U.S. patent application number 10/953453 was filed with the patent office on 2005-03-31 for composition and method for the treatment of dysglucaemia.
This patent application is currently assigned to METCON MEDICINE AB. Invention is credited to Hansson, Henri, Hansson, Kerstin, Lake, Mats.
Application Number | 20050070502 10/953453 |
Document ID | / |
Family ID | 26655276 |
Filed Date | 2005-03-31 |
United States Patent
Application |
20050070502 |
Kind Code |
A1 |
Hansson, Henri ; et
al. |
March 31, 2005 |
Composition and method for the treatment of dysglucaemia
Abstract
Dysglucaemia is treated and/or prevented by the administration
of granulated starch, enzymatically degraded and releasing reducing
sugars at a rate, adjusted to the metabolism of the patient,
suffering from dysglucaemia. For example nocturnal hypoglycaemia in
diabetic patients is prevented by administering to said patients a
granulate or tablets comprising granulated cornstarch, and
preferably also heat treated cornstarch and a low calorie
sweetener. The inventive granulation minimises the available
surface area and retards the enzymatic degradation of the
cornstarch and ensures a controlled, e.g. a substantially linear
release of reducing sugars, such as glucose, and a stable blood
glucose level during several hours. The granulate or tablets are
low in calories and contain no free sugar.
Inventors: |
Hansson, Henri;
(Helsingborg, SE) ; Lake, Mats; (Lidingo, SE)
; Hansson, Kerstin; (Lund, SE) |
Correspondence
Address: |
YOUNG & THOMPSON
745 SOUTH 23RD STREET
2ND FLOOR
ARLINGTON
VA
22202
US
|
Assignee: |
METCON MEDICINE AB
Lindingo
SE
|
Family ID: |
26655276 |
Appl. No.: |
10/953453 |
Filed: |
September 30, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10953453 |
Sep 30, 2004 |
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10002417 |
Oct 25, 2001 |
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6815433 |
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60243072 |
Oct 25, 2000 |
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Current U.S.
Class: |
514/60 |
Current CPC
Class: |
A23P 10/30 20160801;
A23L 29/212 20160801; A23P 10/35 20160801; A61K 9/2054 20130101;
A61K 31/718 20130101; A23L 29/30 20160801; A61P 3/10 20180101; A61K
9/205 20130101 |
Class at
Publication: |
514/060 |
International
Class: |
A61K 031/718 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 25, 2000 |
SE |
SE 0003877-8 |
Claims
1. A method for the prevention of dysglucaemia in a patient, the
method involving a minimal supply of calories, wherein an effective
amount of starch is administered orally to said patient in
granulated form having a reduced surface available for enzymatic
degradation, wherein granulation delays the enzymatic degradation
of the starch into reducing sugars to a duration and level,
adjusted to the metabolism of the patient.
2. A method for the long term prevention of nocturnal and/or
morning hypoglycaemia in patients suffering from insulin dependent
diabetes (IDDM), wherein a predetermined amount of starch is
administered orally to the patient in granulated form, wherein
granulation delays the enzymatic degradation of the starch into
reducing sugars to a duration and level, adjusted to the metabolism
of the patient.
3. A method for effective glycaemic control in diabetic patients,
the method involving a minimal supply of calories, wherein a
predetermined amount of starch is administered orally to the
patient in granulated form, wherein granulation delays the
enzymatic degradation of the starch into reducing sugars to a
duration and level, adjusted to the metabolism of the patient.
4. The method according to claim 1, wherein said patients are
patients scheduled to undergo surgical or invasive medical
treatment.
5. The method according to claim 1, wherein said patients are
diabetic patients scheduled for surgical or invasive medical
treatment.
6. The method according to claim 1, wherein said patients are
suffering from a chronic disease-selected from the group consisting
of viral infections, liver disease, hepatitis, alcohol abuse,
cancer, HIV, AIDS, and a combination thereof.
7. The method according to claim 1, wherein said patients are
patients on post-operative medication, having undergone surgical or
invasive treatment.
8. The method according to claim 2, wherein the treatment is given
in conjunction to insulin treatment.
9. The method according to claim 3, characterized in that the
treatment is given in conjunction to insulin treatment.
10. The method according to claim 4, wherein the treatment is given
in conjunction to insulin treatment.
11. The method according to claim 5, wherein the treatment is given
in conjunction to insulin treatment.
12. The method according to claim 6, wherein the treatment is given
in conjunction to insulin treatment.
13. The method according to claim 7, wherein the treatment is given
in conjunction to insulin treatment.
14. The method according to claim 1, wherein said patients are
athletes training or participating in an endurance sport.
15. The method according to claim 2, wherein said patients are
athletes training or participating in an endurance sport.
16. The method according to claim 3, wherein said patients are
athletes training or participating in an endurance sport.
17. The method according to claim 8, wherein said patients are
athletes training or participating in an endurance sport.
18. The method according to claim 9, wherein said patients are
athletes training or participating in an endurance sport.
19. The method according to claim 14, wherein said endurance sport
is selected from the group consisting of long distance running,
long distance skiing and long distance skating.
20. The method according to claim 1, wherein the starch is
encapsulated in a substance selected from the group consisting of
gum arabicum, potassium alginate, guar gum, methyl cellulose, ethyl
cellulose; liquid oils, liquid and hard fats and waxes.
21. The method according to claim 2, wherein the starch is
encapsulated in a substance selected from the group consisting of
gum arabicum, potassium alginate, guar gum, methyl cellulose, ethyl
cellulose; liquid oils, liquid and hard fats and waxes.
22. The method according to claim 3, wherein the starch is
encapsulated in a substance selected from the group consisting of
gum arabicum, potassium alginate, guar gum, methyl cellulose, ethyl
cellulose; liquid oils, liquid and hard fats and waxes.
