Patent Grant
11872306
The present invention relates to the pharmaceutical field, and more particularly to that of galenics.
The invention relates to oral formulations, in particular orodispersible granules and tablets, of an active ingredient with a taste and/or sensation in the mouth that are particularly unpleasant, such as trazodone.
An orodispersible tablet is a solid form which disintegrates or dissolves in the mouth, only on contact with saliva, generally in less than 60 seconds.
Orodispersible tablets represent a galenical form in full expansion, which has developed a great deal over the past few years. Indeed, orodispersible tablets have many advantages and are particularly suitable for patients who have difficulties in swallowing, for example children and the elderly. However, these populations are not the only ones to have swallowing problems or dysphagia, since approximately 30% to 50% of the population is affected by this problem. Also affected are patients who have psychiatric disorders, but also those suffering from thyroid disorders, from Parkinson's disease, from immune system deficiency diseases (AIDS) and from gastrointestinal refluxes, and also patients suffering from nausea, vomiting or motion sickness. Orodispersible tablets are also suitable for individuals who do not have easy access to water, in particular during journeys. Another advantage of said tablets is that they allow practical and discreet use.
In order to allow rapid disintegration, orodispersible tablets have a porous structure and are compressed at pressures lower than conventional tablets, the drawbacks being that they can be more fragile and difficult to handle.
A large number of methods for obtaining orodispersible tablets have been developed over the past few years. However, there are still at the current time certain characteristics which limit the industrial development of orodispersible tablets, in particular their excessive friability and their taste and sensation in the mouth, which are sometimes unpleasant.
Thus, even though orodispersible tablets remain quite a widespread form liked by patients, in particular for their practical and rapid use, a study carried out by the applicant has shown that the taste of a tablet in the mouth appears to be the most important parameter for patients and, thus, the bad taste in the mouth is one of the major causes for non-adherence to medical treatments.
In point of fact, by virtue of their nature, orodispersible tablets are intended to disintegrate in the mouth, that is to say to release the active ingredient which has a very bad taste in the mouth. It is thus essential, for the tablet to be accepted by the patient, to have sufficient taste masking.
Conventionally, the taste masking is carried out by means of coating techniques using solvents or water. However, pharmaceutical regulations are increasingly demanding with regard to the absence of traces of solvents. Furthermore, when the coating is carried out in an aqueous medium, an expensive drying step is necessary. Moreover, the amounts of coating that can be used are limited in order to ensure rapid release of the active ingredient, and they are often insufficient to obtain a taste masking of quality.
In patent applications FR 2 784 895 and EP 1 301 176, the taste masking is carried out without solvent by thermal granulation. However, this technique, which is suitable for masking the taste of ibuprofen, proves to be insufficient for masking the taste of active ingredients with a much more pronounced and unpleasant taste, such as trazodone, even if the amounts of coating are considerably increased. Moreover, it has proven to be the case that the thermal granulation technique is not suitable for using binary compositions.
It is thus important to be able to provide granules of active ingredient which has a very bad taste, such as trazodone, which exhibit satisfactory taste masking, without using solvent, without an excessive amount of taste-masking agents, and which are suitable for preparing orodispersible tablets.
Thus, one of the objectives of the invention is to obtain granules that can be used for an orodispersible tablet which has a pleasant taste in the mouth with an active ingredient of which the taste is acknowledged to be particularly bad, in particular because of its great bitterness, in particular trazodone.
The present inventors have found that this is possible by virtue of a double taste masking carried out on the active ingredient with a hot-melt compound and a thermoplastic polymer.
Thus, according to a first subject, the invention relates to granules of active ingredient, which have a double taste masking achieved with a hot-melt compound selected from waxes, hydrogenated vegetable oils, fatty acids, mono-, di- and triesters of fatty acids and of glycerol, triglycerides, glycerides, polyoxylglycerides, fatty alcohols, and mixtures thereof, and a thermoplastic polymer that is soluble at a pH less than or equal to 5.
According to a second subject, the present invention relates to a specific process for preparing the granules of the invention by carrying out two successive thermal granulation steps.
According to a third subject, the present invention relates to orodispersible tablets containing the granules of the invention.
According to its first subject, the invention relates to a granule of active ingredient which has a very bad taste, such as trazodone, which has a double taste masking.
