KR20150067153A - A solid oral pharmaceutical formulation containing ticagrelor - Google Patents

Abstract

The present invention relates to a process for the preparation of (1S, 2S, 3R, 5S) -3- [7 - [[(1R, 2S) -2- (3,4- difluorophenyl) cyclopropyl] amino] Propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -5- (2-hydroxyethoxy) And at least one non-hygroscopic binder, wherein the filler or binder does not have a disintegrating effect at all. The present invention also provides a solid oral pharmaceutical formulation comprising at least one non-hygroscopic filler and / or at least one non-hygroscopic binder. The preparation of the preparation is possible by wet granulation or dry granulation or direct compression.

Description

TECHNICAL FIELD [0001] The present invention relates to a solid oral pharmaceutical preparation containing ticargellar,

The present invention relates to a solid oral pharmaceutical preparation containing ticagrelor as an active pharmaceutical ingredient and a process for preparing the same.

(1S, 2S, 3R, 5S) -3- [7 - [[(1R, 2S) -2- (3,4- difluorophenyl) cyclopropyl] amino] - 3-yl] -5- (2-hydroxyethoxy) -1, 2-cyclopentanediol The phosphorus compound tikageler may be,

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It is generally described in WO 1999/005143 and specifically mentioned in EP 1 135 391. The document also describes the use of ticagrella in the treatment or prevention of myocardial infarction, stroke, peripheral vascular disease, and the like, as well as its method of manufacture.

WO 2001/092262 describes four polymorphic forms and one amorphous form of tikaglarer. WO 2011/067571 describes cocrystals with various coformers such as glycolic acid, salicylic acid, succinic acid, malonic acid, and 4-hydroxy-3-methoxybenzenecarboxylic acid.

The pharmaceutical preparations are described in WO 2008/024044 by Astra Zeneca, WO 2008/024045. WO 2008/024044 describes solid formulations comprising one or more fillers, one or more binders, preferably one or more disintegrants and preferably one or more lubricants. According to Example 1 of WO 2008/024044, the sodium salt of carboxymethyl starch was used in an amount of 3% by weight as a disintegrant. The above document does not mention at all the example in which the disintegrant is not used. WO2008 / 024045 describes highly similar solid formulations comprising one or more fillers, one or more binders, preferably one or more disintegrants and preferably one or more lubricants. This document suggests that disintegration needs to be used. Specific examples mentioned in this document contain 2-6% by weight of disintegrant which is the sodium salt of carboxymethyl starch.

WO 2011/076749 deals with the particle size of the tikageler used in the formulation, since tikageler is well known as a compound with significantly low solubility. In the examples mentioned in the application, the disintegrant was used in an amount ranging from 4 to 6% by weight.

Tikagarella is marketed in the form of a coated tablet of Brilique for the prevention of atherosclerotic events. Commercially available formulations also contain a sodium salt of carboxymethyl starch as a disintegrant.

The present invention relates to a process for the preparation of (1S, 2S, 3R, 5S) -3- [7 - [[(1R, 2S) -2- (3,4- difluorophenyl) cyclopropyl] amino] Propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -5- (2-hydroxyethoxy) The formulation further comprises at least one non-hygroscopic filler having no disintegrating effect and / or at least one non-hygroscopic binder.

The non-hygroscopic filler may be selected from the group consisting of water soluble fillers, generally preferably sugar alcohols such as glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, raffinose, isomaltose, trehalose, dextrates, , Mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol, compressible sugar. For example, hydroxypropylcellulose or maltose can be used as a non-hygroscopic binder. The composition according to the invention preferably contains from 0.5 to 30% by weight of binder, preferably from 1 to 7% by weight of binder, most preferably from 2 to 4% by weight of binder.

As used herein, the term "non-hygroscopic" refers to a substance that is less capable of accepting and retaining moisture. Or in a better expression, the term "non-hygroscopic" refers to a material having an equilibrium moisture content of less than 6% by weight. Such values are determined by DVS (Dynamic Vapor Sorption) at a relative humidity of 60% and a temperature of 25 ° C. The equilibrium moisture content is determined based on the sorption isothermal curve measured using the DVS method at a relative humidity of 60% and a temperature of 25 ° C.

