BG1302U1 - Pharmaceutical formulation of glimepiride - Google Patents

Abstract

The utility model relates to a pharmaceutical formulation of glimepiride, containing glimepiride from 1 to 4 mg and auxiliary substances in the following percentages relative to the tabletÆs mass: lactose from 10 to 45, microcrystalline cellulose from 10 to 65, pregelatinized starch from 5 to 50 and binder from 0.5 to 7, which is either hydroxypropyl cellulose or hydroxypropylmethylcellulose, disintegrant from 1 to 10, which is either croscarmellose sodium, sodium starch glycolate or crospovidon, preferably croscarmellose sodium, lubricating substance from 0.5 to 3, which is either sodium stearyl fumarate or magnesium stearate. The glimepiride active substance of the pharmaceutical formulation is quickly dissolved and the formulation remains stable for a period of 3 years when stored. Thetablets obtained are hard and have good physicomechanic properties û mechanical strength and disintegration characteristics. The pharmaceutical formulation is also easy to produce, furthermore, the excipients are indifferent to the active substance and the equipment used in the pharmaceutical production, thus ensuring good technological parameters.

Description

Technical field

The utility model refers to an oral dosage form containing glimepiride, which is administered to people suffering from type II diabetes.

BACKGROUND OF THE INVENTION

A known formulation of glimepiride - tablets containing 1,2,3 and 4 mg glimepiride and excipients - microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, povidone 25000, magnesium stearate (Amaiyl - Patient Information). These formulations achieve an organic impurity content of mg / g at the end of the three-year shelf life of not more than:

Sulfonamide / Impurity B / <2.5%

Other impurities <0.5%

Total impurities <1.0%

Total impurities <3.5%

Content of naugimepiride ± 10% / l // Quality and Behavior of Glimepiride Generics Versus Amaryl Under Stressed Conditions, Diabetes Technology & Therapeutics, V. 9, N. 3,2007,287296 / and USP Monograph 32 p. 2498 Glimepiride Tablets 111.

B WO 2007072218, which relates to a dosage form of glimepiride or a pharmaceutically acceptable salt thereof in micronized form with a mean particle size of <3 micrometer, Example 1 describes a tablet form of glimepiride containing glimepiride 2 mg, lactose monohydrate, povidone, microcrystalline cellulose, magnesium stearate, sodium starch glycolate. The compositions according to the invention have been stated to have the following solubility: 70% of glimepiride (of formulation containing 6 mg glimepiride) was dissolved for 15 min in 900 ml pH 6.6 buffer containing 0.2% sodium dodecyl sulfate.

The technical nature of the utility model

The problems that need to be solved with glimepiride based formulation are to ensure both good stability of the dosage form, rapid dissolution of the drug substance and good physico-mechanical properties of the tablet.

Problems are solved by dosage form according to a utility model that contains glimepiride from 1 to 4 mg and excipients in percentage by weight of the tablet: lactose at a concentration of 10 to 45, microcrystalline cellulose from 10 to 65, pregelatinized starch from 5 to 50 and a binder of 0.5 to 7, selected from hydroxypropylcellulose or hydroxypropylmethylcellulose, a disintegrant of 1 to 10, selected from: croscarmellose sodium, sodium glycolate starch or crospovidone, preferably croscarmellose sodium, sliding substance 3, selected from 0.5 of sodium stearyl fumarate or magnesium stearate.

The resulting dosage form according to the utility model achieves a rapid dissolution rate of the drug glimepiride 50% at 10 minutes and is stable over a storage period of 3 years, providing a related substance content for the whole period at room temperature (25 ± 2) ° C / (60 ± 5)% RH and 12 months at (30 ± 2) ° C / (65 ± 5)% RH below the following norms: 3-ethyl-4-methyl-2-oxo-N- [2- (4 sulfonylphenyl) ethyl] -2,3-dihydro-1H-pyrrole1-carboxamide / Sulfonamide / - Impurity B <1.0%

Single impurity / unidentified / <0.2% Total impurity without impurity B <1.0% The obtained tablets are strong with good physico-mechanical properties - mechanical strength and decomposition.

