WO2003035086A1

WO2003035086A1 - Formulation

Info

Publication number: WO2003035086A1
Application number: PCT/GB2002/004433
Authority: WO
Inventors: Thomas Brian Champman; Steven Atkin; Gary Brenner
Original assignee: Thomas Brian Champman; Steven Atkin; Gary Brenner
Priority date: 2001-10-26
Filing date: 2002-10-01
Publication date: 2003-05-01
Also published as: GB0407501D0; GB2396812A; GB2396812B; GB0125662D0

Abstract

The present invention relates to a formulation for treating, reducing or preventing one or more symptoms or complications of type II diabetes comprising one or more soy proteins and at least one phytoestrogen.

Description

FORMULATION

The present invention relates to a formulation for treating, reducing or preventing one or more symptoms or complications of type II diabetes.

Although soy is prominent in the diet of the inhabitants of Asia, its consumption in Western civilisations is relatively low and limited generally to nutritional supplements. Such supplements are a rich source of proteins and calories. Soy oil from the seeds (beans) of the soy plant may be used to prevent or correct essential fatty acid deficiency. Preparations made from whole soy beans utilising soy oil and soy protein are used as the basis of lactose free vegetable milks for infants and patients with lactose or similar disaccharide intolerance.

Pharmaceutical applications of soy remain relatively scarce. However it has recently been recognised that soy may help to reduce heart disease. Soy oil also has emollient properties and is used as a bath additive in the treatment of dry skin conditions.

Type II or late onset diabetes is usually characterised by a number of symptoms including poor glycaemic control, insulin resistance, elevation of cholesterol (in particular LDL cholesterol) and raised systolic blood pressure. These symptoms of type II diabetes are often difficult to address with current medication.

The present invention seeks to improve treatment of one or more symptoms of type II diabetes by providing a formulation comprising one or more soy proteins and one or more phytoestrogens.

Thus viewed from one aspect the present invention provides a formulation for combatting (eg treating, reducing or preventing) one or more of the symptoms of type II diabetes comprising one or more soy proteins and at least one phytoestrogen wherein the ratio of the total weight of phytoestrogens to soy proteins is in the range 0.500:100 to 0.900:100. Preferably the ratio of the total weight of phytoestrogens to soy proteins is in the range 0.550: 100 to 0.850:100, particularly preferably 0.600:100 to 0.800:100, more preferably 0.650: 100 to 0.700:100, especially preferably 0.670:100 to 0.680: 100, most preferably about 0.673:100.

In a preferred embodiment, the one or more phytoestrogens are isoflavones. For example, the isoflavones are obtainable (eg extractable) from a leguminous plant. Preferably the isoflavones are soy isoflavones, particularly preferably selected from one or more of the group consisting of genistin, genistein, daidzin, daidzein, glycitein and glycitin.

In a preferred embodiment, the at least one phytoestrogens are soy isoflavones consisting of 50-90wt% genistin/genistein and 10-50wt% daidzin/daidzein, preferably 60-75 wt% genistin/genistein and 25-40wt% daidzin/daidzein, particularly preferably 65-70wt% genistin/genistein and 30-35wt% daidzin/daidzein, more preferably about 66wt% genistin/genistein and about 30wt% daidzin/daidzein (with the balance if any in each case being glycitin/glycitein typically in the proportion 4-5wt%).

The one or more soy proteins may be selected from the group consisting of glycinin, phaseolin and albumin (eg legumelin or soy legumelin).

In a preferred embodiment, the formulation is obtainable by combining (eg mixing or blending) a first extract containing the one or more soy proteins and a second extract containing the at least one phytoestrogen.

Typically the weight ratio of first extract to second extract is in the range 0.86: 100 to 1.28:100 (eg about 1.05:100).

The first extract may be soy protein rich. For example, the first extract may contain a proportion of soy protein in the range 60 to 70wt%, preferably 62 to 67wt%, particularly preferably about 64wt%. The first extract may take the form of a concentrate and a preferred example is SOLCON or MAICON (available from Solbar Plant Extracts, Israel). The second extract may be soy isoflavone rich. For example, the second extract may contain a proportion of soy isoflavones in the range 38 to 43wt%, preferably 39 to 42wt%, particularly preferably 41wt%. The second extract may contain a small proportion of soy protein typically less than 15wt% (eg about 1 lwt%). A preferred example of the second extract is SOLGEN 40 (available from Solbar Plant Extracts, Israel).

