Immediate-released tablet

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to peroral immediate-released drug in solid form, containing low molecular thrombin inhibitor based on peptide with pH-depending solubility. Claimed drug has size particle less than 300 mum and contains combination of microcrystal cellulose and sodium glycolate starch in amount of more than 35 mass % (calculates as preparation mass).

EFFECT: drug with reduced dependence of thrombin inhibitor dissolution from pH and increased releasing rate from tablet.

17 cl, 3 ex, 3 dwg

 

The scope of the invention

This invention relates to a solid dosage form low molecular weight thrombin inhibitor prepared in the form of tablets with immediate-release (HB), and the method of its preparation. The invention also relates to the medical use of the drug for prevention and/or treatment of thromboembolism.

Background of the invention

Thrombin inhibitor used in the preparation of the present invention is a low molecular weight drug with pH-dependent solubility. It is characterized by low solubility under basic pH values, which dramatically increases the protonated form at acidic pH values. Thus, with the introduction in the traditional HB drugs fast dissolution of the drug is achieved at acidic pH, while noticeably slower dissolution is achieved at more neutral pH values. This variability in the dissolution unacceptable for safe, effective and comfortable therapy. In the present invention is proposed drug immediate-release, based on traditional cooking methods with carefully chosen excipients, which provides a dissolution, independent or very weakly dependent on pH.

Offered some RA the different ways of preparation of solid dosage forms with immediate-release.

Lachman, theory and practice of industrial pharmacy, 1986, 343, appA) describes the composition and preparation of two different standard granulates for HB tablets. These two songs gave very poor quality of the pellets, which was unacceptable tablets with very low strength. These compositions do not operate with a low molecular weight thrombin inhibitors used in connection with the present invention. Tablets do not meet the definition instant medicinal product is presented in the Guidance for Industry. Waiver of in Vivo Bioavailability and Bioequivalens Studies for Immediate Release Solids Dosage Forms Containing Certain Active Moieties/Active Ingredients Based on Biopharmaceutics Classification System (Guide for industry in case of refusal from the study of in vivo bioavailability and bioequivalence studies for solid dosage forms with immediate-release containing certain active groups/active ingredients based on the biopharmaceutical classification system). Tablets should be released 85% or more of a set number within 30 minutes.

Description of the invention

Found that low molecular weight thrombin inhibitors based on the peptide with pH-dependent solubility - including their salts can be prepared in the form of HB tablets with independent or very little pH-dependent dissolution.

Therefore, the purpose of this image is to be placed is the creation of a new pharmaceutical drug, containing low molecular weight thrombin inhibitor-based peptide, in the form of HB tablets with independent or very little depending on the pH of the dissolution and the method of obtaining such a drug.

Thrombin inhibitors referred to in this application are low molecular weight thrombin inhibitors based on the peptide with pH-dependent solubility. The expression "low molecular weight thrombin inhibitors based on peptide", as it is obvious to experts in the field of technology include thrombin inhibitors, peptide bonded in the amount of from one to four and/or with molecular weight below 1000, and covers those inhibitors that are described in General and, more preferably, in detail in a review article Claesson in Blood Coagul. Fibrin. (1994) 5, 411, and also disclosed in U.S. patent No.4346078; international patent applications WO 97/23499, WO 97/02284, WO 97/46577, WO 98/01422, WO 93/05069, WO 93/11152, WO 95/23609, WO 95/35309, WO 96/25426, WO 94/29336, WO 93/18060 and WO 95/01168; and applications to the European patent 623596, 648780, 468231, 559046, 641779, 185390, 526877, 542525, 195212, 362002, 364344, 530167, 293881, 686642, 669317 and 601459.

Preferred low molecular weight thrombin inhibitors based on the peptide include those that are known collectively as "atrani". Specific atrani that may be mentioned include HOOC-CH2(R)Cha-Pic-Nag-H (known as inogatran; see international patent application WO 93/11152 and list of abbreviations in it, noos-CH 2-(R)Cgl-Aze-Pab-H (known as melagatran; international patent application WO 94/29336 and list of abbreviations in it).