In the present invention, the term “active ingredient” is intended to mean any molecule which has a therapeutic activity. The invention relates to active ingredients which have a very bad taste. The term “very bad taste” is intended to mean, without implied distinction, an unpleasant taste and/or sensation in the mouth. Such active ingredients are at least as unpleasant in the mouth as ibuprofen. The invention is particularly suitable for trazodone.
In the present invention, the term “trazodone” is intended to mean trazodone hydrochloride as such, in amorphous form, crystalline form, in base form, in the form of hydrates or of pharmaceutically acceptable salts.
The granules of active ingredient according to the invention have a double taste masking achieved with a hot-melt compound selected from waxes, hydrogenated vegetable oils, fatty acids, mono-, di- and triesters of fatty acids and of glycerol, triglycerides, glycerides, polyoxylglycerides, fatty alcohols, and mixtures thereof, and a thermoplastic polymer that is soluble at a pH less than or equal to 5.
In the granule with double taste masking, a first taste masking is achieved with a hot-melt compound selected from waxes, hydrogenated vegetable oils, fatty acids, mono-, di- and triesters of fatty acids and of glycerol, triglycerides, glycerides, polyoxylglycerides, fatty alcohols, and mixtures thereof, and the second taste masking is achieved with a thermoplastic polymer that is soluble at a pH less than or equal to 5.
According to one embodiment of the invention, the hot-melt compound is selected from the group consisting of waxes, hydrogenated vegetable oils, fatty acids, mono-, di- and triesters of fatty acids and of glycerol, triglycerides, glycerides, polyoxylglycerides, fatty alcohols, and mixtures thereof.
The first taste masking consists of a hot-melt compound, which is solid at ambient temperature and the melting point of which is between 35 and 150° C. This compound is selected from waxes, for example carnauba wax, candelilla wax, beeswax, paraffin wax; hydrogenated vegetable oils, for example hydrogenated cottonseed, castor or soybean oils; fatty acids, for example palmitic, stearic and behenic acids; mono-, di- and triesters of fatty acids and of glycerol, for example glycol distearate; triglycerides, for example tripalmitin and tristearin; glycerides, for example a mixture of mono-di-triglycerides; polyoxylglycerides, for example mixtures of esters of polyethylene glycol, of a glyceride fraction and of free polyethylene glycol; fatty alcohols, for example cetyl alcohol and cetearyl alcohol; and mixtures thereof.
This first taste masking is achieved by thermal granulation of the active ingredient, in particular of trazodone, with said hot-melt compound.
A second taste masking consisting of a thermoplastic polymer, that is soluble at gastric pH up to pH=5, is applied to the granules comprising the hot-melt compound.
Such a thermoplastic polymer, that is soluble at gastric pH up to pH=5, may be a cationic copolymer, in particular a copolymer based on alkyl methacrylate and on alkylamine methacrylate. By way of example, mention may be made of a cationic copolymer of methylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate, in particular that sold by the company Evonik under the trade name Eudragit® E PO. Any other Eudragit® E from the company Evonik can be selected as constituent of the second coating. This second taste masking is achieved by thermal granulation of the granules comprising the hot-melt compound with said thermoplastic compound.
Without wishing to be bound by any theory, the inventors are of the opinion that, during the thermal granulation, the particles of active ingredient are stuck in the hot-melt compound, the latter not forming a homogeneous layer around the particles of active ingredient as in a conventional coating, and then, during the second thermal granulation, these particles which have the hot-melt compound are stuck in the thermoplastic polymer, the latter not forming a homogeneous layer around the particles that have the hot-melt compound as in a conventional coating, but, entirely unexpectedly, the double masking makes it possible to efficiently mask the very unpleasant taste of the active ingredient despite the low quantitative proportion of thermoactive compound and of hot-melt compound.
In the present invention, the efficiency of the taste masking is determined using an Astree electronic tongue of set #2 for pharmaceutical applications, composed of 7 sensory sensors (ZZ, AB, GA, BB, CA, DA, JE), by comparing the values obtained for a formulation devoid of active ingredient (placebo) with the same formulation comprising the active ingredient. The data generated are processed by multidimensional statistical analysis using the AlphaSoft software in its version V14.1. They make it possible to define, for each formulation, the coordinates of a point and thus to calculate the Euclidean distance between these points. The smaller this distance, the better the taste masking will be. A sufficient taste masking is obtained for a formulation-placebo Euclidean distance of less than 300, preferably of less than 260.
