Patent Application
20220072493
The present invention relates to a roller compactor for continuous production of granules, a continuous method of producing granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, a method of producing a solid pharmaceutical composition comprising a) producing granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, a roller compactor for production of ribbons by continuous compaction of ingredients and/or excipients, and a continuous method of producing ribbons comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid according to the present disclosure.
Granules for the forming of solid dosage forms, such as tablets, capsules or sachets can be produced by dry granulation using a roller compactor. Granules are used as an intermediate in the manufacturing of various dosage forms, e.g. tablets, capsules, and sachets. The granules may be used as is or in combination with other excipients.
Roller compactors are used for dry granulation of powders. Dry granulation can be accomplished by several means. When a roller compactor is applied for dry granulation, the process is often referred to as roller compaction. The roller compactor compacts dry powder into ribbons by applying mechanical force on a moving bed of the dry powder using a set of rollers. The resulting ribbons are milled to form granules. Roller compaction is therefore a continuous process transforming dry powder into granules via a ribbon intermediate.
WO2008/056021 A2 relates to roller compaction of powders for producing granulate for tabletting which may comprise an API. The document describes that although dry granulation would in many cases appear to be the best way to produce products such as tablets containing APIs, it has been relatively little used because of the challenges in producing the desired kind of granules as well as managing the granulated material in the manufacturing process. The dry granulation methods known in the prior art produce granules that are seldom usable in a tablet manufacturing process. Conflicting process design parameters often lead to compromises where some qualities of the resulting granule product may be good, but other desirable qualities are lacking or absent. For example, the flow characteristics of the granules may be insufficient, the non-homogeneity of the granules may cause segregation in the manufacturing process or capping in tablets, or some of the granules may exhibit excessive hardness, all of which can make the tableting process very difficult, slow and sometimes impossible. Furthermore, the bulk granules may be difficult to compress into tablets.
US2011/0220745 and U.S. Pat. No. 6,623,756 also describes roller compactors for dry granulating powders for forming a granulate mass for tableting.
U.S. Pat. No. 5,509,612 discloses a roller compacter for continuous mechanical shaping of a particulate material. The roller compactor is shown in
CN 105056832A discloses a roller compacter comprising a housing consisting of plates (18 and 19) and baffles (21 and 22) installed at the discharge end of the feed mechanism (16) sealing of the space towards the two rollers.
A continuous flow of powder, ribbons, and granules through the roller compactor is therefore crucial in order to avoid build-up and ultimately blockage of the roller compactor resulting in unacceptable manufacturing conditions. Build-up within the roller compactor may result as a consequence of e.g. poor flowability, cohesive forces, and electrostatic charging of the powder, ribbons, and granules. Build-up within the roller compactor has a negative impact on the technical performance of the compaction process, product quality, and process yield.
Some of these above mentioned problems can be addressed by adding lubricants to the powder. Lubricants tend to be hydrophobic, so their levels need to be optimized. Under-lubricated blends tend to flow poorly and show sticking problems, and over-lubricated blends can adversely affect tablet hardness, dissolution rate, as well as tablet friability.
CA 2938916 describes a method to prevent sticking/caking, and at the same time reduce the amount of internal lubricant to avoid the negative effects of too much internal lubricant. In CA 2938916 this problem is addressed by a method of external lubrication of the press roll of a roller compaction device by continuous coating of the rotating pressing rollers, wherein the pressing rollers are coated with a thin layer of a lubricant in a continuous and solvent-free manner.
However, despite the above mentioned advances, it is an object of the present invention to provide further devices and methods for enabling continuous dry granulation in a roller compactor. It is a further object of the invention to secure consistent quality of granules, and to be able to provide granules of a consistent quality obtained by continuous processing. It is a further object of the invention to provide methods and devices enabling long term continuous processing without interruptions due to cleaning or maintenance, and whereby the devices and the methods provide cost effective production conditions.
In the present invention the inventors have solved the problem of build-up of material/product by improving the dry granulation equipment and thereby enable continuous production of granules of a sufficiently high quality and homogeneity for an extended time period. As described herein, build-up of granules can be prevented by including an agitator preventing build-up of material below the granulator. Alternatively, or additionally a roller rim stripper can be included to prevent build-up or accumulation of material on the roller rim of the pressing rollers, and thereby prevent that the pressing rollers slow down.
In the disclosure of the present invention, embodiments and aspects will be described which will address one or more of the above objects or which will address objects apparent from the below disclosure as well as from the description of exemplary embodiments.
Thus, in a general aspect of the invention is provided a roller compactor for production of granules by dry granulation, wherein the roller compactor comprises: an inlet and an outlet, a pair of pressing rollers comprising a first and a second pressing roller, and wherein the first pressing roller comprises roller rims, wherein the roller compactor further comprises a granulator, a sieve, and exit slides below the sieve leading towards the outlet, wherein the roller compactor further comprises: a) roller rim strippers (250) and/or b) an agitator (270) adapted for agitating material tending to accumulate at the slides (215.2).
Hereby is provided a roller compactor adapted for preventing build-up or accumulation in the roller compactor. The agitator prevents build-up of powder, granules and ribbons below the granulator, and upstream to the granulator and below the pressing rollers. The roller rim strippers prevent build-up on the roller rims, and thereby prevents a slowing down of the roller rims, and consequently a different pressing time of the inflowing powder. In combination the agitator below the granulator ensures that material can be led away from the pressing rollers, whereby also the tendency to accumulate on the roller rims decreases, and the roller rim strippers ensure a continuous strip off of the product, i.e., the agitator and the roller rim strippers can work individually and in concert to prevent build-up of ribbons and granules in the roller compactor and thereby prevent a negative impact on product quality.
In a further aspect the roller compactor is for continuous production of granules by dry granulation.
In a further aspect the roller compactor is for production of granules by continuous dry granulation.
In a further embodiment adhered material is removed at the edge of the rim stripper, the stripping edge 255, and guided to the outlet
In a further embodiment the stripping edge is less than 180 degrees away from the pressing space on the roller rim circumference in the direction of the rotation.
In a further embodiment the roller compactor further comprises a roller scraper with an edge. Such roller scraper or roller scrapers are adapted to avoid double pressing of the material by scraping of material at one or both of the pressing rollers.
In a further embodiment the roller scraper edge and the stripping edge are both within 90 degrees on the circumference of the pressing roller/roller rim.
In a further embodiment the roller scraper and the rim strippers are integrated in a single unit. In such embodiments the roller scraper edge and the stripping edge are preferably within 45 degrees on the circumference of the pressing roller/roller rim.
In a further embodiment the roller scraper and the rim strippers are separate units.
In a further embodiment the roller scraper edge and the stripping edge (255) are less than 90 degrees away from the pressing space on the circumference of the pressing roller/roller rim in the direction of rotation.
In a further aspect the roller rim strippers (250) extend over more than 45 degrees of the circumferential of the roller rims 213.
In a further aspect the roller rim strippers are adapted for stripping off material tending to accumulate or build-up on the roller rims, and thereby to lead the stripped off material towards the outlet.
In a further aspect the agitator is adapted for agitating material tending to accumulate below the sieve insert.
In a further aspect the roller compactor comprises a channel insert unit adapted to interface the roller rims and provide a clearance between the channel insert unit and the roller rims.
In a further aspect, the agitator is an air blowing insert agitating the product and utilizing the air blow and gravity to lead the agitated product towards the outlet.
In another aspect is provided a method of producing granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid comprising the following steps:
Hereby is provided a method of producing a granule comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid by continuously preventing accumulation of material in the roller compactor, wherein the accumulation is prevented by agitation and strip off during dry granulation.
In a further aspect the roller rim strippers are adapted for stripping off material tending to accumulate or build-up on the roller rims, and thereby lead the stripped off material towards the outlet.
In a further aspect, the agitator is adapted for agitating material tending to accumulate below the sieve insert.
In further embodiments, the methods herein are continuous for more than 5 minutes, such as for more than 10 minutes, such as for more than 20 minutes, such as for more than 30 minutes, such as for more than 45 minutes, such as for more than 1 hour, such as for more than 2 hours, such as for more than 3 hours, such as for more than 5 hours, such as for more than 8 hours.
In another aspect is provided a roller compactor for production of granules by dry granulation of ingredients and/or excipients, wherein the roller compactor comprises: a flow channel for conveying a material from an inlet to an outlet through a pressing space, wherein the material comprises the ingredients and/or the excipients, wherein the material can be in different physical forms comprising the form of powder, particles and the form of granules;
In a further aspect the roller compactor is for production of granules by continuous dry granulation.
In a further aspect the roller compactor is for continuous production of granules by dry granulation.
In a further aspect the agitator is an air blowing insert agitating the material and utilizing the air blow and gravity to lead the agitated material towards the outlet.
In a further aspect, the agitator is a vibrating plate agitating the granules and utilizing vibrational energy and gravity to lead the agitated material towards the outlet.
In a further aspect, the agitator is an automatically movable mechanical brush, scraper or swiping arm agitating the granules and utilizing the automatic movement and gravity to lead the agitated material towards the outlet.
In a further aspect, the agitator is adapted to counteract an accumulation of material at the exit slide below the sieve and the granulator, and thereby counteract the upstream accumulation at the slides below the pressing rollers.
In a further aspect, the material is characterized by poor flowability due to cohesive forces, or electrostatic charging.
In a further aspect, the poor flowability can be observed as a tendency to accumulate at the exit slides below the granulator and the sieve insert and below the pair of rollers.