The formulation of the invention is typically adapted for pharmaceutical use. For example, the formulation comprises one or more pharmaceutically acceptable carriers, additives, adjuvants or excipients. Preferably the formulation further comprises an anti-caking agent (eg colloidal silicon dioxide) .

Typically the formulation of the invention is adapted for oral administration. For example, the formulation may be in solid (eg tablet, capsule or powdered) form or liquid (eg solution, gel or syrup) form for oral administration and may be in admixture with flavourings, stabilisers or preservatives as desired.

A dose of formulation of the invention will typically contain about 129mg of phytoestrogens and about 19.2g of soy proteins and be administered (preferably orally) once daily. The dose of formulation may be conveniently provided in a sachet.

Viewed from a further aspect the present invention provides a process for the preparation of a formulation as hereinbefore defined comprising the steps of: extracting a phytoestrogen rich extract of soy under a first set of extraction conditions; extracting a protein rich extract of soy under a second set of extraction conditions; and combining (eg mixing or blending) the phytoestrogen rich extract and the protein rich extract.

Preferably the phytoestrogen rich extract and the protein rich extract are combined in a ratio by weight in the range 0.86:100 to 1.28:100, preferably 0.95:100 to 1.15:100, particularly preferably 1.00:100 to 1.10:100 (eg about 1.05:100). In a preferred embodiment, the process further comprises: introducing an anti-caking agent.

The anti-caking agent may be a colloid such as colloidal silicon dioxide. Typically the anti- caking agent is introduced so as to be present in an amount in the range 0.30 to 0.34wt% (eg about 0.33wt%).

Preferably the anti-caking agent is introduced into (eg mixed or blended with) the phytoestrogen rich extract and then the protein rich extract is added, preferably portionwise (for example in a plurality of (eg ten) equal proportions).

Viewed from a still further aspect the present invention provides formulation comprising one or more soy proteins and at least one phytoestrogen for use as a medicament. Preferably the formulation or soy protein or phytoestrogen is as hereinbefore defined.

Viewed from a yet further aspect the present invention provides formulation comprising one or more soy proteins and at least one phytoestrogen for use in combatting (eg treating, reducing or preventing) one or more symptoms or complications of type II diabetes. Preferably the formulation or soy protein or phytoestrogen is as hereinbefore defined.

Viewed from an even further aspect the present invention provides the use of (1) soy beans or (2) one or more soy proteins and at least one phytoestrogen for the manufacture of a medicament for combatting (eg treating, reducing or preventing) one or more complications or symptoms of type II diabetes.

Viewed from an even still further aspect the present invention provides a method for combatting (eg treating, reducing or preventing) one or more symptoms or complications of type II diabetes in a subject, said method comprising the step of: administering to the subject an effective amount of a formulation comprising one or more soy proteins and at least one phytoestrogen. Preferably the formulation or soy protein or phytoestrogen is as hereinbefore defined. The one or more symptoms or complications of type II diabetes may include poor glycaemic control, insulin resistance, elevated cholesterol (in particular LDL cholesterol) levels and raised systolic blood pressure and macro-vascular and micro-vascular complications (eg death, myocardial infarction, heart failure, stroke, retinopathy, nephropathy or neuropathy).

Within the scope of this invention are methods and uses in respect of the aforementioned conditions or disorders which might not be symptoms or complications of type II diabetes. In each case, the formulation or soy protein or phytoestrogen is preferably as hereinbefore defined.

Thus viewed from a yet still further aspect the present invention provides formulation comprising one or more soy proteins and at least one phytoestrogen for use in reducing one or more of the group consisting of insulin resistance, LDL cholesterol level, total cholesterol level and systolic blood pressure or for improving glycaemic control.

Viewed from an even still further aspect the present invention provides the use of (1) soy beans or (2) one or more soy proteins and at least one phytoestrogen for the manufacture of a medicament for reducing one or more of the group consisting of insulin resistance, LDL cholesterol level, total cholesterol level and systolic blood pressure or for improving glycaemic control.

