OA21340A - A modified release multiple unit oral dosage form of doxylamine succinate and pyridoxine hydrochloride and a process for its preparation. - Google Patents
A modified release multiple unit oral dosage form of doxylamine succinate and pyridoxine hydrochloride and a process for its preparation. Download PDFInfo
- Publication number
- OA21340A OA21340A OA1202200381 OA21340A OA 21340 A OA21340 A OA 21340A OA 1202200381 OA1202200381 OA 1202200381 OA 21340 A OA21340 A OA 21340A
- Authority
- OA
- OAPI
- Prior art keywords
- pharmaceutically acceptable
- pellets
- optionally
- particle size
- modified release
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 211
- 239000006186 oral dosage form Substances 0.000 title claims abstract description 201
- KBAUFVUYFNWQFM-UHFFFAOYSA-N Doxylamine succinate Chemical compound OC(=O)CCC(O)=O.C=1C=CC=NC=1C(C)(OCCN(C)C)C1=CC=CC=C1 KBAUFVUYFNWQFM-UHFFFAOYSA-N 0.000 title claims description 108
- 229960005008 doxylamine succinate Drugs 0.000 title claims description 107
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 title claims description 103
- 229960004172 pyridoxine hydrochloride Drugs 0.000 title claims description 103
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 title claims description 103
- 239000011764 pyridoxine hydrochloride Substances 0.000 title claims description 103
- 238000002360 preparation method Methods 0.000 title abstract 2
- 239000008188 pellet Substances 0.000 claims abstract description 454
- 239000002245 particle Substances 0.000 claims abstract description 363
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims abstract description 312
- 239000011247 coating layer Substances 0.000 claims abstract description 199
- HCFDWZZGGLSKEP-UHFFFAOYSA-N doxylamine Chemical compound C=1C=CC=NC=1C(C)(OCCN(C)C)C1=CC=CC=C1 HCFDWZZGGLSKEP-UHFFFAOYSA-N 0.000 claims abstract description 184
- 229960005178 doxylamine Drugs 0.000 claims abstract description 183
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Abstract
The present invention relates to modified release multiple unit oral dosage form comprising: a first plurality of modified release pellets of doxylamine comprising: a pharmaceutically acceptable inert nucleus; an inner active coating layer comprising a doxylamine; optionally an intermediate enteric release coating layer; and an external modified release coating layer; and a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof comprising: a pharmaceutically acceptable inert nucleus; an inner active coating layer comprising pyridoxine or a pharmaceutically acceptable salt thereof; and an external modified release coating layer; wherein the particle size of the pharmaceutically acceptable inert nucleus of the first and the second plurality of pellets is such that at least 90% of the inert nucleus have a particle size from 300 µm to 1700 µm and a particle size variability of not more than200 µm measured by analytical sieving. It also relates to a process for its preparation and its use in therapy.
Description
A modified release multiple unit oral dosage form of doxylamine succinate and pyridoxine hydrochloride and a process for its préparation
This application daims the benefît of European Patent Application EP203 82227.5 filed March 25th, 2020.
The présent invention relates to a modified release multiple unit oral dosage form of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof and modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof, and a process for its préparation.
Background Art
Doxylamine is the International Non-proprietary Name of (R5)-AA-dimethyl-2-(l-phenyl-lpyridin-2-yl-ethoxy)-ethanamine having the CAS number 469-21-6. Doxylamine is the firstgeneration of antihistamine that competitively, reversibly and non-specifically blocks H1 receptors and is also a non-specific antagonist that can block other receptors such as central or peripheral muscarinic receptors, with marked anticholinergic activity. It is commonly used in form of a sait and particularly in form of its succinate sait (cf. European Pharmacopoeia 10.0. doxylamine hydrogen succinate monograph pp.2476-2477). The structure of doxylamine corresponds to the formula (I):
On the other hand, pyridoxine also known as vitamin EL is the International Non-proprietary Name of 4.5-Bis(hydroxymethyl)-2-methylpyridin-3-ol having the CAS number 65-23-6. Pyridoxine is a water-soluble vitamin factor whose active form is pyridoxal phosphate. It acts as an enzyme co-factor in numerous biochemical reactions involved in the digestive breakdown of proteins and amino acids and, to a lesser extent, lipids and carbohydrates. It is also involved in the metabolism of unsaturated fatty acids and it is also a coenzyme for transaminases and decarboxylases allowing the conversion of tryptophan into nicotinic acid. Pyridoxine is commonly used in form of a sait and particularly in form of its hydrochloride sait (cf. European Pharmacopoeia 10.0. pyridoxine hydrochloride monograph pp.3676-3677). The structure of pyridoxine corresponds to the formula (II):
ho—< OH /—(\ /)— HO '—N (Π)
Doxylamine is commonly used by itself as a short-term sédative and also in combination with other drugs to provide night-time allergy and cold relief. Doxylamine is also used in combination with the analgésies paracétamol (acetaminophen) and codeine as an analgesic/calmative préparation, and is prescribed in combination with pyridoxine to prevent moming sickness in prégnant women.
Modified release oral dosage forms of doxylamine succinate and pyridoxine hydrochloride with different pharmacokinetic and pharmacological properties hâve been disclosed in the State of the art.
Several dual release oral dosage forms of doxylamine succinate and pyridoxine hydrochloride and processes for their préparation hâve been disclosed in the State of the art. These dual release oral dosage forms are formed by at least one immédiate release composition and at least one modified release composition having each one of composition one or more of the active ingrédients. This dosage System allows having an immédiate release of one of the active ingrédients and a modified release of the other active ingrédients separately (cf. WO2013123569 and WO2016029290).
On the other hand, hard capsules filled with modified release pellets of doxylamine succinate and modified release pellets of pyridoxine hydrochloride are marketed with the name of Cariban (INIBSA GINECOLOGIA: “SPC Cariban lOmg/lOmg modified release capsules”, internet citation, 1 march 2016, available at the following URL address: https://inibsa.com/wpcontent/uploads/2016/10/En-spc-V 1 .pdf and retrieved on 2019-03-07)). Cariban is used for the 2 symptomatic treatment of nausea and vomiting. In fact, Cariban is indicated for the symptomatic treatment of nausea and vomiting during pregnancy (NVP) who do not respond to conservative management. In particular, the effect of doxylamine and pyridoxine begins to be noted five hours after ingestion, which is advantageous because allows a prolonged therapeutic effect and a réduction of the drug intakes. The therapeutic effect of the multiple unit dosage forms is conditioned by the dissolution profile of the active ingrédients from each one of the pellets and in tum from the inter-pellets’ homogeneity.
It is known in the State of the art that a lack of inter-pellets homogeneity can affect the dissolution profile of the active ingrédients and also compromise the dosification of these pellets in the final multiple unit oral dosage form and its uniformity.
Therefore, from what is known in the art it is derived that there is still the need of providing a modified release multiple unit oral dosage form comprising homogeneous plurality of modified release pellets of both active ingrédients doxylamine and pyridoxine, exhibiting the appropriate dissolution profile for being used in therapy.
Summary of Invention
Inventors hâve found that the multiple unit oral dosage form of the présent invention which comprises the claimed first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof; and the claimed second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof allows having a modified sustained release of both active ingrédients for at least 8 hours after administration. It is advantageous because the modified sustained release composition of the présent invention has a dual effect, one immédiate just after the administration and a prolonged release for the entire day, particularly after getting up.
Without being bound to any theory, the inventors surprisingly found that the use of pharmaceutically acceptable inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm, and that at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of not more than 200 pm allows obtaining each one of the pellets of the first and the second plurality of pellets with a determinate particle size. It implies that a high inter-pellet homogeneity of the content of the active ingrédient is maintained without compromising the target dissolution profile. It also implies that variability of the dissolution profile among different unit dosages of the multiple unit oral dosage form of the présent invention is reduced. Also, it implies that the use of the claimed pharmaceutically acceptable inert nucléus also minimize the formation of aggregates and/or powdered mixtures.
In particular, the inventors hâve surprisingly observed the above-mentioned effects by the use of pharmaceutically acceptable inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm, and that at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of not more than 150 pm, of not more than 100 pm and also of not more than 75 pm.
Furthermore, the high homogeneity of the particle size (expressed by the low particle size variability of the pharmaceutically inert nucléus) of both plurality of pellets implies that these pellets are easier to handle allowing a high uniformity in dosification and reducing the stucking of dosing machine and other problems related to the dosification (for example reducing the frequency of need to re-adjust within acceptable range the filling weight with conséquent less production interruptions). It means that the machine occupation is reduced and therefore, the cost for the préparation of the multiple unit dosage form containing them is also reduced.
As it is mentioned above, the multiple unit oral dosage form of the présent invention comprises a two plurality of pellets having a high homogeneity of the content of active ingrédient. It means that each pellet has about the same amount of active ingrédient and then, it assures that the multiple unit oral dosage form comprising those pellets always hâve the same therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, and pyridoxine or a pharmaceutically acceptable sait thereof. It means that infra- and supra dosification of active ingrédients in the multiple unit oral dosage is minimized by using the process of the présent invention.
Furthermore, inventors hâve found that the process for the préparation of the homogeneous batches of the multiple unit oral dosage of the présent invention is cheaper, more robust, reproducible and ease to scale-up in comparison with the processes of the State of the art. In fact, the process of the invention allows obtaining the homogenous batches of both plurality of pellets of both active ingrédients and the préparation of the multiple unit oral dosage form in a high yield without the need of intermediate sieving steps during the process of préparation of both pluralities of pellets to remove undesired powderish material and aggregates, reducing to a minimum level also the loss of yield in an optional final sieving step, or even being able to perform the process of préparation of both pluralities of pellets without the need of any of these additional undesirable sieving steps. Finally, the inventors hâve found that this process allows preparing the modified release coating of the both plurality of pellets of the présent invention which exhibits the target dissolution profile.
Then, the first aspect of the invention relates to a modified release multiple unit oral dosage form comprising:
a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising:
- a pharmaceutically acceptable inert nucléus;
- an inner active coating layer comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, one or more coating agents, one or more anticaking agents, optionally one or more pore-forming agent; and optionally one or more pharmaceutically acceptable excipients;
- optionally an intermediate enteric release coating layer comprising one or more enteric coating agents, one or more anticaking agents, optionally one or more pore-forming agent; and optionally one or more pharmaceutically acceptable excipients, and
- an extemal modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; and a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof comprising:
- a pharmaceutically acceptable inert nucléus;
- an inner active coating layer comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and
- an extemal modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients;
wherein:
the particle size of the pharmaceutically acceptable inert nucléus of the first and the second plurality of pellets is such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nucléus hâve a particle size variability of not more than 200 pm measured by analytical sieving; particularly of not more than 150 pm; particularly of not more than 100 pm and particularly of not more than 75 pm.
Particularly, the présent invention relates to a modified release multiple unit oral dosage form comprising:
a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising:
- a pharmaceutically acceptable inert nucléus;
- an inner active coating layer comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, one or more coating agents, one or more anticaking agents, optionally one or more pore-forming agent; and optionally one or more pharmaceutically acceptable excipients;
- an intermediate enteric release coating layer comprising one or more enteric coating agents, one or more anticaking agents, optionally one or more pore-forming agent; and optionally one or more pharmaceutically acceptable excipients, and
- an extemal modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; and a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof comprising:
- a pharmaceutically acceptable inert nucléus;
- an inner active coating layer comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and
- an extemal modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients;
wherein:
the particle size of the pharmaceutically acceptable inert nucléus of the first and the second plurality of pellets is such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nucléus hâve a particle size variability of not more than 200 pm measured by analytical sieving; particularly of not more than 150 pm; particularly of not more than 100 pm and particularly of not more than 75 pm.
The second aspect of the invention relates to a process for the préparation of the modified release multiple unit oral dosage form as defined in the first aspect of the invention comprising: (al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and optionally the intermediate enteric coating layer by adding the one or more enteric coating agents, the one or more modified release coating agents, the one or more anticaking agents, optionally one or more pore-forming agent, and optionally one or more pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of not more than 200 pm measured by analytical sieving; particularly of not more than 150 pm; particularly of not more than 100 pm and particularly of not more than 75 pm. 5 and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by adding the one or more enteric coating agents, the one or more modified release coating agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of not more than 200 pm measured by analytical sieving; particularly of not more than 150 pm; particularly of not more than 100 pm and particularly of not more than 75 pm.
Detailed description of the invention
Ail terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more spécifie définitions for certain terms as used in the présent application are as set forth below and are intended to apply uniformly through-out the spécification and claims unless an otherwise expressly set out définition provides a broader définition.
For the purposes of the présent invention, any ranges given include both the lower and the upper end-points of the range. Ranges and values given, such as températures, times, and the like, should be considered approximate, unless specifically stated.
The terms “percentage (%) by weight” or “percentage (%) w/w” hâve the same meaning and are used interchangeable. This term refers to the percentage of a component in relation to the total weight.
The term about or “around” as used herein refers to a range of values ± 10% of a specified value. For example, the expression about 10 or “around 10” includes ± 10% of 10, i.e. from 9 to 11.
The terms “relation” and “relationship” hâve the same meaning and are used interchangeable. This term is used in the présent invention for having the relation between the spray average flow rate of the mixture comprising the coating agents and the average of the solid addition rate of the mixture in solid form.
The term “multiple unit dosage form” defines a dosage form which consists of more than one unit which contains the effective amount of doxylamine and pyridoxine. Usually the multiple unit dosage forms are based on subunits such as granules, pellets or minitablets. They are usually delivered in hard gélatine capsules or transformed into tablets.
As it is known in the State of the art, the term “administration” refers to a method of delivering a formulation to a desired site. The terms ”oral” and “oral administration” hâve the same meaning and they are used interchangeable. Specifically, they refer to ingesting a drug by swallowing or chewing. Preferably, by swallowing.
______________________________________J
As it is disclosed above, the multiple unit dosage form of the présent invention including two plurality of pellets. The term “pellet” refers to small particles with approximately uniform shapes and sizes produced by an extrusion process or by coating of pharmaceutically acceptable inert nucléus. A “small particle” refers to a particle of which diameter, length, height, width, or the like is from 100 pm to 3000 μιη, particularly from 300 pm to 1700. Small particles hâve approximately uniform sizes if the diameter, length, height, width, or the like of the smallest particle is at least about one half of the average diameter, length, height, width, or the like of the particles and if the diameter, length, height, width, or the like of the largest particle is at most about twice the average diameter, length, height, width, or the like of the particles. Then, the term “pellet”, “spherical pellet”, “beads”, “beadlets”, “spherical particles”, “spheroids” and “microspheres” hâve the same meaning and are used interchangeable. The term “granule” refers to small particles without approximately uniform shapes and sizes obtained by a granulation process. Generally, granules are less uniform in size or shape than pellets. Thus, granules hâve a lower uniformity due to their irregular surfaces and afford unacceptable dose uniformity and an inappropriate dissolution profile. Therefore, for the purpose of the invention the term “pellet” and “granule” are not the same and they are not interchangeable.
The term “modified release” dosage form and “modified delivery dosage form” as well as “modifîed release” pellet and “modified delivery” pellet hâve the same meaning and are interchangeable. Both ternis are to be understood as a dosage form or pellet that exhibits a slower release of the active agents than that of a conventional immédiate release pharmaceutical composition administered by the same route. In general, the term “modified release” refers that the active ingrédient is released from the pharmaceutical dosage form in a controlled, sustained, prolonged or extended release.
For the purposes of the présent invention, the term “modified release” refers to a multiple unit oral dosage form that exhibits a dissolution profile according to which: from 5% to 35% by weight of doxylamine content is dissolved at lsth in 0.1 N HCl medium (pH = 1); then, the medium is replaced by a pH = 4.5 medium (0.05 M acetate buffer) and at 4th h from an accumulated more than 35% to 75% by weight of doxylamine initial content is dissolved; then, the medium is replaced by a pH = 6.8 medium (0.05 M phosphate buffer) and at 7th h at least an accumulated more than 75% by weight of doxylamine initial content is dissolved; and from 5% to 35% by weight of pyridoxine content is dissolved at lsth in 0.1 N HCl medium (pH =1); then, the medium is replaced by a pH = 4.5 medium (0.05 M acetate buffer) and at 4th h from an 9 accumulated more than 35% to 75% by weight of pyridoxine initial content is dissolved; then, the medium is replaced by a pH = 6.8 medium (0.05 M phosphate buffer) and at 7th h at least an accumulated more than 75% by weight of pyridoxine initial content is dissolved; wherein the dissolution profile is measured using an appropriate method. Commonly an appropriate method is a USP method such as for example by using a USP type 2 apparatus (basket), placing the composition in 900mL of the corresponding media / buffered 37°C ± 0.5 °C and 100 rpm (révolution per minute) or using a USP type 3 apparatus (reciprocating cylinder), placing the composition in 250mL of the corresponding media / buffered at 37°C ± 0.5 °C and 15 dpm (dipping per minute). In the présent invention, the measurement of the dissolution profile of the multiple unit oral dosage form is performed by USP type 2 apparatus (basket), placing the composition in 900mL of the corresponding media / buffered 37°C ± 0.5 °C and 100 rpm (révolution per minute).
In an embodiment, the multiple unit oral dosage form that exhibits a dissolution profile according to which: from 10% to 35% by weight of doxylamine content is dissolved at lsth in 0.1 N HCl medium (pH =1); then, the medium is replaced by a pH = 4.5 medium (0.05 M acetate buffer) and at 4th h from an accumulated 45% to 70% by weight of doxylamine initial content is dissolved; then, the medium is replaced by a pH = 6.8 medium (0.05 M phosphate buffer) and at 7th h at least an accumulated 80% by weight of doxylamine initial content is dissolved; and from 10% to 35% by weight of pyridoxine content is dissolved at lsth in 0.1 N HCl medium (pH = 1); then, the medium is replaced by a pH = 4.5 medium (0.05 M acetate buffer) and at 4th h from an accumulated 40% to 65% by weight of pyridoxine initial content is dissolved; then, the medium is replaced by a pH = 6.8 medium (0.05 M phosphate buffer) and at 7th h at least an accumulated 80% by weight of pyridoxine initial content is dissolved; wherein the dissolution profile is measured using an appropriate method.
In the context of the invention, the terni “coating agents” and “film-forming coating agents” hâve the same meaning and are used interchangeable. Both terms are to be understood as an agent capable of forming a thin coat to a solid dosage form or dosage form intermediate such as tablet and pellets. Examples of each one of the types of coating agents are disclosed below.
In an embodiment, the multiple unit oral dosage form of the présent invention is one wherein the coating agent of the inner active coating layer of the first and the second plurality of pellets are independently selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, microcrystalline cellulose, calcium carbonate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethylcellulose sodium enzymatically-hydrolyzed, cellaburate, cellacefate, cellulose acetate, cetyl alcohol, chitosan, coconut oil, hydrogenated, copovidone, corn syrup solids, ethylcellulose, ethylcellulose aqueous dispersion, ethylcellulose dispersion type b, ethylene glycol and vinyl alcohol graft copolymer, gelatin, glaze pharmaceutical, glucose liquid, glyceryl behenate, glyceryl dibehenate, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, isomalt, alpha-lactalbumin, maltitol, maltodextrin, methacrylic acid polymers and copolymers commercially available under the trade name of Eudragit® (Rohm Pharma; Westerstadt, Germany) such as Eudragit® E , Eudragit® NE, Eudragit® NM, Eudragit® RL and Eudragit® RS, methylcellulose, palm kernel oil, palm oil, palm oil hydrogenated, polydextrose, polydextrose hydrogenated, polyethylene glycol, polyethylene glycol 3350, polyethylene oxide, polyvinyl alcohol, pullulan, rapeseed oil fully hydrogenated, rapeseed oil superglycerinated fully hydrogenated, shellac, starch pregelatinized modified, sucrose, sugar confectioner's, sunflower oil, titanium dioxide, wax camauba, wax microcrystalline, xylitol and zinc oxide, alginic acid, copovidone, dibutyl phthalate, diethyl phthalate, pyroxylin, sodium alginate, and a mixture thereof. In an embodiment, the multiple unit oral dosage form of the présent invention is one wherein the coating agent of the inner active coating layer of the first and the second plurality of pellets are independently selected from the group consisting of polyvinylpyrrolidone, shellac, hypromellose, hydroxypropyl cellulose, microcrystalline cellulose and a mixture thereof.
In particular, the term “modified release coating agent” refers to an agent capable of forming films which allow the delivery of the drug at a predetermined rate and/or location according to the needs of the body and disease States for a definite time of period. Illustrative but nonlimitative examples of “modified release polymers” and “modified delivery polymers” are polymers which provide a controlled release, a sustained release, a prolonged release or an extended release. Examples of modified release coating agent include without limitation acrylic polymers, celluloses and their dérivatives, shellac, hydrogenated vegetable oil, hydrogenated castor oil, and their mixtures. Examples of suitable acrylic polymers include methacrylic acid polymers and copolymers commercially available under the trade name of Eudragit® (Rohm Pharma; Westerstadt, Germany) such as Eudragit® E , Eudragit® NE, Eudragit® NM, Eudragit® RL and Eudragit® RS. Examples of modified release coating agent include without limitation alginic acid, carbomer copolymer, carbomer homopolymer, carbomer interpolymer, carboxymethylcellulose sodium, carrageenan, cellaburate, ethylcellulose, ethylcellulose aqueous 11 dispersion, ethylcellulose dispersion type b, glyceryl monooleate, glyceryl monostearate, guar gum, hydroxypropyl betadex, hydroxypropyl cellulose, hypromellose, polyethylene oxide, shellac, sodium alginate, starch, pregelatinized, starch, pregelatinized modified or xanthan gum. Preferably, the modified release coating agent is shellac, particularly dewaxed shellac. The modified release polymers can be accompanied by plasticizers such as triethyl citrate (TEC), polyethylene glycol (PEG), cetyl and stearyl alcohol, acetyltributyl citrate, acetyltriethyl citrate, benzyl benzoate, castor oil, chlorobutanol, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, mannitol, polyethylene glycol, polyethylene glycol 3350, polyethylene glycol monomethyl ether, propylene glycol, pullulan, sorbitol, sorbitol sorbitan solution, sucrose diacetate hexaisobutyrate, triacetin, tributyl citrate, triethyl citrate and vitamin E; surface-active agents such as sodium lauryl sulphate, polysorbate and poloxamer; pigments such as titanium dioxide, iron sesquioxide; lubricants such as talc, magnésium stéarate,glyceryl monostearate, behenoyl polyoxylglycerides, calcium stéarate, castor oil hydrogenated, coconut oil hydrogenated, glyceryl behenate, glyceryl dibehenate, glyceryl mono and dicaprylate, glyceryl mono and dicaprylocaprate, glyceryl monocaprylate, glyceryl monocaprylocaprate, glyceryl monostearate, glyceryl tricaprylate, glyceryl tristearate, lauric acid, magnésium stéarate, minerai oil light, myristic acid, palm oil hydrogenated, palmitic acid, poloxamer, polyethylene glycol, polyethylene glycol 3350, polyoxyl 10 oleyl ether, polyoxyl 15 hydroxystearate, polyoxyl 20 cetostearyl ether, polyoxyl 35 castor oil, polyoxyl 40 castor oil hydrogenated, polyoxyl 40 stéarate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stéarate, sodium stearyl fumarate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, stearic acid, stearic acid purified, sucrose stéarate, talc, vegetable oil hydrogenated, type I, zinc stéarate and mixtures thereof.
In an embodiment, the multiple unit oral dosage form of the présent invention is one wherein the modified release coating agents are independently selected from the group consisting of polyvinylpyrrolidone and shellac, particularly polyvinylpyrrolidone and dewaxed shellac and a mixture thereof.
The term “enteric release” refers to a composition or layer of a dosage form that is formulated to release the active ingredient(s) upon exposure to a characteristic aspect of the gastrointestinal tract. In an embodiment, the enteric material is pH-sensitive and is affected by changes in pH encountered within the gastrointestinal tract (pH-sensitive release). The enteric material typically 12 .
remains insoluble at gastric pH, then allows for release of the active ingrédient in the higher pH environment of the downstream gastrointestinal tract (e.g. often the duodénum, or sometimes the colon). In another embodiment, the enteric material comprises enzymatically degradable polymers that are degraded by bacterial enzymes présent in the lower gastrointestinal tract, particularly in the colon. Optionally, the unit dosage form is formulated with a pH-sensitive enteric material designed to resuit in a release within about appropriate hours when at or above a spécifie pH. In various embodiments, the spécifie pH can for example be from about 4 to about 7, such as about 4.5, 5, 5.5, 6, 6.5, 6.8 or 7. In the context of the invention, the term “enteric release coating agent” refers to an agent capable of forming films which allow the delivery of doxylamine and pyridoxine upon exposure to a characteristic aspect of the gastrointestinal tract as defined above. Materials used for enteric release formulations, for example as coatings, are well known in the art and include, but are not limited to, cellulosic polymers such as, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate and cellulose acetate trimellitate;, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl méthacrylate and/or ethyl méthacrylate, and other methacrylic resins that are commercially available under the trade-name Acryl-EZE® (Colorcon, USA), Eudragit® (Rohm Pharma; Westerstadt, Germany), including Eudragit® L30D-55 and L100-55 (soluble atpH 5.5 and above), Eudragit® L100 and L12.5 (soluble at pH 6.0 and above), Eudragit® S, S 12.5 and FS 30D (soluble at pH 7.0 and above, as a resuit of a higher degree of estérification); vinyl polymers and copolymers formed from vinyl acetate, vinyl acetate phthalate, vinyl acetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer; enzymatically degradable polymers such as azo polymers; and zein. Combinations of different enteric materials may also be used. Multi-layer coatings using different polymers may also be applied. The properties, manufacture and design of enteric delivery Systems are well known to those of ordinary skill in the art. In a particular embodiment, the enteric coating agent is selected from the group consisting of copolymer of methacrylic acid and methyl méthacrylate, copolymer of methacrylic acid and methyl acrylate, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate and a mixture thereof. More particularly, Eudragit L® such as for example Eudragit L100 (sold by Evonik). In an embodiment, the multiple unit oral dosage form of the présent invention is one wherein the enteric coating agents are independently selected from the group consisting of methacrylic acid-methyl méthacrylate copolymer, methacrylic acid-methyl acrylate copolymer, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate and a mixture thereof. In an embodiment, the multiple unit oral dosage form of the présent invention is one wherein the enteric coating agent is a methacrylic acid-methyl méthacrylate copolymer, particularly Eudragit L100.
As it is defined above, the multiple unit oral dosage form of the présent invention comprises a first plurality of pellets which comprises a therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof and a second plurality of pellets which comprises a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof.
The terni therapeutically effective amount as used herein, refers to the amount of an active ingrédient per multiple unit dosage form that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed. The particular dose of compound administered according to this invention will be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and the similar considérations.