The granule according to the invention with double taste masking is free of any trace of solvent. This is because the granule according to the invention is obtained by thermal granulation. It thus consists only of the active ingredient, in particular trazodone, of the hot-melt compound selected from waxes, hydrogenated vegetable oils, fatty acids, mono-, di- and triesters of fatty acids and of glycerol, triglycerides, glycerides, polyoxylglycerides, fatty alcohols, and mixtures thereof, and of a thermoplastic polymer that is soluble at a pH less than or equal to 5.
The granule of the invention is also characterized in that the hot-melt compound and the thermoplastic polymer are each applied separately and successively by means of 2 different thermal granulations.
According to one embodiment, the granule consists, for 100 parts by weight:
According to one particular embodiment, the granule according to the invention consists, for 100 parts by weight:
According to another aspect, the present invention relates to a process for producing the granules described above.
The present inventors have tried to produce granules coated by thermal granulation of a mixture of hot-melt compound and of polymer described above, but this thermal granulation has proved to be impossible (see comparative example 2).
In order to overcome this difficulty, the present inventors have developed the process according to the invention wherein two successive thermal granulation steps are carried out.
Thus, the present process for producing the granules with double taste masking comprises:
According to one particular embodiment, the process comprises:
The process according to the invention is carried out in a high-shear granulator, for example of Diosna P-VAC 10 type, which comprises two successive thermal granulation steps. Each thermal granulation step is divided up into 3 phases according to the Temperature/Power couple registered:
The setpoint parameters of the granulator which make it possible to control the power and the temperature of the mixture during the process are: the paddle speed, the lump breaker speed and the setpoint temperature of the jacket.
In the present invention, the paddle speed and the lump breaker speed are expressed in revolutions per minute (rpm).
Thus, according to the invention, the process comprises two successive thermal granulation steps:
The mean dimension D[4,3], measured by dry laser diffraction (for example on a Mastersizer 2000 equipped with the Scirocco 2000 module), of the granules finally obtained is from 50 μm to 500 μm, preferably from 100 μm to 300 μm, preferably approximately 200 μm.
The present invention also relates to orodispersible tablets containing the granules according to the invention or prepared according to the invention.
For the purposes of the present invention, an orodispersible tablet is a tablet which disintegrates or dissolves in the mouth, only on contact with saliva, without the provision of water and without being chewed, in less than 60 seconds, preferably in less than 40 seconds, and even more preferentially in less than 30 seconds, while forming a suspension that is easy to swallow.
The disintegration (or disaggregation) time in the mouth corresponds to the duration which separates, on the one hand, the moment the tablet is placed in the mouth in contact with saliva and, on the other hand, the moment the suspension resulting from the disintegration (disaggregation) of the tablet in contact with saliva is swallowed. This disintegration time corresponds to the in vivo disintegration time.
The in vitro disintegration time of the orodispersible tablets according to the invention can also be measured. This disintegration time is measured according to the European Pharmacopeia 2.9.1 on an Erweka ZT 31 instrument or any other instrument for measuring the disintegration time of tablets corresponding to European Pharmacopeia 2.9.1. The in vitro disintegration time of the tablets according to the invention is from 10 to 30 seconds.
The orodispersible tablet of the invention comprises coated granules of active ingredient, as defined above, and a mixture of compression excipients selected from the group comprising a diluent, a disintegrant, a sweetener, a humectant, a lubricant, a flavoring agent, a dye and mixtures thereof. It can also contain a binder and/or a wetting agent.
The diluent is selected from the group comprising mannitol, xylitol, sorbitol, maltitol and mixtures thereof.
The disintegrant is selected from the group comprising crospovidone, sodium croscarmellose (AcDiSol®), sodium carboxymethyl starch (Explotab®) and mixtures thereof.
The sweetener is selected from the group comprising aspartame, potassium acesulfame, sodium saccharinate, sucralose and mixtures thereof.
The humectant is selected from the group comprising silica, preferably that sold under the name Syloid® 244 FP, hydrophobic colloidal silica, preferably that sold under the name Aerosil® R 972, precipitated silica, preferably that sold under the name Aerosil® 200, and mixtures thereof.
The lubricant is selected from the group of hydrophobic lubricants, such as magnesium stearate, or hydrophilic lubricants selected from the group comprising sodium stearyl fumarate and sodium lauryl sulfate.
