A modified release multiple unit oral dosage form of doxylamine succinate and pyridoxine hydrochloride and a preparation method thereof

Abstract

A modified release multi-unit oral dosage form of doxylamine succinate and pyridoxine hydrochloride and a method for preparing the same. The present invention relates to a modified release multi-unit oral dosage form, comprising: a plurality of first modified release pellets of doxylamine, comprising: a pharmaceutically acceptable inert core; an inner active coating layer comprising doxylamine; optionally an intermediate enteric release coating layer; and an outer modified release coating layer; and a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, comprising: a pharmaceutically acceptable inert core; an inner active coating layer comprising pyridoxine or a pharmaceutically acceptable salt thereof; and an outer modified release coating layer; wherein the particle size of the pharmaceutically acceptable inert core of the plurality of first and second pellets is such that at least 90% of the inert cores have a particle size of 300 μm to 1700 μm as measured by analytical sieving, and a particle size variability of no more than 200 μm. The present invention also relates to a method for preparing the same and its use in treatment.

Description

[0001] This application claims the benefit of European patent application EP20382227.5 filed on March 25, 2020. Technical Field

[0002] The present invention relates to a modified release multiple unit oral dosage form of modified release micropellets of doxylamine or a pharmaceutically acceptable salt thereof and modified release micropellets of pyridoxine or a pharmaceutically acceptable salt thereof and a preparation method thereof. Background Art

[0003] Doxylamine is the international non-proprietary name of (RS)-N,N-dimethyl-2-(1-phenyl-1-pyridin-2-yl-ethoxy)-ethylamine, with a CAS number of 469-21-6. Doxylamine is a first-generation antihistamine that competitively, reversibly and non-specifically blocks H1 receptors. It is also a non-specific antagonist that can block other receptors such as central or peripheral muscarinic receptors and has significant anticholinergic activity. It is usually used in the form of a salt, especially in the form of its succinate (see European Pharmacopoeia 10.0. Monograph on doxylamine hydrogen succinate, pages 2476 to 2477). The structure of doxylamine corresponds to formula (I):

[0004]

[0005] On the other hand, pyridoxine, also known as vitamin B6, is the international non-proprietary name of 4.5-bis(hydroxymethyl)-2-methylpyridine-3-ol, and CAS number is 65-23-6. Pyridoxine is a water-soluble vitamin factor, and its active form is pyridoxal phosphate. It acts as an enzyme cofactor in many biochemical reactions, which involve the digestion and decomposition of proteins and amino acids, and also involve the digestion and decomposition of lipids and carbohydrates to a lesser extent. It also participates in the metabolism of unsaturated fatty acids, and is also a coenzyme of transaminases and decarboxylases, and can convert tryptophan into nicotinic acid. Pyridoxine is usually used in the form of a salt, particularly in the form of its hydrochloride (see European Pharmacopoeia 10.0. Pyridoxine Hydrochloride Monograph Pages 3676 to 3677). The structure of pyridoxine corresponds to formula (II):

[0006]

[0007] Doxylamine is often used alone as a short-term sedative and is also used in combination with other medications to provide nighttime allergy and cold relief. Doxylamine is also used in combination with the analgesics paracetamol (acetaminophen) and codeine as an analgesic / sedative preparation and with pyridoxine to prevent morning sickness in pregnant women.

[0008] The prior art has disclosed modified release oral dosage forms of doxylamine succinate and pyridoxine hydrochloride having different pharmacokinetic and pharmacological properties.

[0009] The prior art has disclosed several dual release oral dosage forms of doxylamine succinate and pyridoxine hydrochloride and preparation methods thereof. These dual release oral dosage forms are formed by at least one immediate release composition and at least one modified release composition, each composition having one or more active ingredients. This dosage system can release one active ingredient immediately and improve the release of other active ingredients (see WO2013123569 and WO2016029290).

[0010] On the other hand, hard capsules filled with modified-release doxylamine succinate pellets and modified-release pyridoxine hydrochloride pellets are marketed under the name of Cariban (INIBSA ): “SPC Cariban 10mg / 10mg modified-release capsules”, Internet citation, March 1, 2016, obtained from the following URL address: https: / / inibsa.com / wp-content / uploads / 2016 / 10 / En-spc-V1.pdf, retrieved on March 7, 2019). Cariban is used for the symptomatic treatment of nausea and vomiting. In fact, Cariban is indicated for the symptomatic treatment of nausea and vomiting during pregnancy (NVP) that is unresponsive to conservative treatment. In particular, the effects of doxylamine and pyridoxine begin to appear five hours after ingestion, which is advantageous because it can prolong the therapeutic effect and reduce the amount of drug intake. The therapeutic effect of the multiple unit dosage form depends on the dissolution profile of the active ingredient in each pellet, and in turn on the homogeneity between the pellets.

[0011] It is known in the prior art that lack of homogeneity between pellets can affect the dissolution profile of the active ingredient and can also compromise the dosing and uniformity of the pellets in the final multiple unit oral dosage form.

[0012] Therefore, from what is known in the art, it can be concluded that there is still a need to provide a modified release multiple unit oral dosage form comprising a plurality of homogeneous modified release pellets of two active ingredients, doxylamine and pyridoxine, which exhibit a dissolution profile suitable for treatment. Summary of the invention

[0013] The inventors have found that the multiple unit oral dosage form of the present invention can have an improved sustained release of two active ingredients for at least 8 hours after administration, and the multiple unit oral dosage form comprises a plurality of first modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof as claimed, and a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof as claimed. This is advantageous because the improved sustained release composition of the present invention has a dual action, one is immediate release after administration, and the other is extended release throughout the day, especially after waking up.

[0014] Without being bound by any theory, the inventors surprisingly found that the use of a pharmaceutically acceptable inert core enables each of the first and second plurality of pellets to be obtained with a determined particle size, wherein the particle size of the pharmaceutically acceptable inert core is such that at least 90% of the inert cores have a particle size of 300 μm to 1700 μm, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variability of no more than 200 μm. This means that a high homogeneity between the pellets of active ingredient content is maintained without affecting the target dissolution profile. This also means that the variability of the dissolution profile between different unit doses of the multi-unit oral dosage form of the present invention is reduced. In addition, this means that the use of the claimed pharmaceutically acceptable inert core also minimizes the formation of aggregates and / or powder mixtures.

[0015] In particular, the inventors have surprisingly observed the above effects by using a pharmaceutically acceptable inert core having a particle size such that at least 90% of the inert cores have a particle size of 300 μm to 1700 μm, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variability of not more than 150 μm, not more than 100 μm and not more than 75 μm.

[0016] Furthermore, the high homogeneity of the particle size of the multiple two beads (indicated by the low particle size variability of the drug-inert core) means that these beads are easier to handle, enabling high uniformity of dosing and reducing batching machine jams and other issues associated with dosing (e.g., reducing the frequency of needing to readjust the fill weight within an acceptable range, thereby reducing production interruptions). This means reduced machine occupancy and therefore reduced costs for preparing multiple unit dosage forms containing them.

[0017] As described above, the multi-unit oral dosage form of the present invention comprises a plurality of two kinds of pellets, and the pellets have high homogeneity of active ingredient content. This means that each pellet has approximately the same amount of active ingredient, which then ensures that the multi-unit oral dosage form comprising these pellets always has the same therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof and pyridoxine or a pharmaceutically acceptable salt thereof. This means that by using the method of the present invention, underdosing and overdosing of active ingredients in multi-unit oral doses are minimized.

[0018] Furthermore, the inventors have found that the method for preparing homogeneous batches of multiple unit oral dosage forms of the present invention is cheaper, more robust, reproducible and easy to scale up compared to the methods of the prior art. In fact, the method of the present invention enables homogeneous batches of multiple two micropellets of two active ingredients to be obtained, enables the preparation of multiple unit oral dosage forms with high yields without the need for intermediate sieving steps to remove undesirable powdery materials and aggregates during the preparation of multiple two micropellets, and also reduces the yield losses to a minimum level in the optional final sieving step, or even enables the preparation method of multiple two micropellets without any of these additional undesirable sieving steps. Finally, the inventors have found that the method enables the preparation of multiple modified release coatings of the two micropellets of the present invention that show a target dissolution profile.

[0019] Then, a first aspect of the present invention relates to a modified release multiple unit oral dosage form comprising:

[0020] A plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, comprising:

[0021] - a pharmaceutically acceptable inert core;

[0022] - an inner active coating layer comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more coating agents, one or more anti-caking agents, optionally one or more pore-forming agents; and optionally one or more pharmaceutically acceptable excipients;

[0023] - optionally an intermediate enteric release coating layer comprising one or more enteric coating agents, one or more anti-caking agents, optionally one or more pore formers; and optionally one or more pharmaceutically acceptable excipients, and

[0024] - an outer modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, one or more anti-caking agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients; and

[0025] A plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, comprising:

[0026] - a pharmaceutically acceptable inert core;

[0027] - an inner active coating layer comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, one or more coating agents and optionally one or more pharmaceutically acceptable excipients; and

[0028] - an outer modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients;

[0029] in:

[0030] The particle size of the pharmaceutically acceptable inert core of the first and second plurality of pellets is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert core has a particle size variability of no more than 200 μm, particularly no more than 150 μm, particularly no more than 100 μm and particularly no more than 75 μm as measured by analytical sieving.

[0031] In particular, the present invention relates to a modified release multiple unit oral dosage form comprising:

[0032] A plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, comprising:

[0033] - a pharmaceutically acceptable inert core;

[0034] - an inner active coating layer comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more coating agents, one or more anti-caking agents, optionally one or more pore-forming agents; and optionally one or more pharmaceutically acceptable excipients;

[0035] - an intermediate enteric release coating layer comprising one or more enteric coating agents, one or more anti-caking agents, optionally one or more pore formers; and optionally one or more pharmaceutically acceptable excipients, and

[0036] - an outer modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, one or more anti-caking agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients; and

[0037] A plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, comprising:

[0038] - a pharmaceutically acceptable inert core;

[0039] - an inner active coating layer comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, one or more coating agents and optionally one or more pharmaceutically acceptable excipients; and

[0040] - an outer modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients;

[0041] in:

[0042] The particle size of the pharmaceutically acceptable inert core of the first and second plurality of pellets is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert core has a particle size variability of no more than 200 μm, particularly no more than 150 μm, particularly no more than 100 μm and particularly no more than 75 μm as measured by analytical sieving.

[0043] A second aspect of the present invention relates to a method for preparing a modified release multiple unit oral dosage form as defined in the first aspect of the present invention, comprising:

[0044] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and optionally an intermediate enteric coating layer with one or more enteric coating agents, one or more modified-release coating agents, one or more anti-caking 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 core is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert core has a particle size variability of not more than 200 μm, particularly not more than 150 μm, particularly not more than 100 μm, and particularly not more than 75 μm as measured by analytical sieving;

[0045] and

[0046] (b1) preparing a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable salt thereof having an inner active coating layer with one or more enteric coating agents, one or more modified release coating agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert core is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert core has a particle size variability of not more than 200 μm, particularly not more than 150 μm, particularly not more than 100 μm and particularly not more than 75 μm as measured by analytical sieving. DETAILED DESCRIPTION

[0047] Unless otherwise stated, all terms used in this application are to be understood according to their ordinary meanings known in the art. Other more specific definitions of certain terms used in this application are described below and are intended to be uniformly applied throughout the specification and claims, unless otherwise explicitly stated definitions provide a broader definition.

[0048] For the purpose of the present invention, any range given includes the lower and upper endpoints of the range. Unless otherwise specified, given ranges and values, such as temperature, time, etc., should be regarded as approximate values.

[0049] The terms "percent by weight (%)" or "w / w percent (%)" have the same meaning and are used interchangeably. The term refers to the percentage of a component relative to the total weight.

[0050] As used herein, the term "about" or "approximately" refers to a range of values ​​of ±10% of a given value. For example, the expression "about 10" or "approximately 10" includes 10±10%, ie, 9 to 11.

[0051] The terms "relation" and "relationship" have the same meaning and can be used interchangeably. The term is used in the present invention to describe the relationship between the average flow rate of spraying of a mixture containing a coating agent and the average solid addition rate of the mixture in solid form.

[0052] The term "multiple unit dosage form" defines a dosage form consisting of more than one unit containing effective amounts of doxylamine and pyridoxine. Typically, multiple unit dosage forms are based on subunits, such as granules, pellets or mini-tablets. They are usually delivered in hard gelatin capsules or converted into tablets.

[0053] As known in the prior art, the term "administering" refers to the method of delivering a formulation to a desired site. The terms "oral" and "oral administration" have the same meaning, and they can be used interchangeably. Specifically, they refer to taking the drug by swallowing or chewing. Preferably, by swallowing.

[0054] As disclosed above, the multiple unit dosage form of the present invention comprises a plurality of two kinds of pellets. The term "pellet" refers to small particles of approximately uniform shape and size, which are produced by an extrusion process or by coating a pharmaceutically acceptable inert core. "Small particles" refer to particles having a diameter, length, height, width, etc. of 100 μm to 3000 μm, particularly 300 μm to 1700 μm. Small particles have approximately uniform diameter, length, height, width, etc., wherein the smallest particles have at least about half of the average diameter, length, height, width, etc. of the particles, and the largest particles have a diameter, length, height, width, etc. of at most about twice the average diameter, length, height, width, etc. of the particles. Then, the terms "pellet", "spherical pellet", "bead", "bead", "spherical particle", "spheroid" and "microsphere" have the same meaning and can be used interchangeably. The term "granule" refers to small particles obtained by a granulation process, which do not have an approximately uniform shape and size. Generally, granules are not as uniform in size or shape as pellets. Therefore, granules have lower uniformity due to their irregular surface and provide unacceptable dose uniformity and inadequate dissolution profile. Therefore, for the purpose of the present invention, the terms "pellets" and "granules" are different and they are not interchangeable.

[0055] The terms "modified release" dosage form and "modified delivery dosage form" and "modified release" pellets and "modified delivery" pellets have the same meaning and are interchangeable. Both terms should be understood to refer to dosage forms or pellets that release the active agent more slowly than a conventional immediate release pharmaceutical composition administered by the same route. In general, the term "modified release" refers to the release of the active ingredient from a pharmaceutical dosage form in a controlled, sustained, extended or prolonged release manner.

[0056] For the purposes of the present invention, the term "modified release" refers to a multiple unit oral dosage form that exhibits a dissolution profile according to which: 5% to 35% of the doxylamine content by weight is dissolved in a 0.1N HCl medium (pH=1) in the first hour; then, the medium is replaced with a pH=4.5 medium (0.05M acetate buffer), and a cumulative total of more than 35% to 75% of the initial doxylamine content by weight is dissolved in the fourth hour; then, the medium is replaced with a pH=6.8 medium (0.05M phosphate buffer), and at least more than 75% of the initial doxylamine content by weight is dissolved in the seventh hour; and 5% to 35% of the pyridoxine content by weight is dissolved in a 0.1N HCl medium (pH=1) in the first hour. HCl medium (pH = 1); then, the medium is replaced with a pH = 4.5 medium (0.05M acetate buffer), and the cumulative initial content of pyridoxine by weight greater than 35% to 75% is dissolved at the 4th hour; then, the medium is replaced with a pH = 6.8 medium (0.05M phosphate buffer), and at least the cumulative initial content of pyridoxine by weight greater than 75% is dissolved at the 7th hour; wherein the dissolution profile is measured using a suitable method. Typically, a suitable method is a USP method, such as by using a USP 2-type apparatus (basket), placing the composition in 900mL of the corresponding medium / buffered at 37°C ± 0.5°C, 100rpm (revolutions per minute), or by using a USP 3-type apparatus (reciprocating cylinder), placing the composition in 250mL of the corresponding medium / buffered at 37°C ± 0.5°C, 15dpm (immersion per minute). In the present 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 900 mL of the corresponding medium / buffered at 37°C ± 0.5°C, 100 rpm (revolutions per minute).

[0057] In one embodiment, the multiple unit oral dosage form exhibits a dissolution profile according to which: 10% to 35% of the doxylamine content by weight is dissolved in a 0.1N HCl medium (pH=1) in the first hour; then, the medium is replaced with a pH=4.5 medium (0.05M acetate buffer), and a cumulative 45% to 70% of the initial doxylamine content by weight is dissolved in the fourth hour; then, the medium is replaced with a pH=6.8 medium (0.05M phosphate buffer), and at least 80% of the initial doxylamine content by weight is dissolved in the seventh hour; and 10% to 35% of the pyridoxine content by weight is dissolved in a 0.1N HCl medium (pH=1) in the first hour. HCl medium (pH=1); then, the medium is replaced with pH=4.5 medium (0.05M acetate buffer), and a cumulative 40% to 65% by weight of the initial content of pyridoxine is dissolved in the 4th hour; then, the medium is replaced with pH=6.8 medium (0.05M phosphate buffer), and at least a cumulative 80% by weight of the initial content of pyridoxine is dissolved in the 7th hour; wherein the dissolution profile is measured using a suitable method.

[0058] In the context of the present invention, the terms "coating agent" and "film-forming coating agent" have the same meaning and can be used interchangeably. Both terms should be understood as agents that can form a thin coating on solid dosage forms or dosage form intermediates (such as tablets and pellets). Examples of each type of coating agent are disclosed below.

[0059] In one embodiment, in the multiple unit oral dosage form of the present invention, the coating agent of the inner active coating layer of the plurality of first and second micropellets is independently selected from polyvinyl pyrrolidone, hydroxypropyl cellulose, microcrystalline cellulose, calcium carbonate, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, enzymatic hydrolyzed carboxymethyl cellulose sodium, cellulose butyl acetate, cellulose acetate, cellulose acetate, cetyl alcohol, chitosan, hydrogenated coconut oil, copovidone, corn syrup solids, ethyl cellulose, ethyl cellulose aqueous dispersion, b-type ethyl cellulose dispersion, ethylene glycol and vinyl alcohol graft copolymer, gelatin, pharmaceutical glaze, glucose solution, glyceryl behenate, glyceryl dibehenate, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, isomalt, α-lactalbumin, maltitol, maltodextrin, and the like under the trade name (Rohm Pharma; Westerstadt, Germany) commercially available methacrylic acid polymers and copolymers (e.g. E. NE, NM, RL and RS), methylcellulose, palm kernel oil, palm oil, hydrogenated palm oil, polydextrose, hydrogenated polydextrose, polyethylene glycol, polyethylene glycol 3350, polyethylene oxide, polyvinyl alcohol, pullulan, fully hydrogenated rapeseed oil, rapeseed oil superglycerinated fully hydrogenated, shellac, pregelatinized modified starch, confectionery sucrose, sunflower oil, titanium dioxide, carnauba wax, microcrystalline wax, xylitol and zinc oxide, alginic acid, copovidone, dibutyl phthalate, diethyl phthalate, nitrocellulose, sodium alginate and mixtures thereof. In one embodiment, in the multiple unit oral dosage form of the present invention, the coating agent of the inner active coating layer of the plurality of first and second pellets is independently selected from polyvinyl pyrrolidone, shellac, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose and mixtures thereof.

