UA116784C2 - A solid oral pharmaceutical formulation containing ticagrelor - Google Patents

Abstract

The present solution provides a solid oral pharmaceutical formulation containing ticagrelor, in the chemical name (1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol, comprising at least one non-hygroscopic filler and/or at least one non-hygroscopic binder, wherein neither the filler, nor the binder have any disintegration effect. Preparation of the formulation is possible by wet granulation or dry granulation or direct.

Description

Field of invention

The present invention relates to a solid oral pharmaceutical composition containing ticagrelor as an active pharmaceutical ingredient, and a method of preparing such a composition.

Technical level

The compound ticagrelor, which has the chemical name (15,25,3E,55)-3-I7-C1A,25)-2-(3,4-difluorophenyl)cyclopropyl|amino|-5-(propylthio)-Z3H-1, 2,3-triazolo|4,5-4|pyrimidin-Z3-yl|-5-(2-hydroxyethoxy)-1,2-cyclopentanediol, represented by the formula (I), on nm sele nosha A, pno OH (I) is generally described in UMO 1999/005143 and specifically named in EP 1135391. This document also describes the method of its preparation, as well as the use of ticagrelor in the treatment or prevention of myocardial infarction, stroke, peripheral vascular diseases, etc. UMO 2001/092262 describes 4 polymorphs and an amorphous form of ticagrelor. UMO 2011/067571 describes co-crystals with various coformers, such as glycolic, salicylic, succinic, malonic 15. and 4-hydroxy-3-methoxybenzenecarboxylic acids.

Pharmaceutical compositions were described in 2 applications of Aviga 7epesa, MO 2008/024044 and UMO 2008/024045. UMO 2008/024044 describes a solid composition containing one or more fillers, one or more binders, preferably one or more disintegrating agents and preferably one or more lubricants. According to Example 1

UMO2008/024044 the sodium salt of carboxymethyluromalt was used as a disintegrating agent in the amount of C mass. This document does not mention any example without the use of a disintegrating agent. MO2008/024045 describes a very similar solid composition containing one or more fillers, one or more binders, preferably one or more disintegrating agents and preferably one or more lubricants. This document states that the use of disintegrating agents is necessary. Specific examples indicated in the document contain 2-6 wt.95 of a disintegrating agent, which is a sodium salt of carboxymethyl starch.

UMO 2011/076749 describes the size of the ticagrelor particles used in the composition, since ticagrelor is well known as a poorly soluble compound. In the specified examples in this application

The disintegrating agents were used in amounts in the range of 4-6 wt.95.

Ticagrelor is sold under the trade name Vgyidie for the prevention of arteriothrombotic cases in the form of coated tablets. The composition available on the market contains the sodium salt of carboxymethyl starch as a disintegrating agent.

Description of the invention

The present invention relates to a solid oral composition containing ticagrelor with the chemical name (15,25,3К,55)-3-(7-I((18,25)-2-(3,4-difluorophenyl)cyclopropyl|amino | - (propylthio)-ZH-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-5-(2-hydroxyethoxy)-1,2-cyclopentanediol, which additionally contains at least one non-hygroscopic filler and /or at least one non-hygroscopic binder that does not have a disintegrating effect.

Non-hygroscopic filler means a water-soluble filler, sugar alcohols are generally preferred, such as glucose, fructose, sucrose, lactose monohydrate, lactose anhydrous, raffinose, isomaltose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol, compressed sugars. Hydroxypropyl cellulose or maltose, for example, can be used as a non-hygroscopic binder. The composition according to the present invention preferably contains 0.5-30 wt. 90 of a binder, preferably 1-7 wt. 90 of a binder and most preferably 2-4 wt. 95 of a binder.

The term non-hygroscopic, as used in this application, refers to a material that has a low ability to absorb and retain water. Or, even better, the term non-hygroscopic refers to a material that has an equilibrium moisture content of less than 6 wt.9o. This value is determined using the dynamic sorption of steam (0M5) at a relative humidity of 6095 and a temperature of 25 "С. The moisture content at equilibrium is determined by the isothermal sorption curve using the YuUz5 method at a relative humidity of 6095 and a temperature of 25 76.