23. The method according to claim 1, wherein the starch is
encapsulated in ethyl cellulose.
24. The method according to claim 2, wherein the starch is
encapsulated in ethyl cellulose.
25. The method according to claim 3, wherein the starch is
encapsulated in ethyl cellulose.
26. The method according to claim 1, wherein the enzymatic
degradation is delayed to an extent resulting in a linear release
of reducing sugars for more than 4 hours.
27. The method according to claim 2, wherein the enzymatic
degradation is delayed to an extent resulting in a linear release
of reducing sugars for more than 4 hours.
28. The method according to claim 3, wherein the enzymatic
degradation is delayed to an extent resulting in a linear release
of reducing sugars for more than 4 hours.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a division of co-pending application
Ser. No. 10/002,417, filed on Oct. 25, 2001, which claims the
priority benefit of U.S. Provisional Application 60/243,072, filed
Oct. 25, 2000. The entire contents of each of the above-identified
applications are hereby incorporated by reference.
[0002] The present invention concerns a method for long term
prevention and/or treatment of dysglucaemia and/or for improved
glycaemic control, for example the long term prevention of
nocturnal and morning hypoglycaemia in diabetic patients, a
composition for this purpose and a method for its production.
BACKGROUND OF THE INVENTION
[0003] Dysglucaemia is an overall definition, which in the present
description and claims is meant to comprise all irregularities in
blood glucose level in humans, both healthy persons and persons
with a diagnosed disease, irrespective of these irregularities
being chronic or temporary, caused by a metabolic disorder, a
disease or by physical exercise, bad nutritional habits, medical
treatment such as surgery, and desired or undesired pharmaceutical
or chemical influences, such as pharmaceutical treatments or
substance abuse.
[0004] Diabetes mellitus is a complex disorder of the carbohydrate,
fat, and protein metabolism that is primarily a result of a
relative or complete lack of insulin secretion by the beta cells of
the pancreas or of defects of the insulin receptors. The various
forms of diabetes are divided in several categories, the two most
frequent being juvenile-onset diabetes or Type I insulin-dependent
diabetes mellitus (IDDM) and adult-onset diabetes or Type II
non-insulin-dependent diabetes mellitus (NIDDM). Both diseases,
even when correctly diagnosed and medicated, require life-long
medication, good patient compliance, a careful diet and frequent
medical observation to avoid potentially serious sequelae.
[0005] One problem, frequently encountered by patients suffering
from diabetes, is the nocturnal drop in blood glucose levels,
hypoglycaemia, in mild cases resulting in morning dizziness and/or
nausea. Occasionally the blood glucose level sinks so low during
the night, or early in the morning, that the state of hypoglycaemia
becomes severe, leading to unconsciousness or convulsions.
Importantly, severe hypoglycaemia is more likely to occur at night,
when the patient is asleep, rather than during the day, when the
patient can feel the onset of hypoglycaemia and prevent it by
eating carbohydrates, e.g. a lump of sugar or specific glucose
tablets, energy gels or bars, marketed for diabetic patients.
Moreover, both mild (a blood glucose level about 2.4-4.0 mmol/l)
and severe (less than 2.4 mmol/l) hypoglucaemia predisposes the
patient to a condition known as hypoglycaemic unawareness, which in
turn means that hypoglucaemia can occur more frequently and at any
time of the day, due to attenuation of the typical warning symptoms
of a declining blood glucose level, e.g. hunger, perspiration
etc.
[0006] Notably, the incidence of hypoglycaemia is rapidly
increasing as diabetic patients seek better control of their blood
glucose levels, in order to avoid hyperglycaemia. An active life,
involving exercise as prescribed for diabetics, also adds to the
risk of hypoglycaemia unless the patient carefully controls his/her
carbohydrate intake, insulin dosage and regularly monitors their
blood glucose level.
[0007] There is presently no satisfactory therapeutic regime for
the prevention of nocturnal and morning hypoglycaemia. Patients
suffering from diabetes are often recommended to eat a light meal
before bedtime, e.g. potato chips or cereals. This results in an
almost instant peak in blood glucose, followed by a more or less
rapid decline during the night. In order to guarantee a sufficient
blood glucose level throughout the night, the initial level must be
very high, bordering to the unhealthy. When attempting this kind of
crude self-medication, the patients have difficulty finding the
optimal dose and mix of carbohydrates, and over-eating tends to be
the result. There is currently no medication available with an
appropriate kinetic profile to counteract the effect of the
night-time intermediate-acting insulin.
Prior Art
[0008] A method of treating diabetic hypoglycaemia by
administration of uncooked cornstarch is described in WO95/24906.
According to this application, published in September 1995, the
patient is given about 0.1 to 1.0 g starch per kg body weight,
preferably about 0.25 to 0.5 g per kg body weight. Different dosage
formulations are suggested, including a suspension of starch in
milk, sustained release tablets and a snack bar, containing a total
of 30 g carbohydrates, but having about 1/2 to 1/4 of the
carbohydrate in the form of uncooked cornstarch. Although
containing "slow" carbohydrates in the form of cornstarch, this
product contains considerable amounts of free sugar and fats,
resulting both in an initially very high blood glucose peak, and in
the intake of unnecessary calories in the form of fats and surplus
carbohydrates. Further information concerning the sustained release
tablets is not given, apart from a reference to well known
techniques of tablet formulation.
[0009] U.S. Pat. No. 5,605,893 (Kaufman, F.) discloses a specific
method of treating a diabetic patient and preventing hypoglycaemic
episodes, said method consisting of administration to the patient
of a therapeutic food composition comprising per serving or unit
about 20-50 grams of nutrients, including
[0010] about 5-15 g of slowly absorbed complex carbohydrate,
preferably cornstarch;
[0011] about 7-19 g of rapidly absorbed complex carbohydrate;
[0012] about 5-20 g of protein; and
[0013] about 3-7 g of fat,
[0014] said composition being substantially free from simple
sugars.