The flavoring agent and the dye that can go to make up the orodispersible tablets are selected from those which are pharmaceutically acceptable. They are selected according to the organoleptic characteristics desired for the orodispersible tablet, in particular according to the category of patients for whom they are intended. Examples of flavoring agents are banana flavoring, tutti-frutti flavoring, mint flavoring, strawberry flavoring, cranberry flavoring, blackcurrant flavoring, caramel flavoring, coca flavoring, chocolate flavoring. Flavorings that are particularly suitable are strawberry flavoring and chocolate flavoring.
The binder, when it is present, is selected from the group comprising hydroxypropylmethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose with a low degree of substitution, gum arabic, cornstarch, pregelatinized starch, maltodextrins and mixtures thereof.
The wetting agent, when it is present, is selected from the group comprising poloxamers, macrogols, macrogolglycerides, and polysorbates, said wetting agent preferably being the macrogolglycerides sold under the name Gelucire® 44/14.
The orodispersible tablets according to the invention can be produced by direct compression, that is to say by dry compression of the coated granules of active ingredient and of the compression excipients which are optionally pregranulated. According to another embodiment, the orodispersible tablets according to the invention can be produced by compression-molding, as described in patent application FR 2 999 432 in the name of the applicant, in which case it is possible for the mixture of excipients to also comprise a wetting agent and/or a binder.
According to one particular embodiment, the compression excipients are in the form of grains of excipients.
The grains of excipients have a median particle size of between +30% and −30%, preferably between +10% and −10%, relative to the size of the coated granules of active ingredient. Thus, the size of the grains of excipients is from 70 μm to 650 μm, preferably from 180 μm to 440 μm.
According to one embodiment of the invention, the mixture of excipients, optionally in the form of grains, comprises:
According to another embodiment of the invention, the tablet is produced by applying compression forces ranging from 1 to 20 Kn (kNewtons), and preferably from 2 to 6 kN.
By way of example, the orodispersible tablet of the invention has:
Thus, such tablets can easily be placed in the oral cavity, on the tongue where they disintegrate owing to the presence of saliva and the natural pressure exerted between the tongue and the palate when the mouth is closed again.
According to another embodiment, the tablets can comprise at least one notch which enables them to break in order to administer a smaller amount of active ingredient.
The orodispersible tablet according to the invention has a hardness ranging from 20 to 80 N, and preferably from 30 to 65 N. The method for measuring the hardness is that of European Pharmacopeia 2.9.8.
By way of indication, the orodispersible tablet of the invention has a friability ranging from 0.0% to 0.6%, and preferably from 0.1% to 0.4%. The friability is measured on an Erweka TA 10 instrument according to the method described in the European Pharmacopeia (edition 7, chapter 2.9.7.) Because of this satisfactory friability, it is possible to use conventional industrial methods for transferring and packaging the tablets which do not require particular precautions and which enable very fast execution.
The invention will be understood more clearly in the light of the nonlimiting and purely illustrative examples which follow and the figures.
In what follows, the following commercial products are used:
Step 1: Thermal Granulation Using Precirol ATO 5
The active ingredient and the Precirol ATO 5 are introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 1. Depending on the density of the mixture, the total weight introduced is adjusted by those skilled in the art to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
By way of information, the percentages given in the present invention are a weight-to-weight ratio (w/w).
According to example 1, the setpoint parameters used, namely: paddle speed, lump breaker speed and jacket setpoint temperature, are indicated in table 2.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka AR402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grille, at a speed of 10 cpm.
Step 2: Thermal Granulation by Means of Precirol ATO 5 and Eudragit E PO
The grain obtained according to step 1 above is introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 3. Depending on the density of the mixture, the total mass introduced is adjusted to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
The setpoint parameters used are indicated in Table 4.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka R402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grille, at a speed of 10 cpm.
The active ingredient, the Precirol ATO 5 and the Eudragit E PO are introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 5. Depending on the density of the mixture, the total weight introduced is adjusted by those skilled in the art to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
According to example 2, the setpoint parameters used are indicated in table 6.
The thermal granulation by means of a mixture of Precirol ATO 5 and Eudragit E PO is not technically controllable: an overgranulation at the granulation step causes a major overgranulation at cooling. The grain obtained is then in the form of a hard paste which can lead to the high-shear granulator being damaged and can make it impossible to calibrate it in yields compatible with an industrial process.
