dosage of 1 mg to 10 g, 20 mg to 1 g or 20 mg to 400 mg of the lipid, and a daily dosage of 1 to 5000 mg of the hypoglycemic agent. When the hypoglycemic agent is rosiglitazone, the daily dosage may be 4 to 8 mg; when the hypoglycemic agent is pioglitazone, the daily dosage may be 15 to 30 mg; when the hypoglycemic agent is Metformin, the daily dosage may be 500 to 3000 mg.

In addition, the present invention relates to the use of:

• at least one lipid in the form of a carboxylic acid, or a derivative thereof, a carboxylic ester, a carboxylic anhydride, an alcohol or an amide, which lipid is substituted at carbon 2, counted from the functional group, with at least one substituent, or any pharmaceuticlly acceptable complex, salt, solvate or pro-drug thereof, and

• at least one hypoglycemic agent, or any pharmaceutically acceptable complex, solvate or pro-drug thereof, for the manufacture of a pharmaceutical composition for the treatment of a diabetic condition. In particular, the diabetic condition may be diabetes mellitus type 2, a combination of diabetes mellitus type 2 and an overweight condition, or a combination of diabetes mellitus type 2 and elevated blood lipid levels.

The invention also relates to methods for the treatment and/or prevention of the conditions listed above, comprising administering to a mammal in need thereof a pharmaceutically active amount of the combination product.

Further, the present invention relates to a kit comprising:

• a pharmaceutical composition comprising at least one lipid in the form of an acid, or a derivative thereof, an ester, an anhydride, an alcohol or an amide, which lipid is substituted at carbon 2, counted from the functional group, with at least one substituent, or any pharmaceutic!^ acceptable complex, salt, solvate or pro-drug thereof; and

• a pharmaceutical composition comprising at least one hypoglycemic agent, or any pharmaceutically acceptable complex, solvate or pro- drug thereof.

Another embodiment of the invention is a method for the manufacture of a combination product according to the invention.

Brief description of the drawings Fig. 1 Binding of PPARs to the LBD of hPPARα

Fig. 2 Body weight during treatment

Detailed description of the invention

In the research work leading to the present invention, it was surprisingly found that the combination of conventially used anti-diabetic drugs, such as pioglitazone, rosiglitazone, and metformin, and alpha substituted lipid compounds, in particular alpha substituted DHA, EPA and DPA, provides an efficient anti-diabetic treatment, with an accomanying loss of weight of the patient. Polyunsaturated fatty acids are natural ligands to the PPAR receptors mainly PPARα but also PPARy. Effects are rather weak but effects are consistent (Nettleton JA and Katz R, J Am Dietetic Ass 2005; 105:428-440). In particular docosahexaenoic acid (DHA) has demonstrated interesting effects in animal models of obesity (Ruzickova et al, 2004 Lipids 39: 1177-1185) and diabetes (Taouis et al. Am J Physiol Endocrin Metab 2002;282:E664-E671). In order to potentiate the effects of DHA in animal models of obesity a range of omega-3 lipid derivatives, e.g. DHA derivatives, have been synthesized and tested in different models (IB2006/001155). Results of these experiments indicate effects on insulin resistance with potency 10 to 30 times greater than pure DHA. One of the most potent of these DHA derivatives is alpha-ethyl-DHA. This promising compound demonstrated high binding affinity to PPARα as well as PPARy in computerbased docking models of these receptors and also in transfected cells containing the DNA binding domain of PPARα and PPARy.

In contrast to many other anti-diabetics the DHA derivatives induce significant weight reduction. This is especially interesting since overweight and obesity is a regular finding in patients with type 2 diabetes. Furthermore, the DHA derivatives reduce serum triglycerides and free fatty acids which are usually increased in patients with type 2 diabetes.

Most of the peroral antidiabetics used today present only one mode-of- action lowering blood glucose but have no effects or adverse effects on body weight and blood lipids. Therefore a combination of standard anti diabetics with alpha substituted lipids, in particular α-substituted DHA, EPA or DPA derivatives, seems to be a promising approach.

In order to improve the anti-diabetics effects of alfa-ethyl-DHA the compound was combined with rosiglitazone and also metformin in an animal model of the metabolic syndrome with insulin resistance determined by intraperitoneal glucose tolerance test and plasma insulin.

Preferred lipid compounds according to the invention are listed below.

In all the shown examples, the lipid is an omega-3 fatty acids in the form of an ethyl ester.

Lipid = (all-Z)-4,7,10,13,16,19-docasahexaenoic acid (DHA):

Ethyl (all-Z)-2-methyl-4,7,10,13,16,19-docosahexaenoate Substituent in position 2: methyl

Ethyl (all-Z)-2-ethyl-4,7,10,13,16,19-docosahexaenoate (PRB-2) Substituent in position 2: ethyl

Ethyl (all-Z)-2-ethoxy-4,7, 10,13,16,19-docosahexaenoate Substituent in position 2: ethoxy

Ethyl (all-Z)-2,2-dimethyl-4,7, 10,13,16,19-docosahexaenoate

Ethyl (all-Z)-2-thiomethyl-4,7, 10,13,16,19-docosahexaenoate Substituent in position 2: methylthio

Ethyl (all-Z)-2-thioethyl-4,7, 10,13,16,19-docosahexaenoate Substituent in position 2: ethylthio

Ethyl (all-Z)-2,2-diethyl-4,7,10,13,16,19-docosahexaenoate Substituents in position 2: diethyl

Ethyl (all-Z)-2-benzyl-4,7,10,13,16,19-docosahexaenoate Substituent in position 2: benzyl