[0060] In particular, the term "modified release coating agent" refers to an agent capable of forming a film that is capable of delivering a drug at a predetermined rate and / or location over a determined period of time, depending on the needs of the body and the disease state. Illustrative but non-limiting examples of "modified release polymers" and "improved delivery polymers" are polymers that provide controlled release, sustained release, extended release, or prolonged release. Examples of modified release coating agents include, but are not limited to, acrylic polymers, cellulose and its derivatives, shellac, hydrogenated vegetable oils, hydrogenated castor oil, and mixtures thereof. Examples of suitable acrylic polymers include those sold under the trade names (Rohm Pharma; Westerstadt, Germany) Commercially available methacrylic acid polymers and copolymers, such as E. NE, NM, RL and RS. Examples of modified release coating agents include, but are not limited to, alginic acid, carbomer copolymers, carbomer homopolymers, carbomer interpolymers, sodium carboxymethylcellulose, carrageenan, cellulose butyl acetate, ethylcellulose, ethylcellulose aqueous dispersion, b-type ethylcellulose dispersion, glyceryl monooleate, glyceryl monostearate, guar gum, hydroxypropyl beta-cyclodextrin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene oxide, shellac, sodium alginate, pregelatinized starch, pregelatinized modified starch or xanthan gum. Preferably, the modified release coating agent is shellac, in particular dewaxed shellac. The modified release polymers may be accompanied by plasticizers such as triethyl citrate (TEC), polyethylene glycol (PEG), cetyl and stearyl alcohol, acetyl tributyl citrate, acetyl triethyl citrate, benzyl benzoate, castor oil, chlorobutanol, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerol, mannitol, polyethylene glycol, polyethylene glycol 3350, polyethylene glycol monomethyl ether, propylene glycol, pullulan, sorbitol, sorbitan anhydrous solution, sucrose diacetate Hexaisobutyrate, triacetin, tributyl citrate, triethyl citrate and vitamin E; surfactants such as sodium lauryl sulfate, polysorbates and poloxamers; pigments such as titanium dioxide and ferric oxide; lubricants such as talc, magnesium stearate, glyceryl monostearate, behenyl polyoxylglyceride, calcium stearate, hydrogenated castor oil, hydrogenated coconut oil, glyceryl behenate, glyceryl dibehenate, glyceryl mono- and di-caprylate, glyceryl mono- and di-caprylate Glycerides, monocaprylic acid glyceryl, monocaprylic acid capric acid glyceryl, monostearate glyceryl, tricaprylic acid glyceryl, tristearate glyceryl, lauric acid, magnesium stearate, light mineral oil, myristic acid, hydrogenated palm oil, palmitic acid, poloxamer, polyethylene glycol, polyethylene glycol 3350, polyethylene glycol 10 oleyl ether, polyethylene glycol 15 hydroxystearate, polyethylene glycol 20 cetearyl ether, polyethylene glycol 35 castor oil, polyethylene glycol 40 hydrogenated castor oil, polyethylene glycol 40 stearate, polysorbate 60 Sorbitan ester 20, polysorbate 40, polysorbate 60, polysorbate 80, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, stearic acid, purified stearic acid, sucrose stearate, talc, hydrogenated vegetable oil type I, zinc stearate and mixtures thereof.

[0061] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release coating agent is independently selected from polyvinylpyrrolidone and shellac, in particular polyvinylpyrrolidone and dewaxed shellac and mixtures thereof.

[0062] The term "enteric release" refers to a composition or layer of a dosage form that is formulated to release active ingredients when exposed to the characteristics of the gastrointestinal tract. In one embodiment, the enteric material is pH-sensitive and is affected by the pH changes encountered in the gastrointestinal tract (pH-sensitive release). The enteric material is usually kept insoluble at stomach pH, ​​and then the active ingredient is allowed to be released in the higher pH environment of the downstream gastrointestinal tract (e.g., typically the duodenum, or sometimes the colon). In another embodiment, the enteric material comprises an enzyme-degradable polymer that is degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly the colon. Optionally, a unit dosage form is prepared with a pH-sensitive enteric material that is designed to cause release in about an appropriate hour when in or above a specific pH. In different embodiments, the specific pH can be, for example, 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 present invention, the term "enteric release coating agent" refers to an agent that can form a film that allows the delivery of doxylamine and pyridoxine when exposed to the characteristics of the gastrointestinal tract as defined above. Materials for enteric release formulations (e.g., as coatings) are well known in the art and include, but are not limited to, cellulosic polymers such as hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, and cellulose acetate trimellitate; preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate, and marketed under the trade name Acryl- (Colorcon, USA), Other methacrylic acid resins available commercially include L30D-55 and L100-55 (soluble at pH 5.5 and above), L100 and L12.5 (soluble at pH 6.0 and above), S, S12.5 and FS 30D (soluble at pH 7.0 and above due to the higher degree of esterification); vinyl polymers and copolymers formed from vinyl acetate, vinyl acetate phthalate, vinyl acetate crotonic acid copolymers and ethylene-vinyl acetate copolymers; enzyme-degradable polymers, such as azo polymers; and zein. Combinations of different enteric materials can also be used. Multilayer coatings using different polymers can 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 copolymers of methacrylic acid and methyl methacrylate, copolymers of methacrylic acid and methyl acrylate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate and mixtures thereof. More particularly, For example, Eudragit L100 (sold by Evonik). In one embodiment, in the multiple unit oral dosage form of the present invention, the enteric coating agent is independently selected from methacrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate and mixtures thereof. In one embodiment, in the multiple unit oral dosage form of the present invention, the enteric coating agent is methacrylic acid-methyl methacrylate copolymer, in particular Eudragit L100.

[0063] As defined above, the multiple unit oral dosage form of the present invention comprises a plurality of first pellets comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof and a plurality of second pellets comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof.

[0064] As used herein, the term "therapeutically effective amount" refers to the amount of active ingredient per multiple unit dosage form, which, when administered, is sufficient to prevent the progression of one or more symptoms of the disease being treated, or to alleviate the symptoms to some extent. The specific dosage of the compound administered according to the present invention will be determined by the specific circumstances surrounding the case, including the compound administered, the route of administration, the specific condition being treated, and similar considerations.

[0065] The term "pharmaceutically acceptable salt" as used herein encompasses any salt formed by a pharmaceutically acceptable non-toxic acid (including an inorganic acid or an organic acid). There are no restrictions on salts, except that if used for therapeutic purposes, they must be pharmaceutically acceptable. Since doxylamine and pyridoxine are alkaline compounds, salts can be prepared from pharmaceutically acceptable non-toxic acids (including inorganic acids or organic acids). Such acids especially include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid or p-toluenesulfonic acid. The preparation of pharmaceutically acceptable salts of doxylamine and pyridoxine can be carried out by methods known in the art. For example, they can be prepared by conventional chemical methods from parent compounds containing alkaline or acidic moieties. Typically, such salts are prepared, for example, by reacting the free acid or base forms of these compounds with a stoichiometric amount of a suitable pharmaceutically acceptable base or acid in water or an organic solvent or in a mixture thereof. In one embodiment, the multiple unit oral dosage form of the present invention comprises a pharmaceutically acceptable salt of doxylamine and a pharmaceutically acceptable salt of pyridoxine. In one embodiment, the multiple unit oral dosage form of the present invention comprises doxylamine succinate and pyridoxine hydrochloride.

[0066] As mentioned above, the particle size of the pharmaceutically acceptable inert core of the plurality of first and second micropellets is such that at least 90% of the inert cores have a particle size of 300 μm to 1700 μm measured by analytical sieving, and at least 90% of the inert cores have a particle size variability of no more than 200 μm, particularly no more than 150 μm, particularly no more than 100 μm and particularly no more than 75 μm measured by analytical sieving. This means that the pharmaceutically acceptable inert core of the plurality of two micropellets has a particle size value and a particle size variability value that fall within the scope of the present invention. The values ​​of the particle size and particle size variability of the plurality of first micropellets and the plurality of second micropellets may be equal or different, but both fall within the scope of the present invention.

[0067] In one embodiment, the multiple unit oral dosage form of the present invention comprises a pharmaceutically acceptable inert core having a particle size of at least 90% of the inert cores measured by analytical sieving having a particle size of 300 μm to 1700 μm, and at least 90% of the pharmaceutically acceptable inert cores measured by analytical sieving having a particle size variability of no more than 200 μm in a given value of 500 μm to 1400 μm. In one embodiment, the multiple unit oral dosage form of the present invention comprises a pharmaceutically acceptable inert core having a particle size of at least 90% of the inert cores measured by analytical sieving having a particle size of 300 μm to 1400 μm, and at least 90% of the pharmaceutically acceptable inert cores measured by analytical sieving having a particle size variability of no more than 150 μm in a given value of 450 μm to 1250 μm. In one embodiment, the multiple unit oral dosage form of the present invention comprises a pharmaceutically acceptable inert core having a particle size such that at least 90% of the inert cores have a particle size of 600 μm to 1180 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variability of no more than 100 μm in a given value of 710 μm to 1000 μm as measured by analytical sieving. In one embodiment, the multiple unit oral dosage form of the present invention comprises a pharmaceutically acceptable inert core having a particle size such that at least 90% of the inert cores have a particle size of 710 μm to 1000 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variability of no more than 75 μm in a given value of 800 μm to 900 μm as measured by analytical sieving.

[0068] The term "inert core" refers to neutral microspheres that contain at least one of the following substances in their composition: sorbitol, mannitol, sucrose, saccharose, starch, microcrystalline cellulose, lactose, glucose, trehalose, maltitol, fructose, colloidal silicon dioxide. In one embodiment, the pharmaceutically acceptable inert core is a neutral microsphere of a mixture of sucrose and starch.

[0069] In one embodiment, in a multiple unit oral dosage form, the pellet size of the plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size of 400 μm to 2000 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 200 μm in a given value of 600 μm to 1800 μm as measured by analytical sieving. In one embodiment, in a multiple unit oral dosage form, the pellet size of the plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size of 600 μm to 1600 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 150 μm in a given value of 800 μm to 1400 μm as measured by analytical sieving. In one embodiment, in a multiple unit oral dosage form, the pellet size of the plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size of 710 μm to 1400 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 100 μm in a given value of 850 μm to 1250 μm as measured by analytical sieving. In one embodiment, in a multiple unit oral dosage form, the pellet size of the plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size of 800 μm to 1400 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 75 μm in a given value of 900 μm to 1180 μm as measured by analytical sieving.

[0070] In one embodiment, in the multiple unit oral dosage form, the pellet size of the plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size of 400 μm to 2000 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 200 μm in a given value of 600 μm to 1800 μm as measured by analytical sieving. In one embodiment, in the multiple unit oral dosage form, the pellet size of the plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size of 600 μm to 1600 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 150 μm in a given value of 800 μm to 1400 μm as measured by analytical sieving. In one embodiment, in the multiple unit oral dosage form, the pellet size of the plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size of 710 μm to 1400 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 100 μm in a given value of 850 μm to 1250 μm as measured by analytical sieving. In one embodiment, in the multiple unit oral dosage form, the pellet size of the plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size of 800 μm to 1400 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 75 μm in a given value of 900 μm to 1180 μm as measured by analytical sieving.

[0071] In one embodiment, the multiple unit oral dosage form of the present invention comprises a pharmaceutically acceptable inert core having a particle size such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert core has a particle size variability of no more than 200 μm in a given value of 500 μm to 1400 μm as measured by analytical sieving; and a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof have a pellet size such that at least 90% of the pellets have a particle size of 300 μm to 1700 μm as measured by analytical sieving. The amount of the second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof has a particle size of 400 μm to 2000 μm and at least 90% of the pellets have a particle size variability of no more than 200 μm in a given value of 600 μm to 1800 μm as measured by analytical sieving; and the pellet particle size of the plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size of 400 μm to 2000 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 200 μm in a given value of 600 μm to 1800 μm as measured by analytical sieving.

[0072] In one embodiment, the multiple unit oral dosage form of the present invention comprises a pharmaceutically acceptable inert core having a particle size such that at least 90% of the inert core has a particle size of 300 μm to 1400 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert core has a particle size variability of no more than 150 μm in a given value of 450 μm to 1250 μm as measured by analytical sieving; and a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof having a pellet size such that at least 90% of the pellets have a particle size of 150 μm to 1250 μm as measured by analytical sieving. The amount of the second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof has a particle size of 600 μm to 1600 μm and at least 90% of the pellets have a particle size variability of no more than 150 μm in a given value of 800 μm to 1400 μm as measured by analytical sieving; and the pellet particle size of the plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size of 600 μm to 1600 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 150 μm in a given value of 800 μm to 1400 μm as measured by analytical sieving.

[0073] In one embodiment, the multiple unit oral dosage form of the present invention comprises a pharmaceutically acceptable inert core having a particle size such that at least 90% of the inert core has a particle size of 600 μm to 1180 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert core has a particle size variability of no more than 100 μm in a given value of 710 μm to 1000 μm as measured by analytical sieving; and a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof have a pellet size such that at least 90% of the pellets have a particle size of 600 μm to 1180 μm as measured by analytical sieving. The amount of the second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof has a particle size of 710 μm to 1400 μm and at least 90% of the pellets have a particle size variability of no more than 100 μm in a given value of 850 μm to 1250 μm as measured by analytical sieving; and the pellet particle size of the plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size of 710 μm to 1400 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 100 μm in a given value of 850 μm to 1250 μm as measured by analytical sieving.

[0074] In one embodiment, the multiple unit oral dosage form of the present invention comprises a pharmaceutically acceptable inert core having a particle size such that at least 90% of the inert core has a particle size of 710 μm to 1000 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert core has a particle size variability of no more than 75 μm in a given value of 800 μm to 900 μm as measured by analytical sieving; and a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof having a pellet size such that at least 90% of the pellets have a particle size of 710 μm to 1000 μm as measured by analytical sieving. The amount of the second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof has a particle size of 800 μm to 1400 μm, and at least 90% of the pellets have a particle size variability of no more than 75 μm in a given value of 900 μm to 1180 μm as measured by analytical sieving; and the pellet particle size of the plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size of 800 μm to 1400 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 75 μm in a given value of 900 μm to 1180 μm as measured by analytical sieving.

[0075] The particle size of the pharmaceutically acceptable inert core, pellets, active ingredients and excipients can be measured by any method disclosed in the prior art. Examples of methods commonly used to measure particle size are dynamic light scattering (DLS) reporting number average diameter values, atomic force microscopy (AFM) or transmission electron microscopy (TEM) measuring dry particles; laser diffraction (LaserMastersizer, Mie Theory; ISO 13320-1) and sedimentation analysis (Sedigraph-Stoke law; ISO 13317-3) and analytical sieving. For the purposes of the present invention, it is preferred to measure the particle size of the pharmaceutically acceptable inert core and the plurality of first and second pellets defined herein by analytical sieving, in particular according to the instructions of the European Pharmacopoeia (see European Pharmacopoeia Chapter 2.9.38).

[0076] The terms "variability" and "dispersion" have the same meaning and can be used interchangeably. They refer to the degree of dispersion of a set of data. Variability provides a way for people to describe the amount of variation in a data set. In particular, the term "granularity variability" refers to the degree of distribution of granularity for a given value.

[0077] The expression "at least 90% […] have a particle size between X and Y μm" means that 90% of the total number of particles have a particle size between X and Y μm. For the purposes of the present invention, the expression "at least 90% of the pharmaceutically acceptable inert cores or pellets have a particle size variability of not more than 200 μm" means that, from a given value, 90% of the pharmaceutically acceptable inert cores or pellets have a particle size of ±200 μm from the given value. For example, for a given value of 500 μm, at least 90% of the pharmaceutically acceptable inert cores have a particle size of 300 μm to 700 μm (i.e. ±200 μm). The particle size variability of pharmaceutically acceptable inert cores or pellets can be measured by any method disclosed in the prior art. Examples of methods commonly used to measure particle size variability are dynamic light scattering (DLS) reporting number average diameter values, atomic force microscopy (AFM) or transmission electron microscopy (TEM) measuring dry particles; laser diffraction (Laser Mastersizer, Mie Theory; ISO 13320-1) and sedimentation analysis (Sedigraph-Stoke's law; ISO 13317-3), analytical sieving and optical microscopy. For the purposes of the present invention, particle size variability is measured by analytical sieving.

[0078] In one embodiment, in the multiple unit oral dosage form, the particle size of doxylamine or a pharmaceutically acceptable salt thereof is characterized as having a D90 equal to or less than 250 μm. In one embodiment, in the multiple unit oral dosage form, the particle size of pyridoxine or a pharmaceutically acceptable salt thereof is characterized as having a D90 equal to or less than 250 μm. In one embodiment, in the multiple unit oral dosage form: the particle size of doxylamine or a pharmaceutically acceptable salt thereof is characterized as having a D90 equal to or less than 250 μm; and the particle size of pyridoxine or a pharmaceutically acceptable salt thereof is characterized as having a D90 equal to or less than 250 μm.

[0079] In one embodiment, in the multiple unit oral dosage form, the particle size of one or more anti-caking agents is characterized by having a D90 equal to or less than 250 μm. In one embodiment, in the multiple unit oral dosage form, the particle size of one or more optional pore forming agents is characterized by having a D90 equal to or less than 250 μm.

[0080] The DX value indicates that a certain percentage X of particles has a weight / volume / number equal to or less than a certain limit. D90 indicates that 90% of the particles have a weight / volume / number equal to or less than a certain limit. D90 can be expressed by volume, weight or number. For the purposes of the present invention, the D90 of the active ingredient (doxylamine and pyridine) is expressed by volume. In addition, the D90 of an anti-caking agent (such as talc) is expressed by weight. For example, a D90 value of doxylamine or pyridoxine equal to or less than 250 μm means that 90% of the particles by volume have a diameter equal to or less than 250 μm. In addition, a D90 value of talc equal to or less than 250 μm means that 90% of the particles by weight have a diameter equal to or less than 250 μm. DX (particularly D90) can be measured using any suitable method (e.g., analytical sieving) disclosed above for measuring the particle size of the pharmaceutically acceptable inert core, coated pellets, active ingredient and excipients of the present invention. In particular, among the above-mentioned suitable methods, the Malvern method (LaserMastersizer, Mie Theory; ISO 13320-1) is a preferred choice for determining the D90 and particle size distribution of doxylamine or a pharmaceutically acceptable salt thereof and the D90 of pyridoxine or a pharmaceutically acceptable salt thereof.

[0081] In one embodiment, the multiple unit oral dosage form comprises a plurality of first pellets, the first pellets comprising a therapeutically effective amount of a pharmaceutically acceptable salt of doxylamine, in particular doxylamine succinate. In one embodiment, the multiple unit oral dosage form comprises a plurality of first pellets, the first pellets comprising 5 to 50 mg per oral dosage form per multiple unit dosage form, in particular 6 to 40 mg, 7 to 30 mg, more particularly 8 to 22 mg of doxylamine or a pharmaceutically acceptable salt thereof. In one embodiment, the multiple unit oral dosage form comprises a plurality of first pellets, the first pellets particularly having 5 to 50 mg per oral dosage form per multiple unit dosage form, in particular 6 to 40 mg, 7 to 30 mg, more particularly 8 to 22 mg, and still more particularly 9 to 11 mg of doxylamine succinate. In a more particular embodiment, the multiple unit oral dosage form comprises a plurality of first pellets, the first pellets having 10 mg of doxylamine or a pharmaceutically acceptable salt thereof, in particular doxylamine succinate, per multiple unit dosage form. In another embodiment, the multiple unit oral dosage form comprises a plurality of first pellets, the first pellets particularly having 19 mg to 21 mg of doxylamine or a pharmaceutically acceptable salt thereof, particularly doxylamine succinate. In another more particular embodiment, the multiple unit oral dosage form comprises a plurality of first pellets, the first pellets having 20 mg of doxylamine or a pharmaceutically acceptable salt thereof, particularly doxylamine succinate per multiple unit dosage form.

[0082] In one embodiment, the multiple unit oral dosage form comprises a plurality of second pellets, the second pellets comprising a therapeutically effective amount of a pharmaceutically acceptable salt of pyridoxine, in particular pyridoxine hydrochloride. In one embodiment, the multiple unit oral dosage form comprises a plurality of second pellets, the second pellets comprising 5 mg to 50 mg, in particular 6 mg to 40 mg, 7 mg to 30 mg, more particularly 8 mg to 22 mg of pyridoxine or a pharmaceutically acceptable salt thereof per oral dosage form per multiple unit dosage form. In one embodiment, the multiple unit oral dosage form comprises a plurality of second pellets, the second pellets in particular having 5 mg to 50 mg, in particular 6 mg to 40 mg, in particular 7 mg to 30 mg, more particularly 8 mg to 22 mg, and still more particularly 9 mg to 11 mg of pyridoxine hydrochloride per oral dosage form per multiple unit dosage form. In a more particular embodiment, the multiple unit oral dosage form comprises a plurality of second pellets, the second pellets having 10 mg of pyridoxine or a pharmaceutically acceptable salt thereof, in particular pyridoxine hydrochloride per multiple unit dosage form. In another embodiment, the multiple unit oral dosage form comprises a plurality of second pellets, the second pellets particularly having 19 mg to 21 mg of pyridoxine or a pharmaceutically acceptable salt thereof, particularly pyridoxine hydrochloride. In another more particular embodiment, the multiple unit oral dosage form comprises a plurality of second pellets, the second pellets having 20 mg of pyridoxine or a pharmaceutically acceptable salt thereof, particularly pyridoxine hydrochloride per multiple unit dosage form.