The tenu “pharmaceutically acceptable salt(s)” used herein encompasses any sait formed from pharmaceutically acceptable non-toxic acids including inorganic or organic acids. There is no limitation regarding the salts, except that if used for therapeutic purposes, they must be pharmaceutically acceptable. As doxylamine and pyridoxine are basic compounds, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include among others acetic, benzene sulfonic, benzoic, camphor sulfonic, citric, ethansulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic, methanesulfonic, phosphoric, succinic, sulphuric, tartaric or p-toluensulfonic acid. The préparation of pharmaceutically acceptable salts of doxylamine and pyridoxine can be carried out by methods known in the art. For instance, they can be prepared from the parent compound, which contains a basic or acidic moiety, by conventional Chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate pharmaceutically acceptable base or acid in water or in an organic solvent or in a mixture of them. In an embodiment, the multiple unit oral dosage form of the présent invention is one which comprises a pharmaceutically acceptable sait of doxylamine and a pharmaceutically acceptable sait of pyridoxine. In an embodiment, the multiple unit oral dosage form of the présent invention is one which comprises doxylamine succinate and pyridoxine hydrochloride.
As it is mentioned above, the particle size of the pharmaceutically acceptable inert nucléus of the first and the second plurality of pellets is such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nucléus hâve a particle size variability of not more than 200 pm measured by analytical sieving; particularly of not more than 150 pm; particularly of not more than 100 pm; and particularly of not more than 75 pm. It means that the pharmaceutically acceptable inert nucléus of both plurality of pellets hâve a particle size value and a particle size variability value falling within the scope of the présent invention. It encompasses that the values of the particle size and particle size variability of the first plurality of pellets and the second plurality of pellets can be equal or different, but both falling within the ranges of the présent invention.
In an embodiment, the multiple unit oral dosage form of the présent invention comprises pharmaceutically acceptable inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving, and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of not more than 200 pm from a given value comprised from 500 pm and 1400 pm measured by analytical sieving. In an embodiment, the multiple unit oral dosage form of the présent invention comprises pharmaceutically acceptable inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1400 pm measured by analytical sieving, and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of not more than 150 pm from a given value comprised from 450 pm and 1250 pm measured by analytical sieving. In an embodiment, the multiple unit oral dosage form of the présent invention comprises pharmaceutically acceptable inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm measured by analytical sieving and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of not more than 100 pm from a given value comprised from 710 pm and 1000 pm measured by analytical sieving. In an embodiment, the multiple unit oral dosage form of the présent invention comprises pharmaceutically acceptable inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 710 pm to 1000 pm measured by analytical sieving and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of not more than 75 pm from a given value comprised from 800 pm and 900 pm measured by analytical sieving.
The term “inert nucléus” refers to neutral microspheres which comprises in their composition at least one of the following substances: sorbitol, mannitol, sucrose, saccharose, starch, microcrystalline cellulose, lactose, glucose, trehalose, maltitol, fructose, colloïdal Silicon dioxide. In an embodiment, the pharmaceutically acceptable inert nucléus are neutral microspheres of a mixture of sucrose and starch.
In an embodiment, the multiple unit oral dosage form is one wherein the particle size of the pellets of the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 400 pm to 2000 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 200 pm from a given value comprised from 600 pm and 1800 pm measured by analytical sieving. In an embodiment, the multiple unit oral dosage form is one wherein the particle size of the pellets of the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 600 pm to 1600 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 150 pm from a given value comprised from 800 pm and 1400 pm measured by analytical sieving. In an embodiment, the multiple unit oral dosage form is one wherein the particle size of the pellets of the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 710 pm to 1400 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 100 pm from a given value comprised from 850 pm and 1250 pm measured by analytical sieving. In an embodiment, the multiple unit oral dosage form is one wherein the particle size of the pellets of the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 800 pm to 1400 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 75 pm from a given value comprised from 900 pm and 1180 pm measured by analytical sieving.
In an embodiment, the multiple unit oral dosage form is one wherein the particle size of the pellets of the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 400 pm to 2000 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 200 pm from a given value comprised from 600 pm and 1800 pm measured by analytical sieving. In an embodiment, the multiple unit oral dosage form is one 16 wherein the particle size of the pellets of the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 600 pm to 1600 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 150 pm from a given value comprised from 800 pm and 1400 pm measured by analytical sieving. In an embodiment, the multiple unit oral dosage form is one wherein the particle size of the pellets of the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 710 pm to 1400 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 100 pm from a given value comprised from 850 pm and 1250 pm measured by analytical sieving. In an embodiment, the multiple unit oral dosage form is one wherein the particle size of the pellets of the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 800 pm to 1400 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 75 pm from a given value comprised from 900 pm and 1180 pm measured by analytical sieving.
In an embodiment, the multiple unit oral dosage form of the présent invention comprises pharmaceutically acceptable inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving, and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of not more than 200 pm from a given value comprised from 500 pm and 1400 pm measured by analytical sieving; the particle size of the pellets of the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 400 pm to 2000 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 200 pm from a given value comprised from 600 pm and 1800 pm measured by analytical sieving and the particle size of the pellets of the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 400 pm to 2000 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 200 pm from a given value comprised from 600 pm and 1800 pm measured by analytical sieving.
In an embodiment, the multiple unit oral dosage form of the présent invention comprises pharmaceutically acceptable inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1400 pm measured by analytical sieving and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of not more than 150 pm from a given value comprised from 450 pm and 1250 pm measured by analytical sieving; the particle size of the pellets of the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 600 pm to 1600 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 150 pm from a given value comprised from 800 pm and 1400 pm measured by analytical sieving; and the particle size of the pellets of the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 600 pm to 1600 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 150 pm from a given value comprised from 800 pm and 1400 pm measured by analytical sieving.
In an embodiment, the multiple unit oral dosage form of the présent invention comprises pharmaceutically acceptable inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm measured by analytical sieving and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of not more than 100 pm from a given value comprised from 710 pm and 1000 pm measured by analytical sieving; the particle size of the pellets of the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets haye a particle size from 710 pm to 1400 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 100 pm from a given value comprised from 850 pm and 1250 pm measured by analytical sieving; and the particle size of the pellets of the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 710 pm to 1400 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 100 pm from a given value comprised from 850 pm and 1250 pm measured by analytical sieving.
In an embodiment, the multiple unit oral dosage form of the présent invention comprises pharmaceutically acceptable inert nucléus having a particle size such that at least 90% of the 18 inert nucléus hâve a particle size from 710 pm to 1000 pm measured by analytical sieving and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of not more than 75 pm from a given value comprised from 800 pm and 900 pm measured by analytical sieving; the particle size of the pellets of the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 800 pm to 1400 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 75 pm from a given value comprised from 900 pm and 1180 pm measured by analytical sieving; and the particle size of the pellets of the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 800 pm to 1400 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 75 pm from a given value comprised from 900 pm and 1180 pm measured by analytical sieving.
The particle size of the pharmaceutically acceptable inert nucléus, the pellets, the active ingrédients and the excipients can be measured by any method disclosed in the state of the art. Examples of methods commonly used for measuring the particle size is Dynamic light scattering (DLS) reporting the number average diameter value, Atomic force microscopy (AFM) or transmission électron microscopy (TEM) to measure dried particles; laser diffraction (Laser Mastersizer, Mie Theory; ISO 13320-1) and by sédimentation analysis (Sedigraph-Stoke’s Law; ISO 13317-3) and by analytical sieving. For the purpose of the présent invention, the particle size of the pharmaceutically acceptable inert nucléus and of the pellets of the first and the second plurality as defined herein is preferably measured by analytical sieving, particularly as directed by European Pharmacopoeia (cf. European Pharmacopoeia chapter 2.9.38).
The ternis “variability” and “dispersion” hâve the same meaning and are used interchangeable. They refer to how spread out a set of data is. Variability gives you a way to describe how much data sets vary. In particular, the tenu “particle size variability” refers to how spread out the particle size of a given value is.
The expression “at least the 90% [...] hâve a particle size from X to Y pm means that the 90% of the totality of the population of particles has a particle size comprised from X and Y pm. For the purpose of the invention, the expression “at least the 90% of the pharmaceutically acceptable inert nucléus or pellets hâve a particle size variability of not more than 200 pm” means that from 19 a given value, the 90% of the population of pharmaceutically acceptable inert nucléus or pellets hâve a particle size comprised from ± 200 pm from a given value. For instance, for the given value 500 pm, at least the 90% of the population of pharmaceutically acceptable inert nucléus hâve a particle size from 300 pm to 700 pm (i.e. ± 200 pm).The particle size variability of the pharmaceutically acceptable inert nucléus or the pellets can be measured by any method disclosed in the State of the art. Examples of methods commonly used for measuring the particle size variability is Dynamic light scattering (DLS) reporting the number average diameter value, Atomic force microscopy (AFM) or transmission électron microscopy (TEM) to measure dried particles; laser diffraction (Laser Mastersizer, Mie Theory; ISO 13320-1), by sédimentation analysis (Sedigraph-Stoke’s Law; ISO 13317-3), by analytical sieving and optical microscopy. For the purpose of the présent invention, the particle size variability is measured by analytical sieving.
In an embodiment, the multiple unit oral dosage form is one wherein the particle size of doxylamine or a pharmaceutically acceptable sait thereof is characterized for having a D90 equal to or below than 250 pm. In an embodiment, the multiple unit oral dosage form is one wherein the particle size of pyridoxine or a pharmaceutically acceptable sait thereof is characterized for having a D90 equal to or below than 250 pm. In an embodiment, the multiple unit oral dosage form is one wherein: the particle size of doxylamine or a pharmaceutically acceptable sait is characterized for having a D90 equal to or below than 250 pm; and the particle size of pyridoxine or a pharmaceutically acceptable sait thereof is characterized for having a D90 equal to or below than 250 pm.
In an embodiment, the multiple unit oral dosage form is one wherein the particle size of the one or more anticaking agent is characterized for having a D90 equal to or below than 250 pm. In an embodiment, the multiple unit oral dosage form is one wherein the particle size of the one or more optionally présent pore-forming agents is characterized for having a D90 equal to or below than 250 pm.
The DX value indicates that a certain percentage X of the particles has a weight/volume/number equal to or below a certain limit. A D90 indicates that the 90% of the particles has a weight/volume/number equal to or below a certain limit. The D90 may be expressed by volume, by weight or by number. For the purpose of the présent invention, the D90 of the active ingrédients (doxylamine and pyridine) are expressed by volume. And, the D90 of the anticaking 20 agents, such as talc, is expressed by weight. For instance, a D90 value of doxylamine or pyridoxine equal to or below than 250 pm means that 90 % by volume of the particles hâve a diameter equal to or below than 250 pm. And a D90 value of talc equal to or below 250 pm means that 90 % by weight of the particles hâve a diameter equal to or below than 250 pm. The DX (and particularly the D90) can be measured using any appropriate method disclosed above for the measurement of the particle size of the pharmaceutically acceptable inert nucléus, the coated pellets, the active ingrédients and the excipients of the présent invention, such as for example analytical sieving. Particularly, among the suitable methods above mentioned, a Malvem method (Laser Mastersizer, Mie Theory; ISO 13320-1) is the préférable option for determining the D90 and the particle size distribution of doxylamine or a pharmaceutically acceptable sait, and also the D90 of pyridoxine or a pharmaceutically acceptable sait thereof.
In an embodiment, the multiple unit oral dosage form comprises a first plurality of pellets which comprises a therapeutically effective amount of a pharmaceutically acceptable sait of doxylamine, particularly doxylamine succinate. In an embodiment, the multiple unit oral dosage form comprises the first plurality of pellets which comprises from 5 mg to 50 mg per oral dosage form of doxylamine or a pharmaceutically acceptable sait thereof per multiple unit dosage form, particularly from 6 mg to 40 mg, from 7 mg to 30 mg, more particularly from 8 mg to 22 mg. In an embodiment, the multiple unit oral dosage form comprises the first plurality of pellets having particularly from 5 mg to 50 mg per oral dosage form of doxylamine succinate per multiple unit dosage form, particularly from 6 mg to 40 mg, from 7 mg to 30 mg, more particularly from 8 mg to 22 mg; much more particularly from 9 mg to 11 mg of doxylamine succinate. In a more particular embodiment, the multiple unit oral dosage form comprises the first plurality of pellets having 10 mg of doxylamine or a pharmaceutically acceptable sait thereof; particularly doxylamine succinate per multiple unit dosage form. In another embodiment, the multiple unit oral dosage form comprises the first plurality of pellets having particularly from 19 mg to 21 mg of doxylamine or a pharmaceutically acceptable sait thereof; particularly doxylamine succinate. In another more particular embodiment, the multiple unit oral dosage form comprises the first plurality of pellets having 20 mg of doxylamine or a pharmaceutically acceptable sait thereof; particularly doxylamine succinate per multiple unit dosage form.
In an embodiment, the multiple unit oral dosage form comprises a second plurality of pellets which comprises a therapeutically effective amount of a pharmaceutically acceptable sait of pyridoxine, particularly pyridoxine hydrochloride. In an embodiment, the multiple unit oral 21 dosage form comprises the second plurality of pellets which comprises from 5 mg to 50 mg per oral dosage form of pyridoxine or a pharmaceutically acceptable sait thereof, per multiple unit dosage form, particularly from 6 mg to 40 mg, from 7 mg to 30 mg, more particularly from 8 mg to 22 mg. In an embodiment, the multiple unit oral dosage form comprises the second plurality of pellets having particularly from 5 mg to 50 mg per oral dosage form of pyridoxine hydrochloride per multiple unit dosage form, particularly from 6 mg to 40 mg, particularly from 7 mg to 30 mg, more particularly from 8 mg to 22 mg; much more particularly from 9 mg to 11 mg of pyridoxine hydrochloride. In a more particular embodiment, the multiple unit oral dosage form comprises the second plurality of pellets having 10 mg of pyridoxine or a pharmaceutically acceptable sait thereof; particularly pyridoxine hydrochloride per multiple unit dosage form. In another embodiment, the multiple unit oral dosage form comprises the second plurality of pellets having particularly from 19 mg to 21 mg of pyridoxine or a pharmaceutically acceptable sait thereof; particularly pyridoxine hydrochloride. In another more particular embodiment, the multiple unit oral dosage form comprises the second plurality of pellets having 20 mg of pyridoxine or a pharmaceutically acceptable sait thereof; particularly pyridoxine hydrochloride per multiple unit dosage form.
In an embodiment, the multiple unit oral dosage form comprises the first plurality of pellets which comprises doxylamine or a therapeutically effective amount of a pharmaceutically acceptable sait thereof, particularly doxylamine succinate; and the second plurality of pellets which comprises a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, particularly the pyridoxine hydrochloride. In an embodiment, the multiple unit oral dosage form comprises the first plurality of pellets which comprises from 5 mg to 50 mg of doxylamine or a pharmaceutically acceptable sait thereof; particularly doxylamine succinate per multiple unit dosage form, particularly 10 mg or 20mg of doxylamine or a pharmaceutically acceptable sait thereof; particularly doxylamine succinate per multiple unit dosage form; and the second plurality of pellets which comprises from 5 mg to 50 mg of pyridoxine or a pharmaceutically acceptable sait thereof; particularly pyridoxine hydrochloride per multiple unit dosage form, particularly 10 mg or 20mg of pyridoxine or a pharmaceutically acceptable sait thereof; particularly pyridoxine hydrochloride per multiple unit dosage form. In a particular embodiment, the multiple unit oral dosage form comprises the first plurality of pellets which comprises 10 mg of doxylamine or a pharmaceutically acceptable sait thereof; particularly doxylamine succinate per multiple unit dosage form and the second plurality of pellets comprising 10 mg of pyridoxine or a pharmaceutically acceptable sait thereof; particularly pyridoxine hydrochloride per multiple unit dosage form. In another particular embodiment, the multiple unit oral dosage form comprises the first plurality of pellets which comprises 20 mg of doxylamine or a pharmaceutically acceptable sait thereof; particularly doxylamine succinate per multiple unit dosage form and the second plurality of pellets comprising 20 mg of pyridoxine or a pharmaceutically acceptable sait thereof; particularly pyridoxine hydrochloride per multiple unit dosage form.
In an embodiment, the multiple unit dosage form comprises from 20 mg to 220 mg of the first plurality of pellets which comprises a therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, particularly doxylamine succinate. In an embodiment, the multiple unit dosage form comprises from 40 mg to 140 mg of the first plurality of pellets which comprises a therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, particularly doxylamine succinate.
In an embodiment, the multiple unit dosage form comprises about 60 mg of the first plurality of pellets which comprises a therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, particularly doxylamine succinate.
In another embodiment, the multiple unit dosage form comprises about 120 mg of the first plurality of pellets which comprises a therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, particularly doxylamine succinate.
In an embodiment, the multiple unit dosage form comprises from 20 mg to 220 mg of the second plurality of pellets which comprises a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, particularly pyridoxine hydrochloride. In an embodiment, the multiple unit dosage form comprises from 40 mg to 140 mg of the second plurality of pellets which comprises a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, particularly pyridoxine hydrochloride. In an embodiment, the multiple unit dosage form comprises about 60 mg of the second plurality of pellets which comprises a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, particularly pyridoxine hydrochloride. In another embodiment, the multiple unit dosage form comprises about 120 mg of the second plurality of pellets which comprises a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, particularly pyridoxine hydrochloride.
In an embodiment, the multiple unit dosage form comprises from 20 mg to 220 mg of the first plurality of pellets which comprises a therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, particularly doxylamine succinate; and from 20 mg to 220 mg of the second plurality of pellets which comprises a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, particularly pyridoxine hydrochloride. In an embodiment, the multiple unit dosage form comprises from 40 mg to 140 mg, more particularly about 60mg, of the first plurality of pellets which comprises from 5 mg to 50 mg of doxylamine succinate, particularly 10 mg of doxylamine succinate; and from 40 mg to 140 mg, more particularly 60mg, of the second plurality of pellets which comprises from 5 mg to 50 mg of pyridoxine hydrochloride, particularly 10 mg of pyridoxine hydrochloride.
In another embodiment, the multiple unit dosage form comprises from 40 mg to 140 mg, more particularly about 120 mg, of the first plurality of pellets which comprises from 5 mg to 50 mg of doxylamine succinate, particularly 20 mg of doxylamine succinate; and from 40 mg to 140 mg, more particularly 120 mg, of the second plurality of pellets which comprises from 5 mg to 50 mg of pyridoxine hydrochloride, particularly 20 mg of pyridoxine hydrochloride.
In an embodiment, the multiple unit dosage form comprises the first plurality of pellets which comprises from 5 mg to 50 mg of doxylamine succinate, particularly 10 mg of doxylamine succinate; and the second plurality of pellets which comprises from 5 mg to 50 mg of pyridoxine hydrochloride, particularly 10 mg of pyridoxine hydrochloride. In a particular embodiment, the multiple unit dosage form comprises the first plurality of pellets which comprises 10 mg of doxylamine succinate and the second plurality of pellets comprising 10 mg of pyridoxine hydrochloride.
In another embodiment, the multiple unit dosage form comprises the first plurality of pellets which comprises from 5 mg to 50 mg of doxylamine succinate, particularly 20 mg of doxylamine succinate; and the second plurality of pellets which comprises from 5 mg to 50 mg of pyridoxine hydrochloride, particularly 20 mg of pyridoxine hydrochloride. In a particular embodiment, the multiple unit dosage form comprises the first plurality of pellets which comprises 20 mg of doxylamine succinate and the second plurality of pellets comprising 20 mg of pyridoxine hydrochloride.
The term “anticaking agent” or “anticaking agents” refers to any pharmaceutically acceptable agent capable to reduce surface tackiness and the incidence of nucléus or pellets sticking together during coating and consequently improve process efficiency, coating uniformity, and appearance, preventing the formation of lumps (aggregates) and allows easing packaging, transport, flowability, filling into final dosage form and consumption. Examples of anticaking agents include, but are not limited to, calcium stéarate, magnésium stéarate, silica, silicates, talc, flour, starch calcium phosphate tribasic, calcium silicate, cellulose powdered, magnésium oxide, magnésium silicate, magnésium trisilicate, silica dental-type, silica hydrophobie colloïdal, Silicon dioxide colloïdal, sodium stéarate and a mixture thereof. In an embodiment, the multiple unit dosage form comprises one or more anticaking agents selected from the group consisting of talc and silica (colloïdal silicone dioxide; particularly Aerosil) and a mixture thereof. In an embodiment, the multiple unit dosage form comprises talc as anticaking agent. In an embodiment, the multiple unit dosage form comprises one or more anticaking agents having a particle size distribution characterized for having a D90 equal to or below than 250 pm; particularly lower than 150 pm; more particularly lower than 100 pm. In an embodiment, the multiple unit dosage form comprises one or more anticaking agents having a particle size distribution characterized for having a D90 equal to or below than 75 pm. In an embodiment, the multiple unit dosage form comprises talc as anticaking agent having a D90 particle diameter lower than 250 pm; particularly lower than 150 pm; more particularly lower than 100 pm. In an embodiment, the multiple unit dosage form comprises talc as anticaking agent having a D90 particle diameter lower than 75 pm.
The term “pore-forming agent” refers to any pharmaceutically acceptable agent capable of forming one or more pores in the shell/coating to allow the modified release of the active ingrédients. The pore-forming agent can be organic or inorganic, or any combination thereof. Examples of pore-forming agent include, but are not limited to, polyethylene glycol (PEG), propylene glycol, isopropyl alcohol, glycerol, lactose, glucose, sucrose, mannitol, sorbitol, sodium chloride, potassium chloride, talc, hydroxypropyl cellulose, micronized sugar, hydroxypropyl methyl cellulose (HPMC), polyvinyl alcohols, methacrylic acid copolymers, or a mixture therefore. In an embodiment, the pore-forming agent is selected from the group consisting of talc, micronized sugar, sodium or potassium chloride and a mixture thereof. As it is mentioned above, the modified release multiple unit oral dosage form of the présent invention optionally comprises one or more pore-forming agents. In an embodiment, the one or more poreforming agents as defined above are présent in the multiple unit oral dosage form. In an 25 embodiment, the one or more pore-forming agents as defined above are absent in the multiple unit oral dosage form.
The term “pharmaceutically acceptable” refers to any composition, compound or material suitable for use in the pharmaceutical technology. For the purpose of the présent invention, the term “pharmaceutically acceptable excipients or carriers” refers to that excipients or carriers for preparing compositions with medical use. The appropriate excipients and/or carriers, and their amounts, can readily be determined by those skilled in the art according to the type of formulation being prepared. In an embodiment, the modified release multiple unit dosage form of the présent invention further comprises one or more binders, glidants, fillers, lubricants, wicking agents and mixtures thereof. In an embodiment, the process comprises preparing a multiple unit dosage form which can comprise one or more pharmaceutically acceptable excipients or carriers.
As it is mentioned above, the modified release multiple unit oral dosage form of the présent invention optionally comprises one or more pharmaceutically acceptable excipients or carriers. In an embodiment, the modified release multiple unit oral dosage form comprises one or more pharmaceutically acceptable excipients or carriers.
In an embodiment, the multiple unit oral dosage form comprises: one or more pore-forming agents as defined above; and one or more pharmaceutically acceptable excipients or carriers.
The term “binder” refers to any pharmaceutically acceptable compound having binding properties. Materials commonly used as binders include microcrystalline cellulose, polyvinylpyrrolidone (also called povidone or PVP), methylcellulose polymers, hydroxyethyl cellulose, hydroxypropyl cellulose, L-hydroxypropyl cellulose (low substituted), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose, carboxymethylene, carboxymethyl hydroxyethyl cellulose and other cellulose dérivatives, starches or modified starches, polyethylene glycol (PEG) 6000, guar gum, starch or shellac and mixture thereof. Examples of binders include acacia, agar, alginic acid, calcium carbonate, calcium lactate, carboxymethylcellulose sodium, cellulose, microcrystalline cellulose, copovidone, dextrates, dextrin, ethylcellulose, gelatin, glucose liquid, glyceryl behenate, glyceryl dibehenate, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl cellulose low-substituted, hypromellose, hypromellose acetate succinate, inulin, invert sugar, lactose monohydrate, maltodextrin, maltose, methylcellulose, polydextrose hydrogenated, polyethylene oxide,
J polyvinylpyrrolidone (also called povidone or PVP), pullulan, shellac, sodium alginate, starch pregelatinized, starch pregelatinized modified, starch corn, starch hydroxypropyl corn, starch pregelatinized hydroxypropyl corn, starch pea, starch hydroxypropyl pea, starch pregelatinized hydroxypropyl pea, starch potato, starch hydroxypropyl potato, starch pregelatinized hydroxypropyl potato, starch tapioca, starch wheat, starch hydrolysate hydrogenated, sucrose, sunflower oil, syrup, trehalose, vegetable oil hydrogenated, vitamin E polyethylene glycol succinate.
In an embodiment, the multiple unit oral dosage form is one wherein the pharmaceutically acceptable excipients or carriers comprises one or more binder; preferably comprises shellac and polyvinylpyrrolidone (PVP), and more particular embodiment are dewaxed shellac and PVPK30.
The term “glidant” refers to a pharmaceutically acceptable substance which improves the flow characteristics of powder mixtures in the dry State. Materials commonly used as a glidant include magnésium stéarate, silica (colloïdal Silicon dioxide; particularly Aerosil) or talc. In an embodiment, the multiple unit oral dosage form is one wherein the pharmaceutically acceptable excipients or carriers comprises one or more glidant; preferably comprises colloïdal Silicon dioxide, and more preferably Aerosil 200 Pharma.
The term lubricanf ' refers to a pharmaceutically acceptable substance that prevents composition ingrédients from dumping together and from sticking to the tablet punches or capsule filling machine and improves flowability of the composition mixture. Materials commonly used as a lubricant include sodium oleate, sodium stéarate, sodium benzoate, sodium stéarate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stéarate, magnésium stéarate, magnésium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acid, zinc, polyethylene glycol, talc and mixtures thereof. Examples of lubricants include behenoyl polyoxylglycerides, calcium stéarate, castor oil hydrogenated, coconut oil hydrogenated, glyceryl behenate, glyceryl dibehenate, glyceryl mono and dicaprylate, glyceryl mono and dicaprylocaprate, glyceryl monocaprylate, glyceryl monocaprylocaprate, glyceryl monostearate, glyceryl tricaprylate, glyceryl tristearate, lauric acid, magnésium stéarate, minerai oil light, myristic acid, palm oil hydrogenated, palmitic acid, poloxamer, polyethylene glycol, polyethylene glycol 3350, polyoxyl 10 oleyl ether, polyoxyl 15 hydroxystearate, polyoxyl 20 cetostearyl ether, polyoxyl 35 castor oil, polyoxyl 40 castor oil hydrogenated, polyoxyl 40 stéarate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, potassium benzoate, sodium benzoate, sodium lauryl sulfate, 27 sodium stéarate, sodium stearyl fùmarate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, stearic acid, stearic acid purified, sucrose stéarate, talc, vegetable oil hydrogenated type I and zinc stéarate. The presence of a lubricant is particularly preferred when the composition is a tablet to improve the tableting process.