In a further aspect, the poor flowability is defined as a production stop, in a reference roller compactor without the agitator, due to a material accumulation at the exit slides below the granulator and sieve insert before the completion of a production cycle without cleaning the slides below the granulator or without agitation of the granules below the granulator of a period longer than a time within the interval 1 minute to 120 minutes, or preferably longer than 6 minutes.
In a further aspect, for the purpose of defining poor flowability, the reference roller compactor is defined as a roller compactor wherein the mechanical parts, with the exception of the agitator, are identical to the mechanical parts of the embodiment according to the present disclosure.
In a further aspect the roller compactor is adapted for ensuring consistent quality of the granules by counteracting accumulation of material in the roller compactor.
In a further aspect the roller compactor is adapted for ensuring consistent quality of the granules by extending the period of a continuous production cycle, without interruption by cleaning cycles.
In a further aspect the roller compactor is adapted for enhancing the yield of the dry granulation process by counteracting accumulation of material in the roller compactor.
In a further aspect the roller compactor is adapted for enhancing the dry granulation process by extending the period of a continuous production cycle, without interruption by cleaning cycles.
In a further aspect the roller compactor is adapted for dry granulation of a powder comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
In a further aspect the roller compactor is adapted for production of granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
In a further aspect the roller compactor is adapted for forming the powder into ribbons, and for forming the ribbons into granules.
In another aspect is provided a method of producing granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid according to the present disclosure, the method comprises:
In another aspect is provided a roller compactor for production of ribbons by compaction of ingredients and/or excipients, wherein the roller compactor comprises: a flow channel for conveying a material from an inlet to an outlet through a pressing space, wherein the material comprises the ingredients and/or the excipients, wherein the material can be in different physical forms comprising the form of powder, particles and the form of granules;
In a further aspect the roller compactor is for production of ribbons by continuous compaction.
In a further aspect the roller compactor is for continuous production of ribbons by compaction.
In a further aspect, the roller compactor comprises a channel insert unit adapted to interface the roller rims and provide a clearance between the channel insert unit and the roller rims.
In a further aspect, the roller compactor further comprises: a granulator arranged in the housing downstream to the pair of pressing rollers, and a sieve insert mounted in the housing adjacent and downstream to the granulator.
In a further aspect, the channel insert unit comprises side walls adapted to be inserted upstream and adjacent to the pair of rollers and for interfacing with the first pressing roller, wherein the channel insert unit is adapted to provide a channel portion from the inlet to the pressing space between the pair of rollers, and wherein the side walls are adapted to interface the roller rims and provide clearance between the channel unit insert and the roller rims.
In a further aspect, the channel insert unit further comprises a first lower curved surface adapted to interface the roller rims and provide the clearance.
In a further aspect, the clearance is adapted to minimize friction upon rotation of the roller rims but also to restrict powder from escaping the intended flow path through the pressing space during the dry granulation.
In a further aspect, the roller rims and the channel insert unit are adapted to create friction, in response to formation of a material layer due to material accumulation on the roller rims, wherein the material layer exceeds a threshold, whereby rotational speed of the rollers will slow down.
In a further aspect, the roller rim strippers are adapted to ensure that the material layer is prevented in exceeding the threshold.
In a further aspect, the roller rims comprise two roller rims and the roller rim strippers comprise two roller rim strippers.
In a further aspect, the material is characterized by poor flowability due to cohesive forces, or electrostatic charging.
In a further aspect, the poor flowability can be observed as a tendency to accumulate on the roller rim stripper.
In a further aspect, the poor flowability can be defined as a production stop, in a reference roller compactor without the roller rim strippers, due to a material accumulate on the roller rims before the completion of a production cycle without cleaning or stripping of the roller rims of a period longer than a time within the interval 1 minute to 120 minutes, or preferably longer than 30 minutes.
In a further aspect, for the purpose of defining poor flowability, the reference roller compactor is defined as a roller compactor wherein essentially all the mechanical parts, with the exception of the roller rim strippers, are identical to the embodiment according the present disclosure.
In a further aspect, the roller compactor is adapted for ensuring consistent quality of the granules by counteracting accumulation of material in the roller compactor, and thereby ensure that the rotational speed of the first roller is not reduced.
In a further aspect, the roller compactor is adapted for enhancing the yield of the dry granulation process by counteracting accumulation of material in the roller compactor.
In a further aspect, the roller compactor is adapted for enhancing the yield of the dry granulation process by extending the period of a continuous production cycle, without interruption by cleaning cycles.
In a further aspect, the roller compactor is adapted for dry granulation of a powder comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
In a further aspect, the roller compactor is adapted for production of ribbons comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
In a further aspect, the roller compactor is adapted for forming the powder into ribbons, and wherein the ingredients and/or excipients further composes the ribbons.
In another aspect is provided a method of producing ribbons comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid according to the present disclosure, the method comprises:
In another aspect is provided, a roller compactor for production of granules by dry granulation of ingredients and/or excipients, wherein the roller compactor comprises: a flow channel for conveying a material from an inlet to an outlet through a pressing space, wherein the material comprises the ingredients and/or the excipients, wherein the material can be in different physical forms comprising the form of powder, particles and the form of granules;
In another aspect is provided a method of producing granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid according to the present disclosure, the method comprises:
In further embodiments the roller compactors and methods described herein are for continuous production of granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
In another aspect is provided, a method of producing a solid pharmaceutical composition comprising the steps of
In one embodiment the method comprise a step of blending said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant, such as magnesium stearate prior to step a).
In a further embodiment the method comprise a step of blending said granules obtained in a) with a lubricant, such as magnesium stearate prior to step b).
In a further embodiment the method of producing a solid pharmaceutical composition comprising the steps of:
In one embodiment the granules comprise 1-5 mg magnesium stearate per 100 mg SNAC.
In a further embodiment the solid pharmaceutical formulation comprises a pharmaceutical active ingredient.
In a further embodiment the method of producing a solid pharmaceutical composition comprising the steps of:
In a further embodiment the method of producing a solid pharmaceutical composition comprising the steps of:
In a further embodiment the method of producing a solid pharmaceutical composition comprising the steps of:
In a further embodiment the method of producing a solid pharmaceutical composition comprising the steps of:
In further such embodiments the pharmaceutical active ingredient is semaglutide
In the following embodiments of the invention will be described with reference to the drawings:
In the figures like structures are mainly identified by like reference numerals. Numbers e.g. 200, 201, 202 are used to denote features on the drawing. Numbers combined with letters e.g. 212a, 212b are used to denote features with a similar function, and these features can be referred to individually as 212a and 212b or in common as 212. Further details of a feature can be denoted by a number followed by a dot and a running number of 1 or 2 digits. Further details of a feature can be denoted by a number combined with a letter followed by a dot and a running number of 1 or 2 digits.
When in the following terms such as “upper” and “lower”, “right” and “left”, “horizontal” and “vertical” or similar relative expressions are used, these only refer to the appended figures and not necessarily 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. When the term member is used for a given component it can be used to define a unitary component or a portion of a component, having one or more functions.
In the following detailed description, numerous specific details are set forth in order to provide a thorough understanding of the present disclosure. However, it will be apparent to one of ordinary skill in the art that the present disclosure may be practiced without these specific details. In other instances, well-known methods, procedures, components, circuits, and networks have not been described in detail so as not to unnecessarily obscure aspects of the embodiments.
It will also be understood that, although the terms first, second, etc. may be used herein to describe various elements, these elements should not be limited by these terms. These terms are only used to distinguish one element from another. For example, a first subject could be termed a second subject, and, similarly, a second subject could be termed a first subject, without departing from the scope of the present disclosure. The first subject and the second subject are both subjects, but they are not the same subject. Furthermore, the terms “subject,” “user,” and “patient” are used interchangeably herein.
As used herein, the term “if” may be construed to mean “when” or “upon” or “in response to determining” or “in response to detecting,” depending on the context. Similarly, the phrase “if it is determined” or “if [a stated condition or event] is detected” may be construed to mean “upon determining” or “in response to determining” or “upon detecting [the stated condition or event]” or “in response to detecting [the stated condition or event],” depending on the context.
As used herein, the term “continuous” is used to describe a period without interruption or uninterrupted extension. A “continuous method” is used to describe a method which can be continued without interruption due to external conditions determined by the nature of the process, e.g., the process is stopped due to required cleaning of the equipment or the process is stopped due to excessive accumulation which blocks the process or prevents the functioning of the equipment.
A “pharmaceutical active ingredient” is as used herein preferably a GLP-1 receptor agonist, such as a GLP-1 analogue comprising a fatty acid or fatty diacid substituent extending the half-life of the peptide. Example compounds are described in WO2006/097537, WO2011/080103 and WO2012/140117 and includes semaglutide (WO2006/097537, Example 4), Example 2 of WO2011/080103 or Example 31 of WO2012/140117. In a preferred embodiment said pharmaceutical active ingredient is semaglutide. In a further preferred embodiment said pharmaceutical active ingredient is Nε27-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]-acetyl], Nε36-[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]-butanoyl]amino]-ethoxy]-ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Aib8,Glu22,Arg26,Lys27, Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly. In a further preferred embodiment said pharmaceutical active ingredient is named Nε26{2-[2-(2-{2-[2-(2-{(S)-4-Carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}-ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl}, Nε37-{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)-ethoxy]acetylamino}ethoxy)ethoxy]acetyl}-[Aib8,Arg34,Lys37]GLP-1(7-37)-peptide.
Granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid
In the present disclosure, granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid are used as an intermediate for the manufacturing of an orally administered dosage, wherein the dosage can be in the form of a tablet, a capsule, or a sachet. The granules may be used as is or in combination with other excipients.
The granules comprise a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, such as a potassium, calcium or sodium salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. In a preferred embodiment the salt is sodium N-(8-(2-hydroxybenzoyl)amino)caprylic acid (SNAC). In one embodiment the granules comprises a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, such as salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and a lubricant, such as magnesium stearate. In one embodiment the granules comprise SNAC and magnesium stearate. In one embodiment the granules comprise 1-5 mg magnesium stearate per 100 mg SNAC.
SNAC is a delivery agent and has shown to improve the bioavailability of semaglutide as described in WO2012/080471. WO 2013/139694 further describes a preferred dosage form where the solid composition is made up of two types of granulate, a first type comprising SNAC and a second type comprising semaglutide.
In alternative embodiments the dosage form may comprise a single type of granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (such as SNAC) and a pharmaceutical active ingredient, and wherein said single type of granules are produced according to the present invention.
In some embodiments the granules comprising salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid further comprises a lubricant, such as magnesium stearate. In some embodiments the granules comprising salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid further comprises a filler, such as microcrystalline cellulose. Accordingly, the granules produced according to the invention comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic may further comprise a lubricant and optionally a filler.
In one embodiment the invention relates to granules produced according to the methods described herein, and further to any solid pharmaceutical dosage form comprising granules produced according to the invention. Such solid pharmaceutical dosage form additionally comprises a pharmaceutical active ingredient. In a preferred embodiment said pharmaceutical active ingredient is semaglutide.
In some embodiments the term “granule” refers to powder or particles gathered into larger particles. Such granules can be used to produce a pharmaceutical composition by blending the granules with further excipient. Such further excipients may be in the form of powder, particles or in the form of further granules, such as a second granule. Finally, further excipients may be added by blending prior to finalizing the pharmaceutical composition. Pharmaceutical compositions according to the invention may thus comprise a granular part and an extra-granular part. The pharmaceutical active ingredient may be part of either the granular part or the extra-granular part.
Some embodiments of the present disclosure relates to a solid pharmaceutical composition comprising granules of a first type and optionally a second type, wherein said first type of granules comprises a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and said second type of granules comprises a pharmaceutical active ingredient, and wherein said first type of granules are produced according to the present invention. In some embodiments the granules comprising salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid further comprises a lubricant, such as magnesium stearate. In some embodiments the granules comprising salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid further comprises a filler, such as microcrystalline cellulose. Accordingly, the granules may further comprise a lubricant and optionally a filler.
In embodiments comprising a second type of granules comprising the pharmaceutical active ingredient, the second type of granules may further comprise a filler, such as microcrystalline cellulose. In some embodiments the second type of granules further comprises a binder, such as povidone. Accordingly, the second type of granules may further comprise a filler and optionally a binder. In some embodiments the second type of granules further comprises an extragranular lubricant, such as magnesium stearate.
In some embodiments the first type of granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid does not contain a pharmaceutical active ingredient. In some embodiments the second type of granules comprising a pharmaceutical active ingredient does not contain a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
In some embodiments the first type of granules comprises a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and no pharmaceutical active ingredient, and the second type of granules comprises a pharmaceutical active ingredient and no salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
In some embodiments of the present disclosures relates to a solid pharmaceutical composition comprising granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid and optionally a second type of granules wherein said first type of granules are produced according to the present invention. The solid pharmaceutical composition further comprises a pharmaceutical active ingredient either, and said active ingredient may as described above be comprised by the granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid or alternatively included in the pharmaceutical composition in separate granules or extra-granulate.
In the present disclosure, a roller compactor generally used for dry granulation of a powder, and it is particularly used for dry granulation of powder comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. The roller compactor compress the dry powder into ribbons by applying mechanical force on a moving bed of the dry powder using a set of rollers. The resulting ribbons are milled to form granules. The roller compaction is therefore a continuous process transforming the dry powder into granules via a ribbon intermediate.
Roller Compaction
The present disclosure relates to a process of roller compaction, wherein a material is conveyed from an inlet to an outlet. The material comprises the active ingredients and/or excipients of the manufacturing process. The material has different forms depending on the processes that have been applied, but the material has substantially the same composition of ingredients and/or excipients through the process. The transformation from one form to another is accomplished by a processing step. The different forms of the material in the disclosed method of roller compaction comprises: powder, ribbons and granules. However, the material may comprise other forms or intermediate forms. At all stages and in all forms from the inlet to outlet the material can also be referred to as a product to indicate the value or purpose of the material. For the disclosed roller compaction process the powder is the starting product, which has been provided as a blend of powders, if there is more than one ingredient and/or excipient. The ribbons are defined as an intermediate product obtained by compression of the blend of powders, having the appearance of a long narrow strip. The granules are defined as the end product or final product and is obtained by comminution of the ribbons. However, for a further process step of e.g. tabletting the granules, the granules can be regarded as a starting product or an intermediate product, and the tablet will be regarded as the final product.
The roller compactor 200 illustrated in
As also illustrated in
A blend or mixture of powder can be conveyed from a proportioning device at the inlet 201 during operation of a stuffing screw and a proportioning screw (screws and proportioning device not shown on the figure). The powder is conveyed from the inlet and into the pressing space 214 of the pressing rollers 212a, 212b, which run against each other. The pressing roller 212a is mounted on a laterally fixed first rotatable shaft and the roller 212b is mounted on a laterally movable second rotatable shaft, which is laterally biased towards the first shaft, whereby a biasing force provides a constant compression on the pressing space 214. The first rotatable shaft 212a.1 is mounted below and laterally spaced from the second rotatable shaft 212b.1, whereby a direction through the first and second axle defines an angle 207 to the X-axis. In this way the roller 212a is adapted to draw a larger fraction of product into the pressing space 214 than the roller 212b.
Roller scrapers 230a, 230b with edges 232a, 232b are provided to avoid double pressing of the product, by removing excess of product adhering to the rollers 212a, 212b (the edge 232a is not shown on
Channel Insert Unit
Each of the channel side walls 243a, 243b comprises a first lower curved surface 243a.1, 243b.1 adapted to interface either the front roller rim 213a or the rear roller rim 213b. Each of the channel side walls 243a, 243b further comprises a second lower curved surface 243a.2 exposed to the internal volume downstream to the pressing space 214 of the roller compactor 200, and an upper surface 243a.3 (see
Each of the first lower curved surfaces 243a.1, 243b.1 of the channel side walls 243 further comprises a first curved guide structure 243a.4, 243b.4 adapted to cooperate with a curved circumferentially extending second curved guide structure 213a.1, 213b.1 on the roller rims 213 (see
Roller Rim Stripper
The roller rim strippers 250 for the roller compactor counteracts the build-up of powder and ribbons on the roller rims 213 as the roller rim strippers 250 ensures that powder and ribbons continuously are prevented from entering the roller rims and removed from the roller rims. The entry of powder and ribbons on the roller rims is prevented by the roller rim strippers physically blocking the access by extending along the circumference of the roller rim 213. The removal is caused by the stripper design in the form for a stripping edge, i.e., an acute angle. The stripping edge is formed on the upstream edge of the roller rim stripper 250. A small clearance is provided between the roller rim and the roller rim stripper to prevent damage of the roller rim stripper.
Referring back to
Air Blowing Insert
Again with reference to
With further reference to
With further reference to
A continuous flow of powder, ribbons, and granules through the roller compactor is crucial in order to avoid build-up and ultimately blockage of the roller compactor resulting in unacceptable manufacturing. Ideally, the continuous flow of product is provided in a steady state condition wherein the mass inflow balances the mass outflow. In reality the balance will fluctuate around this ideal condition, but over a long production cycle with continuous flow the fraction between the total mass inflow and the total mass outflow will converge. Build-up of product within the roller compactor may result as a consequence of e.g. poor flowability, cohesive forces, and electrostatic charging of the powder, ribbons, and granules. Build-up of product within the roller compactor has a negative impact on the process technical performance of the roller compactor, product quality, and process yield. Especially build-up of product in the roller compactor of powder and ribbons on rollers and their rims and build-up of ribbons and granules beneath rollers and granulators have a high negative impact on product quality.
By providing a modified roller compactor comprising an air blowing insert and a roller rim stripper, build-up of ribbons and granules in the granulator and build-up of powder and ribbons on the roller rims does not reach a level that result in a negative impact on the technical performance of the process, process yield, and product quality.
In some embodiments the modified roller compactor comprises an air blowing insert. Alternatively, in some embodiments the modified roller compactor comprises roller rim strippers. Alternatively, in some embodiments the modified roller compactor comprises an air blowing insert and roller rim strippers positioned at a lower portion of the roller rims.
The air blowing unit 270 and the roller rim strippers 250 are designed so that they do not interfere with the normal assembly of the roller compactors and do not require modifications of the standard Gerteis roller compactor parts. Furthermore, the positions of the air blowing unit and the roller rim stripper in the assembled roller compactors do not compromise the intended function of the roller compactors.
The functions of the air blowing unit 270 and the roller rim stripper are, without compromising other functionalities of the roller compactor, adapted to prevent build-up of ribbons and granules under the granulator and of powder and ribbons on the roller rims, respectively. Design variations of the air blowing unit, agitating and inducing the granule flow, and of the roller rim strippers clearing the rims mechanically are in scope of the present disclosure. The invention may be applied for other productions using roller compaction and for other powders than powders containing SNAC.
