Patent Application
20240335388
The invention relates to a tablet comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, its medical use as well as to a method of producing a tablet comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
About 70% of all medication is administered as tablets. Yet, injections are the most common means for administering protein and peptide drugs. Patient compliance with drug administration regimens by any of these parenteral routes is generally poor and severely restricts the therapeutic value of the drug, particularly for diseases such as diabetes.
Oral administration presents a series of attractive advantages over injection. These advantages are particularly relevant for the treatment of paediatric patients and include the avoidance of pain and discomfort associated with injections and the elimination of possible infections caused by inappropriate use or reuse of needles. Moreover, oral formulations are less expensive to produce, because they do not need to be manufactured under sterile conditions. However, poor bioavailability of proteins and peptides makes the development of oral dosage forms comprising peptides challenging.
N-(8-(2-hydroxybenzoyl)amino)caprylates such as sodium N-(8-(2-hydroxybenzoyl)amino)caprylate have been found to increase oral bioavailability of GLP-1 analogues as described in e.g. WO 2010/020978, WO 2012/080471, WO 2013/189988, WO 2013/139694, WO 2013/139695 and WO 2014/177683.
Despite these findings, there is still a need to further optimise oral dosage forms comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a GLP-1 peptide.
Tablets are solid formulations having a certain shape and are a widely used dosage form in pharmaceutical products. Tablets are often manufactured by powder compaction to be a certain shape (called “tableting”). A tablet typically comprises a body and two opposing cups. Based on the shape of the body of the tablet, tablets are often broadly categorised as either “rounds” or “shapes”. The tableting specification manual of the American Pharmacists Association (7th edition) describes the general terminology with respect to tablet design. For instance, a round tablet has a configuration in which all axes are equal from the centre point of the tip face. Round tablets have a substantially circular body and have a minor and major axis that are of substantially the same length. Shaped tablets include the following configuration according to the tableting specification manual of the American Pharmacists Association (7th edition): capsule, modified capsule, oval and geometric shapes. Examples of shaped tablets are oval tablets and capsule shaped tablets. Oval or oval-shaped tablets have a body comprising an end radius, a side radius, a core height, a major and a minor axis, where the ratio between the major and the minor axis is above 1.0. Capsule tablets or capsule-shaped tablets have a body comprising an end radius, a core height, and a major and a minor axis, where the ratio between the major and the minor axis is above 1.0.
In addition to different shapes of the tablet body, a tablet may also be defined by the shape of the tablet cup. For instance, a convex oval tablet, is an oval-shaped tablet having at least one convex cup. In the industry, the term concave is used to describe both the concave surface of a punch cup and the surface of the produced tablet. Technically, the punch cup is usually a concavity and therefore produces a tablet with a convex cup. There are two commonly cup designs: standard cup and compound cup. A compound cup design is one in which at least two arcs or radii are generated from the cup's centre point across the cup's diameter, minor axis or major axis. A standard cup design is one in which a single arc is generated from the cup's centre point across the cup's diameter, minor axis or major axis.
An underestimated factor, which however plays a vital role in patient compliance, is the organoleptic aspect of a tablet. The organoleptic properties of a tablet basically determine the willingness of a patient to swallow a tablet. For instance, certain shapes have better organoleptic properties than others, because they appear to be easier to swallow. Also, or alternatively, tablets having distinct defects and flaws in or on their surface may be perceived as faulty and close to falling apart by consumers/patients, which leads to consumers rejecting such tablets and failure to comply with their medication scheme.
Thus, a major problem that can occur during or after tablet manufacture is cracking. This can manifest itself in a number of ways. It can range from surface cracking through to capping and lamination. Even though certain tablet shapes are generally less prone to the formation of cracks or other flaws on the tablet surface, such shapes are not always suitable for a given pharmaceutical composition and hence other solutions have to be found.
Thus, it is an object of the present disclosure to provide a tablet comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid which has good organoleptic properties. It is a further object that the tablet design is optimised such that the occurrence of cracks on the surface of the tablet are reduced during manufacturing.
The present invention relates to a tablet comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid such as sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC). The tablet according to the invention is elongated. The tablet according to the invention has two compound cups and may have an oval-shaped or capsule-shaped body. The present invention is based on the realisation that when a pharmaceutical composition comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid such as sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC) is compressed into a tablet, such as an oval-shaped tablet, one or more irregular crack(s) may form on or across the tablet cup more or less straight along and/or parallel to the major axis of the tablet upon tablet ejection.
