Use of carbohydrate-containing compositions in tablet form for treatment of hypoglycemic states

Abstract

The invention relates to the use of specific carbohydrate-containing compositions, in particular in tablet form, for production of agents for treatment of hypoglycemia, in particular nocturnal hypoglycemia. The compositions are easy to dose and do not leave a sweet taste in the mouth, but do release the carbohydrates present rapidly in the stomach and are therefore particularly suitable for treatment of in particular nocturnal hypoglycemia.

Description

[0001] Use of carbohydrate-containing compositions in tablet form for the treatment of hypoglycaemia

[0002] The invention relates to the use of special carbohydrate-containing compositions, in particular in tablet form, for the production of agents for the treatment of forms of hypoglycaemia, in particular nocturnal hypoglycaemia.

[0003] Diabetes mellitus is a metabolic disorder that affects the metabolism of carbohydrates. It is primarily caused by a lack of insulin and can lead to chronic hyperglycemia, which can cause numerous complications.

[0004] In the body's digestive system, the carbohydrates ingested with food are broken down into glucose, which is transferred through the intestinal wall into the blood and distributed throughout the body. The body's own hormone insulin causes the glucose contained in the blood to enter the cells, where it is used to generate energy. The insulin required for this is produced primarily in the pancreas. If the body produces no or insufficient insulin, glucose cannot be transported into the body's cells and therefore remains in the blood. To avoid the consequences of excessively high blood sugar levels, diabetes mellitus is usually treated with insulin. This presents the problem of dosing the correct amount of insulin, i.e., adjusting it to the amount of carbohydrate. If too little insulin is administered, too much glucose remains in the blood. If the insulin dosage is too high, this can lead to low blood sugar (hypoglycemia).Such hypoglycemia is a serious disorder that can be fatal in the worst case.

[0005] People suffering from diabetes therefore often carry carbohydrate-containing foods with them so that they can quickly ingest carbohydrates in the event of hypoglycemia. Commonly used remedies are glucose tablets, fruit juices, or bread. Hypoglycemia can also occur at night. In the event of hypoglycemia, people suffering from diabetes wake up at night, for example, with sweating or are awakened by warning devices. This can happen, for example, if the person in question has eaten a meal in the evening or at night whose exact carbohydrate content is unknown. The person is then dependent on estimating the carbohydrate content in order to then administer the appropriate amount of insulin. If the amount of carbohydrate is overestimated, the aforementioned hypoglycemia can occur after insulin administration.

[0006] Affected individuals often find it unpleasant, especially at night, to eat glucose tablets, (sweet) fruit juices, or bread to compensate for hypoglycemia. To compensate for the sweet taste in the mouth, they would have to get up at night and, for example, brush their teeth again. The challenge, therefore, is to provide a composition capable of specifically raising blood sugar levels in the event of hypoglycemia, which is easy to dose, yet at the same time does not leave an unpleasant sweet taste in the mouth, allowing affected individuals to continue sleeping. This task is solved by using the compositions described below.

[0007] The following publications are known from the state of the art:

[0008] Document US2014 / 0180224 A1 describes compositions for the treatment of nocturnal hypoglycemia. However, these compositions are described as "delayed and sustained release compositions." The compositions are intended to be taken before bedtime and ensure a steady supply of carbohydrates throughout the night. Treatment of acute nocturnal hypoglycemia is not possible due to the delayed release.

[0009] Document CN 115226896 describes other sustained release formulations of various carbohydrates that are also not suitable for the treatment of acute nocturnal hypoglycemia.

[0010] Document DE 2246013 A describes a process for producing porous, carbohydrate-containing tablets intended to solve various manufacturing problems of tablet formulations. Nocturnal hypoglycemia treatment is not mentioned here.

[0011] Document WO20157148742 A1 describes compositions for producing cell cultures. These compositions are said to contain carbohydrates and are described as sustained-release compositions. Use for the treatment of nocturnal hypoglycemia is not mentioned here.