Preferred low molecular weight thrombin inhibitor-based peptide selected from the group consisting of inogatran, ([2R-[2S]]-N-[2-[2-[[[3-[(aminoiminomethyl)amino]propyl]amino]carbonyl]-1-piperidinyl]-1-(cyclohexylmethyl)-2-oxoethyl]glycine), melagatran ([2R-[2S]]-N-[2-[2-[[[[4(aminoiminomethyl)phenyl]methyl]amino]the carbonyl]-1-azetidine]-1-cyclohexyl-2-oxoethyl]-glycine) and compound A (ethyl ester of [S-(R*, S*)]-N-[1-cyclohexyl-2-[2-[[[[4-[(hydroxyimino)aminomethyl]phenyl]methyl]amino]carbonyl]-1-azetidine]-2-oxoethyl]glycine).

Particularly preferred low molecular weight thrombin inhibitor Compound And effective for the treatment of thromboembolism. Connection As described in the international patent application WO 97/23499. The compound a is a low molecular weight thrombin inhibitor with good oral bioavailability, low volatility and limited interaction with food. Not reported no solid dosage forms containing this inhibitor of thrombin.

To prepare tablets, providing for dissolution, which is not affected or very little depends on the pH, the connection And should have a particle size less than 300 microns, preferably less than 150 microns and the preferred average particle size of men who e than 80 μm. For other low molecular weight thrombin inhibitor with a low solubility under basic pH values and pH-dependent solubility requirements for particle size will depend on the extent of the low solubility.

Discovered that by careful selection of excipients dependence of dissolution from pH can be reduced, and the release of the tablet may comprise more than 85% in 30 minutes in both acidic and neutral environment. This is despite the fact that the Connection And is extremely pH-dependent solubility.

The preparation according to the invention includes a thrombin inhibitor, a filler or combination of fillers, and the specified filler/fillers are loosening properties (due to swelling) and may not swelling(s) filler(s), baking powder(and)that bind(s) substance(s) and/or lubricant(s) substance(s).

The amount of filler/fillers having loosening properties, is more than 35% (wt./mass.), preferably more than 50% (wt./mass.) drug.

Some excipients can serve several purposes, for example to be filled and at the same time the baking powder. Excipient used in large quantities than 35%, the present invention is defined as the filler, but can carry other important drug properties, such as razril the tion, linking or streaks.

Filler with loosening properties selected from the group consisting of cellulose itself (such as microcrystalline cellulose, super fine grain cellulose), starch itself (such as maize starch, starch glycolate, sodium, potato starch, rice starch, wheat starch).

Nanabhai filler selected from the group of sugars such as mannitol, sorbitol, glucose, xylitol, sucrose, lactose).

Baking powder selected from the group consisting of cellulose itself (such as microcrystalline cellulose, super fine grain cellulose, Poperechnaya sodium carboxymethylcellulose, Poperechnaya hydroxypropylcellulose, starch itself (such as starch glycolate, sodium, pre-gelatinizing starch, maize starch, potato starch, rice starch, wheat starch), and other (such as poperechnyy polyvinylpyrrolidone, cation exchange resin).

Binder selected from the group consisting of cellulose itself (such as sodium carboxymethylcellulose, hydroxypropylcellulose, hypromellose, methylcellulose), polymers (such as polyvinylpyrrolidone, polyethylene glycol), types of gelatin (such as hydrolyzed gelatin) and traditional binding substances (such as grahm is l, natural gum).

Lubricating substance selected from the group consisting of insoluble lubricants (such as magnesium stearate, calcium stearate, zinc stearate, stearic acid, oil, talc, sodium fumarate) and soluble lubricants (such as polyethylene glycol, sodium benzoate, sodium lauryl sulphate).

In the preparation according to the invention preferably included different components in the following proportions, calculated in percent mass./mass. end tablets:

Thrombin inhibitor: 1-35%, preferably 1-15%.

Filler: 35-90%, preferably 45-80%, in the case of microcrystalline cellulose 50-90%, preferably 60-80%, and most preferably 72-76%, in the case nanobuduschego filler 0-50%, in the case of mannitol, 0-15%, preferably 5-10%.

Baking powder: 0-35%, preferably 7-35%, in the case of starch glycolate, sodium 3-20%, preferably 5-10%.

Binder: 0-15%, preferably 4-12%, in the case of polyvinylpyrrolidone 3-15%, preferably 5-10%.

Grease: 0-5%, preferably 0.5 to 1.5%, in the case of fumarate sodium 0.5 to 1.5%, preferably more than 1%.