The inventors have surprisingly found that it is advantageous to have a cup design, viewed from the front, where the central part of the cup is flattened while a rapid increase in cup depth at the periphery of the cup is maintained. Put differently, the inventors have surprisingly found that the formation of cracks during the tabletting process is drastically reduced when the index value is 0.67 or below. In addition, the inventors have found that a tablet height to width ratio of 0.9 or below, a tablet height to cup depth ratio of above 4.3, and a minor major radius to width ratio of above 1.15 can lead to good organoleptic properties.
In the disclosure of the present invention, embodiments and aspects will be described which will address the above object or which will address objects apparent from the below disclosure as well as from the description of exemplary embodiments.
Thus, in a first aspect, the invention relates to a tablet such as an elongated, oval-shaped compound cup tablet, comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid in a total amount of about 60 to 99.8% in weight based on the total weight of the tablet, the tablet having
The salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC). The salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid such as SNAC may be granulated.
The tablet according to the first aspect may further comprise an active pharmaceutical ingredient such as a peptide. In some embodiments, the peptide may be a GLP-1 agonist. The GLP-1 agonist may be semaglutide. In some embodiments, the peptide may be present in a total amount of about 0.1 to 40% in weight based on the total weight of the tablet. In some embodiments, the tablet may further comprise a lubricant. The lubricant may be present in a total amount of about 0.1-7% in weight based on the total weight of the tablet. The lubricant may be magnesium stearate.
In some embodiments, the tablet may further comprise one or more pharmaceutically acceptable excipient.
In a second aspect, there is provided a process for preparing a tablet according to the first aspect.
In a third aspect, there is provided a punch set comprising an upper punch, a lower punch, and a die for making a tablet according to the first aspect.
In a fourth aspect, there is provided a tablet according to the first aspect of the invention for use in medicine.
In an alternative fourth aspect, there is provided a method for treatment of diabetes or obesity comprising administering a tablet according to first aspect to a patient in need thereof. In some embodiments, the tablet is administered orally. In some embodiments, the tablet is administered once daily or less frequent such as once weekly.
In a fifth aspect, there is provided a tablet according to the first aspect of the invention for use in the treatment of diabetes or obesity.
In the following, embodiments of the invention will be described with reference to the drawings, wherein
The figures are schematic and simplified for clarity, and they just show details, which are essential to the understanding of the invention, while other details are left out. Throughout, the same reference numerals are used for identical or corresponding parts.
When in the following terms like “upper” and “lower”, “right” and “left”, “horizontal” and “vertical”, “clockwise” and “counter clockwise”, “front”, “end”, and “side” or similar relative expressions are used, these only refer to the appended figures and not to an actual situation of use. The shown figures are schematic representations for which reason the configuration of the different structures as well as their relative dimensions are intended to serve illustrative purposes only.
In the present specification, the use of the singular includes the plural, and the words “a”, “an” and “the” means “at least one”, unless specifically stated otherwise. Furthermore, the use of the term “including”, as well as other forms such as “includes” and “included”, is not limiting. As used herein, the conjunction “and” is intended to be inclusive and the conjunction “or” is not intended to be exclusive, unless otherwise indicated. For example, the phrase “or, alternatively” is intended to be exclusive. As used herein, the term “and/or” refers to any combination of the foregoing features including using a single feature.
Detailed descriptions are given below to specific embodiments of the present invention with reference to the drawing.
According to a first aspect, there is provided tablet 1 comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid in a total amount of about 60 to 99.8% in weight based on the total weight of the tablet, the tablet having
The tablet 1 according to the first aspect of the invention is elongated and may also be referred to as an oval-shaped or a capsule-shaped compound cup tablet.
The tablet 1 may have an identification such as an engraving. In some embodiments, the tablet according to the invention is a debossed tablet. In some embodiments, the tablet according to the invention is an embossed tablet.
The total amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be about 65 to 99% in weight based on the total weight of the tablet. In some embodiments, the total amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be about 70 to 99% in weight based on the total weight of the tablet. In some embodiments, the total amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be about 75 to 99% in weight based on the total weight of the tablet. In some embodiments, the total amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be about 80 to 99% in weight based on the total weight of the tablet. In some embodiments, the total amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be about 85 to 99% in weight based on the total weight of the tablet. In some embodiments, the total amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be about 90 to 99% in weight based on the total weight of the tablet. In some embodiments, the total amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be about 70 to 98% in weight based on the total weight of the tablet. In some embodiments, the total amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be about 75 to 98% in weight based on the total weight of the tablet. In some embodiments, the total amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be about 80 to 98% in weight based on the total weight of the tablet. In some embodiments, the total amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be about 85 to 98% in weight based on the total weight of the tablet. In some embodiments, the total amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be about 90 to 98% in weight based on the total weight of the tablet. In some embodiments, the total amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be about 85 to 97% in weight based on the total weight of the tablet. In some embodiments, the total amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be about 90 to 97% in weight based on the total weight of the tablet. In some embodiments, the total amount of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be about 79 to 90% in weight based on the total weight of the tablet.
The salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be granulated.
In some embodiments, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC), such as granulated SNAC.
The total weight of the tablet 1 may be about 50-1200 mg, such as about 100 mg or about 300 mg or about 500 mg or about 700 mg or about 1050 mg.
In some embodiments, the total weight of the tablet 1 is about 90-190 mg, such as about 100-175 mg. In some embodiments, the total weight of the tablet 1 is about 190-290 mg, such as about 200-280 mg. In some embodiments, the total weight of the tablet 1 is about 290-390 mg, such as about 300-380 mg. In some embodiments, the total weight of the tablet 1 is about 390-490 mg, such as about 400-485 mg. In some embodiments, the total weight of the tablet 1 is about 490-590 mg, such as about 500-585 mg. In some embodiments, the total weight of the tablet 1 is about 590-850 mg, such as about 600-830 mg. In some embodiments, the total weight of the tablet 1 is about 850-1200 mg, such as about 860-1150 mg.
The tablet 1 according to the first aspect, may further comprise an active pharmaceutical ingredient (API) such as a peptide and optionally a lubricant.
The active pharmaceutical ingredient may be present in a total amount of about 0.1 to 40% in weight based on the total weight of the tablet. In some embodiments the API is a peptide. In some embodiments, the peptide is a GLP-1 agonist. In some embodiments, the API is semaglutide.
The lubricant such as magnesium stearate may be present in a total amount of about 0.1-7%, such as 0.5-3% in weight based on the total weight of the tablet. In some embodiments, the lubricant is present in a total amount of about 1.5-2.5%. In some embodiment, the lubricant is present in an amount of about 1.5% or 1.6% or 1.7% or 1.8% or 1.9% or 2.0% or 2.1% or 2.2% or 2.3% or 2.4% or 2.5%.
The lubricant may be talc, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, glyceryl debehenate, behenoyl polyoxyl-8 glycerides, polyethylene oxide polymers, sodium lauryl sulphate, magnesium lauryl sulphate, sodium oleate, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oils, silicon dioxide and/or polyethylene glycol. In some embodiments, the lubricant is magnesium stearate.
As shown in
As shown in
The ratio between the length of the tablet and the width of the tablet is also referred herein as “length to width ratio”. If the length to width ratio is above 1.0, the tablet may also be referred to as an elongated tablet. Examples of an elongated tablet are capsule shaped or oval shaped tablets. The length to width ratio can be calculated according to formula (I).
As shown in
Each cup 8 further has a minor major radius 14 and a minor minor radius 15. Tablet 1 may also comprise a land 16. If the tablet 1 does not comprise a land 16 then the cup width 12 corresponds to the width W of the tablet
Each cup 8 has a cup depth 11 and a cup width 12. The total height 13 of the tablet 1 may be calculated by adding the cup depth 11 of each cup 8 and the core height 7.
The cup may be defined as shallow, standard, deep, extra-deep or modified ball according to the tableting specification manual (TMS) of the American Pharmacists Association (7th Edition, Section 3, page 54, TMS-N23).
Having a compound cup instead of a standard cup allows for a greater volume. Increasing the volume of the cup will reduce the core height of the tablet, making the tablet appear thinner and easier to swallow. However, the intersection of the land with the major minor and minor minor cup radii becomes a high-stress point for the punch/punches, which is prone to failure under extreme loading, and therefore has a much lower maximum compression force than the standard cup. Extreme loading is not uncommon with the compound cup configuration. The compound cup has more volume; therefore as the upper punch cup enters the die, it entraps a larger air volume, which then must be expelled during compression. For this reason, the use of a compound cup may require slower die rotational speed and/or higher compression force and/or multiple cycles of compression forces than a standard cup and thus limiting the tableting speed and broad applicability.
The inventors have surprisingly found that when the ratio between the part of the cup width constituted by the minor minor radius (formula II) and the cup width 12 is 0.67 or below, the formation of cracks during tabletting can be drastically reduced. The ratio between the two minor minor radii parts of the cup width and the cup width 12 is defined herein as index value. Hence, tablet 1 has an index value of 0.67 or below. The index value defines the cup edge rounding and can be calculated according to formula (III) and assures that the cup is rounded narrowly enough at the sides of the cup from the land. An index value of 0.67 or below can lead to less lateral movement of powder in the cup during compression and less air may be entrapped in the centre of the cup during compression.
