A solid oral pharmaceutical formulation containing ticagrelor
The present invention relates to a solid oral pharmaceutical formulation containing ticagrelor as the active pharmaceutical constituent and a preparation method of this formulation.
The compound ticagrelor with the chemical name (lS,2S,3R,5S)-3-[7-[[(lR,2S)-2-(3,4- difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-l,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5- (2-h droxyethoxy)-l,2-cyclopentanediol, which is represented by formula (I),
was generically described in WO 1999/005143 and specifically mentioned in EP 1 135 391. This document also describes a method of its preparation, as well as the use of ticagrelor in treatment or prevention of myocardial infarction, stroke, diseases of peripheral vessels, etc. WO 2001/092262 describes 4 polymorphous and an amorphous form of ticagrelor. WO 2011/067571 describes cocrystals with various coformers such as glycolic, salicylic, succinic, malonic and 4-hydroxy-3-methoxybenzenecarboxylic acids.
Pharmaceutical formulations have been described in 2 applications of the company Astra Zeneca, WO 2008/024044 and WO 2008/024045. WO 2008/024044 describes a solid formulation that comprises 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 carboxymethylstarch was used as a disintegrant in the amount of 3 % by weight. The document does not mention any example where no disintegrant would be used. WO2008/024045 describes a very similar solid formulation that comprises one or more fillers, one or more binders, preferably one or more disintegrants and preferably one or more lubricants. This document indicates that the use of disintegrants is necessary. Particular
examples mentioned in the document contain 2-6 % by weight of a disintegrant, which is the sodium salt of carboxymethylstarch.
WO 2011/076749 deals with the particle size of ticagrelor which was used in the formulation as ticagrelor is well-known as a poorly soluble compound. In the quoted examples of this application disintegrants were used in amounts in the range of 4-6% by weight.
Ticagrelor is sold under the trade name Brilique for prevention of arteriothrombotic events in the form of coated tablets. The marketed formulation also contains the sodium salt of carboxymethylstarch as the disintegrant. Disclosure of Invention
This invention relates to a solid oral pharmaceutical formulation containing ticagrelor with the chemical name (lS,2S,3R,5S)-3-[7-[[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino]-5- (propylthio)-3H-l,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-l,2- cyclopentanediol, which further contains at least one non-hygroscopic filler and/or at least one non-hygroscopic binder that do not have a disintegrating effect.
The non-hygroscopic filler means a water-soluble filler, sugar alcohols being generally preferred, such as glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, raffinose, isomaltose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol, lactitol, compressible sugars. Hydroxypropyl cellulose or maltose, for example, can be used as the non-hygroscopic binder. The composition in accordance with this invention preferably contains 0.5- 30% by weight of the binder, preferably 1-7% by weight of the binder and most preferably 2-4% by weight of the binder.
The term non-hygroscopic, as used in this invention, refers to a material that has a low capability of receiving and holding water. Or, put it in a better way, the term non-hygroscopic refers to a material that has an equilibrium moisture content lower than 6% by weight. This value is determined by Dynamic Vapour Sorption (DVS) at the relative humidity of 60% and temperature of 25 °C. The equilibrium moisture content is determined based on the sorption isothermal curve measured using the DVS method at the relative humidity of 60% and temperature of 25 °C.
An expert in the art knows that the use of disintegrants in a formulation does not need to have an impact on increasing the biological availability of the active substance. This property is
more influenced by sufficient humidification of the active substance present in the formulation. If such a composition can be prepared that will dissolve sufficiently quickly without the use of disintegrants, disintegrants only become a superfluous constituent that does not have any real effect.
Disintegrants represent a class of excipients that are generally considered as special excipients. The price of special excipients, i.e. disintegrants, is much higher than the price of commonly used excipients such as fillers. The price of disintegrants such as the sodium salt of carboxymethylstarch or the sodium salt of croscarmellose may normally be several times higher than the price of general fillers as mannitol or calcium hydrogen phosphate.
The way disintegrants act is not clear so far. Mechanisms assumed in the past include, e.g., soaking with water, swelling, shape memory, repellency to the other constituents, heating during humidification. The ability of disintegrants to bring water to the porous network of the tablet is essential for efficient disintegration. This explanation was provided by the Encyclopaedia of Pharmaceutical Technology, 3rd issue, Informa Healthcare USA, Inc., 2007. As a natural consequence of the ability to bring water to tablets disintegrants are generally hygroscopic or very hygroscopic materials. According to the Handbook of Pharmaceutical Excipients, 6th issue, Pharmaceutical Press, 2009 the sodium salt of croscarmellose and sodium salt of carboxymethylstarch exhibit the same characteristics.
Due to the hygroscopic character of the excipients it is necessary to pack the ticagrelor formulation in PVC/PVDC blisters. The use of non-hygroscopic blister packs makes it possible to replace expensive PVS/PVDC with more affordable PVC blisters. With regard to lower costs of excipients and lower packing costs it is desirable to prepare a formulation that contains non-hygroscopic excipients that do not have any disintegration effect.
WO2008/024045 describes that the use of a composition that contains one or more fillers, one or more binders, preferably one or more disintegrants and preferably one or more lubricants is suitable for efficient releasing of at least 90% of ticagrelor. Contrary to the findings of the prior art we have found out that a ticagrelor composition with any known form of ticagrelor (crystalline, amorphous or in a cocrystal form) that contains at least one non-hygroscopic filler
and/or at least one non-hygroscopic binder that do not feature the disintegration effect will achieve efficient release of at least 90% of ticagrelor.
