EA042784B1 - IN-ORAL DISSOLBLE TABLET - Google Patents

Description

The field of technology to which the invention belongs

The present invention relates to rapidly disintegrating oral dosage forms in the form of tablets, in particular tablets containing a compound of formula I:

but ⁴ OH(I).

The compound of formula (I) is commonly referred to as (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)- 3H-[1,2,3]-triazolo[4,5^]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol and hereinafter referred to as ticagrelor.

Background of the invention

Ticagrelor is the active ingredient in the drug product known as BRILINTA® (or BRILIQUE in Europe) which has been approved for use in many jurisdictions, including the US and Europe. Ticagrelor is disclosed as an ADP receptor antagonist in International Patent Application No. PCT/SE99/02256 (Publication No. WO 00/34283). The discovery of ticagrelor is discussed in Humphries B., et al., Daring to be Different’: the Discovery of Ticagrelor, The Handbook of Medicinal Chemistry, Principles and Practice, 2015, The Royal Society of Chemistry, UK; and Springthorpe, B., et al., Biorg. Med. Chem. Lett. 17 (2007) 6013-6018.

BRILINTA® is currently marketed as 60mg and 90mg immediate release tablets. International Patent Application No. PCT/SE2007/000736 (Publication No. WO 2008/024045) discloses certain pharmaceutical formulations containing ticagrelor for oral administration.

A significant proportion of stroke patients have difficulty swallowing (dysphagia) in the acute phase, and many have persistent problems. This can potentially lead to poor patient compliance if such patients are administered oral formulations that should be swallowed whole. Other patients may also suffer from dysphagia, as it is common in all age groups and occurs in approximately 35% of the general population, as well as in no more than 60% of the elderly inpatient population and in approximately 20% of all inpatients. institutions for the chronically ill.

The present invention relates to alternative dosage forms of ticagrelor that can be administered, for example, to such patients. Such dosage forms are rapidly disintegrating oral dosage forms containing ticagrelor, which include dosage forms that provide bioavailability of ticagrelor substantially comparable to currently marketed immediate-release dosage forms of 60 mg or 90 mg.

The listing or discussion of a previously published document in this specification should not necessarily be taken as an admission that such document is part of the prior art or public knowledge.

Disclosure of invention

According to a first aspect of the present invention, there is provided a tablet comprising (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)cyclopentan-1,2-diol and at least one excipient, ensuring disintegration;

wherein the tablet has a crush strength of from about 50 to about 150N and a disintegration time of less than about 3 minutes. Such compositions are referred to hereinafter as tablets of the present invention.

The tablets of the present invention are pharmaceutical formulations that rapidly disintegrate in the oral cavity. In one embodiment, the tablets of the present invention have a disintegration time of less than about 2 minutes, or preferably less than about 1 minute. In a specific embodiment, the tablets of the present invention have a disintegration time of less than about 60, 55, 50, 45, 40, 35, or 30 seconds. The rapid disintegration in the oral cavity makes it possible, in particular, to administer ticagrelor to the patient without having to simultaneously drink liquid in order to swallow the composition. In addition, the rapid disintegration ensures that ticagrelor is more readily available to patients and in particular pediatric and elderly patients, as well as other patients who may have difficulty swallowing (eg patients who have had a stroke).

The disintegration time can be measured in accordance with the method described in the monograph

- 1 042784

701 United States Pharmacopeia (USP). This method acts as an oral disintegration model and provides an in vitro disintegration time determination that can be used as a guide to understanding oral disintegration rates.

Formulations that disintegrate within 3 minutes when tested according to this method can be considered orally dispersible according to the European Pharmacopoeia (8th ed.). US-FDA guidelines recommend that the term orally disintegrating tablet be associated with solid oral preparations that rapidly disintegrate in the oral cavity with an in vitro disintegration time of about 30 seconds or less when tested according to this method. The tablets of the present invention may thus be considered as orally dispersible tablets or orally disintegrating tablets.

The tablets of the present invention are also suitable for nasogastric delivery to a patient. Nasogastric delivery requires that the constituents of the tablet be suspendable or water soluble so that the contents of the tablet can be administered to a patient via a nasogastric tube.

It is also important that oral disintegrating formulations maintain an acceptable disintegration rate after storage. The disintegration time of tablets can be adversely affected by a number of factors, including exposure to gases, moisture, and light. It is important to minimize changes in formulation during storage, which may increase ticagrelor particle aggregation during disintegration, as this slows down the dissolution of ticagrelor in the oral cavity. Tablets can be administered to patients many months after their original receipt, and it has been found that the tablets of the present invention retain an acceptable disintegration time after storage.

In a preferred embodiment, the tablet has a disintegration time of less than 3 minutes (preferably less than 60 seconds) after storage for at least 1 month. Specific storage conditions that may be mentioned in this connection include storage at 25° C. and 60% relative humidity. In other embodiments, the tablet has a disintegration time of less than 3 minutes (preferably less than 60 seconds) after storage for longer periods of time (e.g., 3, 6, or 12 months) and/or under more stringent conditions (e.g., 40°C and relative humidity 75%). Tablets that are stored in sealed containers, such as the blister packs described herein, have also been shown to retain disintegration times of less than 3 minutes and even less than 60 seconds after storage for no more than 12 months.

Increasing the rate of disintegration in the oral cavity facilitates administration in some patients. Examples of tablets that are considered rapidly disintegrating are described in US Patent No. 3,885,026 and US Patent Application Publication No. US 2013/280327.

It is important that the tablets of the present invention exhibit rapid dispersion of ticagrelor (eg in the form of granules) in physiological solutions (eg saliva). This rapid dispersion facilitates the swallowing of the drug by the patient. The dissolution rate of ticagrelor must also be maintained within acceptable parameters. Tablets are generally considered to have a suitable dissolution profile if they meet the following requirements: Q=70% after 45 minutes. Suitable conditions for such Ph Eur measurements include a device of 2, 75 rpm, 90 ml, 0.2% (w/v) Tween 80. In a further embodiment, the dissolution profile of a tablet of the present invention is such that Q=70% after 45 min.

One property that is desirable for a rapidly disintegrating oral dosage form is the bioavailability of ticagrelor. The bioavailability of a drug is the amount of an administered dose that reaches the general circulation in unchanged form. Therefore, sufficient bioavailability is important to achieve a therapeutically active concentration at the site of action. Both the release of the drug from the formulation and the stability of the formulation will affect its bioavailability. Thus, it is important that the drug formulation rapidly release a sufficient amount of the drug. In vitro drug release can be measured using tests known in the art, e.g. using a standard dissolution device and a standard 'bio-appropriate' dissolution medium according to the United States Pharmacopeia (USP), e.g. FaSSIF (Galia, E., et al., Pharm. Res. 1998, 15 (5), 698-705). Such tests may provide some insight into the likely in vivo performance of the formulation.

The tablets of the present invention contain at least one disintegrating aid. Said disintegrating aid may be a single substance, or it may be a mixture of substances (referred to herein as a disintegrating aid preblend) wherein said mixture of substances functions as a leavening agent. In one embodiment, the disintegrating aid is a disintegrating aid.

- 2 042784 agent that provides rapid disintegration in the oral cavity. The use of an adjuvant that provides rapid disintegration in the oral cavity increases the rate of disintegration of the oral dosage form. Rapid disintegrating adjuvants in the oral cavity are adjuvants which are suitable for use in pharmaceutical and/or nutraceutical formulations and which allow the manufacture of tablets which have an oral disintegration time of less than 3 minutes. Preferably, the disintegrating aids referred to in the embodiments disclosed herein are premixtures of the disintegrating aid.

Disintegrants that are suitable for use as disintegrating aids in the tablets of the present invention include, but are not limited to, low substituted hydroxypropyl cellulose and in particular crospovidone, microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate, and mixtures thereof. Commercially available disintegrant premixtures such as F-melt type C, F-melt type M, Ludiflash, GalenIQ, Prosolv and Pharmaburs can also be used in the tablets of the present invention.

F-melt type C, F-melt type M, Ludiflash, GalenIQ, Prosolv and Pharmaburst are examples of fast disintegrating adjuvants in the mouth. F-melt (Fuji Chemicals) can be supplied as F-melt type C or F-melt type M. F-melt type C is a formulation consisting of mannitol (65%), xylitol (5%), anhydrous dibasic calcium phosphate (4%), crospovidone (8%) and microcrystalline cellulose (18%). Type C F-melt is formed by co-spray drying the above ingredients. F-melt type M is a formulation consisting of mannitol, xylitol, magnesium aluminometasilicate, crospovidone and microcrystalline cellulose. Ludiflash (BASF Fine Chemicals) is a formulation consisting of mannitol (90%), crospovidone (Kollidon CL-SF) (5%) and polyvinyl acetate (Kollicoat SR 30D) (5%). GalenIQ (721 grades; Beneo-Palatinit) is a formulation containing a disaccharide alcohol in a 3:1 ratio of 6-O-aD-glucopyranosyl-D-sorbitol and 1-O-α-D-glucopyranosyl-D-mannitol dihydrate. Prosolv ODT G2 (JRS Pharma) is a formulation containing microcrystalline cellulose, colloidal silicon dioxide, mannitol, fructose and crospovidone. Pharmaburst (SPI Pharma) is a formulation containing mannitol, sorbitol, crospovidone, croscarmellose sodium, and colloidal silicon dioxide.

In one embodiment of the present invention, the adjuvant is selected from the group consisting of F-melt type C, F-melt type M, Ludiflash, GalenIQ, Prosolv, and Pharmaburst. F-melt type C and F-melt type M are particularly preferred because they have been found to be excellent in terms of processability with good flowability and no sticking or sticking to tablet punches in combination with an acceptable disintegration time compared to tablets. containing Prosolv and Pharmaburst.

A number of disintegrating aid premixtures, including a variety of commercially available rapid disintegrating aids in the mouth, contain at least one carbohydrate excipient and at least one disintegrant. As used herein, the term carbohydrate includes sugars (eg, monosaccharides, disaccharides, and oligosaccharides such as maltose and dextrin) as well as their derivatives (eg, polyhydric alcohol derivatives such as mannitol, xylitol, and sorbitol). Specific carbohydrate excipients that may be mentioned in this connection include maltose, dextrin, mannitol, xylitol, sorbitol, and mixtures thereof. Mannitol is the most preferred carbohydrate excipient, although other excipients (including non-carbohydrate excipients) may be present in the tablets of the present invention. Such materials exhibit a number of properties that make them particularly suitable for use in the tablets of the present invention, including providing rapid dissolution, uniform chewing, and excellent compressibility to the final tablet. In one embodiment of the present invention, at least one disintegrating aid contains mannitol. Disintegrators that are generally useful in disintegrating aids and tablets of the present invention include low substituted hydroxypropyl cellulose and in particular crospovidone, microcrystalline cellulose, croscarmellose sodium, sodium starch glycolate and mixtures thereof. Crospovidone is particularly preferred in this regard. Thus, in a further embodiment, at least one disintegrating aid comprises crospovidone.

Type C F-melt is the most preferred disintegrating aid for use in the tablets of the present invention. Thus, in one embodiment, the at least one disintegrating aid is a disintegrating aid preblend containing mannitol, xylitol, anhydrous dibasic calcium phosphate, crospovidone, and microcrystalline cellulose. In a further embodiment, at least one disintegrating aid preblend contains type C F-melt.

The tablets of the present invention must contain a sufficient amount of at least one disintegrating aid to cause the tablet to disintegrate within a sufficiently short period of time. However, the amount of at least one disintegrating aid should not be so high as to cause difficulty in tablet manufacture due to the stickiness and/or stickiness of ticagrelor. Surprisingly, it has been found that the tablets of the present invention wherein at least one disintegrating aid is a preblended disintegrating aid present in an amount ranging from about 50% to about 80% by weight tablets have an acceptable disintegration time (eg, less than 3 minutes) while simultaneously providing sufficient resistance to the stickiness and/or stickiness of ticagrelor during tablet manufacture. Thus, in a further embodiment, the at least one disintegrating aid is a disintegrating aid preblend present in an amount ranging from about 50% to about 80% by weight of the tablet. As discussed herein above, it is particularly preferred that at least one disintegrating aid is a rapid disintegrating aid in the mouth such as Type C F-melt, however, only a portion of the disintegrant may be which is generally classified as a baking powder. In the case of the composition described in example 7, the total amount of disintegrant (ie crospovidone and microcrystalline cellulose) in the tablet is approximately 19% by weight of the tablet. However, the disintegrating aid (i.e. F-melt type C) is a mixture containing mannitol and other excipients, and this disintegrating aid is present at approximately 64.8% by weight of the tablet. . Thus, for the avoidance of ambiguity, the above embodiment includes examples in which the tablet contains an oral disintegrating aid (e.g., F-melt type C) in an amount ranging from about 50% to about 80 % by weight of the tablet.

In a further embodiment, the tablet contains at least one disintegrant (e.g., as a component of at least one disintegrating aid) in a total amount of at least about 10% by weight of the tablet, such as from about 10 to about 30 % by weight of the tablet.

Excipients other than carbohydrates that may be present in the tablets of the present invention include dibasic calcium phosphate dihydrate or tricalcium phosphate, or in particular anhydrous dibasic calcium phosphate or magnesium aluminometasilicate, or mixtures of any of the foregoing. In a preferred embodiment, the tablet of the present invention contains anhydrous dibasic calcium phosphate.

It will be appreciated that a particular adjuvant may act as both binder and filler, or as binder, filler and disintegrant. Typically, the combined amount of filler, binder and disintegrant is, for example, from 50 to 90%, for example, from 70 to 85% by weight of the tablet.

The tablets of the present invention contain ticagrelor, (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H- [1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2hydroxyethoxy)cyclopentan-1,2-diol. Surprisingly, ticagrelor has been found to exhibit a high degree of tackiness and stickiness of ticagrelor. These properties cause sticking and sticking of the composition during tabletting, which is undesirable as it results in poor tablet weight uniformity as well as unacceptable tablet appearance. The tackiness and/or stickiness of ticagrelor also causes other problems associated with the manufacture of the product.

In one embodiment of the present invention, ticagrelor is present in an amount of from about 10% to about 18% by weight of the tablet. Preferably, ticagrelor is present in an amount of from about 12% to about 17% by weight of the tablet. In an additional embodiment, the tablet contains about 60 mg or about 90 mg of ticagrelor. When used in this context, the term approximately covers options ranging from 90% to 110% of the absolute amount of ticagrelor. That is, about 60 mg is in the range of 54 to 66 mg of ticagrelor, and about 90 mg is in the range of 81 to 99 mg of ticagrelor. In a preferred embodiment, the tablet contains 57 to 63 mg or 85 to 95 mg of ticagrelor. Tablets which contain approximately 90 mg of ticagrelor are particularly preferred.

The tablets of the present invention are characterized by a disintegration time of less than

- 4 042784 approx. 3 min. In order to achieve this, various aspects of the tablet formulation and method of its manufacture should be controlled, including the compression forces used in the tableting step. The compression forces used in the tableting step for the tablets of the present invention are generally less than those used to form traditional oral tablets, and the tablets of the present invention generally have a lower crush strength as a result. This in turn ensures faster disintegration of the tablet in the oral cavity and thereby facilitates the dissolution of ticagrelor. The tablet of the present invention has a crush strength of from about 50 to about 150 N. In one embodiment, the tablet has a crush strength of from about 50 to about 130 N, such as from about 50 to about 120 N, or preferably from about 50 to about 100 N. In a more preferred embodiment, the tablet of the present invention has a crush strength of about 55 to about 90 N. The relatively low crush strength of these tablets makes them prone to breakage when removed from traditional squeeze blister packs. . Thus, the tablets of the present invention are particularly suitable for use in blister packs according to the eighth aspect of the present invention described herein below.

The tablets of the present invention may contain at least one anti-caking agent. For tablets that are prepared by a process that includes a granulation step (e.g., the wet granulation step described herein), said at least one anti-caking agent may be provided as one of the ingredients in the granulation step (i.e. as an intragranular anti-caking agent). Alternatively or additionally, said at least one anti-caking agent or glidant may be added to the product obtained from the granulation step (i.e. as an extra-granular anti-caking agent or glidant) . In preferred embodiments of the present invention that provide a tablet that can be prepared by a granulation process, at least one anti-caking agent may be included as one or more intragranular and one or more extragranular anticaking agents. caking. For the avoidance of ambiguity, said intragranular and extragranular anti-caking agents may be the same or different. In addition, a substance can be selected that has the properties of both an anti-caking agent and a slip agent, such as colloidal anhydrous silica.

An anti-caking agent is typically added to counteract the stickiness and/or stickiness of ticagrelor. In a preferred embodiment of the present invention, at least one anti-caking agent is present in an amount of from about 0.5 to about 1% by weight of the tablet.

In one embodiment, the tablets of the present invention contain one or more lubricants. In another embodiment, the tablets of the present invention contain a single lubricant.

Other suitable lubricants and additional adjuvants that may be used are described in the Handbook of Pharmaceutical Excipients, ^2nd Edition, American Pharmaceutical Association; The Theory and Practice of Industrial Pharmacy, ^2nd Edition, Lachman, Leon, 1976; Pharmaceutical Dosage Forms: Tablets Volume 1, ^2nd Edition, Lieberman, Hebert A., et al, 1989; Modern Pharmaceutics, Banker, Gilbert and Rhodes, Christopher T, 1979; and Remington's Pharmaceutical Sciences, 15th Edition, 1975.

Suitable lubricants include, for example, magnesium stearate, stearic acid, palmitic acid, calcium stearate, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols, and sodium stearyl fumarate.

In one embodiment, the lubricant is selected from magnesium stearate and sodium stearyl fumarate. In another embodiment, the lubricant is sodium stearyl fumarate.

It has been found that the use of an increased amount of lubricant in the tablets improves the flowability of the powder during tabletting and increases the disintegration time of the tablet. In embodiments of the tablets of the present invention that contain a lubricant, the lubricant is present in an amount of from about 1% to about 3% by weight of the tablet. In another embodiment, the lubricant is present in an amount of from about 1 to about 2% by weight. It has been found that the use of a lubricant in a given amount provides a tablet with acceptable quality levels while maintaining an acceptable disintegration time.

Additional traditional aids that can be added include

- 5 042784 preservatives, stabilizers and/or antioxidants. In a preferred embodiment, the tablet of the present invention does not contain preservatives, stabilizers or antioxidants. In a further preferred embodiment, the tablet consists essentially of the ingredients listed in Example 7. The ratios for any of the ingredients listed in Example 7 can be changed in accordance with the ratios described elsewhere herein.

In one embodiment of the present invention, the tablet contains ticagrelor, hydroxypropyl cellulose, anhydrous colloidal silica, mannitol, xylitol, anhydrous dibasic calcium phosphate, microcrystalline cellulose, crospovidone, and sodium stearyl fumarate.

In a preferred embodiment of the present invention, the tablet consists essentially of ticagrelor, hydroxypropyl cellulose, anhydrous colloidal silica, mannitol, xylitol, anhydrous dibasic calcium phosphate, microcrystalline cellulose, crospovidone and sodium stearyl fumarate.

In another embodiment of the present invention, the tablet contains ticagrelor in an amount of from about 10 to about 18% by weight of the tablet;

hydroxypropyl cellulose in an amount of from about 0.9 to about 2% by weight of the tablet;

colloidal anhydrous silica in an amount of from about 0.5 to about 1% by weight of the tablet;

mannitol in an amount of from about 47% to about 67% by weight of the tablet;

xylitol in an amount of from about 2.5 to about 4% by weight of the tablet;

anhydrous dibasic calcium phosphate in an amount of from about 2 to about 3.5% by weight of the tablet;

microcrystalline cellulose in an amount of from about 9 to about 15% by weight of the tablet;

crospovidone in an amount of from about 5 to about 9% by weight of the tablet; and sodium stearyl fumarate in an amount of from about 1 to about 2% by weight of the tablet.

In a further embodiment, ticagrelor is present in an amount of from about 12% to about 17% by weight of the tablet. In an additional embodiment, the tablet contains about 60 mg or about 90 mg of ticagrelor. In an additional embodiment, the tablet contains approximately 60 mg of ticagrelor. In a preferred embodiment, the tablet contains approximately 90 mg of ticagrelor. In further embodiments, such tablets have a disintegration time of less than 3 minutes (preferably less than 60 seconds) after storage for at least 1 month, such as storage at 25° C. and 60% relative humidity. In further embodiments, such tablets have a disintegration time of less than 3 minutes (preferably less than 60 seconds) after storage for longer periods of time (e.g., 3, 6, or 12 months) and/or under more severe conditions (e.g., , 40°C and relative humidity 75%). In additional embodiments, tablets having the disintegration times described for the above embodiments also have acceptable crush strength (e.g., about 50 to about 150 N, about 50 to about 130 N, about 50 to about 120 N, from about 50 to about 100 N, or about 55 to about 90 N).