The tablet height to cup depth ratio can be calculated according to formula (IV). A tablet height to cup depth ratio of above 4.3 assures that the cup is shallow or standard as defined by the tableting specification manual (TMS) of the American Pharmacists Association (7th Edition, Section 3, page 54, TMS-N23). An overly deep cup may exacerbate the crack formation and may prevent measures intended to reduce the crack formation. More lateral movement of powder from the periphery of the cup towards the centre of the cup may occur for deeper cups, which may cause air entrapment in the centre of the cup.
The minor major radius to width ratio defines the cup flatness and can be calculated according to formula (V). A minor major radius to width ratio above 1.15 assures that the centre part of the cup is not overly rounded as that may exacerbate the crack formation and may prevent measures intended to reduce the crack formation. More lateral movement of powder from the periphery of the cup towards the centre of the cup may occur for rounder cups, which may lead to air entrapment in the centre of the cup.
The tablet height to width ratio can be calculated according to formula (VI). A tablet height to width ratio of ≤0.9 assures that the tablet height is smaller than the width.
Without wishing to be bound by theory, it is believed that a small radius at the periphery of the cup (viewed from the front) and a much larger radius at the centre of the cup such that a large flat area is obtained where a crack would occur results in a reduction of the formation of cracks, i.e. a reduction of the number of tablets having a crack compared to the number of tablets not having a crack is obtained.
The tablet composition may comprise a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid such as SNAC, a peptide such a GLP-1 agonist, a lubricant such as magnesium stearate and optionally at least one pharmaceutically acceptable excipient. The tablet composition may be granulated.
Salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid
The structural formula of N-(8-(2-hydroxybenzoyl)amino)caprylate is shown in chemical formula (VII).
In some embodiments the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid comprises one monovalent cation, two monovalent cations or one divalent cation. In some embodiments the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is selected from the group consisting of the sodium salt, potassium salt and/or calcium salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. In one embodiment the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is selected from the group consisting of the sodium salt, potassium salt and/or the ammonium salt. In one embodiment the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is the sodium salt or the potassium salt. Salts of N-(8-(2-hydroxybenzoyl)amino)caprylate may be prepared using the method described in e.g. WO96/030036, WO00/046182, WO01/092206 or WO2008/028859. The salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be crystalline and/or amorphous. In some embodiments the delivery agent comprises the anhydrate, monohydrate, dihydrate, trihydrate, a solvate or one third of a hydrate of the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid as well as combinations thereof. In some embodiments the delivery agent is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid as described in WO 2007/121318.
In some embodiments the delivery agent is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (referred to as “SNAC” herein), also known as sodium 8-(salicyloylamino) octanoate.
According to a second aspect, there is provided a process for preparing a tablet according to the first aspect. Preparation of a tablet composition according to the invention may be performed according to methods known in the art.
The process for preparing a tablet of the invention may comprise the steps of:
In some embodiments, components of the tablet composition such as a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid such as SNAC, a peptide such as a GLP-1 agonist, a lubricant such as magnesium stearate and optionally at least one pharmaceutically acceptable excipient may be provided.
The excipients provided in step a, may be weighed, optionally delumped or sieved and then combined by mixing of the components. Mixing may be carried out until a homogeneous blend is obtained.
The blended or mixed excipients of step b may be granulated as explained below. In some embodiments, the excipients are dry granulated. In some embodiments the excipients are wet granulated.
If granules are to be used in the tabletting material, granules may be produced in a manner known to a person skilled in the art, for example using wet granulation methods known for the production of “built-up” granules or “broken-down” granules. Methods for the formation of built-up granules may operate continuously and comprise, for example simultaneously spraying the granulation mass with granulation solution and drying, for example in a drum granulator, in pan granulators, on disc granulators, in a fluidized bed, by spray-drying, spray-granulation or spray-solidifying, or operate discontinuously, for example in a fluidized bed, in a rotary fluid bed, in a batch mixer, such as a high shear mixer or a low shear mixer, or in a spray-drying drum. Methods for the production of broken-down granules, which may be carried out discontinuously and in which the granulation mass first forms a wet aggregate with the granulation solution, which is subsequently comminuted or by other means formed into granules of the desired size and the granules may then be dried. Alternatively, the granulation liquid might be solid upon addition to the granulation mass and then melted while mixing together with the granulation mass and thus forming granules when solidified after cooling. Suitable equipment for the wet granulation step are planetary mixers, low shear mixers, high shear mixers, fluidized beds, spray-driers, extruders and spheronizers, such as an apparatus from the companies Loedige, Glatt, Diosna, Fielder, Collette, Aeschbach, Alexanderwerk, Ytron, LB Bohle, GEA, Wyss & Probst, Werner & Pfleiderer, HKD, Loser, Fuji, Nica, Caleva and Gabler. Granules may also be formed by dry granulation techniques in which one or more of the excipient(s) and/or the active pharmaceutical ingredient is compressed to form relatively large moldings, for example slugs or ribbons, which are comminuted by grinding, and the ground material serves as the tabletting material to be later compacted. Suitable equipment for dry granulation is, but not limited to, roller compaction equipment from Alexanderwerk, Freund-Vector, Gerteis, and LB Bohle.