One of skill in the art knows that the use of a disintegrant in a formulation does not need to affect the biological availability of the active ingredient. Such properties are more influenced by sufficient humidification of the active ingredients present in the formulation. When a composition capable of being dissolved at a sufficiently high rate without the use of a disintegrant can be prepared, the disintegrant becomes an unnecessary constituent which has just no real effect.

Disintegrants represent one class of excipients which are generally considered special excipients. The cost of special excipients, i.e. disintegrants, is much higher than the cost of commonly used excipients such as fillers. The disintegrants such as the sodium salt of carboxymethyl starch or the sodium salt of croscarmellose may normally be 7 to 8 times more expensive than a conventional filler such as mannitol or calcium hydrogen phosphate.

The way disintegration works is not yet clear. Previously suspected mechanisms include, for example, water immersion, swelling, shape memory, repellency to other components, heating during humidification, and the like. The ability of the disintegrant to draw moisture to the porous network of tablets is essential for effective disintegration. Such description is provided in the ^{Encyclopaedia of Pharmaceutical Technology, 3 rd issue} , Informa Healthcare USA, Inc., 2007. As a natural consequence of the ability to draw moisture to the tablet, the disintegrant is generally hygroscopic or a significant hygroscopic material. According to the Handbook of Pharmaceutical Excipients, 6 ^th issue, Pharmaceutical Press, 2009, the sodium salt of croscarmellose and the sodium salt of carboxymethyl starch exhibit the same properties.

Because of the hygroscopic nature of the excipients, it is necessary to package the tikageler formulation in a PVC / PVDC clear container. The use of non-hygroscopic transparent blister packaging makes it possible to use less expensive PVC transparent containers instead of expensive PVS / PVDC. With respect to more economical excipients and low cost packaging, it is desirable to prepare formulations containing non-hygroscopic excipients which have no disintegration effect.

WO2008 / 024045 describes that the use of a composition containing one or more fillers, one or more binders, preferably one or more disintegrants and preferably one or more lubricants is suitable for at least 90% efficient release of tikageler. In contrast to the discovery of the prior art, we have found that the addition of one or more non-hygroscopic fillers and / or one or more non-hygroscopic binders that do not have a disintegrating effect, and tikageler of all known forms (crystalline, amorphous or co- Of the present invention achieves efficient release of at least 90% of the tikaglarer.

As used herein, the term "disintegration " refers to any material that is swelled or drowned in contact with water. The term "disintegrating" includes, for example, the following group of compounds: povidone, crospovidone, starch, pregelatinized starch, sodium salt of carboxymethylcellulose, hydroxypropyl starch, microcrystalline cellulose , Calcium salt of carboxymethylcellulose, sodium salt of crosslinked carboxymethylcellulose, potassium salt of polacrilin, low-substituted hydroxypropylcellulose, sodium alginate or calcium alginate, sodium docusate, methylcellulose, agar, guar gum, chitosan And alginic acid. The tikagarrel composition preferably contains less than 2% disintegrant.

In a most preferred embodiment, the pharmaceutical composition of ticarguler is substantially free of disintegrants.

The tikagaler composition contains a non-hygroscopic filler. Generally, water-soluble fillers are preferred. Suitable fillers include, for example, monosaccharides, fructose and sugar alcohols such as glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, raffinose, isomaltose, trehalose, dextrates, mannitol, Lithol, sorbitol, maltitol, xylitol and lactitol, compressible sugars, calcium hydrogen phosphate dihydrate and mixtures thereof. Lactose, mannitol, and xylitol are preferred.

The tikagaler composition contains a non-hygroscopic binder. Suitable binders include, for example, povidone, copovidone, powder, crystalline or microcrystalline cellulose, silicone-added microcrystalline cellulose, cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose and hydroxypropylmethylcellulose, starch, Gelatinized starch, polymethacrylate, and mixtures thereof. In a preferred composition, the tikageler formulation contains from 0.5 to 30% by weight of binder, preferably from 1 to 7% by weight, most preferably from 2 to 4% by weight of binder.

Tikageler compositions typically contain at least one surfactant. Suitable surfactants include, for example, anionic, cationic, amphoteric and / or non-ionic surfactants such as the sodium salt of lauryl sulfate, cetrimide, N-dodecyl-N, N-dimethyl- Polysorbates (e.g., Tweens ^® ), poloxamers, and mixtures thereof. The sodium salt of lauryl sulfate is the preferred compound. The surfactant is used in the tikageler formulation in an amount of 0.1 to 4.0 wt%, most preferably in the range of 0.5 to 2.0 wt%.

