BG66008B1 - Medicamentous preparation of changeable release - Google Patents

Abstract

The medicamentous preparation based on (1RS,2RS)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride with generic name of tramadol hydrochloride is administered in medical practice in moderate, acute and chronic pains of different origin, as well as in diagnostic and surgical intervention. It is of simplified composition, the selected auxiliary substances ensuring excellent physico-mechanical characteristics, release in stages in vitro of the medicamentous substance in the course of 24 h and therapeutic plasma levels within 48 h, proven by biologically available investigations. The matrix tablets contain the following components in mg: from 200 to 600 tramadol hydrochloride, microcrystalline cellulose from 15 to 100, hydroxypropylmethgyl cellulose K15M from 100 to 400,calcium hydrogen phosphate, anhydrous, from 10 to 80, copovidon from 10 to 25, magnesium stearate from 1 to 10 and colloidal silicon dioxide from 0.5 to 5.

Description

Technical field

The invention relates to a modified-release drug containing (1 RS, 2RS) -2 - [(dimethylamino) methyl] -1- (3methoxyphenyl) cyclohexanol hydrochloride by the generic name tramadol hydrochloride and is used in medical practice for moderate, acute and chronic pain of various origins, as well as in diagnostic and surgical intervention.

BACKGROUND OF THE INVENTION

A multiplicative dosage form (Per. No. 103158, application EP 1997/003934) is known, consisting of depot granules containing tramadol hydrochloride, which provide an analgesic effect for at least 24 hours and show an in vitro rate of drug dissolution over a period of 12 h.

The formulation is obtained as tramadol hydrochloride in powder form and is applied to a starting material composed of neutral cores (Nonpareilles, Sugar Spheres USP) with a suitable solution of ethylcellulose / shellac binder in a ratio of 1: 9 to 9: 1. These applications of the drug substance are made in layers, which determines its uneven distribution on the neutral nuclei. Finally, the resulting cores are dried and sieved, coated with one or more membrane layers of acrylic copolymers, thereby achieving a sustained release of the drug. They are filled into hard gelatin capsules or tableted with suitable excipients.

This form is very technologically complicated, and the acrylic copolymers, ethylcellulose and shellac used in the long-term bearing age and adversely affect the rate and rate of drug dissolution of the nuclei obtained.

A known controlled release drug for 12 to 24 hours containing oral tramadol or its pharmacologically acceptable salts, in particular hydrochloride and excipients: lactose, microcrystalline cellulose, ethylcellulose (Surrelease 25%), cetyl alcohol, magnesium stearate , talc, hydrogenated vegetable oils, film formers based on low-viscosity HPMC in the group of methocel E5 and E15 (EP 0624366A _p US 6326027V _(and DE 4315525AJ. The medicinal preparation is obtained as the active ingredient tramadol hydrochloride the lactose is homogenized and granulated in a fluidized bed equipment with ethylcellulose (Surrelease 25%) and water, the granules are dried at 60 ° C, sieved through a 1 mm sieve, and molten cetyl alcohol is added to the warm granules and mixed very much. well, and after cooling, they are sieved through a 1.6 mm sieve, magnesium stearate and talc are added to the mixture and then tableted with appropriate punches on a rotary tablet machine, and in vitro assays for the dissolution rate of tramadol hydrochloride from the obtained tablets are carried out. period from 12 to 24 h.

Another patent is known (EP 0914823A0 for the preparation of a sustained release drug containing tramadol hydrochloride based on cetyl alcohol, microcrystalline cellulose, magnesium stearate, and film-forming agents - polymethacrylates, titanium dioxide, talc and the like. the said patents.

In all of these patents, multiple polymer coatings used may result in uneven release of the drug from the matrix both in vitro and in vivo. In addition, upon preparation of the high fat fat matrix drug - cetyl with a melting point of 49 ° C, it leads to technological difficulties - the sticking of the tablets on the pansons and dies during the tableting process as a result of developing mechanical heat.