[0083] In one embodiment, the multiple unit oral dosage form comprises a plurality of first pellets, the first pellets comprising doxylamine or a pharmaceutically acceptable salt thereof in a therapeutically effective amount, in particular doxylamine succinate; and a plurality of second pellets, the second pellets comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, in particular pyridoxine hydrochloride. In one embodiment, the multiple unit oral dosage form comprises a plurality of first pellets, the first pellets comprising 5 to 50 mg of doxylamine or a pharmaceutically acceptable salt thereof, in particular doxylamine succinate per multiple unit dosage form, in particular 10 or 20 mg of doxylamine or a pharmaceutically acceptable salt thereof, in particular doxylamine succinate per multiple unit dosage form; and a plurality of second pellets, the second pellets comprising 5 to 50 mg of pyridoxine or a pharmaceutically acceptable salt thereof, in particular pyridoxine hydrochloride per multiple unit dosage form, in particular 10 or 20 mg of pyridoxine or a pharmaceutically acceptable salt thereof, in particular pyridoxine hydrochloride per multiple unit dosage form. In a particular embodiment, the multiple unit oral dosage form comprises a plurality of first pellets, the first pellets comprising 10 mg of doxylamine or a pharmaceutically acceptable salt thereof, in particular doxylamine succinate, per multiple unit dosage form; and a plurality of second pellets, the second pellets comprising 10 mg of pyridoxine or a pharmaceutically acceptable salt thereof, in particular pyridoxine hydrochloride, per multiple unit dosage form. In another particular embodiment, the multiple unit oral dosage form comprises a plurality of first pellets, the first pellets comprising 20 mg of doxylamine or a pharmaceutically acceptable salt thereof, in particular doxylamine succinate, per multiple unit dosage form; and a plurality of second pellets, the second pellets comprising 20 mg of pyridoxine or a pharmaceutically acceptable salt thereof, in particular pyridoxine hydrochloride, per multiple unit dosage form.

[0084] In one embodiment, the multiple unit dosage form comprises a plurality of first pellets of 20 mg to 220 mg, the first pellets comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, in particular doxylamine succinate. In one embodiment, the multiple unit dosage form comprises a plurality of first pellets of 40 mg to 140 mg, the first pellets comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, in particular doxylamine succinate.

[0085] In one embodiment, the multiple unit dosage form comprises a plurality of first pellets of about 60 mg, wherein the first pellets comprise a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, particularly doxylamine succinate.

[0086] In another embodiment, the multiple unit dosage form comprises a plurality of first pellets of about 120 mg, wherein the first pellet comprises a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, particularly doxylamine succinate.

[0087] In one embodiment, the multiple unit dosage form comprises a plurality of second pellets of 20 mg to 220 mg, the second pellets comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, in particular pyridoxine hydrochloride. In one embodiment, the multiple unit dosage form comprises a plurality of second pellets of 40 mg to 140 mg, the second pellets comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, in particular pyridoxine hydrochloride. In one embodiment, the multiple unit dosage form comprises a plurality of second pellets of about 60 mg, the second pellets comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, in particular pyridoxine hydrochloride. In another embodiment, the multiple unit dosage form comprises a plurality of second pellets of about 120 mg, the second pellets comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, in particular pyridoxine hydrochloride.

[0088] In one embodiment, the multiple unit dosage form comprises a plurality of first pellets of 20 mg to 220 mg, the first pellets comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, in particular doxylamine succinate; and a plurality of second pellets of 20 mg to 220 mg, the second pellets comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, in particular pyridoxine hydrochloride. In one embodiment, the multiple unit dosage form comprises a plurality of first pellets of 40 mg to 140 mg, more particularly about 60 mg, the first pellets comprising 5 mg to 50 mg of doxylamine succinate, in particular 10 mg of doxylamine succinate; and a plurality of second pellets of 40 mg to 140 mg, more particularly 60 mg, the second pellets comprising 5 mg to 50 mg of pyridoxine hydrochloride, in particular 10 mg of pyridoxine hydrochloride.

[0089] In one embodiment, the multiple unit dosage form comprises 40 mg to 140 mg, more particularly about 120 mg of a plurality of first pellets, the first pellets comprising 5 mg to 50 mg of doxylamine succinate, particularly 20 mg of doxylamine succinate; and 40 mg to 140 mg, more particularly 120 mg of a plurality of second pellets, the second pellets comprising 5 mg to 50 mg of pyridoxine hydrochloride, particularly 20 mg of pyridoxine hydrochloride.

[0090] In one embodiment, the multiple unit dosage form comprises a plurality of first pellets, the first pellets comprising 5 mg to 50 mg of doxylamine succinate, in particular 10 mg of doxylamine succinate; and a plurality of second pellets, the second pellets comprising 5 mg to 50 mg of pyridoxine hydrochloride, in particular 10 mg of pyridoxine hydrochloride. In a particular embodiment, the multiple unit dosage form comprises a plurality of first pellets, the first pellets comprising 10 mg of doxylamine succinate; and a plurality of second pellets, the second pellets comprising 10 mg of pyridoxine hydrochloride.

[0091] In another embodiment, the multiple unit dosage form comprises a plurality of first pellets, the first pellets comprising 5 mg to 50 mg of doxylamine succinate, in particular 20 mg of doxylamine succinate; and a plurality of second pellets, the second pellets comprising 5 mg to 50 mg of pyridoxine hydrochloride, in particular 20 mg of pyridoxine hydrochloride. In a particular embodiment, the multiple unit dosage form comprises a plurality of first pellets, the first pellets comprising 20 mg of doxylamine succinate; and a plurality of second pellets, the second pellets comprising 20 mg of pyridoxine hydrochloride.

[0092] The term "anti-caking agent" or "anti-caking agents" refers to any pharmaceutically acceptable agent that can reduce surface stickiness and the incidence of cores or pellets sticking together during coating, thereby improving process efficiency, coating uniformity and appearance, preventing the formation of lumps (aggregates), and facilitating packaging, transportation, flowability, filling into the final dosage form and consumption. Examples of anti-caking agents include, but are not limited to, calcium stearate, magnesium stearate, silicon dioxide, silicates, talc, flour, starch calcium phosphate tribasic, calcium silicate, powdered cellulose, magnesium oxide, magnesium silicate, magnesium trisilicate, dental silica, silica hydrophobic colloid, silica colloidal, sodium stearate and mixtures thereof. In one embodiment, the multiple unit dosage form comprises one or more anti-caking agents selected from talc and silicon dioxide (colloidal silicon dioxide; in particular Aerosil) and mixtures thereof. In one embodiment, the multiple unit dosage form comprises talc as an anti-caking agent. In one embodiment, the multiple unit dosage form comprises one or more anti-caking agents, the particle size distribution of which is characterized by D90 equal to or less than 250 μm, particularly less than 150 μm, more particularly less than 100 μm. In one embodiment, the multiple unit dosage form comprises one or more anti-caking agents, the particle size distribution of which is characterized by D90 equal to or less than 75 μm. In one embodiment, the multiple unit dosage form comprises talc as an anti-caking agent, the D90 particle diameter of the talc is less than 250 μm, particularly less than 150 μm, more particularly less than 100 μm. In one embodiment, the multiple unit dosage form comprises talc as an anti-caking agent, the D90 particle diameter of the talc is less than 75 μm.

[0093] The term "pore former" refers to any pharmaceutically acceptable agent capable of forming one or more holes in the shell / coating to allow for improved release of the active ingredient. The pore former can be organic or inorganic, or any combination thereof. Examples of pore formers include, but are not limited to, polyethylene glycol (PEG), propylene glycol, isopropanol, glycerol, lactose, glucose, sucrose, mannitol, sorbitol, sodium chloride, potassium chloride, talc, hydroxypropyl cellulose, micronized sugar, hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol, methacrylic acid copolymers, or mixtures thereof. In one embodiment, the pore former is selected from talc, micronized sugar, sodium chloride or potassium chloride and mixtures thereof. As mentioned above, the modified release multiple unit oral dosage form of the present invention optionally comprises one or more pore formers. In one embodiment, one or more pore formers as defined above are present in the multiple unit oral dosage form. In one embodiment, one or more pore formers as defined above are not present in the multiple unit oral dosage form.

[0094] The term "pharmaceutically acceptable" refers to any composition, compound or material suitable for pharmaceutical technology. For the purposes of the present invention, the term "pharmaceutically acceptable excipient or carrier" refers to an excipient or carrier for preparing a composition with medical use. Suitable excipients and / or carriers, and their amounts can be easily determined by those skilled in the art according to the type of preparation prepared. In one embodiment, the modified release multiple unit dosage form of the present invention further comprises one or more adhesives, glidants, fillers, lubricants, wicking agents and mixtures thereof. In one embodiment, the method includes preparing a multiple unit dosage form, which may include one or more pharmaceutically acceptable excipients or carriers.

[0095] As mentioned above, the modified release multiple unit oral dosage form of the present invention optionally comprises one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the modified release multiple unit oral dosage form comprises one or more pharmaceutically acceptable excipients or carriers.

[0096] In one embodiment, the multiple unit oral dosage form comprises: one or more pore formers as defined above; and one or more pharmaceutically acceptable excipients or carriers.

[0097] The term "binder" refers to any pharmaceutically acceptable compound having adhesive properties. Materials commonly used as binders include microcrystalline cellulose, polyvinyl pyrrolidone (also known as povidone or PVP), methylcellulose polymers, hydroxyethylcellulose, hydroxypropylcellulose, L-hydroxypropylcellulose (low-substituted), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose, carboxymethylcellulose, carboxymethylhydroxyethylcellulose and other cellulose derivatives, starch or modified starch, polyethylene glycol (PEG) 6000, guar gum, starch or shellac, and mixtures thereof. Examples of binders include gum arabic, agar, alginic acid, calcium carbonate, calcium lactate, sodium carboxymethylcellulose, cellulose, microcrystalline cellulose, copovidone, dextran, dextrin, ethylcellulose, gelatin, glucose solution, glyceryl behenate, glyceryl dibehenate, guar gum, hydroxyethylcellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate, inulin, invert sugar, lactose monohydrate, maltodextrin, maltose, methylcellulose, hydrogenated polydextrose, polyoxyethylene cellulose, Ethane, polyvinylpyrrolidone (also known as povidone or PVP), pullulan, shellac, sodium alginate, 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, hydrogenated starch hydrolysate, sucrose, sunflower oil, syrup, trehalose, hydrogenated vegetable oil, vitamin E polyethylene glycol succinate.

[0098] In one embodiment, in a multiple unit oral dosage form, the pharmaceutically acceptable excipient or carrier comprises one or more binders, preferably comprising shellac and polyvinylpyrrolidone (PVP), a more particular embodiment being dewaxed shellac and PVP-K30.

[0099] The term "glidant" refers to a pharmaceutically acceptable substance that improves the flow characteristics of a powder mixture in a dry state. Materials commonly used as glidants include magnesium stearate, silicon dioxide (colloidal silicon dioxide; in particular Aerosil) or talc. In one embodiment, in a multiple unit oral dosage form, the pharmaceutically acceptable excipient or carrier comprises one or more glidants; preferably comprises colloidal silicon dioxide, more preferably Aerosil 200Pharma.

[0100] The term "lubricant" refers to a pharmaceutically acceptable substance that prevents the composition ingredients from caking and sticking to the tablet punch or capsule filling machine and improves the fluidity of the composition mixture. Materials commonly used as lubricants include sodium oleate, sodium stearate, sodium benzoate, sodium stearate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acids, zinc, polyethylene glycol, talc, and mixtures thereof. Examples of lubricants include behenyl polyoxylglycerides, calcium stearate, hydrogenated castor oil, hydrogenated coconut oil, glyceryl behenate, glyceryl dibehenate, mono- and di-caprylic glyceryl, mono- and di-caprylic capric glyceryl, mono-caprylic glyceryl, mono-caprylic capric glyceryl, mono-stearic glyceryl, tri-caprylic glyceryl, tri-stearic glyceryl, lauric acid, magnesium stearate, light mineral oil, myristic acid, hydrogenated palm oil, palmitic acid, poloxamer, polyethylene glycol, polyethylene glycol 3350, polyethylene glycol 10 oleyl ether, polyethylene glycol 15 hydroxystearate, polyethylene glycol 20 Cetearyl ether, polyethylene glycol 35 castor oil, polyethylene glycol 40 hydrogenated castor oil, polyethylene glycol 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, stearic acid, purified stearic acid, sucrose stearate, talc, type I hydrogenated vegetable oil and zinc stearate. When the composition is a tablet, it is particularly preferred that a lubricant is present to improve the tableting process.

[0101] The terms "filler" and "diluent" have the same meaning and can be used interchangeably. They refer to any pharmaceutically acceptable excipient or carrier (material) that fills the size of the composition, making it suitable for production and convenient for consumer use. Materials commonly used as fillers include calcium carbonate, calcium phosphate, calcium hydrogen phosphate, tricalcium sulfate, calcium carboxymethylcellulose, cellulose, cellulose products such as microcrystalline cellulose and its salts, dextrin derivatives, dextrin, glucose (dextrose), fructose, lactitol, lactose, starch or modified starch, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, sorbitol, starch, sucrose, sugar, xylitol, erythritol and mixtures thereof. In one embodiment, in a multiple unit oral dosage form, the pharmaceutically acceptable excipient or carrier comprises one or more fillers; preferably sucrose, starch or microcrystalline cellulose. Examples of fillers include aminomethacrylate copolymers; ammonium methacrylate copolymers; ammonium methacrylate copolymer dispersions; calcium carbonate; dibasic calcium phosphate anhydrous; dibasic calcium phosphate dihydrate; tribasic calcium phosphate; calcium sulfate; cellulose butyl acetate; microcrystalline cellulose; silicified microcrystalline cellulose; powdered cellulose; cellulose acetate; corn syrup; corn syrup solids; dextrate; dextrin; glucose; glucose excipients; erythritol; ethyl acrylate and methyl methacrylate copolymer dispersions; fructose; invert sugar; isomalt; kaolin; alpha-lactalbumin; lactitol; anhydrous lactose; lactose monohydrate; magnesium carbonate; magnesium oxide; maltitol; maltodextrin; maltose; glycerol dew alcohol; methacrylic acid and ethyl acrylate copolymer; methacrylic acid and ethyl acrylate copolymer dispersion; methacrylic acid and methyl methacrylate copolymer; polydextrose; polyethylene glycol; polyethylene glycol 3350; propylene glycol monocaprylate; pullulan; simethicone; sodium chloride; sorbitol; 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; hydrogenated starch hydrolysate; sucrose; compressible sugar; confectionery sugar; sugar spheres; sunflower oil; talc; trehalose; and xylitol.

[0102] The term "wicking agent" refers to a pharmaceutically acceptable material that can draw water into the porous network of a delivery device. It has the ability to physically adsorb water. The role of the wicking agent is to act as a carrier and promote the entry of water into the inner surface of the core. Materials commonly used as wicking agents include sodium lauryl sulfate, kaolin, titanium dioxide, alumina, bentonite, magnesium aluminum silicate, povidone and colloidal silicon dioxide (Aerosil). In one embodiment, in the multiple unit oral dosage form of the present invention, the pharmaceutically acceptable excipient or carrier comprises one or more wicking agents; preferably kaolin, titanium dioxide, alumina, bentonite, magnesium aluminum silicate, povidone and colloidal silicon dioxide (Aerosil). In one embodiment, in the multiple unit oral dosage form of the present invention, the pharmaceutically acceptable excipient or carrier comprises one or more wicking agents; preferably comprises povidone or colloidal silicon dioxide (Aerosil) or a mixture thereof.

[0103] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises: a plurality of first modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the pellets comprising an inner active coating layer, the inner active coating layer comprising 6 to 20% by weight of one or more coating agents relative to the total weight of the inner active coating layer.

[0104] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises: a plurality of first modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the pellets comprising an inner active coating layer, the inner active coating layer comprising 15 to 30% by weight of one or more anti-caking agents relative to the total weight of the inner active coating layer.

[0105] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises: a plurality of first modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the pellets comprising an inner active coating layer, the inner active coating layer comprising: 6 to 20% by weight of one or more coating agents relative to the total weight of the inner active coating layer, 15 to 30% by weight of one or more anti-caking agents relative to the total weight of the inner active coating layer, and optionally one or more pore formers, the sum of the components being up to 100% by weight relative to the weight of the inner active coating layer.

[0106] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises a plurality of first modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the pellets comprising an intermediate enteric release coating layer, the intermediate enteric release coating layer comprising 45 to 65% by weight of one or more enteric coating agents relative to the total weight of the intermediate enteric release coating layer.

[0107] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises a plurality of first modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the pellets comprising an intermediate enteric release coating layer, the intermediate enteric release coating layer comprising 35 to 55% by weight, relative to the total weight of the intermediate enteric release coating layer, of one or more anti-caking agents and optionally one or more pore forming agents.

[0108] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises a plurality of first modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the pellets comprising an intermediate enteric release coating layer, the intermediate enteric release coating layer comprising: 45 to 65% by weight of one or more enteric coating agents relative to the total weight of the intermediate enteric release coating layer, 35 to 55% by weight of one or more anti-caking agents and optionally one or more pore formers, and optionally one or more pharmaceutically acceptable excipients, the sum of the components being up to 100% by weight relative to the weight of the intermediate enteric release coating layer.

[0109] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises a plurality of first modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the pellets comprising an outer modified release coating layer, the outer modified release coating layer comprising 7 to 14% by weight of one or more enteric coating agents relative to the total weight of the outer modified release coating layer.

[0110] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises a plurality of first modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the pellets comprising an outer modified release coating layer, the outer modified release coating layer comprising 38 to 46% by weight of one or more modified release coating agents relative to the total weight of the outer modified release coating layer.

[0111] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises a plurality of first modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the pellets comprising an outer modified release coating layer, the outer modified release coating layer comprising 42 to 52% by weight, relative to the total weight of the outer modified release coating layer, of one or more anti-caking agents and optionally one or more pore forming agents, the sum of the components being up to 100% by weight relative to the weight of the outer modified release coating layer.

[0112] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises a plurality of first modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the pellets comprising an outer modified release coating layer, the outer modified release coating layer comprising: 7 to 14% by weight of one or more enteric coating agents; 38 to 46% by weight of one or more modified release coating agents relative to the total weight of the outer modified release coating layer; 42 to 52% by weight of one or more anti-caking agents and optionally one or more pore formers, relative to the total weight of the outer modified release coating layer; and optionally one or more pharmaceutically acceptable excipients, the sum of the components being up to 100% by weight relative to the weight of the outer modified release coating layer.

[0113] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises a plurality of first modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the pellets comprising:

[0114] - an inner active coating layer, the inner active coating layer comprising:

[0115] a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof;

[0116] 6 to 20% by weight relative to the total weight of the inner active coating layer of one or more coating agents and

[0117] 15 to 30% by weight relative to the total weight of the inner active coating layer of one or more anti-caking agents and optionally one or more pore formers;

[0118] optionally one or more pharmaceutically acceptable excipients; and

[0119] the sum of the components up to 100% by weight relative to the weight of the inner active coating layer;

[0120] -Optionally an intermediate enteric release coating layer, the intermediate enteric release coating layer comprising:

[0121] 45 to 65% by weight of one or more enteric coating agents relative to the total weight of the intermediate enteric-release coating layer; and

[0122] 35 to 55% by weight relative to the total weight of the intermediate enteric release coating layer of one or more anti-caking agents and optionally one or more pore formers,

[0123] optionally one or more pharmaceutically acceptable excipients; and

[0124] the sum of the components up to 100% by weight relative to the weight of the intermediate enteric-release coating layer;

[0125] - an outer modified release coating layer, said outer modified release coating layer comprising:

[0126] 7 to 14% by weight of one or more enteric coating agents relative to the total weight of the outer modified release coating layer;

[0127] 38 to 46% by weight of one or more modified release coating agents relative to the total weight of the outer modified release coating layer; and

[0128] 42 to 52% by weight relative to the total weight of the outer modified release coating layer of one or more anti-caking agents and optionally one or more pore forming agents;

[0129] optionally one or more pharmaceutically acceptable excipients; and

[0130] The sum of the components up to 100% by weight relative to the weight of the outer modified release coating layer.