Roller compaction of powder comprising sodium N-(8-(2-hydroxybenzoyl)amino)caprylic acid (SNAC)
During roller compaction of powder comprising SNAC, formed granules build up on the exit slides 215a.2, i.e., the wall structure portion 215a underneath the granulator. As granules continue to build up during the process, the flow towards the exit chute 203 eventually becomes blocked, which is seen in
Impact on Technical Performance
In order to ensure the technical performance of a roller compactor, and as disclosed in the present disclosure to ensure the technical performance for the Gerteis roller compactors, for the SNAC granulation process. The roller compactor has to be partially disassembled and reassembled when product build-up occurs. Therefore, to enable large scale production of granules, the roller compactor has to be disassembled and reassembled several times. This is necessary to remove product build-up of powder, ribbons, and granules around and in the granulator and on the roller rims in order to prevent blockage of the material flow in the roller compactor and to prevent slowing down and eventually stop the rotation of the rollers. During roller compaction of the SNAC powder mixture, the roller compactor potentially has to go through a cycle of disassembling, removal of granulator build-up, and reassembling after 6th minutes of manufacturing. Furthermore, every 30th minute of manufacturing (i.e. 5×6 minutes of manufacturing) the dis- and reassembling cycle has to additionally include a cleaning of the roller rims to remove build-up on the roller rims. Each of such cleaning cycles are time consuming, as a cleaning cycle of the roller rims takes approximately 30 minutes and a cleaning cycle including the granulator takes approximately 6 hours. Each “granulator cycle”, which cycle comprises 6 minutes of manufacturing and “removal of build-up below the granulator ” takes approximately 6+30 minutes, and each “rim cycle”, which cycle comprises 5 “granulator cycles” and “removal of build-up below granulator and cleaning of roller rims” takes approximately 180+330 minutes. Hence, large scale production of granules requiring more than 6 minutes of granulation can be shortened substantially. A “rim cycle” of 510 minutes as referred to above can instead be performed as a continuous production taking just 30 minutes resulting in a 17 fold increase in production capacity.
Impact on Yield
Build-up of ribbons and granules in the granulator and beneath the rollers potentially has to be removed every 6th minutes of manufacturing. Likewise, build-up of powders and ribbons on the roller rims potentially has to be removed every 30th minutes of manufacturing. These multiple build up removals of powder, ribbons, and granules to enable manufacturing of SNAC granules will significantly reduce the yield of the process because the removed powders, ribbons, and granules are scrapped.
Impact on Quality
The quality of the granules may be compromised when ribbons and granules build up in the granulator and beneath the rollers. The reason for this is that ribbons and granules might reside within the granulator for a longer time than intended which in turn results in excessive comminution of the granules and ribbons. This results in granules with a smaller particle size than intended. Furthermore, the quality of the granules may be compromised when powder and ribbons build up on the roller rims as the rotational speed of the rollers might slow down which in turn impacts the granule size, densities, and tableting properties.
Roller Compaction of SNAC Granules Comprising Cleaning Cycles
Thus in an embodiment of the present disclosure is provided a method of producing granules comprising SNAC according to the present disclosure, the method comprises: (i) providing a powder comprising SNAC, (ii) dry granulating the powder by using a roller compactor, comprising a pair of pressing rollers 212 with roller rims 213, a granulator 216, a sieve 218, and an exit slide 215a.2 below the sieve 218, wherein the dry granulation is conducted in a plurality of production cycles (iii) performing a first cleaning cycle of disassembling, cleaning and reassembling the roller compactor to clean and remove accumulated product from the exit slide 215a.2 below the granulator, (iv) performing a second cleaning cycle of disassembling, cleaning and reassembling the roller compactor to clean and remove accumulated product from the exit slide 215a.2 and slides 215a.1 below the pressing rollers 212, wherein one of the cleaning cycles are conducted after each production cycle, and wherein the first cleaning cycle is conducted at a higher frequency than the second cleaning cycle.
In an embodiment of the present disclosure, the powder, granules and intermediate products are characterized by poor flowability due to cohesive forces, or electrostatic charging. The poor flowability can be observed as a tendency to build-up below the granulator and the sieve insert and below the pair of rollers 212. The poor flowability can be measured as a production stop due to a product build-up below the granulator before the completion of a production cycle without cleaning below the granulator of a period longer than 1 minute to 120 minutes, or preferably longer than 6 minutes.
Thus in another embodiment of the present disclosure is provided a method of producing granules comprising SNAC according to the present disclosure, the method comprises: (i) providing a powder comprising SNAC, (ii) dry granulating the powder by using a roller compactor comprising a housing 210, a pair of pressing rollers 212, wherein a first pressing roller 212a comprises roller rims 213, and wherein the first pressing roller is rotatingly mounted in the housing, a granulator 216, a sieve 218, and an exit slide below the sieve 218.
Thus in an embodiment of the present disclosure, the roller compactor further comprises a rigidly mounted channel insert unit 240 comprising sidewalls adapted to be inserted upstream and adjacent to the pair of rollers 212 and for interfacing with the first pressing roller 212a, wherein the channel insert unit 240 is adapted to provide a channel portion 248 from a feeding unit 220 to a pressing space 214 between the pair of rollers 212, each of the side walls 243 comprises a first lower curved surface 243a.1, 243b.1 adapted to interface the roller rims 213, wherein a clearance is provided between the side walls 243 and the roller rims 213, and wherein the clearance is adapted to minimize friction upon rotation of the roller rims 213 but also to restrict powder from escaping the intended flow path through the pressing space 214 during the dry granulation, and wherein, in response to product build up on the roller rims 213, friction will be generated between the sidewalls and the roller rims to cause the rotational speed to slow down.
Thus in an embodiment of the present disclosure is provided a method of producing granules comprising SNAC according to the present disclosure, the method comprises: (i) providing a powder comprising SNAC, (ii) dry granulating the powder by using a roller compactor, comprising a pair of pressing rollers 212 with roller rims 213, a granulator 216, a sieve 218, and an exit slide below the sieve 218, wherein the dry granulation is conducted in a plurality of production cycles, wherein the method further comprises (iii) performing a first cleaning cycle of disassembling, cleaning and reassembling the roller compactor to clean and remove accumulated product from the exit slide below the granulator 216, (iv) performing a second cleaning cycle of disassembling, cleaning and reassembling the roller compactor to clean and remove accumulated product from the exit slide and the roller rims 213, wherein one of the cleaning cycles are conducted after each production cycle within the plurality of production cycles, and wherein the first cleaning cycle is conducted at a higher frequency than the second cleaning cycle.
In an embodiment of the present disclosure, the powder, granules and intermediate products are characterized by poor flowability due to cohesive forces, or electrostatic charging. The poor flowability can be observed as a tendency to build-up below the granulator and the sieve insert, below the pair of rollers 212, and/or on the roller rims 213.
The poor flowability can be measured as a production stop due to a product build-up below the granulator before the completion of a production cycle without cleaning below the granulator of a period longer than 1 minute to 120 minutes, or preferably longer than 6 minutes, and/or as a production stop due to a product build-up on the roller rims 213 before the completion of a production cycle without cleaning of the roller rims of a period longer than 1 minute to 120 minutes, or preferably longer than 30 minutes.
Continuous Roller Compaction of SNAC Granules
In order to be able to produce granules comprising SNAC in an efficient manner the present disclosure provides a roller compactor adapted for extending the continuous run time of the roller compactor and/or reducing the number of cleaning cycles, when compared to a production under similar conditions using an unmodified or conventional roller compactor. By continuous production is hereby meant continuous in the sense that the production is not stopped due to the necessity of cleaning the roller compactor.
In an embodiment of the present disclosure the problem of product build-up or accumulation in the exit slide below the sieve insert and on the slides below the pressing rollers 212, is addressed, by providing an agitator for the roller compactor 200, wherein the agitator is adapted for agitating product tending to accumulate or build-up below the sieve insert 218. The agitator can be in the form of an air blowing insert 270, as described later, a vibrating plate agitating the granules and utilizing vibrational energy and gravity to lead the agitated granules toward the outlet 202, mechanical brushes or scrapers agitating the product on the slides 215a.2 by brushing or scraping. As accumulation on the slides below the sieve and the granulator is prevented, so is the upstream accumulation on the slides 215a.1 below the pressing rollers 212.
For an embodiment of the present disclosure, is provided a roller compactor 200 for production of granules by continuous dry granulation of powders, wherein the roller compactor comprises: a flow channel for conveying a product from an inlet 201 to an outlet 202 through a pressing space 214, wherein the product can be in the form of powder, ribbons or granules. The roller compactor 200 further comprises: a housing 210, a pair of rollers 212 for forming the pressing space 214 enclosed by the housing 210, wherein the pair of pressing rollers 212 comprises two pressing rollers 212a, 212b, and wherein the first pressing roller 212a comprises roller rims 213. The roller compactor 200 further comprises: a granulator 216 arranged in the housing 210 downstream to the pair of pressing rollers 212, and a sieve insert 218 mounted in the housing 210 adjacent and downstream to the granulator 216. The roller compactor 200 further comprises an agitator adapted for agitating product tending to accumulate or build-up at the exit slides 215.2 below the sieve insert 218, and thereby lead the agitated product toward the outlet 202.