In a preferred embodiment of the present invention, the tablet consists essentially of ticagrelor in an amount of from about 10% to about 18% by weight of the tablet;

hydroxypropyl cellulose in an amount of from about 0.9 to about 2% by weight of the tablet;

colloidal anhydrous silica in an amount of from about 0.5 to about 1% by weight of the tablet;

mannitol in an amount of from about 47% to about 67% by weight of the tablet;

xylitol in an amount of from about 2.5 to about 4% by weight of the tablet;

anhydrous dibasic calcium phosphate in an amount of from about 2 to about 3.5% by weight of the tablet;

microcrystalline cellulose in an amount of from about 9 to about 15% by weight of the tablet;

crospovidone in an amount of from about 5 to about 9% by weight of the tablet; and sodium stearyl fumarate in an amount of from about 1 to about 2% by weight of the tablet.

In another additional preferred embodiment, the tablet consists essentially of the ingredients listed in example 7, at the values of the relative content specified in this document. To avoid ambiguity, the relative content values for any of the ingredients listed in Example 7 can be adjusted, for example, in accordance with

- 6 042784 values of the relative content described in the embodiments above and below.

In another embodiment of the present invention, the tablet contains approximately 60 mg of ticagrelor;

approximately 259 mg F-MELT type C;

approximately 59.1 mg of mannitol in addition to the mannitol content of F-MELT type C;

approximately 8 mg of crospovidone in addition to the crospovidone content of F-MELT type C;

approximately 6 mg sodium stearyl fumarate;

about 5 mg hydroxypropyl cellulose; and about 2.5 mg colloidal anhydrous silica.

When used in this context, indications of the amount of F-Melt type C contained in a tablet are intended to indicate the amount of F-Melt type C used in the preparation of the tablet. This does not imply that any or all of this material retains an identical physical form in the final tablet. In a further embodiment, the tablet has a disintegration time of less than 3 minutes (preferably less than 60 seconds) after storage for at least 1 month, such as storage at 25° C. and 60% relative humidity. In additional embodiments, the tablet has a disintegration time of less than 3 minutes (preferably less than 60 seconds) after storage for longer periods of time (e.g., 3, 6, or 12 months) and/or under more stringent conditions (e.g., 40°C and relative humidity 75%). In additional embodiments, tablets having the disintegration times described for the above embodiments also have acceptable crush strength (e.g., about 50 to about 150 N, about 50 to about 130 N, about 50 to about 120 N, about 50 to about 100 N or about 55 to about 90 N).

In another embodiment of the present invention, the tablet contains approximately 90 mg of ticagrelor;

approximately 389 mg F-MELT type C;

approximately 88.6 mg mannitol in addition to the mannitol content of F-MELT type C;

approximately 12 mg of crospovidone in addition to the crospovidone content of F-MELT type C;

approximately 9 mg sodium stearyl fumarate;

about 7.5 mg of hydroxypropyl cellulose; and about 3.8 mg of colloidal anhydrous silica.

When used in this context, indications of the amount of F-Melt type C contained in a tablet are intended to indicate the amount of F-Melt type C used in the preparation of the tablet. This does not imply that any or all of this material retains an identical physical form in the final tablet. In a further embodiment, the tablet has a disintegration time of less than 3 minutes (preferably less than 60 seconds) after storage for at least 1 month, such as storage at 25° C. and 60% relative humidity. In additional embodiments, the tablet has a disintegration time of less than 3 minutes (preferably less than 60 seconds) after storage for longer periods of time (e.g., 3, 6, or 12 months) and/or under more stringent conditions (e.g., 40°C and relative humidity 75%). In additional embodiments, tablets having the disintegration times described for the above embodiments also have acceptable crush strength (e.g., about 50 to about 150 N, about 50 to about 130 N, about 50 to about 120 N, about 50 to about 100 N or about 55 to about 90 N).

According to a further aspect of the present invention, the tablet of the present invention may be prepared by a process involving granulation, eg wet granulation, of ticagrelor.

Granulation is a process by which primary particles (powders) are brought together to form larger objects in the form of a plurality of particles called granules. Granulation usually begins after the initial dry mixing of the powdered ingredients, so that a sufficiently uniform distribution of the ingredients in the mixture is achieved. Granulation methods can be divided into two types: wet granulation methods in which a liquid is used to form granules, and dry methods in which it is not used.

In dry granulation processes, the primary powder particles are aggregated under pressure (or compression). There are two main methods: a large tablet (also known as a slug) is produced by a heavy tablet press, or powdered particles are compressed between two rollers to form a sheet or 'strip' of material (a method known as rolling). In both cases, the compacted material is ground using a suitable grinding technique to obtain a granular material. The granules can then be pressed into a standard

- 7 042784 nom tablet press to obtain tablets.

Wet granulation involves the concentration of primary powder particles using a granulation liquid. The liquid contains a solvent that can be removed by drying and is non-toxic. The granulation fluid can be used alone or more typically with a binder (binder) to ensure that the particles stick together when dry. Binders can be added to the system as a binder solution (as part of the granulation liquid) or as a dry material mixed with the primary powder particles. There are four main types of wet granulators: shear granulators (such as planetary mixers), high shear mixer granulators (such as Fielder or Diosna), twin screw granulators (such as ConsiGma), and fluid bed granulators (such as Aeromatic or Glatt).

It has been found that wet granulation of a mixture containing ticagrelor overcomes the difficulties associated with the binding ability and/or adhesiveness of ticagrelor, and thereby provides an improvement in the workability of the active agent, compared with tabletting methods that involve simple direct compression of the powder.

Thus, according to a second aspect of the present invention, there is provided a tablet which can be prepared by a process comprising wet granulation of ticagrelor and at least one anti-caking agent. In a preferred embodiment of this aspect of the present invention, the tablet is a tablet according to the first embodiment. That is, it is preferred that a tablet that can be prepared by a process involving wet granulation of ticagrelor and at least one anti-caking agent has a crush strength of from about 50 to about 150 N and a disintegration time of less than about 3 min.

In one embodiment, the wet granulation method involves wet granulating a mixture containing ticagrelor in an amount of at least about 30% by weight of the dry ingredients in the mixture. In another embodiment, the wet granulation method involves wet granulating a mixture containing ticagrelor in an amount of at least about 35% by weight of the dry ingredients in the mixture. Incorporating higher concentrations of ticagrelor into the wet granulate results in higher levels of disintegrating aids in the tablet, thereby improving disintegration time.

In a further embodiment, the wet granulation method comprises wet granulating a mixture containing ticagrelor in an amount of no more than about 70% by weight of the dry ingredients in the mixture. In another further embodiment, the wet granulation method comprises wet granulating a mixture containing ticagrelor in an amount of from about 35% to about 70% by weight of the dry ingredients in the mixture. It has surprisingly been found that wet granulation of ticagrelor is facilitated by reducing the level of ticagrelor present in the granulation mixture. Without wishing to be bound by theory, it is believed that many of the manufacturing difficulties, and especially the wet granulation step, arise from the stickiness and/or stickiness of ticagrelor. This can be counteracted by lowering the level of ticagrelor in the granulation mixture and/or by increasing the relative amount of anti-caking agent present in the granulation mixture.

Thus, in a further preferred embodiment of the present invention, such as one in which a tablet is prepared by a wet granulation process comprising wet granulating a mixture containing ticagrelor in an amount of not more than about 70% by weight of the dry ingredients in the mixture, the mixture used in the process wet granulation contains an anti-caking agent in an amount ranging from about 0.1 to about 1% by weight of the dry ingredients in the mixture.

In another embodiment, the present invention relates to a pharmaceutical composition obtained by high shear wet granulation. In yet another further embodiment, the present invention relates to a pharmaceutical composition obtained by a twin screw wet granulation process.

High shear wet granulation is a process that involves intensive dry mixing of primary powders and subsequent addition of a granulation liquid which results in the formation of granules. The granulation fluid contains a volatile solvent (usually water) and may also contain a binder; providing adhesion of particles (binders can also be added in dry form as powders to the bulk of the composition to be granulated). Granules have major advantages over the powders of which they are composed in terms of improved flow properties, reduced risk of delamination, increased uniformity. (Information taken from Aulton ME, Pharmaceutics The Science of Dosage Form Design, ^2nd Edition, 2002, Churchill Livingstone).

In one embodiment, the granular product obtained by the process

- 8 042784 wet granulation, described in this document, contains granules, characterized by a value of D (v, 0.9), constituting less than about 1600 microns. In a preferred embodiment, the D(v, 0.9) value is less than about 1200 µm. In another embodiment, the granular product obtained by the wet granulation process described herein contains granules having a D(v, 0.1) value of less than about 10 microns. The particle size distribution in the granules obtained by the granulation process can be determined using techniques that are known to the person skilled in the art.

Specific techniques that may be mentioned in this connection include laser diffraction techniques.

In one embodiment referred to herein above, after the wet granulation step is completed, the product of the granulation step may be mixed with a second amount of at least one anti-caking agent (in addition to any anti-caking agent that may be present in the granulate), after completion. This extra-granular anti-caking agent may be the same as or different from said anti-caking agent in the granulate. Alternatively, the product of the granulation step can be mixed with a glidant. In one embodiment, the second amount of anti-caking agent or glidant (i.e. extragranular anti-caking agent or glidant) is present in an amount of from about 0.2 to about 0.6% by weight pills. Advantageously, the presence of an extragranular anti-caking agent or glidant has been found to improve the flowability of the mixture during tabletting without significantly affecting the disintegration time, in particular when present in an amount of at least 0.3% by weight of the tablet. Therefore, in another embodiment, the second amount of anti-caking agent or glidant (i.e. extragranular anti-caking agent or glidant) is present in an amount of from about 0.3 to about 0.6% by tablet weight.

In another embodiment of the second aspect of the present invention, the tablet may be prepared by a process involving wet granulation of ticagrelor, an anti-caking agent, and a binder. Substances that may be suitable for use as binders include hydroxypropylcellulose, alginic acid, sodium carboxymethylcellulose, copovidone and methylcellulose, or a mixture thereof. A particularly preferred binder is hydroxypropyl cellulose.

In one embodiment, the binder is present in the wet granulation mixture in an amount ranging from about 2 to about 6% by weight of the dry ingredients in the mixture. However, it has been found that increasing the amount of binder used in the granulation step (eg wet granulation) shortens the disintegration time of the tablet of the present invention. Thus, in a preferred embodiment, the binder is present in the wet granulation mixture in an amount ranging from about 3 to about 6% by weight of the dry ingredients in the mixture. In a further embodiment, the binder is present in the wet granulation mixture in an amount ranging from about 4 to about 5% by weight of the dry ingredients in the mixture.

The form in which ticagrelor is supplied for the granulation step also affects the disintegration time of the tablet of the present invention. Ticagrelor exists in amorphous form and in four different, essentially crystalline forms (see International Patent Application No. PCT/SE 01/01239 (Publication No. WO 01/92262)). In one embodiment of any of the first or second aspects, the present invention relates to a tablet as defined herein above in which ticagrelor is in crystalline form.

In one embodiment, the present invention relates to a pharmaceutical composition, in which ticagrelor is mainly present in the form of polymorph II. In another embodiment, the present invention relates to a pharmaceutical composition, in which ticagrelor is mainly present in the form of polymorph III. By using the term substantially present in this context, it is meant that ticagrelor is present in a form that is predominantly that of said polymorph, eg, at least 80% by weight of ticagrelor is in the form of said polymorph. More preferably, at least 90% or at least 95% (e.g., at least 96%, at least 97%, at least 98%, or at least 99%) by weight of ticagrelor is in the form of said polymorph ( for example, either polymorph II or polymorph III).

The particle size of ticagrelor prior to incorporation into the tablet of the present invention may also influence the disintegration time of the tablet. Tablets prepared using ticagrelor, characterized by a range of particle sizes, have been found to have the desired dissolving properties.

- 9 042784 incidence. In one embodiment, ticagrelor has a particle size distribution D(v, 0.9) of about 5 µm to about 50 µm. In a further embodiment, ticagrelor has a particle size distribution D(v, 0.9) of about 5 µm to about 40 µm. In a more preferred embodiment, ticagrelor has a particle size distribution D(v, 0.9) of about 10 µm to about 30 µm.

It is desirable that the physical properties of these compositions be stable during storage, since changes in, for example, disintegration time, dissolution rate, or tablet crush strength, among others, can affect the performance of the product. It is possible that reductions in the dissolution rate during storage under the conditions of the International Council for Harmonization of Specifications for Registration of Medicinal Products for Human Use (ICH) used to determine the shelf life of a product may reduce the bioavailability of ticagrelor. The physical property of stability can be measured by the USP methods for testing disintegration and dissolution times discussed elsewhere in this document.

In a third aspect of the present invention, there is provided a method for producing a tablet according to the first and second aspects of the present invention.

Said method involves mixing together ticagrelor and at least one anti-caking agent along with or in liquid, thereby obtaining a wet granulate. In a preferred embodiment, the wet granulate mixture is mixed with a high shear mixer. In yet another further embodiment, the wet granulate mixture is processed using a twin screw granulator. In another embodiment, the liquid used in the wet granulation process is water.

The wet granulate mixture may further comprise a filler and a binder. In one embodiment, the filler is mannitol. In an additional embodiment, the binder is hydroxypropyl cellulose.

In one embodiment of the third aspect of the present invention, the method of making a tablet comprises providing a wet granulation mixture containing ticagrelor in an amount of from about 35 to about 70% by weight of the dry ingredients in the mixture and an anti-caking agent in an amount ranging from about 0 .1 to about 1% by weight of the dry ingredients in the mixture.

In a further embodiment, in addition to the content of ticagrelor and anti-caking agent, at the ratios indicated immediately above, the mixture used in the method further contains a filler in an amount ranging from about 25% to about 60% by weight of dry ingredients in the mixture; and/or a binder in an amount ranging from about 3 to about 6% by weight of the dry ingredients in the mixture.

In each of the embodiments described herein with respect to the third aspect of the present invention, said method may further comprise the following steps:

(I) drying the wet granulate mixture, (II) adding one or more adjuvants to the dried granules, and then (III) forming the mixture into tablets.

The drying process in step (I) above may include any conventional drying method, and in a preferred embodiment, it involves drying in a fluidized bed with an inlet air temperature of approximately 50°C. The granulated product obtained by this can be further crushed in order to obtain granulates with the desired particle size distribution. A mill sieve can additionally be used to achieve this. In one embodiment, the dried granules are crushed to obtain a particle size distribution in which D(v, 0.9) is less than about 1600 microns. Particle size distribution can be determined using techniques known to those skilled in the art, such as the laser diffraction method described herein.

The drying process in step (I) may be preceded by a wet grinding step in order to remove any large lumps that may be present in the wet granulate, thereby facilitating the drying process.

The mixture containing the granulates and one or more excipients can be formed into tablets using any conventional tablet press. In one embodiment, the tablets are compressed using a compression intensity of 6 kN to 15 kN (eg, 7.9 kN to 13.1 kN).

In a further embodiment, the one or more adjuvants introduced in step (II) above comprise at least one adjuvant providing

- 10 042784 baking disintegration agent as defined herein above, a second amount of an anti-caking agent as defined herein above, and/or a lubricant as defined herein above.

Preferences and variations for a given aspect, feature or parameter of the present invention are, unless otherwise indicated in the context, to be considered disclosed in conjunction with any and all preferences and variations for all other aspects, features and parameters of the present invention. For example, any of the disintegrating aids mentioned herein may be used in combination with any of the binders, anticaking agents, and/or lubricants mentioned herein. In addition, these components may be present in the tablets of the present invention at any of the values of the relative content mentioned in this document, or in any combination of these values of the relative content.

The ticagrelor tablets of the present invention act as _P2T receptor antagonists (P2Y _adp or P2T _ac ). Accordingly, the tablets of the present invention are useful in therapy. In particular, the tablets of the present invention are for use in the treatment or prevention of arterial thrombotic complications in patients with coronary artery disease, cerebrovascular disease, or peripheral vascular disease. Arterial thrombotic complications may include unstable angina, primary arterial thrombotic complications of atherosclerosis such as thrombotic or embolic stroke, transient ischemic attacks, peripheral vascular disease, myocardial infarction with or without thrombolysis, arterial complications due to coronary disease procedures such as angioplasty, including coronary angioplasty (PTCA), endarterectomy, stent placement, surgery to install a coronary and other vascular graft, thrombotic complications from surgical or mechanical injury, such as tissue preservation after trauma from accidental or surgical trauma, reconstructive surgery, including skin and muscle flaps, conditions involving a diffuse thrombotic/platelet component such as disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, thrombotic complications of septicemia, adult respiratory distress syndrome, antiphospholipid syndrome, heparin-induced thrombocytopenia, and preeclampsia/eclampsia , or venous thrombosis such as deep vein thrombosis, veno-occlusive disease, hematological conditions such as myeloproliferative disease, including thrombocythemia, sickle cell anemia; or in preventing mechanically induced platelet activation in vivo, such as cardiopulmonary bypass and extracorporeal membrane oxygenation (prevention of microthromboembolism), mechanically induced platelet activation in vitro, such as use for storage of blood products, such as platelet mass, or occlusion bypass, such as in hemodialysis and plasmapheresis, thrombosis due to vascular injury/inflammation such as vasculitis, arthritis, glomerulonephritis, inflammatory bowel disease and organ transplant rejection, conditions such as migraine, Raynaud's phenomenon, conditions in which platelets may contribute the underlying inflammatory disease process in the vessel wall, such as atherosclerotic plaque formation/progression, stenosis/restenosis, and in other inflammatory conditions such as asthma, in which platelets and platelet factors are involved in the immunological disease process. Additional indications include the treatment of CNS disorders and the prevention of the growth and spread of tumors.

Tablets according to the first and second aspects of the present invention may be particularly useful in the treatment or prevention of atherothrombotic events in patients with cardiovascular disease. In one embodiment, the patient suffers from an acute coronary syndrome and/or has a history of myocardial infarction. Thus, according to a fourth aspect of the present invention, there is provided a method for treating or preventing atherothrombotic events in patients with cardiovascular disease, the method comprising administering a tablet according to the first or second aspects of the present invention to a patient suffering from or susceptible to developing such a disorder.

According to a fifth aspect, the present invention provides for the use of a composition comprising (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopronul]αmino}- 5-(pronulthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentan-1,2-diol and at least one auxiliary a disintegrating agent in the manufacture of a medicament for use in the treatment or prevention of atherothrombotic events in patients with cardiovascular disease, wherein the medicament is in the form of a tablet according to the first or second aspects of the present invention.

Specific atherothrombotic events that may be mentioned in this connection include atherothrombotic events selected from the group consisting of death due to cardiac

- 11 042784 vascular disease, myocardial infarction, stroke (eg ischemic stroke) and peripheral arterial disease. The tablets of the present invention may also be useful in the treatment or prevention of atherothrombotic events in diabetic patients.

Ticagrelor is also able to reduce the rate of stent thrombosis in a patient who has a stent placed for the treatment of an acute coronary syndrome. Thus, according to a sixth aspect of the present invention, there is provided a method for treating or preventing stent thrombosis in a patient who has received a stent for the treatment of an acute coronary syndrome, the method comprising administering a tablet according to the first or second aspects of the present invention to said patient.

According to a seventh aspect, the present invention provides for the use of a composition comprising (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]αmuno}- 5-(pronulthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentan-1,2-diol and at least one auxiliary a disintegrating agent in the manufacture of a medicament for use in the treatment or prevention of stent thrombosis, wherein the medicament is in the form of a tablet according to the first or second aspects of the present invention. In a preferred embodiment, the patient is a patient who has received a stent for the treatment of an acute coronary syndrome.

The methods and routes of administration according to the fourth to seventh aspects of the present invention are particularly useful in providing administration of ticagrelor to patients who have difficulty swallowing conventional oral formulations (eg, patients suffering from dysphagia). Such patients include elderly patients. Other patients who may benefit from receiving the tablets of the present invention include patients who have had a previous myocardial infarction or stroke.

By the term treat, treatment or treatment (and their grammatical variants) is meant that the severity of the subject's condition is reduced, at least partially improved or attenuated, and / or that some weakening, mitigation and / or reduction of at least one clinical symptom is achieved, and/or there is a delay in the progression of the disease or disorder.

By the term prevent, prevent, or prevent (and their grammatical variants) is meant that the likelihood that the patient will suffer from the condition is reduced, at least partially reduced or prevented, and/or that some prevention or suppression of at least one clinical symptom is achieved. , and/or there is a delay in the manifestation of the disease or disorder.

A subject in need of the methods of the present invention may be a subject known to have or suspected of having an acute coronary syndrome.

Blister packs

Squeeze-type blister packs are known in the art and provide a simple method of packaging tablets and capsules in a manner that allows patients to release each tablet or capsule at the time of need. However, it has been found that the extrusion action associated with this type of package exerts a force on the tablets and capsules contained therein which can lead to unacceptable levels of disruption. This is especially the case for tablets having a relatively low crush strength, such as tablets according to the first and second aspects of the present invention.

The authors of the present invention have developed a new form of packaging, which overcomes some of these disadvantages.