[0131] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, the pellets comprising an inner active coating layer, the inner active coating layer comprising 13 to 25% by weight of one or more coating agents relative to the total weight of the inner active coating layer; and optionally one or more pharmaceutically acceptable excipients; the sum of the components up to 100% by weight relative to the weight of the inner active coating layer.

[0132] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, the pellets comprising an outer modified release coating layer, the outer modified release coating layer comprising 2 to 8% by weight of one or more enteric coating agents relative to the total weight of the outer modified release coating layer.

[0133] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, the pellets comprising an outer modified release coating layer, the outer modified release coating layer comprising 30 to 49% by weight of one or more modified release coating agents relative to the total weight of the outer modified release coating layer.

[0134] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, the pellets comprising an outer modified release coating layer, the outer modified release coating layer comprising 46 to 65% by weight, relative to the total weight of the outer modified release coating layer, of one or more anti-caking agents and optionally one or more pore formers, the sum of the components being up to 100% by weight relative to the weight of the outer modified release coating layer.

[0135] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, the pellets comprising an outer modified release coating layer, the outer modified release coating layer comprising: 2 to 8% by weight of one or more enteric coating agents relative to the total weight of the outer modified release coating layer; 30 to 49% by weight of one or more modified release coating agents relative to the total weight of the outer modified release coating layer; 46 to 65% by weight of one or more anti-caking agents and optionally one or more pore formers relative to the total weight of the outer modified release coating layer; optionally one or more pharmaceutically acceptable excipients, the sum of the components being up to 100% by weight relative to the weight of the outer modified release coating layer.

[0136] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, the pellets comprising:

[0137] - an inner active coating layer, the inner active coating layer comprising:

[0138] a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof; and

[0139] 13 to 25% by weight of one or more coating agents relative to the total weight of the inner active coating layer;

[0140] optionally one or more pharmaceutically acceptable excipients; and

[0141] the sum of the components up to 100% by weight relative to the weight of the inner active coating layer;

[0142] - an outer modified release coating layer, said outer modified release coating layer comprising:

[0143] 2 to 8% by weight of one or more enteric coating agents relative to the total weight of the outer modified release coating layer;

[0144] 30 to 49% by weight of one or more modified release coating agents relative to the total weight of the outer modified release coating layer; and

[0145] 46 to 65% by weight relative to the total weight of the outer modified release coating layer of one or more anti-caking agents and optionally one or more pore forming agents;

[0146] optionally one or more pharmaceutically acceptable excipients; and

[0147] The sum of the components up to 100% by weight relative to the weight of the outer modified release coating layer.

[0148] In one embodiment, in the multiple unit oral dosage form of the present invention, the modified release multiple unit oral dosage form comprises:

[0149] A plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the pellets comprising:

[0150] - a pharmaceutically acceptable inert core;

[0151] - an inner active coating layer, the inner active coating layer comprising:

[0152] A therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof

[0153] 6 to 20% by weight relative to the total weight of the inner active coating layer of one or more coating agents and

[0154] 15 to 30% by weight relative to the total weight of the inner active coating layer of one or more anti-caking agents and optionally one or more pore formers;

[0155] optionally one or more pharmaceutically acceptable excipients; and

[0156] the sum of the components up to 100% by weight relative to the weight of the inner active coating layer;

[0157] -Optionally an intermediate enteric release coating layer, the intermediate enteric release coating layer comprising:

[0158] 45 to 65% by weight of one or more enteric coating agents relative to the total weight of the intermediate enteric-release coating layer; and

[0159] 35 to 55% by weight relative to the total weight of the intermediate enteric-release coating layer of one or more anti-caking agents and optionally one or more pore formers;

[0160] optionally one or more pharmaceutically acceptable excipients; and

[0161] the sum of the components up to 100% by weight relative to the weight of the intermediate enteric-release coating layer;

[0162] - an outer modified release coating layer, said outer modified release coating layer comprising:

[0163] 7 to 14% by weight of one or more enteric coating agents relative to the total weight of the outer modified release coating layer;

[0164] 38 to 46% by weight of one or more modified release coating agents relative to the total weight of the outer modified release coating layer; and

[0165] 42 to 52% by weight relative to the total weight of the outer modified release coating layer of one or more anti-caking agents and optionally one or more pore forming agents;

[0166] optionally one or more pharmaceutically acceptable excipients; and

[0167] the sum of the components up to 100% by weight relative to the weight of the outer modified release coating layer;

[0168] and

[0169] A plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, the pellets comprising:

[0170] - a pharmaceutically acceptable inert core;

[0171] - an inner active coating layer, the inner active coating layer comprising:

[0172] a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof; and

[0173] 13 to 25% by weight of one or more coating agents relative to the total weight of the inner active coating layer;

[0174] optionally one or more pharmaceutically acceptable excipients; and

[0175] the sum of the components up to 100% by weight relative to the weight of the inner active coating layer;

[0176] - an outer modified release coating layer, said outer modified release coating layer comprising:

[0177] 2 to 8% by weight of one or more enteric coating agents relative to the total weight of the outer modified release coating layer;

[0178] 30 to 49% by weight of one or more modified release coating agents relative to the total weight of the outer modified release coating layer; and

[0179] 46 to 65% by weight relative to the total weight of the outer modified release coating layer of one or more anti-caking agents and optionally one or more pore forming agents;

[0180] optionally one or more pharmaceutically acceptable excipients; and

[0181] The sum of the components up to 100% by weight relative to the weight of the outer modified release coating layer.

[0182] In one embodiment, the modified release multiple unit oral dosage form of the present invention exhibits a dissolution profile according to which:

[0183] 5% to 35% doxylamine content by weight was dissolved in 0.1N HCl medium (pH=1) at the first hour;

[0184] Then, the medium was replaced with pH = 4.5 medium (0.05 M acetate buffer), and cumulatively greater than 35% to 75% of the initial content of doxylamine by weight was dissolved at 4 hours;

[0185] Then, the medium was replaced with a pH=6.8 medium (0.05 M phosphate buffer), and at least more than 75% of the initial content of doxylamine by weight was dissolved at 7 hours; and

[0186] 5% to 35% by weight of pyridoxine content dissolved in 0.1N HCl medium (pH=1) at the first hour;

[0187] Then, the medium was replaced with pH = 4.5 medium (0.05 M acetate buffer), and cumulatively greater than 35% to 75% by weight of the initial content of pyridoxine was dissolved at 4 hours;

[0188] Then, the medium was replaced with a pH=6.8 medium (0.05 M phosphate buffer), and at least more than 75% of the initial pyridoxine content by weight was dissolved at the 7th hour;

[0189] Wherein the dissolution profile is measured using a USP type 2 apparatus (basket), the composition is placed in 900 mL of the respective medium / buffered at 37°C ± 0.5°C, 100 rpm (revolutions per minute).

[0190] In one embodiment, the modified release multiple unit oral dosage form of the present invention exhibits a dissolution profile according to which:

[0191] 10% to 35% doxylamine content by weight was dissolved in 0.1N HCl medium (pH=1) at the first hour;

[0192] Then, the medium was replaced with pH = 4.5 medium (0.05 M acetate buffer), and cumulatively 45% to 70% by weight of the initial content of doxylamine was dissolved at 4 hours;

[0193] Then, the medium was replaced with a pH=6.8 medium (0.05 M phosphate buffer), and at least 80% of the initial content of doxylamine by weight was dissolved at 7 hours; and

[0194] 10% to 35% by weight of pyridoxine content was dissolved in 0.1N HCl medium (pH=1) at the first hour;

[0195] Then, the medium was replaced with pH = 4.5 medium (0.05 M acetate buffer), and a cumulative 40% to 65% by weight of the initial content of pyridoxine was dissolved at 4 hours;

[0196] Then, the medium was replaced with pH=6.8 medium (0.05 M phosphate buffer), and at least 80% of the initial pyridoxine content by weight was dissolved at 7 hours;

[0197] Wherein the dissolution profile is measured using a USP type 2 apparatus (basket), the composition is placed in 900 mL of the respective medium / buffered at 37°C ± 0.5°C, 100 rpm (revolutions per minute).

[0198] As mentioned above, the dosage form of the present invention is a "multi-unit dosage form". In one embodiment, the multi-unit dosage form is a capsule filled with a plurality of first and second pellets of the present invention as subunits with active ingredients. In one embodiment, the multi-unit dosage form is a hard capsule.

[0199] For the purposes of the present invention, hard capsules are understood to be hard capsules suitable for fully automatic capsule filling machines. Typically, these capsules consist of two cylindrical halves, one of which is larger in diameter but shorter in length, called the cap, and the other is shorter in diameter but longer in length, called the body. In one embodiment, the multi-unit oral dosage form is a hard capsule having a capsule size of size 0 to size 5. In one embodiment, the multi-unit oral dosage form is a hard capsule having a capsule size of size 1 to size 5. In one embodiment, the multi-unit oral dosage form is a hard capsule having a capsule size of size 1 to size 4. In one embodiment, the multi-unit oral dosage form is a hard capsule having a capsule size of 3. In one embodiment, the multi-unit oral dosage form is a hard capsule having a capsule size of 2. In one embodiment, the multi-unit oral dosage form is a hard capsule having a capsule size of 1. In one embodiment, the multi-unit dosage form of the present invention is a hard capsule, which is made of a material selected from gelatin, hydroxypropyl methylcellulose (hydroxypropyl methylcellulose, HPMC), pullulan and mixtures thereof. In one embodiment, the multi-unit dosage form of the present invention is a gelatin hard capsule. In one embodiment, the multiple unit dosage form of the present invention is a hydroxypropylmethylcellulose hard capsule.

[0200] In one embodiment, the multiple unit dosage form of the present invention is a hard capsule comprising a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof of 20 mg to 220 mg, and a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof of 20 mg to 220 mg. In one embodiment, the multiple unit dosage form of the present invention is a hard capsule comprising a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof of 40 mg to 140 mg, and a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof of 40 mg to 140 mg.

[0201] In one embodiment, the multiple unit dosage form of the present invention is a hard capsule comprising a plurality of first modified-release pellets of about 60 mg of doxylamine or a pharmaceutically acceptable salt thereof, and a plurality of second modified-release pellets of about 60 mg of pyridoxine or a pharmaceutically acceptable salt thereof; in particular, the hard capsule has a size selected from size 2 or size 3 or size 4, more particularly size 3.

[0202] In one embodiment, the multiple unit dosage form of the present invention is a hard capsule comprising a plurality of first modified-release pellets of about 120 mg of doxylamine or a pharmaceutically acceptable salt thereof, and a plurality of second modified-release pellets of about 120 mg of pyridoxine or a pharmaceutically acceptable salt thereof; in particular, the hard capsule has a size selected from size 1, size 2, and size 3. In one embodiment, the multiple unit dosage form of the present invention is a hard capsule comprising about 10 mg of doxylamine succinate per capsule and about 10 mg of pyridoxine hydrochloride per capsule; in particular, the hard capsule has a size 3. In one embodiment, the multiple unit dosage form of the present invention is a hard capsule comprising about 20 mg of doxylamine succinate per capsule and about 20 mg of pyridoxine hydrochloride per capsule; in particular, the hard capsule has a size selected from size 1, size 2, and size 3.

[0203] For the purposes of the present invention, the multiple unit dosage forms of the present invention (particularly hard capsules) can be kept in suitable packaging. Those skilled in the art can easily determine the type of packaging based on the type of the prepared formulation. In one embodiment, the modified release multiple unit dosage forms of the present invention are packaged in blisters. In one embodiment, the modified release multiple unit dosage forms of the present invention are packaged in bottles, wherein there is no desiccant, or the desiccant is placed in the bottle or integrated with the closed system of the bottle.

[0204] For the purposes of the present invention, the multiple unit dosage forms of the present invention, in particular hard capsules, are primarily packaged in blisters or bottles as defined above and secondarily packaged in outer cartons. The materials commonly used for assembling blisters in which the multiple unit dosage forms of the present invention, in particular hard capsules, are primarily packaged are PVC (polyvinyl chloride), PVdC (polyvinylidene chloride), PE (polyethylene, including HDPE or high density polyethylene and LDPE or low density polyethylene), PET (polyethylene terephthalate), PETG (polyethylene terephthalate), PCTFE (polychlorotrifluoroethylene, with Commercially available), PVC / PE / PVdC ( Commercially available), COC (cyclic olefin copolymer), aluminum or a combination thereof. Materials commonly used to make bottles and associated closures or lids (in which the multiple unit dosage forms of the present invention, especially hard capsules, are primarily packaged) are glass, aluminum and plastic materials. Examples of plastic materials are PE (including HDPE and LDPE), PET, PP (polypropylene), PVC, PETG, PS (polystyrene), COC and / or a mixture of more than one of these plastic materials and / or a mixture of one or more plastic materials with other additives. Examples of plastic material additives are adhesives, desiccants, plasticizers, flame retardants, antioxidants, acid scavengers, light and heat stabilizers, lubricants, pigments, antistatic agents, slip compounds and heat stabilizers. Examples of desiccants are moisture-proof materials, molecular sieves such as zeolites, calcium oxide, activated carbon, calcium sulfate, calcium chloride and silicon dioxide. The desiccant can be mixed / combined with a suitable adhesive into the plastic material used to make the bottle, or placed inside the bottle, or integrated into the closure system of the bottle.

[0205] The inventors surprisingly found that the primary packaging as defined above is advantageous in terms of stability. In particular, they can be stored at 25°C or below and 60% relative humidity. This is advantageous because the multiple unit dosage form of the invention will be suitable for long-term storage, even in climate zone I and II countries (temperate and Mediterranean / subtropical countries), without particular restrictions, such as no need for storage in a refrigerator.

[0206] In one embodiment, the multiple unit dosage form of the present invention is a hard gelatin or HPMC (hydroxypropyl methylcellulose) capsule, which is primarily packaged in a package selected from blisters made of any of the materials mentioned above and plastic bottles made of any of the plastic materials mentioned above without a desiccant. They are particularly advantageous because they are stable and can be stored at 25°C or below and 60% relative humidity.

[0207] In a particular embodiment, the multiple unit dosage form of the present invention is a hard gelatin or HPMC capsule, which is primarily packaged in a blister made of PVC / PVdC (on one side of the blister) and aluminum (on the other side of the blister), which is stable and can be stored at or below 25°C and 60% relative humidity. This is advantageous because this type of blister is widely used and easy to handle in the primary packaging manufacturing step, so it is low-cost.

[0208] In a particular embodiment, the multiple unit dosage forms of the present invention are hard capsules made of gelatin or HPMC, which are primarily packaged in plastic bottles with desiccant. They are particularly advantageous in terms of stability and can be stored at 30°C or below and 75% relative humidity. This is advantageous because the multiple unit dosage forms of the present invention will also be suitable for long-term storage in climate zones III and IV countries (dry heat and humid heat / tropical countries) without special restrictions (e.g., no need to store in a refrigerator). Another advantage is avoiding the use of glass bottles, which are impermeable containers that can provide the greatest degree of moisture protection, but are more fragile and heavier than plastic bottles, and therefore more difficult to handle from a logistics perspective, and the costs and risks for manufacturers and users will increase.

[0209] In one embodiment, the multiple unit dosage form of the present invention is a hard capsule made of gelatin or HPMC, which is primarily packaged in a blister made of the material defined above or a plastic bottle with a desiccant, which is particularly advantageous in terms of stability and can be stored at 30° C. or below and 75% relative humidity. This is advantageous because the multiple unit dosage form of the present invention will also be suitable for long-term storage in climate zones III and IV countries (dry heat and humid heat / tropical countries) without particular restrictions (e.g., no need to store in a refrigerator).

[0210] In one embodiment, the multiple unit dosage form of the present invention is a hard HPMC capsule, which is primarily packed in blisters made of the material defined above, in particular of or in blisters made of aluminum (on one side of the blister) and aluminum (on the other side of the blister). They are advantageous because they are stable and can be stored at 30°C or below and 75% relative humidity. This is more advantageous for users in climate zone III and IV countries (dry heat and humid heat / tropical countries) because it can be stored without special restrictions (e.g., it does not need to be stored in a refrigerator), and the blister is easier to handle than a bottle (e.g., it can be easily carried with you when traveling), and the capsules are individually protected when packed in the blister, so it is safer and more convenient to use.

[0211] The second aspect of the present invention relates to a method for preparing the multiple unit oral dosage form of the first aspect of the present invention. In particular, the method comprises:

[0212] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and optionally an intermediate enteric coating layer with one or more enteric coating agents, one or more modified-release coating agents, one or more anti-caking agents, optionally one or more pore formers, and optionally one or more pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert core is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert core has a particle size variability of not more than 200 μm, particularly not more than 150 μm, particularly not more than 100 μm, and particularly not more than 75 μm as measured by analytical sieving; and

[0213] (b1) preparing a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer with one or more enteric coating agents, one or more modified release coating agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert core is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert core has a particle size variability of not more than 200 μm, particularly not more than 150 μm, particularly not more than 100 μm and particularly not more than 75 μm as measured by analytical sieving. As mentioned above, the method is cheaper, more robust, reproducible and easier to scale up compared to the methods of the prior art. It enables obtaining a plurality of homogeneous batches of the two pellets in high yield without losing a considerable or large amount of yield in the sieving step, thereby obtaining a high final yield. All embodiments disclosed above regarding the particle size and particle size variability of the pharmaceutically acceptable core and the plurality of first and second pellets and combinations thereof disclosed in the first aspect of the present invention are also applicable to the method of the second aspect of the present invention.

[0214] In one embodiment, a method for preparing a multiple unit oral dosage form of the first aspect of the invention comprises:

[0215] (a1) coating the pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and optionally an 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 pausing once or multiple times, and optionally preparing a plurality of first modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof by continuously or discontinuously drying with an air flow; and

[0216] (b1) coating the pellets of pyridoxine or a pharmaceutically acceptable salt thereof having an 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 pausing once or more, and optionally preparing a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by continuously or discontinuously drying with an air flow.

[0217] In one embodiment, steps (a1) and (b1) of the method of the present invention are carried out by continuously spraying a liquid mixture as defined above. In one embodiment, steps (a1) and (b1) of the method of the present invention are carried out by continuously spraying a liquid mixture as defined above and including one or more pause periods. In one embodiment, steps (a1) and (b1) of the method of the present invention are carried out by continuously spraying a liquid mixture as defined above and including one or more pause periods and by drying continuously with a gas stream. In one embodiment, steps (a1) and (b1) of the method of the present invention are carried out by continuously spraying a liquid mixture as defined above and including one or more pause periods and by drying discontinuously with a gas stream.

[0218] In one embodiment, steps (a1) and (b1) of the method of the invention are carried out by discontinuously spraying a liquid mixture as defined above and including one or more pause periods. In one embodiment, steps (a1) and (b1) of the method of the invention are carried out by discontinuously spraying a liquid mixture as defined above and by drying continuously with a gas stream. In one embodiment, steps (a1) and (b1) of the method of the invention are carried out by discontinuously spraying a liquid mixture as defined above and by drying discontinuously with a gas stream. In one embodiment, steps (a1) and (b1) of the method of the invention are carried out by discontinuously spraying a liquid mixture as defined above, including one or more pause periods and by drying discontinuously with a gas stream.

[0219] In one embodiment, a method for preparing a multiple unit oral dosage form of the first aspect of the invention comprises:

[0220] (a1) coating the pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and optionally an 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 simultaneously or alternately adding a mixture in powder form comprising one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, optionally pausing once or more, and optionally preparing a plurality of first modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof by continuously or discontinuously drying with an air flow; and

[0221] (b1) coating the pellets of pyridoxine or a pharmaceutically acceptable salt thereof having an 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 simultaneously or alternately adding a mixture in powder form comprising one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients, optionally performing one or more pauses, optionally one or more pause periods, and optionally preparing a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by continuously or discontinuously drying with an air flow.