Additionally, in an embodiment of the present disclosure the problem of product build-up is addressed by also providing a roller rim stripper 250 for the roller compactor 200, wherein the roller rim stripper 250 is adapted for stripping off product tending to accumulate or build-up on the roller rim 213.
In an embodiment of the present disclosure is provided a method of producing SNAC granules according to the present disclosure, the method comprises: (i) providing a powder comprising SNAC, (ii) dry granulating the powder by using a roller compactor, comprising a pair of pressing rollers 212 with roller rims 213, a granulator 216 and a sieve 218, and an outlet below the sieve 218, wherein the roller compactor further comprises an agitator adapted for agitating product tending to accumulate or build-up below the sieve insert 218 (iii) continuously during dry granulation, agitating and guiding product towards the outlet.
In an embodiment of the present disclosure, the powder, granules and intermediate products are characterized by poor flowability due to cohesive forces, or electrostatic charging. The poor flowability can be observed as a tendency to build-up below the granulator and the sieve insert and below the pair of rollers 212. The poor flowability can be measured as production stop, in a reference roller compactor without the agitator, due to a product build-up below the granulator and sieve insert before the completion of a production cycle without cleaning below the granulator of a period longer than a time within the interval 1 minute to 120 minutes, or preferably longer than 6 minutes.
For the purpose of comparison, the reference roller compactor is defined as a roller compactor wherein all the mechanical parts, with the exception of the agitator, are identical to the embodiment according to the present disclosure. In other words, the embodiment according to the disclosure is the reference roller compactor with the agitator inserted.
Alternatively, in an embodiment of the present disclosure is provided a method of producing SNAC granules according to the present disclosure, the method comprises: (i) providing a powder comprising SNAC, (ii) dry granulating the powder by using a roller compactor, comprising a pair of pressing rollers 212 with roller rims 213, a granulator 216, a sieve 218, an exit slide below the sieve 218 and an agitator adapted to agitate granules at the exit slide.
In an alternative embodiment of the present disclosure the problem of product build-up or accumulation on the roller rims, is addressed, by providing a roller rim stripper for the roller compactor 200, wherein the roller rim stripper is adapted for stripping off product tending to accumulate or build-up on the roller rims and thereby avoid the slowing down of the roller rims and the pressing rollers during production.
For an embodiment of the present disclosure, the roller compactor comprises a flow channel for conveying a product from an inlet 201 to an outlet 202 through a pressing space 214, the roller compactor further comprises a channel insert unit 240 comprising side walls 243 adapted to be inserted upstream and adjacent to the pair of rollers 212 and for interfacing with the first pressing roller 212a, wherein the channel insert unit 240 is adapted to provide a channel portion 248 from an inlet to the pressing space 214 between the pair of rollers 212, each of the side walls comprises a first lower curved surface 243a.1, 243b.1 adapted to interface with the roller rims 213, wherein a clearance is provided between the side walls and the roller rims 213, and wherein the clearance is adapted to minimize friction upon rotation of the roller rims 213 but also to restrict powder from escaping the intended flow path through the pressing space 214 during the dry granulation, and wherein, in response to product build up on the roller rims 213 friction will be generated and cause the rotational speed to slow down, wherein the roller compactor further comprises a roller rim stripper adapted for stripping off product tending to accumulate or build-up on the roller rims and thereby avoid the slowing down of the roller rims and the pressing rollers during production.
In some embodiments, the side walls are flexibly arranged to be movable in a direction away from the pressing roller. In such an embodiment the side walls are adapted to be biased towards the position adjacent to the pressing roller, and thereby provide a biasing force. In this position the small clearance between side wall and roller rims is provided. In response to the side wall being forced away from the pressing roller the biasing force will counteract.
In some embodiments, the roller rim stripper is formed as a scraper adapted for lifting adhered product off the roller rim. In some embodiments a scraper comprises an inclined surface adapted for lifting off adhered product.
In some embodiments, the roller rim stripper is formed as a blocking element adapted for blocking adhered product off the roller rim. In some embodiments a blocking element comprises a blocking surface with a blocking edge, wherein the blocking surface defines a plane normal to a tangent of the roller rim, at the position closest to the blocking edge. Before production a clearance is provided between the blocking edge and the roller rim.
In some embodiment, the roller rim strippers are positioned relative to the roller rims to strip off product from a lower portion of the roller rims, wherein the relative positioning at the lower portion of the roller rims ensure that stripped off product, will be forced away from the roller rims by gravity. Hereby, the direction of gravity defines the lower portion relative to the upper portion. The lower portion defines the 50% by mass that are positioned lower to the upper portion in the direction of gravity.
Alternatively, in an embodiment of the present disclosure is provided a method of producing SNAC granules according to the present disclosure, the method comprises: (i) providing a powder comprising SNAC, (ii) dry granulating the powder by using a roller compactor comprising a flow channel for conveying a product from an inlet 201 to an outlet 202 through a pressing space 214, a channel insert unit 240 comprising side walls 243 adapted to be inserted upstream and adjacent to the pair of rollers 212 and for interfacing with the first pressing roller 212a, wherein the channel insert unit 240 is adapted to provide a channel portion 248 from an inlet to the pressing space 214 between the pair of rollers 212, each of the side walls comprises a first lower curved surface 243a.1, 243b.1 adapted to interface with the roller rims 213, wherein a clearance is provided between the side walls and the roller rims 213, and wherein the clearance is adapted to minimize friction upon rotation of the roller rims 213 but also to restrict powder from escaping the intended flow path through the pressing space 214 during the dry granulation, and wherein, in response to product build up on the roller rims 213 friction will be generated and cause the rotational speed to slow down, wherein the roller compactor further comprises a roller rim stripper adapted for stripping off product tending to accumulate or build-up on the roller rims and thereby avoid the slowing down of the roller rims and the pressing rollers during production, wherein the method further comprises (iii) continuously during dry granulation, stripping accumulated product of the roller rims 213.
In an embodiment, the powder, granules and intermediate products are characterized by poor flowability due to cohesive forces, or electrostatic charging. The poor flowability can be observed as a tendency to build-up below the granulator and the sieve insert, below the roller rims 213. The poor flowability can be measured as a production stop due to a production stop due to a product build-up on the roller rims 213, in a reference roller compactor without roller rim strippers, before the completion of a production cycle without cleaning of the roller rims of a period longer than 1 minute to 120 minutes, or preferably longer than 30 minutes.
For the purpose of comparison, the reference roller compactor is defined as a roller compactor wherein all the mechanical parts, with the exception of the roller rim strippers, are identical to the embodiment according to the present disclosure. In other words, the embodiment according to the disclosure is the reference roller compactor with the roller rim stripper inserted.
In an alternative embodiment of the present disclosure the problem of product build-up or accumulation in the exit slide below the sieve insert, on the slides below the pressing rollers 212 and accumulation on the roller rims, is addressed, by providing an agitator 270 for the roller compactor 200 and a roller rim stripper 250, wherein the agitator is adapted for agitating product tending to accumulate or build-up on the exit slide below the sieve insert 218. As accumulation on the slides below the sieve and the granulator is prevented, so is the upstream accumulation on the slides 215a.1 below the pressing rollers 212. The roller rim stripper is adapted for stripping off product tending to accumulate or build-up on the roller rims and thereby avoid the slowing down of the roller rims and the pressing rollers during production. Using an agitator will minimize the tendency of product to accumulate on the roller rims, but over long production cycles a significant amount may accumulate and slow down the roller rims and thereby the pressing rollers.
In some embodiments, the agitator can be in the form of an air blowing insert 270, as described later, a vibrating plate agitating the granules and utilizing vibrational energy and gravity to lead the agitated granules toward the outlet 202, mechanical brushes or scrapers agitating the product on the slides 215a.2 by brushing or scraping.
In an embodiment of the present disclosure is provided a method of producing SNAC granules according to the present disclosure, the method comprises: (i) providing a powder comprising SNAC, (ii) dry granulating the powder by using a roller compactor, comprising a pair of pressing rollers 212 with roller rims 213, a granulator 216, a sieve 218, and exit slides below the sieve 218, wherein the roller compactor further comprises an agitator adapted for agitating product tending to accumulate or build-up below the sieve insert 218, and a roller rim stripper adapted for stripping off product tending to accumulate or build-up on the roller rim 213 (iii) continuously during dry granulation, agitating and guiding product on the exit slides towards an outlet, and stripping off accumulated product from the roller rim 213.
In some embodiment of the present disclosure, the powder, granules and intermediate products are characterized by poor flowability due to cohesive forces, or electrostatic charging. The poor flowability can be observed as a tendency to build-up below the granulator and the sieve insert, below the pair of rollers 212, and/or on the roller rims 213. The poor flowability can be measured as a production stop due to a product build-up below the granulator, in a reference roller compactor without an agitator and the roller rim strippers, before the completion of a production cycle without cleaning below the granulator of a period longer than 1 minute to 120 minutes, or preferably longer than 6 minutes, and/or as a production stop due to a product build-up on the roller rims 213, in a reference roller compactor without the agitator and the roller rim strippers, before the completion of a production cycle without cleaning of the roller rims of a period longer than 1 minute to 120 minutes, or preferably longer than 30 minutes.
For the purpose of comparison, the reference roller compactor is defined as a roller compactor wherein all the mechanical parts, with the exception of the agitator and the roller rim strippers, are identical to the embodiment according to the present disclosure. In other words, the embodiment according to the disclosure is the reference roller compactor with the agitator and the roller rim stripper inserted, as illustrated in
In some embodiments according to the present disclosure, the slides 215a.2 below the sieve comprises an inclined surface with respect to the direction of gravity, and in some embodiments the problem of accumulation on the slides can be addressed by increasing the inclination.