[0012] Document CN 105963266 A describes glucose tablets that are also intended to be suitable for the treatment of hypoglycemia. Due to their composition, the tablets dissolve in the mouth and produce a sweet taste.

[0013] The present invention relates to the use of carbohydrate-containing compositions, in particular in tablet form, which release the carbohydrates contained only in the gastrointestinal tract, for the treatment of hypoglycaemia, in particular nocturnal hypoglycaemia.

[0014] These compositions initially contain one or more saccharides as carbohydrates, such as dextrose, lactose, maltose, trehalose, sucrose, or mixtures thereof. A well-known carbohydrate mixture is, for example, maltodextrin. Some carbohydrates occur in various hydrate forms, meaning they contain different amounts of water of crystallization. Dextrose, for example, is available as a monohydrate, but also as anhydrous anhydrate. Typically, all available stable hydrate forms can be used to produce the preparations according to the invention.

[0015] The advantage of dextrose is that it acts quickly, whereas other carbohydrates have a delayed onset of action but can potentially produce a longer-lasting effect. Blends of different carbohydrates can produce a rapid initial effect, which can be prolonged by adding more complex carbohydrates.

[0016] For the aforementioned purpose, the composition consists predominantly, i.e., more than 70%, of the saccharide or saccharide mixture. In addition, only conventional agents to improve processability or dissolution properties, such as stearates or cellulose, are added. The saccharide content is up to 95%, typically approximately 80%. The most preferred saccharide according to the invention is dextrose, especially as dextrose monohydrate.

[0017] The composition is first pressed into pellet-shaped tablet cores. The individual tablet cores have diameters between 4 and 10 mm, preferably between 6 and 8 mm, and can have the usual shapes for such compositions, such as spherical, biconvex, faceted, or convex. It goes without saying that, for the purpose of ingestion, they should not have any sharp edges; otherwise, the shape is virtually arbitrary.

[0018] According to the invention, the preformed tablet cores are coated with a tasteless coating that ensures that the tablets do not dissolve in the mouth, but that the saccharides they contain are only released in the stomach. Furthermore, the coating improves the swallowability of the tablets. Such coatings are known in principle. They are usually based on starch and modified cellulose. The decisive factor for the coating is that it does not dissolve in the mouth, but rather quickly releases the tablet core in the stomach. The following substance classes are preferably used for the coating according to the invention:

[0019] • Cellulose and cellulose derivatives, in particular carboxymethylcellulose, hydroxypropylmethylcellulose phthalate, methylcellulose, hydroxypropylmethylcellulose (hypromellose) and / or hydroxypropylcellulose

[0020] • Methacrylic acid copolymers and methacrylic acid esters

[0021] • Polyvinylpyrrolidone (PVP) and derivatives

[0022] • Polyvidone acetate

[0023] • Polyvinyl acetate phthalate

[0024] The most preferred coating agent is hydroxypropylmethylcellulose (hypromellose). The coatings may also contain colorants. Food colorings such as carotenoids (E 160a), berry colorants (anthocyanins, E 163), beetroot colorants (betanin, E 162), carmine (E 120), paprika extract (E 160c), and curcumin (E 100) are preferred. Particularly preferred are strongly coloring plant or fruit extracts such as beetroot, spinach, or elderberry juice, and spices such as saffron and turmeric.

[0025] For practical reasons, the tablet cores are preferably coated in a single step, resulting in modified film-coated tablets (coated tablets). Alternatively, the classic coating with multiple layers is also possible.

[0026] The tablets resulting from the coating of the tablet cores typically have a diameter between 4 and 10 mm and a mass between 50 and 500 mg. Preferably, the individual tablets have a diameter of 7 to 8 mm and a mass of 210 to 270 mg.