[0222] In one embodiment, steps (a1) and (b1) of the method of the present invention are carried out by continuously spraying a liquid mixture as defined above and simultaneously adding a mixture in powder form. In one embodiment, steps (a1) and (b1) of the method of the present invention are carried out by continuously spraying a liquid mixture as defined above and alternately adding a mixture in powder form. In one embodiment, steps (a1) and (b1) of the method of the present invention are carried out by continuously spraying a liquid mixture as defined above, simultaneously adding a mixture in powder form, and continuously drying with a gas stream. In one embodiment, steps (a1) and (b1) of the method of the present invention are carried out by continuously spraying a liquid mixture as defined above, alternately adding a mixture in powder form, and continuously drying with a gas stream. In one embodiment, steps (a1) and (b1) of the method of the present invention are carried out by continuously spraying a liquid mixture as defined above, simultaneously adding a mixture in powder form, and discontinuously drying with a gas stream. In one embodiment, steps (a1) and (b1) of the method of the present invention are carried out by continuously spraying a liquid mixture as defined above, alternately adding a mixture in powder form, and discontinuously drying with a gas stream.

[0223] In one embodiment, steps (a1) and (b1) of the method of the present invention are performed by discontinuously spraying the liquid mixture, adding the mixture in powder form, and pausing one or more times. In one embodiment, steps (a1) and (b1) of the method of the present invention are performed by discontinuously spraying the liquid mixture, adding the mixture in powder form, and drying continuously with a gas stream. In one embodiment, steps (a1) and (b1) of the method of the present invention are performed by discontinuously spraying the liquid mixture, adding the mixture in powder form, and drying discontinuously with a gas stream. In one embodiment, steps (a1) and (b1) of the method of the present invention are performed by discontinuously spraying the liquid mixture, adding the mixture in powder form, pausing one or more times, and drying discontinuously with a gas stream. In one embodiment, steps (a1) and (b1) of the method of the present invention are performed by discontinuously spraying the liquid mixture, alternately adding the mixture in powder form, and pausing one or more times. In one embodiment, steps (a1) and (b1) of the method of the present invention are performed by discontinuously spraying the liquid mixture, alternately adding the mixture in powder form, and drying continuously with a gas stream. In one embodiment, steps (a1) and (b1) of the method of the present invention are carried out by discontinuously spraying the liquid mixture, alternately adding the mixture in powder form, and discontinuously drying with a gas stream. In one embodiment, steps (a1) and (b1) of the method of the present invention are carried out by discontinuously spraying the liquid mixture, alternately adding the mixture in powder form, pausing one or more times, and discontinuously drying with a gas stream. In one embodiment, steps (a1) and (b1) of the method of the present invention are carried out by discontinuously spraying the liquid mixture and simultaneously adding the mixture in powder form. In one embodiment, steps (a1) and (b1) of the method of the present invention are carried out by discontinuously spraying the liquid mixture and alternately adding the mixture in powder form.

[0224] For the purposes of the present invention, the term "liquid mixture" refers to any mixture of one or more components defined in the present invention (e.g., coating, modified release coating, pharmaceutically acceptable excipients, pharmaceutically active ingredients (pyridoxine and doxylamine)), wherein the mixture has liquid behavior. The term "liquid behavior" refers to a mixture or substance that can flow, has no fixed shape, and is not a solid or gas. The mixture can be in the form of a solution or a suspension (or slurry). A solution is a mixture of two or more substances in a homogeneous form. In such a mixture, a solute is a substance that is dissolved in another substance (called a solvent). A suspension is a heterogeneous mixture containing solid particles in a liquid solvent. In fact, the solid particles are insoluble in the liquid solvent.

[0225] The term "liquid solvent" refers to any organic and inorganic liquid solvent or mixture thereof capable of dissolving a compound / component / ingredient to produce a liquid solution, or any liquid capable of producing a suspension or slurry of one or more compounds / components / ingredients. The liquid solvent is preferably selected from volatile liquid solvents (boiling point below 125°C), including one or more organic liquid solvents selected from (C1-C4) alcohols, (C1-C4) alkyl-CO-(C1-C4) alkyl, (C1-C4) alkyl-CO-O-(C1-C4) alkyl, or water, or a mixture thereof. The term "alcohol" refers to an "alkane" in which at least one hydrogen atom is substituted by a hydroxyl group and contains the number of carbon atoms specified in the specification or claims. The term "alkane" refers to a saturated, branched or straight-chain hydrocarbon containing the number of carbon atoms specified in the specification or claims. Examples include methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol and sec-butanol. The term "alkyl" refers to a saturated straight or branched hydrocarbon chain containing the number of carbon atoms specified in the specification or claims. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, among others. In one embodiment, in the method, the mixture comprises one or more organic solvents selected from ethanol, 2-propanol, methanol, acetone, butanone, ethyl acetate, water and mixtures thereof; in particular selected from ethanol, acetone, water and mixtures thereof. There are no restrictions on liquid solvents except that they must be pharmaceutically acceptable if used for therapeutic purposes.

[0226] The term "mixture in powder form" refers to any individual solid compound / component / ingredient or combination thereof as defined herein, which is solid and in powder form. For the purposes of the present invention, a powder form is considered to be a solid in powder form when its D90 is equal to or less than 500 μm, preferably equal to or less than 250 μm, more preferably equal to or less than 150 μm.

[0227] The term "spraying continuously" means spraying continuously over time until all the liquid to be sprayed is consumed in a certain step of the method. The term "spraying discontinuously" means spraying intermittently and cyclically over time. This means spraying for a certain period of time, stopping spraying for another period of time, and repeating this "cycle" as many times as necessary until all the liquid to be sprayed required for a certain stage of the method is consumed.

[0228] The term "simultaneous addition of a mixture in powder form" means the simultaneous addition of the solid relative to the spraying of the liquid mixture during one step of the method. This means that when the powder mixture is added, the liquid mixture is sprayed at the same time. Spraying can be continuous and continuous, or, on the contrary, it is intermittent, although it is always consistent with spraying, whether it is continuous or discontinuous. The term "alternating addition of a mixture in powder form" means the addition of a solid mixture in powder form in a non-simultaneous manner, relative to the spraying of the liquid mixture, which is also intermittent and discontinuous, and this process is repeated cyclically (in a "cycle") until the addition of the solid in the form of a spray of powder and / or liquid mixture is completed.

[0229] The term "continuous drying" means that the pellets are dried with an air stream in the coating pan during all periods of the coating step, whether spraying is continuous or discontinuous, or the addition of solids is simultaneous or alternating. The term "discontinuous drying" means that the pellets are dried with an air stream in the coating pan for only a specific period of time within a "cycle", whether spraying is continuous or discontinuous, or the addition of solids is simultaneous or alternating.

[0230] The term "airflow" refers to a dry airflow with a temperature of 5 to 90°C, expressed in m 3 The unit of measurement is / h.

[0231] The term "pause" refers to a specific period of time in a "cycle" repeated in the coating step, in which there is no spraying of any liquid mixture, no addition of any solid mixture in powder form, and no airflow drying. During this period, the coating pan only rotates, mixes and homogenizes the pellets. The term "cycle" refers to a sequence that lasts for a specific period of time in the coating step, which is repeated as many times as needed until the coating step is completed. The cycle includes at least a specific period of time of spraying of the liquid mixture, which is equal to or less than the cycle time period; optionally a specific period of time of adding the mixture in powder form, which is equal to or less than the cycle time period, optionally one or more pause periods, which are less than the cycle time period; optionally a drying period, which is equal to or less than the cycle time period.

[0232] In one embodiment, a method for preparing a multiple unit oral dosage form according to the second aspect of the invention comprises:

[0233] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and optionally an intermediate enteric coating layer with one or more enteric coating agents, one or more modified-release coating agents, one or more anti-caking agents, optionally one or more pore formers, and optionally one or more pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert core is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert core has a particle size variability of not more than 200 μm, particularly not more than 150 μm, particularly not more than 100 μm and particularly not more than 75 μm as measured by analytical sieving; and the sum of the enteric coating agent and the modified-release coating agent in the spraying liquid mixture is 10% to 49% by weight relative to the weight of the liquid mixture; and

[0234] (b1) preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating pellets of pyridoxine or a pharmaceutically acceptable salt thereof having an inner active coating layer with one or more enteric coating agents, one or more modified-release coating agents, one or more anti-caking 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 core is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert core has a particle size variability of not more than 200 μm, particularly not more than 150 μm, particularly not more than 100 μm and particularly not more than 75 μm as measured by analytical sieving; and the sum of the enteric coating agent and the modified-release coating agent in the spraying liquid mixture is 10 to 49% by weight relative to the weight of the liquid mixture. All embodiments disclosed above regarding the particle size and particle size variability of the pharmaceutically acceptable core and the plurality of first and second pellets and combinations thereof disclosed in the first aspect of the present invention are also applicable to the method of the second aspect of the present invention.

[0235] In one embodiment, a method for preparing a multiple unit oral dosage form of the first aspect of the invention comprises:

[0236] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and optionally an intermediate enteric coating layer with a liquid mixture comprising 1.0 to 7.5% by weight of one or more enteric coating agents, 10.0 to 35.0% by weight of one or more modified-release coating agents, the particle size of the pharmaceutically acceptable inert core being such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert core has a particle size variability of not more than 200 μm, particularly not more than 150 μm, particularly not more than 100 μm and particularly not more than 75 μm as measured by analytical sieving; and

[0237] (b1) coating the pellets of pyridoxine or its pharmaceutically acceptable salt with an inner active coating layer with a liquid mixture containing 1.0 to 7.5% by weight of one or more enteric coating agents, 10.0 to 35.0% by weight of one or more modified release coating agents to prepare a plurality of second modified release pellets of pyridoxine or its pharmaceutically acceptable salt, wherein the particle size of the pharmaceutically acceptable inert core is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert core has a particle size variability of not more than 200 μm, particularly not more than 150 μm, particularly not more than 100 μm and particularly not more than 75 μm as measured by analytical sieving. All embodiments disclosed above regarding the particle size and particle size variability of the pharmaceutically acceptable core and the plurality of first and second pellets and combinations thereof disclosed in the first aspect of the present invention are also applicable to the method of the second aspect of the present invention.

[0238] In one embodiment, a method for preparing a multiple unit oral dosage form of the first aspect of the invention comprises:

[0239] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by continuously or discontinuously spraying a liquid mixture to coat pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and optionally an intermediate enteric coating layer, wherein the weight ratio of one or more enteric coating agents to one or more modified-release coating agents in the spray mixture is 5:95 to 30:70, and the particle size of the pharmaceutically acceptable inert core is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert core has a particle size variability of not more than 200 μm, particularly not more than 150 μm, particularly not more than 100 μm and particularly not more than 75 μm as measured by analytical sieving; and

[0240] (b1) preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by continuously or discontinuously spraying a liquid mixture to coat pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer, wherein the weight ratio of one or more enteric coating agents to one or more modified-release coating agents in the spray mixture is 5:95 to 30:70, and the particle size of the pharmaceutically acceptable inert core is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert core has a particle size variability of not more than 200 μm, particularly not more than 150 μm, particularly not more than 100 μm and particularly not more than 75 μm as measured by analytical sieving. All embodiments disclosed above regarding the particle size and particle size variability of the pharmaceutically acceptable core and the plurality of first and second pellets and combinations thereof disclosed in the first aspect of the present invention are also applicable to the method of the second aspect of the present invention.

[0241] In one embodiment, a method for preparing a multiple unit oral dosage form of the first aspect of the invention comprises:

[0242] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and optionally an intermediate enteric coating layer with a liquid mixture comprising 1.0 to 7.5% by weight of one or more enteric coating agents, 10.0 to 35.0% by weight of one or more modified-release coating agents, wherein the weight ratio of the one or more enteric coating agents to the one or more modified-release coating agents in the spraying mixture is 5:95 to 30:70, and the particle size of the pharmaceutically acceptable inert core is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert core has a particle size variability of not more than 200 μm, particularly not more than 150 μm, particularly not more than 100 μm and particularly not more than 75 μm as measured by analytical sieving; and

[0243] (b1) preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by continuously or discontinuously coating pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer by spraying a liquid mixture comprising 1.0 to 7.5% by weight of one or more enteric coating agents and 10.0 to 35.0% by weight of one or more modified-release coating agents, wherein the weight ratio of the one or more enteric coating agents to the one or more modified-release coating agents in the spraying mixture is 5:95 to 30:70, and the particle size of the pharmaceutically acceptable inert core is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert core has a particle size variability of not more than 200 μm, particularly not more than 150 μm, particularly not more than 100 μm and particularly not more than 75 μm as measured by analytical sieving. All embodiments disclosed above regarding the particle size and particle size variability of the pharmaceutically acceptable core and the plurality of first and second pellets and combinations thereof disclosed in the first aspect of the present invention are also applicable to the method of the second aspect of the present invention.

[0244] In one embodiment, a method for preparing a multiple unit oral dosage form of the first aspect of the invention comprises:

[0245] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the spraying average flow rate of the mixture comprising the coating is 0.30 to 5.00 g / min per kg of the pharmaceutically acceptable inert core; and

[0246] (b1) preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the spraying average flow rate of the mixture comprising the coating agent is 0.30 to 5.00 g / min per kg of the pharmaceutically acceptable inert core.

[0247] In one embodiment, a method for preparing a multiple unit oral dosage form of the first aspect of the invention comprises:

[0248] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the spraying local flow rate of the mixture comprising the coating is 0.30 to 9.00 g / min per kg of the pharmaceutically acceptable inert core; and

[0249] (b1) preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the spraying local flow rate of the mixture comprising the coating is 0.30 to 9.00 g / min per kg of the pharmaceutically acceptable inert core.

[0250] In one embodiment, a method for preparing a multiple unit oral dosage form of the first aspect of the invention comprises:

[0251] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the average solid addition rate of the mixture in solid form is 0.95 to 18 g / min per Kg of pharmaceutically acceptable inert core; and

[0252] (b1) preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the average solid addition rate of the mixture in solid form is 0.10 to 2.25 g / min per kg of pharmaceutically acceptable inert core.

[0253] In one embodiment, a method for preparing a multiple unit oral dosage form of the first aspect of the invention comprises:

[0254] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the local solid addition rate of the mixture in solid form is 0.95 to 40.00 g / min per Kg of pharmaceutically acceptable inert core; and

[0255] (b1) preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the local solid addition rate of the mixture in solid form is 0.10 to 40.00 g / min per Kg of pharmaceutically acceptable inert core.

[0256] In one embodiment, a method for preparing a multiple unit oral dosage form of the first aspect of the invention comprises:

[0257] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the relationship between the spraying average flow rate of the liquid mixture containing the coating agent and the average solid addition rate of the mixture in the solid form is 90:10 to 60:40, in particular 90:10 to 70:30; and

[0258] (b1) preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the relationship between the spraying average flow rate of the liquid mixture containing the coating agent and the average solid addition rate of the mixture in the solid form is 90:10 to 60:40, particularly 80:20 to 60:40.

[0259] In one embodiment, a method for preparing a multiple unit oral dosage form of the first aspect of the invention comprises:

[0260] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the average spraying flow rate of the liquid mixture containing the coating agent is 0.30 to 5.00 g / min per kg of the pharmaceutically acceptable inert core, and the average solid addition rate of the mixture in solid form is 0.95 to 18.00 g / min per kg of the pharmaceutically acceptable inert core; and

[0261] (b1) preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the average spraying flow rate of the liquid mixture containing the coating agent is 0.30 to 5.00 g / min per kg of the pharmaceutically acceptable inert core, and the average solid addition rate of the mixture in solid form is 0.10 to 2.25 g / min per kg of the pharmaceutically acceptable inert core.

[0262] In one embodiment, a method for preparing a multiple unit oral dosage form of the first aspect of the invention comprises:

[0263] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the spraying local flow rate of the liquid mixture containing the coating agent is 0.30 to 9.00 g / min per kg of the pharmaceutically acceptable inert core, and the local solid addition rate of the mixture in solid form is 0.95 to 40.00 g / min per kg of the inert core; and

[0264] (b1) preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the spraying local flow rate of the liquid mixture containing the coating agent is 0.30 to 9.00 g / min per kg of the pharmaceutically acceptable inert core, and the local solid addition rate of the mixture in solid form is 0.10 to 40.00 g / min per kg of the inert core.

[0265] In one embodiment, a method for preparing a multiple unit oral dosage form of the first aspect of the invention comprises:

[0266] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the average spraying flow rate of the liquid mixture containing the coating agent is 0.30 to 5.00 g / min per kg of the pharmaceutically acceptable inert core, the average solid addition rate of the mixture in the solid form is 0.95 to 18.00 g / min per kg of the pharmaceutically acceptable inert core, and the relationship between the average spraying flow rate of the liquid mixture containing the coating agent and the average solid addition rate of the mixture in the solid form is 90:10 to 60:40, in particular 90:10 to 70:30;

[0267] and

[0268] (b1) preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the spraying average flow rate of the mixture comprising the coating agent is 0.30 to 5.00 g / min per kg of the pharmaceutically acceptable inert core, the average solid addition rate of the mixture in solid form is 0.10 to 2.25 g / min per kg of the pharmaceutically acceptable inert core, and the relationship between the average spraying flow rate of the liquid mixture comprising the coating agent and the average solid addition rate of the mixture in solid form is 90:10 to 60:40, in particular 80:20 to 60:40.

[0269] In one embodiment, a method for preparing a multiple unit oral dosage form of the first aspect of the invention comprises:

[0270] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the spraying local flow rate of the mixture containing the coating is 0.30 to 9.00 g / min per kg of pharmaceutically acceptable inert core, and the local solid addition rate of the mixture in solid form is 0.95 to 40.00 g / min per kg of inert core; and

[0271] (b1) preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the spraying local flow rate of the mixture comprising the coating is 0.30 to 9.00 g / min per kg of the pharmaceutically acceptable inert core, and the local solid addition rate of the mixture in solid form is 0.10 to 40.00 g / min per kg of the inert core.

[0272] In one embodiment, a method for preparing a multiple unit oral dosage form of the first aspect of the invention comprises:

[0273] (a1) coating the doxylamine or pharmaceutically acceptable salt thereof pellets having an inner active coating layer and optionally an intermediate enteric coating layer with a liquid mixture comprising 1.0 to 7.5% by weight of one or more enteric coating agents, 10.0 to 35.0% by weight of one or more modified release coating agents in a weight ratio of 5:95 to 30:70, and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a mixture in powder form comprising one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients to prepare a plurality of first modified-release pellets of doxylamine or pharmaceutically acceptable salt thereof,

[0274] wherein: the average spraying flow rate of the mixture comprising the coating is 0.30 to 5.00 g / min per kg of the pharmaceutically acceptable inert core; the average solid addition rate of the mixture in solid form is 0.05 to 1.50 g / min per kg of the pharmaceutically acceptable inert core; and the relationship between the average spraying flow rate of the mixture comprising the coating agent and the average solid addition rate of the mixture in solid form is 90:10 to 60:40, in particular 90:10 to 70:30; and

[0275] (b1) coating the pellets of pyridoxine or a pharmaceutically acceptable salt thereof having an inner active coating layer with a liquid mixture comprising 1.0 to 7.5% by weight of one or more enteric coating agents, 10.0 to 35.0% by weight of one or more modified release coating agents in a weight ratio of 5:95 to 30:70, and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a mixture in powder form comprising one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients to prepare a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof,

[0276] wherein: the average spraying flow rate of the mixture comprising the coating agent is 0.30 to 5.00 g / min per kg of the pharmaceutically acceptable inert core; the average solid addition rate of the mixture in solid form is 0.10 to 2.25 g / min per kg of the pharmaceutically acceptable inert core; and the relationship between the average spraying flow rate of the mixture comprising the coating agent and the average solid addition rate of the mixture in solid form is 90:10 to 60:40, in particular 80:20 to 60:40.

[0277] In one embodiment, a method for preparing a multiple unit oral dosage form of the first aspect of the invention comprises:

[0278] (a1) coating the doxylamine or pharmaceutically acceptable salt thereof pellets having an inner active coating layer and optionally an intermediate enteric coating layer with a liquid mixture comprising 1.0 to 7.5% by weight of one or more enteric coating agents, 10.0 to 35.0% by weight of one or more modified release coating agents in a weight ratio of 5:95 to 30:70, and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a mixture in powder form comprising one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients to prepare a plurality of first modified-release pellets of doxylamine or pharmaceutically acceptable salt thereof,

[0279] wherein: the spraying local flow rate of the mixture comprising the coating is 0.30 to 9.00 g / min per kg of pharmaceutically acceptable inert core, and the local solid addition rate of the mixture in solid form is 0.95 to 40.00 g / min per Kg of inert core; and

[0280] (b1) coating the pellets of pyridoxine or a pharmaceutically acceptable salt thereof having an inner active coating layer with a liquid mixture comprising 1.0 to 7.5% by weight of one or more enteric coating agents, 10.0 to 35.0% by weight of one or more modified release coating agents in a weight ratio of 5:95 to 30:70, and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a mixture in powder form comprising one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients to prepare a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein: the spraying local flow rate of the mixture comprising the coating is 0.30 to 9.00 g / min per kg of the pharmaceutically acceptable inert core, and the local solid addition rate of the mixture in solid form is 0.10 to 40.00 g / min per kg of the inert core.