Ethyl (all-Z)-2-methoxy-4,7, 10,13,16,19-docosahexaenoate Substituent in position 2: methylthio

Lipid = (aII-Z)-7,10,13,16,19-docosapentaenoic acid (DPA)

Ethyl (all-Z)-2-methyl-7,10,13,16,19-docosapentaenoate Substituent in position 2: methyl

Ethyl (all-Z)-2-ethyl-7, 10,13,16,19-docosapentaenoate Substituent in position 2: ethyl

Ethyl (all-Z)-2-methoxy-7, 10,13,16,19-docosapentaenoate Substituent in position 2: methoxy

Ethyl (all-Z)-2-ethoxy-7 ,10,13,16,19-docosapentaenoate Substituent in position 2: ethoxy

Lipid = (all-Z)-5,8,11 ,14,17-eicosapentaenoic acid (EPA)

Ethyl (all-Z)-2-methyI-5,8,11 ,14,17-eicosapentaenoate Substituent in position 2: methyl

Ethyl (all-Z)-2-ethy I-5 ,8,11 ,14,17-eicosapentaenoate Substituent in position 2: ethyl

Ethyl (all-Z)-2-methoxy-5,8,11 ,14,17-eicosapentaenoate Substituent in position 2: methoxy

Ethyl (all-Z)-2-ethoxy-5,8,11 ,14,17-eicosapentaenoate Substituent in position 2: ethoxy

Lipid = (all-Z)-9,12,15-octadecatrienoic acid (Alpha-linolenic acid (ALA))

Ethyl (all-Z)-2-methyl-9,12,15-octadecatrienoate Substituent in position 2: methyl

Ethyl (all-Z)-2-ethyl-9, 12, 15-octadecatrienoate Substituent in position 2: ethyl

Ethyl (all-Z)-2-methoxy-9, 12,15-octadecatrienoate Substituent in position 2: methoxy

Ethyl (all-Z)-2-ethoxy-9, 12,15-octadecatrienoate Substituent in position 2: ethoxy

Preferred hypoglycemic agents according to the invention are listed below: Glitazones

Pioglitazone (Actos)

5-[[4-[2-(5-ethylpyridin-2-yl)ethoxy]phenyI]methyl]thiazolidine-2,4-dione

Rosiglltazone (Avandia)

5-[[4-[2-(methyl-pyridin-2-yl-amino)ethoxy]phenyl]methyl]thiazoIidine-2,4- dione

and Rosiglitazone maleate.

Metformin

2-(N,N-dimethylcarbamimidoyl)guanidine

Metformin is a biguanide hypoglycaemic agent, an agent which lower the blood glucose level, used in the treatment of non-insulin-dependent diabetes mellitus not responding to dietary modification. Metformin improves glycaemic control by improving insulin sensitivity and decreasing intestinal absorption of glucose.

Further examples of hypoglycemic agents according to the invention are:

• 2,4-thiazolidinedione (Substance Name) • 2-bromopalmitate (Substance Name)

• 2-tetradecylglycidic acid (Substance Name)

• Acarbose (MeSH Term)

• Acetohexamide (MeSH Term)

• AICA ribonucleotide (Substance Name) • allicin (Substance Name) • alliin (Substance Name)

• BRL 26830A (Substance Name)

• Buformin (MeSH Term)

• Butoxamine (MeSH Term) • Carbutamide (MeSH Term)

• Chlorpropamide (MeSH Term)

• ciglitazone (Substance Name)

• CL 316243 (Substance Name)

• copper bis(3,5-diisopropylsalicylate) (Substance Name) • cryptolepine (Substance Name)

• diphenyleneiodonium (Substance Name)

• emeriamine (Substance Name)

• englitazone (Substance Name)

• ethyl 2-(5-(4-chlorophenyl)pentyl)oxiran-2-carboxylate (Substance Name)

• etomoxir (Substance Name)

• fenugreek seed meal (Substance Name)

• Gliclazide (MeSH Term)

• glimepiride (Substance Name) • Glipizide (MeSH Term)

• gliquidone (Substance Name)

• glucuronyl glucosamine glycan sulfate (Substance Name)

• Glyburide (MeSH Term)

• gusperimus (Substance Name) • inositol phosphate glycan (Substance Name)

• Insulin (MeSH Term)

• insulin LISPRO (Substance Name)

• insulin, Asp(B28)- (Substance Name)

• Insulin, lsophane (MeSH Term) • Insulin, Long-Acting (MeSH Term)

• KAD 1229 (Substance Name)

• meglitinide (Substance Name)

• methyl 2-tetradecylglycidate (Substance Name)

• midaglizole (Substance Name) • miglitol (Substance Name)

• nateglinide (Substance Name)

• peroxovanadate (Substance Name) • Phenformin (MeSH Term)

• phenyl biguanide (Substance Name)

• ponalrestat (Substance Name)

• pramlintide (Substance Name) • repaglinide (Substance Name)

• Tolazamide (MeSH Term)

• Tolbutamide (MeSH Term)

• troglitazone (Substance Name)

• vanadyl sulfate (Substance Name) • voglibose (Substance Name)

• zopolrestat (Substance Name)

Examples of combination products according to the invention are:

• PRB2 + rosiglitazone or pioglitazone

• Ethyl (all-Z)-2-ethoxy-4,7,10,13,16,19~docosahexaenoate + rosiglitazone or pioglitazone

• Ethyl (all-Z)-2-methoxy-4,7,10,13,16,19-docosahexaenoate + rosiglitazone or pioglitazone • PRB2 + Metformin