[0015] U.S. Pat. No. 5,843,921 (Kaufman, F.) discloses a
therapeutic food composition for treatment of diabetic patients and
preventing hypoglycaemic episodes, comprising per serving or unit
about 20-50 grams of nutrients, including
[0016] about 5-15 g of slowly absorbed complex carbohydrate,
preferably cornstarch;
[0017] about 7-19 g of rapidly absorbed complex carbohydrate;
[0018] about 5-20 g of protein; and
[0019] about 3-7 g of fat;
[0020] wherein the amount of simple sugars other than fructose in
said composition is less than about 3 g per unit.
[0021] U.S. Pat. No. 5,866,555 (Bell, S. J. et al.) discloses a
diabetic supplement bar for the treatment or prevention of night
time hypoglycaemia in a diabetic patient, made by blending simple
carbohydrates, proteins, lipids, complex carbohydrates, and any
additional additives, and homogenising the mixture into a food bar.
Sucrose is presented as the preferred source of simple
carbohydrates, whereas uncooked cornstarch is the preferred source
of complex carbohydrates. The final fat concentration of the
product is high, from 2 to 40% by weight. The remaining ingredients
are:
[0022] about 10-60% by weight sucrose;
[0023] about 1-25% by weight protein;
[0024] about 1-60% by weight complex carbohydrate.
[0025] The high fat content of the above products
accounts--together with the naturally slow degradation of uncooked
cornstarch--for the delayed glucose release, as fat delays gastric
emptying, thereby slowing the rate at which nutrients enter the
intestines and become digested.
[0026] Another product, available on the market under the trade
mark NiteBite.RTM. (Optim Nutrition Inc.) contains three sources of
glucose: sucrose, protein and uncooked cornstarch. These components
are digested more or less consecutively and are claimed to deliver
glucose into the blood during a period of 6 hours or more.
[0027] U.S. Pat. No. 5,545,410 discloses the coating of a core of a
carbohydrate in a food or pharmaceutical grade coating such as
stearic acid, hydrogenated or partially hydrogenated oils, calcium
stearate, stearyl alcohol, wax etc. The claims of U.S. Pat. No.
5,545,410 mention sucrose, glucose, lactose, dextrins,
monosaccharides, disaccharides, oligosaccharides, and
polysaccharides, as well as pregelatinized starches, raw starches,
and modified starches. A limitation is however that the coated core
has a particle size from 30-1000 .mu.m. The resulting product
consists of individually coated particles or granulates thereof,
the properties of the coating regulating the release of the core
compound.
[0028] The related patent U.S. Pat. No. 5,360,614 discloses the
above coated carbohydrated cores, further defining their size to
the interval of 75-500 .mu.m, and the coating as providing for the
release of substantially all said metabolizable carbohydrate into
the digestive system for one-half to four hours after
ingestion.
[0029] The prior art compositions fail to provide an entirely
satisfactory solution for long term treatments when all effects and
consequences are taken into account. The sucrose included in some
preparations can lead to initial hyperglycaemia and may
additionally contribute to caries and tooth decay. The proteins,
and in particular the fat included in some of the above
preparations provide unnecessary additional calories to patients,
who in many cases already battle with weight problems.
[0030] The objective of the present invention is thus to accurately
and reliably regulate blood glucose levels in humans and prevent
dysglucaemia, in particular long term prevention of dysglucaemia.
This objective can be divided in the prevention of dysglucaemia in
diabetic patients, and in particular the prevention of nocturnal
dysglucaemia in diabetic patients. Another related objective is to
prevent nocturnal hypoglycaemia in diabetic patients and in
particular in type 1 and type 2 diabetics on insulin
medication.
[0031] A further problem is how to prevent and/or treat
dysglucaemia in both healthy subjects, such as athletes, and in
unhealthy, such as patients undergoing surgery, chemotherapy etc,
and in particular diabetic patients undergoing medical
treatment.
[0032] Further, it is desirable to make available a simple and yet
reliable way of improving the glycaemic control or stabilising the
oscillating blood sugar levels typical for diabetic patients, and
avoiding both the high and low blood sugar levels, both conditions
injurious to the health, especially when occurring repeatedly or
for prolonged periods of time. It is particularly desirable to make
available a method and composition giving a controlled, delayed
enzymatic digestion of the starch and preferably a substantially
linear glucose release curve and thus guaranteeing a
pre-determined, stable and sufficient blood sugar level during at
least 5 hours, preferably about 8 hours.
[0033] A practical problem encountered in pursuing the above
objectives is how to make available a cornstarch composition having
an agreeable taste and texture, suitable for daily consumption and
life long treatment. This is not without significance, as a tasty
product advances good compliance.
SUMMARY OF THE INVENTION
[0034] The present inventors have surprisingly found that the
conversion of starch into sugar and in particular the enzymatic
conversion of cornstarch into glucose, can be regulated or delayed
in a controlled manner and adapted to the metabolism of the
patient, without relying on the delaying effect of fat. Thus the
blood sugar level can be held at a desired level, e.g. a level
accurately adjusted to the metabolic needs of the patient, avoiding
both peaks with the associated risk of hyperglycaemia, and low
levels, and the corresponding risk of hypoglycaemia. Importantly,
this can now be achieved without the administration of unnecessary
surplus calories. Further, the present invention makes available a
tasty and palatable product consisting substantially of native
cornstarch.
[0035] The problems associated with the prior art products are
solved, and the above objectives of the invention are achieved by a
novel composition and a method comprising administering to the
patient in question a starch product with minimised available
surface area, such as a granulated and/or partially encapsulated
starch, preferably native cornstarch. The method of treatment, the
pharmaceutical composition itself and the process for its
production are as disclosed in the attached claims.