The tikagreler composition typically contains one or more lubricants and / or an anti-adhesive compound selected from the following: magnesium stearate, stearic acid, hydrogenated vegetable oil, hardened castor oil, talc , Sodium stearyl fumarate, colloidal silicon dioxide, magnesium trisilicate, and mixtures thereof. Stearic acid, magnesium stearate, sodium stearyl fumarate, and colloidal silicon dioxide are particularly preferred.

The tablets of Tikagelera may suitably be coated with any suitable coating. Suitable coatings for tikagellular tablets include, for example, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, acrylic acid polymers, ethylcellulose, cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, Polyvinyl alcohols, sodium salts of carboxymethyl cellulose, cellulose acetate, gelatin, copolymers of methacrylic acid, polyethylene glycol, shellac, sucrose, titanium dioxide, and carnauba wax. Polyethylene glycol, hydroxypropyl methylcellulose and polyvinyl alcohol are preferable.

Yes

Example 1

Wet Granulation

1A 1 B 1 C 1 D 1 E 1 F 1 G 1 H Tikagueler Active ingredient 90.0 90.0 90.0 90.0 90.0 90.0 90.0 90.0 Lactose
Monohydrate Filler 90.0 150.0 Xylitol Filler 90.0 150.0 Mannitol Filler 150.0 90.0 Maltitol Filler 150.0 90.0 Hydroxypropylcellulose Binder 3.6 3.6 3.6 3.6 maltose Binder 3.6 3.6 3.6 3.6 Sodium lauryl
Sulfate Surfactants 3.0 3.0 3.0 3.0 Lactose
Monohydrate Filler 107.4 50.4 Xylitol Filler 110.4 107.4 Mannitol Filler 47.4 110.4 Isomaltose Filler 50.4 maltose Filler 47.4 Stearic acid
magnesium slush 6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 Total (mg) 300.0 300.0 300.0 300.0 300.0 300.0 300.0 300.0

Ticargellar with either lactose monohydrate or xylitol or one of mannitol or maltitol in wet condition (using granulation by kneading or using a conventional granulator with a fluidized bed), either hydroxypropylcellulose or one of maltose ≪ / RTI > in an aqueous solution. Preferably, sodium lauryl sulfate is added to the granulation solution. The obtained granules were dried and then passed through a 1 mm sieve. The sieved granules were then mixed with lactose monohydrate or xylitol or mannitol or isomaltose or maltose in a suitable mixer for 20 minutes. After such pre-mixing, magnesium stearate was added to the mixture and then stirred for another 3 minutes to obtain a suitable tableting mixture. The mixture was then compressed into tablets from a rotary tablet machine.

Example 2

deflation Granulation

2a 2 B 2 C 2 D 2 E 2 F Tikagueler Active ingredient 90.0 90.0 90.0 90.0 90.0 90.0 Mannitol Filler 120.0 160.0 Lactose monohydrate Filler 120.0 160.0 Xylitol Filler 120.0 160.0 Sodium lauryl sulfate Surfactants 3.0 3.0 3.0 Lactose monohydrate Filler 81.0 Xylitol Filler 84.0 Mannitol Filler 81.0 Isomaltose Filler 44.0 maltose Filler 41.0 Lactitol Filler 44.0 Magnesium stearate slush 6.0 6.0 6.0 6.0 6.0 6.0 Total (mg) 300.0 300.0 300.0 300.0 300.0 300.0

Tikagelerer was granulated with mannitol or lactose monohydrate or xylitol, preferably with sodium lauryl sulfate, in a variety of gap sizes in a rotary-type rotary compressor. The obtained granules were passed through a 1 mm sieve. The sieved granules were mixed with lactose monohydrate or xylitol or mannitol or isomaltose or either maltose or lactitol in a suitable mixer for 20 minutes. After pre-mixing, magnesium stearate was added to the mixture and then stirred for another 3 minutes to obtain a mixture for tabletting. The mixture was then compressed into tablets from a rotary tablet machine.