• Ethyl (aII-Z)-2-ethoxy-4,7,10,13,16,19~docosahexaenoate + Metformin

• Ethyl (all-Z)-2-methoxy-4,7,10,13,16,19-docosahexaenoate + Metformin

• Ethyl (all-Z)-2-methyl-7,10,13,16,19-docosapentaenoate + rosiglitazone or pioglitazone

• Ethyl (all-Z)-2-ethyl-7,10,13,16,19-docosapentaenoate + rosiglitazone or pioglitazone

• Ethyl (all-Z)-2-methoxy-7,10,13,16,19-docosapentaenoate + rosiglitazone or pioglitazone • Ethyl (all-Z)-2-ethoxy-7,10,13,16,19-docosapentaenoate + rosiglitazone or pioglitazone

• Ethyl (all-Z)-2-methyl-5,8,11 ,14,17-eicosapentaenoate + rosiglitazone or pioglitazone

• Ethyl (all-Z)-2-ethy 1-5,8,11 ,14,17-eicosapentaenoate + rosiglitazone or pioglitazone

• Ethyl (all-Z)-2-methoxy-5,8,11,14,17-eicosapentaenoate + rosiglitazone or pioglitazone • Ethyl (all-Z)-2-ethoxy-5,8,11 ,14,17-eicosapentaenoate + rosiglitazone or pioglitazone

As used herein, the term "hypoglycaemic agent" relates to a substance which lowers the blood glucose level. As used herein, the term "lipid" relates to long chain polyunsaturated fatty acids or mono-, di-, or triglycerides thereof, long chain polyunsaturated esters, long chain polyunsaturated anhydrides, long chain polyunsaturated alcohols and long chain polyunsaturated amides. Omega-3 fatty acids constitute a suitable example of a lipid according to the invention. A derivative of a carboxylic acid may be a phospholipid, or a tri-, di-, or monoglyceride, i.e. the compound according to the invention may exist in the form of a phospholipid, a tri-, di- or monoglyceride, or in the form of a free acid.

As used herein, the term "PPAR y modulator" relates to partial PPAR y agonists modulating PPAR y activity.

The lipid and the hypoglycaemic agent may be administered simultaneously or consecutively. When administered consecutively, either the lipid compound is administered first and thereafter the hypoglycemic agent, or the hypoglycemic agent is administered first and thereafter the lipid compound. The interval between the administrations depends on the drug characteristics, and may e.g. vary from hours to days. However, shorter and longer intervals may be used.

"Pro-drugs" are entities which may or may not possess pharmacological activity as such, but may be administered (such as orally or parenterally) and thereafter subjected to bioactivation (for example metabolization) in the body to form the agent of the present invention which is pharmacologically active.

Where the lipid is present in the form of a carboxylic acid, the present invention also includes salts of the carboxylic acid. Suitable pharmaceutically acceptable salts of carboxy groups includes metal salts, such as for example alkali metal salts such as lithium, sodium or potassium, alkaline metal salts such as calcium or magnesium and ammonium or substituted ammonium salts.

A "pharmaceutically active amount" relates to an amount that will lead to the desired pharmacological and/or therapeutic effects, i.e. an amount of the combination product which is effective to achieve its intended purpose. While individual patient needs may vary, determination of optimal ranges for effective amounts of the combination product is within the skill of the art. Generally, the dosage regimen for treating a condition with the combination product of this invention is selected in accordance with a variety of factors, including the type, age, weight, sex, diet and medical condition of the patient. By "a pharmaceutical composition" is meant a combination product according to the invention in any form suitable to be used for a medical purpose.

"Treatment" includes any therapeutic application that can benefit a human or non-human mammal. Both human and veterinary treatments are within the scope of the present invention. Treatment may be in respect of an existing condition or it may be prophylactic.

The combination product may be used on its own, but will generally be administered in association with a pharmaceutically acceptable carrier, excipient or diluent (including combinations thereof). Acceptable carriers, excipients and diluents for therapeutic use are well known in the pharmaceutical art, and can be selected with regard to the intended route of administration and standard pharmaceutical practice. Examples encompass binders, lubricants, suspending agents, coating agents, solubilising agents, preserving agents, wetting agents, emulsifiers, sweeteners, colourants, flavouring agents, odourants, buffers, suspending agents, stabilising agents, and/or salts.

A pharmaceutical composition according to the invention is preferably formulated for oral administration to a human or an animal. The pharmaceutical composition may also be formulated for administration through any other route where the active ingredients may be efficiently absorbed and utilized, e.g. intravenously, subcutaneously, intramuscularly, intranasally, rectally, vaginally or topically.

In a specific embodiment of the invention, the pharmaceutical composition is shaped in form of a capsule, which could also be a microcapsule generating a powder or a sachet. The capsule may be flavoured. This embodiment also includes a capsule wherein both the capsule and the encapsulated composition according to the invention is flavoured. By flavouring the capsule it becomes more attractive to the user. For the above- mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. In one embodiment the combination product according to the invention is presented in liquid form or as an emulsion.

In the context of the present invention, "a daily dosage" relates to the dosage per 24 hours. The dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. Typically, a physician will determine the actual dosage which will be most suitable for an individual subject. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy. The combination product of the present invention may be administered in accordance with a regimen of from 1 to 10 times per day, such as once or twice per day. For oral and parenteral administration to human patients, the daily dosage level of the agent may be in single or divided doses.