The granules provided in step c and alternatively other excipients, may be weighed, optionally delumped or sieved and then combined by mixing. Mixing may be carried out until a homogeneous blend is obtained.
An excess quantity of the tableting material such as the granulated excipients obtainable in step c. and/or d. may be supplied to the die cavity with a lower punch and an upper punch. Consecutively, an exact quantity of the tableting material may be metered out to match the desired tablet weight by pushing out excess tableting material. Subsequently, the excess quantity may be removed by a scraping action. The supply of the tableting material can be facilitated by gravity or mechanically forced by use of e.g. rotating baffles placed just above the die cavity.
The metered out tableting material may be compacted inside the die cavity by a set of punches such as an upper punch and a lower punch exerting a pressure obtained by reducing the distance between the tips of the upper and lower punches. Pressure can be applied once or multiple times. Pressure may be applied twice. Applying pressure in a first round, also referred to as “pre-compression” can remove air and can orient particles of the tableting material in a denser packing. Subsequently, pressure is applied again in a second round, also referred to as “main compression” allowing the particles to fragment and deform elastically and/or plastically to result in the desired tablet properties. The pressure of the pre-compression can be lower than the pressure of the main compression. The pressure of the pre-compression can also be high enough to result in particle fragmentation and elastic and/or plastic deformation. The main pressure and the pre-compression may be derived by measuring the force required for bringing the punch tips closer to each other and then transforming that into a pressure by compensating for the cup area and optionally for the shape of body. Subsequently, the tablet can be ejected from the die cavity by first removing the upper punch and then by pushing the tablet out of the die cavity by use of the lower punch. A guide or scraper may be used to direct the ejected tablet automatically away from the die table and onto a chute leading the tablet out from the tableting machine. The thickness of the so-obtained tablet is related to the minimum distance between the tips of the upper and lower punches during the main compression. The breaking force of the so-obtained tablets is related to the number of times pressure is exerted, the maximally reached pressure and the dwell time for exerting the pressure. Suitable tablet presses include, but are not limited to, rotary tablet presses and eccentric tablet presses such as an apparatus from Fette, Korsch, Manesty, GEA, Courtoy, and Riva Piccola.
In a third aspect, there is provided a punch set comprising an upper punch, a lower punch, and a die or die cavity, also called a punch set, a tooling set, or a station, for making a tablet according to the first aspect. The punches can have a single tip or multiple tips. The die or die cavity can be tapered or non-tapered.
In some embodiments, the punch set enables (a) a tablet height to width ratio of 0.9 or below, such as of about 0.05-0.9; (b) a tablet height to cup depth ratio of above 4.3, such as of about 4.4-100; (c) a minor major radius to width ratio of above 1.15, such as of about 1.16-100; and/or (d) an index value of 0.67 or below, such as of about 0.05-0.55.
In a fourth aspect, there is provided a tablet according to the first aspect of the invention for use in medicine. The composition of the invention may be used for the following medical treatments, all preferably relating one way or the other to diabetes and/or obesity:
In some embodiment, the indication is selected from the group consisting of (i)-(iii) and (v)-(iix), such as indications (i), (ii), and/or (iii); or indication (v), indication (vi), indication (vii), and/or indication (iix). In another particular embodiment, the indication is (i). In a further particular embodiment the indication is (v). In a still further particular embodiment the indication is (iix). In some embodiments the indications are type 2 diabetes and/or obesity.
In a fifth aspect, there is provided a tablet according to the first aspect of the invention for use in the treatment of diabetes or obesity.
In an alternative fourth aspect, there is provided method of treating a subject in need thereof, comprising administering a tablet according to the first aspect to a patient in need thereof. In one embodiment, the tablet is administered orally. In one embodiment the method of treatment is for treatment of diabetes or obesity and/or the further indications specified above. In some embodiments, the tablet is administered once daily or less frequent such as once weekly.
