RU2359677C2 - Oral tablets with modified release and way of their reception - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention concerns area of medical products, in particular to structure for oral tablets with the modified release, containing fine gliclazide for depression of level of a glucose in blood with defined granulat metric structure, and also the agent modifying liberation, for gliclazide release control; and fine gliclazide for depression of level of a glucose in blood has certain profiles of dissolution in the cleared water. Besides the invention concerns the way of reception of the specified structure.

EFFECT: decrease of level of glucose in the blood during long period of time.

8 cl, 3 dwg, 9 tbl, 8 ex

Description

The scope of the present invention

The present invention relates to modified release oral tablet formulations. In particular, it relates to compositions that contain: a pharmaceutically effective amount of a finely divided active ingredient (particle size up to 1 μm), designed to reduce blood glucose, a modified release agent containing hydrophilic polymers, as well as a method for producing a new composition for oral tablets with a modified release.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a chronic disease with a symptom of hyperglycemia, which is the result of many causes, this disease is always accompanied by retinopathy, glomerulosclerosis, and some neutral or vascular damage to the kidneys. This disease was the fifth leading cause of death in Taiwan, it rose sharply from 0.37 people (for every 10,000 population) in 1960 to 4.1 people in 1999. Diabetes is often divided into type I and type II diabetes; type I diabetes is insulin-dependent (IDDM), it was previously called "juvenile diabetes", acute ketoacidosis easily occurs in patients with this type of diabetes if an insulin injection was not given. Type 2 diabetes, non-insulin dependent diabetes (NIDDM), is often referred to as adult diabetes. The onset of this disease is mainly related to the process of abnormal metabolism (such as insulin resistance and functional defect of β-cells), and therefore patients with non-insulin-dependent diabetes need treatment with oral medications designed to lower blood glucose levels.

In general, orally administered drugs designed to lower blood glucose can be divided into 4 categories: sulfonylureas, biguanides, thiazolidinediones, and α-glucosidase inhibitors. Sulfonylureas are a type of orally administered drug designed to lower blood glucose in adult diabetics, they are mainly prescribed to patients who are not overweight, and whose β-cells still function normally. The mechanism of action of sulfaurea is to stimulate the secretion of insulin by the pancreas, and degranulation of β-cells containing insulin, which leads to the release of insulin. In addition, it is possible to reduce the process of insulin metabolism in the liver, and make the number of insulin receptors increase. Side effects of sulfaurea are rare, mainly - suppression of iodine intake in the thyroid gland, hyperglycemia in case of overdose, nausea, vomiting or itching. In hospitals in Taiwan, second-generation sulfaureas are often prescribed, such as gliclazide, glipizide and glibenclamide. From the point of view of hypoglycemia, biguanides are less dangerous than sulfaurea preparations and therefore they are the best drug for patients with overweight. The therapeutic mechanism of thiazolidinediones is that insulin resistance of muscles and adipose tissue is reduced, and therefore, the synthesis of endogenous glucose is reduced. An α-glucosidase inhibitor serves to suppress the absorption of amylogen and disaccharides by inhibiting α-glucosidase in the villi around the small intestine, therefore, the increase in blood glucose after eating is reduced; however, this medicine is often prescribed in combination with other medicines to lower blood glucose.