The ternis filler and diluent hâve the same meaning and are used interchangeably. They refer to any pharmaceutically acceptable excipient or carrier (material) that fill out the size of a composition, making it practical to produce and convenient for the consumer to use. Materials commonly used as filler include calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, calcium carboxymethyl cellulose, cellulose, cellulose products such as micro crystalline cellulose and its salts, dextrin dérivatives, dextrin, dextrose, fructose, lactitol, lactose, starches or modified starches, magnésium carbonate, magnésium oxide, maltitol, maltodextrins, maltose, mannitol, sorbitol, starch, sucrose, sugar, xylitol, erythritol and mixtures thereof. In an embodiment, the multiple unit oral dosage form is one wherein the pharmaceutically acceptable excipients or carriers comprises one or more fillers; preferably comprises sucrose, starch or microcrystalline cellulose. Examples of fillers include amino méthacrylate copolymer; ammonio méthacrylate copolymer; ammonio méthacrylate copolymer dispersion; calcium carbonate; calcium phosphate, dibasic, anhydrous; calcium phosphate, dibasic, dihydrate; calcium phosphate, tribasic; calcium sulfate; cellaburate; cellulose, microcrystalline; cellulose, silicified microcrystalline; cellulose, powdered; cellulose acetate; corn syrup; corn syrup solids; dextrates; dextrin; dextrose; dextrose excipient; erythritol; ethyl acrylate and methyl méthacrylate copolymer dispersion; fructose; invert sugar; isomalt; kaolin; alpha-lactalbumin; lactitol; lactose, anhydrous; lactose, monohydrate; magnésium carbonate; magnésium oxide; maltitol; maltodextrin; maltose; mannitol; methacrylic acid and ethyl acrylate copolymer; methacrylic acid and ethyl acrylate copolymer dispersion; methacrylic acid and methyl méthacrylate copolymer; polydextrose; polyethylene glycol; polyethylene glycol 3350; propylene glycol monocaprylate; pullulan; simethicone; sodium chloride; sorbitol; starch, pregelatinized; starch, pregelatinized modified; starch, corn; starch, hydroxypropyl corn; starch, pregelatinized hydroxypropyl corn; starch, pea; starch, hydroxypropyl pea; starch, pregelatinized hydroxypropyl pea; starch, potato; starch, hydroxypropyl potato; starch, pregelatinized hydroxypropyl potato; starch, tapioca; starch, wheat; starch hydrolysate, hydrogenated; sucrose; sugar, compressible; sugar, confectioner's; sugar spheres; sunflower oil; talc; trehalose; and xylitol.
The term “wicking agents” refers to the pharmaceutically acceptable material that has the ability to draw water into the porous network of a delivery device. It has the ability to undergo physisorption with water. The rôle of a wicking agent is to act like a carrier and facilitate the entry of water to the inner surfaces of the core. Materials commonly used as wicking agent include sodium lauryl sulfate, kaolin, titanium dioxide, alumina, bentonite, magnésium aluminium silicate, povidone and colloïdal Silicon dioxide (Aerosil). In an embodiment, the multiple unit oral dosage form of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprises one or more wicking agents; preferably kaolin, titanium dioxide, alumina, bentonite, magnésium aluminium silicate, povidone and colloïdal Silicon dioxide (Aerosil). In an embodiment, the multiple unit oral dosage form of the invention is one wherein the pharmaceutically acceptable excipients or carriers comprises one or more wicking agents; preferably comprises povidone or colloïdal Silicon dioxide (Aerosil) or a mixture thereof.
In an embodiment, the multiple unit oral dosage form of the invention is one wherein the modified release multiple unit oral dosage form comprises: a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising an inner active coating layer comprising from 6 to 20 % by weight of one or more coating agents in relation to the total weight of the inner active coating layer.
In an embodiment, the multiple unit oral dosage form of the invention is one wherein the modified release multiple unit oral dosage form comprises: a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising an inner active coating layer comprising from 15 to 30 % by weight of one or more anticaking agent in relation to the total weight of the inner active coating layer.
In an embodiment, the multiple unit oral dosage form of the invention is one wherein the modified release multiple unit oral dosage form comprises: a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising an inner active coating layer comprising: from 6 to 20 % by weight of one or more coating agents in relation to the total weight of the inner active coating layer; from 15 to 30 % by weight of one or more anticaking agent in relation to the total weight of the inner active coating layer and optionally one or more pore forming agent, being the sum of the components up to 100% by weight in relation to the weight of the inner active coating layer.
In an embodiment, the multiple unit oral dosage form of the invention is one wherein the modified release multiple unit oral dosage form comprises a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising an intermediate enteric release coating layer comprising from 45 to 65 % by weight of one or more enteric coating agents in relation to the total weight of the intermediate enteric release coating layer.
In an embodiment, the multiple unit oral dosage form of the invention is one wherein the ' modified release multiple unit oral dosage form comprises a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising an intermediate enteric release coating layer comprising from 35 to 55 % by weight of one or more anticaking agent in relation to the total weight of the intermediate enteric release coating layer and optionally one or more pore forming agent.
In an embodiment, the multiple unit oral dosage form of the invention is one wherein the modified release multiple unit oral dosage form comprises a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising an intermediate enteric release coating layer comprising: from 45 to 65 % by weight of one or more enteric coating agents in relation to the total weight of the intermediate enteric release coating layer; from 35 to 55 % by weight of one or more anticaking agent in relation to the total weight of the intermediate enteric release coating layer and optionally one or more pore forming agent; and optionally one or more pharmaceutically acceptable excipients being the sum of the components up to 100% by weight in relation to the weight of the intermediate enteric release coating layer.
In an embodiment, the multiple unit oral dosage form of the invention is one wherein the modified release multiple unit oral dosage form comprises a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising an extemal modified release coating layer comprising from 7 to 14 % by weight of one or more enteric coating agents in relation to the total weight of the extemal modified release coating layer.
In an embodiment, the multiple unit oral dosage form of the invention is one wherein the modified release multiple unit oral dosage form comprises a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising an extemal modified release coating layer comprising from 38 to 46 % by weight of one or more modified release coating agents in relation to the total weight of the extemal modified release coating 30 layer.
In an embodiment, the multiple unit oral dosage form of the invention is one wherein the modified release multiple unit oral dosage form comprises a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising an extemal modified release coating layer comprising from 42 to 52 % by weight of one or more anticaking agent in relation to the total weight of the extemal modified release coating layer and optionally one or more pore forming agent, being the sum of the components up to 100% by weight in relation to the weight of the extemal modified release coating layer.
In an embodiment, the multiple unit oral dosage form of the invention is one wherein the modified release multiple unit oral dosage form comprises a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising an extemal modified release coating layer comprising: from 7 to 14 % by weight of one or more enteric coating agents; from 38 to 46 % by weight of one or more modified release coating agents in relation to the total weight of the extemal modified release coating layer; from 42 to 52 % by weight of one or more anticaking agent in relation to the total weight of the extemal modified release coating layer and optionally one or more pore forming agent; and optionally one or more pharmaceutically acceptable excipients, being the sum of the components up to 100% by weight in relation to the weight of the extemal modified release coating layer.
In an embodiment, the multiple unit oral dosage form of the invention is one wherein the modified release multiple unit oral dosage form comprises a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising:
- an inner active coating layer comprising:
a therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof;
from 6 to 20 % by weight of one or more coating agents in relation to the total weight of the inner active coating layer and from 15 to 30 % by weight of one or more anticaking agent in relation to the total weight of the inner active coating layer and optionally one or more pore forming agents; optionally one or more pharmaceutically acceptable excipients; and being the sum of the components up to 100% by weight in relation to the weight of the inner active coating layer;
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- optionally an intermediate enteric release coating layer comprising:
from 45 to 65 % by weight of one or more enteric coating agents in relation to the total weight of the intermediate enteric release coating layer; and from 35 to 55 % by weight of one or more anticaking agents in relation to the total weight of the intermediate enteric release coating layer and optionally one or more pore forming agents, optionally one or more pharmaceutically acceptable excipients; and beihg the sum of the components up to 100% by weight in relation to the weight of the intermediate enteric release coating layer;
- an extemal modified release coating layer comprising:
from 7 to 14 % by weight of one or more enteric coating agents in relation to the total weight of the extemal modified release coating layer;
from 38 to 46 % by weight of one or more modified release coating agents in relation to the total weight of the extemal modified release coating layer; and from 42 to 52 % by weight of one or more anticaking agent in relation to the total weight of the extemal modified release coating layer and optionally one or more pore-forming agent;
optionally one or more pharmaceutically acceptable excipients; and being the sum of the components up to 100% by weight in relation to the weight of the extemal modified release coating layer.
In an embodiment, the multiple unit oral dosage form of the invention is one wherein the modified release multiple unit oral dosage form comprises a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof comprising an inner active coating layer comprising from 13 to 25 % by weight of one or more coating agents in relation to the total weight of the inner active coating layer; and optionally one or more pharmaceutically acceptable excipients; being the sum of the components up to 100% by weight in relation to the weight of the inner active coating layer.
In an embodiment, the multiple unit oral dosage form of the invention is one wherein the modified release multiple unit oral dosage form comprises a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof comprising an extemal modified release coating layer comprising from 2 to 8% by weight of one or more enteric coating agents in relation to the total weight of the extemal modified release coating layer.
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In an embodiment, the multiple unit oral dosage form of the invention is one wherein the modified release multiple unit oral dosage form comprises a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof comprising an extemal modified release coating layer comprising from 30 to 49 % by weight of one or more modified release coating agents in relation to the total weight of the extemal modified release coating layer.
In an embodiment, the multiple unit oral dosage form of the invention is one wherein the modified release multiple unit oral dosage form comprises a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof comprising an extemal modified release coating layer comprising from 46 to 65% by weight of one or more anticaking agents in relation to the total weight of the extemal modified release coating layer and optionally one or more pore forming agents, being the sum of the components up to 100% by weight in relation to the weight of the extemal modified release coating layer.
In an embodiment, the multiple unit oral dosage form of the invention is one wherein the modified release multiple unit oral dosage form comprises a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof comprising an extemal modified release coating layer comprising: from 2 to 8 % by weight of one or more enteric coating agents in relation to the total weight of the extemal modified release coating layer; from 30 to 49 % by weight of one or more modified release coating agents in relation to the total weight of the extemal modified release coating layer; from 46 to 65 % by weight of one or more anticaking agents in relation to the total weight of the extemal modified release coating layer and optionally one or more pore forming agents; optionally one or more pharmaceutically acceptable excipients being the sum of the components up to 100% by weight in relation to the weight of the extemal modified release coating layer.
In an embodiment, the multiple unit oral dosage form of the invention is one wherein the modified release multiple unit oral dosage form comprises a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof comprising:
- an inner active coating layer comprising:
a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof; and from 13 to 25 % by weight of one or more coating agents in relation to the total weight of 33 the inner active coating layer;
optionally one or more pharmaceutically acceptable excipients; and being the sum of the components up to 100% by weight in relation to the weight of the inner active coating layer;
- an extemal modified release coating layer comprising:
from 2 to 8 % by weight of one or more enteric coating agents in relation to the total weight of the extemal modified release coating layer;
from 30 to 49 % by weight of one or more modified release coating agents in relation to the total weight of the extemal modified release coating layer; and from 46 to 65 % by weight of one or more anticaking agents in relation to the total weight of the extemal modified release coating layer and optionally one or more pore forming agents;
optionally one or more pharmaceutically acceptable excipients; and being the sum of the components up to 100% by weight in relation to the weight of he extemal modified release coating layer.
In. an embodiment, the multiple unit oral dosage form of the invention is one wherein the modified release multiple unit oral dosage form comprises:
a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising
- a pharmaceutically acceptable inert nucléus;
- an inner active coating layer comprising:
a therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof from 6 to 20 % by weight of one or more coating agents in relation to the total weight of the inner active coating layer and from 15 to 30 % by weight of one or more anticaking agent in relation to the total weight of the inner active coating layer and optionally one or more pore forming agents;
optionally one or more pharmaceutically acceptable excipients; and being the sum of the components up to 100% by weight in relation to the weight of the inner active coating layer;
- optionally an intermediate enteric release coating layer comprising:
from 45 to 65 % by weight of one or more enteric coating agents in relation to the total weight of the intermediate enteric release coating layer; and from 35 to 55 % by weight of one or more anticaking agents in relation to the total weight of the intermediate enteric release coating layer and optionally one or more pore forming agents;
optionally one or more pharmaceutically acceptable excipients; and being the sum of the components up to 100% by weight in relation to the weight the intermediate enteric release coating layer;
- an extemal modified release coating layer comprising:
from 7 to 14 % by weight of one or more enteric coating agents in relation to the total weight of the extemal modified release coating layer;
from 38 to 46 % by weight of one or more modified release coating agents in relation to the total weight of the extemal modified release coating layer; and from 42 to 52 % by weight of one or more anticaking agent in relation to the total weight of the extemal modified release coating layer and optionally one or more pore-forming agent;
optionally one or more pharmaceutically acceptable excipients; and being the sum of the components up to 100% by weight in relation to the Weight the extemal modified release coating layer;
and a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof comprising:
- a pharmaceutically acceptable inert nucléus;
- an inner active coating layer comprising:
a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof; and from 13 to 25 % by weight of one or more coating agents in relation to the total weight of the inner active coating layer;
optionally one or more pharmaceutically acceptable excipients; and being the sum of the components up to 100% by weight in relation to the weight of the inner active coating layer;
- an extemal modified release coating layer comprising:
from 2 to 8 % by weight of one or more enteric coating agents in relation to the total weight of the extemal modified release coating layer;
from 30 to 49 % by weight of one or more modified release coating agents in relation to the total weight of the extemal modified release coating layer; and from 46 to 65 % by weight of one or more anticaking agents in relation to the total weight of the extemal modified release coating layer and optionally one or more pore forming agents;
optionally one or more pharmaceutically acceptable excipients; and being the sum of the components up to 100% by weight in relation to the weight of the extemal modified release coating layer.
In an embodiment, the modified multiple unit oral dosage form of the présent invention is one which exhibits a dissolution profile according to which:
from 5% to 35% by weight of doxylamine content is dissolved at lsth in 0.1 N HCl medium (pH = i);
then, the medium is replaced by a pH = 4.5 medium (0.05 M acetate buffer) and at 4th h from an accumulated more than 35% to 75% by weight of doxylamine initial content is dissolved;
then, the medium is replaced by a pH = 6.8 medium (0.05 M phosphate buffer) and at 7thh at least an accumulated more than 75% by weight of doxylamine initial content is dissolved; and from 5% to 35% by weight of pyridoxine content is dissolved at lsth in 0.1 N HCl medium (pH = i);
then, the medium is replaced by a pH = 4.5 medium (0.05 M acetate buffer) and at 4th h from an accumulated more than 35% to 75% by weight of pyridoxine initial content is dissolved;
then, the medium is replaced by a pH = 6.8 medium (0.05 M phosphate buffer) and at 7thh at least an accumulated more than 75% by weight of pyridoxine initial content is dissolved; wherein the dissolution profile is measured using a USP type 2 apparatus (basket), placing the composition in 900mL of the corresponding media / buffered at 37°C ± 0.5 °C and 100 rpm (révolution per minute).
In an embodiment, the modified multiple unit oral dosage form of the présent invention is one which exhibits a dissolution profile according to which:
from 10% to 35% by weight of doxylamine content is dissolved at lsth in 0.1 N HCl medium (pH = i);
then, the medium is replaced by a pH = 4.5 medium (0.05 M acetate buffer) and at 4th h from an accumulated 45% to 70% by weight of doxylamine initial content is dissolved;
then, the medium is replaced by a pH = 6.8 medium (0.05 M phosphate buffer) and at 7thh at least an accumulated 80% by weight of doxylamine initial content is dissolved; and from 10% to 35% by weight of pyridoxine content is dissolved at lsth in 0.1 N HCl medium (pH = i);
then, the medium is replaced by a pH = 4.5 medium (0.05 M acetate buffer) and at 4th h from an accumulated 40% to 65% by weight of pyridoxine initial content is dissolved;
then, the medium is replaced by a pH = 6.8 medium (0.05 M phosphate buffer) and at 7thh at least an accumulated 80% by weight of pyridoxine initial content is dissolved;
wherein the dissolution profile is measured using a USP type 2 apparatus (basket), placing the composition in 900mL of the corresponding media / buffered at 37°C ± 0.5 °C and 100 rpm (révolution per minute).
As it is mentioned above, the dosage form of the présent invention is a “multiple unit dosage form”. In an embodiment, the multiple unit dosage form is a capsule filled with the first and the second plurality pellets of the présent invention as subunits having the active ingrédient. In an embodiment, the multiple unit dosage form is a hard capsule.
For the purpose of the invention, the hard capsule is understood as a hard capsule suitable to be used in fully automatic capsule filling machine. Commonly, these capsules are made up of two cylindrical halves, wherein one of them is large in diameter but shorter in length called cap and other is shorter in diameter but longer in length called body. In an embodiment, the multiple unit oral dosage form is a hard capsule having a capsule size from size 0 to size 5. In an embodiment, the multiple unit oral dosage form is a hard capsule having a capsule size from size 1 to size 5. In an embodiment, the multiple unit oral dosage form is a hard capsule having a capsule size from size 1 to size 4. In an embodiment, the multiple unit oral dosage form is a hard capsule having a capsule size of 3. In an embodiment, the multiple unit oral dosage form is a hard capsule having a capsule size of 2. In an embodiment, the multiple unit oral dosage form is a hard capsule having a capsule size of 1. In an embodiment, the multiple unit dosage form of the présent invention is a hard capsule made of a substance selected from the group consisting of gélatine, hydroxypropyl methylcellulose (hypromellose, HPMC), pullulan and a mixture thereof. In an embodiment, the multiple unit dosage form of the présent invention is a gélatine hard capsule. In an embodiment, the multiple unit dosage form of the présent invention is a hydroxypropyl methylcellulose hard capsule.
In an embodiment, the multiple unit dosage form of the présent invention is a hard capsule and comprises from 20 mg to 220 mg of the first plurality of modified release pellets of doxylamine 37 or a pharmaceutically acceptable sait thereof; and from 20 mg to 220 mg of the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof. In an embodiment, the multiple unit dosage form of the présent invention is a hard capsule and comprises from 40 mg to 140 mg of the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof; and from 40 mg to 140 mg of the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof.
In an embodiment, the multiple unit dosage form of the présent invention is a hard capsule and comprises about 60 mg of the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof; and about 60 mg of the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof; particularly the hard capsule has a size selected from size 2 or size 3 or size 4, more particular has a size 3.
In an embodiment, the multiple unit dosage form of the présent invention is a hard capsule and comprises about 120 mg of the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof; and about 120 mg of the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof; particularly the hard capsule has a size selected from size 1, size 2 and size 3. In an embodiment, the multiple unit dosage form of the présent invention is a hard capsule and comprises about 10 mg per capsule of doxylamine succinate and about 10 mg per capsule of pyridoxine hydrochloride; particularly the hard capsule has a size 3. In an embodiment, the multiple unit dosage form of the présent invention is a hard capsule and comprises about 20 mg per capsule of doxylamine succinate and about 20 mg per capsule of pyridoxine hydrochloride; particularly the hard capsule has a size selected from size 1, size 2 and size 3.
For the purpose of the présent invention, the multiple unit dosage form of the présent invention, particularly hard capsules, can be conditioned in appropriate package. The type of package can readily be determined by those skilled in the art according to the type of formulation being prepared. In an embodiment, the modified release multiple unit dosage form of the présent invention is packaged in blisters. In an embodiment, the modified release multiple unit dosage form of the présent invention is packaged in bottles with or without desiccant placed inside the bottle or integrated in the closure System of the bottle).
For the purpose of the invention, the multiple unit dosage form of the présent invention, 38 particularly hard capsules, is primary packaged in blisters or bottles as defined above and secondary packaged in an outer carton. Materials commonly used for assembling the blisters in which the multiple unit dosage form of the présent invention, particularly hard capsules, are primary packaged are PVC (polyvinylchloride), PVdC (polyvinylidene chloride), PE (polyethylene comprising HDPE or high-density polyethylene and LDPE or low-density polyethylene), PET (polyethylene terephthalate), PETG (poly-ethylene terephthalate glycol), PCTFE (polychlorotrifluoroethylene, commercially available as polyAclar®), PVC/PE/PVdC (commercially available as AquaBa®), CGC (Cyclic olefin copolymer), Aluminium or a combination thereof. Materials commonly used for making bottles and the relevant closures or caps, in which the multiple unit dosage form of the présent invention, particularly hard capsules, are primary packaged are glass, aluminium and plastic materials. Example of plastic material are PE (comprising HDPE and LDPE), PET, PP (polypropylene), PVC, PETG, PS (polystyrène), COC, and/or a mixture of more than one plastic material thereof and/or a mixture of one or more plastic material with further additives. Example of plastic material additives are binders, desiccants, plasticizers, flame retardants, antioxidants, acid scavengers, light and heat stabilizers, lubricants, pigments, antistatic agents, slip compounds and thermal stabilizers. Example of desiccants are moisture barrier materials, molecular sieve such as for example zeolites, calcium oxide, activated charcoal, calcium sulphate, calcium chloride and silica. The desiccant can be either mixed/incorporated with a suitable binder in the plastic material used to make the bottle or placed inside the bottle or integrated in the closure System of the bottle.
The inventors hâve surprisingly found out that the primary packaging as defined above, is advantageous in terms of stability. Particularly, they allow the storage at or below 25°C and 60% Relative Humidity. This is advantageous as the multiple unit dosage form of the présent invention would be suitable for long term storage, even in climatic zone I and II countries (temperate and Mediterranean/subtropical zone countries), without particular restrictions for instance without the need to store in a refrigerator.
In an embodiment, the multiple unit dosage form of the présent invention is hard gélatine or HPMC (hydroxypropyl methyl cellulose) capsules having a primary packaged selected from the group consisting of blister made with any of the material mentioned above and plastic bottle made with any plastic material mentioned above without desiccant. They are especially advantageous because are stable allowing storage at or below 25°C and 60% Relative Humidity.
In a particular embodiment, the multiple unit dosage form of the présent invention is hard gélatine or HPMC capsules having a primary packaged in blister made of PVC/PVdC (on one side of the blister) and aluminium (on the other side of the blister) being stable allowing storage at or below 25°C and 60% Relative Humidity. This is advantageous as this type of blister is broadly used and easy to handle from a primary packaging manufacturing step and it is therefore costless.
In a particular embodiment, the multiple unit dosage form of the présent invention is hard capsule made of gélatine or HPMC having a primary packaged in plastic bottles with a desiccant. They are specially advantageous in ternis of stability allowing storage at or below 30°C and 75% Relative Humidity. This is advantageous as the multiple unit dosage form of the présent invention would be suitable for long term storage also in climatic zone III and IV countries (hot dry and hot humid / tropical zone countries) without particular restrictions (for example without the need to store in a refrigerator). An additional advantage is the avoidance of the use of glass bottles that are imperméable containers and can offer maximum protection against moisture but are more fragile and heavier when compared to plastic bottles and are therefore much more difficult to handle from a logistic stand point with increased cost and risk for the manufacturer and the user.
In an embodiment, the multiple unit dosage form of the présent invention is a hard capsule made of gélatine or HPMC having a primary packaged in blister made with materials as define above or plastic bottles with desiccant as a primary package is frirther advantageous in ternis of stability allowing storage at or below 30°C and 75% Relative Humidity. This is advantageous as the multiple unit dosage form of the présent invention would be suitable for long term storage also in climatic zone III and IV countries (hot dry and hot humid / tropical zone countries) without particular restrictions (for example without the need to store in a refrigerator).
In an embodiment, the multiple unit dosage form of the présent invention is hard HPMC capsules having a primary packaged in blister made with materials as defined above and particularly made in AquaBa® or Aluminium (one side of the blister) and Aluminium (the other side of the blister). They are advantageous because they are stable allowing storage at or below 30°C and 75% Relative Humidity. This is further advantageous for the user in climatic zone III and IV countries (hot dry and hot humid / tropical zone countries) because not only it allows storage without particular restrictions (for example without the need to store in a refrigerator) but 40 also because blisters are easier to handle than bottles (for example can be easily kept on hand in case of travelling) and the capsules are individually protected when packed in blister thus allowing a safer and more convenient use.
The second aspect of the présent invention relates to a process for the préparation of the multiple unit oral dosage form of the first aspect of the invention. In particular, this process comprises: (al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and optionally the intermediate enteric coating layer by adding the one or more enteric coating agents, the one or more modified release coating agents, the one or more anticaking agents, optionally one or more pore-forming agent, and optionally one or more pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nucléus hâve a particle size variability of not more than 200 pm; particularly of not more than 150 pm; particularly of not more than 100 pm; and particularly of not more than 75 pm measured by analytical sieving; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by adding the one or more enteric coating agents, the one or more modified release coating agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: wherein the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nucléus hâve a particle size variability of not more than 200 pm; particularly of not more than 150 pm; particularly of not more than 100 pm; and particularly of not more than 75 pm measured by analytical sieving. As it is mentioned above, this process is cheaper, more robust, reproducible and easier to scale-up in comparison with the processes of the State of the art. It allows obtaining homogenous batches of both plurality of pellets in a high yield without losing a considérable or large amount of yield in sieving steps, obtaining a high final yield. Ail embodiments disclosed above for the particle size and particle size variability of the pharmaceutically acceptable nucléus and the first and the second plurality of the pellets, and combination thereof disclosed in the first aspect of the invention also applies for the process of the second aspect of the invention.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and optionally the intermediate enteric coating layer by continuously or discontinuously spraying a liquid mixture comprising one or more enteric coating agents, one or more modified release coating agents, and optionally one or more pharmaceutically acceptable excipients; optionally by doing one or more pauses; and optionally by continuously or discontinuously drying with airflow; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising one or more enteric coating agents, one or more modified release coating agents, and optionally one or more pharmaceutically acceptable excipients; optionally by doing one or more pauses; and optionally by continuously or discontinuously drying with airflow.
In an embodiment, the steps (al) and (bl) of the process of the invention is performed by continuously spraying a liquid mixture as defined above. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by continuously spraying a liquid mixture as defined above and comprising one or more pause periods of time. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by continuously spraying a liquid mixture as defined above and comprising one or more pause periods of time; and by continuously drying with airflow. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by continuously spraying a liquid mixture as defined above and comprising one or more pause periods of time; and by discontinuously drying with airflow.
In an embodiment, the steps (al) and (bl) of the process of the invention is performed by discontinuously spraying a liquid mixture as defined above and comprising one or more pause periods of time. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by discontinuously spraying a liquid mixture as defined above and by continuously drying with airflow. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by discontinuously spraying a liquid mixture as defined above and by discontinuously 42 drying with airflow. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by discontinuously spraying a liquid mixture as defmed above, comprising one or more pause periods of time and by discontinuously drying with airflow.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and optionally the intermediate enteric coating layer by continuously or discontinuously spraying a liquid mixture comprising one or more enteric coating agents, one or more modified release coating agents, and optionally one or more pharmaceutically acceptable excipients; and adding simultaneously or alternately a mixture in powder form comprising one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; optionally by doing one or more pauses; and optionally by continuously or discontinuously drying with airflow; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising one or more enteric coating agents, one or more modified release coating agents, and optionally one or more pharmaceutically acceptable excipients; and adding simultaneously or alternately a mixture in powder form comprising the one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; optionally by doing one or more pauses;
optionally one or more pause periods of time; and optionally by continuously or discontinuously drying with airflow.