SHORT DESCRIPTION OF THE DRAWINGS
[0036] The present invention will be described in closer detail in
the following description, examples and enclosed drawings, in
which
[0037] FIG. 1 shows the in vitro degradation profiles for different
compositions according to the invention, compared to the profile
for untreated cornstarch;
[0038] FIG. 2 shows the average fasting and postprandial blood
glucose levels in healthy, fasting volunteers, after ingestion of 4
different compositions according to the invention;
[0039] FIG. 3 shows the correspondence between rates of
digestion/degradation as measured by in vivo and in vitro
techniques;
[0040] FIG. 4 shows the in vivo blood glucose contribution in a
diabetic patient after intake of a light meal compared to native
cornstarch; and
[0041] FIG. 5 shows the in vivo blood glucose curve of a diabetic
patient having taken the inventive composition, compared to
control, excipients only, during ongoing insulin infusion according
to the glucose clamp technique. The upper curve thus shows the
contribution of the inventive composition.
DESCRIPTION
[0042] Starch is the main storage polysaccharide in plants, an
important source of carbohydrates and an ingredient in food. More
than half of the carbohydrates ingested by humans is starch. Starch
also has many technical uses, accounting for large volumes of the
starch produced. Examples include the use as a sizing agent in
paper industry, a raw material and/or additive in the production of
plastics, textiles etc. and as a carrier and bulk agent in
pharmaceutical industry. Starch is also used as a non-adherence
agent for surgical gloves. Apart from these purely technical uses,
it is not know to the present inventors that native starch as such
would have a purely therapeutic, internal use, nor that it would
have constituted the active ingredient in a pharmaceutical
composition, such as a tablet as disclosed in the present
description and claims.
[0043] Pure starch, although theoretically a good source of glucose
and free from surplus calories, is practically impossible to
ingest. The starch powder itself lacks taste and feels extremely
dry, chalky or sandy in the mouth. A suspension on the other hand,
e.g. a suspension in water, tends to sediment quickly, and has a
disagreeable taste and texture. Cornstarch consists of granules
sized 2-32 .mu.m, mainly comprising two components, amylose and
amylopectin. Amylose has a linear structure while amylopectin is
branched. Both amylose and amylopectin consist of
.alpha.-(1,4)-linked glucose residues while amylopectin also has
.alpha.-(1,6)-linked glucose residues. The starch granules are
insoluble in cold water and swell in warm. The swelling is
reversible until the temperature reaches about 55 to 65.degree. C.
At this temperature the starch granules gelatinise and loose their
crystalline structure.
[0044] The degradation of starch is catalysed by .alpha.-amylase,
which in humans is present in the saliva and in the small
intestine. The digestibility of starch, both in vivo and in vitro
depends on the source of starch as well as its pre-treatment (e.g.
native, fine/coarse, gelatinised or chemically modified). In the
present description, claims and examples, the term "native starch"
is used to define starch that has not been subjected to
heat-treatment or chemical treatment. The term "native starch" thus
comprises both the vegetable and/or plant seeds, kernels or grains,
as well as mechanically treated fractions, such as the milled and
sieved product, granules and flour.
[0045] The present inventors have now surprisingly found, that the
enzymatic degradation of the starch in vivo can be regulated in an
accurate and repeatable manner by minimising the surface area
available to enzymatic action, preferably by granulating the starch
granules with a substance, resulting in aggregated granules being
at least partially encapsulated in the substance.
[0046] Suitable substances are non-toxic substances, suitable for
ingestion, such as substances generally recognised as safe (GRAS)
and approved for use in pharmaceutical applications and/or in food
products. A non-exclusive list of suitable substances includes
polymers such as gum arabicum, potassium alginate, guar gum, methyl
cellulose, ethyl cellulose; liquid oils, liquid and hard fats and
waxes, such as paraffin, hydrogenated cottonseed oil, beeswax, and
camauba wax.
[0047] Tests conducted in vitro, have shown that a controlled
enzymatic digestion and a substantially linear release profile is
achieved when the amount of reducing sugars is plotted against
time. Test conducted in vivo, using healthy volunteers, have shown
that a modulated release profile is achieved. This makes it
possible to achieve a long term delivery of reducing sugars,
adjusted in level and duration to the metabolic needs of the
patient. An additional in vivo test, conducted on a diabetic
patient, confirms the performance of the inventive composition and
the feasibility of the inventive method. This test was performed
after the priority date, but before the international filing date.
The present invention makes available a method and composition for
the long term prevention and/or treatment of dysglucaemia, e.g. the
prevention of nocturnal and/or morning hypoglycaemia in patients
suffering from diabetes, including both IDDM and NIDDM, wherein a
predetermined amount of starch is administered to the patient in
granulated and at least partially encapsulated form, most
preferably in the form of tablets, which granulation delays the
enzymatic degradation of the starch into reducing sugars, such as
glucose. The starch is preferably native cornstarch.
[0048] The present invention also makes available a method and
composition for the prevention of dysglucaemia in situations, where
the blood glucose level is disturbed or altered by exercise,
pharmaceutical or surgical therapy, by a disease or a syndrome,
involving multiple diseases or metabolic disorders. Examples
include athletes, patients weakened by chemotherapy, fasting
patients and patients suffering from diseases or disorders
disturbing or altering the sugar metabolism, or patients undergoing
treatment of such and other diseases or disorders. The method is
characterised in that a predetermined amount of starch is
administered to the patient in granulated and at least partially
encapsulated form, preferably in the form of tablets, which
granulation delays the enzymatic degradation of the starch into
reducing sugars, such as glucose. The starch is preferably native
cornstarch. The present invention also makes available a method and
composition for improved glycaemic control, i.e. for stabilising
the blood sugar levels and avoiding the oscillation between
unhealthy high and low blood sugar levels. Lack of glycaemic
control is associated inter alia with microvascular damage, such as
diabetic retinopathy, and diabetic ketoacidosis or so called
diabetic coma.