As regards treatment tactics, in order to reduce the blood glucose level in diabetic patients, it is highly necessary to use modified-release drugs; this is necessary in order to obtain a stable and consistent therapeutic effect. In particular, diabetics are always obliged to take medicines for a long time to monitor the condition of the disease, and therefore, it is necessary to develop such a medication that would bring the maximum therapeutic effect to those patients who need to continue taking this medicine; at the same time, side effects caused by its administration should be eliminated. The duration of action of the drug is achieved by using drugs with a modified release, since the maintenance of an effective amount of this drug in the blood is prolonged. The result of this is such advantages as a possible reduction in the frequency of administration of the drug, as well as a large degree of similarity in the rate and profile of the release of physical therapy and chronic treatment. In addition, as a means of prolonging the effectiveness of drugs, high dosages are not necessary and therefore the likely side effects and resistance are reduced. For example, finely divided gliclazide can be administered twice daily in an 80 mg dosage, but an active ingredient that is not finely ground may not provide clinically effective treatment because poor solubility prevents the complete release of the drug. US patents No. 6,451,339 and No. 6,537,578 relate to the production of agents that promote controlled release of drugs. The aim of the present invention, in accordance with the above, is the creation of oral tablets intended for diabetics, these tablets have a modified release obtained by controlling the solubility of drugs; as a result, you can get higher safety and effectiveness of these funds.

Summary of the present invention

An object of the present invention relates to a composition of a modified release oral tablet. The specified composition is characterized in that it contains a finely divided active ingredient, designed to reduce blood glucose levels, as well as a modified release agent, designed to control the release of the specified active ingredient.

According to the dissolution test, the dissolution rate of a composition containing a finely divided active ingredient designed to lower blood glucose, as well as a modified release agent, is higher than a composition that contains a finely divided active ingredient and which is designed to lower blood glucose for a period of time.

Another objective of the present invention relates to a method for producing the modified release oral tablet formulation described above. First of all, the active ingredient for reducing blood glucose levels is subjected to fine grinding, in which the particle size is up to 1 micron; in this case, the following particle size dispersion takes place: (1) at least 50% of the particles have a size of ≤5 μm; (2) at least 90% of the particles have a size of ≤15 microns; (3) at least 95% of the particles have a size of ≤25 μm. After that, the ground active ingredient to reduce blood glucose is mixed with a modified release agent, granulated, dried and trimmed. The resulting granulate is tabletted by adding a filler, and tablets are obtained whose hardness is from 4 to 8 kg.

Another objective of the present invention is the provision of a finely divided composition for modified release oral tablets and a method for preparing said composition; moreover, the composition obtained according to the present invention has a higher stability to absorption.

Another objective of the present invention is the fine grinding of the main ingredient, which is carried out to a size of less than 1 micron, using special technology. Due to this, in order to obtain efficacy similar to that achieved by the clinical use of modern therapeutic dosages, a lower dosage of the main ingredient is sufficient.

Brief Description of the Drawings

Figure 1 shows the dissolution profile of the composition of an oral tablet of the present invention containing the active ingredient gliclazide finely ground in purified water, designed to lower blood glucose levels over a period of time.

Figure 2 presents for comparison; the dissolution profile of the composition of an oral tablet containing the finely divided active ingredient gliclazide (indicated by diamonds), designed to reduce blood glucose and the dissolution profile of the composition of the oral tablet containing the finely divided active ingredient (purified by rectangles) in purified water, designed to reduce blood glucose, for a period of time.

Figure 3 presents the change in the blood concentration profile of the composition of the present invention over a period of time.

Detailed Description of Preferred Embodiments of the Present Invention

The present invention relates to a new composition of modified release oral tablets; its ingredients are generally finely divided (particle size up to 1 μm) active ingredient for lowering blood glucose and a modified release agent containing hydrophilic polymers; this achieves the effect of a modified release of the active ingredient in order to reduce blood glucose levels.

The specified active ingredient for lowering blood glucose levels can be any active ingredient used in any drugs to lower blood glucose levels; according to the present invention, sulfonoureas are preferably used as the active ingredient. If necessary, in order to achieve better therapeutic efficacy, two or more active ingredients selected from glycazide, glipizide, glibenclamide, glycidonem, glimepiride, and a combination thereof can be combined. The amount of active ingredient (e.g., glyclazide) in such a composition is preferably 30-60 mg. The specified active ingredient is characterized in that it is subjected to fine grinding (particle size up to 1 μm); preferably, the following particle size distribution takes place: (1) at least 50% of the particles have a size of ≤5 μm; (2) at least 90% of the particles have a size of ≤15 microns; (3) at least 95% of the particles have a size of ≤25 μm.