The term "disintegrant", used here, refers to any material that swells or soaks in contact with water. The term disintegrant comprises, e.g., the group of compounds such as: povidone, crospovidone, starch, pregelatinized starch, sodium salt of carboxymethyl cellulose, hydroxypropyl starch, microcrystalline cellulose, calcium salt of carboxymethylcellulose, sodium salt of crosslinked carboxymethylcellulose, potassium salt of polacrilin, low- substituted hydroxypropyl cellulose, sodium or calcium alginate, sodium docusate, methyl cellulose, agar, guar gum, chitosan and alginic acid. The composition of ticagrelor conveniently contains no or less than 2% of a disintegrant.
In the most preferable embodiment the pharmaceutical composition of ticagrelor contains substantially no disintegrant.
The composition of ticagrelor contains a non-hygroscopic filler. Generally, a water-soluble filler is preferred. Suitable fillers are, e.g., monosaccharides, oligosaccharides and sugar alcohols such as glucose, fructose, sucrose, lactose monohydrate, anhydrous lactose, raffinose, isomaltose, trehalose, dextrates, mannitol, erythritol, sorbitol, maltitol, xylitol and lactitol, compressible 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, e.g., povidone, copovidone, powdered, crystalline or microcrystalline cellulose, siliconized microcrystalline cellulose, cellulose derivatives such as hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropylmethyl cellulose, starch, pregelatinized starch, polymethacrylates and their mixtures. In a preferred composition the formulation of ticagrelor contains 0.5 to 30% by weight of the binder, preferably from 1 to 7%, and most conveniently from 2 to 4% by weight of the binder.
The composition of ticagrelor typically contains at least 1 surfactant. Suitable surfactants are, e.g., anionic, cationic, ampholytic and/or non-ionic surfactants such as the sodium salt of lauryl sulphate, cetrimide, N-dodecyl-N,N-dimethyl betaine, polysorbates (e.g. T weens®),
poloxamers and their mixtures. The sodium salt of lauryl sulphate is the preferred compound. The surfactant is used, in the formulation of ticagrelor, in an amount of from 0.1 to 4.0% by weight, most preferably in the range of from 0.5 to 2.0%. The composition of ticagrelor typically contains at least 1 lubricant and/or anti-adhesive compound selected, e.g., among magnesium stearate, stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, talc, sodium stearyl fumarate, colloidal silicon dioxide, magnesium trisilicate and their mixtures. Stearic acid, magnesium stearate, sodium stearyl fumarate and colloidal silicon dioxide are especially preferred.
The tablet of ticagrelor can be conveniently coated with any suitable coating. A suitable coating agent for ticagrelor tablets is selected, e.g., from methyl cellulose, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polymers of acrylic acid, ethyl cellulose, cellulose acetate phtalate, polyvinyl acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol, sodium salt of carboxymethyl cellulose, cellulose acetate, gelatine, copolymers of methacrylic acid, polyethylene glycol, shellac, sucrose, titanium dioxide and camauba wax. Polyethylene glycol, hydroxypropylmethyl cellulose and polyvinyl alcohol are preferred. Examples
1 A 1 B 1 C 1 D 1 E 1 F 1 G 1 H
Ticagrelor 90.0 90.0 90.0 90.0 90.0 90.0 90.0 90.0 substance
Xylitol Filler 90.0 150.0
Mannitol Filler 150.0 90.0
Maltitol Filler 150.0 90.0
3.6 3.6 3.6 3.6
Maltose Binder 3.6 3.6 3.6 3.6
Sodium lauryl Surfactant
3.0 3.0 3.0 3.0 sulphate
Xylitol Filler 110.4 107.4
Mannitol Filler 47.4 110.4
Isomaltose Filler 50.4
Maltose Filler 47.4
6.0 6.0 6.0 6.0 6.0 6.0 6.0 6.0 stearate
Total (mg) 300.0 300.0 300.0 300.0 300.0 300.0 300.0 300.0
Ticagrelor is granulated in wet conditions together with either lactose monohydrate or xylitol or mannitol or maltitol (either using granulation by kneading or with the use of a common granulator with a fluidized bed) with an aqueous solution of either hydroxypropyl cellulose or maltose. Sodium lauryl sulphate is preferably added to the granulation solution. The obtained granulate is dried and screened through a 1mm sieve. The sieved granulate is then mixed with either lactose monohydrate or xylitol or mannitol or isomaltose or maltose in a suitable mixing device for 20 minutes. After this pre-mixing magnesium stearate is added to the mixture and the mixture is stirred for another 3 minutes so that a suitable tabletting mixture can be obtained. This mixture is then compressed into tablets in a rotary tabletting device.
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 Lubricant 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
Ticagrelor was granulated in dry conditions together with mannitol or lactose monohydrate or xylitol and preferably with sodium lauryl sulphate in a rotary compactor with a variable gap size. The obtained granulate was screened through a 1mm sieve. The sieved granulate is mixed with either 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 is added to the mixture and the mixture is stirred for another 3 minutes so that a mixture ready for tabletting can be obtained. This mixture is then compressed into tablets in a rotary tabletting device. Example 3
Ticagrelor is 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 is added to the mixture and the mixture is stirred for another 3 minutes so that a mixture ready for tabletting in a rotary tabletting device can be obtained.
Example 4 Tablet coating
Tablets obtained in accordance with Examples 1 to 3 are conveniently coated with a common coating material
Constituents of the coating mixture are dissolved or suspended in a sufficient quantity of water to provide the coating solution. Then, tablets are coated with this solution in a suitable device and finally they are dried.