[0281] The term "spraying average flow rate" refers to the average spraying rate during one cycle, which also corresponds to the average spraying rate of the corresponding coating step, which is understood as the result of the total amount of spraying during one cycle divided by the time required to complete the cycle, which is also the same result of the total amount of liquid mixture to be sprayed during the coating step divided by the time required to complete the coating step, usually expressed as g / min, or in this document, also expressed as g / min per kg of pharmaceutically acceptable inert core. The spraying average flow rate can be measured by any known method in the prior art. In addition, the term "spraying local flow rate" refers to the actual flow rate, taking into account that one or more spray guns are working in parallel in the spray gun system at the same time, when the spray gun is working (spraying), the combination (sum) of all spray guns of the spray gun system provides the flow rate. The spraying local flow rate can be measured by any known method in the prior art. For the purpose of the present invention, the spraying amount is divided by the pump working time for a certain pumping value by pre-calibrating the corresponding pump of the spray gun, or the "spraying local flow rate" is measured using a mass sensor or flow meter during spraying. Therefore, the difference between "spraying average flow rate" and "spraying local flow rate" is that the local flow rate is the actual flow rate provided by the spray gun system when it is working (spraying), and the average spray flow rate is the average value during one cycle or coating step (grams of liquid mixture sprayed per minute). Obviously, when the liquid mixture is sprayed discontinuously, the average spray flow rate is lower than the local spray flow rate, and when the liquid mixture is sprayed continuously, the average spray flow rate is equal to the local spray flow rate.

[0282] The term "average solid addition rate" refers to the average addition rate of the solid mixture in powder form during one cycle, which also corresponds to the average powder addition rate of the corresponding coating step, which is understood as the total amount added during one cycle divided by the time required to complete the cycle, which is also the same result of the total amount of solids / powders / mixtures to be added during the coating step divided by the time required to complete the coating step, usually expressed in g / min, or in this document also expressed as g / min per kg of pharmaceutically acceptable inert core. The average solid addition rate can be measured by any known method in the prior art. In addition, the term "local solid addition rate" refers to the actual solid addition rate provided by the corresponding powder screw feeder, or even the addition rate corresponding to the amount manually added in a short time required for manual addition of solids. The local solid addition rate can be measured by any known method in the prior art. For the purposes of the present invention, the "local solid addition rate" is measured by pre-calibration of the corresponding screw feeder or by weighing the amount of powder added manually during the time period required for local addition. Therefore, the difference between the "average solid addition rate" and the "local solid addition rate" is that the local solid addition rate is the actual addition rate provided by the screw feeder, or the actual addition rate provided by manual addition (with a shovel) when the powder addition is working, and the average powder addition rate is the average value during the cycle or coating step (grams of powder added per minute). Obviously, when the liquid mixture is sprayed discontinuously and the powder is added simultaneously or alternately, and when the liquid mixture is sprayed continuously but the powder is added alternately, the average powder addition rate is lower than the local powder addition rate. Only when the liquid mixture is sprayed continuously and the powder is added simultaneously, the average powder addition rate is equal to the local powder addition rate.

[0283] The expression "relationship between the spraying average flow rate of the mixture comprising the coating agent and the average solid addition rate" refers to the relationship between these two rates. This relationship can be measured by dividing one by the other. In addition, the expression "relationship between the spraying local flow rate of the mixture comprising the coating agent and the local solid addition rate" refers to the relationship between these two rates. This relationship can be measured by dividing one by the other.

[0284] As 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, the intermediate enteric release coating layer comprising one or more enteric coating agents, one or more anti-caking agents, optionally one or more pore forming agents; and optionally one or more pharmaceutically acceptable excipients.

[0285] In one embodiment, the method of the present invention comprises preparing a multiple unit dosage form of the first aspect of the invention as defined above, said dosage form comprising an intermediate enteric release coating layer, said intermediate enteric release coating layer comprising one or more enteric coating agents, one or more anti-caking agents, optionally one or more pore forming agents; and optionally one or more pharmaceutically acceptable excipients.

[0286] In one embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, the process further comprises the separate preceding steps of:

[0287] (a2) coating the pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients; and

[0288] (b2) coating a pharmaceutically acceptable inert core by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients.

[0289] In one embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, the process further comprises the separate preceding steps of:

[0290] (a2) coating the pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a mixture of a solid form comprising one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients; and

[0291] (b2) coating a pharmaceutically acceptable inert core 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 a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof in powder form and optionally one or more pharmaceutically acceptable excipients.

[0292] In one embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, the process further comprises the separate preceding steps of:

[0293] (a2) coating the pellets of doxylamine or its pharmaceutically acceptable salt having an inner active coating layer by continuously or discontinuously spraying a liquid mixture containing 5 to 15% by weight of one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding 5.0 to 6.5 g of a mixture in powder form containing one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients per kg of the mixture in solid form;

[0294] and

[0295] (b2) coating a pharmaceutically acceptable inert core by simultaneously or alternately spraying with a liquid mixture comprising 20% ​​to 45% by weight of one or more coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients in powder form.

[0296] In one embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, the process further comprises the separate preceding steps of:

[0297] (a2) coating the micropellets of doxylamine or its pharmaceutically acceptable salt having an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a mixture of a solid form comprising one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients; wherein: the average spraying flow rate of the mixture comprising the enteric coating agent is 0.30 to 3.00 g / min per kg of the pharmaceutically acceptable inert core; and

[0298] (b2) coating a pharmaceutically acceptable inert core 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 a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof in powder form and optionally one or more pharmaceutically acceptable excipients; wherein: the average spraying flow rate of the mixture comprising the coating agent is 0.30 to 4.50 g / min per Kg of pharmaceutically acceptable inert core.

[0299] In one embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, the process further comprises the separate preceding steps of:

[0300] (a2) coating the micropellets of doxylamine or its pharmaceutically acceptable salt having an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a mixture of a solid form comprising one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients; wherein: the local spraying flow rate of the mixture comprising the enteric coating agent is 0.3 to 8.0 g / min per kg of the pharmaceutically acceptable inert core; and

[0301] (b2) coating a pharmaceutically acceptable inert core 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 a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof in powder form and optionally one or more pharmaceutically acceptable excipients; wherein: the local spraying flow rate of the mixture comprising the coating agent is 0.30 to 9.0 g / min per Kg of pharmaceutically acceptable inert core.

[0302] In one embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, the process further comprises the separate preceding steps of:

[0303] (a2) coating the micropellets of doxylamine or its pharmaceutically acceptable salt having an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a solid form mixture comprising one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients; wherein: the average solid addition rate of the solid form mixture is 0.025 to 0.40 g / min per Kg of pharmaceutically acceptable inert core; and

[0304] (b2) coating a pharmaceutically acceptable inert core 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 a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients in powder form; wherein: the average solid addition rate of the powder is 0.50 to 9.0 g / min per Kg of pharmaceutically acceptable inert core.

[0305] In one embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, the process further comprises the separate preceding steps of:

[0306] (a2) coating the micropellets of doxylamine or its pharmaceutically acceptable salt having an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a solid form mixture comprising one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients; wherein: the local solid addition rate of the solid form mixture is 0.025 to 40.0 g / min per Kg of pharmaceutically acceptable inert core; and

[0307] (b2) coating a pharmaceutically acceptable inert core 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 a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients in powder form; wherein: the local solid addition rate of the powder is 0.95 to 40.0 g / min per Kg of pharmaceutically acceptable inert core.

[0308] In one embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, the process further comprises the separate preceding steps of:

[0309] (a2) coating the micropellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a mixture of a solid form comprising one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients; wherein: the relationship between the average spraying flow rate of the mixture comprising the coating agent and the average solid addition rate of the solid form mixture is 85:15 to 95:5; and

[0310] (b2) coating a pharmaceutically acceptable inert core 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 a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof in powder form and optionally one or more pharmaceutically acceptable excipients; wherein: the relationship between the average spraying flow rate of the mixture comprising the coating agent and the average solid addition rate is 25:75 to 40:60.

[0311] In one embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, the process further comprises the separate preceding steps of:

[0312] (a2) coating the micropellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a solid form mixture comprising one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients; wherein: the average spraying flow rate of the mixture comprising the enteric coating agent is 0.30 to 3.00 g / min per kg of the pharmaceutically acceptable inert core, the average solid addition rate of the solid form mixture is 0.025 to 0.40 g / min per kg of the pharmaceutically acceptable inert core, and the relationship between the average spraying flow rate of the mixture comprising the coating agent and the average solid addition rate of the solid form mixture is 85:15 to 95:5; and

[0313] (b2) coating a pharmaceutically acceptable inert core 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 a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof in powder form and optionally one or more pharmaceutically acceptable excipients; wherein: the average spraying flow rate of the mixture comprising the coating agent is 0.30 to 4.50 g / min per Kg of pharmaceutically acceptable inert core, the average solid addition rate of the powder is 0.50 to 9.0 g / min per Kg of pharmaceutically acceptable inert core, and the relationship between the average spraying flow rate of the mixture comprising the coating agent and the average solid addition rate is 25:75 to 40:60.

[0314] In one embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, the process further comprises the separate preceding steps of:

[0315] (a2) coating the micropellets of doxylamine or its pharmaceutically acceptable salt having an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a mixture of a solid form comprising one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients; wherein: the local spraying flow rate of the mixture comprising the enteric coating agent is 0.3 to 8.0 g / min per kg of the pharmaceutically acceptable inert core, and the local solid addition rate of the solid form mixture is 0.025 to 40.0 g / min per kg of the pharmaceutically acceptable inert core; and

[0316] (b2) coating a pharmaceutically acceptable inert core 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 a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof in powder form and optionally one or more pharmaceutically acceptable excipients; wherein: the local spray flow rate of the mixture comprising the coating agent is 0.30 to 9.0 g / min per Kg of pharmaceutically acceptable inert core, and the local solid addition rate of the powder is 0.95 to 40.0 g / min per Kg of pharmaceutically acceptable inert core.

[0317] In one embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, the process further comprises the separate preceding steps of:

[0318] (a2) coating the pellets of doxylamine or its pharmaceutically acceptable salt having an inner active coating layer by continuously or discontinuously spraying a liquid mixture containing 5 to 15% by weight of one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding 5.0 to 6.5 g of a mixture in powder form containing one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients per kg of the pharmaceutically acceptable inert core of the mixture in solid form; wherein: the average spraying flow rate of the mixture containing the enteric coating agent is 0.30 to 3.00 g / min per kg of the pharmaceutically acceptable inert core, the average solid addition rate of the mixture in solid form is 0.025 to 0.400 g / min per kg of the pharmaceutically acceptable inert core, and the relationship between the average spraying flow rate of the mixture containing the coating agent and the average solid addition rate of the mixture in solid form is 85:15 to 95:5; and

[0319] (b2) coating a pharmaceutically acceptable inert core by simultaneously or alternately spraying a liquid mixture containing 20% ​​to 45% by weight of one or more coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof in powder form and optionally one or more pharmaceutically acceptable excipients; wherein: the average spraying flow rate of the mixture containing the coating agent is 0.30 to 4.50 g / min per Kg of pharmaceutically acceptable inert core, the average solid addition rate of the powder is 0.50 to 9.00 g / min per Kg of pharmaceutically acceptable inert core, and the relationship between the average spraying flow rate of the mixture containing the coating agent and the average solid addition rate is 25:75 to 40:60.

[0320] In one embodiment, wherein the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric release coating layer, the process further comprises the separate preceding steps of:

[0321] (a2) coating the pellets of doxylamine or its pharmaceutically acceptable salt having an inner active coating layer by continuously or discontinuously spraying a liquid mixture containing 5 to 15% by weight of one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding 5.0 to 6.5 g of a mixture in powder form containing one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients per kg of the mixture in solid form; wherein: the local spraying flow rate of the mixture containing the enteric coating agent is 0.3 to 8.0 g / min per kg of the pharmaceutically acceptable inert core, and the local solid addition rate of the mixture in solid form is 0.025 to 40.0 g / min per Kg of the pharmaceutically acceptable inert core; and

[0322] (b2) coating a pharmaceutically acceptable inert core by simultaneously or alternately spraying a liquid mixture comprising 20% ​​to 45% by weight of one or more coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients in powder form; wherein: the local spray flow rate of the mixture comprising the coating agent is 0.30 to 9.0 g / min per Kg of pharmaceutically acceptable inert core, and the local solid addition rate of the powder is 0.95 to 40.0 g / min per Kg of pharmaceutically acceptable inert core.

[0323] In one embodiment, the method of the present invention comprises preparing a multiple unit dosage form of the first aspect of the present invention as defined above, the dosage form does not include an intermediate enteric release coating layer, the intermediate enteric release coating layer comprises one or more enteric coating agents, one or more anti-caking agents, optionally one or more pore formers; and optionally one or more pharmaceutically acceptable excipients. In one embodiment, wherein the multiple unit dosage form of the first aspect of the present invention as defined above does not include an intermediate enteric release coating layer, the method further comprises performing step (b2) as defined above. All embodiments of step (b2) of the method for preparing a multiple unit dosage form comprising an intermediate enteric release coating layer disclosed above are also applicable to the method for preparing a multiple unit dosage form that does not include an intermediate enteric release coating layer.

[0324] In one embodiment, the method for preparing the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises in a prior step (a3) ​​coating the pharmaceutically acceptable inert core by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients.

[0325] In one embodiment, the process for preparing the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises in a prior step (a3) ​​coating the pharmaceutically acceptable inert core 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 a mixture in powder form comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more anti-caking agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients.

[0326] In one embodiment, the process for preparing a multiple unit oral dosage form of the first aspect of the invention as defined above further comprises in a prior step (a3) ​​coating a pharmaceutically acceptable inert core by continuously or discontinuously spraying a liquid mixture comprising 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 a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, 18 to 36% by weight of one or more anti-caking agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients.

[0327] In one embodiment, the method for preparing the multiple unit oral dosage form of the first aspect of the present invention as defined above further comprises in a prior step (a3) ​​coating a pharmaceutically acceptable inert core 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 a mixture in powder form comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients, wherein: the average spraying flow rate of the mixture comprising the coating agent is 0.30 to 4.50 g / min per Kg of pharmaceutically acceptable inert core.

[0328] In one embodiment, the method for preparing the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises in a prior step (a3) ​​coating a pharmaceutically acceptable inert core 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 a mixture in powder form comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients, wherein: the local spraying flow rate of the mixture comprising the coating agent is 0.30 to 9.0 g / min per Kg of pharmaceutically acceptable inert core.

[0329] In one embodiment, the method for preparing the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises in a prior step (a3) ​​coating a pharmaceutically acceptable inert core 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 a mixture in powder form comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients, wherein: the average solid addition rate of the mixture in powder form is 0.95 to 18.0 g / min per Kg of pharmaceutically acceptable inert core.

[0330] In one embodiment, the method for preparing the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises in a prior step (a3) ​​coating a pharmaceutically acceptable inert core 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 a mixture in powder form comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more anti-caking agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients, wherein: the local solid addition rate of the mixture in powder form is 0.95 to 40.0 g / min per Kg of pharmaceutically acceptable inert core.

[0331] In one embodiment, the method for preparing the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises in a prior step (a3) ​​coating a pharmaceutically acceptable inert core 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 a mixture in powder form comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more anti-caking agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients, wherein: the relationship between the average spraying flow rate of the mixture comprising the coating agent and the average solid addition rate of the mixture in powder form is 15:85 to 30:70.

[0332] In one embodiment, the method for preparing the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises in a prior step (a3) ​​coating a pharmaceutically acceptable inert core 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 a mixture in powder form comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more anti-caking agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients, wherein: the average spraying flow rate of the mixture comprising the coating agent is 0.30 to 4.50 g / min per Kg of pharmaceutically acceptable inert core, the average solid addition rate of the mixture in powder form is 0.95 to 18.0 g / min per Kg of pharmaceutically acceptable inert core, and in particular the relationship between the average spraying flow rate of the mixture comprising the coating agent and the average solid addition rate of the mixture in powder form is 15:85 to 30:70.

[0333] In one embodiment, the method for preparing the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises in a prior step (a3) ​​coating a pharmaceutically acceptable inert core 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 a mixture in powder form comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more anti-caking agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients, wherein: the local spray flow rate of the mixture comprising the coating agent is 0.30 to 9.0 g / min per Kg of pharmaceutically acceptable inert core, and the local solid addition rate of the mixture in powder form is 0.95 to 40.0 g / min per Kg of pharmaceutically acceptable inert core.

[0334] In one embodiment, the method for preparing a multiple unit oral dosage form of the first aspect of the invention as defined above further comprises in a prior step (a3) ​​coating a pharmaceutically acceptable inert core by continuously or discontinuously spraying a liquid mixture comprising 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 a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, 18 to 36% by weight of one or more anti-caking agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients, wherein: the average spraying flow rate of the mixture comprising the coating agent is 0.30 to 4.50 g / min per Kg of pharmaceutically acceptable inert core, the average solid addition rate of the mixture in powder form is 0.95 to 18.0 g / min per Kg of pharmaceutically acceptable inert core, and the relationship between the average spraying flow rate of the mixture comprising the coating agent and the average solid addition rate of the mixture in powder form is 15:85 to 30:70.

[0335] In one embodiment, the method for preparing the multiple unit oral dosage form of the first aspect of the invention as defined above further comprises in a prior step (a3) ​​coating a pharmaceutically acceptable inert core by continuously or discontinuously spraying a liquid mixture comprising 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 a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, 18 to 36% by weight of one or more anti-caking agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients, wherein: the local spray flow rate of the mixture comprising the coating agent is 0.30 to 9.0 g / min per Kg of pharmaceutically acceptable inert core, and the local solid addition rate of the mixture in powder form is 0.95 to 40.0 g / min per Kg of pharmaceutically acceptable inert core.

[0336] In one embodiment, the method for preparing the multi-unit oral dosage form of the first aspect of the present invention comprises coating the pellets of doxylamine or its pharmaceutically acceptable salt by performing steps (a2) and (a1) as defined above to prepare a plurality of first modified-release pellets of doxylamine or its pharmaceutically acceptable salt. In one embodiment, the method for preparing the multi-unit oral dosage form of the first aspect of the present invention comprises coating a pharmaceutically acceptable inert core by performing steps (a3), (a2) and (a1) as defined above to prepare a plurality of first modified-release pellets of doxylamine or its pharmaceutically acceptable salt. In one embodiment, the method for preparing the multi-unit oral dosage form of the first aspect of the present invention comprises coating the pellets of doxylamine or its pharmaceutically acceptable salt by performing steps (a3) ​​and (a1) as defined above to prepare a plurality of first modified-release pellets of doxylamine or its pharmaceutically acceptable salt.

[0337] In one embodiment, the method for preparing the multiple unit oral dosage form of the first aspect of the invention comprises preparing a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating a pharmaceutically acceptable inert core with steps (b2) and (b1).

[0338] In one embodiment, the method for preparing the multiple unit oral dosage form of the first aspect of the present invention comprises: preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating the pellets with doxylamine or a pharmaceutically acceptable salt thereof by performing steps (a2) and (a1) as defined above; and preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating a pharmaceutically acceptable inert core by performing steps (b2) and (b1), respectively.

[0339] In one embodiment, the method for preparing the multiple unit oral dosage form of the first aspect of the present invention comprises: preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating a pharmaceutically acceptable inert core by performing steps (a3), (a2) and (a1) as defined above; and preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating a pharmaceutically acceptable inert core by performing steps (b2) and (b1), respectively.