SUMMARY OF THE INVENTION

A modified release drug containing tramadol hydrochloride of 200 mg to 600 mg and excipients in a weight ratio of 2: 1 to 1: 1 has been developed,

66008 B1 which are distributed as follows: microcrystalline cellulose 15 to 100 mg, anhydrous calcium hydrogen phosphate 10 to 80 mg, hydroxypropyl methylcellulose KI 5M 100 to 400 mg, copovidone 10 to 25 mg, magnesium stearate 1 to 10 mg and colloidal silica from 0.5 to 5 mg.

The principle of incorporation of the drug into a matrix structure using high molecular weight polymers such as hydroxypropylmethylcellulose, its ethers or esters is used to create a modified release drug of tramadol hydrochloride for 24 hours or more. The solubility of the drug from the matrix is influenced by the rate of hydration of the polymer used, which forms a gel layer around the surface of the matrix tablet and causes the diffusion principle to release the drug substantially over a longer period.

Cellulose polymer and in particular hydroxypropylmethylcellulose type 2208 fast hydrating (K) containing methoxy groups from 19 to 24% and hydroxypropoxy groups from 7 to 12% and a viscosity of 2% aqueous solution from 11250 to 21000 cP were used as the structure forming agent at 20 ° C, and as a binder copovidone (copolymer vinylpyrrolidone - vinyl acetate 6: 4) with a K-value of 26 to 34, a bulk density of 0.24 to 0.28 g / ml and a viscosity of 1% aqueous solution 1, 18 to 1.31 mPas at 25 ° C.

The method for preparing the modified release drug according to the invention is as follows. The specified amount of the drug is mixed with calcium hydrogen phosphate anhydrous and part of hydroxypropyl methylcellulose K15M and moistened with the prepared solution of copovidone and 96% ethanol. The humidified mass is granulated and dried at 40-45 ° C to a residual moisture of not more than 2%. The dry granulate was calibrated through a 0.8 mm sieve, to which was added the starting dose of the drug, microcrystalline cellulose, the rest of hydroxypropyl methylcellulose K15M, magnesium stearate and colloidal silica. The mixture was homogenized and tableted on a rotary tablet machine of circular double-convex punches with a diameter of 13 mm. The finished tablet cores are coated with an Opadry II HP aqueous slurry to mask the bitter taste.

The modified release drug according to the invention has the following advantages: a simplified composition which is readily reproducible in existing pharmaceutical equipment, the selected excipients provide very good physico-mechanical properties and the in vitro release of the drug within 24 hours and therapeutic plasma levels for more than 48 h, demonstrated by comparative bioavailability studies (Example 8).

Another advantage is the use of copovidone as a binder, in accordance with its hygroscopic properties impedes the influence of moisture during storage of the drug and determines the preparation of matrix tablets with a certain mechanical strength, an important indicator of the degree of dissolution of the drug, confirmation of this are in vitro studies.

The pharmacological action of the drug is guaranteed by the rates of dissolution of the drug, which are in accordance with the mode of dosing of the drug and meet modern requirements. This is expressed by the results obtained in Examples 2,4 and 6.

For the modified-release drug (MR) with tramadol hydrochloride 300 mg, the following dissolution rates have been established:

after 1 hour from 15 to 35 percent of the announced content after 2 hours from 20 to 45 percent of the announced content;

after 6 hours from 35 to 70 percent of the announced content;

after 8 hours from 55 to 80 percent of the announced content;

after 12 hours from 65 to 90 percent of the announced content;

after 18 hours from 75 to 95 percent of the announced content;

after 24 hours not less than 90 percent of the announced content.

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The proposal is illustrated by the following examples.