As used herein, the term “about” or “approximately”, when used together with a numeric value (e.g. 5, 10%, ⅓), refers to a range of numeric values that can be less or more than the number. In some embodiments, the term “about” as used herein means±10% of the value referred to, and includes the value. For example, “about 5” refers to a range of numeric values that are 10%, 5%, 2%, or 1% less or more than 5, e.g. a range of 4.5 to 5.5, or 4.75 to 5.25, or 4.9 to 5.1, or 4.95 to 5.05.
Unless the context dictates the contrary, all ranges set forth herein should be interpreted as being inclusive of their endpoints and open-ended ranges should be interpreted to include only commercially practical values. Similarly, all lists of values should be considered as inclusive of intermediate values unless the context indicates the contrary.
The term “excipient” as used herein broadly refers to any component other than the active therapeutic ingredient(s) or active pharmaceutical ingredient(s) (API(s)).
The excipient may be a pharmaceutically inert substance, an inactive substance, and/or a therapeutically or medicinally non-active substance. The excipient may serve various purposes, e.g. as a carrier, vehicle, filler, binder, lubricant, glidant, disintegrant, flow control agent, crystallization inhibitors solubilizer, stabilizer, colouring agent, flavouring agent, surfactant, emulsifier or combinations of thereof and/or to improve administration, and/or absorption of the therapeutically active substance(s) or active pharmaceutical ingredient(s). The amount of each excipient used may vary within ranges conventional in the art. Techniques and excipients which may be used to formulate oral dosage forms are described in Handbook of Pharmaceutical Excipients, 8th edition, Sheskey et al., Eds., American Pharmaceuticals Association and the Pharmaceutical Press, publications department of the Royal Pharmaceutical Society of Great Britain (2017); and Remington: the Science and Practice of Pharmacy, 22nd edition, Remington and Allen, Eds., Pharmaceutical Press (2013).
The term “tablet composition” as used herein is an umbrella term to encompass the excipients of the tablet according to the invention.
By “tableting” we mean the function of compressing a volume of powder or granular material into a single unit of hard form.
“Tableting material” is an umbrella term for the various components/excipients making up the tablet and/or tablet composition as described herein.
The term “body” of the tablet as used herein refers to the volume between the opposing cups.
The term “band” of the tablet as used herein refers to the outside area of the surface of the body between the opposing cups.
By “compound cup” we mean a cup design in which multiple arcs or radii are generated from the cup's centre point across the cup's diameter, minor axis or major axis.
The term “radius” such as e.g. “major major radius”, “major minor radius”, “minor major radius”, “minor minor radius” refers to a single arc generated from a centre point. The term “circle” refers to the circle generated by the radius. A graphical example is provided in
A “standard cup” design is a cup design in which a single arc or radius is generated from the cup's centre point across the cup's diameter, minor, or major axis.
“Cup depth” is the distance from the cup's lowest point (usually the cup's centre point) to its highest point (usually the highest point of the land). By “land” we mean a narrow plane perpendicular to the tablet's band, which creates a junction between the band and the cup.
“Capping” is when the upper or lower cup of the tablet separates horizontally either partially or completely, from the body of the tablet.
“Chipping” is a defect in the tablet in which a piece has broken off around the edge.
“Organoleptic properties” are the aspects of food, water or other substances that create an individual experience via the senses-including taste, sight, smell, sound, and touch. As used herein, the term mainly addresses the “swallowability” of a tablet e.g. the willingness of a patient to swallow a tablet based on the appearance of a tablet in terms of size as well as in terms of the presence of cracks and flaws on the tablet's surface.
As used herein, the “median particle size (D50)” refers to the particle size value where 50% of the particle sizes are smaller and 50% of the particle sizes are larger.
The terms “granulate” and “granules” are used interchangeably herein to refer to particles of composition material which may be prepared as described above.
The term “maximum compression force” includes pre-compression force(s) and main compression force as well as a combination there of.
The term “tablet density” as used herein refers to the tablet mass divided by the tablet envelope volume where the tablet envelope volume can be derived from the measured tablet height, the cup volume, the cup depth, and the cross-sectional area of the body 2 (the area as shown in the plan top view of
The term “tablet porosity” as used herein refers to the fraction of void space inside the tablet (such as internal pores and cavities) calculated as a percentage between 0-100% of the tablet volume (such as the tablet envelope volume as described above). To calculate the tablet porosity, the tablet density is calculated as described above, and assuming a maximum tablet density (i.e. at 0% porosity and thus at a solid fraction equalling 1) of 1.28 g/mL, the solid fraction can be calculated as the tablet density divided by the maximum tablet density of 1.28 g/mL. The porosity is then 1 minus the solid fraction and converted into a percentage between 0-100%.