In an embodiment, the steps (al) and (bl) of the process of the invention is performed by continuously spraying a liquid mixture as defmed above and adding simultaneously the mixture in powder form. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by continuously spraying a liquid mixture as defmed above and adding alternately a mixture in powder form. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by continuously spraying a liquid mixture as defmed above, adding simultaneously the mixture in powder form; and by continuously drying with airflow. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by continuously 43 spraying a liquid mixture as defined above, adding altemately a mixture in powder form; and by continuously drying with airflow. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by continuously spraying a liquid mixture as defined above, adding simultaneously the mixture in powder form; and by discontinuously drying with airflow. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by continuously spraying a liquid mixture as defined above, adding altemately a mixture in powder form; and by discontinuously drying with airflow.
In an embodiment, the steps (al) and (bl) of the process of the invention is performed by discontinuously spraying the liquid mixture, adding simultaneously the mixture in powder form, and by doing one or more pauses. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by discontinuously spraying the liquid mixture, adding simultaneously the mixture in powder form, and continuously drying with airflow. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by discontinuously spraying the liquid mixture, adding simultaneously the mixture in powder form, and discontinuously drying with airflow. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by discontinuously spraying the liquid mixture, adding simultaneously the mixture in powder form, by doing one or more pauses; and discontinuously drying with airflow. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by discontinuously spraying the liquid mixture, adding altemately the mixture in powder form and by doing one or more pauses. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by discontinuously spraying the liquid mixture, adding altemately the mixture in powder form and continuously drying with airflow. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by discontinuously spraying the liquid mixture, adding altemately the mixture in powder form and discontinuously drying with airflow. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by discontinuously spraying the liquid mixture, adding altemately the mixture in powder form, by doing one or more pauses; and discontinuously drying with airflow. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by discontinuously spraying the liquid mixture and adding simultaneously the mixture in powder form. In an embodiment, the steps (al) and (bl) of the process of the invention is performed by discontinuously spraying the liquid mixture and adding altemately the mixture in powder form.
For the purpose of the invention, the term “liquid mixture” refers to any mixture of one or more of the components as defined in the présent invention, such as for example the coating agents, the modified release coating agents, the pharmaceutically acceptable excipients, the pharmaceutical active ingrédients (pyridoxine and doxylamine) wherein the mixture hâve a liquid State behaviour. The term “liquid state behaviour” refers to a mixture or substance that can flow, has no fixed shape, and is not a solid or a gas. This mixture can be in form of solution or in form of a suspension (or slurry). A solution is a type of homogeneous mixture composed of two or more substances. In such a mixture, a soluté is a substance dissolved in another substance, known as a solvent. A suspension is a heterogeneous mixture that contains solid particles in a liquid solvent. In fact, the solid particles do not dissolve in the liquid solvent.
The term “liquid solvent” refers to any organic and inorganic liquid solvent or a mixture thereof able to solve a compound/component/ingredient creating a liquid solution, or refers to any liquid able to create a suspension or slurry of one of the compounds/components/ingredients or more. The liquid solvent is selected preferably from de group of volatile liquid solvent (boiling point below 125 °C), comprising one or more organic liquid solvent selected from the group consisting of (Ci-C4)alcohol, (Ci-C4)alkyl-CO-(Ci-C4)alkyl, (Ci-C4)alkyl-CO-O-(Ci-C4)alkyl, or water, or mixtures thereof. The term “alcohol” refers to an “alkane” wherein at least one hydrogen atom is substituted by a hydroxyl group and which contains the number of carbon atoms specified in the description or daims. The term alkane refers to a saturated, branched or linear hydrocarbon which contains the number of carbon atoms specified in the description or daims. Examples include methanol, éthanol, n-propanol, iso-propanol, butanol, iso-butanol, and sec-butanol. The term “alkyl” refers to a saturated straight, or branched hydrocarbon chain which contains the number of carbon atoms specified in the description or daims. Examples include, among others, the group methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. In an embodiment, the process is one wherein the mixture comprises one or more organic solvents selected from the group consisting of éthanol, 2-propanol, methanol, acetone, butanone, ethyl acetate, water and a mixture thereof; particularly selected from éthanol, acetone, water and a mixture thereof. There is no limitation regarding the liquid solvent, except that if used for therapeutic purposes, they must be pharmaceutically acceptable.
The term “mixture in powder form” refers to any individual solid compounds/components/ingredients or combination thereof as defined in the présent invention which are solids and in powder form. For the purpose of the invention powder form is considered 45 a solid in powder form when it has a D90 equal to or below than 500 pm, preferably equal to or below than 250 pm, and more preferably equal to or below than 150 pm.
The term “spraying continuously” refers to spraying, during a certain step of the process, continuously over time until ail the liquid to be sprayed is consumed. The term “spraying discontinuously” refers to intermittent and cyclical spraying over time. This means spraying during a certain period of time, stop spraying for another period of time and repeat this “cycle” as many times as necessary until ail the liquid to be sprayed necessary for a spécifie stage of the process is consumed.
The term “adding simultaneously a mixture in powder form” refers to the addition of solids simultaneously over time with respect to the spraying of a liquid mixture during one step of the process. This means that when the powder mixture is added the liquid mixture is also sprayed at the same time. It is possible that the spraying is permanent and continuous or that, on the contrary, it is intermittent, although it always coïncides with the spraying, whether it is continuous or discontinuous spraying. The term “adding altemately a mixture in powder form” refers to the addition of a mixture of solids in powder form a non-simultaneous manner, which is intermittent and discontinuous with respect to the spraying of liquid mixtures that is also intermittently and discontinuously, cyclically (in a “cycle”) repeating this process until completing the addition of solids in the form of powder and / or liquid mixture spray.
The term “continuously drying” refers to the fact of drying with airflow the pellets into the coating pan during ail the period of time the coating step is in progress, regardless of whether the spraying is continuous or discontinuous, or the addition of solid is simultaneous or altemate. The term “discontinuously drying” refers to the fact of drying with airflow the pellets into the coating pan only for a certain period of time within a “cycle” regardless of whether the spraying is continuous or discontinuous, or the addition of solid is simultaneous or altemate.
The term “airflow” refers to a dry air flow, at a température from 5 to 90 °C, measured in m3 / h.
The term “pause” refers to a certain period of time during a “cycle” repeated during a coating step, wherein there’s no spray of any liquid mixture, no addition of any solid mixture in powder form and no drying with airflow. During this time, the coating pan is only spinning and mixing and homogenizing the pellets. The term “cycle” refers to a sequence that lasts a certain period of 46 time of a coating step, this sequence is repeated continuously as many times as necessary until completing the coating step. This cycle comprises at least a certain period of spraying a liquid mixture, equal to or below than the cycle period of time; optionally a certain period of adding a mixture in powder form, equal to or below than the cycle period of time, optionally one or more pause periods of time, lower than the cycle period of time; optionally a drying period of time, equal to or below than the cycle period of time.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the second aspect of the invention comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and optionally the intermediate enteric coating layer by adding the one or more enteric coating agents, the one or more modified release coating agents, the one or more anticaking agents, optionally one or more pore-forming agent, and optionally one or more pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nucléus hâve a particle size variability of not more than 200 pm; particularly a particle size variability of not more than 150 pm; particularly a particle size variability of not more than 100 pm; and particularly a particle size variability of not more than 75 pm measured by analytical sieving; and the sum of the enteric coating agents and the modified release coating agents in the spraying liquid mixture is from 10% to 49% by weight in relation to the weight of the liquid mixture; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by adding the one or more enteric coating agents, the one or more modified release coating agents, the one or more anticaking agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nucléus hâve a particle size variability of not more than 200 pm; particularly a particle size variability of not more than 150 pm; particularly a particle size variability of not more than 100 pm; and particularly a particle size variability of not more than 75 pm measured by analytical sieving;
and the sum of the enteric coating agents and the modified release coating agents in the spraying liquid mixture is from 10% to 49% by weight in relation to the weight of the liquid mixture. Ail embodiments disclosed above for the particle size and particle size variability of the pharmaceutically acceptable nucléus and the first and the second plurality of the pellets, and combination thereof disclosed in the first aspect of the invention also applies for the process of the second aspect of the invention.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and optionally the intermediate enteric coating layer by continuously or discontinuously spraying a liquid mixture comprising from 1.0 to 7.5 % by weight of the one or more enteric coating agents, from 10.0 to 35.0 % by weight of the one or more modified release coating agents and the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nucléus hâve a particle size variability of not more than 200 pm; particularly a particle size variability of not more than 150 pm; particularly a particle size variability of not more than 100 pm; and particularly a particle size variability of not more than 75 pm measured by analytical sieving, and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising from 1.0 to 7.5 % by weight of the one or more enteric coating agents, from 10.0 to 35.0 % by weight of the one or more modified release coating agents and the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nucléus hâve a particle size variability of not more than 200 pm; particularly a particle size variability of not more than 150 pm; particularly a particle size variability of not more than 100 pm and particularly a particle size variability of not more than 75 pm measured by analytical sieving. Ail embodiments disclosed above for the particle size and particle size variability of the pharmaceutically acceptable nucléus and the first and the second plurality of the pellets, and combination thereof disclosed in the first aspect of the invention also applies for the process of the second aspect of the invention.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and optionally the intermediate enteric coating layer by continuously or discontinuously spraying a liquid mixture wherein the weight ratio between the one or more enteric coating agents and the one or more modified release coating agents in the spraying mixture is from 5:95 to 30:70, and the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nucléus hâve a particle size variability of not more than 200 pm; particularly a particle size variability of not more than 150 pm; particularly a particle size variability of not more than 100 pm; and particularly a particle size variability of not more than 75 pm measured by analytical sieving, and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture wherein the weight ratio between the one or more enteric coating agents and the one or more modified release coating agents in the spraying mixture is from 5:95 to 30:70 and the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nucléus hâve a particle size variability of not more than 200 pm; particularly a particle size variability of not more than 150 pm; particularly a particle size variability of not more than 100 pm; and particularly a particle size variability of not more than 75 pm measured by analytical sieving. Ail embodiments disclosed above for the particle size and particle size variability of the pharmaceutically acceptable nucléus and the first and the second plurality of the pellets, and combination thereof disclosed in the first aspect of the invention also applies for the process of the second aspect of the invention.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and optionally the intermediate enteric coating layer 49 by continuously or discontinuously spraying a liquid mixture comprising from 1.0 to 7.5 % by weight of the one or more enteric coating agents, from 10.0 to 35.0 % by weight of the one or more modified release coating agents, wherein the weight ratio between the one or more enteric coating agents and the one or more modified release coating agents in the spraying mixture is from 5:95 to 30:70 and the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nucléus hâve a particle size variability of not more than 200 pm; particularly a particle size variability of not more than 150 pm; particularly a particle size variability of not more than 100 pm; and particularly a particle size variability of not more than 75 pm measured by analytical sieving, and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising from 1.0 to 7.5 % by weight of the one or more enteric coating agents, from 10.0 to 35.0 % by weight of the one or more modified release coating agents, wherein the weight ratio between the one or more enteric coating agents and the one or more modified release coating agents in the spraying mixture is from 5:95 to 30:70 and the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nucléus hâve a particle size variability of not more than 200 pm; particularly a particle size variability of not more than 150 pm; particularly a particle size variability of not more than 100 pm; and particularly a particle size variability of not more than 75 pm measured by analytical sieving. Ail embodiments disclosed above for the particle size and particle size variability of the pharmaceutically acceptable nucléus and the first and the second plurality of the pellets, and combination thereof disclosed in the first aspect of the invention also applies for the process of the second aspect of the invention.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof, wherein the spray average flow rate of the mixture comprising the coating is from 0.30 to 5.00 g/min per kg of pharmaceutically acceptable inert nucléus; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof, wherein the spray average flow rate of the mixture comprising the coating agents is from 0.30 to 5.00 g/min per kg of pharmaceutically acceptable inert nucléus.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof, wherein the spray local flow rate of the mixture comprising the coating is from 0.30 to 9.00 g/min per kg of pharmaceutically acceptable inert nucléus; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof, wherein the spray local flow rate of the mixture comprising the coating is from 0.30 to 9.00 g/min per kg of pharmaceutically acceptable inert nucléus.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof, wherein the average of the solid addition rate of the mixture in solid form is from 0.95 to 18 g/min per Kg of pharmaceutically acceptable inert nucléus; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof, wherein; the average of the solid addition rate of the mixture in solid form is from 0.10 to 2.25 g/min per Kg of pharmaceutically acceptable inert nucléus.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof, wherein the local solid addition rate of the mixture in solid form is from 0.95 to 40.00 g/min per Kg of pharmaceutically acceptable inert nucléus; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof, wherein the local solid addition rate of the mixture in solid form is from 0.10 to 40.00 g/min per Kg of pharmaceutically acceptable inert nucléus.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof, wherein the relation between the spray average flow rate of the liquid mixture comprising the coating agents and the average of the solid addition rate of the mixture in solid form is from 90:10 to 60:40, particularly from 90:10 to 70:30; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof, the relation between the spray average flow rate of the liquid mixture comprising the coating agents and the average of the solid addition rate of the mixture in solid form is from 90:10 to 60:40, particularly from 80:20 to 60:40.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof, wherein the spray average flow rate of the liquid mixture comprising the coating agents is from 0.30 to 5.00 g/min per kg of pharmaceutically acceptable inert nucléus and the average of the solid addition rate of the mixture in solid form is from 0.95 to 18.00 g/min per Kg of pharmaceutically acceptable inert nucléus; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof, wherein the spray average flow rate of the liquid mixture comprising the coating agents is from 0.30 to 5.00 g/min per kg of pharmaceutically acceptable inert nucléus; the average of the solid addition rate of the mixture in solid form is from 0.10 to 2.25 g/min per Kg of pharmaceutically acceptable inert nucléus.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof, wherein the spray local flow rate of the liquid mixture comprising the coating agents is from 0.30 to 9.00 g/min per kg of pharmaceutically acceptable inert nucléus, and the local solid addition rate of the mixture in solid form is from 0.95 to 40.00 g/min per Kg of inert nucléus; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof, wherein the spray local flow rate of the liquid mixture comprising the coating agents is from 0.30 to 9.00 g/min per kg of pharmaceutically acceptable inert nucléus, and the local solid addition rate of the mixture in solid form is from 0.10 to 40.00 g/min per Kg of inert nucléus.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof, wherein: the spray average flow rate of the liquid mixture comprising the coating agents is from 0.30 to 5.00 g/min per kg of pharmaceutically acceptable inert nucléus, the average of the solid addition rate of the mixture in solid form is from 0.95 to 18.00 g/min per Kg of pharmaceutically acceptable inert nucléus, and the relation between the spray average flow rate of the liquid mixture comprising the coating agents and the average of the solid addition rate of the mixture in solid form is from 90:10 to 60:40, particularly from 90:10 to 70:30;
and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof, wherein: the spray average flow rate of the mixture comprising the coating agents is from 0.30 to 5.00 g/min per kg of pharmaceutically acceptable inert nucléus; the average of the solid addition rate of the mixture in solid form is from 0.10 to 2.25 g/min per Kg of pharmaceutically acceptable inert nucléus, and the relation between the average spray flow rate of the liquid mixture comprising the coating agents and the average of the solid addition rate of the mixture in solid form is from 90:10 to 60:40, particularly from 80:20 to 60:40.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof, wherein: the spray local flow rate of the mixture comprising the coating is from 0.30 to 9.00 g/min per kg of pharmaceutically acceptable inert nucléus, and the local solid addition rate of the mixture in solid form is from 0.95 to 40.00 g/min per Kg of inert nucléus; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof, wherein: the spray local flow rate of the mixture comprising the coating is from 0.30 to 9.00 g/min per kg of pharmaceutically acceptable inert, nucléus, and the local solid addition rate of the mixture in solid form is from 0.10 to 40.00 g/min per Kg of inert nucléus.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and optionally the intermediate enteric coating layer by continuously or discontinuously spraying a liquid mixture comprising from 1.0 to 7.5 % by weight of the one or more enteric coating agents, from 10.0 to 35.0 % by weight of the one or more modified release coating agents in a weight ratio between them from 5:95 to 30:70, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising the one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the spray average flow rate of the mixture comprising the coating is from 0.30 to 5.00 g/min per kg of pharmaceutically acceptable inert nucléus; the average of the solid addition rate of the mixture in solid form is from 0.05 to 1.50 g/min per Kg of pharmaceutically acceptable inert nucléus; and the relation between the spray average flow rate of the mixture comprising the coating agents and the average of the solid addition rate of the mixture in solid form is from 90:10 to 60:40, particularly from 90:10 to 70:30; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising from 1.0 to 7.5 % by weight of the one or more enteric coating agents, from 10.0 to 35.0 % by weight of the one or more modified release coating agents in a weight ratio from 5:95 to 30:70; and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the spray average flow rate of the mixture comprising the coating agents is from 0.30 to 5.00 g/min per kg of pharmaceutically acceptable inert nucléus; the average of the solid addition rate of the mixture in solid form is from 0.10 to 2.25 g/min per Kg of pharmaceutically acceptable inert nucléus; and the relation between the spray average flow rate of the mixture comprising the coating agents and the average of the solid addition rate of the mixture in solid form is from 90:10 to 60:40, particularly from 80:20 to 60:40.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and optionally the intermediate enteric coating layer by continuously or discontinuously spraying a liquid mixture comprising from 1.0 to 7.5 % by weight of the one or more enteric coating agents, from 10.0 to 35.0 % by weight of the one or more modified release coating agents in a weight ratio between them from 5:95 to 30:70, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising the one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the spray local flow rate of the mixture comprising the coating is from 0.30 to 9.00 g/min per kg of pharmaceutically acceptable inert nucléus, and the local solid addition rate of the mixture in solid form is from 0.95 to 40.00 g/min per Kg of inert nucléus; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising from 1.0 to 7.5 % by weight of the one or more enteric coating agents, from 10.0 to 35.0 % by weight of the one or more modified release coating agents in a weight ratio from 5:95 to 30:70; and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the spray local flow rate of the mixture comprising the coating is from 0.30 to 9.00 g/min per kg of pharmaceutically acceptable inert nucléus, and the local solid addition rate of the mixture in solid form is from 0.10 to 40.00 g/min per Kg of inert nucléus.
The term “spray average flow rate” refers to the average rate of spraying during a cycle, which corresponds also to the average rate of spraying of the corresponding coating step, understanding it as the resuit of dividing the total amount sprayed during a cycle by the period of time required to complété this cycle, which is the same resuit of dividing the total amount of liquid mixture to be sprayed during a coating step by the time required to complété the coating step, commonly expressed in g/min or in this document also in g/min per kg of pharmaceutically acceptable inert nucléus. The spray average flow rate can be measured by any known method of the State of the art. And, the term “spray local flow rate” refers to the real flow rate, considering one or more guns working in parallel at the same time in a gun System, that the combination (sum) of ail the guns of this gun System is offering when the guns are working (spraying). The spray local flow rate can be measured by any known method of the State of the art. For the purpose of the présent invention the “spray local flow rate” is measured by a previous calibration of the corresponding pump of the spraying guns, for a certain pumping value, dividing the sprayed volume by the time the pump is working, or using a massic sensor or a flowmeter during the spraying period of time. Thus, the différence between the “spray average flow rate” and the “spray local flow rate” is that the local flow rate is the real flow rate the guns System is offering when is working (spraying) and the average spraying flow rate is the average during a cycle or the coating step (g of sprayed liquid mixture per minute). Obviously, the average spraying flow rate is lower than the local spraying flow rate when the liquid mixture is sprayed discontinuously and equal when the liquid mixture is sprayed continuously.
The term “average of the solid addition rate” refers to the average rate of addition of a solid mixture in powder form during a cycle, which corresponds also to the average rate of powder addition of the corresponding coating step, understanding it as the resuit of dividing the total added amount during a cycle by the period of time required to complété this cycle, which is the same resuit of dividing the total amount of solid/powder/mixture to be added during a coating step by the time required to complété this coating step, commonly expressed in g/min or in this document also in g/min per kg of pharmaceutically acceptable inert nucléus. The average of the solid addition rate can be measured by any known method of the State of the art. And, the term “local solid addition rate” refers to the real solid addition rate the corresponding powder screw feeder is offering, or even the addition rate which corresponds to the amount added by hands in the short period of time required to add the solid by hands. The local solid addition rate can be measured by any known method of the state of the art. For the purpose of the présent invention the “local solid addition rate” is measured by a previous calibration of the corresponding screw feeder or by weighting the amount of powder added by hands during the period of time required for the local addition. Thus, the différence between the “average of the solid addition rate” and the “local solid addition rate” is that the local powder addition rate is the real addition rate the screw feeder is offering or the addition by hands (with a shovel) is also offering when the powder addition is working, and the average powder addition rate is the average during a cycle or during the coating step (g of added powder per minute). Obviously, the average powder addition rate is lower than the local powder addition rate when the liquid mixture is sprayed discontinuously and the powder is added simultaneously or altemately, and when the liquid mixture is sprayed continuously but the powder is added altemately, and is equal than the local powder addition rate only when the liquid mixture is sprayed continuously and the powder is added simultaneously.
The expression “relation between the spray average flow rate of the mixture comprising the coating agents and the average of the solid addition rate” refers to the relationship between both rates. This relation can be measured by dividing one by the other. And, the expression “relation between the spray local flow rate of the mixture comprising the coating agents and the local solid addition rate” refers to refers to the relationship between both rates. This relation can be measured by dividing one by the other.
As it is disclosed above, the multiple unit dosage form of the first aspect of the invention as defined above optionally comprises an intermediate enteric release coating layer comprising one or more enteric coating agents, one or more anticaking agents, optionally one or more pore-forming agent; and optionally one or more pharmaceutically acceptable excipients.
In an embodiment, the process of the invention comprises preparing a multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer comprising one or more enteric coating agents, one or more anticaking agents, optionally one or more pore-forming agent; and optionally one or more pharmaceutically acceptable excipients.
In an embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, then the process further comprises a previous step of coating separately:
(a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, and optionally one or more pharmaceutically acceptable excipients; and , (b2) the pharmaceutically acceptable inert nucléus by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients.
In an embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, then the process further comprises a previous step of coating separately:
(a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in solid form comprising the one or more anticaking agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; and (b2) the pharmaceutically acceptable inert nucléus by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding in powder form the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients.
In an embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, then the process further comprises a previous step of coating separately:
(a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising from 5 to 15% by weight of the one or more enteric coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form from 5.0 to 6.5 g per kg of pharmaceutically acceptable inert nucléus of the mixture in solid form comprising the one or more anticaking agents, optionally the one or more poreforming agents, and optionally one or more pharmaceutically acceptable excipients;
and (b2) the pharmaceutically acceptable inert nucléus with a simultaneously or altemately spraying a liquid mixture comprising from 20% to 45% by weight of one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding in powder form the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients.
In an embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, then the process further comprises a previous step of coating separately:
(a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or alternately adding a mixture in solid form comprising the one or more anticaking agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; wherein: the average of the spray flow rate of the mixture comprising the enteric coating agents is from 0.30 to 3.00 g/min per kg of pharmaceutically acceptable inert nucléus; and (b2) the pharmaceutically acceptable inert nucléus by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or alternately adding in powder form the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients; wherein: the average spray flow rate of the mixture comprising the coating agents is from 0.30 to 4.50 g/min per Kg of pharmaceutically acceptable inert nucléus.
In an embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defmed above comprises an intermediate enteric release coating layer, then the process further comprises a previous step of coating separately:
(a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or alternately adding a mixture in solid form comprising the one or more anticaking agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; wherein: the local spray flow rate of the mixture comprising the enteric coating agents is from 0.3 to 8.0 g/min per kg of pharmaceutically acceptable inert nucléus; and (b2) the pharmaceutically acceptable inert nucléus by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or alternately adding in powder form the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients; wherein: the local spray flow rate of the mixture comprising the coating agents is from 0.30 to 9.0 g/min per Kg of pharmaceutically acceptable inert nucléus.
In an embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, then the process further comprises a previous step of coating separately:
(a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in solid form comprising the one or more anticaking agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; wherein: the average of the solid addition rate of the mixture in solid form is from 0.025 to 0.40 g/min per Kg of pharmaceutically acceptable inert nucléus; and (b2) the pharmaceutically acceptable inert nucléus by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding in powder form the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients; wherein: the average of the solid addition rate of the powder is from 0.50 to 9.0 g/min per Kg of pharmaceutically acceptable inert nucléus.
In an embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, then the process further comprises a previous step of coating separately:
(a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in solid form comprising the one or more anticaking agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; wherein: the local solid addition rate of the mixture in solid form is from 0.025 to 40.0 g/min per Kg of pharmaceutically acceptable inert nucléus; and (b2) the pharmaceutically acceptable inert nucléus by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or alternately adding in powder form the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients; wherein: the local solid addition rate of the powder is from 0.95 to 40.0 g/min per Kg of pharmaceutically acceptable inert nucléus.
In an embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, then the process further comprises a previous step of coating separately:
(a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or alternately adding a mixture in solid form comprising the one or more anticaking agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; wherein: the relation between the average spray flow rate of the mixture comprising the coating agents and the average of solid addition rate of the mixture in solid form is from 85:15 to 95:5; and (b2) the pharmaceutically acceptable inert nucléus by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or alternately adding in powder form the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients; wherein: the relation between the average spray flow rate of the mixture comprising the coating agents and the average of the solid addition rate is from 25:75 to 40:60.
In an embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, then the process further comprises a previous step of coating separately:
(a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or alternately adding a mixture in solid form comprising the one or more anticaking agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; wherein: the average of the spray flow rate of the mixture comprising the enteric coating agents is from 0.30 to 3.00 g/min per kg of pharmaceutically acceptable inert nucléus, the average of the solid addition rate of the mixture in solid form is from 0.025 to 0.40 g/min per Kg of pharmaceutically acceptable inert nucléus; and the relation between the average spray flow rate of the mixture comprising the coating agents and the average of solid addition rate of the mixture in solid form is from 85:15 to 95:5; and (b2) the pharmaceutically acceptable inert nucléus by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding in powder form the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients; wherein: the average spray flow rate of the mixture comprising the coating agents is from 0.30 to 4.50 g/min per Kg of pharmaceutically acceptable inert nucléus, the average of the solid addition rate of the powder is from 0.50 to 9.0 g/min per Kg of pharmaceutically acceptable inert nucléus, and the relation between the average spray flow rate of the mixture comprising the coating agents and the average of the solid addition rate is from 25:75 to 40:60.
In an embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, then the process further comprises a previous step of coating separately:
(a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in solid form comprising the one or more anticaking agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; wherein: the local spray flow rate of the mixture comprising the enteric coating agents is from 0.3 to 8.0 g/min per kg of pharmaceutically acceptable inert nucléus and the local solid addition rate of the mixture in solid form is from 0.025 to 40.0 g/min per Kg of pharmaceutically acceptable inert nucléus; and (b2) the pharmaceutically acceptable inert nucléus by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding in powder form the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients; wherein: the local spray flow rate of the mixture comprising the coating agents is from 0.30 to 9.0 g/min per Kg of pharmaceutically acceptable inert nucléus and the local solid addition rate of the powder is from 0.95 to 40.0 g/min per Kg of pharmaceutically acceptable inert nucléus.