[0049] The present invention further makes available a composition
for controlled release of reducing sugars, e.g. glucose, wherein
said composition contains granulated and at least partially
encapsulated starch, a low calorie sweetener and optionally also
unsaturated fat. The starch is preferably native cornstarch.
[0050] According to one embodiment of the invention, the native
starch is granulated with and at least partially encapsulated in a
substance chosen among non-toxic substances, suitable for
ingestion, such as substances generally recognised as safe (GRAS)
and approved for use in pharmaceutical applications and/or in food
products. A non-exclusive list of suitable substances includes
polymers such as gum arabicum, potassium alginate, guar gum, methyl
cellulose, ethyl cellulose; liquid oils, liquid and hard fats and
waxes, such as paraffin, hydrogenated cottonseed oil, beeswax, and
carnauba wax.
[0051] Preferably the substance is chosen among guar gum and ethyl
cellulose, most preferably ethyl cellulose.
[0052] According to the invention, the enzymatic degradation is
delayed to an extent resulting in a controlled and substantially
linear release of reducing sugars, e.g. glucose, accurately adapted
to the metabolism of the patient for more than 4 hours, preferably
more than 6 hours, most preferably about 8 hours or longer.
[0053] According to one embodiment, the composition comprises
starch in two forms; a first amount of native starch, and a second
amount of heat treated starch. Preferably the second amount of heat
treated starch is about 0.1 to 15% by weight of the total amount of
starch, preferably about 5% by weight.
[0054] According to a preferred embodiment the heat treated and
un-encapsulated starch is in the form of flakes of baked starch
having a size in the interval of about 0.5-1.0 mm.
[0055] According to one embodiment, the inventive composition for
controlled release of glucose comprises the following
ingredients:
[0056] about 60-90% by weight native cornstarch encapsulated in a
substance,
[0057] optionally about 0.1-15% by weight heat treated cornstarch
in the form of flakes;
[0058] about 5-25% by weight low calorie sweetener, e.g. isomalt,
sorbitol, xylitol, or the like, preferably isomalt.
[0059] According to another embodiment, the inventive composition
for controlled release of glucose comprises the following
ingredients:
[0060] about 60-90% by weight native cornstarch encapsulated in a
substance,
[0061] optionally about 0.1-15% by weight heat treated cornstarch
in the form of flakes;
[0062] about 0.1-10%, preferably 0.1-5% by weight unsaturated
fat;
[0063] 0.01-25% by weight low calorie sweetener, e.g. isomalt,
sorbitol, xylitol, saccharin, or the like, preferably isomalt.
[0064] Preferably the heat treated flakes have a size in the
interval of 0.5 to 1.0 mm and the unsaturated fat is olive oil. The
composition may further contain optional additives, such as
additives giving the final product its colour and taste.
[0065] The heat treated starch may be added in the form of baked
flakes, which give the product a crispy texture and a pleasant
taste. Flakes suitable for this purpose are made of a mixture of
cornstarch, water, sodium chloride and sweetener. The flakes are
heated above gelatinisation temperature and subsequently dried at
about 90.degree. C. The dried flakes are milled and sieved. Flakes
in the interval of about 0.5-1.0 mm are then mixed with the
granulated and at least partially encapsulated cornstarch.
[0066] Preferably the substance which encapsulates the starch is
chosen among non-toxic substances, suitable for ingestion, such as
substances generally recognised as safe (GRAS) and approved for use
in pharmaceutical applications and/or in food products. A
non-exclusive list of suitable substances includes polymers such as
gum arabicum, potassium alginate, guar gum, methyl cellulose, ethyl
cellulose; liquid oils, liquid and hard fats and waxes, such as
paraffin, hydrogenated cottonseed oil, beeswax, and camauba wax.
Preferably the substance is chosen among guar gum and ethyl
cellulose, most preferably ethyl cellulose.
[0067] According to a preferred embodiment, an organic acid is
added to the inventive composition. The organic acid is preferably
one of ascorbic acid, tartaric or citric acid. The inventive
composition may further comprise minor amounts of technical
additives, such as conventional tabletting agents, lubricants and
glidants.
[0068] The present invention discloses a method for production of a
composition for the controlled delayed degradation of starch,
wherein the method comprises the following steps
[0069] granulation and at least partial encapsulation of native
cornstarch in a substance which delays the degradation,
[0070] wet sieving and drying of the encapsulated granules,
[0071] adding a low calorie sweetener and an organic acid, and
[0072] pressing the mixture into tablets.
[0073] As one embodiment, the present invention further discloses a
method for production of a composition for the delayed degradation
of starch, wherein the method comprises the following steps
[0074] granulation and at least partial encapsulation of native
cornstarch in a substance which delays the degradation,
[0075] wet sieving and drying of the encapsulated granules,
[0076] mixing the granules with heat treated flakes of
cornstarch,
[0077] adding a low calorie sweetener, an organic acid and
unsaturated fat to the mixture, and
[0078] pressing the mixture into tablets.
[0079] The tablets are then packaged according to conventional
methods, in a package suitable for storage, delivery and sale.
Optionally, the granulate is not pressed into tablets but weighed
and packaged according to conventional methods, in a package
suitable for storage, delivery and sale.
[0080] The substance which delays the degradation is chosen among
non-toxic substances, suitable for ingestion, such as substances
generally recognised as safe (GRAS) and approved for use in
pharmaceutical applications and/or in food products. A
non-exclusive list of suitable substances includes polymers such as
gum arabicum, potassium alginate, guar gum, methyl cellulose, ethyl
cellulose; liquid oils, liquid and hard fats and waxes, such as
paraffin, hydrogenated cottonseed oil, beeswax, and carnauba wax.