A specialist in this field knows that the use of disintegrating agents in the composition does not necessarily have an effect on increasing the bioavailability of the active substance. This property is more influenced by sufficient hydration of the active substance present in the composition. If such a composition can be obtained that will dissolve quickly enough without the use of disintegrating agents, the disintegrating agents only become an extra ingredient that has no real effect.

Disintegrating agents are a class of excipients that are generally considered specialty excipients. The price of special excipients, that is, disintegrating agents, is much higher than the price of commonly used excipients, such as fillers. The cost of disintegrating agents such as carboxymethyl starch sodium or croscarmellose sodium can typically be several times the cost of traditional bulking agents such as mannitol or calcium hydrogen phosphate.

The mode of action of disintegrating agents is still unknown. Mechanisms that have been hypothesized in the past include, for example, water infiltration, swelling, shape memory, repulsion of other ingredients, heating during hydration. The ability of disintegrating agents to absorb water into the porous network of the tablet is essential for effective disintegration, this explanation was provided by Epsusioraedia oi Rpagtaseciisa! Tesppoiodu, Zga ie5ce, Iptopta Neayysage

BA, Ips., 2007. As a natural consequence of the ability to absorb water in tablets, disintegrating agents are generally hygroscopic or very hygroscopic materials. According to NaparookKoi

Rpaptaseshiisa! Ehsiriepi5, the battle will arise, Rpagtaseciysa! Rge55, 2009 sodium salt of croscarmellose and sodium salt of carboxymethyl starch show the same characteristics.

Due to the hygroscopic nature of the excipients, it is necessary to pack the composition of ticagrelor in

RMS/RUMOS blisters. The use of non-hygroscopic blister packs provides an opportunity to replace expensive RMB/RMOS with more affordable RMS blisters. Regarding the lower price of excipients and lower packaging costs, it is desirable to obtain a composition containing non-hygroscopic excipients that do not have any disintegrating action.

In UMO2008/024045 it is described that the use of a composition containing one or more excipients, one or more binders, preferably one or more disintegrating agents and preferably one or more lubricants is suitable for the effective release of at least 9095 ticagrelor. Contrary to what is described in the prior art, we have found that a composition of ticagrelor with any known form of ticagrelor (crystalline, amorphous or semi-crystalline form) containing at least one non-hygroscopic excipient and/or at least one non-hygroscopic binder a substance that does not have a disintegrating effect will contribute to the effective release of at least 9090 ticagrelor.

The term "disintegrating agent" as used in this application refers to any material that swells or oozes when in contact with water. The term disintegrating agent includes, for example, a group of compounds such as: povidone, crospovidone, starch, peptized starch, carboxymethyl cellulose sodium, hydroxypropyl starch, microcrystalline cellulose, carboxymethyl cellulose calcium, cross-linked carboxymethyl cellulose sodium, polacrilin potassium, low hydroxypropyl cellulose , sodium or calcium alginate, sodium docusate, methylcellulose, agar, guar gum, chitosan, and alginic acid. The formulation of ticagrelor traditionally contains no or less than 295 disintegrating agents.

In the most preferred embodiment, the pharmaceutical composition of ticagrelor is essentially free of a disintegrating agent.

The composition of ticagrelor contains a non-hygroscopic filler. In general, a water-soluble filler is preferred. Suitable excipients are, for example, monosaccharides, oligosaccharides and sugar alcohols such as glucose, fructose, sucrose, lactose monohydrate, lactose anhydrous, raffinose, isomaltose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol and lactitol, compressed sugars , calcium hydrogen phosphate dihydrate and their mixtures. Lactose, mannitol and xylitol are preferred.