In an embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, then the process further comprises a previous step of coating separately:
(a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising from 5 to 15% by weight of the one or more enteric coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form from 5.0 to 6.5 g per kg of pharmaceutically acceptable inert nucléus of the mixture in solid form comprising the one or more anticaking agents, optionally the one or more poreforming agents, and optionally one or more pharmaceutically acceptable excipients; wherein: the average of the spray flow rate of the mixture comprising the enteric coating agents is from 0.30 to 3.00 g/min per kg of pharmaceutically acceptable inert nucléus; the average of the solid addition rate of the mixture in solid form is from 0.025 to 0.400 g/min per Kg of pharmaceutically acceptable inert nucléus; and the relation between the average spray flow rate of the mixture comprising the coating agents and the average of solid addition rate of the mixture in solid form is from 85:15 to 95:5; and (b2) the pharmaceutically acceptable inert nucléus with a simultaneously or altemately spraying a liquid mixture comprising from 20% to 45% by weight of one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding in powder form the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients: wherein the average spray flow rate of the mixture comprising the coating agents is from 0.30 to 4.50 g/min per Kg of pharmaceutically acceptable inert nucléus; the average of the solid addition rate of the powder is from 0.50 to 9.00 g/min per Kg of pharmaceutically acceptable inert nucléus; and the relation between the average spray flow rate of the mixture comprising the coating agents and the average of the solid addition rate is from 25:75 to 40:60.
In an embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, then the process further comprises a previous step of coating separately:
(a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising from 5 to 15% by weight of the one or more enteric coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form from 5.0 to 6.5 g per kg of pharmaceutically acceptable inert nucléus of the mixture in solid form comprising the one or more anticaking agents, optionally the one or more poreforming agents, and optionally one or more pharmaceutically acceptable excipients; wherein: the local spray flow rate of the mixture comprising the enteric coating agents is from 0.3 to 8.0 g/min per kg of pharmaceutically acceptable inert nucléus and the local solid addition rate of the mixture in solid form is from 0.025 to 40.0 g/min per Kg of pharmaceutically acceptable inert nucléus; and (b2) the pharmaceutically acceptable inert nucléus with a simultaneously or altemately spraying a liquid mixture comprising from 20% to 45% by weight of one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding in powder form the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients, wherein: the local spray flow rate of the mixture comprising the coating agents is from 0.30 to 9.0 g/min per Kg of pharmaceutically acceptable inert nucléus and the local solid addition rate of the powder is from 0.95 to 40.0 g/min per Kg of pharmaceutically acceptable inert nucléus.
In an embodiment, the process of the invention comprises preparing a multiple unit dosage form of the first aspect of the invention as defined above which does not comprises an intermediate enteric release coating layer comprising one or more enteric coating agents, one or more anticaking agents, optionally one or more pore-forming agent; and optionally one or more pharmaceutically acceptable excipients. In an embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above does not comprises the intermediate enteric release coating layer, then the process further comprises performing step (b2) as defined above. Ail the embodiments disclosed above for step (b2) of the process for preparing a multiple dosage form of the présent invention comprising the intermediate enteric release coating layer also apply for the process for preparing the multiple unit dosage form which does not comprises the intermediate enteric release coating layer.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises a previous step (a3) of coating the pharmaceutically acceptable inert nucléus with a continuously or discontinuously spraying a 64 liquid mixture comprising one or more coating agents, the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises a previous step (a3) of coating the pharmaceutically acceptable inert nucléus with a continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, one or more anticaking, optionally one or more poreforming agents, and optionally one or more pharmaceutically acceptable excipients.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises a previous step (a3) of coating the pharmaceutically acceptable inert nucléus with a continuously or discontinuously spraying a liquid mixture comprising from 15% to 40% by weight of one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, from 18 to 36% by weight of the one or more anticaking, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises a previous step (a3) of coating the pharmaceutically acceptable inert nucléus with a continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, one or more anticaking, optionally one or more poreforming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the average spray flow rate of the mixture comprising the coating agents is from 0.30 to 4.50 g/min per Kg of pharmaceutically acceptable inert nucléus.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises a previous step (a3) of coating the pharmaceutically acceptable inert nucléus with a continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, one or more anticaking, optionally one or more poreforming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the local spray flow rate of the mixture comprising the coating agents is from 0.30 to 9.0 g/min per Kg of pharmaceutically acceptable inert nucléus. ,
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises a previous step (a3) of coating the pharmaceutically acceptable inert nucléus with a continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, one or more anticaking, optionally one or more poreforming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the average of the solid addition rate of the mixture in powder form is from 0.95 to 18.0 g/min per Kg of pharmaceutically acceptable inert nucléus.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention as defined above fùrther comprises a previous step (a3) of coating the pharmaceutically acceptable inert nucléus with a continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, one or more anticaking, optionally one or more poreforming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the local solid addition rate of the mixture in powder form is from 0.95 to 40.0 g/min per Kg of pharmaceutically acceptable inert nucléus.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises a previous step (a3) of coating the pharmaceutically acceptable inert nucléus with a continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, one or more anticaking, optionally one or more poreforming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the relation between the average spray flow rate of the mixture comprising the coating agents and the average of the solid addition rate of the mixture in powder form is from 15:85 to 30:70.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises a previous step (a3) of coating the pharmaceutically acceptable inert nucléus with a continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, one or more anticaking, optionally one or more poreforming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the average spray flow rate of the mixture comprising the coating agents is from 0.30 to 4.50 g/min per Kg of pharmaceutically acceptable inert nucléus and the average of the solid addition rate of the mixture in powder form is from 0.95 to 18.0 g/min per Kg of pharmaceutically acceptable inert nucléus; and particularly the relation between the average spray flow rate of the mixture comprising the coating agents and the average of the solid addition rate of the mixture in powder form is from 15:85 to 30:70.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises a previous step (a3) of coating the pharmaceutically acceptable inert nucléus with a continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, one or more anticaking, optionally one or more poreforming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the 67 local spray flow rate of the mixture comprising the coating agents is from 0.30 to 9.0 g/min per Kg of pharmaceutically acceptable inert nucléus and the local solid addition rate of the mixture in powder form is from 0.95 to 40.0 g/min per Kg of pharmaceutically acceptable inert nucléus. In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention as defîned above further comprises a previous step (a3) of coating the pharmaceutically acceptable inert nucléus with a continuously or discontinuously spraying a liquid mixture comprising from 15% to 40% by weight of one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, from 18 to 36% by weight of the one or more anticaking, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; wherein: the average spray flow rate of the mixture comprising the coating agents is from 0.30 to 4.50 g/min per Kg of pharmaceutically acceptable inert nucléus; the average of the solid addition rate of the mixture in powder form is from 0.95 to 18.00 g/min per Kg of pharmaceutically acceptable inert nucléus; and the relation between the average spray flow rate of the mixture comprising the coating agents and the average of the solid addition rate of the mixture in powder form is from 15:85 to 30:70.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises a previous step (a3) of coating the pharmaceutically acceptable inert nucléus with a continuously or discontinuously spraying a liquid mixture comprising from 15% to 40% by weight of one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, from 18 to 36% by weight of the one or more anticaking, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; wherein: the local spray flow rate of the mixture comprising the coating agents is from 0.30 to 9.0 g/min per Kg of pharmaceutically acceptable inert nucléus and the local solid addition rate of the mixture in powder form is from 0.95 to 40.0 g/min per Kg of pharmaceutically acceptable inert nucléus.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or 68 a pharmaceutically acceptable sait thereof by performing steps (a2) and (al) as defined above. In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pharmaceutically acceptable inert nucléus by performing steps (a3), (a2) and (al) as defined above. In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof by performing steps (a3) and (al) as defined above.
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pharmaceutically acceptable inert nucléus performing steps (b2) and (bl).
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises preparing separately: the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof by performing steps (a2) and (al) as defined above; and the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating pharmaceutically acceptable inert nucléus performing steps (b2) and (bl).
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises preparing separately: the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pharmaceutically acceptable inert nucléus performing steps (a3), (a2) and (al) as defined above; and the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pharmaceutically acceptable inert nucléus performing steps (b2) and (bl).
In an embodiment, the process for the préparation of the multiple unit oral dosage form of the first aspect of the invention comprises preparing separately: the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pharmaceutically acceptable inert nucléus performing steps (a3) and (al) as defmed above; and the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pharmaceutically acceptable inert nucléus performing steps (b2) and (bl).
In an embodiment, each one of the coating steps of the process of the invention are performed at an air température from 5°C to 80°C; particularly from 20°C to 70°C; more particularly from 25°C to 65°C and much more particularly from 25°C to 55°C. In an embodiment, each one of the coating steps of the process of the invention are performed at an airflow from 0 a 20 m3/h per Kg of pharmaceutically acceptable inert nucléus; particularly from 0 to 6 m3 /h per Kg of pharmaceutically acceptable inert nucléus. The airflow is controlled using an anemometer type air inlet détection System. In an embodiment, each one of the coating steps of the process of the invention are performed at an air température from 5°C to 80°C and at an airflow from 0 a 20 m3/h per Kg of pharmaceutically acceptable inert nucléus.
In an embodiment, each one of the coating steps of the process of the invention which comprises a spraying mixture of one or more enteric coating agents and one or more modified release coating agents as defined above; particularly the enteric coating is methacrylic acid-methyl méthacrylate copolymer; and the modified release coating agent is shellac. In an embodiment, each one of the coating steps of the process of the invention which comprises a spraying mixture of one or more enteric coating agents and one or more modified release coating agents, the enteric coating is methacrylic acid-methyl méthacrylate copolymer, particularly methacrylic acid-methyl méthacrylate copolymer (1:1) (Eudragit L); and the modified release coating agent is shellac. In an embodiment, each one of the coating steps of the process of the invention which comprises a spraying mixture comprising one or more enteric coating agents and one or more modified release coating agents, the enteric coating is methacrylic acid-methyl méthacrylate copolymer, particularly methacrylic acid-methyl méthacrylate copolymer (1:1) (Eudragit L); and the modified release coating agent is shellac in a weight ratio from 5:95 to 30:70; particularly from 8:92 to 20:80.
In an embodiment, in the coating step of step (al) of the process of the invention which comprises a spraying mixture comprising one or more enteric coating agents and one or more modified release coating agents, the spraying mixture comprises from 4 to 7% by weight of the enteric coating agents, particularly methacrylic acid-methyl méthacrylate copolymer (1:1) (Eudragit L) and from 15 to 25 % by weight of modified release coating agent, particularly (dewaxed) shellac. In an embodiment, in the coating step of step (al) of the process of the invention which comprises a spraying mixture comprising one or more enteric coating agents and one or more modified release coating agents, the spraying mixture comprises from 4 to 7% by weight of the enteric coating agents, particularly methacrylic acid-methyl méthacrylate copolymer (1:1) (Eudragit L) and from 15 to 25 % by weight of modified release coating agent, particularly (dewaxed) shellac in a weight ratio from 15:85 to 30:70. In an embodiment, in the coating step of step (bl) of the process of the invention which comprises a spraying mixture comprising one or more enteric coating agents and one or more modified release coating agents, the spraying mixture comprises from 2.0 to 7.5% by weight of the enteric coating agents and from 10 to 35% of the modified release coating agents; particularly from 20 to 35%. In an embodiment, in the coating step of step (bl) of the process of the invention which comprises a spraying mixture comprising one or more enteric coating agents and one or more modified release coating agents, the spraying mixture comprises from 2.0 to 7.5% by weight of the enteric coating agents and from 10 to 35% of the modified release coating agents; particularly from 20 to 35% in a weight ratio from 5:95 to 15:85.
In an embodiment, in the coating step of step (bl) of the process of the invention which comprises a spraying mixture comprising one or more enteric coating agents and one or more modified release coating agents, the spraying mixture comprises from 2.0 to 7.5% by weight of methacrylic acid-methyl méthacrylate copolymer (1:1) (Eudragit L) as the enteric coating agents and from 10 to 35% by weight of (dewaxed) shellac as the modified release coating agents; particularly from 20 to 35%. In an embodiment, in the coating step of step (bl) of the process of the invention which comprises a spraying mixture comprising one or more enteric coating agents and one or more modified release coating agents, the spraying mixture comprises from 2.0 to 7.5% by weight of methacrylic acid-methyl méthacrylate copolymer (1:1) (Eudragit L) as the enteric coating agents and from 10 to 35% by weight of (dewaxed) shellac as the modified release coating agents; particularly from 20 to 35% in a weight ratio from 5:95 to 15:85.
In an embodiment, in the coating step (a3) of the process of the invention, the coating agents are selected from the group consisting of polyvinylpyrrolidone, shellac, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and microcrystalline cellulose and mixture thereof; particularly a mixture of polyvinylpyrrolidone and shellac. In an embodiment, in the coating step (a3) of the process of the invention, the coating agent is a mixture of polyvinylpyrrolidone, particularly K30, and shellac in a weight ratio from 20:80 to 30:70. In an embodiment, in the coating step (a3) of the process of the invention, the spraying mixture comprises from 30 to 40% by weight of one or more coating agents as defined above. In a particular embodiment, in the coating step (a3) the spraying mixture comprises from 30 to 40% by weight of a mixture of polyvinylpyrrolidone K30 and (dewaxed) shellac in a weight ratio from polyvinylpyrrolidone and shellac from 20:80 to 30:70. In a particular embodiment, in the coating step (a3) the spraying mixture comprises one or more organic solvents as defrned above and below; particularly, the mixture comprises an amount of solvent concentration from 0 to 70% by weight. In a particular embodiment, in the coating step (a3) the spraying mixture is a solution of polyvinylpyrrolidone K-30 20% in éthanol and a solution of (dewaxed) shellac 40% w/w in éthanol in a weight ratio from 20:80 to 40:60; particularly 30:70.
In an embodiment, in the coating step (b2) of the process of the invention, the spraying mixture comprises from 20 to 45% of one or more coating agents. In an embodiment, in the coating step (b2) of the process of the invention, the coating agents are selected from the group consisting of microcrystalline cellulose, hydroxypropyl methyl cellulose (HPMC), polyvinyl pyrrolidone (PVP), shellac, polyethylene glycol (PEG) 6000, guar gum and starch; particularly (dewaxed) shellac; particularly shellac. In a particular embodiment, in the coating step (b2) the spraying mixture comprises from 30 to 45% by weight of a (dewaxed) shellac. In a particular embodiment, in the coating step (b2) the spraying mixture comprises one or more organic solvents as defrned above and below; particularly éthanol.
In an embodiment, in the coating step (a2) of the process of the invention, the enteric coating agents are those defrned above and below; particularly methacrylic acid-methyl méthacrylate copolymer (Eudragit L). In an embodiment, in the coating step (a2) of the process of the invention, the spraying mixture comprises from 5 to 15% by weight of one or more enteric coating agents.
In an embodiment, in coating step (a2) of the process of the invention, the spraying mixture comprises from 5 to 15% by weight of one or more enteric coating agents, and the process comprises adding from 5.0 to 6.5 g per kg of pharmaceutically acceptable inert nucléus of the anticaking agent in powder form. In a particular embodiment, in the coating step (a2) the spraying mixture comprises one or more organic solvents as defrned above and below; particularly acetone, or a mixture of acetone, éthanol and water. In a particular embodiment, in 72 the coating step (a2) the spraying mixture comprises one or more solvents in a concentration from 85% to 95% by weight, more particularly in a 90% by weight of solvents.
In an embodiment, in each one of the coating steps (al) and (bl) of the process of the invention which comprises a spraying mixture comprising coating agents, the spraying mixture further comprises one or more organic solvents as defined above in an amount from 85 to 1200 g of solvent per Kg of pharmaceutically acceptable inert nucléus; particularly from 85 to 650 g of solvent per Kg of pharmaceutically acceptable inert nucléus. In an embodiment, each one of the coating steps of the process of the invention which comprises a spraying mixture comprising coating agents, the spraying mixture further comprises one or more organic solvents as defmed above in an amount from 270 to 285 g of solvent per Kg of pharmaceutically acceptable inert nucléus for (al) and in an amount from 85 to 100 g of solvent per Kg of pharmaceutically acceptable inert nucléus for (bl).
In an embodiment, each one of the coating steps of the process of the invention is performed at airflow from 0 a 20 m3/h per Kg of pharmaceutically acceptable inert nucléus; particularly from 0 to 6 m3 /h per Kg of pharmaceutically acceptable inert nucléus.
In an embodiment, in each one of the coating steps of the process of the invention the température of the inert nucléus (core) of the pellets during the coating step is from 5°C to 50 °C; particularly from 10°C to 30°C. In an embodiment, in each one of the coating steps of the process of the invention the température of the inert nucléus (core) of the pellets during the coating step is from 19°C to 30 °C. The température is controlled using a calibrated PT100 sensor being directly in contact with the pellets being coated, but it could be controlled using an équivalent System.
In an embodiment, in each one of the spraying steps (al), (a2), (a3), (bl) and (b2), the liquid mixture is sprayed at a gun atomization pressure from 0.6 to 2.2 bar and an open pattern pressure from 0.6 to 2.5 bar.
The coating steps of the process of the second aspect of the invention can be performed by any known method disclosed in the State of the art. In an embodiment, the coating steps are performed by a method selected from the group consisting of a pan-coating method and a fluidbed coating method. In an embodiment, the coating steps are performed by a pan-coating method 73 and the dépréssion inside the pan-coating is from 0 to 200 Pa. In an embodiment, the coating steps are performed by a pan-coating method and the dépréssion inside the pan-coating is from 0 to 100 Pa.
In an embodiment, the process of the présent invention is one wherein one or more of the coating steps is performed in the absence of drying steps.
In an embodiment, the process of the présent invention is one wherein one or more of the coating steps further comprises one or more drying steps. In an embodiment, the process of the présent invention is one which further comprises an additional step of drying separately each one of the plurality of pellets obtained after the préparation of each coating layer (inter-coating drying steps). It means, for the first plurality of pellets after the préparation of the inner active coating layer, the intermediate enteric release coating layer, and the extemal modified release coating layer; and for the second plurality of pellets after the préparation of the inner active coating layer and/ or the extemal modified release coating layer.
In an embodiment, the each one of the drying steps of the process of the invention is performed at a température from 15 °C to 60 °C; particularly from 25°C to 45°C. In an embodiment, the each one of the drying steps of the process of the invention is performed at an airflow equal to or higher than 1 m3/ (h per kg of inert nucléus) for the appropriate period of time for having an amount of each of the solvents lower than 5000 ppm. In an embodiment, the each one of the drying steps of the process of the invention is performed at a température from 15 °C to 60 °C and at an airflow equal to or higher than 1 m3/(h per kg of inert nucléus) for the appropriate period of time for having an amount of each of the solvents lower than 5000 ppm.
In a particular embodiment, the inter-coating drying steps are carried out during not less than 1 h at a température; particularly from 15°C to 45 °C and at an airflow higher than 1 m3 / h per kg of pharmaceutically acceptable inert nucléus. In a particular embodiment, the drying step of the extemal coating of both plurality of pellets is carried out during not less than 8 h and not more than 12 h; particularly at a température from 15 °C to 60 °C, preferably from 25°C to 50 °C; more particularly from 40°C to 45 °C at an airflow higher than 2 m3 / h per kg of pharmaceutically acceptable inert nucléus.
In a particular embodiment, the drying steps of the process of the invention is performed in any appropriate equipment; particularly in a coating pan at a speed from 0 to lOrpm.
In an embodiment, the coating steps of the process of the invention is performed in a coating pan and at a rotation speed from 0 to 50 rpm, particularly from 2 to 25 rpm; more particularly from 10 to 2 rpm. The rotation pan speed can be controlled by any method known in the State of the art. In particular, the method used in the présent invention is by using a révolution counter.
In an embodiment, the process of the présent invention further comprises one or more additional steps of sieving separately each one of the plurality of pellets obtained in each one of the coating steps if agglomération of powder into granules is observed. In an embodiment, the process of the présent invention further comprises one or more additional steps of sieving separately the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising: the pharmaceutically acceptable inert nucléus; the inner active coating layer; the intermediate enteric release coating layer, and the extemal modified release coating layer; and/or the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof comprising: the pharmaceutically acceptable inert nucléus; the inner active coating layer; and the extemal modified release coating layer.
In an embodiment, the process of the présent invention further comprises one or more additional steps of sieving as defined above until having a particle size such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving, and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of not more than 200 pm measured by analytical sieving; particularly a particle size variability of not more than 150 pm, particularly a particle size variability of not more than 100 pm, and more particularly a particle size variability of not more than 75 pm; the particle size of the pellets of the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 400 pm to 2000 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 200 pm; particularly a particle size variability of not more than 150 pm; particularly a particle size variability of not more than 100 pm; and more particularly a particle size variability of not more than 75 pm; measured by analytical sieving; and the particle size of the pellets of the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 400 pm to 75
2000 μηι measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 200 pm; particularly a particle size variability of not more than 150 pm; particularly a particle size variability of not more than 100 pm; and more particularly a particle size variability of not more than 75 pm measured by analytical sieving. Ail ernbodiments disclosed above for the particle size and particle size variability of the pharmaceutically acceptable nucléus and the first and the second plurality of the pellets, and combination thereof disclosed in the first aspect of the invention also applies for the process of the second aspect of the invention.
In an embodiment, wherein when the multiple unit oral dosage form is a hard capsule, then the process of the présent invention further comprises an additional step of filling a hard capsule with a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof; and a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof. The process of filling the capsule can be performed using the known method disclosed in the State of the art. Examples of filling machines appropriate for the présent invention include, without limitation, automatic filling machine using intermittent or continuous motion. Common capsule fillers that use intermittent or continuous motion include machines from Bosch, IMA Zanasi, Doit Bonapace and MG2. In the case, of the présent invention, the filling of the hard capsules is performed using an automatic filling machine using intermittent motion. In an embodiment, wherein when the multiple unit oral dosage form is a hard capsule, then the process of the présent invention further comprises an additional step of filling a hard capsule comprising filling individually and separately the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof and a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof. In an embodiment, wherein when the multiple unit oral dosage form is a hard capsule, then the process of the présent invention further comprises an additional step of filling a hard capsule firstly, comprising: firstly filling the body of the capsule with the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof; and secondly, filling the body of the capsule a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof; or vice versa; and fitting the cap of the capsule over the body of the capsule. In an embodiment, wherein when the multiple unit oral dosage form is a hard capsule, then the process of the présent invention further comprises an additional step of filling a hard capsule comprising filling a combination of the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof and a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof.
The use of the first and the second plurality of pellets disclosed in the présent invention allows having an accuracy of the individual amount of each plurality of pellets filled into the capsule from less than or equal to ± 5% by weight of the theoretical filling weight. For the purpose of the invention, the term “theoretical filling weight” refers to the target filling weight calculated based upon actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride so as to assure the theoretical content of X mg of doxylamine succinate (where X is for example 10.0 or 20.0 mg) and Y mg (where Y is for example 10.0 or 20.0 mg) of pyridoxine hydrochloride per capsule, which can be measured by a suitable balance.
In an embodiment, wherein when the multiple unit oral dosage form is a hard capsule, then the filling capsule step comprises adding one or more pharmaceutically acceptable excipients.
Examples of appropriate pharmaceutically acceptable excipients for being used in the filling capsule step are selected from lubricants, fillers, diluents, glidants and anticaking agents or a mixture thereof.
In an embodiment, wherein when the multiple unit oral dosage form is a hard capsule, then the process further comprises an additional step of filling the capsule with the first plurality of pellets comprising the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof and the second plurality of pellets comprising the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof; particularly having from 5 mg to 50 mg per capsule of doxylamine succinate and from 5 mg to 50 mg per capsule of pyridoxine hydrochloride.
Ail the embodiment disclosed above and below for the multiple unit oral dosage form of the first aspect of the invention also apply for the process for its préparation of the second aspect of the invention.
The multiple unit oral dosage form of the first aspect of the invention may be defmed by its préparation process as defmed above in the second aspect of the invention and therefore, the multiple unit oral dosage form of the first aspect of the invention obtainable by the process of the invention is considered part of the invention. For the purposes of the invention, the expressions 77 obtainable, obtained and équivalent expressions are used interchangeably, and in any case, the expression obtainable encompasses the expression obtained.
Ail the embodiments disclosed above for the multiple unit oral dosage form of the first aspect of the invention, as well as for the process for its préparation, also apply for the multiple unit oral dosage form of the invention obtainable by the process for préparation.
Finally, it is also part of the invention the multiple unit oral dosage form of the first aspect of the invention for use in therapy. In particular, the multiple unit oral dosage form of the first aspect of the invention for use in the symptomatic treatment of nausea and vomiting. In an embodiment, the multiple unit oral dosage form of the first aspect of the invention for use in the symptomatic treatment of nausea and vomiting associated with prégnant women (NVP). In an embodiment, the multiple unit oral dosage form of the first aspect of the invention for use in the symptomatic treatment of nausea and vomiting associated with oncologie treatments, for instance chemotherapy or radiotherapy. This aspect could be also formulated as the use of multiple unit oral dosage form of the first aspect of the invention as defined above for the préparation of a médicament for the symptomatic treatment of nausea and vomiting. It also relates to a method for the prophylaxis and/or treatment of a mammal suffering, or susceptible to suffer, from nausea and vomiting, wherein the method comprises administering to said mammal the multiple unit oral dosage form of the first aspect of the invention as defined above. In an embodiment, the nausea and vomiting are associated with prégnant women (NVP) or with oncologie treatments, for instance chemotherapy or radiotherapy. Ail the embodiments disclosed above for the multiple unit oral dosage form of the first aspect of the invention also apply for the multiple unit oral dosage form of the first aspect of the invention limited by its use.
Throughout the description and daims the word comprise and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word “comprise” encompasses the case of “consisting of’. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be leamed by practice of the invention. The following examples are provided by way of illustration, and they are not intended to be limiting of the présent invention. Furthermore, the présent invention covers ail possible combinations of particular and preferred embodiments described herein.
Ëxamples General considérations
D90 measurement values of the active ingrédients (doxylamine and pyridoxine) were performed using a Malvem method (Laser Mastersizer, Mie Theory; ISO 13320-1).
The measurement of the D90 value of doxylamine or a pharmaceutically acceptable sait was performed using the Malvem method (Laser Mastersizer, Mie Theory; ISO 13320-1) under the following main used parameters:
Sample, Dispersion Medium 250 mg, 5 mL Isopar G + 5 %w/w Lecithin
Ultrasound Time 20 seconds
Dispersant (volume) Isopar G (ca. 100 mL)
Washing Media (volume)
Acetone (ca. 50 mL), Toluene (ca. 50 mL) and Isopar G (ca. 50 mL)
Particle Refractive Index 1,52
Particle Absorption 0,1
Dispersant Refractive Index 1,42
Analysis Model General Purpose - Normal Sensitivity
Particle Shape Irregular
Repeats 3 measurements per aliquot
Delay Between Measurements 10 Seconds
Sample Measuring Time 15 Seconds
Background Measuring Time 15 Seconds
Obscuration Range 15 - 30 %
Suspension Stirring Rate 2500 ±10 rpm
The samples were measured employing the following procedure:
Procedure: The sample vial was subjected to a standard mixing cycle in a Bio Grant PTR-30 rotatory mixer. Approximately 250 mg of the sample were transferred into a 10 mL vial and 5 mL of 5% w/w Lecithin solution in Isopar G were added. The suspension was sonicated for 20 seconds using a Bandelin Sonopuls HD3100 with a sonication probe (MS72 tip at 20 % intensity). Under continuous circulation (2500 rpm), the sample suspension was added to the measuring medium (ca. 100 mL of Isopar G) until the obscuration value reached 15 - 30 %. Measurements were performed immediately aller sample addition and aller 3 minutes to ensure dispersion stability. Each resuit is the average of three consecutive measurements of 15000 swipes. The abovementioned procedure was carried out by triplicate.