The combination product according to the present invention has primarily shown the following pharmaceutical activities: • anti-diabetic activity

• reduction of weight and/or prevention of weight gain;

• reduction of glucose and insulin in plasma;

• activation and/or modulation of the human peroxisome proliferator- activated receptor (PPAR) isoforms, preferably PPARα and/or y; and • reduction elevated blood lipid levels, such as triglyceride levels.

There are two major forms of diabetes mellitus. One is type 1 diabetes, which is known as insulin-dependent diabetes mellitus (IDDM), and the other one is type 2 diabetes, which is also known as non-insulin-dependent diabetes mellitus (NIDDM). Type 2 diabetes is related to obesity/overweight and lack of exercise, often of gradual onset, usually in adults, and caused by reduced insulin sensitivity, so called periferral insulin resistance. This leads to a compensatory increase in insulin production. This stage before developing full fetched type 2 diabetes is called the metabolic syndrome and characterized by hyperinsulinemia, insulin resistance, obesity, glucose intolerance, hypertension, abnormal blood lipids, hypercoagulopathia, dyslipidemia and inflammation. The combination product according to the invention may be used for treatment and/or prevention of metabolic syndrome, and the conditions mentioned above. Later when insulin production seizes, type 2 diabetes mellitus develops. In one embodiment, the combination product may be used for the treatment of type 2 diabetes.

The combination product according to the invention may also be used for the treatment of other types of diabetes selected from the group consisting of secondary diabetes, such as pancreatic, extrapancreatic/endocrine or drug-induced diabetes, or exceptional forms of diabetes, such as lipoatrophic, myatonic or a disease caused by disturbance of the insulin receptors.

Suitably, the combination product may activate nuclear receptors, preferably PPAR (peroxisome proliferator-activated receptor) α and/or γ.

Methods

Binding of alpha substituted derivatives to PPARα

To study whether alpha substituted polyunsaturated lipid derivatives

(PRBs) bind to the LBD of PPARα, a chimeric construct was made from human (h) LBDs as shown in Figure 1. The DBD of PPARα was substituted with GAL4DBD.

The following plasmid construct was made: pSG5-GAL4-hPPARα Another construct (5XUAS-LUC) was also made which contains the DNA binding sites for GAL4. UAS = upstream activation sequences is cloned to a reporter gene, luciferase (LUC). The plasmids, chimera's and the reporter LUC, were transfected into COS-1 cells and luciferase protein was analyzed as described in methods.

Fatty acids/ligands Rosiglitazone (BRL), WY-14,643, Clofibrate and PRBs (stock solutions) were solubilized to 0.1 M final concentration in DMSO. Then, solubilized to 1OmM in DMSO and stored in 1.5 ml tubes (homoplymer, plastic tubes) flushed with argon and stored at -20⁰C.

Cell cultures

COS-1 cells (ATCC no. CRL 1650) were cultured in DMEM supplemented with L-glutamine (2MM), penicillin (50 U/ml), streptomycin (50 μG/mL), fungizone (2.5 μg/mL), and 10% inactivated FBS. The cells were incubated at 37°C in a humidified atmosphere of 5% CO2 and 95% air and used for transient transfections. Every third day, the cells in each flask were split into new flasks containing fresh media.

Transfection

Cells (1.5X1 mil) were plated in 30mm tissue dishes (six-well plates), 1d before transfection. Transient transfection by lipofectamin 2000 was performed as described (Invitrogen, Carlsbad, CA). Each well received 990 ng plasmid: 320 ng reporter ((UAS)5-tk-LUC (UAS=upstream activating sequence and LUC=luciferase), 640 ng pGL3 basic (empty vector) and 30 ng expression plasmid of either pSG5-GAL4-hPPARα, which are chimera expression constructs containing the ligand binding domain (LBD) of human (h) PPARα.10 μM of PRBs or fatty acids and DMSO (control) was added to the media 5h after transfection. Transfected cells were maintained for 24h before lysis by reporter lysis buffer. Binding of PRBs or fatty acids to the LBD of PPAR activates GAL4 binding to UAS, which in turn stimulates the tk promoter to drive luciferase expression. Luciferase activity was measured using a luminometer (TD-20/20 luminometer; Turner Designs, Sunnycvale, CA) and normalized against protein content.

Results

Synthetic compounds that induce peroxisomal proliferation in rodents and hypolipidemic agents such as clofibrate and WY- 14,643 have been shown to specifically bind to and activate PPARα.

In our study we have compared the activation of these compounds on human PPARα with the activation of the 2-substituted (all-Z)-4,7,10,13,16,19- docosahexaenoic acid (PRBs). Theses results are shown in figure 1 , wherein:

PRB1 is ethyl (all-Z)-2-methyl-4,7,10,13,16,19-docosahexaenoate PRB2 is ethyl (all-Z)-2-ethyl-4,7,10,13,16,19-docosahexaenoate

PRB3 is ethyl (all-Z)-2-ethoxy-4,7,10,13,16,19-docosahexaenoate PRB5 is ethyl (all-Z^^-dimethyMJ.IO.IS.Iδ.iθ-docosahexaenoate PRB6 is ethyl (all-Z)-2-thiomethyl-4,7,10,13,16,19-docosahexaenoate PRB7 is ethyl (all-Z)-2-thioethyl-4,7,10,13,16,19-docosahexaenoate PRB8 is ethyl (all-Z)-2,2-diethyl-4,7,10,13,16,19-docosahexaenoate

PRB9 is ethyl (all-Z)-2-benzyl-4,7,10,13,16,19-docosahexaenoate PRB14 is ethyl (all-Z)-2-methoxy-4,7,10,13,16,19-docosahexaenoate At a concentration of 10 μM all the PRBs showed increased effects as activators of the GAL-hPPARα chimera in the transfection assay compared to clofibrate and WY-14,643. The most potent PPARs showed a sixth fold activation of hPPARαcompared to clofibrate. PRB-2 is one of the most potent activators, increasing the activation five fold compared to clofibrate.