Example 3

Direct compression

3a 3 B 3 C 3 D 3 E 3 F Tikagueler Active ingredient 90.0 90.0 90.0 90.0 90.0 90.0 Lactose monohydrate Filler 204.0 Xylitol Filler 204.0 Mannitol Filler 204.0 Isomaltose Filler 204.0 maltose Filler 204.0 Lactitol Filler 204.0 Magnesium stearate slush 6.0 6.0 6.0 6.0 6.0 6.0 Total (mg) 300.0 300.0 300.0 300.0 300.0 300.0

Tikageler was mixed with lactose monohydrate or xylitol or mannitol or isomaltose or either maltose or lactitol in a suitable mixer for 20 minutes. After pre-mixing, magnesium stearate was added to the mixture, which was then stirred for another 3 minutes to obtain a tableting mixture in a rotary tabletting machine.

Example 4

Tablet coating

Tablets obtained according to Examples 1 to 3 were suitably coated with common coating materials.

4A 4 B 4 C Hydroxypropylmethylcellulose 7.0 Polyvinyl alcohol 7.0 Hydroxypropylcellulose 7.0 Polyethylene glycol 1.5 1.5 1.5 talc 0.5 0.5 0.5 Titanium dioxide 0.5 0.5 0.5 Yellow ferric oxide 0.5 0.5 0.5 Total (mg) 10.0 10.0 10.0

The components of the coating mixture were dissolved or suspended in a sufficient amount of water to provide a coating solution. The tablet was then coated with the solution in a suitable machine and finally it was dried.

Claims (13)

(1S, 2S, 3R, 5S) -3- [7 - [[(1R, 2S) -2- (3,4- difluorophenyl) cyclopropyl] amino] 3-yl] -5- (2-hydroxyethoxy) -1,2-cyclopentanediol, ticagrelor, ≪ RTI ID = 0.0 > a < / RTI > solid pharmaceutical formulation,
Characterized in that it comprises at least one non-hygroscopic filler and / or at least one non-hygroscopic binder. The solid pharmaceutical formulation according to claim 1, wherein the non-hygroscopic filler and the non-hygroscopic binder have no disintegrating effect. The non-hygroscopic filler according to claim 2, wherein the non-hygroscopic filler is selected from the group consisting of sugar alcohols such as glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, raffinose, isomaltose, trehalose, dextrates dextrate, mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol, and compressible sugar. The solid pharmaceutical formulation according to claim 2, wherein the non-hygroscopic binder is selected from hydroxypropyl cellulose and maltose. 5. The composition according to any one of claims 1 to 4, wherein the formulation further comprises one or more lubricants, optionally one or more surfactants, and preferably one or more disintegrants in an amount ranging from 0 to 2% by weight ≪ / RTI > 6. The composition of claim 5 wherein the additional binder is selected from the group consisting of povidone, copovidone, powder, crystalline or microcrystalline cellulose, siliconized microcrystalline cellulose, cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose, Hydroxypropylmethylcellulose, hydroxypropylmethylcellulose, starch, pregelatinized starch, polymethacrylate, and mixtures thereof. ≪ Desc / Clms Page number 19 > 6. The solid pharmaceutical formulation according to claim 5, characterized in that the lubricant is selected from stearic acid, magnesium stearate or sodium stearyl fumarate. 6. The composition of claim 5, wherein the surfactant is selected from the group consisting of anionic, cationic, ampholytic or non-ionic surfactants such as the sodium salt of lauryl sulfate, cetrimide, N-dodecyl-N, N -Dimethyl-betaine, polysorbate, poloxamer, and mixtures thereof. ≪ RTI ID = 0.0 > 11. < / RTI > 6. The composition of claim 5 wherein the additional disintegrant is selected from the group consisting of povidone, crospovidone, starch, pregelatinized starch, sodium salt of carboxymethylcellulose, hydroxypropyl starch, microcrystalline cellulose, calcium salt of carboxymethylcellulose, ≪ / RTI > sodium salt of a hydroxypropyl cellulose, and a low-substituted hydroxypropylcellulose. 10. A solid pharmaceutical formulation according to any one of claims 1 to 9, characterized in that the formulation comprises a coating. 11. A process for the preparation of a formulation according to any one of claims 1 to 10,
Characterized in that the preparation is prepared by wet granulation. 11. A process for the preparation of a formulation according to any one of claims 1 to 10,
Characterized in that the preparation is prepared by dry granulation. 11. A process for the preparation of a formulation according to any one of claims 1 to 10,
Characterized in that the preparation is produced by direct compression.