KR20070007166A - Oral modified-release lozenges and their preparation method - Google Patents

Abstract

This invention relates to oral modified-release lozenges characterized in that they contain micronized active components as antidiabetic and modified-release agents. This invention also provides such lozenges preparation method. Compared with conventional formulations comprising the same active components, the oral modified-release lozenges of this invention possess more excellent solubility, more persistent absorptivity, and more effective curative effect. ® KIPO & WIPO 2007

Description

ORAL MODIFIED-RELEASE LOZENGES AND THEIR PREPARATION METHOD}

The present invention relates to a modified-release oral tablet composition, in particular a release mitigating agent and a novel composition formulated by at least a pharmaceutically effective amount of a micronized active ingredient and a hydrophilic polymer for lowering blood sugar The present invention relates to a method for preparing an oral tablet composition for alleviating the release.

Diabetes is a type of chronic disease that causes high blood sugar caused by many different causes. This causes retinopathy, glomerulosclerosis, and other kidney, nerve, and vascular symptoms or complications and is the fifth highest among Taiwan's top ten signs, 4.1 patients per ten thousand at 0.37 patients per ten thousand in 1960. Increased in number. Diabetes is mainly classified into type 1 and type 2, in which type 1 is insulin-dependent diabetes mellitus (hereinafter referred to as "IDDM"), which is called pediatric diabetes in the early stages and injected with insulin. If you do not, you are prone to acute ketoacidosis. Type 2 diabetes, on the other hand, is insulin-independent diabetes, also referred to as adult diabetes, and is caused by impaired metabolic functions, namely insulin resistance and lack of beta cells, and must be treated with oral hypoglycemic agents.

Generally, oral hypoglycemic agents are classified into four types of sulfonylureas, biguanides, thiazolidinedione, and alpha glucosidase inhibitors. Sulfonylureas are oral hypoglycemic agents of adult diabetes mellitus, which stimulate the spleen to secrete insulin, degranulate the granules containing insulin in beta cells, and release insulin in the granules. In urging the increase of insulin body by reducing the metabolic function of insulin in the liver, it is mainly used in patients who are not overweight and still have beta cells. Its side effects are relatively small and are commonly used to inhibit the entry of iodine ions into the thyroid gland and, in excess, cause hypoglycemia and cause earthenware, vomiting and pruritus. In Taiwan hospitals, drugs of second-generation sulfonylureas such as glyclazide, glipizide, glibenclamide and the like are generally used. In addition, since biguanide drugs do not stimulate insulin secretion, the risk of causing hypoglycemia is lower than that of sulfonylureas and is optimal for overweight patients. The action of thiazolidinediones is to reduce the composition of endogenous glucose, mainly by reducing the resistance of insulin to muscle and adipose tissue. The action of the alpha glucosidase inhibitor is always used in combination with other oral hypoglycemic agents by suppressing the absorption of carbohydrates and disaccharides by reducing the intestinal alpha glucosidase, thereby reducing the rise in blood glucose levels after meals.

Achieving continuous therapeutic effects using drugs that control the release of hypoglycemia is very important as disease management for diabetics, especially those with diabetes who have to take long-term medications to control symptoms. In situations where doses are essential, drugs should be developed to give the patient the best possible treatment, while at the same time avoiding the side effects of taking these drugs. In addition, the drug for mitigation release can extend the maintenance of the effective amount of the drug in the blood to sustain the effect of the drug, thus reducing the number of doses and matching the release rate and mode to physiological and chronic treatment. Have Moreover, since the drug effect lasts relatively calmly, it is not necessary to use it as a means of achieving a long drug effect by using a relatively high drug amount, and the side effect or the probability of resistance are thereby lowered. As an example, it can be treated by taking 80 mg of undifferentiated glyclazide twice daily, but the undifferentiated active ingredient cannot be completely released because of poor solubility, and thus can not achieve a clinically effective therapeutic effect. For example, U.S. Patent Nos. 6,451,339 and 6,537,578 disclose the manufacture of a medicament that is performed for controlling the release of the medicament. The present invention relates to the manufacture of oral tablets for the alleviation of release to meet the above objectives mainly by means such as drug dissolution control in diabetic patients, and to achieve better safety and therapeutic effect on the drug.

Accordingly, the present invention provides an oral tablet composition for mitigating release, which is constituted by at least an undifferentiated blood sugar lowering active ingredient and a release releasing agent that regulates the release of the active ingredient.