The grain produced at the end of step 1 of example 1 is used in the production of tablets containing a dose of 30 mg of trazodone hydrochloride. The mixing and then the lubrication are carried out according to the proportions indicated in table 7 by means of a cubic mixer equipped with a tank of suitable size or any other item of equipment ensuring good mixture homogeneity.
The mixture is compressed on a Fette 102i rotary press equipped with a gravity distributor and 3 sets of matrix/round punches, diameter 8 mm, and a splitting bar. The target unit weight is 200 mg and the compression force is adjusted to obtain a target hardness of 60 N.
The grain produced according to example 1 is used in the production of orodispersible tablets containing a 30 mg dose of trazodone hydrochloride. The mixing and then the lubrication are carried out according to the proportions indicated in table 8 by means of a cubic mixer equipped with a tank of suitable size or any other item of equipment ensuring good mixture homogeneity.
The mixture is compressed on a Fette 102i rotary press equipped with a gravity distributor and 3 sets of matrix/round punches, diameter 8 mm, and 1 splitting bar. The target unit weight is 200 mg and the compression force is adjusted so as to obtain a target hardness of 35N.
According to example 4, the flavoring used can be a strawberry or chocolate flavoring (flavorings supplied by Firmenich, pharmaceutical grade).
The grain produced according to example 1 is used in the production of orodispersible tablets, containing a 90 mg dose of trazodone hydrochloride. The mixing and then the lubrication are carried out according to the proportions indicated in Table 9 by means of a cubic mixer equipped with a tank of suitable size or any other item of equipment ensuring good mixture homogeneity.
The mixture is compressed on a Fette 102i rotary press equipped with a gravity distributor and 3 sets of matrix/round punches, diameter 11 mm. The target unit weight is 400 mg and the compression force is adjusted so as to obtain a target hardness of 30 N.
Step 1: Thermal Granulation by Means of Dynasan 114+Trazodone
The active ingredient and the Dynasan 114 are introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 10. Depending on the density of the mixture, the total weight introduced is adjusted by those skilled in the art to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
The setpoint parameters used, namely: the paddle speed, the lump breaker speed and the setpoint temperature of the jacket, are indicated in table 11.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka AR402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grille, at a speed of 10 cpm.
Step 2: Thermal Granulation by Means of Dynasan 114 and Eudragit E PO
The grain obtained in step 1 is introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 12. Depending on the density of the mixture, the total weight introduced is adjusted to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
The setpoint parameters used are indicated in table 13.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka AR402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grid, at a speed of 10 cpm.
The grain produced according to example 6 is used in the production of tablets containing a 60 mg dose of trazodone hydrochloride. The mixing and then the lubrication are carried out according to the proportions indicated in table 14 by means of a cubic mixer equipped with a tank of suitable size or any other item of equipment ensuring good mixture homogeneity.
The mixture is compressed on a Fette 102i rotary press equipped with a gravity distributor and 3 sets of matrix/convex round punches, diameter 10 mm, and a splitting bar. The target unit weight is 300 mg and the compression force is adjusted so as to obtain a target hardness of 22 N.
Step 1: Thermal Granulation by Means of Softisan 154+Trazodone
The active ingredient and the Softisan 154 are introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 15. Depending on the density of the mixture, the total weight introduced is adjusted by those skilled in the art to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
The setpoint parameters used, namely: the paddle speed, the lump breaker speed and the setpoint temperature of the jacket, are indicated in table 16.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka AR402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grid, at a speed of 10 cpm.
Step 2: Thermal Granulation by Means of Softisan 154 and Eudragit E PO
The grain obtained in step 1 is introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 17. Depending on the density of the mixture, the total weight introduced is adjusted to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
The setpoint parameters used are indicated in table 18.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka AR402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grid, at a speed of 10 cpm.
The grain produced according to example 8 is used in the production of tablets containing a 60 mg dose of trazodone hydrochloride. The mixing and then the lubrication are carried out according to the proportions indicated in table 19 by means of a cubic mixer equipped with a tank of suitable size or any other item of equipment ensuring good mixture homogeneity.
The mixture is compressed on a Fette 102i rotary press equipped with a gravity distributor and 3 sets of matrix/convex round punches, diameter 10 mm, and a splitting bar. The target unit weight is 300 mg and the compression force is adjusted so as to obtain a target hardness of 25 N.