- The measurement of the D90 value of pyridoxine or a pharmaceutically acceptable sait was performed using the Malvem method (Laser Mastersizer, Mie Theory; ISO 13320-1) under the following main used parameters:
Sample, Dispersion Medium 70 to 100 mg, 10 mL Toluene
Ultrasound Time 20 seconds
Dispersant (volume) Toluene (ca. 100 mL)
Washing Media (volume) 2x Acetone (ca. 50 mL) and Toluene (ca. 50 mL)
Particle Refractive Index 1,52
Particle Absorption 0,1
Dispersant Refractive Index 1,49 .
Analysis Model General Purpose - Normal Sensitivity
Particle Shape Irregular
Repeats 3 measurements per aliquot
Delay Between Measurements 10 Seconds
Sample MeasuringTime 15 Seconds
Background Measuring Time 15 Seconds
Obscuration Range 15 - 30 %
Suspension Stirring Rate 2500 ±10 rpm
The samples were measured employing the following procedure:
Procedure: The sample vial was subjected to a standard mixing cycle in a Bio Grant PTR-30 rotatory mixer. Approximately 70-250 mg of the sample were transferred into a 20 mL vial and 10 mL of Toluene were added. The suspension was sonicated for 20 seconds using a Bandelin Sonopuls HD3100 with a sonication probe (MS72 tip at 20 % intensity). Under continuous circulation (2500 rpm), the sample suspension was added to the measuring medium (ca. 100 mL of Toluene) until the obscuration value reached 15-30 %. The sample vial was rinsed with ca. 5 mL of Toluene. Measurements were performed immediately after sample addition and after 3 minutes to ensure dispersion stability. Each resuit is the average of three consecutive measurements of 15000 swipes. The abovementioned procedure was carried out by triplicate.
1. Capsules of pellets of doxylamine succinate and pyridoxine hydrochloride of the présent invention
1.1. Quantitative composition per hard capsule
The amount of each one of the ingrédients per capsule is as foliows:
1.1.1 Hard gélatine capsules of Doxylamine succinate 1 Omg and Pyridoxine hydrochloride lOmg.
Hard gélatine capsules filled with pellets of doxylamine succinate and pyridoxine hydrochloride of the présent invention obtained starting from inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of the pharmaceutically acceptable inert nucléus having a particle size variability of not more than 200 pm measured by analytical sieving.
Ingrédient | Quantity per capsule (mg) | Function |
Active ingrédients | ||
Doxylamine succinate (D90 < 250 pm) | 10.0 | Active ingrédient |
Pyridoxine hydrochloride (D90 < 250 pm) | 10.0 | Active ingrédient |
Excipients | ||
Sugar spheres of sucrose and starch(1) | 79.5 | Pharmaceutically acceptable inert nucléus |
(dewaxed) Shellac | 7.6 | Coating agent/ binder solution |
Polyvinylpyrrolidone (Povidone K-30) | 0.2 | Coating agent/ binder solution |
Talc (D90 equal to or below 250pm) | 9.5 | Anticaking agent |
Methacrylic acid-methyl méthacrylate copolymer (1:1) (Eudragit L) | 1.1 | Enteric coating agent |
Silica colloïdal anhydrous (Aerosil) | 0.7 | Anticaking, gliding agent |
Hard gélatine capsule, size 3 | about 48 (3) | Packing of dose unit |
Capsule fill weight | each capsule is filled with about 60mg (-2> of pellets of doxylamine succinate having the composition as provided in example 1.2.1 and about 60mg(2) of |
pellets of pyridoxine hydrochloride having the composition provided in example 1.2.2 |
(1) at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of not more than 200 pm from a given value comprised from 500 pm and 1400 pm measured by analytical sieving.
(2) 60mg +/- 10%, practical target filling weight_is calculated based upon actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride so as to assure the theoretical content of 10.0 mg of doxylamine succinate and 10.0 mg of pyridoxine hydrochloride per capsule (3) 48 mg +/-10%, based upon capsule supplier spécifications
1.1.2 Hard HPMC capsules of Doxylamine succinate lOmg and Pyridoxine hydrochloride IQmg Hard HPMC capsules filled with pellets of doxylamine succinate and pyridoxine hydrochloride of the présent invention obtained starting from inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of the inert nucléus having a particle size variability of not more than 200 pm measured by analytical sieving.
Ingrédient | Quantity per capsule (mg) | Function |
Active ingrédients | ||
Doxylamine succinate (D90 <250 pm) | 10.0 | Active ingrédient |
Pyridoxine hydrochloride (D90 < 250 pm) | 10.0 | Active ingrédient |
Excipients | ||
Sugar spheres of sucrose and starch(I) | 79.5 | Pharmaceutically acceptable inert nucléus |
(dewaxed) Shellac | 7.6 | Coating agent/ binder solution |
Polyvinylpyrrolidone (Povidone K-30) | 0.2 | Coating agent/ binder solution |
Talc (D90 equal to or below 250pm) | 9.5 | Anticaking agent |
Methacrylic acid-methyl méthacrylate | 1.1 | Enteric coating agent |
copolymer (1:1) (Eudragit L) | ||
Silica colloïdal anhydrous (Aerosil) | 0.7 | Anticaking, gliding agent |
Hard HPMC(4) capsule, size 3 | about 47 (3) | Packing of dose unit |
Capsule fill weight | each capsule is filled with about 60mg(2) of pellets of doxylamine succinate having the composition as provided in example 1.2.1 and about 60mg(2) of pellets of pyridoxine hydrochloride having the composition as provided in example 1.2.2 |
(1) at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm and at least the 90% of the inert nucléus hâve a particle size variability of not more than 200 pm from a given value comprised from 500 pm and 1400 pm measured by analytical sieving.
(2) 60mg +/- 10%, practical target filling weight_is calculated based upon actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride so as to assure the theoretical content of 10.0 mg of doxylamine succinate and 10.0 mg of pyridoxine hydrochloride per capsule (3) 47 mg +/- 10%, based upon capsule supplier spécifications (4) HPMC (hydroxypropyl methylcellulose or hypromellose)
1.1.3 Hard gélatine capsules of Doxylamine succinate lOmg and Pyridoxine hydrochloride lOmg Hard gélatine capsules filled with pellets of doxylamine succinate and pyridoxine hydrochloride of the présent invention obtained starting from inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm measured by analytical sieving and at least the 90% of the inert nucléus having a particle size variability of not more than 100 pm measured by analytical sieving.
Ingrédient | Quantity per capsule (mg) | Function |
Active ingrédients | ||
Doxylamine succinate (D90 <250 pm) | 10.0 | Active ingrédient |
Pyridoxine hydrochloride (D90 < 250 pm) | 10.0 | Active ingrédient |
Excipients | ||
Sugar spheres of sucrose and starch(1) | 79.5 | Pharmaceutically acceptable |
inert nucléus | ||
(dewaxed) Shellac | 7.6 | Coating agent/ binder solution |
Polyvinylpyrrolidone (Povidone K-30) | 0.2 | Coating agent/ binder solution |
Talc (D90 equal to or below 250pm) | 9.5 | Anticaking agent |
Methacrylic acid-methyl méthacrylate copolymer (1:1) (Eudragit L) | 1.1 | Enteric coating agent |
Silica colloïdal anhydrous (Aerosil) | 0.7 | Anticaking, gliding agent |
Hard gélatine capsule, size 3 | about 48 (3) | Packing of dose unit |
Capsule fill weight | each capsule is filled with about 60mg(2) of pellets of doxylamine succinate having the composition as provided in example 1.2.1 and about 60mg(2) of pellets of pyridoxine hydrochloride having the composition as provided in example 1.2.2 |
(1) at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm and at least the 90% of the inert nucléus hâve a particle size variability of not more than 100 pm from a given value comprised from 710 pm and 1000 pm measured by analytical sieving.
(2) 60mg +/-10%, practical target filling weight_is calculated based upon actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride so as to assure the theoretical content of 10.0 mg of doxylamine succinate and 10.0 mg of pyridoxine hydrochloride per capsule (3) 48 mg +/-10%, based upon capsule supplier spécifications
1.1.4 Hard HPMC capsules of Doxylamine succinate IQmg and Pyridoxine hydrochloride IQmg
Hard HPMC capsules filled with pellets of doxylamine succinate and pyridoxine hydrochloride of the présent invention obtained starting from inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm measured by analytical sieving and at least the 90% of the inert nucléus having a particle size variability of not more than 100 pm measured by analytical sieving.
Ingrédient | Quantity per capsule (mg) | Function |
Active ingrédients |
Doxylamine succinate (D90 < 250 pm) | 10.0 | Active ingrédient |
Pyridoxine hydrochloride (D90 < 250 pm) | 10.0 | Active ingrédient |
Excipients | ||
Sugar spheres of sucrose and starch(1) | 79.5 | Pharmaceutically acceptable inert nucléus |
(dewaxed) Shellac | 7.6 | Coating agent/ binder solution |
Polyvinylpyrrolidone (Povidone K-30) | 0.2 | Coating agent/ binder solution |
Talc (D90 equal to or below 250pm) | 9.5 | Anticaking agent |
Methacrylic acid-methyl méthacrylate copolymer (1:1) (Eudragit L) | 1.1 | Enteric coating agent |
Silica colloïdal anhydrous (Aerosil) | 0.7 | Anticaking, gliding agent |
Hard HPMC(4) capsule, size 3 | about 47 (3) | Packing of dose unit |
Capsule fill weight | each capsule is filled with about 60mg(2) of pellets of doxylamine succinate having the composition as provided in example 1.2.1 and about 60mg(2) of pellets of pyridoxine hydrochloride having the composition provided in example 1.2.2 |
(1) at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm and at least the 90% of the inert nucléus hâve a particle size variability of not more than 100 pm from a given value comprised from 710 pm and 1000 pm measured by analytical sieving.
(2) 60mg +/-10%, practical target filling weight_is calculated based upon actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride so as to assure the theoretical content of 10.0 mg of doxylamine succinate and 10.0 mg of pyridoxine hydrochloride per capsule (3) 47 mg +/-10%, based upon capsule supplier spécifications (4) HPMC (hydroxypropyl methylcellulose or hypromellose)
1.1.5 Hard gélatine capsules of Doxylamine succinate IQmg and Pyridoxine hydrochloride lOmg Hard gélatine capsules filled with pellets of doxylamine succinate and pyridoxine hydrochloride of the présent invention obtained starting from inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 710 pm to 1000 pm measured by analytical sieving and at least the 90% of the inert nucléus having a particle size variability of not more than 75 pm measured by analytical sieving.
Ingrédient | Quantity per capsule (mg) | Function |
Active ingrédients | ||
Doxylamine succinate (D90 < 250 pm) | 10.0 | Active ingrédient |
Pyridoxine hydrochloride (D90 < 250 pm) | 10.0 | Active ingrédient |
Excipients | ||
Sugar spheres of sucrose and starch | 79.5 | Pharmaceutically acceptable inert nucléus |
(dewaxed) Shellac | 7.6 | Coating agent/ binder solution |
Polyvinylpyrrolidone (Povidone K-30) | 0.2 | Coating agent/ binder solution |
Talc (D90 equal to or below 250pm) | 9.5 | Anticaking agent |
Methacrylic acid-methyl méthacrylate copolymer (1:1) (Eudragit L) | 1.1 | Enteric coating agent |
Silica colloïdal anhydrous (Aerosil) | 0.7 | Anticaking, gliding agent |
Hard gélatine capsule, size 3 | about 48 (3) | Packing of dose unit |
Capsule fill weight | each capsules is fil of doxylamine suce provided in examp] pellets of pyridoxin composition as pro1 | ed with about 60mg(2) of pellets inate having the composition as e 1.2.1 and about 60 mg(2) of e hydrochloride having the rided in example 1.2.2 |
(1) at least 90% of the inert nucléus hâve a particle size from 710 pm to 1000 pm and at least the
90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of not more than 75 pm from a given value comprised from 800 pm and 900 pm measured by analytical sieving.
(2) 60mg +/- 10%, practical target filling weightjs calculated based upon actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride so as to assure the theoretical content of 10.0 mg of doxylamine succinate and 10.0 mg of pyridoxine hydrochloride per capsule (3) 48 mg +/- 10%, based upon capsule supplier spécifications.
1.1.6 Hard HPMC capsules of Doxylamine succinate IQmg and Pyridoxine hydrochloride IQmg Hard HPMC capsules filled with pellets of doxylamine succinate and pyridoxine hydrochloride 5 of the présent invention obtained starting from inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 710 pm to 1000 pm measured by analytical sieving and at least the 90% of the inert nucléus having a particle size variability of not more than 75 pm measured by analytical sieving.
Ingrédient | Quantity per capsule (mg) | Function |
Active ingrédients | ||
Doxylamine succinate (D90 < 250 pm) | 10.0 | Active ingrédient |
Pyridoxine hydrochloride (D90 <250 pm) | 10.0 | Active ingrédient |
Excipients | ||
Sugar spheres of sucrose and starch(1) | 79.5 | Pharmaceutically acceptable inert nucléus |
(dewaxed) Shellac | 7.6 | Coating agent/ binder solution |
Polyvinylpyrrolidone (Povidone K-30) | 0.2 | Coating agent/ binder solution |
Talc (D90 equal to or below 250pm) | 9.5 | Anticaking agent |
Methacrylic acid-methyl méthacrylate copolymer (1:1) (Eudragit L) | 1.1 | Enteric coating agent |
Silica colloïdal anhydrous (Aerosil) | 0.7 | Anticaking, gliding agent |
Hard HPMC(4) capsule, size 3 | about 47 (3) | Packing of dose unit |
Capsule fill weight | each capsule is filled with about 60mg(2) of pellets of doxylamine succinate having the composition as provided in example 1.2.1 and about 60 mg(2) of pellets of pyridoxine hydrochloride having the composition provided in example 1.2.2 |
(1) at least 90% of the inert nucléus hâve a particle size from 710 pm to 1000 pm and at least the
90% of the inert nucléus hâve a particle size variability of not more than 75 pm from a given value comprised from 800 pm and 900 pm measured by analytical sieving (2) 60mg +/- 10%, practical target filling weight_is calculated based upon actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride so as to assure the theoretical content of 10.0 mg of doxylamine succinate and 10.0 mg of pyridoxine hydrochloride per capsule (3) 47 mg +/- 10%, based upon capsule supplier spécifications (4) HPMC (hydroxypropyl methylcellulose or hypromellose)
1.1.7 Hard gélatine capsules of Doxylamine succinate 20mg and Pyridoxine hydrochloride 20mg 10 Hard gélatine capsules filled with pellets of doxylamine succinate and pyridoxine hydrochloride of the présent invention obtained starting from inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm measured by analytical sieving and at least the 90% of the inert nucléus having a particle size variability of not more than 100 pm measured by analytical sieving.
Ingrédient | Quantity per capsule (mg) | Function |
Active ingrédients | ||
Doxylamine succinate (D90 < 250 pm) | 20.0 | Active ingrédient |
Pyridoxine hydrochloride (D90 < 250 pm) | 20.0 | Active ingrédient |
Excipients | ||
Sugar spheres of sucrose and starch(1) | 159.0 | Pharmaceutically acceptable inert nucléus |
(dewaxed) Shellac | 15.2 | Coating agent/ binder solution |
Polyvinylpyrrolidone (Povidone K-30) | 0.4 | Coating agent/ binder solution |
Talc (D90 equal to or below 250pm) | 19.0 | Anticaking agent |
Methacrylic acid-methyl méthacrylate copolymer (1:1) (Eudragit L) | 2.2 | Enteric coating agent |
Silica colloïdal anhydrous (Aerosil) | 1.4 | Anticaking, gliding agent |
Hard gélatine capsule, size 2 | about 61 (3) | Packing of dose unit |
Capsule fill weight | each capsule is filled with about 120mg(2) of pellets |
of doxylamine succinate having the composition as provided in example 1.2.1 and about 120 mg® of pellets of pyridoxine hydrochloride having the composition provided in example 1.2.2 |
(1) at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm and at least the 90% of the inert nucléus hâve a particle size variability of not more than 100 pm from a given value comprised from 710 pm and 1000 pm measured by analytical sieving.
(2) 120mg +/-10%, practical target filling weight_is calculated based upon actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride so as to assure the theoretical content of 20.0 mg of doxylamine succinate and 20.0 mg of pyridoxine hydrochloride per capsule (3) 61 mg +/-10%, based upon capsule supplier spécifications
1.1.8 Hard HPMC capsules of Doxylamine succinate 20mg and Pyridoxine hydrochloride 20mg
Hard HPMC capsules filled with pellets of doxylamine succinate and pyridoxine hydrochloride of the présent invention obtained starting from inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm measured by analytical sieving and at least the 90% of the inert nucléus having a particle size variability of not more than 100 pm measured by analytical sieving.
Ingrédient | Quantity per capsule (mg) | Function |
Active ingrédients | ||
Doxylamine succinate (D90 < 250 pm) | 20.0 | Active ingrédient |
Pyridoxine hydrochloride (D90 < 250 pm) | 20.0 | Active ingrédient |
Excipients | ||
Sugar spheres of sucrose and starch® | 159.0 | Pharmaceutically acceptable inert nucléus |
(dewaxed) Shellac | 15.2 | Coating agent/ binder solution |
Polyvinylpyrrolidone (Povidone K-30) | 0.4 | Coating agent/ binder solution |
Talc (D90 equal to or below 250pm) | 19.0 | Anticaking agent |
Methacrylic acid-methyl méthacrylate copolymer (1:1) (Eudragit L) | 2.2 | Enteric coating agent |
Silica colloïdal anhydrous (Aerosil) | 1.4 | Anticaking, gliding agent |
Hard HPMC(4) capsule, size 2 | about 61 (3) | Packing of dose unit |
Capsule fill weight | each capsule is filled with about 120mg of pellets of doxylamine succinate having the composition as provided in example 1.2.1 and about 120 mg(2) of pellets of pyridoxine hydrochloride having the composition provided in example 1.2.2 |
(1) at least 90% of the inert nucléus hâve a particle size from 600 μπι to 1180 μιη and at least the 90% of the inert nucléus hâve a particle size variability of not more than 100 μιη from a given value comprised from 710 μιη and 1000 μπι measured by analytical sieving.
(2) 120mg +/- 10%, practical target filling weight_is calculated based upon actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride so as to assure the theoretical content of 20.0 mg of doxylamine succinate and 20.0 mg of pyridoxine hydrochloride per capsule (3) 61 mg +/-10%, based upon capsule supplier spécifications (4) HPMC (hydroxypropyl methylcellulose or hypromellose)
1.1.9 Hard gélatine capsules of Doxylamine succinate 20mg and Pyridoxine hydrochloride 20mg Hard gélatine capsules filled with pellets of doxylamine succinate and pyridoxine hydrochloride of the présent invention obtained starting from inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm measured by analytical sieving and at least the 90% of the inert nucléus having a particle size variability of not more than 100 pm measured by analytical sieving.
Ingrédient | Quantity per capsule (mg) | Function |
Active ingrédients | ||
Doxylamine succinate (D90 < 250 pm) | 20.0 | Active ingrédient |
Pyridoxine hydrochloride (D90 < 250 pm) | 20.0 | Active ingrédient |
Excipients |
Sugar spheres of sucrose and starch1·1* | 159.0 | Pharmaceutically acceptable inert nucléus |
(dewaxed) Shellac | 15.2 | Coating agent/ binder solution |
Polyvinylpyrrolidone (Povidone K-30) | 0.4 | Coating agent/ binder solution |
Talc (D90 equal to or below 250pm) | 19.0 | Anticaking agent |
Methacrylic acid-methyl méthacrylate copolymer (1:1) (Eudragit L) | 2.2 | Enteric coating agent |
Silica colloïdal anhydrous (Aerosil) | 1.4 | Anticaking, gliding agent |
Hard gélatine capsule, size 1 | about 76 (3) | Packing of dose unit |
Capsule fill weight | each capsule is filled with about 120mg(2) of pellets of doxylamine succinate having the composition as provided in example 1.2.1 and about 120mg(2) of pellets of pyridoxine hydrochloride having the composition as provided in example 1.2.2 |
(1) at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm and at least the 90% of the inert nucléus having a particle size variability of not more than 100 pm from a given value comprised from 710 pm and 1000 pm measured by analytical sieving.
(2) 120mg +/- 10%, practical target filling weight is calculated based upon actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride so as to assure the theoretical content of 20.0 mg of doxylamine succinate and 20.0 mg of pyridoxine hydrochloride per capsule (3) 76 mg +/- 10%, based upon capsule supplier spécifications
1.1.10 Hard HPMC capsules of Doxylamine succinate 20mg and Pyridoxine hydrochloride 20mg
Hard HPMC capsules filled with pellets of doxylamine succinate and pyridoxine hydrochloride of the présent invention obtained starting from inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm measured by analytical sieving and at least the 90% of the inert nucléus having a particle size variability of not more than 100 pm measured by analytical sieving.
Ingrédient | Quantity per capsule (mg) | Function |
Active ingrédients | ||
Doxylamine succinate (D90 < 250 pm) | 20.0 | Active ingrédient |
Pyridoxine hydrochloride (D90 < 250 pm) | 20.0 | Active ingrédient |
Excipients | ||
Sugar spheres of sucrose and starch (1) | 159.0 | Pharmaceutically acceptable inert nucléus |
(dewaxed) Shellac | 15.2 | Coating agent/ binder solution |
Polyvinylpyrrolidone (Povidone K-30) | 0.4 | Coating agent/ binder solution |
Talc (D90 equal to or below 250pm) | 19.0 | Anticaking agent |
Methacrylic acid-methyl méthacrylate copolymer (1:1) (Eudragit L) | 2.2 | Enteric coating agent |
Silica colloïdal anhydrous (Aerosil) | 1.4 | Anticaking, gliding agent |
Hard HPMC(4) capsule, size 1 | about 76 (3) | Packing of dose unit |
Capsule fill weight | each capsule is filled with about 120mg(2) of pellets of doxylamine succinate having the composition as provided in example 1.2.1 and about 120 mg(2) of pellets of pyridoxine hydrochloride having the composition provided in example 1.2.2 |
(1) at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm and at least the 90% of the inert nucléus having a particle size variability of not more than 100 pm from a given value comprised from 710 pm and 1000 pm measured by analytical sieving.
(2) 120mg +/- 10%, practical target filling weight_is calculated based upon actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride so as to assure the theoretical content of 20.0 mg of doxylamine succinate and 20.0 mg of pyridoxine hydrochloride per capsule (3) 76 mg +/-10%, based upon capsule supplier spécifications (4) HPMC (hydroxypropyl methylcellulose or hypromellose)
Dissolution Profile: The capsules of pellets of doxylamine succinate and pyridoxine hydrochloride of the présent invention of examples 1.1.1 to 1.1.10 exhibit a dissolution profile according to the target dissolution profile measured using a USP type 2 apparatus (basket), placing the composition in 900mL of the corresponding media / buffered 37°C ±0.5 °C and 100 rpm (révolution per minute) as it is shown below.
1.2. Quantitative composition per plurality of pellets
1.2.1 Composition of the pellets of doxylamine succinate of the présent invention obtained starting from inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm and at least the 90% of the inert nucléus having a particle size variability of not more than 100 pm from a given value comprised from 710 pm and 10 1000 pm and with doxylamine succinate active ingrédient having a particle size characterized for having a D90 equal to or below than 250 pm and with talc anticaking agent having a particle size characterized for having a D90 equal to or below than 250 pm.
The amount of each one of the ingrédients per a batch of about 25 Kg or about 180 Kg pf the 15 pellets of doxylamine succinate is as follows:
Layer of the pellet | Ingrédients | function | Amount (kg) per a batch of about 25Kg | Amount (kg) per a batch of about 180 Kg |
Core | Sugar spheres of sucrose and starch | Pharmaceutically acceptable inert nucléus | 15.625 | 112.564 |
Inner active coating layer | Doxylamine succinate | Active ingrédient | 4.192 | 30.200 |
Talc | Anticaking agent | 1.397 | 10.067 | |
Silica colloïdal anhydrous (Aerosil 200 pharma) | Anti-caking agent, gliding agent | 0.279 | 2.013 | |
Polyvinyl pyrrolidone 20% solution in éthanol (Povidone K-30) | Coating agent solution/ binder solution | 0.4188 | 3.020 | |
(dewaxed) Shellac 40% | Coating agent | 1.169 | 8.419 |
solution in éthanol | solution/ binder solution | |||
Intermediate enteric release layer | Talc | Pore-forming agent | 0.0890 | 0.641 |
Methacrylic acid and methyl méthacrylate copolymer (1:1) (Eudragit L) 10% in acetone (*) | Enteric release coating agent mixture | 0.890 | 6.406 | |
Extemal modified release layer | Methacrylic acid and methyl méthacrylate copolymer (1:1) (Eudragit L) 10% in acetone (*) | Enteric release coating agent mixture | 2.950 | 21.155 |
(dewaxed) Shellac 40% solution in éthanol | Modified release coating agent solution | 2.937 | 21.156 | |
Talc | Pore-forming agent | 1.308 | 9.425 | |
Total dry weight | 25.000 | 180.14 |
(*) if necessary purified water or éthanol can be added as processing aid to facilitate the obtainment of the enteric release coating agent solution
The obtained pellets of doxylamine succinate hâve a particle size such that at least 90% of pellets 5 hâve a particle size from 710 pm to 1400 pm measured by analytical sieving and at least the 90% of the pellets having a particle size variability of not more than 100 pm from a given value comprised from 850 pm and 1250 pm measured by analytical sieving. The homogeneity of the particle size of pellets and the inter-pellet homogeneity of the content of the active ingrédient is such that the pellets are easier to handle allowing a high uniformity in dosification, assuring the 10 desired content of active ingrédient and the desired dissolution profile as described in examples above.
1.2.2 Composition of the pellets of pyridoxine hydrochloride of the présent invention obtained starting from inert nucléus having a particle size such that at least 90% of the inert nucléus hâve 15 a particle size from 600 pm to 1180 pm and at least the 90% of the pharmaceutically acceptable inert nucléus having a particle size variability of not more than 100 pm from a given value comprised from 710 pm and 1000 pm and with pyridoxine hydrochloride active ingrédient having a particle size characterized for having a D90 equal to or below than 250 pm and with talc as anticaking agent having a particle size characterized for having a D90 equal to or below 5 than 250 pm.