Combination treatment of mice by alpha-substituted lipid derivative, rosiglitazone and metformin admixed to a high-fat diet

Method

Adipose prone mice of the C57BL/6 strain develop leptin resistance after 16 days on a high fat diet (van Heek et al. J Clin Invest 1997;99:385- 390). When fed high fat diet over a longer period of time they are getting obese (Fig. 1) and develop insulin resistance which can be documented by elevated plasma insulin levels and a high area-under-the-curve (AUC) value in the intraperitoneal glucose tolerance test. The C57BL/6 mice are ideal for testing of compounds with effects on lipid and glucose metabolism and obesity.

Experiment

All experiments were performed on male C57BL/6N mice (supplier: Charles River, Germany), fed ad libitum and maintained at 22⁰C, with 12 h light/dark cycle (light from 7 am to 7 pm). At the beginning of the experiment animals were 14-week-old and maintained (since weaning) on a standard chow diet (STD; with protein, fat and carbohydrate forming 33, 9, and 58 energy %, respectively; ssniff R/M-H from SSNIFF Spezialdieten GmbH, Soest, Germany). One week before the start of the treatment by different diets (see below), animals were sorted according to their body weights and assigned to 7 subgroups (n = 9) of similar mean body weight. There were 3 mice per cage. The treatment included the following diets: (i) The STD diet, (ii) high-fat diet prepared in the laboratory (cHF), i.e. high-fat composite diet with protein, fat and carbohydrate forming 15, 59, and 26 energy %, respectively, and well characterized fatty acid composition (with most of the lipids coming from corn oil; see Ruzickova et al, 2004 Lipids 39: 1177-1185), (iii) the cHF diet as above, but with 1.5% of its lipids replaced by alfa- ethyl-DHA ethyl- ester, PRB-2 (PRB2-1.5%), (iv) the cHF diet as above, but with 2 g metformin/kg diet (Met), (v) the cHF diet as above, but with 10 mg rosiglitazone/kg diet (Rosi), (vi) the cHF diet as above, but with 2 g metformin /kg diet, and with

1.5% of its lipids replaced by PRB-2 (M+P), (vii) the cHF diet as above, but with 10 mg rosiglitazone/kg diet, and with 1.5% of its lipids replaced by PRB-2 (R+P). Since the beginning of the dietary treatment, body weight of mice was monitored once a week and food consumption was measured per cage. After 8 weeks of the treatment, EDTA-plasma was collected through tail bleeds for the measurement of insulin. Two days later, intraperitoneal (i.p.) glucose tolerance test (GTT) was performed. The test was performed by i.p. injections of D-glucose (1 mg/g body wt.) into fasted animals (overnight; ~ 15 hr) to measure the area under the curve (AUC) of blood glucose elimination obtained for each mouse by sampling blood glucose from a tail vein at the time intervals 15, 30, 60, 120, and 180 min after the glucose injection. Blood samples for the measurement of fasting blood glucose were also taken. Glucose levels in the whole blood were measured by the use of calibrated glucometers (OneTouch Ultra, LifeScan, USA).

Results

Feeding the control mice by cHF diet induced obesity (Fig. 2) and after 8 weeks of cHF feeding the body weight of these animals was significantly higher compared with mice fed the STD diet. This difference was apparent since the first week of the treatment. While Met had no effect on the final body weight, it was significantly reduced by Rosi compared with the cHF mice. However, at a higher dose, Rosi increased body weight (not shown). Since the first week of the treatment, the PRB2-1.5%, M+P, and R+P mice had significantly lower body weight compared with all the other subgroups. Starting from around 4 weeks of the treatment, mice treated by the combination of PRB-2 with either metformin (M+P) or rosiglitazone (R+P) tended to weight less than the PRB2-1.5% animals. This difference tended to be more pronounced between the PRB2-1.5% and M+P groups than the difference between the PRB2-1.5% and R+P group. Similar conclusions can be drawn from the evaluation of body weight gains during the treatment (Table 1).

Table 1. The effect of the treatments on body weight gain after 8 weeks

Moreover, food intake (expressed as grams/mouse per day) was measured weekly, always at the beginning of a given week. Initial food intake measurements were performed at the beginning of the second week of treatment, when mice adapted to various experimental diets.

Average food intake expressed in grams/mouse per day was higher in the STD group compared with the other groups, but it was similar in all the subgroups if expressed in calories/mouse per day.

During the last week of the treatment, markers of glucose homeostasis, i.e. plasma insulin levels and AUC for glucose were estimated (Table 3). In the cHF mice, insulin levels were 4-fold higher compared to the STD mice, indicating the induction of insulin resistance by feeding mice a high-fat diet. PRB2-1.5% lowered the insulin levels significantly, even when compared with STD mice. Compared with cHF, Met had no effect, while Rosi significantly lowered insulin levels by about 2-fold. Importantly, in spite of the fact that PRB2-1.5% lowered plasma insulin below the level found in the STD mice, the combination of PRB2-1.5% with either Met (M+P) or Rosi (R+P) tended to lower insulin levels even more than PRB2-1.5% alone. This effect was more pronounced with the R+P than with M+P combination.