Thus, in an eighth aspect of the present invention, a blister pack is provided which is suitable for use with pharmaceutical formulations, in particular tablets and capsules. The blister pack contains a cellular base sheet with which a cover sheet is connected, the cellular base sheet also contains one or more cells. There is a notch in the cellular base sheet and the cover sheet so that the blister pack is capable of being torn along the notch to open one of the cells. Such a blister pack is referred to hereinafter as the pack of the present invention.

Embodiments of the packaging of the present invention are shown in figures 1A, 1B, 2A, 2B, 3A and 3B. The package of the present invention is intended to provide a form of storage that is easy to open by patients, in particular the elderly or infirm. The packaging also suggests suitability for tablets that are brittle (eg tablets having a high friability). The package is opened by a tearing action which serves to open the contents of one of the cells in the blister pack and thereby release the tablet or capsule contained in the cell. Tablets and capsules can be packed individually in each cell.

The package of the present invention contains a sheet containing a cellular base sheet 10, with

- 12 042784 which is associated with the cover sheet 11, while there is one or more cells between the cellular base sheet and the cover sheet. The blister pack 20 has an outer edge 21 which contains one or more notches 22. These notches 22, which may also be referred to as tear slits, are notches in both the honeycomb base sheet 10 and the cover sheet 11. The notches function to provide a rupture site. on the edge of the blister pack, so that the blister pack is tearable. When breaking along a notch, the tearing action opens one of the cells 23 in order to reveal its contents. Typically, each cell contains one tablet or 12 capsule.

The user can tear open the blister pack by grasping the parts of the blister pack that are located on both sides 24, 25 of the notch and then pulling these parts apart. The action of pulling these sections away from each other causes a break along the notch. Therefore, in one embodiment, the notch separates two areas on the edge of the blister pack that are designed to be gripped and pulled away from each other to break the cellular base sheet and the cover sheet.

In one embodiment, the notch 22 (or notch) is located adjacent to one of the cells 23. By positioning the notch 22 adjacent to one of the cells 23, a fracture initiated by the notch is more likely to follow a path that intersects one of the cells, and thereby ensures its opening.

In a further embodiment, the blister pack comprises a plurality of said notches 22 on the outer edge 21. In such cases, more than one notch can be associated with each cell in the blister, thereby providing a plurality of points at which a user can initiate rupture of the package. By using the phrase related to, it is meant that the notch is in close proximity to the cell, or it is positioned such that a fracture triggered by that notch follows a fracture path that intersects the cell. In one embodiment, the notch 22 is located adjacent to the cell 23. Preferably, the blister pack contains one notch 22 associated with each cell 23. Thus, in a further embodiment, the blister pack contains at least one notch 22 located adjacent to each cell 23 .

In a preferred embodiment, the blister pack 20 contains a plurality of cells, eg 4 to 24 cells (eg 6 to 14 cells). In a specific embodiment, the blister pack contains 8 or 10 cells.

In embodiments in which the blister pack contains a plurality of cells, the blister pack contains a plurality of said notches 22. Preferably, the number of notches equals the number of cells, and the blister pack contains one notch 22 associated with (for example, located adjacent to) each cell 23.

The notch may be of any shape, configuration, or size suitable for facilitating tearing of the blister pack in the manner described herein. In one embodiment, the notch is a slot 31 or cut 32.

The term slit refers to cutting into the outer edge of the blister pack where material has been removed from the base and cover sheets to form a notch. The slit may be of any suitable shape that facilitates the initiation of a tear along the notch when the edge portions of the blister pack located on both sides of the notch are pulled away from each other. Typically, this is achieved by ensuring that the slot contains an inflection point 33 (ie the shape of a singular point) at which a break can be initiated. In one embodiment, slot 31 is triangular. In another embodiment, the edges of the slot are concave inward (ie, into the slot), thus giving a shape similar to the inflection point of the astroid. By using a slit with curved edges, the area of the base and cover sheets that can be gripped by the user is increased.

The term slit refers to a linear or curved slit extending inwardly from the outer edge of the honeycomb base sheet 20. If the slit is in the form of a slit 32, little or no portion of the blister pack is removed when the gap is formed, and this also increases the area of the base and cover sheets, which can be captured by the user. The innermost end of the slit (ie, the end of the slit that does not lie on the outer edge of the blister pack) is the inflection point.

The notch should be small enough to avoid leakage around the cells prior to rupture. As a rule, the minimum distance between the cell 23 and the nearest notch 22 (or the edge of the blister pack) should be at least 3 mm.

Typically, the inflection point 33 of the notch (eg, where the notch is a slot or cut) is the innermost point, and therefore the point of the notch that is closest to any given cell 23. Thus, in a further embodiment, the innermost part 33 of the notch is at least 3 mm from the nearest cell 23.

Notch 22 must also be of sufficient size to initiate a rupture of the blister pack when a rupture force is applied. As a rule, the notch should extend inwardly from the outer edge 21 for a distance of at least about 1 mm and preferably at least

- 13 042784 measure approximately 2 mm.

Both the honeycomb base sheet 10 and the cover sheet 11 must be formed from a material (e.g., a plurality of materials in the form of a laminated sheet) that can be torn apart by a user by applying sufficient tear force, the honeycomb base sheet and the cover sheet must also be sufficiently wear resistant to minimizing the risk of breaking the integrity of the package before tearing by the user.

In one embodiment, the cellular base sheet 10 comprises an aluminum layer or a polymer layer. Preferably, the honeycomb base sheet 10 comprises an aluminum layer. In embodiments in which the cellular base sheet comprises an aluminum layer, said aluminum layer may have a thickness of from about 30 to about 60 microns, preferably about 45 microns.

In an alternative embodiment, the cellular base sheet 10 does not contain an aluminum layer. In such alternative embodiments, the cellular base sheet comprises at least one layer formed from a polymer such as polyvinyl chloride (PVC), polypropylene, polyester (eg PET) or polyamide.

In another embodiment, the honeycomb base sheet 10 comprises a plurality of layers. For example, one of said plurality of layers may be the aluminum layer described above. Other materials that can be used in such multilayer sheets include polymers such as polyvinyl chloride (PVC), polypropylene, polyester (eg PET) and polyamide. Other materials that can be used in a cellular base sheet containing a plurality of layers include a sealant. Typically, the sealant forms the innermost layer, which can therefore come into contact with the contents of the cells. Still other additional materials that can be used include coatings such as polyvinylidene chloride (PVDC). Such materials can provide advantages in reducing the permeability of the blister pack to gas and moisture. This is especially important for tablets according to the first and second aspects of the present invention, since such tablets are characterized by a relatively high hygroscopicity.

In embodiments in which the cellular base sheet 10 comprises a plurality of layers, the cellular base sheet may have a thickness of from about 100 to about 200 microns.

In a further embodiment, the cellular base sheet 10 comprises (or consists essentially of) an aluminum layer, a PVC layer, and a polyamide layer. In an example according to this embodiment, the PVC layer is the innermost layer and the polyamide layer is the outermost layer. Adhesive layers may also be present in such embodiments between the aluminum, OVC, and polyamide layers to bond them together. One or more layers of lacquer may also be present on the cellular base sheet. Layers of lacquer may be used to assist in the formation of thermal insulation between the cellular base sheet and the cover sheet. In a further example of said cellular base sheet, the cellular base sheet 10 has a thickness of about 100 to about 200 microns.

In one embodiment, the cover sheet 11 comprises an aluminum layer. In embodiments in which the cover sheet comprises an aluminum layer, said aluminum layer may have a thickness of from about 10 to about 30 microns, preferably about 20 microns.

In another embodiment, the cover sheet 11 comprises a plurality of layers. For example, one of said plurality of layers may be the aluminum layer described above. Other materials that can be used in such multilayer sheets include polymers such as polyvinyl chloride (PVC), polypropylene, polyester (eg PET) and polyamide. Other materials that can be used in this regard are paper. The use of paper as the topmost layer facilitates ink printing on blister packs. One or more layers of lacquer may also be present in the cover sheet. Layers of lacquer may be used to assist in the formation of thermal insulation between the cellular base sheet and the cover sheet.

In embodiments in which the cover sheet 11 comprises a plurality of layers, the cover sheet may have a thickness of from about 15 microns to about 60 microns.

In a further embodiment, the cover sheet 11 comprises (or consists essentially of) an aluminum layer, a PVC layer and a polyamide layer. In the example according to this embodiment, the lacquer layer is the innermost layer. In a further example of said cover sheet, the cover sheet has a thickness of from about 15 µm to about 60 µm, such as from about 15 µm to about 45 µm. The printing may further be applied to the outermost surface of the cover sheet.

In embodiments in which the blister pack contains a plurality of cells, the package may be provided in a form in which one or more such cells can be separated from others without any of the cells being sealed. This can be achieved through the use of a perforated area 26 of the blister pack, which facilitates the separation by the user of one or

- 14 042784 several cells from the remaining ones. The perforated region 26 should form a rupture path that extends between the two said cells, such that a blister pack rupture initiated at one end of the perforated region results in a rupture along the perforate. This fracture path is different from that associated with any of the notches mentioned herein above because it does not facilitate the formation of a fracture that traverses one or more cells.

Thus, in yet another further embodiment, the blister pack comprises at least two cells and further comprises a perforated region which forms a tear path extending between two of said cells.

As indicated above, the blister packs of the present invention may be applied to any tablet, capsule or other suitable pharmaceutical formulation 27. However, the blister packs according to the eighth aspect of the present invention are particularly suitable for use in storing tablets 27 according to the first or second aspects of the present invention. Thus, in one embodiment, the blister pack 20 of the present invention contains one or more tablets or capsules 27. In a further embodiment, the blister pack of the present invention contains one or more tablets in accordance with the first or second aspects of the present invention.

Blister packs without notches at the outer edge can be made by methods known to those skilled in the art. The main methods that are used to form blister packs are hot forming methods and cold forming methods.

Thermoformed blister packs contain a molding film of a (usually) transparent polymer, usually based on PVC. The blister cells are made by heating the film to soften it and then pushing the film into the cells on a steel tool, usually using compressed air.

The cold formed blister packs are made from a forming foil which is an aluminum foil (base sheet). Cells are obtained by pressing a steel tool on the foil. No heat is used to form cells in cold-formed blister packs.

For both types of blister packs, the aluminum cover foil is sealed to the forming foil by applying heat in a sealing station.

Suitable materials and methods for making blister packs are disclosed in Pilchik R., Pharmaceutical Blister Packaging, Part I (Rationale and Materials), Pharmaceutical Technology NOVEMBER 2000, 668.

The introduction of a notch into the outer edge of the blister packs of the present invention can be easily achieved through the use of a perforating or cutting tool. After sealing the forming film/foil (ie the base sheet) and the cover foil, the individual blister packs (or blister sheets) are punched with sharp punching tools. At this stage of the process, the outer edge of the blister packs can be shaped and perforations can be added in the interior areas of the blister packs between cells. Punching is a standard technique that is generally used as the last step on blister equipment, so the insertion of one or more notches into the outer edge of blister packs can be achieved at very low cost.

The term approximately, as used herein in the context of a measurable value such as the amount of an adjuvant, time, temperature, etc., refers to fluctuations of 20, 10, 5, 1, 0.5, or even 0.1% of the specified amount. , unless otherwise specified.

Graphic materials

In FIG. 1A and 1B show sectional views of a blister pack. The tablets are shown in a blister pack in FIG. 1B.

In FIG. 2A and 2B show top views of one blister. The tablet is shown in a blister in FIG. 2B.

In FIG. 3A shows a top view of a portion of a slit blister pack. In FIG. 3B is a top view of a section of a blister pack.

In FIG. 4 shows FBRM data of ticagrelor beads.

In FIG. 5 shows FBRM data for F-Melt beads.

In FIG. 6 shows FBRM and dissolution data for batches of ticagrelor prior to storage.

In FIG. 7 shows FBRM and dissolution data for batches of ticagrelor after storage at 40°C, 75% RH.

In FIG. 8 shows the dissolution of the orodispersible and film-coated tablets containing 90 mg of ticagrelor administered in Clinical Study A in 0.2% (w/v) Tween 80, mean values (n=6). Error bars represent minimum and maximum values.

In FIG. 9 is a photograph of a squeeze-type blister pack that has been modified to include triangular notches (in the form of tear cuts).

Analytical methods

In the examples described below, various parameters were measured according to the following analyses.

- 15 042784 lytic ways.

Friability was measured according to the method set forth in USP 1216 (Tablet Friability).

Crushing strength was measured according to the method set forth in USP 1217 and PhEur 2.9.8 (Resistance to Crushing of Tablets).

Disintegration time was measured according to the method set forth in USP 701 (Disintegration).

The dissolution time was measured according to the method set forth in USP 711 (Dissolution).

Particle size distribution values for ticagrelor as received from suppliers and for granulates used in tableting processes were measured using a laser diffraction method (wet and dry conditions). In wet methods, drug particles are suspended in a suitable suspending liquid (e.g., 0.5% v/v sorbitan trioleate in cyclohexane) and the particle size of the suspension is analyzed by laser diffraction using a Malvern Mastersizer 2000. size (usually for granules) was carried out by laser diffraction using dry material, i.e. without the aid of a suspending fluid. Unless otherwise indicated, particle size measurements were made under standard measurement conditions suitable for this technique.

Focused Beam Reflection Measurement (FBRM) analyzes were performed in dissolution studies. The FBRM technique inserts the sensor directly into the process stream at an angle to ensure that particles can easily pass through the sensor orifice where the measurement takes place. The laser beam is passed through a sensor tube through a combination of optical elements and focused into a narrow beam spot on a sapphire window. The optical elements rotate at a fixed speed (typically 2 m/s), which results in the beam spot moving rapidly over the particles as they pass the window. As the focused beam passes through the particle system, individual particles or particle structures will reflect the laser light back to the detector. These individual pulses of reflected light are detected, counted, and the duration of each pulse is multiplied by the scan rate to calculate the distance for each particle. This distance is defined as chord length, a fundamental measurement of a particle related to particle size, and an accurate and highly sensitive chord length distribution can be determined in real time, thus tracking how particle size and number change over time. During measurements, the sensor diameter was approximately 6 mm and there was a sapphire window at the end of the sensor. The integration time was set to 5 s. The device was set to the coarse mode, and the scanning speed of the focal spot was set to 2 m/s. The sensor was placed 2 cm above the blade.

The present invention may be illustrated by the following non-limiting examples.

In these examples, F-melt type M and F-melt type C (also referred to herein as Fmelt in the examples) were supplied by Fuji Chemicals, Ludiflash was supplied by BASF, and GalenIQ (grade 721) was supplied by Beneo-Palatinit, mannitol was supplied by Roquette, crospovidone ( Kollidon CL-SF and Kollidon CL-F) were supplied by BASF. Sodium stearyl fumarate was supplied by JRS Pharma, hydroxypropyl cellulose was supplied by Ashland, colloidal anhydrous silica was supplied by Cabot GmbH.

Example 1 Evaluation of tablets obtained by direct compression.

Four batches of 500 g tablets obtained by direct compression (DC), was obtained using the formulations of the compositions described in detail in table. 1.

Table 1

Compositions of batches of tablets obtained by direct compression

Component The consignment 1 2 3 4 Ticagrelor 15.0 15.0 15.0 15.0 F-MELT, type M 71.0 — — — F-MELT, type C 10.0 — — — Ludiflash — 81.0 — — GalenIQ — — 81.0 75.0 Crospovidone — — — 7.0

- 16 042784

Colloidal Anhydrous Silica 1.0 1.0 1.0 1.0 Sodium fumarate 3.0 3.0 3.0 3.0 Total 100.0 100.0 100.0 100.0

All values are presented in weight percent.

The first three batches differed in the use of a fast disintegrating aid in the oral cavity. F-MELT type M and C, Ludiflash or GalenIQ were used. Colloidal anhydrous silica was added to overcome the adhesive and binding nature of ticagrelor. Sodium stearyl fumarate was included as a lubricant. It was shown that the composition containing GalenIQ has a long disintegration time, for this reason, a fourth experiment was carried out using a composition containing GalenIQ and 7% disintegrant, which is crospovidone.

The main observation during tablet compression was that formulations containing FMELT (batch 1) and Ludiflash (batch 2) had poor flowability, while those based on GalenIQ (batch 3 and batch 4) had good flowability (see Table 2). ). This is reflected in the crush strength and weight analysis where the F-MELT and Ludiflash based formulations showed high variability (RSD value), while the opposite was observed for the two GalenIQ based formulations.

table 2

Observations and results

quality characteristic The consignment 1 2 3 4 F-MELT Ludiflash GalenIQ GalenIQ+cross Flowability bad bad Good Good Sticking/sticking Missing T Missing T Missing T Absent Strength on crush, n=10 Average value (N) 60.3 67.4 37.3 35.4 RSD (%) 21.6 27.2 7.78 9.60 Tablet weight, n=10 Average value (mg) 617.9 613.4 605.8 598.0 RSD (%) 4.35 3.54 1.04 1.95 Abrasion (%) 0.8 0.9 1.9 1.2 Disintegration (s), n=6 28 29 62 60

Generally, the preferred RSD values for crush strength measurements are less than 20%. Generally, preferred RSD values for tablet weight measurements are less than 4.0%. As a rule, the preferred values for abrasion are less than 1.0%. As a general rule, decay times of less than 30 seconds are preferred.

None of the tablet formulations showed any signs of a tendency to stick or stick. Friction and disintegration analysis showed that F-MELT and Ludiflash provided good tablet disintegration properties (disintegration time of approximately 30 seconds) and acceptable friability (less than 1%). The GalenIQ based composition, on the other hand, showed neither acceptable disintegration time nor abrasion. The addition of 7% disintegrant, which is crospovidone, does not significantly reduce the disintegration time of the GalenIQ formulation.

For tablets containing F-MELT or Ludiflash, there was a risk of non-compliance with QCA (critical quality characteristics) regarding the uniformity of unit dosage forms

- 17 042784 due to low flowability. For tablets containing GalenIQ, on the other hand, there was a risk of non-compliance with the CQA analysis (due to high friability) and disintegration. Conducted additional studies (see examples 2-6), in which particles of ticagrelor were introduced into granules to try to counteract the difficulties in terms of flowability.

Example 2 Evaluation of tablets obtained by wet granulation.

This experiment was designed to evaluate wet granulation of ticagrelor followed by dry mixing with other excipients prior to tablet compression. It has been shown that the inclusion of a rapid oral disintegration aid, either F-MELT or Ludiflash, provided favorable disintegration properties. In this and all subsequent examples, only type C F-melt was evaluated and not type M F-melt. The F-melt formulations used in this and subsequent examples are type C F-melt unless otherwise noted.

In table. 3 describes in detail the composition for obtaining batches for granulation of this example. Water was chosen as the granulation liquid and the hydroxypropyl cellulose binder was added dry. To reduce the binder and adhesive nature of ticagrelor, colloidal anhydrous silica was used as an anti-caking agent. There were three batches of 100 g ticagrelor granules. The last two batches were duplicated to evaluate the granules with both Ludiflash and F-MELT in the tablet formulation.

Table 3

Composition for obtaining batches for granulation

Component The consignment 5 6 7 Ticagrelor 95.0 95.0 95.0 Hydroxypropylcellulose 5.0 4.5 4.5 colloidal anhydrous dioxide silicon θ.5 0.5 Purified water ^a 30.0 30.0 30.0

^a Removed during the manufacturing process

All values are presented in weight percent.

The ticagrelor granules were included in two batches of 500 g tablets, one containing Ludiflash and the other containing F-MELT, see table. 4 for compositions. In order to further improve the disintegration time of the tablets, 5% crospovidone was added to the composition. Also included were sodium stearyl fumarate and colloidal anhydrous silica as lubricant and glidant, respectively.

Granulation of ticagrelor without colloidal anhydrous silica showed poor processability. The powder stuck to the walls of the granulator and was subjected to caking. For this reason, the silica-free batch of ticagrelor granules (batch 5) was not evaluated for tablet compression. When 0.5% (w/w) silica was added to the granular mixture, the problem was reduced and two other batches of ticagrelor granules could be evaluated for tablet formulations.

Table 4

Composition for making batches of tablets

Components Batch (Batch for granulation) 6 7 ticagrelor granules 15.8 15.8 F-MELT type C 77.0 — Ludiflash — 77.0

- 18 042784

Crospovidone 5.00 5.00 Sodium fumarate 2.00 2.00 colloidal anhydrous silica 0.20 0.20

All values are presented in weight percent.

In table. 5 summarizes the results and observations regarding the compression of tablets containing two granules mixed with either Ludiflash or F-MELT and compares the results with the results of the two batches of Example 1 with either Ludiflash or F-MELT where ticagrelor was not present. granulated. Characteristics of sticking, sticking and flowability in table. 5 are visual observations during compression, while the other four qualitative characteristics were analyzed in the manufactured tablets.