[0027] A person suffering from hypoglycemia can dose the composition according to the invention in tablet form using simple dosing devices, for example, a dosing spoon. The spoon can be designed so that a total number of tablets is taken up at a time, corresponding to a specific amount of carbohydrate, for example, one carbohydrate unit, the typical calculation unit for diabetics. As needed, one or more carbohydrate units can then be taken from a storage container and taken orally. A sip of water can be helpful in swallowing the tablets completely. As already described above, the tablets do not release any carbohydrates in the mouth within approximately 15 seconds, thus avoiding their sweet taste. The tablets only dissolve in the stomach and there quickly release the saccharides they contain, which then combat hypoglycemia by raising the blood sugar level.Within one minute of swallowing, more than 80% of the carbohydrate content of the tablets is released on an empty stomach. This avoids the otherwise typical sweet taste of carbohydrate-containing products. At the same time, the need for subsequent tooth brushing for the purpose of caries prevention is eliminated. In the event of nocturnal hypoglycemia, the affected person can then immediately return to sleep.

[0028] The properties of the tablets described also allow their use in hypoglycemia states not related to diabetes, such as in endurance sports. For example, marathon runners may experience what is known as "hunger fever," which is a form of hypoglycemia not related to diabetes. Another form of non-diabetic hypoglycemia can occur when people have not eaten for a long time or have eaten only a very low-carbohydrate diet ("fasting hypoglycemia"). Taking the tablets described in a controlled manner can also overcome such hypoglycemia states.

[0029] A particular advantage of the tablets described is that, when taken as directed, hypoglycemia can be treated without the risk of triggering sugar addiction. Experts believe that such sugar addiction is promoted by the association of sweet taste with the immediate subsequent rise in blood sugar, as occurs when consuming common sweets (e.g., chocolate bars, gummy bears). Due to the absence of the sweet taste in the mouth, the brain's reward system is apparently not activated, thus preventing addictive effects.

[0030] Examples

[0031] The following examples further illustrate the invention without intending to be limiting. Those skilled in the art can develop further embodiments of the invention based on the examples without having to engage in inventive activity.

[0032] Example 1

[0033] Tablet core:

[0034] To produce the tablet cores, the components listed above are mixed and pressed into tablet cores. The coating is then applied with the composition specified below.

[0035] Coating: Biogrund AquaPolish F pink 040.344 or AquaPolish F pink 044.419

[0036] After drying, the tablets can be packaged.

[0037] Product description:

[0038] Tablet size: 7 or 8 mm tablet cores (curved)

[0039] Tablet core mass: 238 mg

[0040] Tablet mass (with 247 mg

[0041] Coating) Example 2

[0042] Tablet core:

[0043] To produce the tablet cores, the components listed above are mixed and

[0044] Tablet cores are pressed. The coating then follows, using the composition specified below.

[0045] Coating: Biogrund AquaPolish F pink 040.344 or AquaPolish F pink 044.419

[0046] After drying, the tablets can be packaged.

[0047] Product description:

[0048] Tablet size: 7 or 8 mm tablet cores (curved)

[0049] Tablet core mass: 238 mg

[0050] Tablet mass (with 247 mg

[0051] Coating)

[0052] Example 3a

[0053] Tablet core:

[0054] To produce the tablet cores, the components listed above are mixed and

[0055] Tablet cores are pressed. The coating then follows, using the composition specified below.

[0056] Coating: Biogrund AquaPolish F pink 040.344 or AquaPolish F pink 044.419

[0057] After drying, the tablets can be packaged.

[0058] Product description:

[0059] Tablet size: 7 or 8 mm tablet cores (curved)

[0060] Tablet core mass: 238 mg

[0061] Tablet mass (with 247 mg

[0062] Coating)

[0063] Example 3b

[0064] Dragee core:

[0065] To produce the coated cores, the components listed above are mixed and pressed into coated cores. The coating is then applied using the composition specified below.

[0066] Coating: Biogrund Aquapolish F green 074.133 MS

[0067] Pantone 7425

[0068] After drying, the dragees can be packaged.