In the time-dissolved dissolution test, the composition composed of the undifferentiated blood glucose lowering active ingredient and the release releasing agent has an optimal dissolution rate than the composition containing no undifferentiated blood sugar lowering active ingredient.

Another object of the present invention is to provide at least a blood glucose lowering active ingredient, wherein (1) ≤ 5 micron particles account for at least 50% of the total proportion, (2) ≤ 15 micron particles account for at least 90% of the total proportion, (3) micronizing the particles having a particle size of ≤ 25 microns to account for more than 95% of the total proportion, mixing the micronized hypoglycemic active ingredient with the release releasing agent, preparing the granules, drying and purifying, and adding an excipient to purify the product. To provide a method of producing an oral tablet composition for mitigating release comprising the step of preparing a tablet having a hardness (hardness) of 4 ~ 8Kg.

It is also an object of the present invention to provide an undifferentiated release alleviating oral tablet composition having a relatively good absorption stability in the prepared composition, and a method for producing the same.

Another object of the present invention is to use micronized technology to micronize the main ingredient and then to achieve the therapeutic effect it currently has with relatively low dosages in clinical use.

1 is a dissolution curve diagram of an oral tablet composition containing the micronized active ingredient glyclazide for lowering blood glucose of the present invention in purified water over time.

FIG. 2 shows an oral tablet composition in which tablets containing undifferentiated active ingredient glyclazide for lowering blood sugar (diamond type) and tablets containing undifferentiated active ingredient glyclazide for lowering blood sugar (square) are used in purified water. Dissolution curves presented for comparison over time.

Figure 3 is a curve diagram showing the relationship between blood concentration and time release of oral tablet composition for mitigating the present invention.

Hereinafter, exemplary embodiments of the present invention will be described in detail with reference to the accompanying drawings. Detailed descriptions of well-known functions and configurations that may unnecessarily obscure the subject matter of the present invention will be omitted in the following description and the accompanying drawings.

The present invention relates to a novel release alleviating oral tablet composition, which is mainly composed of an undifferentiated blood glucose lowering active ingredient and a release emollient containing a hydrophilic polymer, and achieves the effect of release relaxation controlling the blood glucose lowering active ingredient.

The blood glucose lowering active ingredient may be an active ingredient employed among known blood glucose lowering agents, and preferably sulfonyl ureas as the blood sugar lowering active ingredient of the present invention, and if necessary, two or more types of active ingredients, for example, glycla Zide, glypizide, glybenclamide, glyquidonem, glymepiride can be selected and combined. The content range in the composition is, for example, glyclazide, preferably 30 to 60 mg. This active ingredient is characterized by being capable of micronized treatment, preferably the particle size range can be expressed as follows.

(1) ≤ 5 micron particles account for more than 50% of the total proportion.

(2) ≤ 15 microns of particles account for more than 90% of the total proportion.

(3) ≤ 25 microns of particles account for more than 95% of the total proportion.

The release modifier used in the present invention is preferably the following substances: hydroxypropylmethyl cellulose, methyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, vinyl acetate air It is preferably selected from vinylacetate copolymers, polyethylene oxides, and combinations thereof, and at the same time preferably has a viscosity of 4,000 cps to 100,000 cps, and those skilled in the art will appreciate that The ingredients can be adjusted and the release mitigation effects can be optimized. Emollients comprise 10-40% of the tablet composition.

In the preparation of the tablets of the invention, various excipients which can be added to the composition at a suitable time and which do not readily react with the hypoglycemic active ingredient, such as bulking agents, diluents, lubricants Tablets, for example sucrose, titanium dioxide (TiO ₂ ), microcrystalline, by addition of ), Sorbitol, magnesium stearate, talc and the like can be prepared. It may be added before the purification step or before mixing the hypoglycemic active ingredient with the release mitigant. The tablet hardness after the purification step is about 4-8 Kg.

In the dosage form of the tablet of the present invention, one or two tablets are taken orally once daily, and these tablets are used for the treatment of diabetes mellitus, but the use thereof is not limited thereto.

(Example 1)

The components of the oral tablet composition containing the hypoglycemic agent glyclazide are prepared as follows.