Compositions based on both F-MELT and Ludiflash showed improved flow when granulated ticagrelor compared to the non-granulated powder mixture of Example 1. This is reflected in the lower variability in crush strength and tablet weight, see RSD values in Table 1. 5. Of the two formulations containing granules, one containing F-MELT exhibited better flowability than the other containing Ludiflash, but both formulations provided tablets with a disintegration time of less than about 30 seconds and an acceptable friability of less than 1%.

The inclusion of ticagrelor granules in the formulation reduced the risk of non-compliance with CQA in terms of uniformity of the unit dosage form and maintained the required CQA analysis (associated with low attrition) and disintegration. This result supports the inclusion of a ticagrelor granulation step in a process for the manufacture of orodispersible tablets containing ticagrelor. Additionally, only F-melt was evaluated as it showed better flowability than Ludiflash as evidenced by the improved RSD value for crush strength. The RSD value in relation to weight was also the best for batches containing F-melt rather than Ludiflash, and this is further evidence of the improved flowability observed when using F-melt instead of Ludiflash.

Table 5

Results and Observations from Examples 1 and 2

quality characteristics Party (explained) 6 1 7 2 F-MELT (grain) F-MELT (DC) Ludiflash (Grand) Ludiflash (DC) Sticking/sticking Absent Absent Absent Absent Flowability Good bad Moderate bad Strength on crush, n=10 Average value (N) 44.0 60.3 46.0 67.4 RSD (%) 6.8 21.6 21.3 27.2 Tablet weight, n=10 Average value (mg) 603.4 617.9 606.4 613.4 RSD (%) 1.95 4.35 2.57 3.54 Abrasion (%) 0.5 0.8 0.6 0.9 Disintegration (s), n=6 28 28 29 28

Generally, the preferred RSD values for crush strength measurements are less than 20%. Generally, preferred RSD values for tablet weight measurements are less than 4.0%. As a rule, the preferred values for abrasion are less than 1.0%. As a general rule, decay times of less than 30 seconds are preferred.

Example 3 - Evaluation of the composition for granulation.

The aim of this study was to gain knowledge as well as to improve granulation and tablet formulation. The granulation process was scaled from 100 g to 500 g batches. The batch size of the tablets was still 500 g.

In table. 6 describes in detail the composition for obtaining batches for granulation, included

- 19 042784 nyh in the study. Beads containing various amounts of ticagrelor were evaluated, 95% (batch 8), 64% (batch 10) and 48% (batch 9). In the last two of the three batches, part of the ticagrelor was replaced with a mannitol excipient, where the small size was chosen in order to obtain homogeneous granules.

Table 6

Composition for obtaining batches for granulation from example 3

Components The consignment 8 9 10 Ticagrelor 95.0 48.38 64.30 Mannitol — 48.38 32.20 Hydroxypropylcellulose 4.50 3.00 3.00 colloidal anhydrous silica 0.50 0.25 0.50 Purified water ^a 30.0 30.0 30.0

^a Removed during the process

All values are presented in weight percent.

Granulation lots were evaluated in subsequent tablet compression. In table. 7 describes in detail the composition for obtaining batches of tablets included in the study. The tablet compression experiment was divided into two sub-experiments. The first was two lots of tablets (lots 9A and 10A) containing either 48% (from lot 9) or 64% (from lot 10) ticagrelor granules, respectively. Scaling of granules containing 95% ticagrelor showed poor workability in the granulation step of the process and hence these granules were not compressed into tablets, see conclusion section for details.

Second, a 48% ticagrelor granule (batch 9) was used for an additional five tablet lots (batch 9B-9F) where tablet excipients were varied, see Table. 7. In one lot, colloidal anhydrous silica was excluded (batch 9B), in one lot, the amount of sodium stearyl fumarate was reduced from 1% (w/w) to 0.5% (batch 9C), and in three lots the quality and quantity were examined baking powder. In Lot 9D, the amount of disintegrant was increased from 5% (w/w) to 8%, in Lot 9E, half of the amount of crospovidone was replaced with croscarmellose sodium, and in Lot 9F, crospovidone, whose particle size quality in all lots has so far been very fine , were replaced with a somewhat cruder quality of crospovidone. When evaluating two types of quality of crospovidone, they are called crospovidone SF (in other words, very fine) and crospovidone F (in other words, fine), respectively.

Table 7

Composition for making batches of tablets

Components Tablet batch (granulation batch included in tablet composition) 9A 10A 9B 9C 9D 9E 9F ticagrelor granules 31.0 23.3 31.0 31.0 31.0 31.0 31.0 F-MELT, type C 62.8 70.5 63.0 63.3 59.8 62.8 62.8 Crospovidone SF 5.00 5.00 5.00 5.00 8.00 2.50 — Crospovidone F — — — — — — 5.00 Croscarmellose sodium — — — — — 2.50 — Sodium fumarate 1.00 1.00 1.00 0.50 1.00 1.00 1.00 colloidal anhydrous silica 0.20 0.20 — 0.20 0.20 0.20 0.20

All values are presented in weight percent.

Scaling the composition to produce 95% ticagrelor granules (batch 8) from 100 g to 500 g affected the processability in the granulation step of the process. A large amount of material adhered to the walls of the vessel as well as to the paddle, causing strong friction between the paddle and the bottom of the vessel. The process had to be stopped several times to scrape off the material. It has been concluded that the composition will never work on an industrial scale and hence these granules are not compressed into tablets.

- 20 042784

It has been found that reducing the amount of ticagrelor in the granule formulation and instead adding mannitol as a filler improves processability by providing less sticking of the material to the vessel walls and paddles. It was still necessary to stop the process a few times and scrape off some of the material, but the composition was found to be workable. Beads containing 64% (batch 10) and 48% ticagrelor (batch 9) with mannitol as filler were evaluated and material adhesion was more extensive with 64% ticagrelor. In the case of granulation batches containing 48% ticagrelor, only some material adhered to the vessel and paddle.

In table. 8 summarizes the results and observations regarding the compression of tablets from various granules. With regard to visual observations during pressing, the only two batches with workability problems were batch 9C, where the amount of lubricant was reduced from 1.0% to 0.5% (wt./wt.), which showed moderate flowability and a tendency to adhesion and batch 9B where no glidant was included and poor flow was observed during tablet compression. All other batches showed excellent machinability. It was therefore concluded that the proper amount of lubricant was 1.0% (w/w) where no sticking or sticking tendencies were observed and flowability was good and that the amount of silica should be 0.2% (w/w). /wt.) to obtain a powder mixture with good flowability.

A comparison of a tablet containing granules with 64% and 48% (w/w) ticagrelor showed that the higher amount of ticagrelor in the granules resulted in a slightly shorter disintegration time, see Lot 9A and Lot 10A. With a higher drug loading in the granules, fewer granules are included in the tablet formulation (which must always contain the prescribed amount of ticagrelor) and hence more of the fast disintegrating adjuvant in the mouth. Although a short disintegration time is important for the product, it was decided that lot 9, containing 48% ticagrelor and mannitol as excipient, should be used for additional composition evaluation studies due to processability issues shown in the process step. granulation earlier.

Comparison of Lot 10A (5% crospovidone SF) with Lot 9D (8% crospovidone SF), Lot 9E (2.5% crospovidone SF and 2.5% croscarmellose sodium) and 9F (5% crospovidone F) showed that increasing the amount of disintegrant from 5% to 8% did not reduce the decay time, on the contrary, it increased from 28 to 43 s. Replacing half of the baking powder with croscarmellose sodium did not affect the disintegration time (both batches 28 s). However, replacing crospovidone SF with crospovidone F reduced the disintegration time from 28 to 22 seconds and resulted in the selection of crospovidone F for use in the tablet formulation.

- 21 042784

Table 8

Observations and results from example 3

quality characteristics and 9A 10A 9V 9C 9D 9E 9F 48% grn. 64% gran. Glidant-free 0.5% lubricant substances a 8% C-SF 2.5%+2.5% 5% C-F Flowability I'm good I'm good bad Moderate I'm good I'm good I'm good Harassment/pr orsleeping Absent Absent Absent Present Absent Absent Absent Crushing strength, n=10 Average value (N) 52.6 54.3 61.8 64.8 60.3 59.1 61.6 RSD (%) 3.68 3.29 12.2 4.80 9.90 8.41 5,I tablet weight, n=10 Average value (mg) 603.2 605.7 595.9 598.9 600.3 603.4 602.9 RSD (%) 0.51 0.49 1.26 0.52 0.99 0.82 0.52 Abrasion (%) 0.5 0.5 0.6 0.5 0.4 0.5 0.5 Disintegration (s), n=6 31 28 38 29 43 28 22

Generally, the preferred RSD values for crush strength measurements are less than 20%. Generally, preferred RSD values for tablet weight measurements are less than 4.0%. As a rule, the preferred values for abrasion are less than 1.0%. As a general rule, decay times of less than 30 seconds are preferred.

Briefly, the workability of ticagrelor granules was improved by reducing the ticagrelor content from 95% to 48%. Replacing crospovidone with a slightly coarser quality provided a better margin for meeting the CQA in terms of disintegration. With a lubricant content of 1.0% and a glidant content of 0.2%, flowability was ensured during tablet compression and thereby reduced the risk of CQA non-homogeneity of the unit dosage form. On the basis of these results, the composition for the production of tablets batch 9F was chosen for further evaluation, see table. 9.

- 22 042784

Table 9

Prototype composition of an orodispersible tablet containing ticagrelor, 90 mg

Components Quantity per party (%) Amount per tablet (mg) Function Ticagrelor ³ 15.0 90.0 medicinal substance F-MELT, type C ^{b c} 62.8 377 Filler Mannitol ³ 15.0 90.0 Filler ^Crospovidone 5.00 30.0 Baking powder Sodium fumarate ^b 1.00 6.00 Lubricating substance Hydroxypropylcellulose A 0.93 5.58 Binder Components Quantity per party (%) Amount per tablet (mg) Function Colloidal anhydrous silicon dioxide ^{3'b ,c1} 0.28 1.68 Glider/anti-caking agent Water® qs qs Fluid for granulation

^a Incorporated into granules. The granule consists of ticagrelor (48.4%), mannitol (48.4%), hydroxypropyl cellulose (3.00%), silica (0.25%) ^b Dry blended with ticagrelor granules (31.25%) c ^c F-MELT type C is a mixture formed by co-spray drying of mannitol (65%), microcrystalline cellulose (18%), crospovidone (8%), xylitol (5%) and anhydrous dibasic calcium phosphate (4%) ^d Total silica, both intragranular (0.08%) and extragranular (0.20%) ^e With removal during fabrication qs quantum satis

Example 4: Evaluation of baking powder.

Since disintegration is one of the primary characteristics for an orodispersible tablet, Example 4 was set up to evaluate the quantity and quality of the disintegrant to be used.

The lead formulation from the previous study contained 5% disintegrant, which is crospovidone, a fine particle size class, herein referred to as crospovidone F[1]. It was compared with crospovidone from another supplier, referred to in this document as crospovidone F[2] (Table 10). Both were characterized by approximately the same particle size distribution. The included amounts were 0, 2 and 5% (w/w) of crospovidone and the amount was offset by F-MELT type C in the formulation. All batches contained the same batch of ticagrelor beads, with the following composition: 48.4% ticagrelor, 48.4% mannitol, 3.00% hydroxypropyl cellulose and 0.25% silica, all expressed as weight percent.

- 23 042784

Table 10

Disintegrant in tablet batches

The consignment Baking Powder (Crospovidone) Quantity (wt%) eleven — oh oh 12 Crospovidone F[1 ] 5.0 13 Crospovidone F[2] 5.0 14 Crospovidone F[1 ] 2.0 15 Crospovidone F[2] 2.0

In table. 11 summarizes the result of the baking powder evaluation experiments in Example 4.

Table 11

Observations and results

quality characteristics Batch (quantity and quality of crospovidone) eleven 12 13 14 15 0% 5% F[l] 5% F[2] 2% F[l] 2% F[2] Flowability Good Good Good aya I'm good I'm good Harassment/adv ilation Absent Absent Absent Absent Absent Strength on crush, n=10 Average value (N) 63.3 61.0 65.8 62.3 58.9 RSD (%) 7.06 6.73 Yu,1 4.59 5.04 tablet weight, n=10 Average value (mg) 604.6 607.9 602.8 598.0 595.3 RSD (%) 0.74 0.68 1, Yu 0.48 0.50 Abrasion (%) oh, s 0.5 0.7 0.5 0.5 Disintegration (s), n=6 29 26 25 21 21 Degree dissolution after 45 min. (%) 92.9 94.5 NT 94.3 NT after 60 min. (%) 93.9 95.4 NT 95.2 NT

NT - not tested

Generally, the preferred RSD values for crush strength measurements are less than 20%. Generally, preferred RSD values for tablet weight measurements are less than 4.0%. As a rule, the preferred values for abrasion are less than 1.0%. As a general rule, decay times of less than 30 seconds are preferred. In general, preferred dissolution thresholds are at least 75% at 45 minutes and at least 80% at 60 minutes.

- 24 042784

As can be seen, all five batches showed good workability with good flowability and no sticking or sticking to tablet punches. Good flowability is reflected in low variability in crush strength and tablet weight (RSD value) and all three quality characteristics are good indicators that the risk of non-compliance with the CQA for unit dosage form uniformity in an industrial scale process is low. Disintegration was clearly influenced by the amount of crospovidone. As can be seen, 2% of either crospovidone F[l] or crospovidone F[2] provided the shortest disintegration time. Comparison of the dissolution of tablets containing 0, 2 and 5% crospovidone F[l] showed that the amount of crospovidone does not appear to have a significant effect on dissolution. Based on these results, it was decided that crospovidone F[l] should continue to be formulated and that the preferred amount of crospovidone is closer to 2% than 5%.

Example 5. Evaluation of the composition for the production of tablets.

The purpose of this study was to study the composition of the composition for obtaining tablets. A 4+3 fractional factor design experiment was performed with three factors: the amount of sodium stearyl fumarate, colloidal anhydrous silica, and crospovidone.

The formulations for the batches of tablets in this study are detailed in Table 12. Crospovidone ranges from 1.0 to 4.0% (w/w), sodium stearyl fumarate from 1.0 to 3.0% (w/w). .) and finally silicon dioxide from 0.2 to 0.6% (w/w). One 600 g granulation batch was made to provide all of the tablet formulations in the study. The composition for the preparation of the granules was as follows: 48.4% ticagrelor, 48.4% mannitol, 3.00% hydroxypropyl cellulose and 0.25% silica, all expressed as weight percent.

Table 12

Composition for obtaining batches of tablets from example 5 (% wt./wt.)

Components The consignment 16 17 18 19 20 21 22 ticagrelor granules 31.0 31.0 31.0 31.0 31.0 31.0 31.0 F-MELT, type C 63.8 64.8 66.4 61.4 64.1 64.1 64.1 Crospovidone 4.00 1.00 1.00 4.00 2.50 2.50 2.50 Sodium fumarate 1.00 3.00 1.00 3.00 2.00 2.00 2.00 colloidal anhydrous. silica 0.20 0.20 0.60 0.60 0.40 0.40 0.40 Total 100 100 100 100 100 100 100

All values are presented in weight percent.

Observations and results of the study are described in detail in Table. 13. Visual observations were noted during tablet compression such as flowability and sticking/sticking. The tablets were analyzed for variation in weight and crush strength, friability, disintegration and dissolution. The results were examined and compared separately, and also evaluated using the Modde® experiment design tool (v 9.0 Umetrics AB, Sweden).

As can be seen in Table. 13, all seven batches showed good workability with good flowability and no sticking or sticking to tablet punches. Good flowability is reflected in low variability in crush strength and tablet weight (RSD value). All batches met the preferred wear threshold.

The results indicated that lower amounts of both crospovidone and sodium stearyl fumarate resulted in shorter disintegration times. The amount of silica did not significantly affect the disintegration time, but both sodium stearyl fumarate and silica improved flowability. Increased amounts of both sodium stearyl fumarate and crospovidone provided slightly faster dissolution rates, although all met the preferred dissolution thresholds Q=70 at 45 minutes and Q=75 at 60 minutes.

-25 042784

Table 13

Observations and results

quality characteristics and The consignment 16 17 18 19 20 21 22 Flowability Good aya Good aya Good aya Good aya Good aya Good aya Good aya Molesting/Snubbing Absent Absent Absent Absent Absent Absent Absent Crushing strength, n=10 Average value(N) 45.8 55.4 54.1 47.2 49.6 52.3 55.0 RSD (%) 9.21 4.97 4.49 4.98 4.49 4.81 5.57 tablet weight, n=10 Average value (mg) 593 604 599 602 592 605 607 RSD (%) 1.24 0.58 0.86 0.99 0.53 0.62 0.57 Abrasion (%) 0.5 0.5 0.5 0.5 0.5 oh, s 0.5 Disintegration (s), n=6 28 28 23 thirty 24 25 23 Degree dissolution after 45 min. (%) 92.5 91.3 89.9 92.9 91.0 NT NT after 60 min. (%) 93.2 92.0 90.8 93.8 91.8 NT NT

NT - not tested

Generally, the preferred RSD values for crush strength measurements are less than 20%. Generally, preferred RSD values for tablet weight measurements are less than 4.0%. As a rule, the preferred values for abrasion are less than 1.0%. As a general rule, decay times of less than 30 seconds are preferred. In general, preferred dissolution thresholds are at least 75% at 45 minutes and at least 80% at 60 minutes.

These results led to additional trials for tablet formulations where the amount of crospovidone was reduced from 5.0% to 2.0% because it was shown to provide the shortest disintegration time and because both sodium stearyl fumarate and (extragranular ) silica improved flowability, the amounts were slightly increased for sodium stearyl fumarate from 1.00% to 1.50% and for silica from 0.20% to 0.40%.

Example 6 Evaluation of the granulation composition and drying method.

In order to further study the composition for obtaining granules, a fractional factorial scheme of the experiment was carried out with 4 + 3 samples. Variable factors were the amount of ticagrelor, hydroxypropyl cellulose, and colloidal anhydrous silica.

In the studies detailed in examples 2-5, the granules were dried in trays. Two repetitions of two tests were carried out, where the granules were dried in a fluid bed dryer in order to find out if this did not affect the quality of the tablet. Fluid Dryer Applications

- 26 042784 layer is typical for production on an industrial scale.

Compositions for obtaining granular samples in the study are described in detail in table. 14 below. The content of ticagrelor ranged from 38 to 58%, hydroxypropyl cellulose from 2 to 6%, and finally silica from 0.25 to 0.75%. Since a tablet must always contain 90 mg of ticagrelor, the tablet formulation included 25.9 to 39.5% ticagrelor granules, see Table 1. 15 below. The varying amount of granules was compensated for by F-MELT type C in tablet formulations. With regard to other tableting auxiliaries, all batches of tablets contained 2.0% crospovidone, 1.5% sodium stearyl fumarate, and 0.4% silica. Everything is expressed in weight percent.

Table 14

Composition for obtaining batches of granules

Components Lot (sample number) 23 24 25 26 27 28 29 N1 N2 N3 N4 N5 N6 N7 Ticagrelor 38.0 58.0 38.0 58.0 48.0 48.0 48.0 Mannitol 59.25 39.75 55.75 35.25 47.50 47.50 47.50 Hydroxypropylcell yulose 2.00 2.00 6.00 6.00 4.00 4.00 4.00 colloidal anhydrous. silica 0.75 0.25 0.25 0.75 0.50 0.50 0.50 Total 100 100 100 100 100 100 100

All values are presented in weight percent.

Table 15

Composition for making batches of tablets

Components Lot (sample number) ^a thirty 32 34 35 36 31 33 N1 N3 N5 N6 N7 N2 N4 ticagrelor granules 39.47 31.25 25.86 F-MELT, type C 56.63 64.85 70.24 Crospovidone 2.00 2.00 2.00 Sodium fumarate 1.50 1.50 1.50 colloidal anhydrous. silica 0.40 0.40 0.40 Total 100 100 100

a Samples N1 and N3 contain 38% ticagrelor beads, N5-N7 contain 48% ticagrelor beads, and N2 and N4 contain 58% ticagrelor beads

All values are presented in weight percent.

Observations were noted during the manufacturing process, such as workability during granulation and flowability, as well as sticking/sticking during tablet compression. The tablets were analyzed for crush strength, weight, friability, disintegration and dissolution. The results were examined and compared separately, and also evaluated using the Modde® experiment design tool (v 9.0 Umetrics AB, Sweden). In table. 16 summarizes the observational result and the results from Example 6.

During the granulation process, an increase in the amount of ticagrelor included in the granules resulted in an increase in processing complexity. The sticky, sticky and small particles of ticagrelor were prone to sticking to the walls of the granulator and it was necessary to stop the process and scrape the material off the walls a couple of times during the process. On the other hand, the results of the analysis of the tablets showed that the greater the amount of ticagrelor in the granules, the shorter the time

- 27 042784 disintegration of tablets, which occurs because the inclusion of large amounts of ticagrelor in granules leads to the need for less granules included in the tablet formulation, and therefore more F-MELT, which promotes disintegration. These results confirm the results from example 3, where the pellets were compared with 95%, 64% and 48% (w/w) ticagrelor.