The composition of ticagrelor contains a non-hygroscopic binder. Suitable binders are, for example, povidone, copovidone, powdered, crystalline or microcrystalline cellulose, siliconized microcrystalline cellulose, cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylmethylcellulose, starch, peptized starch, polymethacrylates and mixtures thereof. A preferred composition of ticagrelor 60 contains from 0.5 to 30 wt.95 of a binder, preferably from 1 to 795 and most traditionally from 2 to 4 wt.90 of a binder.

The ticagrelor formulation typically contains at least 1 surfactant.

Suitable surfactants are, for example, anionic, cationic, ampholytic and/or nonionic surfactants, such as sodium lauryl sulfate, cetrimide, M-dodecyl-M,M-dimethylbetaine, polysorbates (e.g. Tueep5F), poloxamers and their mixture

Sodium lauryl sulfate is the preferred compound. The surfactant is used in the composition of ticagrelor in an amount in the range from 0.1 to 4.0 wt.95, most preferably in the range from 0.5 to 2.095.

The ticagrelor formulation typically contains at least 1 lubricant and/or anti-adhesive compound selected from, for example, magnesium stearate, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearin fumarate, colloidal silicon dioxide, magnesium trisilicate, and mixtures thereof. Stearic acid, magnesium stearate, sodium stearin fumarate and colloidal silicon dioxide are particularly preferred.

The ticagrelor tablet may be conventionally coated with any suitable coating.

A suitable coating agent for ticagrelor tablets is selected from, for example, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl dmellose, acrylic acid polymers, ethyl cellulose, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl alcohol, sodium carboxymethyl cellulose, cellulose acetate, gelatin, methacrylic acid copolymers, polyethylene glycol, shellac, sucrose, titanium dioxide and carnauba wax. Polyethylene glycol, hydroxypropyl methylcellulose, and polyvinyl alcohol are preferred.

Examples

Example 1

Wet granulation 1111111171171717171717171717171717171717LA twist | tE | that ts | tn Active

Ticagrelor substance

Lactose monohydrate | Filler | 800. | 11,500, 1

Xylitol Filler 1,800| | 1 (1506, 1 1

Manit Filler! | (15001 1 1 18001 1

Maltite Filler 31.1 11506| 11 8003

Hydroxypropyl Binding roxypr in zv | 3.6 zv | 3.6 cellulose substance

Binding

Maltose U 36 | 3.6 36 | 3.6 substance

Surface-

Active sodium lauryl sulfate 3.0 3.0 3.0 3.0 substance

Lactose monohydrate | Filler | 1074 | 111 185041

Xylitol Filler 102, 3111 11074,

Manit Filler| | 1274! 1 1 1 104

Maltose Filler! 011701, 574, | 1

Stearathmate | Lubricant | 60 1 60 6060 60 601 601 60

Total (mg) 13000 |300.0| 300.0 | 300.0 | 300.0 | 300.0 | 300.0 | 300.0

Ticagrelor is wet granulated with lactose monohydrate or xylitol, or mannitol, or maltitol (using kneading granulation or using a conventional fluidized bed granulator) with an aqueous solution of hydroxypropyldelulose or maltose. Sodium lauryl sulfate was preferably added to the granulation solution.

The obtained granulate was dried and sieved through a 1 mm sieve. The sieved granulate was then mixed with lactose monohydrate or xylitol or mannitol or isomaltose or maltose in a suitable mixing device for 20 minutes. After this preliminary mixing, magnesium stearate was added to the mixture and the mixture was stirred for another 3 minutes in such a way that a suitable mixture for tableting could be obtained. This mixture was then compressed in a rotary tabletting device.

Example 2

Dry granulation 71777771 2A | 2 in | 26 | 20 | 2E | ge tyuetyutr oyesha | 500 | ab | wow | vno in oo

Ticagrelor substance

Mant 00000 Filler; 1200 | 1 |600| M 1

Monohydrolactose |Filler| 00012001 1.1 1600| 5.