The modified release agent used in the present invention is preferably selected from the following substances: hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, vinyl acetate copolymers, polyethylene oxides, and combinations thereof. Therefore, people skilled in this technology, in order to optimize the effectiveness of the modified release, are able to select the components of the specified modified release agent in accordance with the selected active ingredient to reduce blood glucose. The amount of the modified release agent is about 10-40% by weight of the composition of the tablet.

In the process of producing tablets according to the present invention, pharmaceutically acceptable and inert excipients, such as diluents, lubricants, flavoring agents, spraying agents, binders, colorants or sweeteners, can be incorporated into the composition. While mixing the active ingredient to reduce blood glucose and a modified release agent, sucrose, titanium dioxide, microcrystalline compound, sorbitol, magnesium stearate or talc can be added. The tablet hardness after the tabletting step is preferably about 4-8 kg.

The proposed frequency of use of tablets according to the present invention is once a day for 1-2 tablets. The use of the tablets of the present invention is not limited to the treatment of diabetes.

Example 1

The composition of an oral tablet containing gliclazide to lower blood glucose is prepared from the following components:

Finely ground (particle size up to 1 μm) gliclazide 30 mg Lactose 30 mg SiO ₂ 1.6 mg Hydroxypropyl methylcellulose 84 mg Polyvinylpyrrolidone 8 mg Polysorbate 80 3.2 mg Magnesium stearate 1.6 mg Talc 1.6 mg Total 160 mg

The ingredients of the composition described above were processed according to the processes below, in order to obtain the tablets of the present invention:

(1) mixing finely ground (particle size up to 1 μm) glycazide, lactose, SiO ₂ , hydroxypropyl methylcellulose and polyvinylpyrrolidone;

(2) dissolving polysorbate 80 in an aqueous solution of ethanol;

(3) pouring the solution (2) into a mixed powder (1); the resulting wet agglomerate is subjected to granulation, followed by drying and sieving (20 mesh sieve);

(4) further mixing the granulate obtained in step (3) with magnesium stearate and talc;

(5) tableting using a rotary tabletting unit.

Example 2

The composition of an oral tablet containing gliclazide to lower blood glucose is prepared from the following components:

Finely ground (particle size up to 1 μm) gliclazide 60 mg Lactose 60 mg SiO ₂ 3.2 mg Hydroxypropyl methylcellulose 168 mg Polyvinylpyrrolidone 16 mg Polysorbate 80 6.4 mg Magnesium stearate 3.2 mg Talc 3.2 mg Total 320 mg

Example 3

The composition of an oral tablet containing gliclazide to lower blood glucose is prepared from the following components:

Finely ground (particle size up to 1 μm) gliclazide 30 mg Mannitol 90 mg SiO ₂ 1.6 mg Methyl cellulose 25.6 mg Polyvinylpyrrolidone 16 mg Sodium Lauryl Sulfate 3.2 mg Magnesium stearate 1.6 mg Talc 1.6 mg Total 160 mg

Example 4

The composition of an oral tablet containing gliclazide to lower blood glucose is prepared from the following components:

Finely ground (particle size up to 1 μm) gliclazide 60 mg Mannitol 180 mg SiO ₂ 3.2 mg Cellulose 51.2 mg Polyvinylpyrrolidone 12.8 mg Sodium Lauryl Sulfate 6.4 mg Magnesium stearate 3.2 mg Talc 3.2 mg Total 320 mg

Example 5

The composition of an oral tablet containing gliclazide to lower blood glucose is prepared from the following components:

Finely ground (particle size up to 1 μm) gliclazide 30 mg Microcrystalline cellulose 60 mg Lactose 30 mg SiO ₂ 1.6 mg Hydroxypropyl methylcellulose 24 mg Polyvinylpyrrolidone 4.8 mg Polysorbate 80 6.4 mg Magnesium stearate 1.6 mg Talc 1.6 mg Total 160 mg