Viewed from a yet even still further aspect the present invention provides a method for reducing one or more of the group consisting of insulin resistance, LDL cholesterol level, total cholesterol level and systolic blood pressure or for improving glycaemic control in a subject, said method comprising the step of: administering to the subject an effective amount of a formulation comprising one or more soy proteins and at least one phytoestrogen.

The present invention will now be described in a non-limitative sense with reference to the following example and report of a clinical study. Example

315mg of an extract of non-genetically modified soy beans containing phytoestrogens (SOLGEN 40) was mixed in a suitable stainless steel mixer with lOOmg of colloidal silicon dioxide. To this was added a total of 30g of a concentrate of non-genetically modified soy beans containing soy proteins (SOLCON) in ten aliquots (ie ten 3g portions).

The resultant mixture of powders was accurately weighed and sealed in a suitable sized package (sachet) made from polyethylene paper aluminium foil.

Clinical Study

A study was conducted in a UK National Health Service teaching hospital under the rules of the Helsinki Convention in which patients were randomly allocated to the test article or a placebo and then the trial was crossed over. Suitable patients were those female patients who were: diabetes type II diagnosed on WHO criteria with a body mass index of more than 30 having had Amenorrhea for twelve months or more and biochemical menopause. The physician, the patient and the medication were blinded to eliminate bias.

Patients were given one sachet per day for twenty four weeks. Various parameters were tested before, during and after the course of treatment in each patient. At the end of the trial, all of the results were statistically analysed. The following table lists mean results by way of comparison between placebo and the formulation for the various parameters.

Effect of a formulation of the invention vs a placebo on Fasting Glucose, Glycated Haemoglobin, Fasting Insulin, Insulin Resistance, Fasting Lipids and Blood Pressure.

From this table it will be seen that fasting insulin levels, insulin resistance (HOMA), LDL cholesterol, systolic blood pressure and glycated HbAlC were all reduced by administration of the formulation of the invention.

The reduction in parameters caused by administration of a formulation of the invention has great significance. According to UK prospective diabetes study (UKPDS), improved blood glucose control and control of blood pressure has major effects on macro-vascular and micro-vascular complications. Furthermore, the UKPDS shows that reduction in risk due to a 1% fall in Hb Ale was:

21% for any end point related to diabetes;

21% for deaths related to diabetes;

14% for myocardial infarction;

37%) for micro-vascular complications (retinopathy, nephropathy, neuropathy)

and the risk reduction on blood pressure control was:

24% for any end point related to diabetes; 32% for deaths related to diabetes; 44% for stroke; 37% for micro-vascular complications; and 56% for heart failure.

Recently in the micro Hope study it was noted that there was a composite reduction of 25% in stroke myocardial infarction and cardiovascular death for a blood pressure reduction of 2mm of mercury.

Claims

1. A formulation for combatting one or more of the symptoms of type II diabetes comprising one or more soy proteins and at least one phytoestrogen wherein the ratio of the total weight of phytoestrogens to soy proteins is in the range 0.500:100 to 0.900:100.

2. A formulation as claimed in claim 1 wherein the ratio of the total weight of phytoestrogens to soy proteins is in the range 0.550:100 to 0.850:100.

3. A formulation as claimed in claim 1 or 2 wherein the ratio of the total weight of phytoestrogens to soy proteins is in the range 0.600:100 to 0.800:100.

4. A formulation as claimed in any preceding claim wherein the ratio of the total weight of phytoestrogens to soy proteins is in the range 0.650:100 to 0.700:100.

5. A formulation as claimed in any preceding claim wherein the ratio of the total weight of phytoestrogens to soy proteins is in the range 0.670:100 to 0.680:100.

6. A formulation as claimed in any preceding claim wherein the ratio of the total weight of phytoestrogens to soy proteins is about 0.673:100.

7. A formulation as claimed in any preceding claim wherein the one or more phytoestrogens are isoflavones.

8. A formulation as claimed in claim 7 wherein the isoflavones are obtainable from a leguminous plant.

9. A formulation as claimed in claim 7 or 8 wherein the isoflavones are soy isoflavones.

10. A formulation as claimed in claim 9 wherein the isoflavones are selected from one or more of the group consisting of genistin, genistein, daidzin, daidzein, glycitein and glycitin. -lO- l l . A formulation as claimed in any preceding claim wherein the at least one phytoestrogens are soy isoflavones consisting of 50-90wt% genistin/genistein and 10- 50wt% daidzin/daidzein.