Example 1. Composition of a modified-release tablet containing 300 mg tramadol hydrochloride

Tramadol hydrochloride 300 mg

Hydroxypropyl methylcelluloseK15M 233 mg

Calcium hydrogen phosphate anhydrous 20 mg

Microcrystalline cellulose20 mg

Copovidone20 mg

Magnesium stearate 5 mg

Colloidal silica 2 mg Film coating20 mg

2,700 kg of tramadol hydrochloride are used to prepare 10,000 modified-release tablets according to the composition described; 2,030 kg of hydroxypropyl methylcellulose KI 5M and 0,200 kg of anhydrous calcium hydrogen phosphate, which are moistened with a solution of 0,200 kg of copovidone and 1,500 kg of 96% ethanol. The wetted mass is granulated through a sieve with a 2.5 mm bright opening. Dry at 40-45 ° C to a residual moisture content of not more than 2%. It is calibrated through a sieve with a 0.8 mm bright aperture. The starting dose of 0.300 kg tramadol hydrochloride, 0.300 kg hydroxypropyl methylcellulose K15M, 0.200 kg microcrystalline cellulose, 0.050 kg magnesium stearate and 0.020 kg colloidal silica were added to the dry granulate. After homogenisation in a turbulence mixer for 30 min, the mixture was tableted on a rotary tablet machine with circular double-convex punches of 13 mm diameter at a mechanical strength of the tablet over 10 kg. The tablets are coated with Opadry II HP aqueous slurry.

Example 2. In vitro test results for the degree of dissolution of tramadol hydrochloride from the composition of the proposed modified-release preparation containing 300 mg of tramadol hydrochloride (Table 1) The degree of dissolution of tramadol hydrochloride from the matrix tablets over a period of 24 h by the European Pharmacopoeia with Paddle method at a speed of 75 rpm at 37 ° C ± 0,5 ° C of the dissolution medium and pH 1,2 for the first 2 h and pH 6,8 to end of test (24 h).

Evaluation of the results of in vitro tests for the degree of dissolution of tramadol hydrochloride from the proposed modified release drug of example 1

Table 1

Tablet No Amount of dissolved tramadol hydrochloride, one hundred percent of the declared contents after 1 hour 2hm bye Sometimes 12 hour * 18 Hours 24 hours 1 192 292 53,6 63,4 77.0 89,1 100,1 2 192 29.0 523 61,1 76,9 86,9 982 3 182 27.6 50.7 59,7 73,0 85.5 96.7 4 19.5 29.0 53.5 63.5 76,3 892 101,7 5 19.8 28.5 54.5 63.5 77.1 893 100,0 6 19,9 29.7 55,4 63.5 78,9 892 100,1 Average value 19.3 28,8 53,4 62.5 762 88,3 99.6 Standard deviation 0.81 0.72 1.63 1.65 1.59 1.66 1.81 Relative standard deviation 3.18 2.50 3.05 2.64 2.09 1.88 1.81 Confidence interval! 0.64 0.76 1.71 1.73 2.19 1.74 1.90

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The data obtained indicate that the rates of dissolution of the drug substance from the matrix tablets, determined at hourly intervals of up to 24 ^ hours, are within the indicated norms with low values of standard deviation and relative standard deviation, which confirm the optimum selected composition and are a prerequisite for a very good bioavailability (see Example 8).

Example 3. Composition of a modified-release tablet containing 300 mg tramadol hydrochloride

Tramadol hydrochloride 300 mg Hydroxypropylmethylcellulose- vine K15M 200 mg Calcium hydrogen phosphate anhydrous 30 mg Microcrystalline cellulose 30 mg Copovidone 15 mg Magnesium stearate 5 mg

Colloidal silica 2 mg

2,700 kg of tramadol hydrochloride are used to prepare 10,000 tablets; the total amount of 2,000 kg of hydroxypropyl methylcellulose K15M, 0,300 kg of calcium hydrogen phosphate anhydrous, which are moistened with a solution of 0,150 kg of copovidone and 1,300 kg of 96% ethanol.