Step 1: Thermal Granulation by Means of Lipoxol 3350+Trazodone
The active ingredient and the Lipoxol 3350 are introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 20. Depending on the density of the mixture, the total weight introduced is adjusted by those skilled in the art to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
The setpoint parameters used, namely: the paddle speed, the lump breaker speed and the setpoint temperature of the jacket, are indicated in table 21.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka AR402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grid, at a speed of 10 cpm.
Step 2: Thermal Granulation by Means of Lipoxol 3350 and Eudragit E PO
The grain obtained in step 1 is introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 22. Depending on the density of the mixture, the total weight introduced is adjusted to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
The setpoint parameters used are indicated in table 23.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka AR402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grid, at a speed of 10 cpm.
The grain produced according to example 10 is used in the production of tablets containing a 60 mg dose of trazodone hydrochloride. The mixing and then the lubrication are carried out according to the proportions indicated in table 24 by means of a cubic mixer equipped with a tank of suitable size or any other item of equipment ensuring good mixture homogeneity.
The mixture is compressed on a Fette 102i rotary press equipped with a gravity distributor and 3 sets of matrix/convex round punches, diameter 10 mm, and a splitting bar. The target unit weight is 300 mg and the compression force is adjusted so as to obtain a target hardness of 18 N.
Step 1: Thermal Granulation by Means of Compritol HD5 ATO+Trazodone
The active ingredient and the Compritol HD5 ATO are introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 25. Depending on the density of the mixture, the total weight introduced is adjusted by those skilled in the art to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
The setpoint parameters used, namely: the paddle speed, the lump breaker speed and the setpoint temperature of the jacket, are indicated in table 26.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka AR402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grid, at a speed of 10 cpm.
Step 2: Thermal Granulation by Means of Compritol HD5 ATO and Eudragit E PO
The grain obtained in step 1 is introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 27. Depending on the density of the mixture, the total weight introduced is adjusted to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
The setpoint parameters used are indicated in table 28.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka AR402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grid, at a speed of 10 cpm.
The grain produced according to example 12 is used in the production of tablets containing a 60 mg dose of trazodone hydrochloride. The mixing and then the lubrication are carried out according to the proportions indicated in table 29 by means of a cubic mixer equipped with a tank of suitable size or any other item of equipment ensuring good mixture homogeneity.
The mixture is compressed on a Fette 102i rotary press equipped with a gravity distributor and 3 sets of matrix/convex round punches, diameter 10 mm, and a splitting bar. The target unit weight is 300 mg and the compression force is adjusted so as to obtain a target hardness of 27 N.
Step 1: Thermal Granulation by Means of Montane 60 PHA+Bitrex
A mixture of Bitrex and of 200M lactose representing the active ingredient and also the Montane 60 PHA are introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 30. Depending on the density of the mixture, the total weight introduced is adjusted by those skilled in the art to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
The setpoint parameters used, namely: the paddle speed, the lump breaker speed and the setpoint temperature of the jacket, are indicated in table 31.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka AR402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grid, at a speed of 10 cpm.
Step 2: Thermal Granulation by Means of Montane 60 PHA and Eudragit E PO
The grain obtained in step 1 is introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 32. Depending on the density of the mixture, the total weight introduced is adjusted to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
The setpoint parameters used are indicated in table 33.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka AR402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grid, at a speed of 10 cpm.
The grain produced according to example 14 is used in the production of tablets containing a 60 mg dose of a mixture of 200M lactose and of Bitrex. The mixing and then the lubrication are carried out according to the proportions indicated in table 34 by means of a cubic mixer equipped with a tank of suitable size or any other item of equipment ensuring good mixture homogeneity.
The mixture is compressed on a Fette 102i rotary press equipped with a gravity distributor and 3 sets of matrix/convex round punches, diameter 10 mm, and a splitting bar. The target unit weight is 300 mg and the compression force is adjusted so as to obtain a target hardness of 18 N.
Step 1: Thermal Granulation by Means of Crodacol CS 50+Bitrex
A mixture of Bitrex and of 200M lactose representing the active ingredient and also the Crodacol CS 50 are introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 35. Depending on the density of the mixture, the total weight introduced is adjusted by those skilled in the art to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
The setpoint parameters used, namely: the paddle speed, the lump breaker speed and the setpoint temperature of the jacket, are indicated in table 36.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka AR402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grid, at a speed of 10 cpm.