The dosage form is convenient for pharmaceutical manufacture, with the excipients being indifferent to the drug substance and the apparatus used and providing good technological performance.

Exemplary embodiments of the utility model

The utility model is illustrated without limitation by the following exemplary embodiments in mg per dosage form:

Example 1

Example 1 Example 2 Example 3 Example 4 Glimepiride 2,000 1,000 3,000 4,000 Lactose monohydrate 99,740 49,870 th most common 99,000 99,000 Hydroxypropylcellulose 1,200 0.600 1,200 1,200 Microcrystalline cellulose 43,000 21,000 43,000 43,000 Pregelatinized starch 28,000 14,000 28,000 28,000 Croscarmellose sodium 4,000 2,000 4,000 4,000 Sodium stearyl fumarate 2,000 1,000 2,000 2,000 Paint, yellow iron oxide E 172 0.030 0.030 0.060 0.060 Paint, blue E 132 - - - 0.030

Purified water*

Ethanol * / 96% / * Not in the final product

Lactose monohydrate, microcrystalline cellulose and a portion of pregelatinized starch are granulated using an aqueous solution, an aqueous-alcoholic and an alcoholic solution of hydroxypropylcellulose. After granulation and drying, the resulting dry granulate is dusted with other excipients and glimepiride.

Table 1 shows the test data of _"with tion stability of the finished tablets.

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Table 1/1

STABILITY TABLE

Product name: Glimepiride 3 mg tablets

Observed batch: 10404

Storage conditions: ____________________ (25 ± 2) ° C / (60 ± 5)% OJ _____

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Table 1/2

STABILITY TABLE

Product name: Glimepiride 2 mg tablets

Observed lot: 20404

Storage conditions: (25 ± 2) ° C / (6 () ± 5)% RH

36 months He responds He responds He responds • t • 1 00 l 4 | 4¾ o 0.08; 0.05 Mr m t — 1 a He responds 24 months He responds He responds He responds 96.5 about τζ about 0.06; 0.04 Fr. Fr. 1.96 J I 18 months He responds He responds | He responds JV 1 f Ό m о 0.05; 0.04 0.09 Thu. 04 I 12 months He responds He responds He responds oo oh 0.18 0.05 0.05 гΟγ 1 1 1 Nine months He responds He responds He responds <D) 1 1 0.12 0.04 0.04 1.98 1 t I 6 months He responds He responds Responsible I magazine t 1 0.10 0.03 © o ' D-1 i I 3 months He responds He responds He responds hh 1 I 0.09 0.03 sp © © σ> 1 1 Initial analysis ί 1 He responds He responds He responds sch 100,7 0.08 0.03 0.03 00 04 ! < He responds Norms Flat, flat tablet with facet and divider on one side, diameter 8 nun Pale green Without smell «N VI 'if <In 1.0 0.2 © τΉ From 1.90 to 2.10 To meet the test 1Name of the indicators outer appearance they tear 5 6 1— < yield, min, not more than heparin dissolution rate of tablets, per cent of (content, after 45 min, less than native substances, one hundred, not more yes o and chic impurity [impurity without impurity B io S 3 ί S £ | g E VO 2 j S n 1 s f- <Kf i) e AND i O / —s 5 sl Щ «η s o 6 A S s rr * microbiological quality