Example 6

The composition of an oral tablet containing gliclazide to lower blood glucose is prepared from the following components:

Finely ground (particle size up to 1 μm) gliclazide 60 mg Microcrystalline cellulose 120 mg Lactose 60 mg SiO ₂ 3.2 mg Hydroxypropyl methylcellulose 48 mg Polyvinylpyrrolidone 9.6 mg Polysorbate 80 12.8 mg Magnesium stearate 3.2 mg Talc 3.2 mg Total 320 mg

Example 7

The composition of an oral tablet containing gliclazide to lower blood glucose is prepared from the following components:

Finely ground (particle size up to 1 μm) gliclazide 30 mg Lactose 90 mg SiO ₂ 1.6 mg Hydroxypropyl methylcellulose 24 mg Polyvinylpyrrolidone 8 mg Polysorbate 80 3.2 mg Magnesium stearate 1.6 mg Talc 1.6 mg Total 160 mg

Example 8

The composition of an oral tablet containing gliclazide to lower blood glucose is prepared from the following components:

Finely ground (particle size up to 1 μm) gliclazide 60 mg Lactose 180 mg SiO ₂ 3.2 mg Hydroxypropyl methylcellulose 48 mg Polyvinylpyrrolidone 16 mg Polysorbate 80 6.4 mg Magnesium stearate 3.2 mg Talc 3.2 mg Total 320 mg

Dissolution test

The analysis of the compositions of the tablets of the present invention for oral administration was carried out in vitro.

The tablets prepared according to example 1, in which finely ground glycazide was used as the active ingredient, were examined at 37 ° C in a Basket USP-type device. The analysis was carried out in 900 ml of purified water at a speed of 100 rpm. The test results are shown in table 1 and figure 1.

Table 1 Time (h) Dissolution Rate (%) 0.5 2.0 1,0 4.0 1,5 6.2 2.0 9.5 2.5 12.9 3.0 16.6 3,5 21,2 4.0 25.8 4,5 30.6 5,0 35.6 5.5 40.8 6.0 46.2 6.5 51.5 7.0 56.6 7.5 61,4 8.0 66.5 8.5 71.5 9.0 76.0 9.5 80.6 10.0 85,2 10.5 89.3 11.0 93.0 11.5 96.5 12.0 100.1

From the above results, it is seen that after dissolution within 2 hours, approximately 5 ~ 15% of glycoslazide is released, after dissolution within 4 hours, approximately 15 ~ 35% of glycoslazide, after dissolution within 8 hours, approximately 50 ~ 80% of glycoslazide is released, and after dissolving within 12 hours, approximately ≥80% of gliclazide is released.

In the dissolution test, the dissolution of the oral tablet formulations of the present invention (test group) was compared with oral tablet formulations designed to lower blood glucose, the active ingredient of which was not micronized (up to 1 μm) (control group).

отмечены данные, касающиеся таблеток, активный ингредиент которых тонкоизмельчен, а значком прямоугольной формы

- данные для неизмельченного активного ингредиента. Приведенные результаты показывают, что таблетки по настоящему изобретению обладают лучшей скоростью растворения, чем после продолжительного времени растворения таблетки с гликлазидом, таблетки которого не были подвержены тонкому измельчению; при этом неизмельченная форма не может обеспечить полного высвобождения.Fine gliclazide (Example 1) and non-fine-gliclazide were used as the active ingredient for tablets that were tested at 37 ° C in a Basket USP device. The analysis was carried out in 900 ml of purified water at a speed of 100 rpm. The results are shown in figure 2. Diamond Shaped Icon

data for tablets whose active ingredient is finely divided and with a rectangular shape

- data for unmilled active ingredient. The above results show that the tablets of the present invention have a better dissolution rate than after a long dissolution time of a tablet with glyclazide, the tablets of which were not subject to fine grinding; however, the unmilled form cannot provide complete release.