Step 2: Thermal Granulation by Means of Crodacol CS 50 and Eudragit E PO
The grain obtained in step 1 is introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 37. Depending on the density of the mixture, the total weight introduced is adjusted to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
The setpoint parameters used are indicated in table 38.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka AR402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grid, at a speed of 10 cpm.
The grain produced according to example 16 is used in the production of tablets containing a 60 mg dose of a mixture of 200M lactose and of Bitrex. The mixing and then the lubrication are carried out according to the proportions indicated in table 39 by means of a cubic mixer equipped with a tank of suitable size or any other item of equipment ensuring a good mixture homogeneity.
The mixture is compressed on a Fette 102i rotary press equipped with a gravity distributor and 3 sets of matrix/convex round punches, diameter 10 mm, and a splitting bar. The target unit weight is 300 mg and the compression force is adjusted so as to obtain a target hardness of 19 N.
Step 1: Thermal Granulation by Means of Crodacol S 95+Bitrex
A mixture of Bitrex and of 200M lactose representing the active ingredient and also the Crodacol S 95 are introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 40. Depending on the density of the mixture, the total weight introduced is adjusted by those skilled in the art to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
The setpoint parameters used, namely: the paddle speed, the lump breaker speed and the setpoint temperature of the jacket, are indicated in table 41.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka AR402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grid, at a speed of 10 cpm.
Step 2: Thermal Granulation by Means of Crodacol S 95 and Eudragit E PO
The grain in step 1 is introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 42. Depending on the density of the mixture, the total weight introduced is adjusted to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
The setpoint parameters used are indicated in table 43.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka AR402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grid, at a speed of 10 cpm.
The grain produced according to example 18 is used in the production of tablets containing a 60 mg dose of a mixture of 200M lactose and of Bitrex. The mixing and then the lubrication are carried out according to the proportions indicated in table 44 by means of a cubic mixer equipped with a tank of suitable size or any other item of equipment ensuring a good mixture homogeneity.
The mixture is compressed on a Fette 102i rotary press equipped with a gravity distributor and 3 sets of matrix/convex round punches, diameter 10 mm, and a splitting bar. The target unit weight is 300 mg and the compression force is adjusted so as to obtain a target hardness of 16 N.
Step 1: Thermal Granulation by Means of Crodacol C 95+Bitrex
A mixture of Bitrex and of 200M lactose representing the active ingredient and also the Crodacol C 95 are introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 45. Depending on the density of the mixture, the total weight introduced is adjusted by those skilled in the art to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
The setpoint parameters used, namely: the paddle speed, the lump breaker speed and the setpoint temperature of the jacket, are indicated in table 46.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka AR402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grid, at a speed of 10 cpm.
Step 2: Thermal Granulation by Means of Crodacol C 95 and Eudragit E PO
The grain obtained in step 1 is introduced into a high-shear granulator of Diosna P-VAC10 type in the proportions indicated in table 47. Depending on the density of the mixture, the total weight introduced is adjusted to the filling volume of the tank of the granulator so as to guarantee homogenization thereof throughout the thermal granulation process (ideally ⅔ of the volume).
The setpoint parameters used are indicated in table 48.
Once it has returned to ambient temperature, the grain obtained is discharged and calibrated by means of an Erweka AR402 drive unit equipped with an FGS-type oscillating calibrator on a 500 μm grid, at a speed of 10 cpm.
The grain produced according to example 20 is used in the production of tablets containing a 60 mg dose of a mixture of 200M lactose and of Bitrex. The mixing and then the lubrication are carried out according to the proportions indicated in table 49 by means of a cubic mixer equipped with a tank of suitable size or any other item of equipment ensuring a good mixture homogeneity.
The mixture is compressed on a Fette 102i rotary press equipped with a gravity distributor and 3 sets of matrix/convex round punches, diameter 10 mm, and a splitting bar. The target unit weight is 300 mg and the compression force is adjusted so as to obtain a target hardness of 14 N.
The active ingredient is used in the production of tablets containing a 30 mg dose of trazodone hydrochloride. The mixing and then the lubrication are carried out according to the proportions indicated in table 50 by means of a cubic mixer equipped with a tank of suitable size or any other item of equipment ensuring good mixture homogeneity.
The mixture is compressed on a Fette 102i rotary press equipped with a gravity distributor and 3 sets of matrix/round punches, diameter 8 mm, and 1 splitting bar. The target unit weight is 200 mg and the compression force is adjusted so as to obtain a target hardness of 60 N.