[0340] In one embodiment, the method for preparing the multiple unit oral dosage form of the first aspect of the present invention comprises: preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating a pharmaceutically acceptable inert core by performing steps (a3) ​​and (a1) as defined above; and preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating a pharmaceutically acceptable inert core by performing steps (b2) and (b1), respectively.

[0341] In one embodiment, each coating step of the method of the present invention is carried out at an air temperature of 5°C to 80°C, particularly 20°C to 70°C, more particularly 25°C to 65°C, and still more particularly 25°C to 55°C. In one embodiment, at 0 to 20 m3 / kg of pharmaceutically acceptable inert core, 3 / h, especially 0 to 6 m / h per kg of pharmaceutically acceptable inert core 3 Each coating step of the method of the present invention is carried out under an air flow of 1000 g / min. The air flow is controlled using an anemometer-type air intake detection system. In one embodiment, the coating step is carried out under an air temperature of 5°C to 80°C and an air flow of 0 to 20 m / min per kg of pharmaceutically acceptable inert core. 3 Each coating step of the method of the present invention is carried out under an air flow of 1000 g / min.

[0342] In one embodiment, each coating step of the method of the present invention comprises a spraying mixture of one or more enteric coating agents and one or more modified release coating agents as defined above; in particular, the enteric coating agent is methacrylic acid-methyl methacrylate copolymer; and the modified release coating agent is shellac. In one embodiment, each coating step of the method of the present invention comprises a spraying mixture of one or more enteric coating agents and one or more modified release coating agents, the enteric coating agent is methacrylic acid-methyl methacrylate copolymer, in particular methacrylic acid-methyl methacrylate copolymer (1:1) (Eudragit L); and the modified release coating agent is shellac. In one embodiment, each coating step of the method of the present invention comprises a spraying mixture of one or more enteric coating agents and one or more modified release coating agents, the enteric coating agent is methacrylic acid-methyl methacrylate copolymer, in particular methacrylic acid-methyl methacrylate copolymer (1:1) (Eudragit L); and the modified release coating agent is shellac; the weight ratio is 5:95 to 30:70, in particular 8:92 to 20:80.

[0343] In one embodiment, in the coating step of step (a1) of the process of the present invention comprising spraying a mixture comprising one or more enteric coating agents and one or more modified release coating agents, the spray mixture comprises 4 to 7% by weight of an enteric coating agent, in particular methacrylic acid-methyl methacrylate copolymer (1:1) (Eudragit L), and 15 to 25% by weight of a modified release coating agent, in particular (dewaxed) shellac. In one embodiment, in the coating step of step (a1) of the process of the present invention comprising spraying a mixture comprising one or more enteric coating agents and one or more modified release coating agents, the spray mixture comprises 4 to 7% by weight of an enteric coating agent, in particular methacrylic acid-methyl methacrylate copolymer (1:1) (Eudragit L), and 15 to 25% by weight of a modified release coating agent, in particular (dewaxed) shellac, in a weight ratio of 15:85 to 30:70. In one embodiment, in the coating step of step (b1) of the method of the present invention comprising spraying a mixture comprising one or more enteric coating agents and one or more modified release coating agents, the spray mixture comprises 2.0 to 7.5% by weight of enteric coating agent and 10 to 35%, in particular 20 to 35% by weight of modified release coating agent. In one embodiment, in the coating step of step (b1) of the method of the present invention comprising spraying a mixture comprising one or more enteric coating agents and one or more modified release coating agents, the spray mixture comprises 2.0 to 7.5% by weight of enteric coating agent and 10 to 35%, in particular 20 to 35% by weight of modified release coating agent, in a weight ratio of 5:95 to 15:85.

[0344] In one embodiment, in the coating step of step (b1) of the method of the present invention comprising spraying a mixture comprising one or more enteric coating agents and one or more modified release coating agents, the spraying mixture comprises 2.0 to 7.5% by weight of methacrylic acid-methyl methacrylate copolymer (1:1) (Eudragit L) as enteric coating agent and 10 to 35%, in particular 20 to 35% by weight of (dewaxed) shellac as modified release coating agent. In one embodiment, in the coating step of step (b1) of the method of the present invention comprising spraying a mixture comprising one or more enteric coating agents and one or more modified release coating agents, the spraying mixture comprises 2.0 to 7.5% by weight of methacrylic acid-methyl methacrylate copolymer (1:1) (Eudragit L) as enteric coating agent and 10 to 35%, in particular 20 to 35% by weight of (dewaxed) shellac as modified release coating agent in a weight ratio of 5:95 to 15:85.

[0345] In one embodiment, in the coating step (a3) ​​of the method of the present invention, the coating agent is selected from polyvinyl pyrrolidone, shellac, hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose and mixtures thereof, in particular a mixture of polyvinyl pyrrolidone and shellac. In one embodiment, in the coating step (a3) ​​of the method of the present invention, the coating agent is a mixture of polyvinyl pyrrolidone, in particular K30 and shellac, in a weight ratio of 20:80 to 30:70. In one embodiment, in the coating step (a3) ​​of the method of the present invention, the spray mixture comprises 30 to 40% by weight of one or more coating agents as defined above. In a particular embodiment, in the coating step (a3), the spray mixture comprises 30 to 40% by weight of a mixture of polyvinyl pyrrolidone K30 and (dewaxed) shellac, and the weight ratio of polyvinyl pyrrolidone to shellac is 20:80 to 30:70. In a particular embodiment, in the coating step (a3), the spray mixture comprises one or more organic solvents as defined above and below; in particular, the mixture comprises a solvent concentration of 0 to 70% by weight. In a particular embodiment, in the coating step (a3), the spray mixture is a 20% ethanolic solution of polyvinylpyrrolidone K-30 and a 40% w / w (dewaxed) shellac in an ethanolic solution in a weight ratio of 20:80 to 40:60, in particular 30:70.

[0346] In one embodiment, in the coating step (b2) of the process of the invention, the spray mixture comprises 20 to 45% of one or more coating agents. In one embodiment, in the coating step (b2) of the process of the invention, the coating agent is selected from microcrystalline cellulose, hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), shellac, polyethylene glycol (PEG) 6000, guar gum and starch, in particular (dewaxed) shellac, in particular shellac. In a particular embodiment, in the coating step (b2), the spray mixture comprises 30 to 45% by weight of (dewaxed) shellac. In a particular embodiment, in the coating step (b2), the spray mixture comprises one or more organic solvents as defined above and below, in particular ethanol.

[0347] In one embodiment, in the coating step (a2) of the process of the present invention, the enteric coating agent is those defined above and below, in particular methacrylic acid-methyl methacrylate copolymer (Eudragit L). In one embodiment, in the coating step (a2) of the process of the present invention, the spray mixture comprises 5 to 15% by weight of one or more enteric coating agents.

[0348] In one embodiment, in the coating step (a2) of the method of the present invention, the spray mixture comprises 5 to 15% by weight of one or more enteric coating agents, the method comprising adding 5.0 to 6.5 g of an anti-caking agent in powder form per kg of a pharmaceutically acceptable inert core. In a particular embodiment, in the coating step (a2), the spray mixture comprises one or more organic solvents as defined above and below, in particular acetone, or a mixture of acetone, ethanol and water. In a particular embodiment, in the coating step (a2), the spray mixture comprises one or more solvents in a concentration of 85 to 95% by weight, more particularly 90% by weight of solvent.

[0349] In one embodiment, in each coating step (a1) and (b1) of the method of the present invention comprising spraying a mixture comprising a coating agent, the spraying mixture further comprises one or more organic solvents as defined above in an amount of 85 to 1200 g solvent per Kg of pharmaceutically acceptable inert core, in particular 85 to 650 g solvent per Kg of pharmaceutically acceptable inert core. In one embodiment, in each coating step of the method of the present invention comprising spraying a mixture comprising a coating agent, the spraying mixture further comprises one or more organic solvents as defined above in an amount of 270 to 285 g solvent per Kg of pharmaceutically acceptable inert core for (a1) and 85 to 100 g solvent per Kg of pharmaceutically acceptable inert core for (b1).

[0350] In one embodiment, 0 to 20 m3 / kg of pharmaceutically acceptable inert core 3 / h, especially 0 to 6 m / h per kg of pharmaceutically acceptable inert core 3 Each coating step of the method of the present invention is carried out under an air flow of 1000 g / min.

[0351] In one embodiment, in each coating step of the process of the invention, the temperature of the inert core (core) of the pellets during the coating step is between 5° C. and 50° C., in particular between 10° C. and 30° C. In one embodiment, in each coating step of the process of the invention, the temperature of the inert core (core) of the pellets during the coating step is between 19° C. and 30° C. The temperature is controlled using a calibrated PT100 sensor, which is in direct contact with the coated pellets, but it can also be controlled using an equivalent system.

[0352] In one embodiment, in each of the spraying steps (a1), (a2), (a3), (b1) and (b2), the liquid mixture is sprayed at a spray gun atomization pressure of 0.6 to 2.2 bar and an open pattern pressure of 0.6 to 2.5 bar.

[0353] The coating step of the method of the second aspect of the invention can be carried out by any known method disclosed in the prior art. In one embodiment, the coating step is carried out by a method selected from a pan coating method and a fluidized bed coating method. In one embodiment, the coating step is carried out by a pan coating method, and the pressure difference inside the pan coating is 0 to 200 Pa. In one embodiment, the coating step is carried out by a pan coating method, and the pressure difference inside the pan coating is 0 to 100 Pa.

[0354] In one embodiment, in the process of the invention, one or more coating steps are performed in the absence of a drying step.

[0355] In one embodiment, in the method of the present invention, one or more coating steps further include one or more drying steps. In one embodiment, the method of the present invention further includes an additional step of drying each of the obtained plurality of pellets individually after preparing each coating layer (inter-coating drying step). This means, for the first plurality of pellets after preparing the inner active coating layer, the middle enteric release coating layer and the outer modified release coating layer; and for the second plurality of pellets after preparing the inner active coating layer and / or the outer modified release coating layer.

[0356] In one embodiment, each drying step of the method of the present invention is carried out at a temperature of 15°C to 60°C, in particular 25°C to 45°C. In one embodiment, at a temperature equal to or higher than 1 m 3 Each drying step of the process of the invention is carried out under a gas flow of 1000 g / min (h per kg of inert core) for a suitable time to make the amount of each solvent less than 5000 ppm. In one embodiment, the drying step is carried out under a gas flow of 1000 g / min (h per kg of inert core) for a suitable time to make the amount of each solvent less than 5000 ppm. 3 Each drying step of the process of the present invention is carried out under a gas flow of 1.5 % to 1.5 % (h per kg of inert core) for a suitable time to reduce the amount of each solvent to less than 5000 ppm.

[0357] In a particular embodiment, at a temperature, in particular 15°C to 45°C and at a temperature above 1 m3 / kg of pharmaceutically acceptable inert core. 3 / h air flow for not less than 1 hour. In a particular embodiment, in particular at a temperature of 15°C to 60°C, preferably 25°C to 50°C, more particularly 40°C to 45°C and at a temperature of more than 2 m per kg of pharmaceutically acceptable inert core. 3 The drying step of the outer coating of the two micropellets is carried out for not less than 8 hours and not more than 12 hours at an air flow of 1.50 g / min.

[0358] In a particular embodiment, the drying step of the process of the invention is carried out in any suitable equipment, in particular in a coating pan at a speed of 0 to 10 rpm.

[0359] In one embodiment, the coating step of the method of the present invention is carried out in a coating pan at a rotation speed of 0 to 50 rpm, particularly 2 to 25 rpm, more particularly 10 to 2 rpm. The rotating pan speed can be controlled by any method known in the prior art. In particular, the method used in the present invention is by using a revolution counter.

[0360] In one embodiment, if the powder is observed to aggregate into granules, the method of the present invention further comprises one or more additional steps of separately sieving each of the plurality of pellets obtained in each coating step. In one embodiment, the method of the present invention further comprises one or more additional steps of separately sieving a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof and / or a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, the first modified-release pellets comprising a pharmaceutically acceptable inert core, an inner active coating layer, an intermediate enteric-release coating layer and an outer modified-release coating layer, and the second modified-release pellets comprising a pharmaceutically acceptable inert core, an inner active coating layer and an outer modified-release coating layer.

[0361] In one embodiment, the method of the present invention further comprises one or more additional steps of sieving as defined above until the particle size is such that at least 90% of the inert cores have a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variability of no more than 200 μm, particularly a particle size variability of no more than 150 μm, particularly a particle size variability of no more than 100 μm and more particularly a particle size variability of no more than 75 μm as measured by analytical sieving; the particle size of the first modified-release pellets of a plurality of doxylamine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size of 400 μm to 2000 μm as measured by analytical sieving , and at least 90% of the pellets have a particle size variability of no more than 200 μm, particularly no more than 150 μm, particularly no more than 100 μm and more particularly no more than 75 μm as measured by analytical sieving; and the pellet particle size of the plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size of 400 μm to 2000 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 200 μm, particularly no more than 150 μm, particularly no more than 100 μm and more particularly no more than 75 μm as measured by analytical sieving. All embodiments disclosed above regarding the particle size and particle size variability of the pharmaceutically acceptable core and the plurality of first and second pellets and combinations thereof disclosed in the first aspect of the invention are also applicable to the method of the second aspect of the invention.

[0362] In one embodiment, when the multi-unit oral dosage form is a hard capsule, the method of the present invention further comprises an additional step of filling a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof and a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof into the hard capsule. The process of filling the capsule can be carried out using known methods disclosed in the prior art. Examples of filling machines suitable for the present invention include, but are not limited to, automatic filling machines using intermittent or continuous motion. Common capsule filling machines using intermittent or continuous motion include machines from Bosch, IMA Zanasi, Dott Bonapace, and MG2. In the case of the present invention, an automatic filling machine with intermittent motion is used to fill the hard capsule. In one embodiment, when the multi-unit oral dosage form is a hard capsule, the method of the present invention further comprises an additional step of filling the hard capsule, the step comprising individually and separately filling a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof and a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof. In one embodiment, when the multiple unit oral dosage form is a hard capsule, the method of the present invention further comprises an additional step of filling the hard capsule, the step comprising: first, filling a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof into the body of the capsule, second, filling a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof into the body of the capsule, or vice versa, and mounting the capsule cap on the body of the capsule. In one embodiment, when the multiple unit oral dosage form is a hard capsule, the method of the present invention further comprises an additional step of filling the hard capsule, the step comprising filling a combination of a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof and a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof.

[0363] The use of the plurality of first and second pellets disclosed in the present invention enables the accuracy of the individual amount of each plurality of pellets filled into the capsule to be less than or equal to ±5% by weight of the theoretical fill weight. For the purpose of the present invention, the term "theoretical fill weight" refers to the target fill weight calculated based on the actual potency of doxylamine succinate or pyridoxine hydrochloride of the pellets to ensure the theoretical content of X mg (where X is, for example, 10.0 or 20.0 mg) of doxylamine succinate and Y mg (where Y is, for example, 10.0 or 20.0 mg) of pyridoxine hydrochloride in each capsule, which can be measured with a suitable balance.

[0364] In one embodiment, when the multiple unit oral dosage form is a hard capsule, the capsule filling step includes adding one or more pharmaceutically acceptable excipients. Examples of suitable pharmaceutically acceptable excipients for the capsule filling step are selected from lubricants, fillers, diluents, glidants and anti-caking agents or mixtures thereof.

[0365] In one embodiment, when the multiple unit oral dosage form is a hard capsule, the method further comprises the additional step of filling the capsule with a plurality of first pellets comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof and a plurality of second pellets comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof; in particular, with 5 mg to 50 mg of doxylamine succinate per capsule and 5 mg to 50 mg of pyridoxine hydrochloride per capsule.

[0366] All embodiments disclosed above and below of the multiple unit oral dosage form of the first aspect of the invention are also applicable to the method for its preparation of the second aspect of the invention.

[0367] The multiple unit oral dosage form of the first aspect of the present invention may be defined by its method of preparation as defined above in the second aspect of the present invention, and therefore, the multiple unit oral dosage form of the first aspect of the present invention obtainable by the method of the present invention is considered to be part of the present invention. For the purposes of the present invention, the expressions "obtainable", "obtained" and equivalent expressions may be used interchangeably, and in any case, the expression "obtainable" encompasses the expression "obtained".

[0368] All embodiments of the multiple unit oral dosage form of the first aspect of the present invention and the method for its preparation disclosed above also apply to the multiple unit oral dosage form of the present invention obtainable by the preparation method.

[0369] Finally, the use of the multi-unit oral dosage form of the first aspect of the present invention for treatment is also part of the present invention. In particular, the use of the multi-unit oral dosage form of the first aspect of the present invention for the symptomatic treatment of nausea and vomiting. In one embodiment, the multi-unit oral dosage form of the first aspect of the present invention is used for the symptomatic treatment of nausea and vomiting (NVP) associated with pregnant women. In one embodiment, the multi-unit oral dosage form of the first aspect of the present invention is used for the symptomatic treatment of nausea and vomiting associated with tumor treatment (e.g. chemotherapy or radiotherapy). This aspect can also be expressed as the use of the multi-unit oral dosage form of the first aspect of the present invention as defined above in the preparation of a medicament for the symptomatic treatment of nausea and vomiting. The present invention also relates to a method for preventing and / or treating a mammal suffering from or susceptible to nausea and vomiting, wherein the method comprises administering to the mammal a multi-unit oral dosage form of the first aspect of the present invention as defined above. In one embodiment, nausea and vomiting are associated with pregnant women (NVP), or with tumor treatment, such as chemotherapy or radiotherapy. All embodiments of the multi-unit oral dosage form of the first aspect of the present invention disclosed above also apply to the multi-unit oral dosage form of the first aspect of the present invention limited by its use.

[0370] Throughout the specification and claims, the word "comprise" and variations of the word are not intended to exclude other technical features, additives, components or steps. In addition, the word "comprise" covers the situation of "consisting of ..." Other objects, advantages and features of the present invention will become apparent to those skilled in the art after reviewing the specification, or can be understood by the practice of the present invention. The following examples are provided by way of illustration, and they are not intended to limit the present invention. In addition, the present invention covers all possible combinations of the specific and preferred embodiments described herein.

[0371] Example

[0372] General considerations

[0373] D90 measurements of the active ingredients (doxylamine and pyridoxine) were performed using the Malvern method (Laser Mastersizer, Mie Theory; ISO 13320-1).

[0374] The measurement of the D90 value of doxylamine or a pharmaceutically acceptable salt was carried out using the Malvern method (Laser Mastersizer, Mie Theory; ISO 13320-1) under the following main parameters used:

[0375] Sample, dispersion medium 250 mg, 5 mL Isopar G + 5% w / w lecithin

[0376] Ultrasonication time 20 seconds

[0377] Dispersant (volume) Isopar G (about 100mL)

[0378] Washing medium (volume)

[0379] Acetone (about 50mL), toluene (about 50mL)

[0380] and Isopar G (about 50 mL)

[0381] Particle refractive index 1.52

[0382] Particle absorption 0.1

[0383] Dispersant refractive index 1.42

[0384] Analysis Model General - Normal Sensitivity

[0385] Irregular particle shape

[0386] Each aliquot was measured three times

[0387] Delay between measurements 10 seconds

[0388] Sample measurement time 15 seconds

[0389] Background measurement time 15 seconds

[0390] Shading range 15 to 30%

[0391] Suspension stirring rate 2500±10rpm

[0392] Measure the samples using the following procedure:

[0393] Procedure: The sample vials were subjected to a standard mixing cycle in a Bio Grant PTR-30 rotary mixer. Approximately 250 mg of sample was transferred to a 10 mL vial and 5 mL of a 5% w / w lecithin solution in Isopar G was added. The suspension was sonicated for 20 seconds using a Bandelin Sonopuls HD3100 with an ultrasonic probe (MS72 tip, 20% intensity). The sample suspension was added to the measuring medium (approximately 100 mL of Isopar G) under a continuous cycle (2500 rpm) until an obscuration value of 15 to 30% was reached. Measurements were taken immediately 3 minutes after the addition of the sample to ensure dispersion stability. Each result was the average of three consecutive measurements of 15,000 swipes. The above procedure was performed in triplicate.