The disintegration time was also reduced by adding more hydroxypropyl cellulose to the granules. This can be explained by the fact that more hydroxypropyl cellulose makes the granules harder and less prone to crushing during tablet compression. Grinding the granules will result in the formation of small particles that will bind to the F-MELT and thereby increase the disintegration time. It has also been shown that a larger amount of hydroxypropylcellulose slightly increases the dissolution rate of ticagrelor.

As can be seen in Table. 16, all batches showed good workability with good flowability and no sticking or sticking to tablet punches. Good flowability is reflected in low variability in crushing strength and tablet weight (RSD value), all indicating that the risk of CQA failure to achieve unit dosage form uniformity in an industrial scale process is low. It was also observed that all tablets met the preferred threshold for friability.

The amount of silica in the granules did not appear to affect the quality of the tablet, but since a larger amount facilitates the granulation process by reducing the adhesive and/or binder nature of the ticagrelor particles, it was decided that more silica should be included in the granules.

After the study, the following changes were made to the granulation composition. The amount of hydroxypropyl cellulose was increased from 3.0% to 4.0% as higher amounts have been shown to shorten disintegration time. The amount of silica in the granules was increased from 0.25% to 0.75% in order to reduce the adhesive and/or binder nature of the particles of ticagrelor. The amount of ticagrelor was not changed, as a higher amount appears to have a negative effect on processability, while a lower amount appears to have a negative effect on disintegration time.

Table 16

Observations and results

quality characteristics a Lot (sample number (amount of ticagrelor in granules)) thirty 31 32 33 34 35 36 N1 N2 N3 N4 N5 N6 N7 (38%) (58%) (38%) (58%) (48%) (48%) (48%) Flowability Good Good Good Good Good Good Good and I and I and I and I and I and I and I Harassment/pr Otsuts Otsuts Otsuts Otsuts Otsuts Otsuts Otsuts orsleeping tvuet tvuet tvuet tvuet tvuet tvuet tvuet Crushing strength, n=10

- 28 042784

Average value (N) 56.7 59.6 47.4 50.6 48.8 50.8 54.7 RSD (%) 8.64 4.36 5.70 5.73 6.97 5.91 5.30 tablet weight, n=10 Average value (mg) 604.5 610.6 605.5 601.5 599.3 593.5 603.9 RSD (%) 0.61 0.24 0.54 0.53 0.55 0.62 0.63 Abrasion (%) oh, s 0.5 oh, s 0.5 0.5 0.5 oh, s Disintegration (s), n=6 31 22 26 23 24 26 23 Degree dissolution after 45 min. (%) 92.3 88.7 95.2 93.1 NT 93.7 NT after 60 min. (%) 93.5 90.1 95.8 94.3 NT 94.5 NT

NT - not tested

Generally, the preferred RSD values for crush strength measurements are less than 20%. Generally, preferred RSD values for tablet weight measurements are less than 4.0%. As a rule, the preferred values for abrasion are less than 1.0%. As a general rule, decay times of less than 30 seconds are preferred. In general, preferred dissolution thresholds are at least 75% at 45 minutes and at least 80% at 60 minutes.

In table. 17 and 18 below show data from the analysis of granules and tablets containing granules that were either tray dried or fluid bed dried. The beads in N1 and N1b contain 38% ticagrelor, while the beads in N4 and N4b contain 58% ticagrelor. N1 and N4 were dried in trays, and N1b and N4b were dried in a fluidized bed. As can be seen in Table 17, N4 and N4b have a larger particle size distribution than N1 and N1b, but in both cases, fluidized bed drying produces finer particles than tray drying, which also results in a higher index Carr for both fluidized granules. On the other hand, the two drying methods do not provide a significant difference in terms of tablet quality, see table. 18. Therefore, fluid bed drying has been found to be potentially suitable for commercial manufacture without significantly affecting tablet quality.

Table 17

Comparison of Tray-Dried and Fluid-Dried Granules

Batch of granules 23 23A 26 26A sample number N1 Nlb ^a N4 N4b ^a Carr index (%) 29.1 32.0 31.3 33.3 Particle Size Distribution d(0,l) 8.05 6.64 7.70 7.18 d(0.5) 73.0 57.3 194 132 d(0.9) 874 709 1168 1020

^a Samples #N1b and N4b contain fluid-bed dried pellets (Samples #N1 and N4 contain tray-dried pellets)

- 29 042784

Table 18

Comparison of tablets containing either tray-dried or fluid-bed dried granules

Batch of pills thirty ZOA 33 ZZA sample number N1 Nlb ^a N4 N4b ^a Flowability Good Good Good Good Sticking/sticking Absent Absent Missing T Missing T Strength on crush, n=10 Average value (N) 56.7 55.8 50.6 56.8 RSD (%) 8.64 9.89 5.73 5.85 Tablet weight, n=10 Average value (mg) 604.5 614.5 601.5 610.9 RSD (%) 0.61 1.28 0.53 0.70 Abrasion (%) 0.30 0.45 0.45 0.30 Disintegration (s), n=6 31 thirty 23 26 The degree of dissolution after 45 min. (%) 92.6 91.8 93.1 91.3

^a N1b and N4b contain fluid bed dried granules (N1 and N4 contain tray dried granules)

Example 7 Compositions for the preparation of tablets.

Received the composition shown in table. 19A and is intended to illustrate the present invention.

Table 19A

Composition for preparing tablets containing 90 mg of ticagrelor

Ingredient Quantity per batch (%) Quantity per tablet (mg) Ticagrelor ³ 15.0 90.0 F-MELT type C ^b>c 64.8 389 Mannitol ³ 14.8 88.6 ^Crospovidone 2.00 12.0 Sodium fumarate ^b 1.50 9.00 Hydroxypropylcellulose a ^a 1.25 7.50 Colloidal anhydrous silica ^a ' ^{b c1} 0.63 3.81 Tablet core weight 100 600

^a Incorporated into granules. The granule consists of ticagrelor (48.0%), mannitol (47.25%), hydroxypropyl cellulose (4.00%), silica (0.75%) ^b Dry blended with ticagrelor granules (31.25%) c the formation of the final composition for obtaining tablets ^with F-MELT type C is a mixture formed by co-spray drying of mannitol (65%), microcrystalline cellulose (18%), crospovidone (8%), xylitol (5%) and anhydrous dibasic calcium phosphate (4%) ^d Total silica, both intra-granular (0.23%) and extra-granular

- 30 042784 granular (0.40%) ^e With removal during the manufacturing process qs quantum satis

You can also get the composition shown in table. 19V.

Table 19B

Composition for preparing tablets containing 60 mg of ticagrelor

Ingredient Quantity per batch (%) Quantity per tablet (mg) Ticagrelor ³ 15.0 60.0 F-MELT type C ^{b c} 64.8 259 Mannitol ³ 14.8 59.1 ^Crospovidone 2.00 8.00 Sodium fumarate ^b 1.50 6.00 Hydroxypropylcellulose a ³ 1.25 5.00 Colloidal anhydrous silica ³ ' ^{b c1} 0.63 2.54 Tablet core weight 100 400

^a Incorporated into granules. The granule consists of ticagrelor (48.0%), mannitol (47.25%), hydroxypropyl cellulose (4.00%), silica (0.75%) ^b Dry blended with ticagrelor granules (31.25%) c ^c F-MELT type C is a mixture formed by co-spray drying of mannitol (65%), microcrystalline cellulose (18%), crospovidone (8%), xylitol (5%) and anhydrous dibasic calcium phosphate (4%) ^d Total silica, both intragranular (0.23%) and extragranular (0.40%) ^e With removal during fabrication qs quantum satis

EXAMPLE 8 Manufacture of a tablet.

Tablets weighing 600 mg containing 90 mg of ticagrelor, in accordance with example 7, were made in accordance with the following method. Colloidal anhydrous silica, ticagrelor, hydroxypropyl cellulose and mannitol were dry blended in a high shear mixer for approximately 5 minutes to give a total weight of 9 kg of dry ingredients. Wet granulation was then carried out by adding the granulation liquid (water, 18.4% (w/w)) to the dry ingredients. The wet granular mixture was milled in a rotary paddle sieve mill and then dried in a fluid bed dryer with an inlet air temperature of 50°C. This was followed by grinding in a rotating paddle sieve mill. The final mixing was carried out in a diffuse mixer. The ticagrelor-containing granules, colloidal anhydrous silica, F-MELT type C, crospovidone, and sodium stearyl fumarate were then mixed together for about 20 minutes. The final mixture was compressed into tablets using a mechanized tablet press.

Tablet compression rates of between 7.9 kN and 13.1 kN have been found to be sufficient to provide tablets having a suitable crush strength (about 65 N). These tablets are characterized by acceptable disintegration time, dissolution rate, crush strength and friability.

The process was also scaled up using final mix batch sizes in the region of 256 kg. These tablets also have acceptable disintegration time, dissolution rate, crush strength and friability.

Example 9 Evaluation of the effect of drug particle size and manufacturing parameters on tablet properties.

The effect of (i) drug particle size, (ii) amount of granulation liquid, and (iii) water addition time on tablet manufacture was assessed. The composition for obtaining tablets corresponded to example 7, and the method of manufacture was consistent with example 8, except when otherwise indicated. The tablets obtained in this study were round and flat-faceted.

- 31 042784 flat edge, 14 mm. 8 out of 10 batches tested were also embossed.

Two batches of drug substance with low and high D value (v, 0.9) were selected. The water addition time was varied by using 2 or 4 spray nozzles. The design of the experiment is shown in Table 20. The main responses were analysis, acceptance rate (AV) for content change, disintegration and dissolution.

Table 20

Experimental scheme for the granulation stage

The consignment Particle size of the medicinal substance, D (v, 0.9), µm Quantity of water, kg Adding water Calculated time, minutes Number of nozzles 37 22 10 4.3 4 38 AND 12 10.3 2 39 22 10 4.3 4 40 22 10 8.6 2 41 AND 10 8.6 2 42 AND 12 5.2 4 43 22 12 5.2 4 44 AND 10 4.3 4 45 AND 12 10.3 2 46 22 12 10.3 2

All batches were sampled at three or four different compression intensities before starting to press the batch of tablets. In addition, disintegration was analyzed at each pressing intensity. Tablet crush strength was tested as resistance to rupture under diametrical compression.

A tablet sample was taken for UoDU from the composite sample and the AV value was calculated.

In addition, tablet samples were taken and analyzed according to the method proposed by Garcia (Garcia, Thomas et.al. Recommendations for the assessment of blend and content uniformity: modifications to withdrawn FDA draft stratified sampling guidance, J. Pharm. Innov., 2014 , (DOI) 10.1007/s12247014-9207-0), see below. Samples were taken from 40 locations, 20 locations were selected for analysis (n=3). Samples were analyzed for 4 out of 10 batches.

To meet Garcia's homogeneity acceptance criteria, the RSD of all individual results must be <3.0% (n=1 at 10 locations) or <5.0% (n=3 at 10 locations, provided the cause is not analytical error or sampling error). This criterion was used to obtain information for assessing homogeneity.

Sampling and appearance analysis were performed in 4-5 cases. To evaluate disintegration and friability, samples were taken and analysis was performed in about 5 cases.

Dissolution analyzes were performed on a composite sample.

final mix

The overall goal with respect to the final mixture is to obtain a homogeneous mixture that can be compressed into tablets containing the required dose of ticagrelor at all times. Four batches were analyzed containing samples with low/high water, small/large drug particle size, and short/long water addition times. The results of the analysis of the homogeneity of the powder mixture shown in table. 21 confirm that the powder mixture is sufficiently homogeneous after the final mixing.

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Table 21

Analysis of the final mixture

The consignment Analysis, % of nominal Minimum, % of nominal Maximum, % of nominal SD, % of target 39 96.9 93.3 101.0 2.4 53 98.1 95.6 100.2 1.4 44 98.3 95.2 102.2 2.4 46 99.1 95.4 103.5 2.5

Tablet pressing

The goal of this one-time operation was to compress the mixed powder into tablets that consistently provide the targeted CQA. Tablet property results include analysis and UoDU, weight, crush strength, thickness, friability, disintegration and dissolution.

Analysis and homogeneity of single dosage forms

For a more thorough assessment of UoDU, an assessment based on the method proposed by Garcia was used.

All individual assay results must be between 75.0% and 125.0% of the target strength.

Pass ASTM E2709/E2810 using an acceptance criterion of 90% confidence and 95% coverage of the total number of unit dosage forms analyzed.

All batches that were evaluated by this method successfully met the criterion, see table. 22.

Table 22

Separate analysis and test for compliance with ASTM E2709/E2810

Part nya Analyzed other sample locations Average value, % of nominal Interval adopted for the average value ^a Min. individual tablets, % of nominal foot Max. individual tablets, % of nominal foot Passing or failing the compliance test 39 20 97.2 94.1- 105.9 93.0 104.6 Walkthrough 53 20 97.4 96.2- 103.8 90.5 106.8 Walkthrough 44 20 98.8 90.8- 109.2 95.4 103.7 Walkthrough 46 40 97.8 96.2- 103.8 87.5 107.1 Walkthrough

Calculated interval for the average of the batch that will pass the compliance test, based on the number of tablets analyzed and the distribution of their contents.

The results of the analysis are shown in table. 23. The results show that all but one batch were within the 95 to 105% analysis interval.

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Table 23

Analysis

The consignment Sample Average value, % of nominal Min, % of nominal Max, % of nominal RSD, % 37 Composite 97.2 94.6 101.7 2.2 38 Composite 98.6 92.8 109.0 4.7 39 Composite 94.5 88.4 97.2 3

40 Composite 98.1 90.2 102.8 3.4 41 Composite 97.4 92.4 100.5 2.1 42 Composite 100.6 94.5 107.1 4.4 43 Composite 97.4 93.2 101.8 2.9 44 Composite 99.4 97.1 102.9 2 45 Composite 95.4 91.1 98.8 2.8 46 Composite 97.5 91.1 98.8 3.3

Tablet weight

The results are shown in table. 24 below. Lots ranged from 571 to 615 mg and averaged from 597 to 602 mg. The low variation in tablet weight indicates good flowability of the powder, which therefore provides the ability to deliver a suitable amount of ticagrelor to the final product.

Table 24

Crushing strength, tablet thickness, friability and disintegration The crushing strength and disintegration of the tablet as a function of compression intensity was investigated by obtaining a compression profile for each batch, see table. 25.

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Table 25

Decay time in seconds (n=6) depending on the pressing intensity

The consignment 8 kN 11 kN 14 kN 37 20 23 26 38 24 22 26 39 21 23 28 40 21 26 29 41 18 19 23 42 18 18 18 43 19 21 21 44 23 24 29 45 18 20 22 46 16 18 24

The pressure values required to achieve a crush strength of 65N ranged from 7.9 kN to 13.1 kN between batches. It has been found that the finer the material, measured as D(v, 0.1) in the drug granules, the lower the compression intensity to achieve the same tablet crush strength, in this case 65 N.

The tablet disintegration time for all batches during the continuous tablet compression cycle was below the target CQA of 30 seconds.

The dependence of disintegration on the intensity of pressing is shown in table. 25 above. There is slight curvature with a minimum at about the pressing intensity applied for each batch.

During continuous batch production, the average tablet crush strength and friability were monitored. The results are shown in table. 26.

Table 26

Crush strength, friability and tablet thickness

The consignment Average value (N) Min (H) max (H) RSD (%) Abrasion (%, n=11) Thickness, mm RSD, % 37 67 51 73 7.5 0.1 3.80 0.6 38 66 57 74 6.6 0.1 3.70 0.3 39 61 46 72 8.2 <0.1 3.85 0.4 40 64 51 71 7.5 <o,1 3.80 oh, s 41 64 56 70 6.7 <0.1 3.78 0.5 42 63 55 75 8.3 <0.1 3.76 0.4 43 61 50 67 7.4 <0.1 3.83 0.6 44 64 57 70 5.2 0.1 3.84 0.4 45 63 49 70 8.3 <0.1 3.75 oh, s 46 68 58 84 8.6 0.1 3.75 oh, s

The friability of the tablet was 0.1% or less, which is a low value compared to the requirement in the pharmacopoeia (<1.0%). The decay time was below the target CQA for all batches.

The results show only little variation between and within batches. Height ranged from 3.7 to 3.8 mm overall. The slightly greater thickness in these tablets compared to previously tested tablets is a consequence of the short granulation time and low amount of granulation liquid, resulting in less dense granules and finer particle sizes. A lower compression intensity is needed to achieve the target crush strength of 65N used for these studies, hence slightly thicker tablets.

- 35 042784

In conclusion, low tablet height variation is indicative of the stability of the product with respect to assessed scale changes, process parameter settings, and drug particle size.

Appearance of the tablet

The appearance of the tablets was evaluated visually. Edge damage associated with correction of the scraping mechanism was found in several cases, after correction the damage disappeared. Barely visible patches of slightly pink color were seen in one case and were most likely related to the color of the drug substance. In general, no sticking, sticking, clogging or delamination was observed in any of the batches.

Dissolving the tablet

The amount of dissolved ticagrelor after 45 and 60 minutes is summarized in Table 1. 27.

Table 27

The degree of dissolution after 45 and 60 minutes, % of the indicated on the label, (n=6)

The consignment Average value Min max Average value Min max 45 minutes 60 minutes 37 83 81 87 85 83 89 38 82 80 84 85 82 87 39 84 82 88 86 84 90 40 81 79 83 83 81 85 41 85 80 88 87 82 90 42 84 81 88 86 83 91 43 85 80 87 87 84 89 44 89 87 92 91 89 94 45 84 81 88 87 84 92 46 83 82 86 85 84 89

The amount of dissolved ticagrelor was within target in all batches. It was noted that the granulation factors that were evaluated had little effect on the dissolution rate. The increase in dissolution appears to be due to the short granulation time, the low amount of granulation liquid, and the drug with a small particle size.

Conclusion on Tablet Compression

The results show that the tablet compression step is sufficient to compress the mixed powder into tablets that consistently achieve the target Critical Quality Assurance (CQA). In addition, the use of embossed perforators in this study did not appear to affect the quality of the tablets.

Example 10 Evaluation of the dissolution mechanism of tablets.

Focused beam reflectance measurements were made on a series of ticagrelor beads and type C Fmelt beads, each with a range of particle sizes.

Mechanism of tablet dissolution

In the FBRM device, the probe diameter was approximately 6 mm and had a sapphire window at the end of the probe. The integration time was set to 5 s. The device was set to the coarse mode, and the scanning speed of the focal spot was set to 2 m/s. The sensor was placed 2 cm above the vane and tilted slightly towards the flow. The primary data set contains the values of the total particle size distribution 1-1000 µm with a distribution time of 5 s. Based on this, kinetic curves were calculated with a data set showing fractions of different sizes, and the 40-100 µm fraction was the fraction selected for comparison. This fraction was chosen because the number of counts was higher for this fraction. In addition, inter-kinetic variability was low for fractions with high counts.

The measurements were carried out with a UV sensor, which was placed in a bath having a gap of 2 mm. Dissolution media were 900 ml water with 0.2% tween 80. Paddle speed 75 rpm. In addition, the FBRM sensor was placed in the bath in order to simultaneously measure the particles in the bath.

The results are shown in FIG. 4 and 5.

The FBRM results in FIG. 4 shows fractions with different particle sizes from API granules in a solvent bath. For all sizes, the number of counts initially rises in the bath and then drops to only a few percent after 60 minutes. The initial increase in counts depends on the pellets being added to the bath at time zero and the dissolution kinetics of the particles.

- 36 042784 slower than the time required to distribute the particles in the bath. The time when a count peak occurs will possibly differ depending on the way and time of addition of the pellets to the bath, and is therefore not significant if a peak occurs on the time axis. However, the decrease in slope kinetics is indicative of how fast the particles are dissolving and hence it can be seen that the dissolution of the particles is faster during the first 30 minutes and after that the kinetics are slower.

The FBRM results in FIG. 5 shows fractions with different particle sizes from F-melt in a solvent bath. For all sizes, an initial increase in the number of particles can be seen during the first minutes, after which a slight decrease for several minutes before the number of counts stops at some constant value. The initial increase in counts depends on the pellets being added to the bath at time zero. However, a substantially constant particle count thereafter indicates that the dissolution of the F-melt particles is fast enough, within the first minutes and simultaneously, as the particles are dispersed in the bath, and therefore no additional drop in particle counts is observed. This appears to be consistent with the F-melt material, which contains largely spray-dried mannitol and is therefore designed to dissolve quickly.

Briefly, it was found that the dissolution of tablets, which are dominated by the properties of API granules, while F-Melt causes rapid disintegration, typical of an orodispersible tablet. Thus, it is important to prevent API particles from aggregating during disintegration and dissolution.