The humidified mass is granulated through a sieve with a clear opening of 2.5 mm, dried at 40-45 ° C to a residual moisture of not more than 2%. It is calibrated through a sieve with a light aperture of 0.8 5 mm. A starting dose of 0.300 kg tramadol hydrochloride, 0.300 kg microcrystalline cellulose, 0.150 kg magnesium stearate and 0.020 kg colloidal silica were added to the dry granulate. After homogenization, the mixture is tableted on a rotary tablet machine with round biconvex punches at a mechanical strength of more than 10 kg. The tablets are coated with an aqueous suspension of Opadry II HP.

Example 4. In vitro test results 15 for the degree of dissolution of tramadol hydrochloride from the composition of the proposed modified-release preparation containing 300 mg tramadol hydrochloride (Table 2)

In vitro dissolution rate tests for tramadol hydrochloride from the matrix tablets of Example 3 were performed according to the procedure of Example 1. The results obtained are very good and are shown in Table 2.

Evaluation of in vitro test results 25 for the degree of dissolution of tramadol hydrochloride from the proposed modified release drug of Example 3

Table 2

Tablet No Amount of dissolved tramadol hydrochloride, one hundred of the declared content after 1 hour 2:00 in the hour 8:00 12 hours 18 hours 24 hours 1 2X9 34.4 65,4 74,1 883 93,0 1043 2 2X0 3X8 663 753 883 93,6 1053 3 2X8 33.6 63,8 733 89,7 923 1033 4 24.5 36,1 68,8 77,4 91,1 953 106.0 5 243 34.4 66,7 763 893 94,4 1073 6 2X8 3X9 65,4 783 90,1 943 104,0 Average value 2X63 3437 68.05 75.77 89.70 9X78 105,1 Standard 0.64 0.91 1.67 1.45 0.82 1.08 1.60 Omocmmo sjyodarpi sglpotm » 2.71 2.65 237 1.94 0.91 1.75 132 Dormshmvi is a dead man 0.67 0.95 1,75 1.57 0.86 1.13 1.68

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Example 5. Composition of a modified-release tablet containing 300 mg tramadol hydrochloride

Tramadol hydrochloride 300 mg Hydroxypropylmethylcellulose- 5 vine K15M 170 mg Calcium hydrogen phosphate anhydrous 40 mg Microcrystalline cellulose 40 mg Copovidone 15 mg 10 Magnesium stearate 10 mg Colloidal silica 2 mg

The preparation of 10,000 modified-release tablets containing 300 mg of tramadol hydrochloride in Example 5 is analogous to that of Example 3.

Example 6. In vitro test results for the degree of dissolution of tramadol hydrochloride from the composition of the proposed modified release drug containing 300 mg of tramadol hydrochloride

The results of in vitro assays for the dissolution rate of tramadol hydrochloride from matrix tablets according to Example 5 are shown in Table 3.

The results obtained are in norms with respect to the degree of dissolution of tramadol hydrochloride and show low values of statistical processing for standard and relative standard deviation.

Evaluation of the results of in vitro tests for the degree of dissolution of tramadol hydrochloride from the proposed modified release drug of Example 5

Table 3

Tablet No Amount of dissolved tramadol hydrochloride, per cent of the declared content after 1 hour 2 pieces bye hour 12 pieces 18 hours 2 * scratch 1 223 323 63,4 713 85.1 933 993 2 22, β 32,7 64.0 71,7 86,0 92.7 99.7 3 23.9 34.0 643 723 87,1 95,0 102.0 4 24.4 35,0 67.0 733 873 96.1 101,1 5 24,0 34.6 67.0 75,0 88.9 98.4 103,8 6 23.3 33,0 633 73,7 89.5 983 103,8 Average value 23,4S 33.81 64.93 73.16 87,40 95.81 101.65 By default 0.77 1.00 136 136 1.70 2.46 1.91 Annoying standard ablation 328 0.99 236 1.72 1.94 237 1.88 Confidence interval 0.81 1,05 1.74 132 1.78 238 2.01

Example 7.