In some embodiments according to the present disclosure, the slides215a.1 below the pressing rollers comprises an inclined surface with respect to the direction of gravity, and in some embodiments the problem of accumulation on the slides can be addressed by increasing the inclination.
First List of Embodiments—Roller Compactor Comprising Agitator and Method of using the Roller Compactor
1. A roller compactor 200 for production of granules by continuous dry granulation of ingredients and/or excipients, wherein the roller compactor comprises: a flow channel for conveying a material from an inlet 201 to an outlet 202 through a pressing space 214, wherein the material comprises the ingredients and/or the excipients, wherein the material can be in different physical forms comprising the form of powder, particles and the form of granules;
2. A roller compactor according to embodiment 1, wherein the agitator 270 is an air blowing insert 270 agitating the material and utilizing the air blow and gravity to lead the agitated material towards the outlet.
3. A roller compactor according to embodiment 1, wherein the agitator 270 is a vibrating plate agitating the granules and utilizing vibrational energy and gravity to lead the agitated material toward the outlet 202.
4. A roller compactor according to embodiment 1, wherein the agitator 270 is an automatically movable mechanical brush, scraper or swiping arm agitating the granules and utilizing the automatic movement and gravity to lead the agitated material toward the outlet 202.
5. A roller compactor according to any of the previous embodiments, wherein the agitator is adapted to counteract an accumulation of material at the exit slide below the sieve and the granulator, and thereby counteract the upstream accumulation at the slides below the pressing rollers 212.
6. A roller compactor according to any of the previous embodiments, wherein the material is characterized by poor flowability due to cohesive forces, or electrostatic charging.
7. A roller compactor according to embodiment 6, wherein the poor flowability can be observed as a tendency to accumulate at the exit slides below the granulator and the sieve insert and below the pair of rollers 212.
8. A roller compactor according to any of embodiments 6-7, wherein the poor flowability is defined as a production stop, in a reference roller compactor without the agitator, due to a material accumulation at the exit slides below the granulator and sieve insert before the completion of a production cycle without cleaning the slides below the granulator or without agitation of the granules below the granulator of a period longer than a time within the interval 1 minute to 120 minutes, or preferably longer than 6 minutes.
9. A roller compactor according to embodiment 8, wherein, for the purpose of defining poor flowability, the reference roller compactor is defined as a roller compactor wherein the mechanical parts, with the exception of the agitator, are identical to the mechanical parts of the embodiment according the present disclosure.
10. A roller compactor according to any of the previous embodiments for ensuring consistent quality of the granules by counteracting accumulation of material in the roller compactor.
11. A roller compactor according to any of the previous embodiments for ensuring consistent quality of the granules by extending the period of a continuous production cycle, without interruption by cleaning cycles.
12. A roller compactor according to any of the previous embodiments for enhancing the yield of the dry granulation process by counteracting accumulation of material in the roller compactor.
13. A roller compactor according to any of the previous embodiments for enhancing the dry granulation process by extending the period of a continuous production cycle, without interruption by cleaning cycles.
14. A roller compactor according to any of the previous embodiments for dry granulation of a powder comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
15. A roller compactor according to any of the previous embodiments for production of granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
16. A roller compactor according to any of the previous embodiments, wherein the compactor is adapted for forming the powder into ribbons, and for forming the ribbons into the granules, and wherein the ingredients and/or excipients further composes the ribbons.
17. A continuous method of producing granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid according to the present disclosure, the method comprises:
18. A method according to embodiment 17, wherein the agitator 270 is an air blowing insert 270 agitating the material and utilizing the streaming air and gravity to lead the agitated product towards the outlet, whereby the agitating in step (iii) is provided by blowing a stream of air or gas towards a surface below the sieve insert.
19. A method according to embodiment 17, wherein the agitator 270 is a vibrating plate agitating the granules and utilizing vibrational energy and gravity to lead the agitated material towards the outlet 202, whereby the agitating in step (iii) is provided by vibrating a plate and thereby vibrating a surface below the sieve insert.
20. A method according to any of the embodiments 17-19, wherein the agitator is adapted to counteract accumulation of material below the sieve and the granulator, and thereby counteract the upstream accumulation of material below the pressing rollers 212, wherein the agitation in step (iii) comprises counteracting the accumulation of material at the exit slides below the sieve insert, and thereby counteracting accumulation of product below the rollers 212.
21. A method according to any of the embodiments 17-20, wherein the method comprises ensuring consistent quality of the granules by counteracting accumulation of powder in the roller compactor.
22. A method according to any of the embodiments 17-21, wherein the method comprises ensuring consistent quality of the granules by extending the period of a continuous production cycle, without interruption by cleaning cycles.
23. A method according to any of the embodiments 17-22, wherein the method comprises enhancing the yield of the dry granulation process by counteracting accumulation of powder in the roller compactor.
24. A method according to any of the embodiments 17-23, wherein the method comprises enhancing the dry granulation process by extending the period of a continuous production cycle, without interruption by cleaning cycles.
25. A method according to any of the claims 17-24, wherein the production of granules by continuous dry granulation is continued for a time period longer than a time within the interval 1 minute to 120 minutes, or preferably longer than 6 minutes.
26. A method according to any of the embodiments 17-25, wherein the roller compactor further comprises a roller rim stripper 250 adapted for stripping off material tending to accumulate on the roller rims 213, and wherein the method further comprises (iV) continuously during dry granulation, stripping off accumulated product of the roller rims 213 and leading the stripped off product towards the outlet 202.
27. A method according to any of the claims 17-26, wherein the powder is formed into ribbons, and wherein the ribbons are formed into the granules, and wherein the material comprises the form of ribbons.
Second List of Embodiments—Roller Compactor Comprising Roller Rim Strippers and Method of using the Roller Compactor
1. A roller compactor 200 for production of ribbons, wherein the roller compactor comprises: an inlet 201 and an outlet 202, a pair of pressing rollers 212 comprising a first 212a and a second pressing roller 212b, and wherein the first pressing roller (212a) comprises roller rims (213), wherein the roller compactor further comprises: roller rim strippers (250).
2. A roller compactor 200 according to embodiment 1 for production of ribbons by continuous compaction of ingredients and/or excipients, wherein the roller compactor comprises: a flow channel for conveying a material from an inlet 201 to an outlet 202 through a pressing space 214, wherein the material comprises the ingredients and/or the excipients, wherein the material can be in different physical forms comprising the form of powder, particles and the form of granules;
3. A roller compactor according to any of embodiment 1 or 2 further comprising a channel insert unit (240) adapted to interface the roller rims 213 and provide a clearance between the channel insert unit and the roller rims 213.
4. A roller compactor according to any of embodiment 1, 2 or 3 for production of granules, wherein the roller compactor 200 further comprises: a granulator 216 arranged in the housing 210 downstream to the pair of pressing rollers 212, and a sieve insert 218 mounted in the housing 210 adjacent and downstream to the granulator 216.
5. A roller compactor according to any of the embodiment 3 or 4, wherein the channel insert unit 240 comprises side walls adapted to be inserted upstream and adjacent to the pair of rollers 212 and for interfacing with the first pressing roller 212a, wherein the channel insert unit 240 is adapted to provide a channel portion 248 from the inlet to the pressing space 214 between the pair of rollers 212, and wherein the side walls are adapted to interface the roller rims 213 and provide the clearance between the channel unit insert and the roller rims.
6. A roller compactor according to any of the embodiments 3-5, wherein the channel insert unit 240 further comprises a first lower curved surface 243.1 adapted to interface the roller rims 213 and provide the clearance.
7. A roller compactor according to any of the embodiments 3-6, wherein the clearance is adapted to minimize friction upon rotation of the roller rims 213 but also to restrict powder from escaping the intended flow path through the pressing space 214 during the dry granulation.
8. A roller compactor according to any of the embodiments 3-7, wherein absent roller rim strippers the rotational speed of the rollers will slow down due to material accumulating on the roller rims when a threshold layer of accumulated material is reached.
9. A roller compactor according to any of the embodiments 3-7, wherein the roller rims and the channel insert unit are adapted to create friction, in response to formation of a material layer due to material accumulation on the roller rims 213, wherein the material layer exceeds a threshold, whereby rotational speed of the rollers will slow down.
10. A roller compactor according to any of the embodiments 8 or 9, wherein the roller rim strippers are adapted to ensure that the material layer is prevented in exceeding the threshold.
11. A roller compactor according to any of the previous embodiments, wherein the roller compactor further comprises a roller scraper 230 with a scraper edge 232.
12. A roller compactor according to any of the previous embodiments 1-10, wherein the roller compactor further comprises a roller scraper 230 with an edge 232 adapted to avoid double pressing of the material.
13. A roller compactor according to any of the previous embodiments, wherein the roller rim stripper 250 comprises a stripping edge 255.
14. A roller compactor according to embodiment 13, wherein the stripping edge 255 forms an acute angel to a tangent of the roller rim.
15. A roller compactor according to any of the previous embodiments, wherein adhered material is removed at the stripping edge 255 and guided to the outlet
16. A roller compactor according to any of the previous embodiments, wherein the stripping edge 255 is less than 180 degrees apart from the pressing space on the roller rim circumference in the direction of rotation.
17. A roller compactor according to any of the previous embodiments, wherein the roller scraper edge 232 and the stripping edge 255 are within 45 degrees on the circumference of the pressing roller/roller rim.