Preferably the substance is chosen among guar gum and ethyl
cellulose, most preferably ethyl cellulose. The heat treated starch
may be added in the form of baked flakes, which give the product a
crispy texture and a pleasant taste. Flakes suitable for this
purpose are made of a mixture of cornstarch, water, sodium chloride
and sweetener. The flakes are heated above gelatinisation
temperature and subsequently dried at about 90.degree. C. The dried
flakes are milled and sieved. Flakes in the interval of about
0.5-1.0 mm are then mixed with the granulated and at least
partially encapsulated cornstarch before tablet pressing.
[0081] According to a preferred embodiment, an organic acid is
added to the mixture before tablet pressing, the organic acid being
chosen among ascorbic acid, tartaric acid and citric acid,
preferably tartaric acid. An organic acid has the additional
advantage of stimulating the secretion of saliva. This is
especially advantageous as pure starch and products with a high
starch content have a dry and chalky or sandy mouth feel and bland
or even disagreeable taste.
[0082] The product according to the present invention is delivered
in the form of a granulate, or preferably in the form of pressed
cakes or tablets. The pressed cakes or tablets are preferably
produced with grooves or notches for easy division into even sized
fractions. According to one embodiment of the invention, a
saturated or preferably unsaturated fat is added to the granulate
before tablet pressing. Preferably an unsaturated fat is used, and
most preferably olive oil, added in about 0.1-5% by weight for
tabletted products, and 0.1-10% by weight for granulates.
[0083] According to one embodiment of the invention a low calorie
sweetener is added, and preferably saccharin, isomalt or xylitol is
used as the sweetener. Xylitol imparts a cooling sensation because
of its endothermic dissolution.
[0084] A specific advantage of the method and composition of the
present invention is that practically all of the starch, contained
in the ingested dose, is converted to reducing sugars, mainly
glucose. Thus the amount of glucose can be accurately calculated
and the dose optimised for each patient, e.g. by producing tablets
of different size or by ordinating the patient to take a prescribed
number of tablets. Further, a minimum of surplus calories are
administered to the patient.
[0085] A particular advantage of the present composition and method
is that the release rate and the content of reducing sugars can be
accurately controlled and adjusted to the needs of the specific
patient group, specific application or medical situation, and
adjusted to the metabolism of the patient or patient. A method and
product according to the invention makes possible an exact and
reliable dosage and ease of use.
[0086] Another advantage of the composition according to the
present invention is that undigested starch is prevented from
reaching the colon, where it would be digested by bacteria,
resulting in the formation of gas, especially in the colon.
[0087] Another advantage is that--for the first time known to the
inventors--a substantially pure starch composition has been
formulated as a product with agreeable taste and mouthfeel. As
touched upon above, the sensory qualities of a medical product have
importance for compliance.
EXAMPLES
[0088] In Vitro Degradation Tests
[0089] The tested formulations were prepared using a high shear
mixer (Donsmark QMM-II) and tablets pressed with a hydraulic single
press (Compac DP6-B2) or with a rotary tablet press (Korsch
Pharmapress PH-106). All formulations were based on native
cornstarch (Maizena, Bestfoods Nordic AB). Cornstarch and different
excipients were dry mixed in a granulator and agglomerated with
water or ethanol as granulation fluid, depending on the solubility
of the granulation substance used. The dry granulate was pressed
into tablets. In order to study the enzymatic degradation of starch
in vitro, a novel analytical method was developed, and is the
object of co-pending application PCT/SEQ1/02298. According to this
method, the degradation resistance of starch by the action of
.alpha.-amylase is measured as the concentration free sugar in a
starch suspension incubated at 37.degree. C. after the addition of
enzyme. Samples are taken at regular intervals and the reducing
sugars, e.g. glucose and maltose, are reacted with a reagent
consisting of a filtered 3,5-dinitro salicylate solution in aqueous
NaOH. The formed colour is determined spectrophotometrically by
scanning over the wave length interval of 450-500 nm, detecting the
absorption maximum. Enzymatic degradation is then plotted as sugar
concentration as a function of the incubation time.
Example 1
Cornstarch Granulated with Potassium Alginate (10%) Compared to
Free Cornstarch
[0090] Method of production: Native cornstarch (Maizena, Bestfoods
Nordic AB) was mixed in a high shear mixer with potassium alginate
(10% by weight, Food grade, Danisco) and water added as granulation
fluid. The granules were wet sieved through a 1 mm sieve and dried
in a forced hot air oven (Fermaks) at 35-40.degree. C. The dried
granulate was sieved through a 1 mm sieve and collected on a 0.5 mm
sieve. A small amount of fat was added [5, 8 and 10% olive oil
(food grade, Zeta), or 5, 10 and 20% Akosupp 10 (Karlshamns AB)].
The granulate and/or tablets were tested in vitro according to the
method described below, and in vivo according to the method
described further below, in connection with the in vivo tests.
[0091] Method of analysis: A reagent was made by dissolving
3,5-dinitro salicylate (2.00 g, Aldrich) in aqueous NaOH (70 ml, 1
M). Optionally, the mixture is heated in order to expedite the
formation of a clear solution. Upon cooling, water is added to 100
ml. The reagent solution is stored in a dark place and filtered
through a 0.45 .mu.m filter before use, in order to remove possible
precipitates.
[0092] The reagent solution was added in equal amounts (2 ml) in
test tubes marked "control", " zero", "5 min", "10 min", "20 min",
"30 min", "45 min", "1 h", "1.5 h", "2 h", "2.5 h", "3 h", "3.5 h",
and "4 h". The test tubes were placed in an ice bath awaiting the
analysis. A buffer solution (pH 6.6) was made by mixing
KH.sub.2PO.sub.4 (250.0 ml, 0.20 M, Sigma) and NaOH (89.0 ml, 0.20
M) and adding water to a total volume of 1000 ml. NaCl (0.58 g,
Riedel-de Han) was then added to produce a chloride concentration
of 0.01 M.