Blood was collected from the tail vein of mice (in the fed state), plasma was isolated and insulin levels were measured by RlA. Glucose tolerance tests were applied to assess glucose tolerance in overnigt-fasted mice and estimated as AUC for glucose. * asterisk indicates significant differences vs. cHF group.

Glucose tolerance, expressed as AUC for glucose (as estimated by GTT; Table 3), was higher in the cHF mice compared with the STD mice, indicating again a deterioration of glucose homeostasis and insulin sensitivity induced by a high-fat diet. While Met or Rosi had no effect on AUC value, this parameter of glucose homeostasis was positively affected to a similar extent by PRB2-1.5%, M+P, and R+P, respectively.

Discussion and conclusions

This experiment documented a dramatic preventive effect of PRB-2 on several phenotypes normally associated with a high-fat feeding. Namely, the PRB-2 compound reduced body weight gain and prevented the rise of plasma insulin levels and the induction of glucose intolerance (as measured by GTT). All these effects appeared in the absence of any significant effects on food intake and indicated a potential use of PRB2 in the treatment of obesity, insulin resistance and glucose intolerance. While its effect on plasma insulin levels could be explained by the improvement of insulin sensitivity in various tissues, mainly in the skeletal muscle, the explanation of the effect on glucose tolerance is more complicated and may reflect beneficial action on insulin sensitivity as well as on hepatic glucose production. Type 2 diabetic patients are usually obese and it is very negative that the two antidiabetics pharmaceuticals used in the present experiment do not reduce weight gain at all. The lack of effect on obesity has been shown previously in clinical studies. Some of the glitazones have even induced weight gain, which must be regarded as highly unwanted. The combination with PRB2, however, reduced weight gain significantly compared to the control group (cHF), and even somewhat better than PRB2 alone.

As mentioned previously patients with type 2 diabetes and insulin resistance have high levels of insulin in plasma, at least during the first phase of the disease. Rosiglitazone as well as the other glitazones reduce insulin in plasma by positive interference with insulin resistance. This effect is very relevant again addressing the very pathophysiologic basis for the disease. The combination of rosiglitazone and PRB2 had an even better effect on plasma insulin. This combinative effect has not been shown previously favoring a combination product of both compounds for treatment of type 2 diabetes.

Metformin, on the other hand, does not effect insulin resistance but lowers blood glucose by another mechanisms. Combined with PRB2 a dual effect was obtained indicating that a combination product with metformin and PRB2 could be very interesting by combining two compounds with completely different mode-of-action.

Neither metformin nor rosiglitazone reduced AUC glucose in the intraperitoneal glucose tolerance test in the present experiment. This makes sense for metformin not having an effect on glucose tolerance but not for rosiglitazone. The reason for not being able to improve the glucose tolerance test by rosiglitazone is obscure. The glucose tolerance (GT) test is a sensitive marker of glucose handling by mechanisms induced by insulin. Animals and patients with glucose intolerance have delayed glucose elimination in the GT test. Pharmaceuticals reducing insulin resistance normalise glucose utilisation. Compounds acting as PPARy ligands reduce insulin resistance. It is therefore an unexpected finding that rosiglitazone should not give lower AUC in the GT test. PRB2 on the other hand being a combined PPARy/ PPARα ligand demonstrated significant reduction of the AUC as expected. From the experiment presented it seems that a combination of PRB2 and metformin or rosiglitazone would improve the hypoglycaemic effects of these pharmaceuticals by reducing peripheral insulin resistance. Metformin acts through yet another mode-of-action different from the thiazolidinediones, which is one of the reasons why a new combinative product has been launched on the market for the treatment of type 2 diabetes. A combination of Metformin and PRB2 seems to another logic combination with the potential of addressing several of the pathophysiologic events common for patients witn type 2 diabetes.

In conclusion, the present experiment in adipose prone mice with insulin resistance has demonstrated several beneficial effects of the combination with one exponent for the thiazolidinediones namely rosiglitazone, and Metformin in combination with PRB2. A product with a fix combination of any of these combinations has the potential of addressing the pathophysiologic mechanisms responsible for type 2 diabetes and at the same time reduce the propensity for adverse effects.

The invention shall not be limited to the shown embodiments and examples.

Claims

1. A combination product comprising: • at least one lipid in the form of a carboxylic acid, or a derivative thereof, a carboxylic ester, a carboxylic anhydride, an alcohol or an amide, which lipid is substituted at carbon 2, counted from the functional group, with at least one substituent, or any pharmaceuticlly acceptable complex, salt, solvate or pro-drug thereof; and • at least one hypoglycemic agent, or any pharmaceuticlly acceptable complex, solvate or pro-drug thereof.

2. A combination product according to claim 1 , wherein said lipid has a chain length of 16-24 carbon atoms.

3. A combination product according to claim 1 or 2, wherein said lipid contains at least two double bonds with £ and/or Z configuration.

4. A combination product according to any one of the preceding claims, wherein said lipid is an omega-3 lipid compound.

5. A combination product according to claim 4, wherein said omega-3 lipid compound is selected from the group consisting of:

• (all-Z)-4,7,10,13,16,19-docosahexaenoic acid, • (all-Z)-5,8,11 ,14,17-eicosapentaenoic acid,

• (all-Z)- 9,12,15-octadecatrienoic acid,

• (all-Z)-6,9,12,15-octadecatetraenoic acid,

• (all-Z)-7,10,13,16,19-docosapentaenoic acid,

• (all-Z)-11 ,14,17-eicosatrienoic acid, • (all-Z)-6,9,12,15,18,21-tetracosahexaenoic acid,

• (4E, 8Z, 11 Z, 14Z, 17Z)-eicosapentaenoic acid,

• (5£, 8Z, 11Z, 14Z, 17Z)-eicosapentaenoic acid,

• (all-Z)-8,11 ,14,17-eicosatetraenoic acid, and

• (4£, 7Z, 10Z, 13Z, 16Z, 19Z)-docosahexaenoic acid.