The results of the stability studies of the modified release medicinal product containing 300 mg of tramadol hydrochloride obtained according to examples 1,3 and 5 are presented in Tables 4,5 and 6. The studies show that the norms of the test parameters and profile do not change of in vitro dissolution of the drug for 36 months, the dissolution rate remaining the same within the suggested range at each interval (Tables 4, 5 and 6).

m

O *

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r l θ • »s About x y CM He responds not detected 0.02 0.05 0.07 · · · · · • a ·· · · · · "* In * cm <m yu" b- "a> τ- VI julo b- eo ar ·· O 0 £ o J M ^- s H Ω ^N g N MG ” He responds not detected 0.01 0.03 0.04 a ® ο ο <o y o Ο CO f N y s s · - see y o u s co a 308,0 90 days / 40 ° C  1 year Answers j not detected 0.01 0.04 0.05 * a co o co o a'co'n n co b a T- NIOObOOa 307,8 Initial analysis He responds not detected 0.01 0.04 0.05 n co t yu n m © a '© ri n © y a τ- cm io © yua 308,3 Norms White, round, biconvex 13 mm film coated tablets not more than 0,2 not more than 0,3 not more than 0,2 not more than 0,5 - after 1 hour: 15-35 - after 2 hours: 20-45 - after 6 hours: 35-70 - after 8 hours: 55-80 - after 12 hours: 85-90 - after 6pm: 75-95 - after 24 hours: no more less than 90 300 mg ± 5% (285.0-315.0) Indicators Appearance Content related SUBSTANCES,% - MIXTURE IS E-MIXTURE - EVERY OTHER MIXTURE - TOTAL DEGREE OF DISSOLUTION OF TRAMADOL HYDROCHLORIDE,% OF THE CONTENTS Tramadol hydrochloride content in 1 tablet, mg

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Test results for stability of the proposed modified release drug containing 300 mg tramadol hydrochloride according to Example 3 Monitoring conditions: in a thermostat at (40 ± 2) ° C and (75 ± 5)% RH

Packaging: PVC foil / aluminum foil blisters

e & O ? ° X S O X 2 x n θ n Ci He responds not detected 0.02 0.04 0.05 88-8I-83-J ·. Ο ^β X ο £ V χ U co He responds not detected 0.02 0.03 0.05 CO O MS © T- f * 4 co hg © yo a »sch § SCHP ® N Ο O) ° 303,9 90 days / 40 ° C  1 year He responds not detected 0.01 0.04 0.05 t- co o a »o» a »* 4 aasisss 304,1 Initial analysis He responds not detected 0.01 0.03 0.04 s> n About CO b · CO 'Ί 838E838 303,4 Norms White, round, biconvex 13 mm film coated tablets not more than 0,2 not more than 0,3 not more than 0,2 not more than 0,5 !? 3S888 έ8 to o y o u o u e t N & S © N x O T- <4 U SO CO M CO 'C ΙίΙίίί! 1 1 1 1 1 1 1 300 mg ± 5% (285.0-315.0) Indicators Appearance Content of related substances,% - MIXTURE F - MIXTURE A - EVERY OTHER impurity is “TOTAL Dissolution rate of TRAMADOL HYDROCHLORIDE,% OF THE DECLARED CONTENT Tramadol hydrochloride content in 1 tablet, mg

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Test results for the stability of the proposed modified-release drug containing 300 mg tramadol hydrochloride according to Example 5 Observation conditions: in a thermostat at (40 ± 2) ° C and (75 ± 5)% RH