[0093] A defined amount of starch to be investigated is suspended
in the above buffer and placed in the degradation bath. The
degradation bath is kept at a temperature of 37.degree.
C..+-.0.5.degree. C. and stirred at a speed of 50 rpm.
[0094] An amount corresponding to 15 000 IU .alpha.-amylase (Type
VI-B from porcine pancreas, Sigma) is measured and suspended in
buffer. Before addition of the enzyme solution, a sample of the
degradation bath is taken in order to determine the sugar
concentration at "time zero". The sample is filtered through a 0.8
.mu.m filter and an aliquot (2 ml) is pipetted to the test tube
marked "zero". The same filter can be used throughout the series.
The sample is boiled momentary (5 min) and placed in an ice-bath.
Following this, the enzyme solution is added to the degradation
bath and the time registered. Samples are then taken at
predetermined intervals, such as the times indicated on the test
tubes. The control is prepared by boiling reagent (2 ml) and water
(2 ml) during 5 min and placing the sample in an ice-bath.
[0095] For each sample, the absorption is scanned in the interval
450-500 nm and the peak height registered for each absorption
maximum. In order to determine the concentration free sugars (FS0)
in the native starch, the absorbance of the sample "zero" is
measured against a background of water and reagent, the control
sample. Both samples and control are diluted by adding 11.6 ml
water to 400 .mu.l sample. The reacted and diluted sample solution
is not stable (the reading falling 0.1 to 0.2 absorbancy units
during 3 hours) so all samples are diluted slightly prior to the
UV-spectrophotometric analysis.
Example 2
Cornstarch Granulated with Potassium Alginate (20%) Compared to
Free Cornstarch
[0096] Native cornstarch was granulated with 20% by weight
potassium alginate and analysed as described in Example 1.
Example 3
Cornstarch Granulated with Guar Gum (20%) Compared to Free
Cornstarch
[0097] Native cornstarch was granulated with 20% by weight guar gum
(Scanpharm A/S) and analysed as described in Example 1.
Example 4
Cornstarch Granulated with Ethyl Cellulose Compared to Free
Cornstarch
[0098] Native cornstarch was granulated with 18% by weight ethyl
cellulose (Dow Chemical Co.) and analysed as described in Example
1.
[0099] The results of the in vitro degradation tests are shown in
FIG. 1, where the values for cornstarch encapsulated in ethyl
cellulose (10%) are marked with the symbol (O), cornstarch
encapsulated in ethyl cellulose (20%) with (I), cornstarch
encapsulated in guar gum (20%) being marked with (9) and the values
for untreated cornstarch being marked (6).
[0100] In Vivo Tests
[0101] The blood glucose response was measured by the standard
technique in 4 healthy, lean volunteers (age 35 to 45 years) with
normal glucose tolerance. According to the "golden standard" of
this technique, each substance was studied twice in each volunteer,
and the mean value was calculated. The substances were tested in
randomised order, at least one day apart. Moreover, the testing was
performed under strictly standardised conditions. The subjects came
to the laboratory in the morning, fasted for 10 hours. Physical
activity was avoided right before and during the test. The test
subjects were allowed to drink about 2 dl liquid, free from
carbohydrates (water, tea or coffee) twice during the test; at 0
and 3 hours.
[0102] The capillary blood glucose level was determined in
capillary blood samples (obtained by finger pricking) using a
Glucometer DEX (Bayer Diagnostica AB) following the standard
procedures for glucose measurements. At baseline, three consecutive
blood glucose determinations were performed to ensure a stable
baseline at time 0 hours. Thereafter the test substance (20.0 g)
was ingested together with a standardised amount of water within 5
minutes. All liquids were carefully weighed and the same amounts
ingested at each occasion to avoid variations in transit time
through the gastrointestinal tract. The blood glucose determination
was repeated at 0.5, 1.0, 1.5, 2.0, 3.0, and 4.0 hours. The average
results for the test subjects are shown in FIG. 2. The
correspondence between rates of digestion as measured by in vivo (4
h blood glucose response, ((mmol/l min)*100) and in vitro (as
described in Example 1) techniques is shown in FIG. 3.
Example 5
In Vivo Effect of Cornstarch Granulated with Ethyl Cellulose
(10%)
[0103] The test subjects measured their initial blood glucose after
10 hours of fasting, whereupon they ingested an exactly measured
amount of a formulation of cornstarch granulated with and partially
encapsulated in ethyl cellulose (10%), manufactured according to
the method presented in Example 1 above. Blood glucose was then
measured at 0.5, 1.0, 1.5, 2.0, 3.0, and 4.0 hours. The average
result for all test subjects are presented in FIG. 2, the values
for cornstarch encapsulated in ethyl cellulose (10%) being marked
with (O).
Example 6
In Vivo Effect of Cornstarch Granulated with Ethyl Cellulose
(20%)
[0104] The test subjects measured their initial blood glucose after
10 hours of fasting, whereupon they ingested an exactly measured
amount of a formulation of cornstarch encapsulated in ethyl
cellulose (20%), manufactured according to the method presented in
Example 1 above. Blood glucose was then measured at 0.5, 1.0, 1.5,
2.0, 3.0, and 4.0 hours. The average result for all test subjects
are presented in FIG. 2, the values for cornstarch encapsulated in
ethyl cellulose (20%) being marked with (.DELTA.).
Example 7
In Vivo Effect of Cornstarch Granulated with Guar Gum (20%)
[0105] The test subjects measured their initial blood glucose after
10 hours of fasting, whereupon they ingested a formulation of
cornstarch encapsulated in guar gum (20%) manufactured according to
the method presented in Example 1 above. Blood glucose was then
measured at 0.5, 1.0, 1.5, 2.0, 3.0 and 4.0 hours. The average
result for all test subjects are presented in FIG. 2, the values
for cornstarch encapsulated in guar gum (20%) being marked with
(9).