The term “GLP-1 agonist” as used herein refers to a compound, which fully or partially activates the human GLP-1 receptor. The term is thus equal to the term “GLP-1 receptor agonist” used in other documents. The term GLP-1 agonist as well as the specific GLP-1 agonists described herein are meant to encompass also salt forms hereof.
It follows that the GLP-1 agonist should display “GLP-1 activity” which refers to the ability of the compound, i.e. a GLP-1 analogue or a compound comprising a GLP-1 analogue, to bind to the GLP-1 receptor and initiate a signal transduction pathway resulting in insulinotropic action or other physiological effects as is known in the art.
All headings and sub-headings are used herein for convenience only and should not be constructed as limiting the invention in any way.
The use of any and all examples, or exemplary language (e.g. such as) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
The citation and incorporation of patent documents herein is done for convenience only and does not reflect any view of the validity, patentability, and/or enforceability of such patent documents.
This invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law.
Semaglutide can be prepared according to the method described in WO 2006/097537, Example 4. SNAC can be prepared according to the method described in WO 2008/028859.
The components (e.g. SNAC, MgSt and optionally semaglutide) were mixed at 25 rpm for 50 min using a diffusion blender prior to dry granulation. Dry granulation was carried out by roller compaction on a Gerteis Minipactor using a roll speed of 3-6 rpm, compaction forces of 6-9 kN/cm, and a gap of 1-2 mm. After roller compaction, comminution of the moldings into granules was carried out using a 0.80 mm screen. The so obtained granulated compositions (shown in Table 1) had median particle sizes of 256 to 402 μm and were then formed into tablets.
Tablets were produced on a Fette 102i rotary press mounted with one or more sets of punches and dies and using a die table rotational speed of 20-50 rpm. The fill volume was adjusted to obtain the target weights of the tablets using a force feeder rotating at 20 rpm. The tablets were then compressed at pre-compression forces from 0 to 5 kN and main compression forces from 5 to 17 kN.
Friability testing was performed according to section 2.9.7 in the European Pharmacopoeia 7.5, 7th edition 2012.
70 to 250 tablets were visually inspected for cracks in front of a well-lit white or coloured background. The tablets were visually inspected on one side and hereafter inspected on the other side. The number of tablets detected with cracks were counted and divided by the total number of tablets inspected and reported as a percentage. An example of tablets having cracks is shown in
The median particle size, i.e. the volume distribution of equivalent spherical diameters of particles, was determined by laser diffraction in the dry mode with a dispersive pressure of 1 barg and at an obscuration below 20% in a Malvern Mastersizer 3000 instrument using the non-spherical particle mode in general purpose (Mie approximation) and with a refractive index of 1.55.
Tablet punch sets with the desired tablet designs were manufactured based on the tablet design drawings, prepared in the TabletCAD, tablet design program from Natoli Engineering Company, Inc. (https://natoli.com/lp/tabletcad-ddo/).
Three tablet designs (A-C) were prepared using TabletCAD. The parameters selected are shown in table 2. Composition 1 was used to prepare the tablets according to the procedure described in method 1.
The objective of this example was to determine the effect of tablet dimensions on the formation of cracks and on the tablet friability.
As can be seen from the results shown in Table 2, decreasing the length and width increases the total height of the tablet and leads to an increased percentage of tablets without cracks. In addition, increasing the cup depth decreases the percentage of tablets without cracks. Tablet friability of all tablets designs was found acceptable.
In conclusion, to decrease the number of tablets having cracks it is desirable that the total height of the tablet is as high as possible, while the cup depth remains as shallow as possible.
Four tablet designs (D1-D4) were prepared using TabletCAD. The parameters selected are shown in Table 2. Composition 1 was used to prepare the tablets according to the procedure described in method 1.
The objective of this example was to specifically determine the effect of the minor minor cup radius on the formation of cracks and on the tablet friability.
As can be seen from the results in Table 2, the total tablet height between the tablets are found comparable, as expected with fixed tablet width and length. With the comparable total tablet height and identical cup depth, the results show that decreasing the minor minor radius increases the percentage of tablets without cracks. Tablet friability of all tablets designs was found acceptable.
In conclusion, to decrease the number of tablets having cracks it is desirable that the minor minor radius is as small as possible.
Two tablet designs (E1-E2) were prepared using TabletCAD. The parameters selected are shown in table 2. Composition 2 was used to prepare the tablets according to the procedure described in method 1.
The objective of this example was to specifically determine the effect of cup depth on the formation of cracks and on the tablet friability.