The amount of each one of the ingrédients per a batch of about 25 Kg or about 180 Kg of the pellets of pyridoxine hydrochloride is as follows:
Layer of the pellets | Ingrédients | function | Amount (Kg) per a batch of about 25 Kg | Amount (Kg) per a batch of about 180 (Kg) |
Core | Sugar spheres of sucrose and starch | Pharmaceutically acceptable inert nucléus | 17.962 | 129.285 |
Inner active coating layer | pyridoxine hydrochloride | Active ingrédient | 4.243 | 30.600 |
(dewaxed) Shellac 40% solution in éthanol | Coating agent solution/ binder solution | 2.122 | 15.300 | |
Extemal modified release layer | Methacrylic acid and methyl méthacrylate copolymer (1:1) (Eudragit L) 10% in acetone (*) | Enteric release coating agent mixture | 0.679 | 4.896 |
(dewaxed) Shellac 40% solution in éthanol | Modified release coating agent solution | 1.758 | 12.677 | |
Talc | Anticaking agent | 1.212 | 8.743 | |
Total dry weight: | 25.017 | 180.31 |
(*) if necessary purified water or éthanol can be added as processing aid to facilitate the obtainment of the enteric release coating agent solution
The obtained pellets of pyridoxine hydrochloride hâve a particle size such that at least 90% of the pellets hâve a particle size from 710 pm to 1400 pm measured by analytical sieving and at least the 90% of the pellets having a particle size variability of not more than 100 pm from a given value comprised from 850 pm and 1250 pm measured by analytical sieving. The homogeneity of the particle size of pellets and the inter-pellet homogeneity of the content of the active ingrédient is such that the pellets are easier to handle allowing a high uniformity in dosification, assuring the desired content of active ingrédient and the desired dissolution profile as described in examples above.
1.3. Préparation process by continuously spraying a liquid slurry/suspension
1.3.1. Préparation of a 25 kg scale batch of a plurality of doxylamine succinate pellets
A. Préparation of phases
Phase 1-Liquid coating slurry/suspension mixture for the préparation of the inner active coating layer: A mixture of 84 g of povidone K30, 467 g of (dewaxed) shellac and 4.28 kg of éthanol was prepared. Then, over this mixture, 4.192 kg of doxylamine succinate (having a D90 <250 pm), 0.279 kg aérosol 200 Ph (having a D90 <250 pm) and 1.397 kg of talc (with a D90 <250 pm) were added. The resulting 10.7 kg of mixture were stirred continuously.
Phase 2-Liquid coating slurry/suspension mixture for the préparation of the intermediate coating layer: A mixture of 89 g of Eudradil L 100 and 1064 g of acetone and 133 g of purified water and 45 g of talc (with a D90 <250 pm) were prepared. The resulting 1.331 kg of mixture were stirred continuously.
Phase 3-Liquid coating slurry/suspension mixture for the préparation of the extemal coating layer: 735 g of talc (with a D90 <250 pm) were added to a mixture of 294 g of Eudradil L100, 1175 g of shellac, 10.71 kg of acetone, 7.93 kg of éthanol and 1.19 kg of purified water. The resulting 22.04 kg of mixture were stirred continuously.
B. Préparation process
-inner active coating layer
15.625 kg of inert nucléus (sugar spheres of sucrose and starch) having a particle size such that at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm and at least the 90% of the pharmaceutically acceptable inert nucléus having a particle size variability of not more than 100 pm from a given value comprised from 710 pm and 1000 pm were transferred into a coating pan. Then liquid coating slurry/suspension mixture phase 1 was sprayed continuously over the pellets, at a coating pan rotation rate of 15 rpm, a spray flow rate of 65 g/min, a dépréssion inside the pan-coating <100 Pa, a gun pressure of about 1.0 bar and an open pattern pressure of about 1.2 bar. While the phase 1 was sprayed, simultaneously the pellets were continuously dried by using hot air (airflow about 100 m3/h at 30-35 °C) and keeping the core température of the pellets between 22°C and 26°C. The coated pellets thus obtained were dried during 10 minutes at 35-50 °C by keeping them rotate in the coating pan at a rate comprised from 0 and 10 rpm and with an airflow of about 160 m3/h to obtain the dried coated pellets with the inner active coating layer having the active ingrédient. If necessary, the dried pellets can be sieved and unwanted particle size, powders and aggregates can be discarded.
-intermediate coating layer
On the coated active pellets obtained in previous step, at a coating pan rotation rate of 15 rpm, the phase 2 liquid mixture was continuously sprayed at a spray flow rate of 20 g/min, a dépréssion inside the pan-coating <100 Pa, a gun pressure of about 1.0 bar, and an open pattern pressure of about 1.2 bar. While the phase 2 was sprayed, simultaneously the pellets were continuously dried by using hot air (airflow <100 m3/h at 30-35 °C) and keeping the core température of the pellets between 24°C and 28°C. The obtained coated pellets were dried during 30 min at 35-50 °C by keeping them rotate in the coating pan at a rate comprised from 0 and 10 rpm and with an airflow of about 160 m3/h to obtain the dried coated pellets with the inner active coating layer and the intermediate coating layer.
-extemal modified release coating layer
Then, the phase 3 coating mixture was continuously sprayed over the bi-layered pellets obtained in the previous step, at a coating pan rotation rate of 15 rpm, a spray flow rate of 75 g/min, a dépréssion inside the pan-coating <100 Pa, a gun pressure of about 1.0 bar, and an open pattern pressure of about 1.2 bar. While the phase 3 was sprayed, simultaneously, the pellets were continuously dried by using hot air (airflow >140 m3/h at 45-50 °C) and keeping the core température of the pellets between 25°C and 29°C. The obtained coated pellets were dried during 30 min at about 50 °C by keeping them rotate in the coating pan at a rate comprised from 0 and 97 rpm and with an airflow of about 160 m3/h to obtain the dried coated pellets with the inner active coating layer, the intermediate coating layer and the extemal coating layer
The pellet thus obtained has the target dissolution profile. If necessary, the dried pellets can be sieved and unwanted particle size, powders and aggregates were discarded.
The modified release pellets of doxylamine succinate thus obtained were stored in 25 kg closed double food pharmaceutical grade polyethylene bags inside closed High Density Polyethylene drums.
1.3.2. Préparation of a 25 kg scale batch of a plurality of pyridoxine hydrochloride pellets
A, Préparation of phases
Phase 4-Liquid coating slurry/suspension mixture for the préparation of the inner active coating layer: A mixture of 0.850 kg of (dewaxed) shellac and 3.48 kg of éthanol was prepared. Then, over this mixture, 4.24 kg of pyridoxine hydrochloride (with a D90 <250 pm) were added. The resulting 8.43 kg of mixture were stirred continuously.
Phase 5-Liquid coating slurry/suspension mixture for the préparation of the extemal coating layer: 385 g of talc (with a D90 <250 pm) were added to a mixture of 68 g of Eudradil L100, 702 g of shellac, 610 g of acetone, 9.72 kg of éthanol and 68 g of purified water. The resulting 11.56 kg of mixture were stirred continuously.
B. Préparation process
-inner active coating layer
17.962 kg of inert nucléus (sugar spheres of sucrose and starch) having a particle size such that at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm and at least the 90% of the pharmaceutically acceptable inert nucléus having a particle size variability of not more than 100 pm from a given value comprised from 710 pm and 1000 pm were transferred into a coating pan. Then liquid coating slurry/suspension mixture phase 4 was sprayed continuously over the pellets, at a coating pan rotation rate of 15 rpm, a spray flow rate of 60 g/min, a dépréssion inside the pan-coating <100 Pa, a gun pressure of about 1.0 bar and an open 98 pattern pressure of about 1.2 bar. While the phase 4 was sprayed, simultaneously the pellets were continuously dried by using hot air (airflow about 100 m3/h at 3 8-42 °C) and keeping the core température of the pellets between 21°C and 24°C. The obtained coated pellets were dried during 20 min with hot air (airflow of about 160 m3/h at 40-50 °C) by keeping them rotate in the coating pan at a rotation rate comprised from 0 and 10 rpm, to obtain the dried coated pellets with the inner active coating layer having the active ingrédient. If necessary, the dried pellets can be sieved and unwanted particle size, powders and aggregates were discarded.
-extemal modified release coating layer
Then, the phase 5 coating mixture was continuously sprayed over coated active pellets obtained in previous step, at a coating pan rotation rate of 15 rpm, a spray flow rate of 63 g/min, a dépréssion inside the pan-coating <100 Pa, a gun pressure of about 1.0 bar, and an open pattern pressure of about 1.2 bar. While the phase 5 was sprayed, simultaneously, the pellets were continuously dried by using hot air (airflow >130 m3/h at 50-65 °C) and keeping the core température of the pellets between 26°C and 30°C. The obtained coated pellets were dried during 30 min with hot air (airflow >120 m3/h at 45-55 °C) by keeping them rotate in the coating pan at a rotation rate comprised from 0 and 10 rpm, to obtain the dried coated pellets with the inner active coating layer and the extemal coating layer, in a yield >93%.
The pellet thus obtained has the target dissolution profile. If necessary, the dried pellets can be sieved and unwanted particle size, powders and aggregates were discarded.
The modified release pellets of doxylamine succinate thus obtained were stored in 25 kg closed double food pharmaceutical grade polyethylene bags inside closed High Density Polyethylene drums.
1.4. Préparation process by discontinuously spraying solution and altemately adding solid in powder form
1.4.1. Préparation of a 25 kg scale batch of a plurality of doxylamine succinate pellets
A . Préparation of phases
Phase 1-powdered mixture for the préparation of the inner active coating layer: In a coating pan 99 were mixed 4.192 kg of doxylamine succinate (D90 < 250 pm), 0.279 kg of Aerosil 200 pharma (with a D90 < 250 pm) and 1.397 kg of talc (with a D90 < 250 pm).
Phase 2-binding solution for the préparation of the inner active coating layer: 0.419 kg of povidone K30 20% w/w in éthanol and 1.169 kg of (dewaxed) shellac 40 % w/w in éthanol were mixed.
Phase 3-coating solution for the préparation of the extemal coating: 89 g of Eudragit L 100 were added to 711 g of acetone and the mixture was stirred, then, 89 g of water were added obtaining a clear solution.
Phase 4-coating solution for the préparation of the extemal coating: 2.950 g of Eudragit L 10% w/w in acetone, 300 g of purified water and 2.937 kg of (dewaxed) shellac 40% w/w in éthanol were mixed.
B . Préparation process
-inner active coating layer
The abovementioned amount of inert nucléus (sugar spheres of sucrose and starch) having a particle size such that at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm and at least the 90% of the pharmaceutically acceptable inert nucléus having a particle size variability of not more than 100 pm from a given value comprised from 710 pm and 1000 pm were transferred into a coating pan. Then the rotation started and was maintained a coating pan rotation rate of 20 rpm and a dépréssion inside the pan-coating <100 Pa during ail this coating step while the binding solution phase 2 was discontinuously sprayed repeating cycles with the next sequence:
- 24 s spraying the binding solution Phase-2 at a spray flow rate of 78 g/min at a gun pressure of about 0.8 bar and an open pattern pressure of about 1.0 bar.
- 5 s of pause 1
- 66-s of addition of the powdered mixture Phase 1 at a powder addition rate of 107 g/min -30 s of pause
- 0 s of drying time (no drying).
The core température of the pellets was kept between 21°C and 25°C. The coated pellets thus obtained were dried during 2 h at room température by keeping them rotate in the coating pan at 100 a rate comprised from 0 and 5 rpm and with an airflow >50 m3/h to obtain the dried coated pellets with the inner active coating layer having the active ingrédient. If necessary, the dried pellets can be sieved and unwanted particle size, powders and aggregates were discarded.
-intermediate enteric release coating layer
The coated active pellets obtained in previous step were transferred into a coating pan. Then the rotation started and was maintained a coating pan rotation rate of 20 rpm and a dépréssion inside the pan-coating <100 Pa during this coating step while the coating solution phase 3 was discontinuously sprayed repeating cycles with the next sequence:
- 60 s spraying the coating solution Phase-3 at a spray flow rate of 46 g/min and a gun pressure of about 1.0 bar and an open pattern pressure of about 1.0 bar.
- 15-s of addition of talc (with a D90 <250 pm) at a powder addition rate of 16.2 g/min
- 15 s of pause
- 45 s of drying time (airflow 50 m3/h at 40-45 °C)
The core température of the pellets was kept between 19°C and 24°C. The coated pellets thus obtained were dried during 1 h at room température by keeping them rotate in the coating pan at a rate comprised from 0 and 5 rpm and with an airflow >50 m3/h to obtain the dried coated pellets with the inner active coating layer having the active ingrédient. If necessary, the dried pellets can be sieved and unwanted particle size, powders and aggregates were discarded.
- extemal modified release coating layer
The coated active pellets obtained in previous step were transferred into a coating pan. Then the rotation started and was maintained a coating pan rotation rate of 20 rpm and a dépréssion inside the pan-coating <100 Pa during this coating step while the coating solution phase 4 was discontinuously sprayed repeating cycles with the next sequence:
- 20 s spraying the binding solution Phase-4 at a spraying flow rate of 39 g/min at a gun pressure of about 1.4 bar and an open pattern pressure of about 1.6 bar.
- 10-s of addition of talc (with a D90 <250 pm) at a powder addition rate of 17 g/min
- 20 s of pause
- 0 s of drying time (no drying).
The core température of the pellets was kept between 24°C and 29°C. The coated pellets thus obtained were dried during 12 h at 40-45 °C by keeping them rotate in the coating pan at a rate comprised from 0 and 5 rpm and with an airflow >80 m3/h to obtain the dried coated pellets with
101 the inner active coating layer having the active ingrédient, in a yield equal to higher than 93% calculated by dividing the obtained amount into the theoretical amount x 100.
The pellet thus obtained has the target dissolution profile. If necessary, the dried pellets can be sieved and unwanted particle size, powders and aggregates were discarded.
The modified release pellets of doxylamine succinate thus obtained were stored in 25 kg closed double food pharmaceutical grade polyethylene bags inside closed High Density Polyethylene drums.
1.4.2. Préparation of a 25 kg scale batch of a plurality of pyridoxine hydrochloride pellets
A. Préparation of phases
Phase 5 -coating solution for the préparation of the extemal coating: 0.679 kg of Eudragit L 10% w/w in acetone, 68 g of water and 1.758 kg of (dewaxed) shellac 40 % w/w in éthanol were mixed.
B. Préparation process
-inner active coating layer
The above-mentioned amount of inert nucléus (sugar spheres of sucrose and starch) having a particle size such that at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm and at least the 90% of the pharmaceutically acceptable inert nucléus having a particle size variability of not more than 100 pm from a given value comprised from 710 pm and 1000 pm were transferred into a coating pan. Then the rotation started and was maintained a coating pan rotation rate of 20 rpm and a dépréssion inside the pan-coating <100 Pa during ail this coating step while (dewaxed) shellac 40% w/w in éthanol was discontinuously sprayed repeating cycles with the next sequence:
- 18 s spraying the binding solution Phase at 56 g/min at a gun pressure of about 0.8 bar and an open pattern pressure of about 1.0 bar.
- 5 s of pause 1
- 9-s of addition of pyridoxine hydrochloride (with a D90 <250 pm) at a powder addition rate of 233 g/min
102
- 30 s ofpause 2
- 0 s of drying time (no drying).
The core température of the pellets was kept between 19°C and 24°C. The coated pellets thus obtained were dried during 2 h at room température by keeping them rotate in the coating pan at a rate comprised from 0 and 5 rpm and with an airflow >50 m3/h to obtain the dried coated pellets with the inner active coating layer having the active ingrédient. If necessary, the dried pellets can be sieved and unwanted particle size, powders and aggregates were discarded.
- extemal modified release coating layer
The coated active pellets obtained in previous step were transferred into a coating pan. Then the rotation started and was maintained a coating pan rotation rate of 20 rpm and a dépréssion inside the pan-coating <100 Pa during this coating step while the coating solution phase 4 was discontinuously sprayed repeating cycles with the next sequence:
- 18 s of spraying the binding solution Phase-4 at a spraying flow rate of 40 g/min at a gun pressure of about 1.4 bar and an open pattern pressure of about 1.6 bar.
- 9-s of addition talc (with a D90 <250 pm) at a powder addition rate of 40 g/min
- 20 s of pause
- 0 s of drying time (no drying).
The core température of the pellets was kept between 23°C and 28°C. The coated pellets thus obtained were dried during 12 h at 40-45 °C by keeping them rotate in the coating pan at a rate comprised from 0 and 5 rpm and with an airflow >50 m3/h to obtain the dried coated pellets with the inner active coating layer having the active ingrédient, in a yield >93%.
The pellet thus obtained has the target dissolution profile. If necessary, the dried pellets can be sieved and unwanted particle size, powders and aggregates were discarded.
The modified release pellets of doxylamine succinate thus obtained were stored in 25 kg closed double food pharmaceutical grade polyethylene bags inside closed High Density Polyethylene drums.
- extemal modified release coating layer
On the coated active pellets obtained in previous step, phase 4 was sprayed at flow rate of 100 g/min. While solution phase 4 was sprayed, talc was applied in solid form at a solid addition rate of 50 g/min and a rotation rate of 16 rpm, keeping the core température of the pellets between 103
17°C and 22°C and the airflow lower than 100 m3/h. The obtained coated pellets were dried during not less than 8 h and up to 12 h at 40-45 °C by keeping them rotate in the coating pan at a rate comprised from 0 and 10 rpm and with an airflow >130 m3/h (yield equal to higher than 93%).
The pellet thus obtained has the target dissolution profile. If necessary, the dried pellets can be sieved and unwanted particle size, powders and aggregates were discarded.
The modified release pellets of pyridoxine hydrochloride thus obtained were stored in 50 kg closed double food pharmaceutical grade polyethylene bags inside closed High Density Polyethylene drums.
With the procedures mentioned above for the préparation of the first and the second plurality of the modified release pellets of the présent invention the obtained pellets of doxylamine succinate hâve a particle size such that at least 90% of the pellets hâve a particle size from 710 pm to 1400 pm measured by analytical sieving and at least the 90% of the pellets having a particle size variability of not more than 100 pm from a given value comprised from 850 pm and 1250 pm measured by analytical sieving and the obtained pellets of pyridoxine hydrochloride hâve a particle size such that at least 90% of the pellets hâve a particle size from 710 pm to 1400 pm measured by analytical sieving and at least the 90% of the pellets having a particle size variability of not more than 100 pm from a given value comprised from 850 pm and 1250 pm measured by analytical sieving.
The same procedures mentioned above for the préparation of the first and the second plurality of the modified release pellets of the présent invention can be executed using inert nucléus (sugar spheres of sucrose and starch) but having a particle size such that at least 90% of the inert nucléus hâve a particle size from 710 pm to 1000 pm measured by analytical sieving and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of not more than 75 pm for a given value comprised from 800 pm and 900 pm measured by analytical sieving. In this case the obtained pellets of doxylamine succinate hâve a particle size such that at least 90% of pellets hâve a particle size from 800 pm to 1400 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 75 pm from a given value comprised from 900 pm and 1180 pm measured by analytical sieving; and the obtained pellets of pyridoxine hydrochloride hâve a particle size such that at least 90% of pellets 104 hâve a particle size from 800 pm to 1400 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 75 pm from a given value comprised from 900 pm and 1180 pm measured by analytical sieving.
Capsule filling
Each Hard capsule was filled with about 60 mg of the modified release pellets of doxylamine succinate and about 60 mg of the modified release pellets of pyridoxine hydrochloride of the présent invention as defined above using a Bosch Zanassi E48 automatic capsule-filling machine; to obtain capsules containing about 10 mg of doxylamine succinate and about 10 mg of pyridoxine hydrochloride.
The same procedures mentioned above for the préparation of capsules having about 10 mg of doxylamine succinate and about 10 mg of pyridoxine hydrochloride, can be performed by filling the capsules with about 120 mg of the modified release pellets of doxylamine succinate and about 120 mg of the modified release pellets of pyridoxine hydrochloride of the présent invention as defined above using the Bosch Zanassi E48 automatic capsule-filling machine; to obtain capsules containing about 20 mg of doxylamine succinate and about 20 mg of pyridoxine hydrochloride.
2. Dissolution Test
Dissolution profile
The target dissolution profile requires that both the doxylamine succinate and the pyridoxine hydrochloride were slightly dissolved under the stomach conditions and that the major therapeutic concentration was achieved in the intestinal tract due to its rapid dissolution rate. In particular, the process for the préparation of the présent invention allows obtaining capsules, filled with such a modified release pellets of doxylamine succinate and modified release pellets of pyridoxine hydrochloride, which exhibit a dissolution profile according to which:
from 5% to 35% by weight of doxylamine content is dissolved at lsth in 0.1 N HCl medium (pH = i);
then, the medium is replaced by a pH = 4.5 medium (0.05 M acetate buffer) and at 4th h from an accumulated more than 35% to 75% by weight of doxylamine initial content is dissolved;
105 then, the medium is replaced by a pH = 6.8 medium (0.05 M phosphate buffer) and at 7th h at least an accumulated more than 75% of doxylamine initial content is dissolved from 5% to 35% by weight of pyridoxine content is dissolved at lsth in 0.1 N HCl medium (pH = i);
then, the medium is replaced by a pH = 4.5 medium (0.05 M acetate buffer) and at 4th h from an accumulated more than 35% to 75% by weight of pyridoxine initial content is dissolved;
then, the medium is replaced by a pH = 6.8 medium (0.05 M phosphate buffer) and at 7thh at least an accumulated more than 75% of pyridoxine initiai content is dissolved.
wherein the dissolution profile is measured using a USP type II apparatus (basket), placing the composition in 900mL of the corresponding media / buffered 37°C ±0.5 °C and 100 rpm.
Conditions of the dissolution bath
- Paddle speed: 100 rpm
- Température of dissolution medium: 37 °C ± 0.5 °C
- Dissolution media: hydrochloric acid 0.1N
- Vessel volume: 900 mL
- Time: 1 hour
- Dissolution media: pH 4.5; 0.05 M acetate buffer
- Vessel volume: 900 mL
- Time: From the lst h to the 4th hour
- Dissolution media: pH 6.8; 0.05 M phosphate buffer
- Vessel volume: 900 mL
- Time: From the 4th h to the 7th hour
Conditions of the chromatographie analysis
- Sample préparation: Take an aliquot of approximately 10 ml and filter it through 0.70 pm membrane filter, then filter it through another 0.22 pm membrane filter.
- Flux: 1 mL/min
- Column: Kromasil 100-5 C18, 150 x 4.0 mm
- Phases: methanol in water
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- Injection volume: 100 pL
- Excitation wavelength: 220 nm
- Chromatographie time: 25 min.
- Aqueous phase: Ammonium acetate buffer 0.06 M pH 5.0 + 0.1% sodium hexane sulfonate (PICB6)):
- Gradient:
Time (min) Methanol (%) Aqueous phase (%)
0 | 20 | 80 |
4 | 32.5 | 80 |
8 | 100 | 50 |
13 | 100 | 50 |
17 | 20 | 80 |
25 | 20 | 80 |
Results
The capsules of the présent invention as defined above and below which comprises pellets of doxylamine succinate and pyridoxine hydrochloride exhibit the target dissolution profile. Thus, the dissolution of both doxylamine succinate and pyridoxine hydrochloride when it is submitted to stomach conditions is, at least a 5% of the total amount in 1 hour and at least a 35% of doxylamine succinate and pyridoxine hydrochloride after 4 hours is dissolved when it is submitted to duodenal conditions (pH = 4.5) and at least an 75% of doxylamine succinate and pyridoxine hydrochloride after 7 hours is dissolved when it is submitted to colon conditions.
Packaging and Stability Test
Blisters:
- The capsules of pellets of doxylamine succinate and pyridoxine hydrochloride of the présent invention of examples 1.1.1 to 1.1.10 when primary packaged in blister made of PVC/PVdC (on one side of the blister) and aluminium (on the other side of the blister) are stable allowing storage at or below 25°C and 60% Relative Humidity.
- The capsules of pellets of doxylamine succinate and pyridoxine hydrochloride of the présent invention of examples 1.1.2; 1.1.4 ; 1.1.6 ; 1.1.8 and 1.1.10 when primary packaged in blister made in AquaBa® or Aluminium (one side of the blister) and Aluminium (the other side of the blister) are stable allowing storage at or below 30°C and 75% Relative Humidity.
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Bottles:
- The capsules of pellets of doxylamine succinate and pyridoxine hydrochloride of the présent invention of examples 1.1.1 to 1.1.10 when primary packaged in plastic bottles plus desiccant are stable allowing storage at or below 30°C and 75% Relative Humidity.
For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:
Clause 1. A modified release multiple unit oral dosage form comprising:
a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising:
- a pharmaceutically acceptable inert nucléus;
- an inner active coating layer comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, one or more coating agents, one or more anticaking agents, optionally one or more pore-forming agent; and optionally one or more pharmaceutically acceptable excipients;
- optionally an intermediate enteric release coating layer comprising one or more enteric coating agents, one or more anticaking agents, optionally one or more pore-forming agent; and optionally one or more pharmaceutically acceptable excipients, and
- an extemal modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; and a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof comprising:
- a pharmaceutically acceptable inert nucléus;
- an inner active coating layer comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and
- an extemal modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients;
wherein:
the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the
108 inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nucléus hâve a particle size variability of 200 pm; particularly a particle size variability of 150 pm; particularly a particle size variability of 100 pm; particularly a particle size variability of 75 pm and particularly a particle size variability of 50 pm measured by analytical sieving.
Clause 2. The modified release multiple unit oral dosage form according to clause 1, comprising:
a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising:
- a pharmaceutically acceptable inert nucléus;
- an inner active coating layer comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, one or more coating agents, one or more anticaking agents, optionally one or more pore-forming agent; and optionally one or more pharmaceutically acceptable excipients;
- an intermediate enteric release coating layer comprising one or more enteric coating agents, one or more anticaking agents, optionally one or more pore-forming agent; and optionally one or more pharmaceutically acceptable excipients, and
- an extemal modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; and a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof comprising:
- a pharmaceutically acceptable inert nucléus;
- an inner active coating layer comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and
- an extemal modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients;
wherein:
the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the 109 inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nucléus hâve a particle size variability of 200 pm; particularly a particle size variability of 150 pm; particularly a particle size variability of 100 pm; particularly a particle size variability of 75 pm and particularly a particle size variability of 50 pm measured by analytical sieving.
Clause 3. The modified release multiple unit oral dosage form according to any of the clauses 1 or 2, wherein:
the dosage form comprises pharmaceutically acceptable inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving, and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of 200 pm; particularly a particle size variability of 150 pm, particularly a particle size variability of 100 pm, particularly a particle size variability of 75 pm and more particularly a particle size variability of 50 pm measured by analytical sieving;
particularly, the dosage form comprises pharmaceutically acceptable inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1400 pm measured by analytical sieving, and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of 200 pm; particularly a particle size variability of 150 pm, particularly a particle size variability of 100 pm, particularly a particle size variability of 75 pm and more particularly a particle size variability of 50 pm measured by analytical sieving;
particularly, the dosage form comprises pharmaceutically acceptable inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 600 pm to 1180 pm measured by analytical sieving and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of 150 pm; particularly a particle size variability of 100 pm, particularly a particle size variability of 75 pm and more particularly a particle size variability of 50 pm measured by analytical sieving;
particularly, the dosage form comprises pharmaceutically acceptable inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 710 pm to 1000 pm measured by analytical sieving and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of 100 pm, particularly a particle size variability of 75 pm and more particularly a particle size variability of 50 pm measured by analytical sieving;
particularly, the dosage form comprises pharmaceutically acceptable inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 710 pm to 850 pm measured by analytical sieving and at least the 90% of the pharmaceutically acceptable inert
110 nucléus hâve a particle size variability of 70 pm; and particularly a particle size variability of 50 pm measured by analytical sieving ;
particularly, the dosage form comprises pharmaceutically acceptable inert nucléus having a particle size such that at least 90% of the inert nucléus hâve a particle size from 850 pm to 1000 pm measured by analytical sieving and at least the 90% of the pharmaceutically acceptable inert nucléus hâve a particle size variability of 70 pm; and particularly a particle size variability of 50 pm measured by analytical sieving.