ZhKsylt 0000000 Filler; 10101101 1200) | | 1606

Sodium Surface lauryl sulfate active 3.0 3.0 3.0 substance

Monohydrolactose |Filler| 81011551

Xylt 0000000 Filler), 10101011 8401 30303100 01

Mant 0000 Filler; 11011001 8101 33030311

Pzomaltose 0 |Filler| 10101170 0 | 156

Maltose 0000 Filler) 31010131 40,

Lacquer 000 Filler), 33101011 | 40

Stearathium Lubricant | 60 | 60 | 60 | 60 | 60 | 60

Total (m) 1 | 3000 | 300 | 3000 | 300 | 3000 | 300

Ticagrelor was granulated under dry conditions with mannitol, or lactose monohydrate, or xylitol and preferably with sodium lauryl sulfate in a rotary thickener with a variable gap size. The obtained granulate was dried and sieved through a 1 mm sieve. The sieved granulate was mixed with lactose monohydrate, or xylitol, or mannitol, or isomaltose, or maltose, or lactitol in a suitable mixing device for 20 minutes. After preliminary mixing, magnesium stearate was added to the mixture and the mixture was stirred for another 3 minutes so that a mixture suitable for tableting could be obtained. This mixture was then compressed into tablets in a rotary tabletting device.

Example C

Direct pressing

О07ОЮ5-2020207--1Т , Di - Г13Аи зв з3сИ 30 | ZE ZE tyutenor redvia | 00 500 | ooh ooh ooh

Ticagrelor substance

NOT KT ES NI PON NANNYA ON PAK lactose

Zhksilit 0000 Filler | 0001 2040, 5111

Manto 00000 Filler |From 20401 33311

Psomaltose Filler (13331331 001 2040, 15

Maltose 00 Filler 17303131 12401 565 1

Lactite 0000 (Filler | 33031111 2040

Stearathmate | Lubricant | 601 60 | 60 | 60 601 60

All (mo 1 3000 3000 | 300 | 300.0 | 300.0 3006

Ticagrelor was mixed with lactose monohydrate, or xylitol, or mannitol, or isomaltose, or maltose, or lactitol in a suitable mixing device for 20 minutes. After pre-mixing, magnesium stearate was added to the mixture and the mixture was stirred for another 3 minutes in such a way that a suitable mixture could be obtained for tableting in a rotary tableting device.

Example 4

Tablet coating

Tablets obtained according to Examples 1-3 were traditionally coated with a conventional coating material. 11111111 1 yav | 46

Hydroxypropylmethylcellulose is not available

Polyvinyl alcohol 117

Hydroxypropip cellulose ni p LY

Polyethylene glycol

Titanium dioxide

Iron oxide (HER)

Total (mg)

The ingredients of the coating mixture were dissolved or suspended in a sufficient amount of water to obtain a coating solution. The tablets were then coated with this solution in a suitable device and finally dried.

Claims (4)

FORMULA OF THE INVENTION 1. A solid oral composition containing ticagrelor, which has the chemical name (15,25,3К,55)-3-Г7-ЦШ1 В,25)-2-(3,4-difluorophenyl)cyclopropyl|amino|-5- (propylthio)-3H-1,2,3-triazolo|4,5-a|pyrimidin-3-yl|-5-(2-hydroxyethoxy)-1,2-cyclopentanediol, which differs in that: a) contains at least one non-hygroscopic filler and at least one non-hygroscopic binder, wherein the non-hygroscopic filler and the non-hygroscopic binder do not have any disintegrating action, and where the term "non-hygroscopic" means an equilibrium moisture content below 6 95 by weight as measured by dynamic sorption steam at 25 "C and relative humidity 60 90; p) non-hygroscopic filler is selected from the group consisting of lactose, mannitol or xylitol; c) non-hygroscopic binder is selected from hydroxypropyl cellulose and maltose; a) the composition also contains at least one lubricant; f) the composition essentially does not contain a disintegrating agent. 2. The composition according to claim 1, which differs in that the lubricant is selected from stearic acid, magnesium stearate or sodium stearyl fumarate. 3. The composition according to claim 1 or 2, which differs in that the composition is made with a coating. 4. The method of obtaining the composition defined in claims 1-3, which differs in that the composition Zo is obtained by wet granulation.