6. A combination product according to any one of the preceding claims, wherein said at least one substituent is selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, a carboxy group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group, and an alkylamino group.

7. A combination product according to any one of the claims 1-3, wherein said lipid is an omega-6 lipid compound.

8. A combination product according to claim 7, wherein said omega-6 lipid compound is selected from the group consisting of:

• (all-Z)-9,12-octadecadienoic acid,

• (all-Z)-6,9,12-octadecatrienoic acid, and

• (all-Z)-8,11 ,14-eicosatrienoic acid.

9. A combination product according to claim 7 or 8, wherein said at least one substituent is selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, a halogen atom, an alkoxy group, an acyloxy group, an acyl group, an alkenyl group, an alkynyl group, an aryl group, an alkylthio group, an alkoxycarbonyl group, a carboxy group, an alkylsulfinyl group, an alkylsulfonyl group, an amino group, and an alkylamino group.

10. A combination product according to any one of the claims 1-9, wherein said derivative of a carboxylic acid is in the form of a salt comprising a cation selected from the group consisting of Li⁺, Na⁺, K⁺, NH4⁺, meglumine, tris(hydroxymethyl)aminomethane, diethylamine, arginine, Mg²⁺, Ca²⁺, ethylenediamine, piperazine and chitosan.

11. A combination product according to any one of the claims 1-6, wherein said at least one lipid is (all-Z)-4,7,10,13,16,19-docosahexaenoic acid, and said at least one substituent is an alkyl group.

12. A combination product according to claim 11 , wherein said alkyl group is ethyl or propyl.

13. A combination product according to any one of the claims 1-6, wherein said at least one lipid is (all-Z)-4,7,10,13,16,19-docosahexaenoic acid, and said at least one substituent is an alkoxy group.

14. A combination product according to claim 13, wherein said alkoxy group is methoxy or ethoxy.

15. A combination product according to any one of the claims 1-6, wherein said at least one lipid is (all-Z)-4,7,10,13,16,19-docosahexaenoic acid, and said at least one substituent is an alkylthio group.

16. A combination product according to claim 15, wherein said alkylthio group is thiomethyl or thioethyl.

17. A combination product according to any one of the claims 1 -6, wherein said at least one lipid is (all-Z)-4,7,10,13,16,19-docosahexaenoic acid, and said at least one substituent is an aryl group.

18. A combination product according to claim 17, wherein said aryl group is a benzyl group or a substituted benzyl group.

19. A combination product according to any one of the claims 1-6, wherein said at least one lipid is (all-Z)-5,8,11 ,14,17-eicosapentaenoic acid, and said at least one substituent is an alkyl group.

20. A combination product according to claim 19, wherein said alkyl group is ethyl or propyl.

21. A combination product according to any one of the claims 1-6, wherein said at least one lipid is (all-Z)-5,8,11 ,14,17-eicosapentaenoic acid, and said at least one substituent is an alkoxy group.

22. A combination product according to claim 21, wherein said alkoxy group is methoxy or ethoxy.

23. A combination product according to any one of the claims 1-6, wherein said at least one lipid is (all-Z)-5,8,11 ,14,17-eicosapentaenoic acid, and said at least one substituent is an alkylthio group.

24. A combination product according to claim 23, wherein said alkylthio group is thiomethyl or thioethyl.

25. A combination product according to any one of the claims 1-6, wherein said at least one lipid is (all-Z)-5,8,11 ,14,17-eicosapentaenoic acid, and said at least one substituent is an aryl group.

26. A combination product according to claim 25, wherein said aryl group is a benzyl group or a substituted benzyl group.

27. A combination product according to any one of the claims 1-6, wherein said at least one lipid is (all-Z)-7,10,13,16,19-docosapentaenoic acid, and said at least one substituent is an alkyl group.

28. A combination product according to claim 27, wherein said alkyl group is ethyl or propyl.

29. A combination product according to any one of the claims 1-6, wherein said at least one lipid is (all-Z)-7,10,13,16,19-docosapentaenoic acid, and said at least one substituent is an alkoxy group.

30. A combination product according to claim 29, wherein said alkoxy group is methoxy or ethoxy.

31. A combination product according to any one of the claims 1-6, wherein said at least one lipid is (all-Z)-7,10,13,16,19-docosapentaenoic acid, and said at least one substituent is an alkylthio group.

32. A combination product according to claim 31 , wherein said alkylthio group is thiomethyl or thioethyl.

33. A combination product according to any one of the claims 1-6, wherein said at least one lipid is (all-Z)-7,10,13,16,19-docosapentaenoic acid, and said at least one substituent is an aryl group.

34. A combination product according to claim 33, wherein said aryl group is a benzyl group or a substituted benzyl group.

35. A combination product according to any one of the preceding claims, wherein said lipid is in the form of a carboxylic acid, or a derivative thereof, or an ethyl or methyl ester.

36. A combination product according to claim 35, wherein said derivative of a carboxylic acid is a phospholipid, or a tri-, di-, or monoglyceride.