Clause 4. The modified release multiple unit oral dosage form according to any of the clauses 13, wherein:
the particle size of the pellets of the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 400 pm to 1900 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of 200 pm; particularly a particle size variability of 150 pm; particularly a particle size variability of 100 pm; particularly a particle size variability of 75 pm; and more particularly a particle size variability of 50 pm measured by analytical sieving;
and the particle size of the pellets of the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 400 pm to 1900 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of 200 pm; particularly a particle size variability of 150 pm; particularly a particle size variability of 100 pm; particularly a particle size variability of 75 pm; and more particularly a particle size variability of 50 pm measured by analytical sieving.
Clause 5. The modified release multiple unit oral dosage form according to any of the clauses 14, wherein: the particle size of doxylamine or a pharmaceutically acceptable sait is characterized for having a D90 equal to or below than 250 pm; and the particle size of pyridoxine or a pharmaceutically acceptable sait thereof is characterized for having a D90 equal to or below than 250 pm;
or altematively, the particle size of doxylamine or a pharmaceutically acceptable sait is characterized for having a D90 equal to or below than 250 pm; and the particle size of pyridoxine or a pharmaceutically acceptable sait thereof is characterized for having a D90 equal to or below than 250 pm; the particle size of the one or more anticaking agent is characterized for having a D90 equal to or
111
J below than 250 pm; and optionally, the particle size of the one or more pore-forming agent is characterized for having a D90 equal to or below than 250 pm.
Clause 6. The modified release multiple unit oral dosage form according to any of the clauses 15, which comprises a pharmaceutically acceptable sait of doxylamine and a pharmaceutically acceptable sait of pyridoxine; preferably, comprises doxylamine succinate and pyridoxine hydrochloride.
Clause 7. The modified release multiple unit oral dosage form according to any of the clauses Ιό, which comprises from 5 mg to 50 mg per oral dosage form of doxylamine or a pharmaceutically acceptable sait thereof; and from 5 mg to 50 mg per oral dosage form of pyridoxine or a pharmaceutically acceptable sait thereof.
Clause 8. The modified release multiple unit oral dosage form according to any of the clauses 17, wherein the modified release multiple unit oral dosage form exhibits a dissolution profile according to which:
from 5% to 35% by weight of doxylamine content is dissolved at lsth in 0.1 N HCl medium (pH = i);
then, the medium is replaced by a pH = 4.5 medium (0.05 M acetate buffer) and at 4th h from an accumulated more than 35% to 75% by weight of doxylamine initial content is dissolved;
then, the medium is replaced by a pH = 6.8 medium (0.05 M phosphate buffer) and at 7thh at least an accumulated more than 75% by weight of doxylamine initial content is dissolved; and from 5% to 35% by weight of pyridoxine content is dissolved at lsth in 0.1 N HCl medium (pH = i);
then, the medium is replaced by a pH = 4.5 medium (0.05 M acetate buffer) and at 4th h from an accumulated more than 35% to 75% by weight of pyridoxine initial content is dissolved;
then, the medium is replaced by a pH = 6.8 medium (0.05 M phosphate buffer) and at 7thh at least an accumulated more than 75% by weight of pyridoxine initial content is dissolved;
wherein the dissolution profile is measured using a USP type 2 apparatus (basket), placing the composition in 900mL of the corresponding media / buffered 37°C ± 0.5 °C and 100 rpm.
112
Clause 9. The modified release multiple unit oral dosage form according to any of the clauses 18, which is a capsule; particularly a hard capsule.
Clause 10. A process for the préparation of the modified release multiple unit oral dosage form as defined in any of the clauses 1-9 comprising:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and optionally the intermediate enteric coating layer by adding the one or more enteric coating agents, the one or more modified release coating agents, the one or more anticaking agents, optionally one or more pore-forming agent, and optionally one or more pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nucléus hâve a particle size variability of 200 pm measured by analytical sieving;
particularly of 150 pm; particularly of 100 pm; particularly of 75 pm and particularly of 50 pm; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by adding the one or more enteric coating agents, the one or more modified release coating agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the inert nucléus hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nucléus hâve a particle size variability of 200 pm measured by analytical sieving; particularly of 150 pm; particularly of 100 pm; particularly of 75 pm and particularly of 50 pm.
Clause 11. The process according to clause 10, wherein the process comprises:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and optionally the intermediate enteric coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, the one or more modified release coating agents, and optionally one or more pharmaceutically acceptable excipients; and
113 (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, the one or more modified release coating agents and optionally one or more pharmaceutically acceptable excipients;
or altematively, (al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and optionally the intermediate enteric coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, the one or more modified release coating agents, and optionally one or more pharmaceutically acceptable excipients; and adding simultaneously or altemately a mixture in powder form comprising the one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, the one or more modified release coating agents, and optionally one or more pharmaceutically acceptable excipients; and adding simultaneously or altemately a mixture in powder form comprising the one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients.
Clause 12. The process according to clause 11 comprising:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and optionally the intermediate enteric coating layer by adding the one or more enteric coating agents, the one or more modified release coating agents, the one or more anticaking agents, optionally one or more pore-forming agent, and optionally one or more pharmaceutically acceptable excipients, wherein: the sum of the enteric coating agents and the modified release coating agents in the spraying liquid mixture is from 10% to 49% by weight in relation to the weight of the liquid mixture, and (bl) preparing the second plurality of modified release pellets of pyridoxine or a
114 pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by adding the one or more enteric coating agents, the one or more modified release coating agents, the one or more anticaking agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the sum of the enteric coating agents and the modified release coating agents in the spraying liquid mixture is from 10% to 49% by weight in relation to the weight of the liquid mixture.
Clause 13. The process according to any of the clauses 11 or 12, wherein the process comprises: (al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and optionally the intermediate enteric coating layer by continuously or discontinuously spraying a liquid mixture comprising from 1.0 to 7.5 % by weight of the one or more enteric coating agents, from 10.0 to 35.0 % by weight of the one or more modified release coating agents in a weight ratio between them from 5:95 to 30:70, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising the one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the spray average flow rate of the mixture comprising the coating is from 0.30 to 5.00 g/min per kg of pharmaceutically acceptable inert nucléus; the average of the solid addition rate of the mixture in solid form is from 0.05 to 1.50 g/min per Kg of pharmaceutically acceptable inert nucléus; and the relation between the spray average flow rate of the mixture comprising the coating agents and the average of the solid addition rate of the mixture in solid form is from 90:10 to 60:40, particularly from 90:10 to 70:30; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising from 1.0 to 7.5 % by weight of the one or more enteric coating agents, from 10.0 to 35.0 % by weight of the one or more modified release coating agents in a weight ratio from 5:95 to 30:70; and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients,
115 wherein: the spray average flow rate of the mixture comprising the coating agents is from 0.30 to 5.00 g/min per kg of pharmaceutically acceptable inert nucléus; the average of the solid addition rate of the mixture in solid form is from 0.10 to 2.25 g/min per Kg of pharmaceutically acceptable inert nucléus; and the relation between the spray average flow rate of the mixture comprising the coating agents and the average of the solid addition rate of the mixture in solid form is from 90:10 to 60:40, particularly from 80:20 to 60:40.
Clause 14. The process according to any of the clauses 10-13, wherein the process further comprises a previous step of coating separately:
optionally (a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, and optionally one or more pharmaceutically acceptable excipients; and (b2) the pharmaceutically acceptable inert nucléus by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients;
or altematively, optionally (a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in solid form comprising the one or more anticaking agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; and (b2) the pharmaceutically acceptable inert nucléus by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding in powder form the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients.
Clause 15. The process according to clause 14, wherein the process comprises:
optionally (a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising from 5 to 15% by weight of the one or more enteric coating agents, and optionally 116 one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form from 5.0 to 6.5 g per kg of pharmaceutically acceptable inert nucléus of the mixture in solid form comprising the one or more anticaking agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; wherein: the average of the spray flow rate of the mixture comprising the enteric coating agents is from 0.30 to 3.00 g/min per kg of pharmaceutically acceptable inert nucléus; the average of the solid addition rate of the mixture in solid form is from 0.025 to 0.400 g/min per Kg of pharmaceutically acceptable inert nucléus; and the relation between the average spray flow rate of the mixture comprising the coating agents and the average of solid addition rate of the mixture in solid form is from 85:15 to 95:5; and (b2) the pharmaceutically acceptable inert nucléus with a simultaneously or altemately spraying a liquid mixture comprising from 20% to 45% by weight of one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding in powder form the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients: wherein the average spray flow rate of the mixture comprising the coating agents is from 0.30 to 4.50 g/min per Kg of pharmaceutically acceptable inert nucléus; the average of the solid addition rate of the powder is from 0.50 to 9.00 g/min per Kg of pharmaceutically acceptable inert nucléus; and the relation between the average spray flow rate of the mixture comprising the coating agents and the average of the solid addition rate is from 25:75 to 40:60.
Clause 16. The process according to any of the clauses 14 or 15, wherein the process further comprises an additional step which comprises:
(a3) coating the pharmaceutically acceptable inert nucléus with a continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients;
or altematively (a3) coating the pharmaceutically acceptable inert nucléus with a continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, one or more anticaking, optionally one or more poreforming agents, and optionally one or more pharmaceutically acceptable excipients
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Clause 17. The process according to clause 16, wherein the process comprises:
(a3) coating the pharmaceutically acceptable inert nucléus with a continuously or discontinuously spraying a liquid mixture comprising from 15% to 40% by weight of one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in powder form comprising the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, from 18 to 36% by weight of the one or more anticaking, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients;
wherein: the average spray flow rate of the mixture comprising the coating agents is from 0.30 to 4.50 g/min per Kg of pharmaceutically acceptable inert nucléus; the average of the solid addition rate of the mixture in powder form is from 0.95 to 18.00 g/min per Kg of pharmaceutically acceptable inert nucléus; and the relation between the average spray flow rate of the mixture comprising the coating agents and the average of the solid addition rate of the mixture in powder form is from 15:85 to 30:70.
Clause 18. The process according to any of the clauses 10-17, wherein in each one of the spraying steps (al), (a2), (a3), (bl) and (b2), the liquid mixture is sprayed at a gun atomization pressure from 0.6 to 2.2 bar and an open pattern pressure from 0.6 to 2.5 bar.
Citation List
1. WO2013123569
2. WO2016029290
3. European Pharmacopoeia chapter 2.9.38
4. European Pharmacopoeia Doxylamine hydrogen succinate monograph
5. European Pharmacopoeia Pyridoxine hydrochloride monograph
Claims (27)
1. A modified release multiple unit oral dosage form comprising:
5 a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof comprising:
- a pharmaceutically acceptable inert nucléus;
- an inner active coating layer comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, one or more coating agents, one or more
10 anticaking agents, optionally one or more pore-forming agent; and optionally one or more pharmaceutically acceptable excipients;
- optionally an intermediate enteric release coating layer comprising one or more enteric coating agents, one or more anticaking agents, optionally one or more pore-forming agent; and optionally one or more pharmaceutically acceptable excipients, and
15 - an exterhal modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; and
20 a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof comprising: -
- a pharmaceutically acceptable inert nucléus;
- an inner active coating layer comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, one or more coating agents, and optionally
25 one or more pharmaceutically acceptable excipients; and
- an external modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients;
30 wherein:
the particle size of the pharmaceutically acceptable inert nucléus of the first and the second plurality of pellets is such that at least 90% of the inert nuclei hâve a particle size from 300
119 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nuclei hâve a particle size variability of not more than 200 pm;
from a given value comprised from 500 pm and 1400 pm measured by analytical sieving;
wherein the particle size variability means that from a given value, at least the 90% of the
5 pharmaceutically acceptable inert nuclei of the first and the second plurality of pellets hâve a particle size comprised from +200 pm from the given value.
2. The modified release multiple unit oral dosage form according to claim 1, wherein the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable
10 sait thereof comprises the intermediate enteric release coating layer comprising one or more enteric coating agents, one or more anticaking agents, optionally one or more poreforming agent; and optionally one or more pharmaceutically acceptable excipients.
3. The modified release multiple unit oral dosage form according to any of the daims 1 or
15 2, wherein:
the dosage form comprises pharmaceutically acceptable inert nuclei of the first and the second plurality of pellets having a particle size such that at least 90% of the inert nuclei hâve a particle size from 300 pm to 1400 pm measured by analytical sieving, and at least the 90% of the pharmaceutically acceptable inert nuclei hâve a particle size variability of
20 not more than 150 pm from a given value comprised from 450 pm and 1250 pm measured by analytical sieving; wherein the particle size variability means that from a given value, at least the 90% of the pharmaceutically acceptable inert nuclei of the first and the second plurality of pellets hâve a particle size comprised from +150 pm from the given value.
25
4. The modified release multiple unit oral dosage form according to any of the daims 1-3, wherein:
the particle size of the pellets of the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 400 pm to 2000 pm measured by analytical sieving and at
30 least the 90% of the pellets hâve a particle size variability of not more than 200 pm from a given value comprised from 600 pm and 1800 pm measured by analytical sieving; wherein the particle size variability means that from a given value, the at least 90% of the first
120 plurality of modified release pellets hâve a particle size comprised from + 200 pm from the given value;
and the particle size of the pellets of the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 400 pm to 2000 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 200 pm from a given value comprised from 600 pm and 1800 pm measured by analytical sieving; wherein the particle size variability means that from a given value, the at least 90% of the second plurality of modified release pellets hâve a particle size comprised from + 200 pm from the given value.
5. The modified release multiple unit oral dosage form according to claim 4, wherein: the particle size of the pellets of the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 600 pm to 1600 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 150 pm from a given value comprised from 800 pm and 1400 pm measured by analytical sieving; wherein the particle size variability means that from a given value, the at least 90% of the first plurality of modified release pellets hâve a particle size comprised from +150 pm from the given value. ·
6. The modified release multiple unit oral dosage form according to any of the claims 4 or 5, wherein:
the particle size of the pellets of the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof is such that at least 90% of the pellets hâve a particle size from 600 pm to 1600 pm measured by analytical sieving and at least the 90% of the pellets hâve a particle size variability of not more than 150 pm from a given value comprised from 800 pm and 1400 pm measured by analytical sieving; wherein the particle size variability means that from a given value, the at least 90% of the second plurality of modified release pellets hâve a particle size comprised from +150 pm from the given value.
121 -
7. The modified release multiple unit oral dosage form according to any of the claims 1-6, wherein:
the particle size of doxylamine or a pharmaceutically acceptable sait thereof is
5 characterized for having a D90 equal to or below than 250 pm; and the particle size of pyridoxine or a pharmaceutically acceptable sait thereof is characterized for having a D90 equal to or below than 250 pm;
or alternatively, the particle size of doxylamine or a pharmaceutically acceptable sait is characterized for
10 having a D90 equal to or below than 250 pm; and the particle size of pyridoxine or a pharmaceutically acceptable sait thereof is characterized for having a D90 equal to or below than 250 pm; the particle size of the one or more anticaking agent is characterized for having a D90 equal to or below than 250 pm;
wherein:
15 the D90 of the particle size of doxylamine or a pharmaceutically acceptable sait thereof is expressed by volume; the D90 of the particle size of pyridoxine or a pharmaceutically accepotable sait thereof is expressed by volume; and the D90 of the particle size of the anticaking agents is expressed by weight.
20
8. The modified release multiple unit oral dosage form according to any of the claims 1-7, which comprises a pharmaceutically acceptable sait of doxylamine and a pharmaceutically acceptable sait of pyridoxine.
9. The modified release multiple unit oral dosage form according to claim 8, which
25 comprises doxylamine succinate and pyridoxine hydrochloride.
10. The modified release multiple unit oral dosage form according to any of the claims 1-9, which comprises:
from 5 mg to 50 mg per oral dosage form of doxylamine or a pharmaceutically acceptable 30 sait thereof; and from 5 mg to 50 mg per oral dosage form of pyridoxine or a pharmaceutically acceptable sait thereof.
122
11. The modified release multiple unit oral dosage form according to claim 10, which comprises:
from 10 mg to 20 mg per oral dosage form of doxylamine or a pharmaceutically acceptable sait thereof.
12. The modified release multiple unit oral dosage form according to any of the daims 10 or 11, which comprises:
from 10 mg to 20 mg per oral dosage form of pyridoxine or a pharmaceutically acceptable sait thereof.
13. The modified release multiple unit oral dosage form according to any of the daims 1-
12, ' wherein the modified release multiple unit oral dosage form exhibits a dissolution profile according to which:
from 5% to 35% by weight of doxylamine content is dissolved at lsth in 0.1 N HCl medium (pH =1);
then, the medium is replaced by a pH = 4.5 medium (0.05 M acetate buffer) and at 4th h from an accumulated more than 35% to 75% by weight of doxylamine initial content is dissolved;
then, the medium is replaced by a pH = 6.8 medium (0.05 M phosphate buffer) and at 7th h at least an accumulated more than 75% by weight of doxylamine initial content is dissolved; and from 5% to 35% by weight of pyridoxine content is dissolved at lsth in 0.1 N HCl medium (pH=l);
then, the medium is replaced by a pH = 4.5 medium (0.05 M acetate buffer) and at 4th h from an accumulated more than 35% to 75% by weight of pyridoxine initial content is dissolved;
then, the medium is replaced by a pH = 6.8 medium (0.05 M phosphate buffer) and at 7th h at least an accumulated more than 75% by weight of pyridoxine initial content is dissolved;
123 wherein the dissolution profile is measured using a USP type 2 apparatus (basket), placing the composition in 900mL of the corresponding media / buffered 37°C ± 0.5 °C and 100 rpm.
5
14. The modified release multiple unit oral dosage form according to any of the daims 1-
13, which is a capsule.
15. The modified release multiple unit oral dosage form according to claim 14, which is a hard capsule.
16. The modified release multiple unit oral dosage form according to claim 15, wherein the hard capsule is selected from the group consisting of hard gélatine capsule and a hard hydroxypropyl methylcellulose capsule.
15
17. A process for the préparation of the modified release multiple unit oral dosage form as defîned in any of the daims 1-16 comprising:
(al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and
20 optionally the intermediate enteric coating layer by adding the one or more enteric coating agents, the one or more modified release coating agents, the one or more anticaking agents, optionally one or more pore-forming agent, and optionally one or more pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the inert nuclei hâve a particle size from 300 pm to
25 1700 pm measured by analytical sieving and at least the 90% of inert nuclei hâve a particle size variability of not more than 200 pm measured by analytical sieving ;
and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a
30 pharmaceutically acceptable sait thereof having the inner active coating layer by adding the one or more enteric coating agents, the one or more modified release coating agents, optionally the one or more pore-forming agents, and optionally one or more
124 pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the inert nuclei hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nuclei hâve a particle size variability of not more than 200 pm measured by analytical
5 sieving.
18. The process according to claim 17 wherein in step (al):
the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90% of the inert nuclei hâve a particle size from 300 pm to 1700 pm measured by analytical
10 sieving and at least the 90% of inert nuclei hâve a particle size variability of not more than 150 pm measured by analytical sieving.
19. The process according to any of the claims 17 or 18 wherein in step (bl):
the particle size of the pharmaceutically acceptable inert nucléus is such that at least 90%
15 of the inert nuclei hâve a particle size from 300 pm to 1700 pm measured by analytical sieving and at least the 90% of inert nuclei hâve a particle size variability of not more than 150 pm measured by analytical sieving.
20. The process according to any of the claims 17-19, wherein the process comprises:
20 (al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and optionally the intermediate enteric coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, the one or
25 more modified release coating agents, and optionally one or more pharmaceutically acceptable excipients; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by
30 continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, the one or more modified release coating agents and optionally one or more pharmaceutically acceptable excipients;
125 or alternatively, (al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and
5 optionally the intermediate enteric coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, the one or more modified release coating agents, and optionally one or more pharmaceutically acceptable excipients; and adding simultaneously or altemately a mixture in powder form comprising the one or more anticaking agents, optionally one or more pore-forming agents, 10 and optionally one or more pharmaceutically acceptable excipients; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more
15 enteric coating agents, the one or more modified release coating agents, and optionally one or more pharmaceutically acceptable excipients; and adding simultaneously or altemately a mixture in powder form comprising the one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients.
21. The process according to claim 20 comprising:- (al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and
25 optionally the intermediate enteric coating layer by adding the one or more enteric coating agents, the one or more modified release coating agents, the one or more anticaking agents, optionally one or more pore-forming agent, and optionally one or more pharmaceutically acceptable excipients, wherein: the sum of the enteric coating agents and the modified release coating agents in the spraying liquid mixture is from 10% to 49% by weight in
30 relation to the weight of the liquid mixture, and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a
126 pharmaceutically acceptable sait thereof having the inner active coating layer by adding the one or more enteric coating agents, the one or more modified release coating agents, the one or more anticaking agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the sum of the enteric coating agents and the modified release coating agents in the spraying liquid mixture is from 10% to 49% by weight in relation to the weight of the liquid mixture.
22. The process according to any of the claims 20 or 21, wherein the process comprises: (al) preparing the first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable sait thereof by coating the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer and optionally the intermediate enteric coating layer by continuously or discontinuously spraying a liquid mixture comprising from 1.0 to 7.5 % by weight of the one or more enteric coating agents, from 10.0 to 35.0 % by weight of the one or more modified release coating agents in a weight ratio between them from 5:95 to 30:70, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or alternately adding a mixture in powder form comprising the one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the spray average flow rate of the mixture comprising the coating is from 0.30 to 5.00 g/min per kg of pharmaceutically acceptable inert nuclei; the average of the solid addition rate of the mixture in solid form is from 0.05 to 1.50 g/min per Kg of pharmaceutically acceptable inert nuclei; and the relation between the spray average flow rate of the mixture comprising the coating agents and the average of the solid addition rate of the mixture in solid form is from 90:10 to 60:40,; and (bl) preparing the second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable sait thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising from 1.0 to 7.5 % by weight of the one or more enteric coating agents, from 10.0 to 35.0 % by weight of the one or more modified release coating agents in a weight ratio from 5:95 to 30:70; and optionally one or more pharmaceutically acceptable excipients; and simultaneously or
127 21340 altemately adding a mixture in powder form comprising one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the spray average flow rate of the mixture comprising the coating agents is from
5 0.30 to 5.00 g/min per kg of pharmaceutically acceptable inert nuclei; the average of the solid addition rate of the mixture in solid form is from 0.10 to 2.25 g/min per Kg of pharmaceutically acceptable inert nuclei; and the relation between the spray average flow rate of the mixture comprising the coating agents and the average of the solid addition rate of the mixture in solid form is from 90:10 to 60:40, particularly from 80:20 to 60:40.
23. The process according to any of the daims 17-22, wherein the process further comprises a previous step of coating separately:
optionally (a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid
15 mixture comprising the one or more enteric coating agents, and optionally one or more pharmaceutically acceptable excipients; and (b2) the pharmaceutically acceptable inert nucléus by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, and
20 optionally one or more pharmaceutically acceptable excipients;
or altematively, · optionally (a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising the one or more enteric coating agents, and optionally one or more 25 pharmaceutically acceptable excipients; and simultaneously or altemately adding a mixture in solid form comprising the one or more anticaking agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; and (b2) the pharmaceutically acceptable inert nucléus by continuously or discontinuously
30 spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or altemately adding in powder form the therapeutically effective amount of pyridoxine or a pharmaceutically
128 acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients.
24. The process according to claim 23, wherein the process comprises:
optionally (a2) the pellets of doxylamine or a pharmaceutically acceptable sait thereof
5 having the inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising from 5 to 15% by weight of the one or more enteric coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or alternately adding a mixture in powder form from 5.0 to 6.5 g per kg of pharmaceutically acceptable inert nuclei of the mixture in solid form comprising the one or more anticaking
10 agents, optionally the one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; wherein: the average of the spray flow rate of the mixture comprising the enteric coating agents is from 0.30 to 3.00 g/min per kg of pharmaceutically acceptable inert nuclei; the average of the solid addition rate of the mixture in solid form is from 0.025 to 0.400 g/min per Kg of pharmaceutically acceptable
15 inert nucléus; and the relation between the average spray flow rate of the mixture comprising the coating agents and the average of solid addition rate of the mixture in solid form is from 85:15 to 95:5; and (b2) the pharmaceutically acceptable inert nucléus with a simultaneously or alternately spraying a liquid mixture comprising from 20% to 45% by weight of one or more coating 20 agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or alternately adding in powder form the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients: wherein the average spray flow rate of the mixture comprising the coating agents is from 0.30 to 4.50 g/min per Kg of pharmaceutically
25 acceptable inert nuclei; the average of the solid addition rate of the powder is from 0.50 to 9.00 g/min per Kg of pharmaceutically acceptable inert nuclei; and the relation between the average spray flow rate of the mixture comprising the coating agents and the average of the solid addition rate is from 25:75 to 40:60.
30
25. The process according to any of the claims 23 or 24, wherein the process further comprises an additional step which comprises:
(a3) coating the pharmaceutically acceptable inert nucléus with a continuously or
129
I discontinuously spraying a liquid mixture comprising one or more coating agents, the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, and optionally one or more pharmaceutically acceptable excipients;
or alternatively (a3) coating the pharmaceutically acceptable inert nucléus with a continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or alternately adding a mixture in powder form comprising the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, one or more anticaking, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients.
26. The process according to claim 25, wherein the process comprises:
(a3) coating the pharmaceutically acceptable inert nucléus with a continuously or discontinuously spraying a liquid mixture comprising from 15% to 40% by weight of one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; and simultaneously or alternately adding a mixture in powder form comprising the therapeutically effective amount of doxylamine or a pharmaceutically acceptable sait thereof, from 18 to 36% by weight of the one or more anticaking, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; wherein: the average spray flow rate of the mixture comprising the coating agents is from 0.30 to 4.50 g/min per Kg of pharmaceutically acceptable inert nuclei; the average of the solid addition rate of the mixture in powder form is from 0.95 to 18.00 g/min per Kg of pharmaceutically acceptable inert nuclei; and the relation between the average spray flow rate of the mixture comprising the coating agents and the average of the solid addition rate of the mixture in powder form is from 15:85 to 30:70.
27. The process according to any of the daims 17-26, wherein in each one of the spraying steps (al), (a2), (a3), (bl) and (b2), the liquid mixture is sprayed at a gun atomization pressure from 0.6 to 2.2 bar and an open pattern pressure from 0.6 to 2.5 bar.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP20382227.5 | 2020-03-25 |
Publications (1)
Publication Number | Publication Date |
---|---|
OA21340A true OA21340A (en) | 2024-05-10 |
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