[0069] Product description:

[0070] Dragee size: 7 or 8 mm dragee cores (curved)

[0071] Coated tablet core mass: 238 mg

[0072] Dragee mass (with coating) 247 mg

[0073] Example 3c

[0074] Dragee core:

[0075] To produce the coated cores, the components listed above are mixed and pressed into coated cores. The coating is then applied using the composition specified below.

[0076] Coating: Biogrund Aquapolish F green 074.133 MS or AquaPolish F pink 044.419

[0077] After drying, the dragees can be packaged.

[0078] Product description:

[0079] Dragee size: 7 or 8 mm dragee cores (curved)

[0080] Coated tablet core mass: 238 mg

[0081] Dragee mass (with coating) 247 mg

[0082] Example 4

[0083] Tablet core:

[0084] To produce the tablet cores, the components listed above are mixed and pressed into tablet cores. The coating is then applied with the composition specified below.

[0085] Coating: Biogrund AquaPolish F pink 040.344

[0086] After drying, the tablets can be packaged.

[0087] Product description:

[0088] Tablet size: 7 or 8 mm tablet cores (curved)

[0089] Tablet core mass: 238 mg

[0090] Tablet mass (with 247 mg

[0091] Coating)

[0092] Example 5

[0093] Tablet core:

[0094] To produce the tablet cores, the components listed above are mixed and pressed into tablet cores. The coating is then applied with the composition specified below.

[0095] Coating: Biogrund AquaPolish F pink 040.344

[0096] After drying, the tablets can be packaged.

[0097] Product description:

[0098] Tablet size: 7 or 8 mm tablet cores (curved)

[0099] Tablet core mass: 238 mg

[0100] Tablet mass (with 247 mg

[0101] Coating)

[0102] Example 6a

[0103] Tablet core:

[0104] To produce the tablet cores, the components listed above are mixed and

[0105] Tablet cores pressed with a diameter of 6 mm. Example 6b

[0106] The tablet cores produced according to Example 6a will be coated with a coating having the composition given below.

[0107] Coating: Biogrund Aquapolish F green 074.133 After drying, the tablets can be packaged.

[0108] Product description:

[0109] Tablet size: Approx. 7 mm tablet cores (curved)

[0110] Tablet core mass: 117 mg

[0111] Tablet mass (with 124 mg

[0112] Coating)

[0113] Example 7: Sweet Presence Binary Test to evaluate the sweetness of tablets

[0114] The question of whether a carbohydrate-containing composition produces a sweet taste in the mouth when used according to the invention can be tested by the Sweet Presence Binary Test described below.

[0115] Objective: To determine whether a tablet tastes sweet immediately after remaining in the mouth for 15 seconds.

[0116] Applicability: This protocol is applicable to all types of tablets intended for oral administration that are not intended to be sucked but swallowed directly.

[0117] Materials:

[0118] - Test tablets (product to be tested)

[0119] - Water to rinse the mouth between tests

[0120] Subjects:

[0121] - At least 20 test persons (not sensory trained), preferably about 100 people

[0122] - Age between 18 and 65 years

[0123] - No known taste impairment

[0124] Method: a. Preparation:

[0125] - The test subjects are informed about the purpose of the test and give their consent to participate.

[0126] - Each test subject is instructed not to consume spicy or sweet foods before the test. b. Procedure:

[0127] - Each test subject receives a specific number of test tablets, corresponding to the usual dosage for the product being tested. - The test subjects hold the tablets in their mouths for 15 seconds before swallowing them.

[0128] - Immediately after swallowing, the test subjects indicate whether or not they perceived any sweetness during the time in the mouth. c. Documentation:

[0129] - The answers are recorded in a standardized form which includes:

[0130] - Test person ID

[0131] - Answer to the question whether test tablets lead to a sweet taste during the time in the mouth, (Yes / No) d. Evaluation:

[0132] - The data will be statistically evaluated to determine whether a significant number of testers perceived sweetness in the test tablets during the time in the mouth. e. Reporting:

[0133] - The results are summarized in a final report containing the following information:

[0134] - Number of test subjects who perceived sweetness in the test tablets during the time in the mouth

[0135] - Statistical analysis of the results

[0136] - Conclusions regarding the sweetness of the tested tablets f. Safety and ethical considerations:

[0137] - All test subjects are informed about possible risks and give their written consent.