Packaging: PVC foil / aluminum foil blisters

mg 270 days / 40 ° C = 3 years He responds not detected 0.03 0.05 0.06 • e e her ·· e e its a m « t- <O «h ao <p» · «* · * ·« E »· · <n <o <schu • e **> ι e? - ^! · 180 days / 40 ° C  2 years He responds not detected 0.01 0.05 0.06 io e o »e» <o CM, see co S 'to c £ θ 305,2 1 ................................................. .................................................. .................................................. .................................................. .................................................. ........................................ 90 days / 40 ° C = 1 year He responds not detected 0.02 0.04 0.06 <O CM Yu CO CD 09 CM N CO CO CD 5 X CM «CD K CO O) ° 305,3 t 1 He responds not detected 0.01 0.04 0.05 yu a n v® ®. η η <η S ιό Σ CM to io G- co 6 »° 305,1 about X White, round, biconvex 13 mm film coated tablets not more than 0,2 not more than 0,3 not more than 0,2 not more than 0,5 -after 1 hour: 15-35 - after 2 hours: 20-45 - after 6 hours: 35-70 - after 8 hours: 55-80 - after 12 hours: 65-90 - after 6pm: 75-85 - after 24 hours: no more less than 90 300 mg ± 5% (285.0-315.0) Indicators Appearance Content related SUBSTANCES,% - MIXTURE F - MIXTURE A - EVERY OTHER MIXTURE - TOTAL Dissolution rate of TRAMADOL HYDROCHLORIDE,% of declared content Tramadol hydrochloride content in 1 tablet, mg

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Example 8

Results of comparative bioavailability of a modified release drug containing 300 mg of tramadol hydrochloride of the proposed composition according to Example 1, designated Test and the selected comparative model designated Reference (Table 7 and Figures 1 and 2).

Table 7

TE8T (P “12) Variable geom.meen ari№m.mean SD range metfian AUCO4ast ¹ [pdPjpC 3778.67 3987.26 15439.56 2411.66-8133.92 3439.36 Cmax ¹ [pdjlC 230.34 235.60 54.03 171.85-347.09 225.70 Traxfh] - 4.83 1.11 4.00-8.00 5.00 REFERENCES (ηΜ2) ** - * - butts deot. meen ari№m.mean SD range median AUCfMast ¹ [n0 * MPC 3476.56 3741.25 16829.39 1838.13 - 8339.66 3282.06 Cmax ¹ [ngftmL] 291.73 298.31 67.71 203.07-442.15 285.43 Tmax pi] - 4.83 0.39 4.00-5.00 5.00

Comparative evaluation of rhesus pharmacokinetic studies in diarrhea shows that the mean values of the pharmacokinetic parameters -AUC ^ [ng.h / ml], C _№ [ng / ml] and t _max [h] are the main characteristics of the degree and rate of the absorption of the drug substance according to the proposed composition according to example 1, designated as Test, have better values than the selected sample (Reference), which is a guarantee that a highly effective preparation with a better therapeutic effect is created.

Claims (3)

Claims 1. A modified-release drug containing tramadol hydrochloride and excipients calcium hydrogen phosphate, colloidal silica and magnesium-4θ eu stearate, characterized in that they are in a weight ratio of 2: 1 to 1: 1 and have the following amounts ratios: tramadol hydrochloride 200 to 600 mg, microcrystalline cellulose 15 to 100 mg, calcium hydrogen phosphate anhydrous 45- 10 mg, hydroxypropyl methylcellulose K15M 100 to 400 mg, copovidone 10 to 25 mg, magnesium stearate from 1 to 10 mg and colloidal silica from 0.5 to 5 mg, where 10% of the amount of tramadol hydrochloride is formed as a "starting dose". A medicament according to claim 1, characterized in that the cellulose polymer and in particular hydroxypropyl methylcellulose type 2208 fast hydrating (K) containing methoxy groups of 19 to 24% and hydroxypropoxyl groups of 7 are used as a structure forming agent. to 12% and a viscosity of 2% aqueous solution from 11250 to 21000 cP at 20 ° C. Medicament according to claim 1, characterized in that copovidone, a vinylpyrrolidone-6-vinyl acetate / copolymer copolymer, is used as a binder for granulating tramadol hydrochloride, calcium hydrogen phosphate and hydroxypropylmethylcellulose K15M: 26 to 34, a bulk density of 0.24 to 0.28 g / ml and a viscosity of 1% aqueous solution of 1.18 to 1.31 mPas, at 25 ° C.