Refer to figure 3. The drawing shows a change in the concentration profile of the composition of the present invention, intended for oral tablets with a modified release into the blood over a period of time. Studies were carried out according to the following method. According to the test protocol, healthy candidates were selected, who were asked to take the medicine of the present invention once at a regular time intervals to reduce blood glucose; the tests were carried out for 6 consecutive days. Monitoring the concentration of the drug in the blood was carried out at specially selected points. The results shown in FIG. 3 show that over a long period of time, a certain amount of the drug is sequentially released to lower blood glucose, and thus a modified release effect of the active ingredient to lower blood glucose is achieved.

The documents cited here are incorporated by reference, and each of them can serve as part of the disclosure of the present invention. Skilled in this area, people are able to easily improve the above examples, without deviating from the applicability and principles of the present invention. The present invention is provided with specific examples, however, those skilled in the art will recognize other improvements to these examples that are also within the scope of the present invention.

Claims (8)

1. The composition for oral tablets with a modified release, characterized in that it contains
finely divided gliclazide to reduce blood glucose with a particle size distribution in the following range:
(1) at least 50% of particles having a size of ≤5 μm;
(2) at least 90% of particles having a size of ≤15 μm; and
(3) at least 95% of particles having a size of ≤25 μm; as well as a release modifying agent for controlling the release of gliclazide; moreover, finely ground gliclazide to reduce blood glucose has the following dissolution profiles in purified water:
approximately 5 ~ 15% of the finely divided glyclazide is released after dissolution within 2 hours;
approximately 15 ~ 35% of the finely divided glyclazide is released after dissolution within 4 hours;
approximately 50 ~ 80% of the finely divided gliclazide is released after dissolution within 8 hours; and
approximately ≥85% of the finely divided glyclazide is released after dissolution within 12 hours 2. The modified release oral tablet formulation of claim 1, wherein said release modifying agent is selected from the group consisting of hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl pyrrolidone, hydroxypropyl cellulose, vinyl acetate copolymers, polyethylene oxides, and combinations thereof. 3. The composition for oral modified-release tablets according to claim 1, characterized in that said release modifying agent is 10-40% by weight of the composition of the tablets. 4. The composition for oral tablets with a modified release according to claim 1, characterized in that the glycazide to reduce blood glucose has a weight of from 30 to 60 mg. 5. The composition for oral tablets with a modified release according to claim 1, characterized in that the composition is intended for administration to the subject orally once a day for 1-2 tablets per reception. 6. The composition for modified release oral tablets according to claim 1, characterized in that said composition contains micronized glycoslide, hydroxypropyl methylcellulose, polyvinylpyrrolidone, lactose, SiO ₂ , polysorbate 80, magnesium stearate and talc. 7. The composition for oral tablets with a modified release according to claim 2, characterized in that the viscosity of the specified agent, modifying the release, is from 4000 to 100000 SP. 8. A method of obtaining a composition for oral tablets with a modified release, including:
fine grinding of gliclazide to reduce blood glucose to a particle size distribution in the following range:
(1) at least 50% of particles having a size of ≤5 μm;
(2) at least 90% of particles having a size of ≤15 μm;
(3) at least 95% of particles having a size of ≤25 μm;
mixing finely divided gliclazide to lower blood glucose with a release modifying agent to form a mixture;
granulating the mixture;
drying and cutting the mixture; and
adding a filler to the mixture to obtain oral tablets with a modified release, the hardness of which is from 4 to 8 kg, and the tablet to reduce blood glucose has the following dissolution profiles in purified water:
approximately 5 ~ 15% of the finely divided glyclazide is released after dissolution within 2 hours;
approximately 15 ~ 35% of the finely divided glyclazide is released after dissolution within 4 hours;
approximately 50 ~ 80% of the finely divided gliclazide is released after dissolution within 8 hours; and
approximately ≥85% of the finely divided glyclazide is released after dissolution within 12 hours

Images