18. A roller compactor according to any of the previous embodiments, wherein the roller scraper edge 232 and stripping edge 255 are both less than 90 degrees away from the pressing space on the circumference of the pressing roller/roller rim in the direction of rotation.
19. A roller compactor according to any of the previous embodiments, wherein the roller scraper and the rim stripper are integrated in a single unit.
20. A roller compactor according to any of the previous embodiments 1-18, wherein the roller scraper and the rim stripper are separate units.
21. A roller compactor according to any of the previous embodiments, wherein the roller rim strippers 250 extend over more than 90 degrees of the circumferential of the roller rims 213.
22. A roller compactor according to any of the previous embodiments, wherein the roller rims comprise two roller rims and the roller rim strippers comprise two roller rim strippers 250, such as a front roller rim stripper 250a and a rear roller rim stripper 250b.
23. A roller compactor according to any of the previous embodiments, wherein the material is characterized by poor flowability due to cohesive forces, or electrostatic charging.
24. A roller compactor according to embodiment 23, wherein the poor flowability can be observed as a tendency to accumulate on the roller rim 213.
25. A roller compactor according to any of the embodiments 23-24, wherein the poor flowability can be defined as a production stop, in a reference roller compactor without the roller rim strippers, due to a material accumulate on the roller rims 213 before the completion of a production cycle without cleaning or stripping of the roller rims of a period longer than a time within the interval 1 minute to 120 minutes, or preferably longer than 30minutes.
26. A roller compactor according to embodiment 25, wherein, for the purpose of defining poor flowability, the reference roller compactor is defined as a roller compactor wherein essentially all the mechanical parts, with the exception of the roller rim strippers, are identical to the embodiment according the present disclosure.
27. A roller compactor according to any of the previous embodiments for ensuring consistent quality of the granules by counteracting accumulation of material in the roller compactor, and thereby ensure that the rotational speed of the first roller 212a is not reduced.
28. A roller compactor according to any of the previous embodiments for enhancing the yield of the dry granulation process by counteracting accumulation of material in the roller compactor.
29. A roller compactor according to any of the previous embodiments, for enhancing the yield of the dry granulation process by extending the period of a continuous production cycle, without interruption by cleaning cycles, such as by extending the period of a continuous production cycle to a time period longer than 1 minute , such as longer than 5 minutes and preferably longer than 30 minutes.
30. A roller compactor according to any of the previous embodiments, for dry granulation of a powder comprising a salt of N-(8-(2-hydroxybenzoyl)am2ino)caprylic acid.
31. A roller compactor according to any of the previous embodiments for production of ribbons comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
32. A roller compactor according to any of the previous embodiments, wherein the compactor is adapted for forming the powder into ribbons, and wherein the ingredients and/or excipients further composes the ribbons.
33. The roller compactor according to any of the previous embodiments 1-32, wherein the roller compactor further comprises an agitator (270) adapted for agitating material tending to accumulate below the sieve (218).
34. The roller compactor according to embodiments 50, wherein the roller compactor is further characterized by the embodiments 1-24 here below.
35. A method of producing ribbons comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, wherein the method comprises:
36. A method of producing ribbons comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid according to embodiment 31, wherein the method comprises:
37. A continuous method of producing ribbons comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid according embodiments 31 or 32, wherein the method comprises:
38. A method according to the any of the embodiments 34-37, wherein the method comprises enhancing the yield by counteracting accumulation of powder in the roller compactor.
39. A method according to any of the embodiments 34-38, wherein the method comprises enhancing the yield by extending the period of a continuous production cycle, without interruption by cleaning cycles.
40. A method according to any of the previous embodiments 35-39, for compaction of a powder comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
41. A method according to any of the embodiments 35-40, for production of ribbons comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
42. A method according to any of the embodiments 35-41, wherein the production of ribbons by continuous compaction is continued for a time period longer than a time within the interval 1 minute to 120 minutes, or preferably longer than 30 minutes.
43. A method according to any of the embodiments 35-42, wherein the powder is characterized by poor flowability due to cohesive forces, or electrostatic charging.
44. A method according to any of the embodiments 35-43, wherein the poor flowability can be observed as a tendency to accumulate on the roller rim 213.
45. A method according to any of the embodiments 35-44, wherein the poor flowability can be defined as a production stop, in a reference roller compactor without the roller rim strippers, due to a material accumulate on the roller rims 213 before the completion of a production cycle without cleaning or stripping of the roller rims of a period longer than a time within the interval 1 minute to 120 minutes, or preferably longer than 30 minutes.
46. A method according to any of the embodiments 35-45, wherein, for the purpose of defining poor flowability, the reference roller compactor is defined as a roller compactor wherein essentially all the mechanical parts, with the exception of the roller rim strippers, are identical to the embodiment according the present disclosure.
47. A method according to any of the embodiments 35-46, wherein the method is a method for dry granulation.
48. A method according to any of the embodiments 35-47, wherein the method is a method for producing granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid;
49. A method according to any of the embodiments 35-48, wherein the method comprises a step of obtaining granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
50. A method according to any of the embodiments 35-49, wherein the method comprises a step of obtaining granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
51. A method according to any of the previous embodiments 35-50, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is the sodium salt sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC).
Third List of Embodiments—Roller Compactor Comprising Agitator and Roller Rim Strippers and Method of using the Roller Compactor
1. A roller compactor 200 for production of granules by continuous dry granulation of ingredients and/or excipients, wherein the roller compactor comprises: a flow channel for conveying a material from an inlet 201 to an outlet 202 through a pressing space 214, wherein the material comprises the ingredients and/or the excipients, wherein the material can be in different physical forms comprising the form of powder, particles and the form of granules;
2. A roller compactor according to embodiment 1 further comprising a channel insert unit adapted to interface the roller rims 213 and provide a clearance between the channel insert unit and the roller rims 213.
3. A roller compactor according to any of embodiment 1 or 2, wherein the agitator 270 is an air blowing insert 270 agitating the product and utilizing the air blow and gravity to lead the agitated product towards the outlet.
4. A roller compactor according to any of embodiment 1 or 2, wherein the agitator 270 is a vibrating plate agitating the granules and utilizing vibrational energy and gravity to lead the agitated product toward the outlet 202.
5. A roller compactor according to any of embodiment 1 or 2, wherein the agitator 270 is an automatically movable mechanical brush, scraper or swiping arm agitating the granules and utilizing the automatic movement and gravity to lead the agitated product toward the outlet 202.
6. A roller compactor according to any of the previous embodiments, wherein the agitator is adapted to counteract an accumulation of material below the sieve and the granulator, and thereby counteract the upstream accumulation below the pressing rollers 212.
7. A roller compactor according to any of embodiments 2-6, wherein the channel insert unit 240 comprises side walls 243 adapted to be inserted upstream and adjacent to the pair of rollers 212 and for interfacing with the first pressing roller 212a, wherein the channel insert unit 240 is adapted to provide a channel portion 248 from the inlet to the pressing space 214 between the pair of rollers 212, and wherein the side walls are adapted to interface the roller rims 213 and provide a clearance between the side walls and the roller rims.
8. A roller compactor according to any of the embodiments 2-7, wherein the channel insert unit 240 further comprises a first lower curved surface 243.1 adapted to interface the roller rims 213 and provide the clearance.
9. A roller compactor according to any the embodiments 2-8, wherein the clearance is adapted to minimize friction upon rotation of the roller rims 213 but also to restrict powder from escaping the intended flow path through the pressing space 214 during the dry granulation.
10. A roller compactor according to any of the embodiments 2-9, wherein the roller rims and the channel insert unit are adapted to create friction, in response to formation of a material layer due to material accumulation on the roller rims 213, wherein the material layer exceeds a threshold, whereby rotational speed of the rollers will slow down.
11. A roller compactor according to any of the previous embodiments, wherein the roller rim strippers are adapted to ensure that the material layer is prevented in exceeding the threshold.
12. A roller compactor according to any of the embodiments, wherein the roller rims comprise two roller rims and the roller rim strippers comprise two roller rim strippers 250.
13. A roller compactor according to any of the previous embodiments, wherein the roller compactor further comprises a roller scraper 230 with an edge 232 and adapted to avoid double pressing of products.
14. A roller compactor according to any of the previous embodiments, wherein the material is characterized by poor flowability due to cohesive forces, or electrostatic charging.
15. A roller compactor according to embodiment 14, wherein the poor flowability can be observed as a tendency to accumulate below the granulator and the sieve insert and below the pair of rollers 212.
16. A roller compactor according to any of the embodiments 14-15, wherein the poor flowability is defined as a production stop, in a reference roller compactor without the agitator and the roller rim strippers, due to accumulation of material below the granulator and sieve insert or on the roller rims, before the completion of a production cycle without cleaning below the granulator, without agitation of the granules below the granulator or without cleaning or stripping of the roller rims, of a period longer than a time within the interval 1 minute to 120 minutes, or preferably longer than 6 minutes.
17. A roller compactor according to embodiment 15, wherein, for the purpose of defining poor flowability, the reference roller compactor is defined as a roller compactor wherein essentially all the mechanical parts, with the exception of the agitator and the roller rim strippers, are identical to the embodiment 15.
18. A roller compactor according to any of the previous embodiments for ensuring consistent quality of the granules by counteracting accumulation of material in the roller compactor.
19. A roller compactor according to any of the previous embodiments for ensuring consistent quality of the granules by extending the period of a continuous production cycle, without interruption by cleaning cycles.