In the invention found that a preparation containing the active ingredient with a particle size less than 300 microns, preferably less than 150 microns, with a preferred average particle size of less than 80 μm, fill the Lee (for example, microcrystalline cellulose (50-90%, preferably 74%), mannitol (0-15%, preferably of 8.5%), baking powder (for example, starch glycolate, sodium 3-20%, preferably of 8.5%), moistened with a suitable binding substance (for example, polyvinylpyrrolidone K 90 (3-15%, preferably 8%)and finally mixed with a suitable lubricant (e.g., sodium fumarate (0.5 to 1.5%, preferably 1%)), provides the tablet with good technical properties and very little dependent on the pH of the dissolution.

The preparations according to the invention can be preferably prepared either by pressing or by wet granulation.

Direct pressing

Low molecular weight thrombin inhibitor mixed with a filler or fillers and, if necessary, baking powder. This mixture is then mixed with the lubricant and pressed into tablets.

Wet granulation

Low molecular weight thrombin inhibitor mixed with a filler or fillers and, if necessary, baking powder. This mixture is then moistened with a suitable solvent which can be dissolved binder. After drying, the granulate is milled and then mixed with the lubricant and pressed into tablets.

Working examples

Example 1. The dissolution of drug Stapleton according to the invention

HB tablets thrombin inhibitor, Compound A, was obtained by mixing Compounds And, microcrystalline cellulose, starch glycolate, sodium and mannitol. This mixture was moistened with a suitable amount of polyvinylpyrrolidone To 90 dissolved in water. After drying, the granules were crushed and then mixed with sodium fumarate and compressed into tablets.

The obtained tablets were analyzed in relation to the dissolution of the Connection And using the apparatus for dissolving No. 2 (paddle) according to U.S. Pharmacopeia (USP), 100 rpm, 500 ml of the medium Used for the dissolution had a temperature of 37°C. Used two different environments dissolution, 0.1 M HCl (pH 1 and phosphate buffer pH 6.8 (ionic strength of 0.1). The released amount of the Compound As determined by UV-spectrophotometry.

The results are shown in figure 1. After 30 minutes, the amount of dissolved Compounds And accounted for 94% (average n=3) in 0.1 M HCl and 94% (average n=3) in phosphate buffer pH 6.8.

Example 1B. The dissolution of drug from the tablets according to the invention

HB tablets thrombin inhibitor, Compound A, was obtained by mixing Compounds And, microcrystalline cellulose maize starch, and the mixture was moistened with a suitable quantity of maize starch (paste). After drying, the granules were crushed and then mixed with poperechnoi the m polyvinylpyrrolidone. Finally was mixed into the sodium fumarate, and the granulate was compressed into tablets.

The resulting pellets were analyzed by dissolving Compound a according to the method described in Example 1. The results are shown in figure 2. After 30 minutes, the amount of dissolved Compounds And was 100% (average n=3) in 0.1 M HCl and 97% (average n=3) in phosphate buffer pH 6.8.

Example 2. The dissolution of drug from the tablets according to the link

Lachman, theory and practice of industrial pharmacy, 1986, 343, appA) describes a different composition and preparation of "standard" distributions for HB tablets. HB tablets thrombin inhibitor, Compound A, prepared according to the method of mixing the Compounds a and tricalcium phosphate, and the mixture was moistened pre-gelatinization maize starch dissolved in water. After drying, the granules were crushed and then mixed with talc. Finally, was mixed into mineral oil, and the granulate was compressed into tablets.

The resulting pellets were analyzed by dissolving Compound a according to the method described in Example 1. The results are shown in figure 2. After 30 minutes, the amount of dissolved Compounds And 40% (average n=3) in 0.1 M HCl and 5% (average n=3) in phosphate buffer pH 6.8.

Example 3. The dissolution of drug from the Ableton according to the link

Lachman, theory and practice of industrial pharmacy, 1986, 343, appA) describes the composition and preparation of the other "standard" distributions for HB tablets. HB tablets thrombin inhibitor, Compound A, prepared according to the method of mixing the Compounds a and lactose, and the mixture was moistened starch dissolved in water.

After drying, the granules were crushed and then mixed with the dry starch and talc. Finally, was mixed into mineral oil, and the granulate was compressed into tablets.