Table 1/3

STABILITY TABLE

Product name: Glimepiride 1 mg tablets

Observed batch: 050104

Storage conditions: (25 ± 2) ° C / (60 ± 5)% RH

36 months He responds 1 He responds He responds »·· «Λ 00 » 1 · Oh 40 o ' 0.07; 0.0 $ · . Ma'am __ · _______________ ►W-- 1 Yu o ' He responds 24 months He responds He responds He responds Ά 0.50 0.06 0.06 «0 o ' 1 1 18 months He responds He responds He responds cn ! 0.30 un ο ο 0.05 0.99 1 12 months He responds He responds He responds Midrange 40 0.23 0.04 0.04 sch 1 1 Nine months He responds He responds He responds m 1 04 o ' 0.04 0.04 1.03 1 1 6 months He responds He responds He responds sch 0.08 0.03 0.03 1.04 1 J 3 months He responds He responds He responds cn * and 0.05 1 0.03 0.03 1.02 t 1 1 Initial analysis He responds He responds He responds cn 98.5 0.05 0.03 0.03 Oh, He responds Norms Round, flat, veneered tablets with a dividing line on one side, 7 mm in diameter Pale pink with a light mosaic Without smell 1 / Ί τ — t σ Ο _Λ • ——I 0.2 r- < From 0.95 to 1.05 To meet the test Naming of indicators outer appearance 8 -S. Eiris drop, min, not more than heparin for dissolution of chepiride from tablets, one hundredth of the content after 45 min, less than Honeycomb substances, per cent, not more months rotting impurity good impurity without impurity B m E S § is £ S- S E t E s 2 c S S b S cs ft ffi ίπ Ef Rj ϋ ϋ I 4> / -> gw D ^1/1 cs O E £ microbiological quality

1302 Ul

Comparative study to determine the degree of dissolution of glimepiride from Amaryl® tabl. 3 mg batch. No. 588 and glimepiride from Glipiryl tabl. 3 mg, batch 10404

The study is conducted in accordance with the requirements of EMEA (Note for guidance on the investigation of bioavailability and bioequivalence).

1. Conditions for implementing the definition

Apparatus

Degree of release control with rotating blade (Ph. Eur. 5, 2.9.3.)

Definition Enforcement Environment:

- Sodium lauryl sulfate solution (2 percent) in 0.1 mol / l hydrochloric acid at pH 1.2;

- Sodium lauryl sulfate solution (2 percent) in acetate buffer pH 4.5;

- Sodium lauryl sulfate solution (2 percent) in phosphate buffer pH 6.8;

Medium volume: 600 ml;

Medium temperature: (37 ± 0.5) ° C; Number of tablets in the vessel of the apparatus: 1;

Blades rotational speed: (50 ± 2) rpm;

Definition time: 30 min; Sampling volume: 10 ml.

Figure 1. Comparative dissolution profiles (Q) of glimepiride from Glipiryl® tabl. 3 mg and Amaryl ®table. 3 mg in sodium lauryl sulfate solution (2 percent) in 0.1 mol / l hydrochloric acid at pH 1.2; 12 / similarity factor / = 73.6, at norm Q not less than or equal to 75% for 30min

Figure 2. Comparative profiles of glimepiride dissolution rate from Glipiryl® tabl. 3 mg and Amaryl® tabl. 3 mg in sodium lauryl sulfate solution (2 percent) in acetate buffer pH 4.5; £ 2 / factor of similarity / = 57.3 at norm Q not less than or equal to 75% for PDO

1302 ϋΐ

Tests have shown that a tablet containing 3 mg of active substance has more than 80% release rate in 10 minutes, at norm after 45 minutes, release rate - 75%.

Table 2. Mechanical strength (g) and breakdown of tablets.

Glimepiride lmg Glimepiride 2 mg Glimepiride 3 mg Xsr. = 44N Xsr. = 61N Xcp. = 65N Crumbling X cf. = 1 min X cf. 1 min X Wed = 1 min 10 sec 30 sec

Claims

Claims (1)

A dosage form containing glimepiride from 1 to 4 mg and excipients lactose, microcrystalline cellulose and sodium glycolate starch, characterized in that it contains in% by weight of tablet: lactose in a concentration of 10 to 45, microcrystalline cellulose from 10 to 65, pregelatinized starch from 5 to 50 and a binder of 0.5 to 7 selected from hydroxypropylcellulose or hydroxypropylmethylcellulose, a disintegrating agent from 1 to 10, selected from: croscarmellose sodium, starch glycolate sodium or crospovidone and a sliding agent from 0.5 to 4, selected from sodium stearyl fumarate or magnesium stearate.