20. A roller compactor according to any of the previous embodiments for enhancing the yield of the dry granulation process by counteracting accumulation of material in the roller compactor
21. A roller compactor according to any of the previous embodiments for enhancing the dry granulation process by extending the period of a continuous production cycle, without interruption by cleaning cycles.
22. A roller compactor according to any of the previous embodiments for dry granulation of a powder comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
23. A roller compactor according to any of the previous embodiments for production of granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.
24. A roller compactor according to any of the previous embodiments, wherein the compactor is adapted for forming the powder into ribbons, and for forming the ribbons into granules, and wherein the ingredients and/or excipients further composes the ribbons.
25. A continuous method of producing granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid according to the present disclosure, the method comprises:
26. A method according to embodiment 25, wherein the agitator 270 is an air blowing insert 270 agitating the material and utilizing the streaming air and gravity to lead the agitated product towards the outlet, whereby the agitating in step (iii) is provided by blowing a stream of air or gas towards a surface below the sieve insert.
27. A method according to embodiment 25, wherein the agitator 270 is a vibrating plate agitating the granules and utilizing vibrational energy and gravity to lead the agitated material towards the outlet 202, whereby the agitating in step (iii) is provided by vibrating a plate and thereby vibrating a surface below the sieve insert.
28. A method according to any of the embodiments 25-27, wherein the agitator is adapted to counteract accumulation of material below the sieve and the granulator, and thereby counteract the upstream accumulation of material below the pressing rollers 212, wherein the agitation in step (iii) comprises counteracting the accumulation of material at the exit slides below the sieve insert, and thereby counteracting accumulation of product below the rollers 212.
29. A method according to any of the embodiments 25-28, wherein the method comprises ensuring consistent quality of the granules by counteracting accumulation of powder in the roller compactor.
30. A method according to any of the embodiments 25-29, wherein the method comprises ensuring consistent quality of the granules by extending the period of a continuous production cycle, without interruption by cleaning cycles.
33. A method according to any of the embodiments 25-30, wherein the method comprises enhancing the yield of the dry granulation process by counteracting accumulation of powder in the roller compactor.
34. A method according to any of the embodiments 25-33, wherein the method comprises enhancing the dry granulation process by extending the period of a continuous production cycle, without interruption by cleaning cycles.
35. A method according to any of the claims 25-34, wherein the production of granules by continuous dry granulation is continued for a time period longer than a time within the interval 1 minute to 120 minutes, or preferably longer than 6 minutes.
36. A method according to any of the embodiments 25-35, wherein the roller compactor further comprises a roller rim stripper 250 adapted for stripping off material tending to accumulate on the roller rims 213, and wherein the method further comprises (iV) continuously during dry granulation, stripping off accumulated product of the roller rims 213 and leading the stripped off product towards the outlet 202.
37. A method according to any of the claims 25-36, wherein the powder is formed into ribbons, and wherein the ribbons are formed into the granules, and whereby the material comprises the form of ribbons.
Fourth List of Embodiments—Method Comprising Agitation
1. A continuous method of producing granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid comprising:
a) roller rim strippers 250 and/or b) an agitator 270
2. The method according to embodiment 1, wherein the roller rim strippers 250 are adapted for stripping off material tending to accumulate or build-up on the roller rims 213, and thereby lead the stripped off material towards the outlet 202.
3. The method according to embodiment 1 or 2, wherein the agitator 270 is adapted for agitating material tending to accumulate below the sieve insert 218.
4. The method according to any of the previous embodiments, wherein the method is continuous for more than 10 minutes.
5. A method of producing a solid pharmaceutical composition comprising a) producing granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid according to the method of any of the previous embodiments.
6. The method of producing a solid pharmaceutical composition according to previous embodiment 5, wherein the composition is obtained by:
b) preparing said solid pharmaceutical formulation using the granules obtained by a).
Fifth List of Embodiments—Roller Compactor Comprising Agitator or Roller Rim Strippers
1. A roller compactor (200) for production of granules by dry granulation, wherein the roller compactor comprises: an inlet (201) and an outlet (202), a pair of pressing rollers (212) comprising a first (212a) and a second pressing roller (212b), and wherein the first pressing roller (212a) comprises roller rims (213), wherein the roller compactor further comprises a granulator (216), a sieve (218), and exit slides (215.2) below the sieve (218) leading towards the outlet (202), wherein the roller compactor further comprises: a) roller rim strippers (250) and/or b) an agitator (270) adapted for agitating material tending to accumulate at the slides (215.2).
2. The roller compactor according to embodiment 1, wherein the roller rim strippers (250) are adapted for stripping off material tending to accumulate or build-up on the roller rims (213), and thereby lead the stripped off material towards the outlet (202).
3. The roller compactor according to any of embodiment 1 or 2, wherein the agitator (270) is adapted for agitating material tending to accumulate below the sieve insert (218).
4. The roller compactor according to any of the previous embodiments further comprising a channel insert unit adapted to interface the roller rims (213) and provide a clearance between the channel insert unit and the roller rims (213).
5. The roller compactor according to any of the previous embodiments, wherein the agitator (270) is an air blowing insert (270) agitating the product and utilizing the air blow and gravity to lead the agitated product towards the outlet.
6. A method of producing granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid comprising:
7. The method according to embodiment 6, wherein the roller rim strippers (250) are adapted for stripping off material tending to accumulate or build-up on the roller rims (213), and thereby lead the stripped off material towards the outlet (202).
8. The method according to any of the embodiments 6-7, wherein the agitator (270) is adapted for agitating material tending to accumulate below the sieve insert (218).
9. A method of producing a solid pharmaceutical composition comprising
10. A roller compactor (200) for production of granules by dry granulation of ingredients and/or excipients, wherein the roller compactor comprises: a flow channel for conveying a material from an inlet (201) to an outlet (202) through a pressing space (214), wherein the material comprises the ingredients and/or the excipients, wherein the material can be in different physical forms comprising the form of powder, particles and the form of granules;
11. A method of producing granules comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid according to the present disclosure, the method comprises:
12. A roller compactor (200) for production of ribbons by compaction of ingredients and/or excipients, wherein the roller compactor comprises: a flow channel for conveying a material from an inlet (201) to an outlet (202) through a pressing space (214), wherein the material comprises the ingredients and/or the excipients, wherein the material can be in different physical forms comprising the form of powder, particles and the form of granules;
13. A method of producing ribbons comprising a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid according to the present disclosure, the method comprises:
14. The roller compactor according to any of embodiments 1-5, 10 and 12, wherein the roller compactor is for continuous production of granules or ribbons for more than 10 minutes.
15. The method according to any of embodiments 6-9, 11 and 13, wherein the method is continuous for more than 10 minutes.
Sixth List of Embodiments—Method of Producing a Pharmaceutical Composition
1. A method of producing a solid pharmaceutical composition comprising
2. A method of producing a solid pharmaceutical composition according to embodiment 1, wherein the granules includes a lubricant.
3. A method of producing a solid pharmaceutical composition according to any of the previous embodiments, wherein the granules includes a lubricant, such as magnesium stearate.
4. A method of producing a solid pharmaceutical composition according to any of the previous embodiments, wherein the granules do not include a pharmaceutical active ingredient.
5. A method of producing a solid pharmaceutical composition according to any of the previous embodiments, wherein the granules are mixed with a composition comprising a pharmaceutical active ingredient before step b).
6. A method of producing a solid pharmaceutical composition according to any of the previous embodiments, wherein the granules are mixed with a composition comprising a pharmaceutical active ingredient and optionally further pharmaceutical excipients before step b).
7. A method of producing a solid pharmaceutical composition according to any of the previous embodiments, comprising the steps of
8. A method of producing a solid pharmaceutical composition according to any of the embodiments 7 and 8, wherein the composition comprising a pharmaceutical active ingredient is a second a type of granules.
9. A method of producing a solid pharmaceutical composition according to any of the previous embodiments 1-3, wherein the granules comprise a pharmaceutical active ingredient.
10. A method of producing a solid pharmaceutical composition according to embodiments 9, wherein the granules are directly compressed into said solid pharmaceutical composition.
11. A method of producing a solid pharmaceutical composition according to embodiments 9, wherein the granules are mixed with a composition comprising one or more further pharmaceutical excipient(s) before step b).
12. A method of producing a solid pharmaceutical composition according to any of the previous embodiments 9-11, comprising the steps of p1 a) blending a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, a pharmaceutical active ingredient and a lubricant, such as magnesium stearate,
13. A method of producing a solid pharmaceutical composition according to any of the previous embodiments, wherein the pharmaceutical active ingredient is a GLP-1 receptor agonist.
14. A method of producing a solid pharmaceutical composition according to any of the previous embodiments, wherein the pharmaceutical active ingredient is semaglutide.
15. A method of producing a solid pharmaceutical composition according to any of the previous embodiments, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is Sodium N-(8-(2-hydroxybenzoyl)amino)caprylate.
16. A method of producing a solid pharmaceutical composition according to any of the previous embodiments, wherein the pharmaceutical composition further comprises a filler such as microcrystalline cellulose.
17. A method of producing a solid pharmaceutical composition according to any of the previous embodiments, wherein the pharmaceutical composition further comprises a binder, such as povidone.
| Number | Date | Country | Kind |
|---|---|---|---|
| 19153436.1 | Jan 2019 | EP | regional |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2020/051696 | 1/24/2020 | WO | 00 |