[0138] - The test will be conducted under supervision to ensure compliance with protocols and provide support if needed. g. Results

[0139] When conducting the Sweet Presence Binary Test for the compositions of Examples 1-6, more than 90% of the test subjects, and in the case of Examples 2 (n=100) and 3 (n=50) even more than 95% of the test subjects, stated that they had not perceived any sweet taste.

Claims

Claims:

1. Composition in tablet form, consisting of Tablet cores containing 70-95% dextrose, lactose, maltose, trehalose, sucrose, maltodextrin or mixtures thereof together with customary agents to improve processability or dissolution properties, as well as a Tablet coating selected from the following substance classes a) cellulose and cellulose derivatives, in particular carboxymethylcellulose, hydroxypropylmethylcellulose phthalate, methylcellulose, hydroxypropylmethylcellulose (hypromellose) and / or hydroxypropylcellulose, b) methacrylic acid copolymers and methacrylic acid esters c) polyvinylpyrrolidone (PVP) and derivatives d) polyvidone acetate e) polyvinyl acetate phthalate, wherein the tablets produced from the tablet cores by the coating have a diameter of between 4 and 10 mm and a mass of between 50 and 500 mg, characterized in that the tablets do not release any carbohydrates in the mouth within 15 seconds and that the tablets release more than 80% of the carbohydrates they contain within one minute after swallowing in the stomach.

2. Composition in tablet form according to claim 1, wherein the individual tablets have a diameter of 7 to 8 mm and a mass of 210 to 270 mg.

3. Composition in tablet form according to claim 1 or 2, wherein the tablet cores contain approximately 80% dextrose, lactose, maltose, trehalose, sucrose, maltodextrin or mixtures thereof.

4. A composition in tablet form according to claim 1 or 2, wherein the tablet cores contain maltodextrin.

5. A composition in tablet form according to any one of claims 1 to 4, wherein the tablet coating essentially contains hydroxypropylmethylcellulose.

6. Use of a composition in tablet form for the manufacture of an agent for the treatment of hypoglycemic conditions, the composition consisting of tablet cores containing 70-95% dextrose, lactose, maltose, trehalose, sucrose, maltodextrin or mixtures thereof together with customary agents for improving the processability or dissolution properties, as well as a Tablet coating selected from the following substance classes a) cellulose and cellulose derivatives, in particular carboxymethylcellulose, hydroxypropylmethylcellulose phthalate, methylcellulose, hydroxypropylmethylcellulose (hypromellose) and / or hydroxypropylcellulose, b) methacrylic acid copolymers and methacrylic acid esters c) polyvinylpyrrolidone (PVP) and derivatives d) polyvidone acetate e) polyvinyl acetate phthalate, wherein the tablets resulting from the coating from the tablet cores have a diameter between 4 and 10 mm and a mass between 50 and 500 mg and wherein the tablets do not release any carbohydrates in the mouth within 15 seconds and wherein the tablets release more than 80% of the carbohydrates contained in the stomach within one minute after swallowing.

7. Use of a composition in tablet form according to claim 6, wherein the individual tablets have a diameter of 7 to 8 mm and a mass of 210 to 270 mg.

8. Use of a composition in tablet form according to claim 6 or 7, wherein the tablet cores contain approximately 80% dextrose, lactose, maltose, trehalose, sucrose, maltodextrin or mixtures thereof.

9. Use of a composition in tablet form according to claim 6 or 7, wherein the tablet cores contain maltodextrin.

10. Use of a composition for treating hypoglycemia in tablet form according to any one of claims 6 to 9, wherein the tablet cores contain approximately 80% dextrose. 11.Use of a composition for treating hypoglycaemia in tablet form according to any one of claims 6 to 10, wherein the tablet coating essentially contains hydroxypropylmethylcellulose.

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