Micronized Gliclazide 30mg

Lactose 30mg

SiO ₂ 1.6mg

Hydoxypropylmethyl cellulose 84mg

Polyvinylpyrrolidone 8mg

Polysorbate 80 3.2mg

Magnesium stearate 1.6mg

Talc 1.6mg

160 mg total

By carrying out such a composition component based on the following steps, the tablet of this invention can be obtained.

(1) Undifferentiated glyclazide, lactose, SiO ₂ , hydroxypropyl methyl cellulose, polyvinylpyrrolidone are mixed.

(2) Polysorbate 80 is dissolved in an aqueous solution of ethanol.

(3) The wet agglomeration obtained by adding the solution of (2) into the mixed powder of (1) is prepared into granules, dried and processed (# 20mesh).

(4) The granules obtained in (3) are further mixed with magnesium stearate and talc powder.

(5) A tablet having a hardness of 4 to 8 kg is produced with a rotary tablet.

(Example 2)

The components of the oral tablet composition containing the hypoglycemic agent glyclazide are prepared as follows.

Micronized Gliclazide 60mg

Lactose 60mg

SiO ₂ 3.2mg

Hydoxypropylmethyl cellulose 168mg

Polyvinylpyrrolidone 16mg

Polysorbate 80 6.4mg

Magnesium stearate 3.2mg

Talc 3.2mg

Total 320mg

(Example 3)

The components of the oral tablet composition containing the hypoglycemic agent glyclazide are prepared as follows.

Micronized Gliclazide 30mg

Mannitol 90mg

SiO ₂ 1.6mg

Methyl cellulose 25.6mg

Polyvinylpyrrolidone 6.4mg

Sodium Lauryl Sulfate 3.2mg

Magnesium stearate 1.6mg

Talc 1.6mg

160 mg total

(Example 4)

The components of the oral tablet composition containing the hypoglycemic agent glyclazide are prepared as follows.

Micronized Gliclazide 60mg

Mannitol 180mg

SiO ₂ 3.2mg

Methyl cellulose 51.2mg

Polyvinylpyrrolidone 12.8mg

Sodium Lauryl Sulfate 6.4mg

Magnesium stearate 3.2mg

Talc 3.2mg

Total 320mg

(Example 5)

The components of the oral tablet composition containing the hypoglycemic agent glyclazide are prepared as follows.

Micronized Gliclazide 30mg

Microcrystalline cellulose 60mg

Lactose 30mg

SiO ₂ 1.6mg

Hydoxypropylmethyl cellulose 24mg

Polyvinylpyrrolidone 4.8mg

Polysorbate 80 6.4mg

Magnesium stearate 1.6mg

Talc 1.6mg

160 mg total

(Example 6)

The components of the oral tablet composition containing the hypoglycemic agent glyclazide are prepared as follows.

Micronized Gliclazide 60mg

Microcrystalline cellulose 120mg

Lactose 60mg

SiO ₂ 3.2mg

Hydoxypropylmethyl cellulose 48mg

Polyvinylpyrrolidone 9.6mg

Polysorbate 80 12.8mg

Magnesium stearate 3.2mg

Talc 3.2mg

Total 320mg

(Example 7)

The components of the oral tablet composition containing the hypoglycemic agent glyclazide are prepared as follows.

Micronized Gliclazide 30mg

Lactose 90mg

SiO ₂ 1.6mg

Hydoxypropylmethyl cellulose 24mg

Polyvinylpyrrolidone 8mg

Polysorbate 80 3.2mg

Magnesium stearate 1.6mg

Talc 1.6mg

160 mg total

(Example 8)

The components of the oral tablet composition containing the hypoglycemic agent glyclazide are prepared as follows.

Micronized Gliclazide 60mg

Lactose 180mg

SiO ₂ 3.2mg

Hydoxypropylmethyl cellulose 48mg

Polyvinylpyrrolidone 16mg

Polysorbate 80 6.4mg

Magnesium stearate 3.2mg

Talc 3.2mg

Total 320mg

In vitro test-dissolution test of oral tablet composition of the present invention

Tablets prepared according to Example 1, using the micronized glyclazide as the active ingredient of the oral tablet, are dissolved in 900 ml of purified water at 37 ° C. in a basket device of USP type 1 at a rotational speed of 100 rpm. And the results are shown in FIG. 1.

<Table 1>

Hour 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

As shown in Table 1, about 5 to 15% of the glyclazide after 2 hours of dissolution test, about 15 to 35% of the glyclazide after 4 hours, and about 50 to 80 after 8 hours % Of glyclazide releases about 85% or more of glyclazide after 12 hours, respectively.