Storage impact

Model beads containing ticagrelor were stored at 40° C. at 75% relative humidity (RH) for 1 month in order to study the dissolution behavior using the FBRM method described above. Fresh, i.e. not stored (model), granules were received for comparison. The results are shown in figures 6 and 7. Ticagrelor particles were obtained from three different suppliers: supplier 1 (AZ); vendor 2 (DSM); vendor 3 (Omnichem).

For both the batch of model beads and the batch of stored beads containing ticagrelor supplied by AZ, both profiles show an increase in particle count followed by a decrease in counts. However, for material stored at 40° C. and 75% RH for one month, slower particle dissolution was observed. In addition, more particles remain in the bath after 60 min from the stored material. A similar general pattern was observed for material supplied by other suppliers. The slower dissolution of the particles from the stored material correlates with the release rates of ticagrelor. Comparison of the data shown in Figures 6 and 7 shows that ticagrelor has a slower release from pellets that have been stored for one month compared to non-stored pellets.

Briefly, it was found that the behavior of model ticagrelor-containing pellets after storage was consistent with that of aged tablets. Based on this, it was concluded that drug granules cause a change in dissolution in aged tablets.

Example 11 Effect of storage on drug granule porosity.

Pore volume and pore size distribution were determined using a mercury-embedded porosity measurement (Micromeritics AutoPore III 9410). The determination was carried out in the range of pore diameter 115 μm > Ф > 0.0030 μm (30 A). The surface tension and contact angle of mercury were set to 485 mN/m and 130°, respectively. The blank correction was used to compensate for compression of parts of the penetrometer system at high pressures. The test materials used were ticagrelor granules (3606), final tablet mix (3606 FB); granules F-melt type C (F-melt); ticagrelor particles from supplier 1 (AZ); ticagrelor particles from supplier 2 (DSM); ticagrelor particles from supplier 3 (Omnichem).

To ensure that the porosimeter was showing the correct penetration, a test was performed with an aluminum silicate reference material prior to analysis. One of the penetrometers used for the analysis of the pellets was used for the reference test. The result gave a total pore volume of 0.55 cm ³ /g and a median pore diameter (based on volume) of 73 A. The reference values are 0.56±0.02 cm ³ /g and 75±5 A, respectively. The results are shown in table. 28.

- 37 042784

Table 28

Hg porosity data for test materials before and after storage (1 month at 40°C/75% RH)

Sample Volume nop, CM ³ /r Median value of pore diameter (vol.), µm Median pore diameter (area), µm/A Pore area, m ² /g >8 <8 >8 <8 >8 <8 >8 <8 Before stored it 3606 0.53 0.22 41 0.6 28 42 <0.1 10 3606 FB 0.67 0.28 29 1.8 20 43 0.1 10 AZ 0.62 0.23 24 0.9 21 45 0.1 14 DSM 0.59 0.28 19 1.2 15 44 0.1 13 Omniche m 0.53 0.28 35 0.5 26 41 <0.1 12 f-melt 0.76 0.23 25 2.9 19 41 0.1 3 After storage (1 month) 3606 0.55 0.20 40 0.6 24 39 <0.1 8 3606 FB 0.69 0.26 35 1.7 28 40 <0.1 8 AZ 0.69 0.23 27 1.1 21 41 0.1 14 DSM 0.64 0.29 20 1.5 16 41 0.1 12 Omniche m 0.61 0.18 36 0.5 26 38 <0.1 9 f-melt 0.80 0.21 28 1.6 23 44 0.1 5

The Hg porosity data for the granules, combined with the data in Example 10, indicate that reduced porosity and/or increased aggregation causes a decrease in dissolution rate for aged tablets. The particle size of the drug and the surface properties of the particles appear to influence the parameters of the wet granulation process, resulting in a particular size distribution of the aggregates, which in turn affects the dissolution of the tablets.

Example 12 Effect of particle size on dissolution after storage.

Four batches of tablets were evaluated to investigate the effects of particle size on tablet dissolution rates before and after storage.

Tablets were obtained in accordance with the composition of example 7. The parameters associated with API (D (v, 0.9)) and the manufacture of tablets (fluid for granulation and mixing time) are shown in table. 29.

- 38 042784

Table 29

Effect of porosity on dissolution after storage

The consignment 38 40 43 44 DOE places. D (v, 0.9) and µm 12 kgH ₂ O 10 min. D (v, 0.9) 22 µm SkgH ₂ O 8.6 min. D (v, 0.9) 22 µm 12 kgH ₂ O 5.2 min. D (v, 0.9) and μm YukgH ₂ O 4.3 min. Data about dissolution Data 0 month, 45 min. 82.9 83.4 84.0 86.7 40°C, 75RH, 1 month in 72.0 73.1 73.0 77.8

open, 45 min. 40°C, 75RH, 1 month in closed, 45 min. 76.0 77.0 77.9 81.0 Data about porosity Porosity (<8 µm) Data 0 months 0.411 0.588 0.516 0.572

The decrease in dissolution after 1 month of storage was typically no more than about 10-11%, but in Lot 44 the decrease was about 7%.

Example 13 Effect of ticagrelor particle size and surface properties.

This study was conducted to evaluate the possible effects of starting material variability among vendors, mainly physical characteristics such as particle size/shape and surface properties, on tablet quality and disintegration time.

The parties of the tested medicinal substances are shown in table. thirty.

Table 30

The study of the surface characteristics of TOF-SIMS was carried out on different batches of the drug. TOF-SIMS spectra were obtained in positive and negative ion modes in the high resolution mode of the mass spectrometer for all powders. TOF.SIMS (ION-TOF GmbH, Germany) was used for experiments. 30 keV clusters of Bi ₃ ⁺ ions were primary

- 39 042784 ions. A reading electron projector was used to compensate for the charge on the sample surface.

Samples were analyzed as supplied by dropping the powder from a mini spatula onto double-sided adhesive tape on a 1 cm ² aluminum plate. The plates were oscillated to allow the powders to settle on the adhesive tape. Excess powder was blown off with pure CO3. These samples were Lot 12801, Lot AAAU, Lot 300000-01 Omnichem, and Lot LHCYAA4005 DSM. In addition to the as-supplied analysis, a batch of LHCYAA4005 DSM was cryo-milled by hand in a mortar filled with liquid nitrogen to expose the interior of the particles. The resulting cryopreserved powder was applied as supplied powders.

High resolution mass spectra of as-delivered samples were obtained from 500 µm x 500 µm regions with 128x128 pixels. High resolution mass spectra of the cryo-milled powder were obtained from 200 µm x 200 µm regions with 64x64 pixels. The nominal size of the primary beam in the high resolution mode of the mass spectrometer is approximately 5-6 µm.

Additionally, high resolution spectral imaging was obtained for a batch of LHCYAA4005 DSM powder before and after cryogrinding. Spectral high resolution images were 200 µm x 200 µm (at 1024x1024 pixels) for the sample as shipped and 100 µm x 100 µm (at 512x512 pixels) for the cryo-milled sample. Thus, all images corresponded to a nominal primary beam diameter of 0.2 µm in high spectral resolution mode.

Data analysis was performed using software provided by the instrument supplier (Surface Lab 6.3, Measurement Explorer, ION-TOF GmbH, Germany).

Particle Size Distribution: Approximately 3 ml of dry powder measured at 0.1 bar using a Malvern Mastersizer 2000.

Powders of ticagrelor are characterized by poor flowability, as evidenced, for example, by a larger Hausner ratio (bulk density/bulk density ~1.8-2.0). Particle size distribution (PSD) values typical of the three drug manufacturers are shown in Table 1. thirty.

The larger D(v, 0.9) fraction identified for the AZ Ops delivery has a more elongated particle shape, which in turn results in the lowest flowability (highest Hausner ratio).

For a rapidly disintegrating ticagrelor formulation, drug substance variability is likely to be important to control in formulations.

In addition to variations in drug substance PSD, it is believed that the surface properties of ticagrelor from different batches may also contribute to tablet performance, in particular dissolution rate. TOF-SIMS analysis of different drug lots showed slightly different surface texture for one lot from DSM compared to AZ Ops and Omnichem materials.

In short, it is important to control the physical properties of a drug in order to obtain a reliable large scale manufacturing process. It has been recognized that variations in particle shape and potential particle surface properties in particular can affect the properties of the final product.

Example 14 Evaluation of tablet stability.

Storage effects on the tablets of Example 7 were examined after both open storage under various conditions and storage in aluminium/aluminum blister packs with aluminum multilayer molding foil and aluminum top foil (Al/Al blister). Tablets were made using the method in accordance with that of example 8 above.

Experimental study of stability under adverse conditions

The performance of ticagrelor orodispersible tablets under unfavorable conditions when opened was shown during development. During the study, orodispersible tablets containing ticagrelor were exposed in an open container to various conditions of temperature and humidity. By storing the tablets in an open container, they were subjected to the unfavorable condition of excess moisture, which does not occur when packed in an Al/Al blister.

Stability Study Protocol

Storage conditions and sampling protocols.

The primary batches for stability studies and the auxiliary batch were stored in accordance with ICH Q1A guidelines. Detailed information about the time points of sampling for each condition is presented in Table. 31.

- 40 042784

Table 31

Sampling and storage protocol for primary stability studies

Storage condition (°C/%RH) / container Time (months) 0.5 3 6 9 12 5 - control - (+) (+) (+) (+) 25/60 - blister - + + + + 25/60 - bulk mass - + + + + 40/75 - blister - + + - - 40/75 - bulk mass - + + - - 50/AN - blister - + - - - Light stability ^a + - - - -

RH relative humidity

AH ambient humidity + Sample tested according to the relevant chart

- No sampling

Blister blisters Al/Al

Bulk weight Al bags

5°C control sample to be used as a reference sample when performing the described test ( ) Optional testing if changes are observed under other conditions ^a 1.2 million lux-hours of visible light and 200 watt-hours/m ² UV light; adverse condition Tested on tablets stored in an open container covered with aluminum foil. Temperature was controlled to ±2°C and humidity was controlled to ±5% RH. The stability batch was stored in an open container for no more than 1 month under the following climatic conditions: 25°C/60% RH, 30°C/65% RH, 40°C/75% RH and 50°C/amb.

Light stability

Light stability analysis was performed on one batch from the primary stability study according to ICHQ1B.

Stability tests and tolerance limits.

The stability of ticagrelor 90 mg orally dispersible tablets was evaluated by monitoring the relevant chemical and physical characteristics during a stability study. Testing performed included HPLC analysis, HPLC degradation products, disintegration, dissolution (0.2% Tween 80), microbiological purity, and tablet crush strength. Microbiological purity analysis was performed after 6 months at 40°C/75% RH and after 12, 24 and 36 months at 25°C/60% RH in primary Al/Al ICH blister stability studies.

Results.

Primary ICH stability data and secondary stability data obtained for the tablets of Example 7 in aluminium/aluminum (Al/Al) blister packs are shown in Table 1. 32-39.

Important data on the light stability of ICH obtained for the tablets of example 7, stored in an open container, directly exposed to light, are presented in table. 40.

The stability of the tablets of example 7 was tested under adverse conditions, 50°C/ambient humidity (amb) for no more than 3 months in an Al/Al blister. The results of this study are presented in table. 41-44.

The stability of the tablets of example 7 was tested under adverse conditions, open storage (experimental study) for no more than 1 month under various climatic conditions. The results can be found in tables 45-48. The stability of the tablets of Example 7 stored in a 4-layer aluminum foil bag (Al bag, large pack) was tested under various conditions for up to 6 months. The results can be found in tables 49-54.

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Table 32

Stability data at 25°C/60%RH tablets, Lot 51 stored in Al/Al blisters

Test Stability check times (months) original 3 6 9 12 Description White round convex tablet NCH NCH NCH NCH Analysis (% of labeled) 100 100 100 100 98 Decomposition products (% (w/w)): Unspecified <0.05 <0.05 <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 <0.05 <0.05 Disintegration (seconds) 15-28 21-27 21-31 19-33 19-29 Dissolution rate (% of labeled value) Average value (45 min.) 85 85 92 86 85 Range (45 min.) 83-88 84-87 91-93 84-87 84-86 Average value (60 min.) 88 90 95 89 88 Range (60 min.) 86-91 89-91 93-96 88-91 87-90 Water content (% (w/w)) 0.88 0.87 0.87 0.87 0.90 Crushing strength (N) average value 62 65 57 65 56 Range 48-79 53-82 48-64 50-88 45-76 Microbiological purity ^a Corresponds NT NT NT Reply there is

^a Total aerobic micro-organisms (<10 ³ CFU/g), total combined yeasts and molds (<10 ² CFU/g) and Escherichia coli (should be absent) NCH unchanged

NT not tested

- 42 042784

Table 33

Stability data at 40°C/75%RH tablets, Lot 51 stored in Al/Al blisters

Test Time (months) original 3 6 Description white round biconvex tablet NCH NCH Analysis (% of labeled) 100 98 99 Decomposition products (% (w/w)): Unspecified <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 Disintegration (seconds) 15-28 17-35 17-23 Dissolution rate (% of labeled value) Average value (45 min.) 85 78 88 Range (45 min.) 83-88 77-79 85-92 Average value (60 min.) 88 83 92 Range (60 min.) 86-91 82-83 89-95 Water content (% (weight/weight)) 0.88 0.86 0.89 Crushing strength (N) average value 62 58 60 Range 48-79 40-81 46-76 Microbiological purity A Corresponds NT Corresponds

Total aerobics (<10 ³ cfu/g), total combined yeasts and molds (<10 ² cfu/g) and Escherichia coli (should be absent) NCH unchanged

NT not tested

- 43 042784

Table 34

Stability data at 25°C/60%RH tablets, Lot 52 stored in Al/Al blisters

Test Time (months) original 3 6 9 12 Description White round biconvex tablet NCH NCH NCH NCH Analysis (% of labeled) 99 101 101 101 98 Decomposition products (% (w/w)): Unspecified <0.05 <0.05 <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 <0.05 <0.05 Disintegration (seconds) 15-25 16-44 19-31 19-39 23-24 Dissolution rate (% of labeled value) Average value (45 min.) 83 79 86 80 77 Range (45 min.) 79-85 77-81 85-89 79-80 76-79 Average value (60 min.) 87 84 91 84 82 Range (60 min.) 83-89 82-85 89-93 84-85 80-83 Water content (% (weight/weight)) 0.82 0.80 0.80 0.82 0.83 Crushing strength (N) average value 72 81 76 67 64 Range 55-90 66-91 62-86 46-83 54-81 Microbiological purity A Corresponds NT NT NT Reply there is

Total aerobics (<10 ³ cfu/g), total combined yeasts and molds (<10 ² cfu/g) and Escherichia coli (should be absent) NCH unchanged

NT not tested

- 44 042784

Table 35

Stability data at 40°C/75%RH tablets, Lot 52 stored in Al/Al blisters

Test Time (months) original 3 6 Description White round biconvex tablet NCH NCH Analysis (% of labeled) 99 101 102 Decomposition products (% (w/w)): Unspecified <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 Disintegration (seconds) 15-25 17-22 13-50 Dissolution rate (% of labeled value) Average value (45 min.) 83 82 80 Range (45 min.) 79-85 81-83 78-82 Average value (60 min.) 87 88 84 Range (60 min.) 83-89 87-89 83-85 Water content (% (weight/weight)) 0.82 0.76 0.79 Crushing strength (N) average value 72 73 66 Range 55-90 63-84 58-80 Microbiological purity A Corresponds NT Corresponds

a Total aerobic micro-organisms (<10 ³ CFU/g), total combined yeasts and molds (<10 ² CFU/g) and Escherichia coli (should be absent) NCH unchanged

NT not tested

- 45 042784

Table 36

Stability data at 25°C/60%RH tablets, Lot 53 stored in Al/Al blisters

Average value (60 min.) 91 90 97 91 90 Range (60 min.) 90-92 89-91 94-100 90-91 88-92 Water content (% (w/w)) 0.83 0.84 0.84 0.85 0.84 Crushing strength (N) average value 75 73 69 64 64 Range 60-92 60-84 60-83 50-77 45-81 Microbiological purity ^a Corresponds NT NT NT Reply there is

^a Total aerobic micro-organisms (<10 ³ CFU/g), total combined yeasts and molds (<10 ² CFU/g) and Escherichia coli (should be absent) ^b RRT admixture 1.84

NCH unchanged

NT not tested

Table 37

Stability data at 40°C/75%RH tablets, Lot 53 stored in Al/Al blisters

Test Time (months) original 3 6 Description White round biconvex tablet NCH NCH Analysis (% of labeled) 98 100 99 Decomposition products (% (w/w)): Unspecified 0.06 ^b 0.06 ^{b 0.07b} Total 0.06 0.06 0.07 Disintegration (seconds) 15-31 17-25 15-37 Dissolution rate (% of labeled value) Average value (45 min.) 87 91 87 Range (45 min.) 87-89 88-94 85-90 Average value (60 min.) 91 94 92 Range (60 min.) 90-92 92-96 89-94 Water content (% (weight/weight)) 0.83 0.81 0.84 Crushing strength (N) average value 75 69 66 Range 60-92 55-89 52-78 Microbiological purity a Corresponds NT Corresponds

^a Total aerobic micro-organisms (<10 ³ CFU/g), total combined yeasts and molds (<10 ² CFU/g) and Escherichia coli (should be absent) ^b RRT admixture 1.84

NCH unchanged

NT not tested

- 46 042784

Table 38

Stability data at 25°C/60% RH tablets, Lot 54 stored in Al/Al blisters

Test Time (months) original 3 6 Description White round tablet with flat chamfer NCH NCH Analysis (% of labeled) 98 99 98 Decomposition products (% (w/w)): Unspecified <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 Disintegration (seconds) 26-52 35-45 29-41 Dissolution rate (% of labeled value) Average value (45 min.) 93 86 86 Range (45 min.) 91-94 84-88 85-88 Average value (60 min.) 95 86 89 Range (60 min.) 94-95 85-88 86-90 Water content (% (weight/weight)) 0.82 0.80 0.80 Crushing strength (N) average value 55 NT 66 Range 45-66 NT 58-71 Microbiological purity a Corresponds NT NT

^a Total aerobic micro-organisms (<10 ³ CFU/g), total combined yeasts and molds (<10 ² CFU/g) and Escherichia coli (should be absent) NCH unchanged

NT not tested

- 47 042784

Table 39

Stability data at 40°C/75%RH tablets, Lot 54 stored in Al/Al blisters

Test original Time (months) 3 6 Description White round tablet with flat bevel NCH NCH Analysis (% of labeled) 98 98 98 Decomposition products (% (w/w)): Unspecified <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 Disintegration (seconds) 26-52 17-43 29-35 Dissolution rate (% of labeled value) Average value (45 min.) 93 77 78 Range (45 min.) 91-94 75-79 77-80 Average value (60 min.) 95 80 ^{b 80b} Range (60 min.) 94-95 76-85 ^{b 79-82b} Water content (% (weight/weight)) 0.82 0.79 0.80 Crushing strength (N) average value 55 NT 63 Range 45-66 NT 55-71 Microbiological purity a Corresponds NT Corresponds

Total aerobic organisms (<10 ³ CFU/g), total combined yeasts and molds (<10 ² CFU/g) and Escherichia coli (should be absent) ^b Step 2 requirements were met (12 units tested)

NCH unchanged

NT not tested

- 48 042784

Light stability

Table 40

Data on stability, photostability of tablets, lot 51

Test Time (months) original 0.5 (sample) 0.5 (reference) Description White round biconvex tablet NCH NT Analysis (% of labeled) 100 98 NT Decomposition products (% (weight/weight)): Unspecified <0.05 0.15 ^b <0.05 Total <0.05 0.15 <0.05 Disintegration (seconds) 15-28 16-34 NT Dissolution rate (% of labeled value) Average value (45 min.) 85 84 NT Range (45 min.) 83-88 82-86 NT Average value (60 min.) 88 86 NT Range (60 min.) 86-91 84-88 NT Water content (% (w/w)) 0.88 1.6 NT Crushing strength (N) average value 62 54 NT Range 48-79 46-78 NT Microbiological purity ^a Corresponds NT NT

^a Total aerobics (<10 ³ CFU/g), total combined yeasts and molds (<10 ² CFU/g) and Escherichia coli (should be absent) ^b Impurity at RRT 0.88

NCH unchanged

NT not tested

- 49 042784

Stability studies under adverse conditions

Table 41

Stability data under unfavorable condition, 50°C/amb tablets, lot 51 stored in Al/Al blister

Test original 3 months Description white round biconvex tablet white round biconvex tablet Analysis (% of labeled) 100 99 Decomposition products (% (weight/weight)): Unspecified <0.05 <0.05 Total <0.05 <0.05 Disintegration (seconds) 15-28 17-25 Dissolution rate (% of labeled value) Average value (45 min.) 85 80 ^b Range (45 min.) 83-88 73 - 88 ^b Average value (60 min.) 88 85 ^b Range (60 min.) 86-91 78-93 ^b Water content (% (w/w)) 0.88 0.87 Crushing strength (N) average value 62 52 Range 48-79 46-61 Microbiological purity ^a Corresponds Corresponds