The resulting pellets were analyzed by dissolving Compound a according to the method described in Example 1. The results are shown in Figure 3. After 30 minutes, the amount of dissolved Compounds And was 100% (average n=3) in 0.1 M HCl and 74% (average n=3) in phosphate buffer pH 6.8.

A brief description of graphic materials

Figure 1: Dissolution inhibitor of thrombin Connection And from the tablets according to the invention as described in Example 1. (No graphics for example 1B not shown).

Figure 2: Dissolution inhibitor of thrombin Connection And from the tablets according to the link, as described in Example 2.

Figure 3: Dissolution inhibitor of thrombin Connection And from the tablets according to the link, as described in Example 3.

Conclusion (Examples)

From the Examples it is obvious that a sufficient quality of the product is not achieved when using "Stan artego" granulate. Or technical properties are poor [Example 2 and 3], and/or dissolution in phosphate buffer pH 6.8 does not meet the definition of rapidly dissolving drug products Guidance for Industry. Waiver of in Vivo Bioavailability and Bioequivalens Studies for Immediate Release Solids Dosage Forms Containing Certain Active Moieties/Active Ingredients Based on Biopharmaceutics Classification System. In the preparation according to the invention dissolve in both environments quick and excellent technical properties.

1. Oral immediate-release in solid form, containing (a) a low molecular weight thrombin inhibitor-based peptide, which is dependent on pH solubility and having a particle size less than 300 microns, and (b) a combination of microcrystalline cellulose and starch glycolate, sodium in amounts of more than 35% (wt./wt.) drug.

2. Oral preparation according to claim 1, characterized in that this medication may contain sugar, baking powder, binder and/or grease.

3. Oral preparation according to claim 1, characterized in that the inhibitor of thrombin has a particle size of less than 150 microns and the preferred average particle size less than 80 microns.

4. Oral preparation according to claim 1, characterized in that it further comprises mannitol.

5. Oral preparation according to claim 1, wherein the microcrystalline cellulose is 50-90% (wt./wt.) drug.

6. P is Moralny the drug according to claim 4, wherein the mannitol is 0-15% (wt./wt.) drug.

7. Oral preparation according to claim 1, where the starch glycolate, sodium is 3-20% (wt./wt.) drug.

8. Oral preparation according to claim 1, which contains the binder.

9. Oral preparation of claim 8, where the binder comprises up to 15% (wt./wt.) drug.

10. Oral preparation of claim 8 or 9, where the binder is polyvinylpyrrolidone.

11. Oral preparation according to claim 1, where the inhibitor of thrombin is 1-35% (wt./wt.) drug.

12. Oral preparation according to claim 1, where the thrombin inhibitor is selected from the group consisting of inogatran, melagatran and ethyl ester [S-(R*,S*)]-N-[1-cyclohexyl-2-[2-[[[[4-[(hydroxyimino)aminomethyl]-phenyl]methyl]amino]carbonyl]-1-azetidine]-2-oxoethyl]glycine.

13. Oral preparation according to any one of claims 1 to 12, where the thrombin inhibitor is an ethyl ester of [S-(R*,S*)]-N-[1-cyclohexyl-2-[2-[[[[4-[(hydroxyimino)aminomethyl]phenyl]methyl]amino]carbonyl]-1-azetidine]-2-oxoethyl]glycine.

14. Oral preparation according to claim 1, which contains:

thrombin inhibitor 1-35% (wt./wt.);

microcrystalline cellulose 50-90% (wt./wt.);

the starch glycolate, sodium 3-20% (wt./wt.);

mannitol 0-15% (wt./wt.);

polyvinylpyrrolidone K-90 3-15% (wt./wt.) and

fumarate on who model 0.5 to 1.5% (wt./wt.).

15. Oral preparation according to claim 1 for use in therapy.

16. Oral preparation according to claim 1 for use in the prevention and/or treatment of thromboembolism.

17. Method of preparation of oral drug immediate-release formulation according to claim 1, in which the low molecular weight thrombin inhibitor-based peptide, which is dependent on pH solubility and having a particle size less than 300 microns, is mixed with a combination of microcrystalline cellulose and starch glycolate, sodium in amounts of more than 35% (wt./wt.) preparation and add the appropriate excipients, followed by direct compaction or wet granulation of the mixture.



 

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