In vitro test-dissolution test comparing undifferentiated tablet composition (test group) of the present invention with oral tablet composition (control group) without undifferentiated blood glucose lowering active ingredient

Undifferentiated Glycrazide and undifferentiated Glyclazide, respectively, were prepared as active ingredients of oral tablets, and a 100 ml USP type 1 basket apparatus with a rotational speed of 900 ml of purified water at 37 ° C. The dissolution test was performed in the inside. The obtained result is shown as FIG. Diamond type (◆) represents a tablet prepared by micronizing the active ingredient, square (■) represents a tablet prepared without the micronized active ingredient. As a result, it was proved that the tablet of the present invention exhibited a relatively better dissolution rate than the tablet prepared by undifferentiated glyclazide in a long dissolution test, while at the same time, the undifferentiated tablet did not reach full release.

Figure 3 is a view showing the relationship between the blood concentration and time of the above release oral tablets for release. That is, by selecting the examinee of health that meets the test requirements, the blood glucose lowering agent prepared by the undifferentiated manufacturing process of the present invention is taken once daily and continuously for 6 days, and a blood collection point is designed to measure the blood concentration of the drug. It was. As can be seen in the figure, since the amount of the drug released in the blood of the blood glucose lowering agent is continuously released according to the change over a long time, it is possible to achieve the result of release relaxation controlling the blood glucose lowering active ingredient.

The above embodiments are exemplified in order to explain the present invention in more detail, and the technical spirit of the present invention is not limited to the embodiments, and the present invention is not limited to the following claims. Various modifications such as a design change are possible, of course.

The present invention relates to the manufacture of oral tablets for the alleviation of release to meet the above objectives mainly by means such as drug dissolution control in diabetic patients, and to achieve better safety and therapeutic effect on the drug.

Claims (10)

Micronized particle size and proportionality, (1) ≤ 5 micron particles account for more than 50% of the total proportion, (2) ≤ 15 microns of particles account for more than 90% of the total proportion, (3) ≤ 25 microns of particles account for more than 95% of the total proportion, Undifferentiated blood sugar lowering active ingredient, An oral tablet composition for mitigating release, comprising a release releasing agent for controlling release of an active ingredient. The oral tablet composition according to claim 1, wherein the micronized hypoglycemic active ingredient is selected from sulfonylureas, glyclazide, glyphide, glybenclamide, glycudonem, glymepiride, and combinations thereof. The method of claim 1, wherein the release mitigating agent, An oral tablet composition for mitigating release selected from hydroxypropyl methyl cellulose, methyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, vinyl acetate copolymer, polyethylene oxide, and combinations thereof. The oral tablet composition according to claim 1, wherein the release agent comprises 10-40% of the tablet composition. According to claim 1, wherein the undifferentiated hypoglycemic active ingredient glyclazide weight is 30 ~ 60mg oral tablet composition for mitigation release. The method of claim 5, wherein the micronized hypoglycemic active ingredient, 2 hours after the dissolution test, about 5-15% of glyclazide After 4 hours, about 15-35% of glyclazide After 8 hours, about 50-80% of glyclazide An oral tablet composition for mitigating release wherein at least about 85% of glyclazide is released after 12 hours. The oral tablet composition for mitigating release according to claim 5, wherein 1 to 2 tablets are taken once every hour and once every day. According to any one of claims 1 to 5, wherein the release mitigation oral tablet composition is micronized glyclazide, lactose, SiO ₂ , hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polysorbate 80 Oral tablet composition for relaxation of release, which is composed of magnesium stearate, and talc powder. According to claim 1 or 3, wherein the release agent is a release mitigation oral tablet composition having a viscosity of 4,000 ~ 100,000cps. Blood sugar lowering active ingredients, (1) ≤ 5 micron particles account for more than 50% of the total proportion, (2) ≤ 15 microns of particles account for more than 90% of the total proportion, (3) ≤ 25 microns of particles account for at least 95% of the total proportion Undifferentiating, Mixing, granulating, preparing, drying and purifying the micronized hypoglycemic active ingredient with a release emollient, A method for producing an oral tablet composition for mitigating release, comprising the steps of adding an excipient to perform purification and preparing a tablet having a hardness of 4 to 8 kg.

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