Example 8
In Vivo Effect of Untreated Cornstarch
[0106] The test subjects measured their initial blood glucose after
10 hours of fasting, whereupon they ingested native, untreated
cornstarch (Maizena, Bestfoods Nordic AB). Blood glucose was then
measured at 0.5, 1.0, 1.5, 2.0, 3.0, and 4.0 hours. The average
result for all test subjects are presented in FIG. 2, the values
for untreated cornstarch being marked (6). The in vivo results
clearly show that a marked effect is achieved with the formulations
according to the invention, compared to untreated cornstarch. Most
notably, the initial glucose peak appearing at 0.5, 1.0 and 1.5
hours after ingestion of untreated cornstarch, is entirely absent
for the guar gum encapsulated cornstarch.
[0107] Clinical Trials
Example 10: Comparative Tests Performed with Diabetic Patients
[0108] Study design: The 16 patients in the study will receive the
inventive composition in tablet form (MM005) in different single
doses, 5, 10 and 20 g, respectively, at three different occasions
and the control (excipients only) at one occasion.
[0109] Establishment of baseline (control occasion): The subjects
come to the laboratory in the morning in the fasting state and
without having taken their regular morning insulin dose.
[0110] With the help of a slow i.v. infusion of insulin, combined
with a glucose infusion, the blood glucose level will be stabilised
at 5.5 to 6.5 mmoles/l. The insulin will be administrated by an
infusion rate, aiming at giving a blood insulin concentration of
15-20 mU/l. The glucose concentration will be locked by customary
clamp technique, where blood sugar is measured every 5.sup.th
minute for 1 hour and the glucose infusion rate is adjusted if
necessary to give the desired blood glucose concentration.
Thereafter the control medication is given and the glucose clamp
continued for 6 hours. The amount of glucose administrated during
each hour will be used at the three subsequent test occasions. The
objective is to establish a reference baseline for evaluation of
doses.
[0111] Dose testing: The sequence of the subsequent three test
occasions, i.e. for the three different doses of the
investigational drug, will be randomised. At least one week should
pass between test occasions. Every test day will be started by
glucose and insulin infusion for 1 hour as described above.
Thereafter the investigational drug is administrated orally as a
single dose and the glucose infusion is continued so that the
amount of given glucose during each hour corresponds to the amount
given on day 1 (control occasion). During the three test days blood
samples are withdrawn every 10.sup.th minute during the first 6
hours of the experiment for glucose determination, and also every
60.sup.th minute for insulin determination. The subject will be
asked to return within 1-4 weeks for a new test.
[0112] Dose: The doses are 5 g, 10 g, and 20 g cornstarch, i.e. 3,
6 and 12 tablets. The dose is taken once a day, in the morning, as
a single dose.
[0113] Drug administration: The formulated cornstarch is
administrated orally as chewing tablets formulated according to the
invention, together with 250 ml of water.
[0114] Discussion of Study Design: The aim of this study is to
evaluate the increase in glucose levels following intake of three
cornstarch doses (5, 10, 20 g) as well as the kinetic profile
compared to a control period with inactive medication (excipients
only).
[0115] This is important since the medication is to be used to
prevent hypoglycemia, in particular nocturnal hypoglycemia. This
usually occurs at between 02 and 04 in the morning.
[0116] There is currently no medication available with an
appropriate kinetic profile to counteract an excessive effect of
the night-time intermediate-acting insulin. Thus, diabetic subjects
usually ingest food when they have measured low glucose levels at
bedtime. However, very high early night-time glucose levels are
necessary to provide a sufficient "buffer" at 02-04 o'clock in the
morning. Thus, a medication which provides such an effect should be
an important therapy in diabetes.
[0117] The doses chosen are within the range calculated to be
required to counteract the effect of an excessive nocturnal insulin
dose.
[0118] The use of a control medication (excipients only) provides a
background which makes it possible to evaluate the
glucose-releasing property of the active medication. The number of
subjects included in the study has been calculated to give enough
power to safely evaluate the glucose-releasing profile.
[0119] The subjects should not have any clinically significant
manifestations of the specific diabetic microvascular
disorders.
[0120] The subjects will be given glucose if the blood glucose
levels drop below 3.5 mM, and the test will be discontinued on that
day.
[0121] The first data available from the clinical studies show that
the inventive composition is capable of stabilising the blood
glucose over a period of at least 6 hours, and that the enzymatic
degradation of starch/conversion into glucose exhibits a
substantially linear behaviour.
[0122] In FIG. 4, the glucose contribution of a light meal (.nu.),
is compared to that of native cornstarch (.diamond-solid.). The
benefits of native cornstarch are clearly visible from the diagram.
The native cornstarch formulation totally lacks the initial glucose
peak, and gives a steady contribution still after 8 hours, with the
trend of the curve indicating a considerably longer effect than for
that accountable to a light meal.
[0123] See also FIG. 5 which shows the glucose curve of a diabetic
patient having eaten the inventive composition (.DELTA.), compared
to control, excipients only (O). The results display a pronounced
effect of the inventive composition still after 6 hours, the trend
of the curve indicating that the effect most probably lasts even
longer. These tests were performed after the priority date, but
before the international filing date.
[0124] In organoleptic tests, the test subjects described the
formulations according to the present invention as "tasty",
"crispy" and "easy to swallow".
[0125] Although the invention has been described with regard to its
preferred embodiments, which constitute the best mode presently
known to the inventors, it should be understood that various
changes and modifications as would be obvious to one having the
ordinary skill in this art may be made without departing from the
scope of the invention as set forth in the claims appended
hereto.
* * * * *