12. A formulation as claimed in claim 1 1 wherein the at least one phytoestrogens are soy isoflavones consisting of 60-75wt% genistin/genistein and 25-40wt% daidzin/daidzein.

13. A formulation as claimed in claim 11 or 12 wherein the at least one phytoestrogens are soy isoflavones consisting of 65-70wt% genistin/genistein and 30-35wt% daidzin/daidzein.

14. A formulation as claimed in any of claims 1 1 to 13 wherein the at least one phytoestrogens are soy isoflavones consisting of about 66wt% genistin/genistein and about 30wt% daidzin/daidzein.

15. A formulation as claimed in any of claims 11 to 14 wherein the balance of soy isoflavones is glycitin/glycitein in the proportion 4-5wt%.

16. A formulation as claimed in any preceding claim wherein the one or more soy proteins are selected from the group consisting of glycinin, phaseolin and albumin.

17. A formulation as claimed in any preceding claim obtainable by combining a first extract containing the one or more soy proteins and a second extract containing the at least one phytoestrogen.

18. A formulation as claimed in claim 17 wherein the weight ratio of first extract to second extract is in the range 0.86:100 to 1.28:100.

19. A formulation as claimed in claim 17 or 18 wherein the first extract is soy protein rich.

20. A formulation as claimed in any of claims 17 to 19 wherein the first extract contains a proportion of soy protein in the range 60 to 70wt%.

21. A formulation as claimed in any of claims 17 to 20 wherein the first extract contains a proportion of soy protein in the range 62 to 67wt%.

22. A formulation as claimed in any of claims 17 to 21 wherein the first extract contains a proportion of soy protein of about 64wt%.

23. A formulation as claimed in any of claims 17 to 22 wherein the second extract is soy isoflavone rich.

24. A formulation as claimed in any of claims 17 to 23 wherein the second extract contains a proportion of soy isoflavones in the range 38 to 43wt%.

25. A formulation as claimed in any of claims 17 to 24 wherein the second extract contains a proportion of soy isoflavones in the range 39 to 42wt%.

26. A formulation as claimed in any of claims 17 to 25 wherein the second extract contains a proportion of soy isoflavones of about 41wt%.

27. A formulation as claimed in any of claims 17 to 26 wherein the second extract contains a proportion of soy protein less than 15wt%.

28. A process for the preparation of a formulation as defined in any preceding claim comprising the steps of: extracting a phytoestrogen rich extract of soy under a first set of extraction conditions; extracting a protein rich extract of soy under a second set of extraction conditions; and combining the phytoestrogen rich extract and the protein rich extract.

29. A process as claimed in claims 28 wherein the phytoestrogen rich extract and the protein rich extract are combined in a ratio by weight in the range 0.86:100 to 1.28:100.

30. A process as claimed in either of claims 28 or 29 further comprising: introducing an anti-caking agent.

31. Formulation comprising one or more soy proteins and at least one phytoestrogen for use as a medicament.

32. Formulation comprising one or more soy proteins and at least one phytoestrogen for use in combatting one or more symptoms or complications of type II diabetes.

33. The use of (1) soy beans or (2) one or more soy proteins and at least one phytoestrogen for the manufacture of a medicament for combatting one or more complications or symptoms of type II diabetes.

34. A method for combatting one or more symptoms or complications of type II diabetes in a subject, said method comprising the step of: administering to the subject an effective amount of a formulation comprising one or more soy proteins and at least one phytoestrogen.

35. Formulation comprising one or more soy proteins and at least one phytoestrogen for use in reducing one or more of the group consisting of insulin resistance, LDL cholesterol level, total cholesterol level and systolic blood pressure or for improving glycaemic control.

36. The use of (1) soy beans or (2) one or more soy proteins and at least one phytoestrogen for the manufacture of a medicament for reducing one or more of the group consisting of insulin resistance, LDL cholesterol level, total cholesterol level and systolic blood pressure or for improving glycaemic control.

37. A method for reducing one or more of the group consisting of insulin resistance, LDL cholesterol level, total cholesterol level and systolic blood pressure or for improving glycaemic control in a subject, said method comprising the step of: administering to the subject an effective amount of a formulation comprising one or more soy proteins and at least one phytoestrogen.