37. A combination product according to claim 36, wherein said derivative of a carboxylic acid is in the form of a phospholipid, represented by the formula

wherein

Z is

38. A combination product according to claim 36, wherein said derivative of a carboxylic acid is in the form of a phospholipid, represented by the formula

39. A combination product according to claim 36, wherein said derivative of a carboxylic acid is in the form of a phospholipid, represented by the formula

(III) wherein

, or

40. A combination product according to claim 36, wherein said derivative of a carboxylic acid is in the form of a triglyceride, represented by the formula

O

(IV)

41. A combination product according to claim 36, wherein said derivative of a carboxylic acid is in the form of a 1-monoglyceride, represented by the formula

(V)

42. A combination product according to claim 36, wherein said derivative of a carboxylic acid is in the form of a 2-monoglyceride, represented by the formula

43. A combination product according to any one of the preceding claims, wherein said hypoglycemic agent at least lowers the blood glucose level.

44. A combination product according to any one of the preceding claims, wherein said hypoglycemic agent is a PPAR y agonist, a PPAR v partial agonist, and/or a PPAR \ modulator.

45. A combination product according to any one of the preceding claims, wherein said hypoglycemic agent is a thiazolidinedione (TZD) derivative.

46. A combination product according to claim 45, wherein said thiazolidinedione (TZD) derivative is rosiglitazone or pioglitazone.

47. A combination product according to any one of the claims 1-44, wherein said hypoglycemic agent is Metformin.

48. A combination product according to any one of the preceding claims, for use as a medicament and for use in therapy.

49. A pharmaceutical composition comprising a combination product according to any one of the preceding claims.

50. A pharmaceutical composition according to claim 49, wherein said at least one lipid and said at least one hypoglycemic agent are formulated in different pharmaceutical compositions.

51. A pharmaceutical composition according to claim 49, wherein said at least one lipid and said at least one hypoglycemic agent are formulated in a common pharmaceutical composition.

52. A pharmaceutical composition according to any one of the claims 49-51 , formulated to provide a daily dosage of 1 mg to 10 g of said at least one lipid.

53. A pharmaceutical composition according to claim 52, formulated to provide a daily dosage of 20 mg to 1 g of said at least one lipid.

54. A pharmaceutical composition according to claim 53, formulated to provide a daily dosage of 20 mg to 400 mg of said at least one lipid.

55. A pharmaceutical composition according to any one of the claims 49-51 , formulated to provide a daily dosage of 1 to 5000 mg of said at least one hypoglycemic agent.

56. A pharmaceutical composition according to claim 55, wherein said at least one hypoglycemic agent is rosiglitazone.

57. A pharmaceutical composition according to claim 56, wherein said daily dosage is 4 to 8 mg.

58. A pharmaceutical composition according to claim 55, wherein said at least one hypoglycemic agent is pioglitazone.

59. A pharmaceutical composition according to claim 58, wherein said daily dosage is 15 to 30 mg.

60. A pharmaceutical composition according to claim 55, wherein said at least one hypoglycemic agent is Metformin.

61. A pharmaceutical composition according to claim 60, wherein said daily dosage is 500 to 3000 mg.

62. A pharmaceutical composition according to any one of the claims 49-61 , for use as a medicament and for use in therapy.

63 Use of:

• at least one hypoglycemic agent, or any pharmaceutically acceptable complex, solvate or pro-drug thereof,

for the manufacture of a pharmaceutical composition for the treatment of a diabetic condition.

64. Use according to claim 63, wherein said diabetic condition is diabetes mellitus type 2.

65. Use according to claim 63, wherein said diabetic condition is a combination of diabetes mellitus type 2 and an overweight condition.

66. Use according to claim 63, wherein said diabetic condition is a combination of diabetes mellitus type 2 and elevated blood lipid levels.

67. Use according to any one of the claims 63-66, wherein said at least one lipid and said at least one hypoglycemic agent are formulated in different pharmaceutical compositions.

68. Use according to any one of the claims 63-66, wherein said at least one lipid and said at least one hypoglycemic agent are formulated in a common pharmaceutical composition.

69. A kit comprising:

• a pharmaceutical composition comprising at least one lipid in the form of an acid, or a derivative thereof, an ester, an anhydride, an alcohol or an amide, which lipid is substituted at carbon 2, counted from the functional group, with at least one substituent, or any pharmaceuticlly acceptable complex, salt, solvate or pro-drug thereof; and • a pharmaceutical composition comprising at least one hypoglycemic agent, or any pharmaceutically acceptable complex, solvate or prodrug thereof.

70. A method for the treatment and/or the prevention of a diabetic condition, comprising administering to a mammal in need thereof a pharmaceutically active amount of:

• at least one lipid in the form of a carboxylic acid, or a derivative thereof, a carboxylic ester, a carboxylic anhydride, an alcohol or an amide, which lipid is substituted at carbon 2, counted from the functional group, with at least one substituent, or any pharmaceuticlly acceptable complex, salt, solvate or pro-drug thereof; and

• at least one hypoglycemic agent, or any pharmaceutically acceptable complex, solvate or pro-drug thereof.

71. A method according to claim 70, wherein said diabetic condition is diabetes mellitus, type 2.

72. A method according to claim 70, wherein said diabetic condition is a combination of diabetes mellitus type 2 and an overweight condition.

73. A method according to claim 70, wherein said diabetic condition is a combination of diabetes mellitus type 2 and elevated blood lipid levels.

74. A method according to any one of the claims 70-73, wherein said at least one lipid and said at least one hypoglycemic agent are administered consequtively.

75. A method according to any one of the claims 70-73, wherein said at least one lipid and said at least one hypoglycemic agent are administered simultaneously.

76. A method for the manufacture of a combination product according to any one of the claims 1-48.