As can be seen from the results in Table 2, the reduced cup depth for E2 slightly decreases the total tablet height, however, the tablets are found comparable with the only significant factor varied being the cup depth. The results show that decreasing the cup depth increases the percentage of tablets without cracks. However, a too shallow cup negatively affects the friability of the tablets.
In conclusion, to decrease the number of tablets having cracks it is desirable that the cup depth is as small as possible, yet deep enough to prevent undesirable tablet friability.
1Tablet porosity is calculated based on the maximum tablet density at 1.28 g/mL.
Based on the foregoing it can be concluded that length, width, total height, cup depth, minor major radius, cup width and minor minor radius are parameters that have an effect on the formation of cracks. In particular, it can be concluded that
Tablets based on the tablet designs of Example 1 were produced according to the tabletting procedure described in method 1 using the same compositions 1 and 2 as in Example 1, respectively.
The objective of this example was to determine if increased compression forces and lower die rotational speed could decrease the number of tablets having cracks compared to example 1.
As can be seen from the results in Table 3, decreasing the die rotational speed and increasing the compression force increases in general the number of tablets without cracks. However, the effect of die rotational speed on the increased number of tablets without cracks is found higher than compared to the effect of increased compression force. The effect of decreasing the die rotational speed and increasing the compression force is found insufficient to solve the issue with tablet cracks.
In conclusion, the modifications to the tablet design are required to obtain tablets without cracks as decreasing die rotational speed and increasing compression force are insufficient to prevent tablet cracks and as slower rotational speeds reduces the manufacturing through-put.
Based on the identified parameters in Examples 1 and 2, further tablet designs were prepared using TabletCAD. Designs F, G, and H were prepared with compositions 3, 1, and 4, respectively, and the tablets were prepared according to the procedure described in method 1. The parameters for the tablet designs F-H are shown in Table 4.
The objective of this example was to verify the design requirements set forth in example 1 for a variety of tablet weights ranging from 102.6 to 612.5 mg with respect to obtaining a high number of tablets without cracks.
As can be seen from the results in Table 4, the two optimised tablet designs complying with the design requirements set forth in example 1 (F and H) result in higher number of tablets without cracks whereas the tablet design not complying (G) has a reduced number of tablets without cracks. The results show therefore that the design requirements set forth in example 1 for obtaining high number of tablets without cracks are equally valid for other tablet weights.
1Tablet porosity is calculated based on the maximum tablet density at 1.28 g/mL.
Further tablet designs (I-K) were prepared using TabletCAD for tablet weights ranging from 307.7-1000 mg (Table 5). Design I was prepared with compositions 1 and 5, design J was prepared with compositions 6 and 7 and design K was also prepared with compositions 6 and 7. The tablets were prepared according to the procedure described in method 1 and the parameters for the tablet designs I-K with low and high tablet weights are shown in Table 5.
The objective of this example was to verify the design requirements set forth in example 1 by reducing the ratio of the height to cup as calculated by formula IV within the same tablet design by lowering the tablet weight with respect to obtaining fewer number of tablets without cracks.
As can be seen from the results in Table 5, the optimised tablet designs complying with the design requirements set forth in example 1 (I-high, J-high and K-high) results in higher number of tablets without cracks whereas the tablet designs not complying (I-low, J-low and K-low) have a reduced number of tablets without cracks. The results show therefore that the design requirements set forth in example 1 for obtaining high number of tablets without cracks are equally valid for a range of tablet weights within a tablet design.
1Tablet porosity is calculated based on the maximum tablet density at 1.28 g/mL.
Further tablet designs (L-O) were prepared using TabletCAD for a tablet weight about 512.8 mg (Table 6). Designs L-O were prepared with composition 8 and the tablets were prepared according to the procedure described in method 1. The parameters for the tablet designs L-O are shown in Table 6.
The objective of this example was to verify the design requirements set forth in example 1 for a tablet weight of about 512.8 mg with respect to obtaining high number of tablets without cracks.
As can be seen from the results in Table 6, the optimised tablet designs complying with the design requirements set forth in example 1 (N and O) results in higher number of tablets without cracks whereas the tablet designs not complying (L and M) have a reduced number of tablets without cracks. The results show therefore that the design requirements set forth in example 1 for obtaining high number of tablets without cracks are equally valid for larger tablet weights
1Tablet porosity is calculated based on the maximum tablet density at 1.28 g/mL.
In conclusion, the tablet design requirements for preventing tablet cracks are verified for different tablet weights.
While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.
| Number | Date | Country | Kind |
|---|---|---|---|
| 21185861.8 | Jul 2021 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2022/069704 | 7/14/2022 | WO |