Measurement of the Weight of the Tablets
The weight of the tablets is measured on a Mettler Toledo AG245 balance (precision 0.1/0.01 mg) on a representative sample of 10 tablets.
Measurement of the Hardness
The hardness is measured according to the method described in European Pharmacopeia 8.0 (chapter 2.9.8. “Resistance to crushing of tablets”).
Measurement of the Friability
The friability is measured according to the method described in European Pharmacopeia 8.0 (chapter 2.9.7. “Friability of uncoated tablets”).
Measurement of the Disintegration Time
The disintegration time is measured according to the method described in European Pharmacopeia 8.0 (chapter 2.9.1. “Friability of uncoated tablets”).
The dissolution of the trazodone hydrochloride is measured with continuous stirring after introduction of the tablets into a dissolution apparatus of type 2 described in European Pharmacopeia 8.0 (chapter 2.9.3. “Dissolution test for solid dosage forms”) equipped with paddles (stirring speed 50 rpm). The dissolution medium used consists of 500 ml of 0.01 N HCl and is maintained at a constant temperature of 37° C. (±0.5° C.) The continuous dosage of the active ingredient is measured by UV detection at λ=311 nm (10 mm cuvettes).
The results obtained for the tablets produced according to examples 5 and 6 are reported in
The taste masking is measured using an Astree electronic tongue equipped with set #2 for pharmaceutical applications, composed of 7 sensory sensors (ZZ, AB, GA, BB, CA, DA, JE).
Each tablet is dissolved in deionized water (2 tablets in 50 ml). After complete disintegration with magnetic stirring, the suspensions are filtered through paper (porosity of 10 to 20 μm). The filtered solutions are poured into 25 ml beakers and placed on a 48-position carousel autosampler for immediate analysis.
The analysis conditions are the following:
The signal measured by the electronic tongue is measured at equilibrium (obtained in 100 to 120 seconds on average) on the 7 sensors. The measurement is taken three times for each sample and the sensors are rinsed with deionized water between each measurement.
These measurements are carried out on the tablets of examples 3, 4 and 22.
Placebo tablets are prepared in the same way as the tablets of examples 3, 4 and 22, but without active ingredient. The measurement by electronic tongue is also carried out three times using these placebo tablets.
The data generated are processed by multidimensional statistical analysis using the AlphaSoft software in its version V14.1. For each tablet-placebo pair, the software calculates the Euclidean distance between the values obtained with the formulation containing the active ingredient and the values obtained with the corresponding placebo. The lower this value, the more efficient the masking of the taste of trazodone HCl. The results obtained for examples 3, 4 and 22 are reported in
| Number | Date | Country | Kind |
|---|---|---|---|
| 1460532 | Oct 2014 | FR | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/FR2015/052936 | 10/30/2015 | WO |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2016/066976 | 5/6/2016 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 20070098746 | Nichols | May 2007 | A1 |
| 20100215740 | Pilgaonkar | Aug 2010 | A1 |
| 20140302152 | Da Costa Barrocas | Oct 2014 | A1 |
| Number | Date | Country |
|---|---|---|
| 1 301 176 | Mar 2004 | EP |
| 2 784 895 | Oct 1998 | FR |
| 2784895 | Apr 2000 | FR |
| 2 850 275 | Jan 2003 | FR |
| 2 848 855 | Dec 2012 | FR |
| 2 999 432 | Dec 2012 | FR |
| 2012153665 | Aug 2012 | JP |
| WO-03059349 | Jul 2003 | WO |
| WO-2004066925 | Aug 2004 | WO |
| 2012080048 | Jun 2012 | WO |
| Entry |
|---|
| Diosna (https://servo-lift.com/granulation-equipment/high-shear-granulators/high-shear-granulator-pvac-10-60 (Year: 2019). |
| JP2012-153665_machine_translation (Year: 2012). |
| Geraldine (FR2784895; wherein a machine translation is provided) (Year: 1998). |
| Passerini et al (Melt granulation of pharmaceutical powders: A comparison of high-shear mixer and fluidised bed processes. International Journal of Pharmaceutics 391 (2010) 177-186), (Year: 2010). |
| Wikipedia (https://en.wikipedia.org/wiki/Glass_transition downloaded on Apr. 20, 2021) (Year: 2021). |
| Number | Date | Country | |
|---|---|---|---|
| 20190125663 A1 | May 2019 | US |