^a Total aerobic counts (<10 ³ cfu/g), total combined yeasts and molds (<10 ² cfu/g) and Escherichia coli (should be absent) ^b Stage 2 requirements were met (12 units tested)

- 50 042784

Table 42

Stability data under unfavorable condition, 50°C/amb tablets, lot 52 stored in an Al/Al blister

Test original 3 months Description white round biconvex tablet white round biconvex tablet Analysis (% of labeled) 99 101 Decomposition products (% (weight/weight)): Unspecified <0.05 <0.05 Total <0.05 <0.05 Disintegration (seconds) 15-25 13-30 Dissolution rate (% of labeled value) Average value (45 min.) 83 74 ^b Range (45 min.) 79-85 68 - 81 ^b Average value (60 min.) 87 80 ^b Range (60 min.) 83-89 74-87 ^b Water content (% (w/w)) 0.82 0.77 Crushing strength (N) average value 72 64 Range 55-90 56-80 Microbiological purity ^a Corresponds Corresponds

^a Total aerobic counts (<10 ³ cfu/g), total combined yeasts and molds (<10 ² cfu/g) and Escherichia coli (should be absent) ^b Stage 2 requirements were met (12 units tested)

- 51 042784

Table 43

Stability data under unfavorable condition, 50°C/amb tablets, lot 53 stored in Al/Al blister

Test original 3 months Description white round biconvex tablet white round biconvex tablet Analysis (% of labeled) 98.4 99.3 Decomposition products (% (weight/weight)): Unspecified 0.06 ^b 0.06 ^b Total 0.06 0.06 Disintegration (seconds) 15-31 14-26 Dissolution rate (% of labeled value) Average value (45 min.) 87 87 Range (45 min.) 87-89 84-89 Average value (60 min.) 91 91 Range (60 min.) 90-92 88-95 Water content (% (w/w)) 0.83 0.82 Crushing strength (N) average value 75 58 Range 60-92 48-74 Microbiological purity ^a Corresponds Corresponds

a Total aerobic micro-organisms (<10 ³ CFU/g), total combined yeasts and molds (<10 ² CFU/g) and Escherichia coli (should be absent) ^b RRT admixture 1.84

- 52 042784

Table 44

Stability data under unfavorable condition, 50°C/amb, tablets, lot 54, stored in an Al/Al blister

Test original 3 months Description White round tablet with flat bevel NCH Analysis (% of labeled) 98 99 Decomposition products (% (weight/weight)): Unspecified <0.05 <0.05 Total <0.05 <0.05 Disintegration (seconds) 26-52 15-22 Dissolution rate (% of labeled value) Average value (45 min.) 93 74 ^b Range (45 min.) 91-94 73-76 ^b Average value (60 min.) 95 78 ^b Range (60 min.) 94-95 76-79 ^b Water content (% (w/w)) 0.82 0.78 Crushing strength (N) average value 55 57 Range 45-66 52-63 Microbiological purity ^a Corresponds Corresponds ^a Total aerobic counts (<10 ³ cfu/g), total combined yeasts and molds (<10 ² cfu/g) and Escherichia coli (should be absent) ^b Stage 2 requirements were met (12 units tested)

NCH unchanged

- 53 042784

Stability studies (experimental) under unfavorable conditions when opened Table 45. Stability data under unfavorable conditions, 25°C/60%RH tablets, Lot 45, kept open

Test original 1 Week 2 weeks 1 month Description White round tablet with flat bevel NCH NCH NCH Analysis (% of labeled) 101 NT NT 97 Decomposition products (% (weight/weight)): Unspecified <0.05 NT NT <0.05 Total <0.05 NT NT <0.05 Disintegration (seconds) <60 <60 <60 <60 Dissolution rate (% of labeled value) Average value 83 78 79 ^77a Range 81-87 75-82 78-82 ^73-80a Water content (% (w/w)) 0.9 2.7 2.3 2.2 Tablet strength crush (N) 56 23 26 28

^a Stage 2 requirements were met (12 units tested)

NCH unchanged

NT not tested

Table 46

Stability Data Under Unfavorable Condition, 30°C/65%RH Tablets, Lot 45, Stored Open

Test original 1 Week 2 weeks 1 month Description White round tablet with flat bevel NCH NCH NCH Analysis (% of labeled) 101 NT NT 100 Decomposition products (% (w/w)): Unspecified <0.05 NT NT <0.05 Total <0.05 NT NT <0.05 Disintegration (seconds) <60 <60 <60 <60 Dissolution rate (% of labeled value) Average value 83 76 ^a 75 ^a 74 ^a Range 81-87 73-78 ^a 72-77 ^a 71-76 ^a Water content (% (w/w)) 0.9 2.9 2.4 2.2 Tablet strength crush (N) 56 18 19 20

- 54 042784

Stage 2 requirements were met (12 units tested), NCH unchanged, NT not tested.

Table 47

Stability Data Under Unfavorable Condition, 40°C/75%RH Tablets, Lot 45, Stored Open

Test original 1 Week 2 weeks 1 month Description White round tablet with flat bevel NCH NCH NCH Analysis (% of labeled) 101 NT NT 99 Decomposition products (% (w/w)): Unspecified <0.05 NT NT <0.05 Total <0.05 NT NT 0.10 Disintegration (seconds) <60 <60 <60 <60 Dissolution rate (% of labeled value) Average value 83 73 ^a 74a 72 ^a Range 81-87 70-74 ^a 71-76 ^a 69-75 ^a Water content (% (w/w)) 0.9 3.4 2.7 2.4 Tablet strength crush (N) 56 15 16 15

Stage 2 requirements were met (12 units tested), NCH unchanged, NT not tested.

Table 48

Stability data under unfavorable condition, 50°C/amb tablets, lot 45, stored open

Test original 1 Week 2 weeks 1 month Description White round tablet with flat bevel NCH NCH NCH Analysis (% of labeled) 101 NT NT 99 Decomposition products (% (w/w)): Unspecified <0.05 NT NT <0.05 Total <0.05 NT NT <0.05 Disintegration (seconds) <60 <60 <60 <60 Dissolution rate (% of labeled value) Average value 83 78 77 77 Range 81-87 78-79 75-80 75-78 Water content (% (w/w)) 0.9 oh, s 0.6 0.7 Tablet strength crush (N) 56 56 53 53

NCH without change NT not tested

- 55 042784

Table 49

Stability data at 25°C/60% RH of orodispersible tablets containing 90 mg ticagrelor, lot 51 stored in Al bags

Test original Time (months) 3 6 9 12 Description White round convex tablet NCH NCH NCH NCH Analysis (%) 100 99 100 98 99 Decomposition products (% (weight/weight)): Unspecified <0.05 <0.05 <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 <0.05 <0.05 Disintegration (seconds) 28 48 31 37 23 Dissolution rate (% of labeled value) Average value 88 89 97 89 89 Range 86-91 85-92 95-101 87-91 85-91 Water content (% (w/w)) 0.88 0.90 0.90 0.92 0.95 Microbiological purity ^a Corresponds NT NT NT NT

^a Total aerobic micro-organisms (<10 ³ CFU/g), total combined yeasts and molds (<10 ² CFU/g) and Escherichia coli (should be absent) NCH unchanged

NT not tested

- 56 042784

Table 50

Stability data at 40°C/75% RH of orodispersible tablets containing 90 mg ticagrelor, lot 51 stored in Al bags

Test original Time (months) 3 6 Description white round convex tablet NCH NCH Analysis (%) 100 99 100 Decomposition products (% (weight/weight)): Unspecified <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 Disintegration (seconds) 28 29 25 Dissolution rate (% of labeled value) Average value 88 83 92 Range 86-91 81-85 90-95 Water content (% (w/w)) 0.88 0.86 0.89 Microbiological purity ^a Corresponds NT Corresponds

^a Total aerobic micro-organisms (<10 ³ CFU/g), total combined yeasts and molds (<10 ² CFU/g) and Escherichia coli (should be absent) NCH unchanged

NT not tested

- 57 042784

Table 51

Stability data at 25°C/60% RH of orodispersible tablets containing 90 mg ticagrelor, lot 52 stored in Al bags

Test original Time (months) 3 6 9 12 Description White round convex tablet NCH NCH NCH NCH Analysis (%) 99 99 99 100 99 Decomposition products (% (w/w)): Unspecified <0.05 <0.05 <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 <0.05 <0.05 Disintegration (seconds) 25 35 54 31 26 Dissolution rate (% of labeled value) Average value 87 82 91 83 83 Range 83-89 80-84 88-93 80-85 81-85 Water content (% (weight/weight)) 0.82 0.82 0.85 0.87 0.88 Microbiological purity A Corresponds NT NT NT NT

^a Total aerobic micro-organisms (<10 ³ CFU/g), total combined yeasts and molds (<10 ² CFU/g) and Escherichia coli (should be absent) NCH unchanged

NT not tested

- 58 042784

Table 52

Stability data at 40°C/75% RH of orodispersible tablets containing 90 mg ticagrelor, lot 52 stored in Al bags

Test original Time (months) 3 6 Description white round convex tablet NCH NCH Analysis (%) 99 99 100 Decomposition products (% (weight/weight)): Unspecified <0.05 <0.05 <0.05 Total <0.05 <0.05 <0.05 Disintegration (seconds) 25 29 40 Dissolution rate (% of labeled value) Average value 87 85 84 Range 83-89 82-87 82-91 Water content (% (w/w)) 0.82 0.81 0.86 Microbiological purity ^a Corresponds NT Corresponds

^a Total aerobic micro-organisms (<10 ³ CFU/g), total combined yeasts and molds (<10 ² CFU/g) and Escherichia coli (should be absent) NCH unchanged

NT not tested

- 59 042784

Table 53

Stability data at 25°C/60% RH of orodispersible tablets containing 90 mg ticagrelor, lot 53, stored in Al bags

Test original Time (months) 3 6 9 12 Description White round convex tablet NCH NCH NCH NCH Analysis (%) 98 101 100 100 99 Decomposition products (% (w/w)): Unspecified 0.06 ¹ 0.05 ¹ 0.06 ¹ 0.06 ¹ 0.06 ¹ Total 0.06 0.05 0.06 0.06 0.06 Disintegration (seconds) 31 38 31 31 29 Dissolution rate (% of labeled value) Average value 91 89 97 91 90 Range 90-92 87-91 93-100 89-92 90-92 Water content (% (weight/weight)) 0.83 0.88 0.89 0.88 0.94 Microbiological purity A Corresponds NT NT NT NT

¹ Admixture RRT 1.84 ^a Total aerobic microorganisms (<10 ³ cfu/g), total combined yeast and mold (<10 ² cfu/g) and Escherichia coli (should be absent) NCH unchanged

NT not tested

- 60 042784

Table 54

Stability data at 40°C/75% RH of orodispersible tablets containing 90 mg ticagrelor, lot 53 stored in Al bags

Test original Time (months) 3 6 Description white round convex tablet NCH NCH Analysis (%) 98 98 99 Decomposition products (% (weight/weight)): Unspecified 0.06 ¹ 0.06 ¹ 0.07 ¹ Total 0.06 0.06 0.07 Disintegration (seconds) 31 37 23 Dissolution rate (% of labeled value) Average value 91 98 92 Range 90-92 94-102 90-93 Water content (% (w/w)) 0.83 0.85 0.87 Microbiological purity ^a Corresponds NT Corresponds

¹ Admixture RRT 1.84 ^a Total aerobic micro-organisms (<10 ³ CFU/g), total combined yeasts and molds (<10 ² CFU/g) and Escherichia coli (should be absent)

NCH unchanged

NT not tested

Summary of Results and Discussion Primary ICH Stability Studies

The stability data for tablets stored in Al/Al blisters showed no significant change in terms of description, analysis, degradation products, disintegration or dissolution after 12 months of storage at 25°C/60% RH. When stored under accelerated test conditions at 40°C/75% RH after 6 months, no significant change was shown in terms of description, analysis, degradation products, disintegration or dissolution. Dissolution showed data changing over time, but no trend was observed and all results were within specification.

With respect to water content and microbiological purity, no significant changes were shown after 12 months of storage at 25°C/60% RH. When stored under accelerated test conditions at 40°C/75%RH after 6 months, no significant change was shown.

The crushing strength of a tablet is generally reduced as a result of absorption of moisture, resulting in softening of the tablets. Therefore, the suppression of moisture absorption is advantageous for tablet stability. However, the subjective hardness of the tablets is still good even if the crush strength has decreased due to moisture absorption.

Light stability and unfavorable condition

Stability data for tablets stored in an open container under light stability assay conditions showed that light did not significantly affect tablet stability. The formation of one degradation product was observed at very low levels in the case of tablets that were directly exposed to light. The medicinal product is fully protected in the Al/Al blister pack as it is opaque to light. Under the unfavorable condition of 50° C./ambient humidity, no significant change in description, analysis, degradation products, disintegration, dissolution, water content or microbiological purity was demonstrated after 3 months storage in Al/Al blisters.

- 61 042784

Experimental study of stability under adverse conditions

Stability data obtained during the experimental study show that storage for no more than 1 month in the open state does not adversely affect the description, analysis, degradation products, disintegration or dissolution. An increase in water content was observed for tablets stored under humid conditions. This increase in water appears to affect the crush strength of the tablet as it makes the tablets softer. This is an inherent property of orodispersible tablets as they are designed to absorb water for rapid disintegration.

Example 15 Relative Bioavailability Study (Study A).

A relative bioavailability study (hereinafter referred to as Clinical Study A) compared the orodispersible tablet of Example 7, administered with and without water (hereinafter referred to as the oral dispersion), with a film-coated tablet containing 90 mg of ticagrelor. In Clinical Study A, an orodispersible tablet was also suspended in water and administered via a nasogastric tube and compared to a film-coated tablet.

The orodispersible tablet formulation used in Clinical Study A was identical to that of Example 7 and was made in a batch size of 256 kg.

The film-coated tablet used in Clinical Study A was the equivalent of a commercially available film-coated tablet containing ticagrelor.

The dissolution profiles for the orodispersible and film-coated tablets used in Clinical Study A obtained using the proposed release method (manual sampling applied, and % ticagrelor dissolved measured by UV) are shown in Figure 8. As can be seen, the profiles The dissolutions of orally dispersible and film-coated tablets are similar, resulting in similar effects in vivo.

Research plan and methodology

This study was an open-label, randomized, four-treatment, four-period, cross-over study in healthy male and female subjects without reproductive potential, conducted at the same site. The study consisted of a screening study period of a maximum of 21 days; four treatment periods during which subjects resided at the center until dinner on the night before dosing ticagrelor (Day -1) until at least 48 hours post-dose; discharged in the morning of day 3; and a final visit within 5-10 days after the last administration of ticagrelor.

There was a minimum washout period of 7 days between each dose. Subjects received single doses of ticagrelor via 4 different routes under fasting conditions. After fasting overnight for at least 10 hours, each subject received a single dose of each treatment on 4 occasions, respectively. The treatment protocol is summarized in Table. 55.

Table 55

Treatment Protocol

Type of treatment Product Introduction Dose Type of treatment A Tested product OD tablets containing ticagrelor administered with 200 ml of water 1 x 90 mg Type of treatment IN Tested product OD tablets containing ticagrelor administered without water 1 x 90 mg Type of treatment WITH Tested product OD tablets containing ticagrelor suspended in water to be administered by NG probe into the stomach (total 200 ml of water) 1 x 90 mg Type of treatment D reference product IR tablets containing ticagrelor administered with 200 ml of water 1 x 90 mg

Product tested: OD tablet containing 90 mg ticagrelor according to example 7

Reference product: IR tablet (immediate release) containing 90 mg ticagrelor

- 62 042784

Study subjects of healthy male and female subjects (without reproductive potential) were included in the study and 30 subjects completed it. All subjects were healthy male or female subjects aged 18-55 years with a body mass index of 18.5 to 29.9 kg/m ² , including a weight of at least 50 kg and not more than 100 kg.

Duration of treatment

The duration of participation in the study for each subject was approximately 7-8 weeks, consisting of a screening visit (from day -21 to -1), admission to the clinical department (on day -1 of each treatment period), 4 on-site treatment periods ( days 1-3) with a 7-day washout period between injections of the experimental drug (IMP) in each treatment period and a follow-up visit after treatment period 4.

Subjects received a single dose of IMP on day 1 of each of the 4 on-site treatment periods.

Adherence to treatment

Dosing took place in the PAREXEL early phase clinical unit. After IMP was administered, the subject's mouth and hands were examined. Recorded the exact day and time of the introduction of IMP, as well as the volume of water accompanying the introduction.

Criteria for evaluation

Pharmacokinetic parameters:

PK parameters were evaluated for ticagrelor (parent material) and its active metabolite ARC124910XX based on plasma concentrations.

Primary PK parameters:

_Cmax is the maximum observed plasma concentration,

AUC(o-t) area under the plasma concentration-time curve from time zero to the last measured analyte concentration,

AUC area under the plasma concentration-time curve from zero to infinity.

Secondary PK parameters:

t _max is the time to reach the maximum observed concentration, t _1/2Xz is the half-life associated with the slope of the terminal part (Xz) of the semi-logarithmic concentration-time curve,

MRC _max ratio of metabolite C _max to starting material C _max corrected for differences in molecular weight values,

MRAUC( _0-t ) ratio of AUC( _0-t ) metabolite AUC( _0-t ) of parent material, corrected for differences in molecular weight values,

MRAUC is the ratio of the AUC of the metabolite and the AUC of the starting material, corrected for differences in molecular weight values.

Diagnostic PK parameters have been listed.

Variables for safety assessment

Safety variables included adverse events (AE), vital signs (blood pressure and pulse), 12-lead electrocardiogram (ECG) values, and laboratory tests (hematology, clinical chemistry, and urinalysis).

In addition to the above, physical examination results, pregnancy tests (females only) and concomitant medications were also reported. Viral serology, thyroid stimulating hormone (TSH) and follicle stimulating hormone (FSH) (women only), coagulation, and urinary addictive drugs, alcohol, and cotinine were assessed for compliance.

Statistical methods

Sample size determination.

Based on a bioequivalence in the range of 0.80-1.25 for ticagrelor and its active metabolite AR-C124910XX and a coefficient of variation (CV) among subjects for C _max and AUC of ticagrelor and AR-C124910XX of 24% or less, 28 eligible subjects were needed. assess subjects to achieve a statistical power of 90%.

No more than 36 subjects were randomized according to the Williams design with 4 sequences for 4 periods and 4 treatments: ADBC, BACD, CBDA and DCAB, with the goal of providing at least 28 evaluable subjects at the end of the last treatment period.

Pharmacokinetic analysis.

Pharmacokinetic parameters were summarized for each treatment using descriptive statistics. Where possible, the following descriptive statistics were presented: n, geometric mean, geometric CV, arithmetic mean, arithmetic standard deviation, median, minimum, and maximum. For t _max , only n, median, minimum, and maximum were presented.

Comparison of the bioavailability of treatments A, B, and C (test product) and D (reference product)

- 63 042784 duct) was estimated as a ratio of log-transformed C _max , AUC _0-t and AUC of both ticagrelor and AR-C124910XX using a 2-sided 90% confidence interval (CI) approach based on an analysis of variance (ANOVA) model, including fixed effects for treatment, sequence, period, and subject within the sequence.

All PK parameters were log-transformed prior to analysis. Estimated treatment differences and 90% CI on a logarithmic scale were converted back to give geometric mean ratios for each pair of treatments.

For research purposes, the ANOVA above was repeated for subject random effect within sequence.

Security analysis.

All AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) and listed for each subject. Measurements of vital signs, hematology, clinical chemistry and coagulation values were reported for the subject and time point. 12-channel ECG results were reported for each subject and physical examination results were reported for the body system for each subject.

Pharmacokinetic results

Following administration of ticagrelor 90 mg OD tablets with, without water, or suspended in water to be administered via an NG probe, plasma concentration-time profiles for ticagrelor and metabolite AR-C124910XX were generally similar to those following administration of IR tablets containing 90 mg ticagrelor. The profiles were characterized by rapid uptake of ticagrelor with _Cmax achieved within a median tmax of approximately 2 hours post-dose and rapid formation of the AR-C124910XX metabolite over a median tmax of 2-3 hours post-dose. After reaching _Cmax , the plasma concentration of ticagrelor and metabolite AR-C124910XX decreased with a final mean t _1/2 ^ _z of 7.99-8.21 h and 9.35-9.48 h, respectively. The plasma C _max values of the metabolite AR-C124910XX and AUC were 27.1-30.0% and 38.2-40.5% for ticagrelor plasma C _max and AUC, respectively.

The resulting mean PK parameters were similar for the 4 treatments using ticagrelor and the AR-C124910XX metabolite, suggesting that the uptake rate (C _max and t _max ) and the uptake rate (AUC) among the treatments were similar.

The 90% CI geometric mean ratios for ticagrelor AUC (90.27, 99.89) and AR-C124910XX metabolite AUC (91.36, 98.42) were fully within the 80-125% acceptance interval. The C _max of ticagrelor for OD tablets with water was approximately 15% (90% CI: 76.77, 93.78) lower than for IR tablets, while 90% CI for the C metabolite AR-C124910XX (82.03, 98. 39) was in the range of 80-125%.

90% CI geometric mean ratios for AUC of ticagrelor and AR-C12491OXX ([89.81, 100.99] and [91.78, 99.82], respectively) and _Cmax of ticagrelor and AR-C124910xX ([88.22, 105.79] and [90.53, 104.90] respectively) after taking ticagrelor-containing tablets without water and AUC ([90.26, 98.73] and [93.26, 99.87], respectively) and C _max ([85.59, 99.25] and [90.83, 103, 74], respectively) after administration of ticagrelor-containing OD tablets suspended in water to be administered via an NG probe, were completely within acceptance interval 80-125%.

Intersubject variability was low to moderate and was similar across treatments for both ticagrelor and the AR-C124910XX metabolite; the geometric mean CV% in _Cmax of ticagrelor and the AR-C124910XX metabolite was approximately 25-34%, and in the AUC of ticagrelor and the ARC124910XX metabolite was approximately 19-44%.

Security Results

There were no deaths, serious adverse events, or AEs leading to complete discontinuation of IMPs during this study.

A total of 18 AEs were reported for 9 (25.0%) subjects, all classified as moderate in intensity. All AEs were eliminated by the end of the study.

The most commonly reported AEs were vertigo in the organ system class, referring to nervous system disorders, and thrombophlebitis in the SOC, referring to vascular disorders, in 2 (5.6%) subjects, respectively.

No trends were observed in AE, clinical laboratory values, vital signs measurements, 12-lead ECG values, and physical examination.

This open-label, randomized, cross-over, single-centre, four-period, four-treatment, single-dose, single-dose study was designed to evaluate the bioavailability of ticagrelor-containing OD tablets versus ticagrelor-containing IR tablets in healthy subjects.

The uptake rate (AUC) after administration of ticagrelor-containing OD tablets with, without water, or suspended in water to be administered via an NG probe was equivalent to the absorption rate after administration of ticagrelor-containing IR tablets with 90% CI geometric mean ratios for the AUC of ticagrelor and the metabolite AR-C124910XX, fully within the 80-125% acceptance interval. _Cmax of ticagrelor for OD tablets containing ticagrelor with water is

- 64 042784 was approximately 15% (90% CI: 76.77, 93.78) lower than for ticagrelor containing IR tablets, while 90% CI for C _max metabolite AR-C124910XX as well as C _max ticagrelor and metabolite ARC124910XX for ticagrelor-containing OD tablets without water or suspended in water to be administered via an NG probe were completely within the range of 80-125%.

(i) The absorption rate of the OD tablets containing 90 mg of ticagrelor administered with water was equivalent to the IR of ticagrelor, while its _Cmax was approximately 15% lower than that of the IR tablets containing 90 mg of ticagrelor.

(ii) OD tablets containing 90 mg of ticagrelor administered without water were bioequivalent to IR tablets containing 90 mg of ticagrelor.

(iii) OD tablets containing 90 mg of ticagrelor suspended in water administered via an NG tube into the stomach were bioequivalent to IR tablets containing 90 mg of ticagrelor.

This result demonstrated that the formulation of ticagrelor containing OD tablets as well as the route of administration of ticagrelor containing OD tablets did not significantly affect the pharmacokinetic profiles of ticagrelor and the AR-C124910XX metabolite compared to IR tablets. Overall, in this study, single dose tablets containing 90 mg of ticagrelor in healthy male and female subjects without reproductive potential were considered safe and well tolerated.

Pharmacokinetic parameters and comparisons according to standard bioequivalence criteria are presented in Table. 56.

Table 56

Comparisons of indicators from Clinical Study A of an orodispersible tablet versus a film-coated tablet, according to bioequivalence criteria

Parameter Type of treatment N Average GLS P Pair Average GLS Ratio (%) 90%CI AUC (ng.h/ml) A thirty 3072 thirty A/D 94.96 90.27 99.89 D 33 3236 IN 31 3241 31 B/D 95.24 89.81 100.99 D 33 3404 WITH 33 3220 33 C/D 94.40 90.26 97.73 D 33 3411 Stakh (ng/ml) A thirty 428.3 thirty A/D 84.85 76.77, 93.78 D 33 504.8 IN 31 500.0 31 B/D 96.61 88.22, 105.79 D 33 517.5 WITH 33 477.9 33 C/D 92.16 85.59 99.25 D 33 518.6

ODT - orodispersible tablet

Type of treatment A - ODT with water. ODT, placed on the tongue, after disintegration, swallowed successively with 200 ml of water. Type of treatment B - ODT without water. The ODT, placed on the tongue, is subsequently swallowed with saliva after disintegration. Type of treatment C - ODT suspended in water and introduced through a nasogastric tube (total injected volume of water 200 ml). Type of treatment D - film-coated tablet injected with 200 ml of water.

AUC is the area under the plasma concentration-time curve from time zero to infinity; C _max - the maximum (peak) concentration of the drug in blood plasma after a single dose; N - all subjects in the population subject to pharmacokinetic analysis; n - all subjects included in the population in the statistical analysis; GLS - geometric mean, calculated by the method of least squares; CI - confidence interval.

Example 16 Bioequivalence Assessment (Study B)

A bioequivalence study (Clinical Study B) was also conducted in subjects from Japan. The study was an open-label, randomized, three-treatment, three-period, cross-over study in healthy subjects from Japan.

- 65 042784 (male and female), carried out in one research center.

The study consisted of (i) a screening study for a maximum of 28 days;

(ii) three treatment periods during which subjects resided at the center until dinner the night before dosing ticagrelor (day -1) until at least 48 hours post-dose; discharged in the morning of day 3; and (iii) a final visit within 5-10 days after the last administration of ticagrelor.

There was a minimum washout period of 7 days between each dose. Subjects received single doses of ticagrelor via three different routes under fasting conditions. After fasting overnight for at least 10 hours, each subject received a single dose of each treatment on three occasions, respectively. The treatment protocol is summarized in Table. 57.

Table 57

Treatment protocol

Type of treatment Product Introduction Dose Type of treatment A Product under test (OD tablets containing 90 mg ticagrelor) OD tablets containing ticagrelor administered with 150 ml of water 1 x 90 mg

Type of treatment IN Product under test (OD tablets containing 90 mg ticagrelor) OD tablets containing ticagrelor administered without water 1 x 90 mg Type of treatment WITH Reference product (IR tablets containing 90 mg ticagrelor) IR tablets containing ticagrelor administered with 150 ml of water 1 x 90 mg

The route of administration was oral. Patients received a single dose of either the test product or the reference product. Each subject was enrolled in the study for 7-8 weeks.

Blood samples for determining plasma concentrations of both ticagrelor and its active metabolite AR-C124910XX were collected for each treatment period: 0 hours (pre-dose) and post-dose at 0.5 (30 min), 1, 2, 3, 4, 6, 8, 10, 12, 16, 24, 36 and 48 hours (14 samples per treatment period). Plasma samples were analyzed for ticagrelor and AR-C124910XX using an approved assay.

In the study, an orodispersible tablet containing ticagrelor (according to example 7) was administered with water (after oral dispersion) and without water and compared with a film-coated tablet containing 90 mg of ticagrelor. The same batches as those included in Clinical Study A were used for the test product and the reference product. An orally dispersible tablet containing ticagrelor administered with and without water has been shown to be bioequivalent to a film-coated tablet containing ticagrelor in subjects from Japan. Pharmacokinetic parameters and comparisons according to standard bioequivalence criteria are presented in Table. 58.

- 66 042784

Table 58

Tablets compared to IR tablets containing ticagrelor (population subject to pharmacokinetic analysis)

Pair (test/etal) Parameter (units) AND Geometric mean LS* Pair comparison § Test Reference Respectively # 90%CI# OD with water/IR AUC (h.ng/ml) 41 3515 3595 97.75 94.40, 101.21 AUC(o-t) (h.ng/ml) 41 3457 3536 97.76 94.46, 101.18 Stakh (ng/ml) 41 529.8 568.7 93.16 85.80, 101.15 OD without water/IR AUC (h ng/mL) 41 3468 3594 96.50 93.31, 99.80 AUC(o-t) (h ng/ml) 41 3406 3534 96.38 93.24, 99.63 Stakh (ng/ml) 41 532.7 568.7 93.67 87.88, 99.84

ANOVA: analysis of variance; AUC = area under the plasma concentration-time curve from time zero to infinity; AUQ( _0-t ): area under the plasma concentration curve time from time zero to the last analyte concentration measured; CI: confidence interval; C _max : maximum observed plasma concentration; IR: immediate release; max: maximum; min: minimum; n: number of subjects included in the statistical comparative analysis; OD: Orally dispersible; SD: standard deviation.

*Based on pairwise balanced comparisons and were reverse-transformed.

# The ratio of geometric mean and CI has been reverse-transformed and presented as a percentage.

§ Result based on ANOVA of log-transformed pharmacokinetic parameter with treatment, sequence, period, and subject in sequence as fixed effects.

Comparative Example 17 Evaluation of extrudable blister packs.

The study was conducted with 10 testers (7 women and 3 men aged 22-58) with squeeze blister packs.

Each individual was provided with 10 blister packs, with each blister pack containing 10 tablets (100 tablets per individual in total). The tablets were identical to the orodispersible tablets of Example 7.

Each individual was then asked to squeeze out all of the tablets in the way that they usually do.

Results.

The number of destroyed tablets was as follows.

Average: 2.5 broken tablets per 100 (i.e. per individual).

Range: 0-7 broken tablets per 100 (i.e. per individual).

Example 18 Evaluation of burst blister packs.

Tests performed with standard aluminum extrusion/aluminum blister packs resulted in about 2.5% broken tablets (see Comparative Example 17). An additional study was conducted with 10 testers (4 women and 6 men aged 25-53) using modified squeeze blister packs. Modified blister packs are shown in FIG. 9. The modification consisted of cutting out a triangular portion of the blister pack material at the outer edge adjacent to each of the blisters. The cutting was carried out using a figured perforating tool.

The subjects in this study were different from the subjects in the previous squeeze blister pack study (ie the study from Comparative Example 17).

- 67 042784

Samples of the packaging, including samples containing graphics, were obtained to assess tablet degradation and to see if patients would understand how to open the package. External dimensions 172x88 mm.

Each individual was provided with 10 blister packs, with each blister pack containing 10 tablets (100 tablets per individual in total). The tablets were identical to the orodispersible tablets of Example 7.

Test protocol.

Show the blister pack (10 tablets) with a label containing graphic materials (text and symbols) to the examiner and say approximately the following wording.

We are testing the package on ten individuals to see how the package works. We will ask you to remove all tablets from this blister pack. You can start with any blister pack. Before you start taking out the tablets, please take a look at this blister pack which contains some text on one side. You will then receive an identical blister pack but without any text. From this blister pack, you must then take out all ten tablets. The tablets contain the active ingredient, Brilinta. When you empty one blister pack, I will put all the pills in a plastic container and then I will give you another blister pack. You will take out only 100 tablets i.e. 10 blister packs. When all the pills are taken out, I will ask you some questions.

The first labeled blister pack is then given to the subject. It is taken when the subject has read it. Give one blister pack at a time. The estimated time to read the label was noted. The manner in which the testers begin to take out the tablets (eg tearing, squeezing or other) was noted. The number of destroyed tablets was noted.

If the tester squeezed all the tablets in the first blister pack, he/she was asked to read the label again and prompted to apply the tear. The tester was then expected to burst the 9 remaining blister packs.

After the test, the testers were asked some evaluation questions, including the following.

How easy was it to remove the tablets from the blister pack?

Do you think this package is easier or harder to open than a standard squeeze blister pack?

Results.

The number of destroyed tablets was as follows.

953 tablets were removed using the rupture opening method, of which 1 tablet was destroyed.

the tablets were removed using the extrusion method, of which 7 tablets were destroyed.

The data are summarized in Table. 59.

-

Claims (39)

Table 59 results Floor Age Did you start with a tear or an extrusion? Number of tablets squeezed out Destroyed Number of tablets taken out by rupture Destroyed Easily removed by tearing Is it easier to tear than to extrude? male 27 Squeezed out ing 10 3 90 0 5 Gap nie Female 38 tear up ie 7 1 93 0 4 Gap nie male 41 tear up ie 0 - 100 0 5 Gap nie male 39 Squeezed out ing 10 1 90 0 5 Gap nie male 53 Squeezed out ing 10 1 90 0 4 Gap nie Female 44 tear up ie 0 - 100 1 4 However, during Female 46 tear up ie 0 - 100 0 4 Gap nie male 25 tear up ie 10 1 90 0 4 However, during male 41 tear up ie 0 - 100 0 5 Tearing Female 51 tear up ie 0 - 100 0 3 Extrusion CLAIM 1. Pharmaceutical tablet containing (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)cyclopentan-1,2-diol in an amount of 10 to 18% by weight of the tablet, according to at least one anti-caking agent, which is colloidal anhydrous silica, in an amount of 0.5 to 1% by weight of the tablet, and at least one disintegrating aid; wherein the tablet has a crush strength of 50 to 150 N and a disintegration time of less than 60 seconds, measured using the method set forth in USP 701; where at least one disintegrating aid is a disintegrating aid preblend containing mannitol, xylitol, anhydrous dibasic calcium phosphate, crospovidone and microcrystalline cellulose, and where the disintegrating aid preblend is present in an amount, in the range of 50 to 80% by weight of the tablet. 2. The pharmaceutical tablet of claim 1, wherein the tablet has a disintegration time of less than 30 seconds. 3. A pharmaceutical tablet according to any one of the preceding claims, wherein the tablet contains about 60 mg or about 90 mg of (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4- difluorophenyl)cyclopro - 69 042784 pyl]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentan-1, 2diol. 4. The pharmaceutical tablet of claim 3, wherein the tablet contains approximately 90 mg of (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-3yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol. 5. Pharmaceutical tablet according to any one of the preceding claims, wherein the tablet has a crush strength of 55 to 90 N. 6. Pharmaceutical tablet according to any one of the preceding claims, wherein the tablet is obtained by a method involving wet granulation of (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4difluorophenyl)cyclopropyl ]amino}-5-(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2hydroxyethoxy)cyclopentane-1,2-diol and colloidal anhydrous silicon dioxide. 7. The pharmaceutical tablet of claim 6, wherein the wet granulation method comprises wet granulating a mixture containing (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-(2hydroxyethoxy)cyclopentan-1,2-diol in an amount of at least about 35% by weight of the dry ingredients in the mixture. 8. A pharmaceutical tablet according to claim 6 or 7, wherein the wet granulation method comprises wet granulating a mixture containing (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)cyclopentan-1, 2 diol in an amount not exceeding about 70% by weight of the dry ingredients in the mixture. 9. A pharmaceutical tablet according to any one of claims 6 to 8, wherein the mixture used in the wet granulation process contains said colloidal anhydrous silica in an amount ranging from about 0.1 to about 1% by weight of the dry ingredients in the mixture. 10. A pharmaceutical tablet according to any one of claims 6-9, wherein the product of the wet granulation process contains granules having a D(v, 0.9) value of less than about 1600 microns. 11. A pharmaceutical tablet according to any one of claims 6 to 10, wherein after the wet granulation step is completed, the product is mixed with a second amount of colloidal anhydrous silica. 12. The pharmaceutical tablet of claim 11, wherein the second amount of colloidal anhydrous silica is from about 0.2% to about 0.6%, preferably from about 0.3% to about 0.6% by weight of the tablet. 13. Pharmaceutical tablet according to any one of claims 6 to 12, wherein the tablet is obtained by a wet granulation method (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)cyclopentan-1 ,2-diol; colloidal anhydrous silica and a binder. 14. The pharmaceutical tablet of claim 13 wherein the binder is present in the wet granulation mixture in an amount ranging from about 2% to about 6%, preferably from about 3% to about 6%, by weight of the dry ingredients in the mixture. 15. A pharmaceutical tablet according to any one of the preceding claims, wherein the tablet contains one or more lubricants. 16. The pharmaceutical tablet of claim 15, wherein the lubricant is present in an amount of from about 1 to about 2% by weight. 17. A pharmaceutical tablet according to any of the preceding claims, wherein the tablet contains (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]αmino}- about 10 to about 18% by weight of the tablet; hydroxypropyl cellulose in an amount of from about 0.9 to about 2% by weight of the tablet; colloidal anhydrous silica in an amount of from about 0.5 to about 1% by weight of the tablet; mannitol in an amount of from about 47 to about 67% by weight of the tablet; xylitol in an amount of from about 2.5 to about 4% by weight of the tablet; anhydrous dibasic calcium phosphate in an amount of from about 2 to about 3.5% by weight of the tablet; microcrystalline cellulose in an amount of from about 9 to about 15% by weight of the tablet; crospovidone in an amount of from about 5 to about 9% by weight of the tablet; and sodium stearyl fumarate in an amount of from about 1 to about 2% by weight of the tablet. 18. A pharmaceutical tablet according to any of the preceding claims, wherein (1S,2S,3R,5S)-3-[7{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-( propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidine - 70 042784 3-yl]-5-(2-hydroxyethoxy)cyclopentan-1,2-diol has a particle size distribution D(v, 0.9) of about 5 µm to about 50 µm. 19. A pharmaceutical tablet according to any one of the preceding claims, wherein (1S,2S,3R,5S)-3-[7{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-( propylthio)-3H-[1,2,3]-triazolo[4,5-d]pyrimidin3-yl]-5-(2-hydroxyethoxy)cyclopentan-1,2-diol is mainly present in the form of polymorph II. 20. Pharmaceutical tablet according to any one of claims 1 to 18, wherein (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4difluorophenyl)cyclopropyl]amino}-5 -(propylthio)-3H-[1,2,3]-triazolo[4,5-d]pirimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentan-1,2-diol is mainly present in the form of a polymorph III. 21. A process for preparing a pharmaceutical tablet according to any one of the preceding claims, which comprises the step of mixing together (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)cyclopentane1,2-diol and colloidal anhydrous silica along with or in liquid, thus obtaining a wet granulate. 22. The method of claim 21, wherein the wet granulate mixture is mixed with a high shear mixer. 23. The method of claim 21 or 22, further comprising (i) drying the wet granulate mixture, (ii) adding one or more adjuvants to the dried granulates, and then (iii) forming the mixture into tablets. 24. The method of claim 23, wherein the one or more adjuvants include at least one disintegrating aid as defined in claim 1, a second amount of colloidal anhydrous silica as defined in claim 11 or 12, and/or a lubricant substance as defined in paragraph 15 or 16. 25. The combination of a pharmaceutical tablet according to any one of claims 1 to 20 and a blister pack, where the tablet is provided in said blister pack, and said blister pack contains a cellular base sheet that contains one or more cells, and a cover sheet associated with the base sheet, where the edge of the blister pack contains at least one notch in the cellular base sheet and the cover sheet so that the blister pack is torn at the notch to open the cell. 26. The combination of claim 25, wherein at least one notch is adjacent to one of the cells. 27. A combination according to claim 25 or 26, wherein the notch separates two areas on the edge of the blister pack that are capable of being grasped and pulled away from each other to break the cellular base sheet and the cover sheet. 28. A combination according to any one of claims 25-27, where the notch is a slit or cut. 29. A combination according to any one of claims 25-28, wherein the innermost part of the notch is at least 3 mm from the nearest cell. 30. Combination according to any one of claims 25-29, wherein the blister pack contains at least one notch located adjacent to each cell. 31. A combination according to any one of claims 25 to 30, wherein the cellular base sheet comprises an aluminum layer or a polymer layer. 32. The combination of claim 31 wherein the cellular base sheet has a thickness of from about 100 microns to about 200 microns. 33. A combination according to any one of claims 25 to 32, wherein the cover sheet comprises an aluminum layer. 34. The combination of claim 33 wherein the cover sheet has a thickness of from about 15 µm to about 60 µm. 35. A combination according to any one of claims 25 to 34, wherein the blister pack contains at least two cells and further comprises a perforated area which forms a rupture path extending between two of said cells. 36. A method for treating or preventing atherothrombotic events in patients with cardiovascular disease, the method comprising administering a pharmaceutical tablet according to any one of claims 1 to 20 to a patient suffering from or susceptible to developing such a disorder. 37. Use of a composition containing (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)cyclopentan-1,2-diol and at least one disintegrating aid in the manufacture a medicament for use in the treatment or prevention of atherothrombotic events in patients with cardiovascular disease, wherein the medicament is in the form of a pharmaceutical tablet according to any one of claims 1 to 20. 38. The method of claim 36, wherein the atherothrombotic events are selected from the group consisting of death due to cardiovascular disease, myocardial infarction, stroke, and peripheral arterial disease. 39. Use according to claim 37, where atherothrombotic events are selected from the group consisting of deaths -