[0394] - The determination of the D90 value of pyridoxine or a pharmaceutically acceptable salt is carried out using the Malvern method (Laser Mastersizer, Mie Theory; ISO 13320-1) under the following principally used parameters:

[0395] Sample, dispersion medium 70 to 100 mg, 10 mL toluene

[0396] Ultrasonication time 20 seconds

[0397] Dispersant (volume) Toluene (about 100 mL)

[0398] Washing medium (volume) 2x acetone (approximately 50 mL) and toluene (approximately 50 mL)

[0399] Particle refractive index 1.52

[0400] Particle absorption 0.1

[0401] Dispersant refractive index 1.49

[0402] Analysis Model General - Normal Sensitivity

[0403] Irregular particle shape

[0404] Each aliquot was measured three times

[0405] Delay between measurements 10 seconds

[0406] Sample measurement time 15 seconds

[0407] Background measurement time 15 seconds

[0408] Shading range 15 to 30%

[0409] Suspension stirring rate 2500±10rpm

[0410] Measure the samples using the following procedure:

[0411] Procedure: The sample vials were subjected to a standard mixing cycle in a Bio Grant PTR-30 rotary mixer. Approximately 70 to 250 mg of sample were transferred to a 20 mL vial and 10 mL of toluene were added. The suspension was sonicated for 20 seconds using a Bandelin Sonopuls HD3100 with an ultrasonic probe (MS72 tip, 20% intensity). The sample suspension was added to the measuring medium (approximately 100 mL of toluene) under a continuous cycle (2500 rpm) until the obscuration value reached 15 to 30%. The sample vial was rinsed with approximately 5 mL of toluene. The measurement was performed immediately 3 minutes after the addition of the sample to ensure dispersion stability. Each result is the average of three consecutive measurements of 15,000 slides. The above procedure was performed in triplicate.

[0412] 1. Capsules of doxylamine succinate and pyridoxine hydrochloride pellets of the present invention

[0413] 1.1. Quantitative composition of each hard capsule

[0414] The amounts of each ingredient in each capsule are as follows:

[0415] 1.1.1 Hard gelatin capsules containing 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride

[0416] Hard gelatin capsules filled with pellets of doxylamine succinate and pyridoxine hydrochloride according to the invention, said pellets being obtained starting from an inert core having a particle size such that at least 90% of the inert cores have a particle size of 300 to 1700 μm as measured by analytical sieving and at least 90% of the pharmaceutically acceptable inert cores have a particle size variability of not more than 200 μm as measured by analytical sieving.

[0417]

[0418] (1) at least 90% of the inert cores have a particle size of 300 μm to 1700 μm and at least 90% of the pharmaceutically acceptable inert cores have a particle size variability of not more than 200 μm in a given range of 500 μm to 1400 μm as measured by analytical sieving

[0419] (2) 60 mg + / - 10%, the actual target fill weight is calculated based on the actual potency of doxylamine succinate or pyridoxine hydrochloride in the pellets to ensure the theoretical content of 10.0 mg of doxylamine succinate and 10.0 mg of pyridoxine hydrochloride in each capsule

[0420] (3) 48 mg + / - 10%, based on capsule supplier's specifications

[0421] 1.1.2 Hard HPMC capsules of 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride

[0422] Hard HPMC capsules filled with micropellets of doxylamine succinate and pyridoxine hydrochloride according to the invention, said micropellets being obtained starting from an inert core having a particle size such that at least 90% of the inert cores have a particle size of 300 to 1700 μm measured by analytical sieving and at least 90% of the inert cores have a particle size variability of not more than 200 μm measured by analytical sieving.

[0423]

[0424] (1) At least 90% of the inert cores have a particle size of 300 μm to 1700 μm and at least 90% of the inert cores have a particle size variability of not more than 200 μm in a given value of 500 μm to 1400 μm as measured by analytical sieving

[0425] (2) 60 mg + / - 10%, the actual target fill weight is calculated based on the actual potency of doxylamine succinate or pyridoxine hydrochloride in the pellets to ensure the theoretical content of 10.0 mg of doxylamine succinate and 10.0 mg of pyridoxine hydrochloride in each capsule

[0426] (3) 47 mg + / - 10%, based on capsule supplier's specifications

[0427] (4) HPMC (hydroxypropyl methylcellulose or hydroxypropyl methylcellulose)

[0428] 1.1.3 Hard gelatin capsules containing 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride

[0429] Hard gelatin capsules filled with pellets of doxylamine succinate and pyridoxine hydrochloride according to the invention, said pellets being obtained starting from an inert core having a particle size such that at least 90% of the inert cores have a particle size of 600 to 1180 μm measured by analytical sieving and at least 90% of the inert cores have a particle size variability of not more than 100 μm measured by analytical sieving.

[0430]

[0431] (1) At least 90% of the inert cores have a particle size of 600 μm to 1180 μm and at least 90% of the inert cores have a particle size variability of not more than 100 μm in a given value of 710 μm to 1000 μm as measured by analytical sieving

[0432] (2) 60 mg + / - 10%, the actual target fill weight is calculated based on the actual potency of doxylamine succinate or pyridoxine hydrochloride in the pellets to ensure the theoretical content of 10.0 mg of doxylamine succinate and 10.0 mg of pyridoxine hydrochloride in each capsule

[0433] (3) 48 mg + / - 10%, based on capsule supplier's specifications

[0434] 1.1.4 Hard HPMC capsules of 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride

[0435] Hard HPMC capsules filled with micropellets of doxylamine succinate and pyridoxine hydrochloride according to the invention, said micropellets being obtained starting from an inert core having a particle size such that at least 90% of the inert cores have a particle size of 600 to 1180 μm measured by analytical sieving and at least 90% of the inert cores have a particle size variability of not more than 100 μm measured by analytical sieving.

[0436]

[0437]

[0438] (1) At least 90% of the inert cores have a particle size of 600 μm to 1180 μm and at least 90% of the inert cores have a particle size variability of not more than 100 μm in a given value of 710 μm to 1000 μm as measured by analytical sieving

[0439] (2) 60 mg + / - 10%, the actual target fill weight is calculated based on the actual potency of doxylamine succinate or pyridoxine hydrochloride in the pellets to ensure the theoretical content of 10.0 mg of doxylamine succinate and 10.0 mg of pyridoxine hydrochloride in each capsule

[0440] (3) 47 mg + / - 10%, based on capsule supplier's specifications

[0441] (4) HPMC (hydroxypropyl methylcellulose or hydroxypropyl methylcellulose)

[0442] 1.1.5 Hard gelatin capsules containing 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride

[0443] Hard gelatin capsules filled with pellets of doxylamine succinate and pyridoxine hydrochloride according to the invention, said pellets being obtained starting from an inert core having a particle size such that at least 90% of the inert cores have a particle size of 710 μm to 1000 μm measured by analytical sieving and at least 90% of the inert cores have a particle size variability of not more than 75 μm measured by analytical sieving.

[0444]

[0445]

[0446] (1) at least 90% of the inert cores have a particle size of 710 μm to 1000 μm and at least 90% of the pharmaceutically acceptable inert cores have a particle size variability of no more than 75 μm in a given range of 800 μm to 900 μm as measured by analytical sieving

[0447] (2) 60 mg + / - 10%, the actual target fill weight is calculated based on the actual potency of doxylamine succinate or pyridoxine hydrochloride in the pellets to ensure the theoretical content of 10.0 mg of doxylamine succinate and 10.0 mg of pyridoxine hydrochloride in each capsule

[0448] (3) 48 mg + / - 10%, based on capsule supplier's specifications

[0449] 1.1.6 Hard HPMC capsules of 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride

[0450] Hard HPMC capsules filled with pellets of doxylamine succinate and pyridoxine hydrochloride according to the invention, said pellets being obtained starting from an inert core having a particle size such that at least 90% of the inert cores have a particle size of 710 μm to 1000 μm measured by analytical sieving and at least 90% of the inert cores have a particle size variability of no more than 75 μm measured by analytical sieving.

[0451]

[0452]

[0453] (1) At least 90% of the inert cores have a particle size of 710 μm to 1000 μm and at least 90% of the inert cores have a particle size variability of not more than 75 μm in a given value of 800 μm to 900 μm as measured by analytical sieving

[0454] (2) 60 mg + / - 10%, the actual target fill weight is calculated based on the actual potency of doxylamine succinate or pyridoxine hydrochloride in the pellets to ensure the theoretical content of 10.0 mg of doxylamine succinate and 10.0 mg of pyridoxine hydrochloride in each capsule

[0455] (3) 47 mg + / - 10%, based on capsule supplier's specifications

[0456] (4) HPMC (hydroxypropyl methylcellulose or hydroxypropyl methylcellulose)

[0457] 1.1.7 Hard gelatin capsules containing 20 mg doxylamine succinate and 20 mg pyridoxine hydrochloride

[0458] Hard gelatin capsules filled with pellets of doxylamine succinate and pyridoxine hydrochloride according to the invention, said pellets being obtained starting from an inert core having a particle size such that at least 90% of the inert cores have a particle size of 600 to 1180 μm measured by analytical sieving and at least 90% of the inert cores have a particle size variability of not more than 100 μm measured by analytical sieving.

[0459]

[0460]

[0461] (1) At least 90% of the inert cores have a particle size of 600 μm to 1180 μm and at least 90% of the inert cores have a particle size variability of not more than 100 μm in a given value of 710 μm to 1000 μm as measured by analytical sieving

[0462] (2) 120 mg + / - 10%, the actual target fill weight is calculated based on the actual potency of doxylamine succinate or pyridoxine hydrochloride in the pellets to ensure the theoretical content of 20.0 mg of doxylamine succinate and 20.0 mg of pyridoxine hydrochloride in each capsule

[0463] (3) 61 mg + / - 10%, based on capsule supplier's specifications

[0464] 1.1.8 Hard HPMC capsules of 20 mg doxylamine succinate and 20 mg pyridoxine hydrochloride

[0465] Hard HPMC capsules filled with micropellets of doxylamine succinate and pyridoxine hydrochloride according to the invention, said micropellets being obtained starting from an inert core having a particle size such that at least 90% of the inert cores have a particle size of 600 to 1180 μm measured by analytical sieving and at least 90% of the inert cores have a particle size variability of not more than 100 μm measured by analytical sieving.

[0466]

[0467]

[0468] (1) At least 90% of the inert cores have a particle size of 600 μm to 1180 μm and at least 90% of the inert cores have a particle size variability of not more than 100 μm in a given value of 710 μm to 1000 μm as measured by analytical sieving

[0469] (2) 120 mg + / - 10%, the actual target fill weight is calculated based on the actual potency of doxylamine succinate or pyridoxine hydrochloride in the pellets to ensure the theoretical content of 20.0 mg of doxylamine succinate and 20.0 mg of pyridoxine hydrochloride in each capsule

[0470] (3) 61 mg + / - 10%, based on capsule supplier's specifications

[0471] (4) HPMC (hydroxypropyl methylcellulose or hydroxypropyl methylcellulose)

[0472] 1.1.9 Hard gelatin capsules containing 20 mg doxylamine succinate and 20 mg pyridoxine hydrochloride

[0473] Hard gelatin capsules filled with pellets of doxylamine succinate and pyridoxine hydrochloride according to the invention, said pellets being obtained starting from an inert core having a particle size such that at least 90% of the inert cores have a particle size of 600 to 1180 μm measured by analytical sieving and at least 90% of the inert cores have a particle size variability of not more than 100 μm measured by analytical sieving.

[0474]

[0475]

[0476] (1) At least 90% of the inert cores have a particle size of 600 μm to 1180 μm and at least 90% of the inert cores have a particle size variability of not more than 100 μm in a given value of 710 μm to 1000 μm as measured by analytical sieving

[0477] (2) 120 mg + / - 10%, the actual target fill weight is calculated based on the actual potency of doxylamine succinate or pyridoxine hydrochloride in the pellets to ensure the theoretical content of 20.0 mg of doxylamine succinate and 20.0 mg of pyridoxine hydrochloride in each capsule

[0478] (3) 76 mg + / - 10%, based on capsule supplier's specifications

[0479] 1.1.10 Hard HPMC capsules of 20 mg doxylamine succinate and 20 mg pyridoxine hydrochloride

[0480] Hard HPMC capsules filled with micropellets of doxylamine succinate and pyridoxine hydrochloride according to the invention, said micropellets being obtained starting from an inert core having a particle size such that at least 90% of the inert cores have a particle size of 600 to 1180 μm measured by analytical sieving and at least 90% of the inert cores have a particle size variability of not more than 100 μm measured by analytical sieving.

[0481]

[0482] (1) At least 90% of the inert cores have a particle size of 600 μm to 1180 μm and at least 90% of the inert cores have a particle size variability of not more than 100 μm in a given value of 710 μm to 1000 μm as measured by analytical sieving

[0483] (2) 120 mg + / - 10%, the actual target fill weight is calculated based on the actual potency of doxylamine succinate or pyridoxine hydrochloride in the pellets to ensure the theoretical content of 20.0 mg of doxylamine succinate and 20.0 mg of pyridoxine hydrochloride in each capsule

[0484] (3) 76 mg + / - 10%, based on capsule supplier's specifications

[0485] (4) HPMC (hydroxypropyl methylcellulose or hydroxypropyl methylcellulose)

[0486] Dissolution curve: The capsules of the micropellets of doxylamine succinate and pyridoxine hydrochloride of the present invention of Examples 1.1.1 to 1.1.10 showed a dissolution profile according to the target dissolution profile, as shown below. The dissolution profile was measured using a USP Type 2 apparatus (basket), and the composition was placed in 900 mL of the corresponding medium / buffered at 37°C ± 0.5°C, 100 rpm (revolutions per minute).

[0487] 1.2. Quantitative composition of each multiple pellets

[0488] 1.2.1 The composition of the doxylamine succinate micropellets of the present invention, the micropellets are obtained starting from an inert core, the particle size of the inert core is such that at least 90% of the inert cores have a particle size of 600 μm to 1180 μm, and at least 90% of the inert cores have a particle size variability of no more than 100 μm in a given value of 710 μm to 1000 μm, the particle size of the doxylamine succinate active ingredient is characterized by having a D90 equal to or less than 250 μm, and the particle size of the talc anti-caking agent is characterized by having a D90 equal to or less than 250 μm.

[0489] The amounts of the ingredients in each batch of about 25 kg or about 180 kg of doxylamine succinate pellets are as follows:

[0490]

[0491]

[0492] (*) Purified water or ethanol can be added as a processing aid if necessary to facilitate the preparation of enteric release coating solution.

[0493] The particle size of the obtained doxylamine succinate pellets is such that at least 90% of the pellets have a particle size of 710 μm to 1400 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 100 μm in a given value of 850 μm to 1250 μm as measured by analytical sieving. The homogeneity of the particle size of the pellets and the homogeneity between the pellets of the active ingredient content make the pellets easier to handle, achieve high uniformity of dosage, and ensure the desired content of the active ingredient and the desired dissolution profile as described in the above examples.

[0494] 1.2.2 The composition of the pyridoxine hydrochloride micropellets of the present invention, the micropellets are obtained starting from an inert core, the particle size of the inert core is such that at least 90% of the inert core has a particle size of 600 μm to 1180 μm, and at least 90% of the pharmaceutically acceptable inert core has a particle size variability of no more than 100 μm in a given value of 710 μm to 1000 μm, the particle size of the pyridoxine hydrochloride active ingredient is characterized by having a D90 equal to or less than 250 μm, and the particle size of the talc anti-caking agent is characterized by having a D90 equal to or less than 250 μm.

[0495] The amounts of the ingredients in each batch of about 25 kg or about 180 kg of pyridoxine hydrochloride pellets are as follows:

[0496]

[0497]

[0498] (*) Purified water or ethanol can be added as a processing aid if necessary to facilitate the preparation of enteric release coating solution.

[0499] The particle size of the obtained pyridoxine hydrochloride pellets is such that at least 90% of the pellets have a particle size of 710 μm to 1400 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 100 μm in a given value of 850 μm to 1250 μm as measured by analytical sieving. The homogeneity of the particle size of the pellets and the homogeneity between the pellets of the active ingredient content make the pellets easier to handle, achieve high uniformity of dosage, and ensure the desired content of the active ingredient and the desired dissolution profile as described in the above examples.

[0500] 1.3. Preparation method by continuous spraying of liquid slurry / suspension

[0501] 1.3.1. Preparation of multiple doxylamine succinate pellets in 25 kg batches

[0502] A. Phase Preparation

[0503] Phase 1 - Liquid coating slurry / suspension mixture for preparing inner active coating layer: A mixture of 84 g of povidone K30, 467 g of (dewaxed) shellac and 4.28 kg of ethanol was prepared. Then, 4.192 kg of doxylamine succinate (D90 < 250 μm), 0.279 kg of aerosol 200Ph (D90 < 250 μm) and 1.397 kg of talc (D90 < 250 μm) were added to the mixture. The resulting 10.7 kg mixture was stirred continuously.

[0504] Phase 2 - Liquid coating slurry / suspension mixture for preparing intermediate coating layer: Prepare a mixture of 89 g of Euradil L100 and 1064 g of acetone and 133 g of purified water and 45 g of talc (D90 < 250 μm). The resulting 1.331 kg mixture was stirred continuously.

[0505] Phase 3 - Liquid coating slurry / suspension mixture for preparing outer coating layer: 735 g of talc (D90 < 250 μm) was added to a mixture of 294 g of Eudradil L100, 1175 g of shellac, 10.71 kg of acetone, 7.93 kg of ethanol and 1.19 kg of purified water. The resulting 22.04 kg mixture was stirred continuously.

[0506] B. Preparation Method

[0507] - Inner active coating layer

[0508] 15.625 kg of inert cores (sugar spheres of sucrose and starch) are transferred to the coating pan, the particle size of the inert cores being such that at least 90% of the inert cores have a particle size of 600 μm to 1180 μm, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variability of no more than 100 μm in a given value of 710 μm to 1000 μm. Then, the liquid coating slurry / suspension mixture phase 1 is continuously sprayed onto the pellets, the coating pan speed is 15 rpm, the spray flow rate is 65 g / min, the negative pressure inside the coating pan (depression inside the pan-coating) is <100 Pa, the spray gun pressure is about 1.0 bar, and the open pressure is about 1.2 bar. While spraying phase 1, the pellets are continuously dried using hot air (at 30 to 35°C, air flow of about 100 m 3 / h) and the core temperature of the pellets was maintained at 22°C to 26°C. 3 / h of air flow and rotating the obtained coated pellets in a coating pan at a speed of 0 to 10 rpm to dry the pellets at 35 to 50° C. for 10 minutes to obtain dried coated pellets having an inner active coating layer, the inner active coating layer having an active ingredient. If necessary, the dried pellets may be sieved, and unwanted particle size, powder, and aggregates may be discarded.

[0509] - Middle coating layer

[0510] The phase 2 liquid mixture was continuously sprayed onto the coated active pellets obtained in the previous step, with a coating pan speed of 15 rpm, a spraying flow rate of 20 g / min, a negative pressure inside the coating pan of <100 Pa, a spray gun pressure of about 1.0 bar, and an open pressure of about 1.2 bar. While spraying phase 2, the pellets were continuously dried using hot air (at 30 to 35°C, an air flow of <100 m 3 / h) and the core temperature of the pellets was maintained at 24°C to 28°C. 3 / h of air flow and rotating the obtained coated pellets in a coating pan at a speed of 0 to 10 rpm to dry the pellets at 35 to 50°C for 30 minutes to obtain dry coated pellets having an inner active coating layer and an intermediate coating layer.

[0511] - External modified release coating

[0512] Then, the phase 3 coating mixture was continuously sprayed onto the double-layer pellets obtained in the previous step, with a coating pan speed of 15 rpm, a spray flow rate of 75 g / min, a negative pressure inside the coating pan of <100 Pa, a spray gun pressure of about 1.0 bar, and an open pressure of about 1.2 bar. While spraying phase 3, the pellets were continuously dried using hot air (at 45 to 50°C, with an airflow of >140 m 3 / h) and the core temperature of the pellets was maintained at 25°C to 29°C. 3 / h of air flow and rotating the obtained coated pellets in a coating pan at a speed of 0 to 10 rpm to dry the pellets at about 50°C for 30 minutes to obtain dry coated pellets having an inner active coating layer, an intermediate coating layer and an outer coating layer.

[0513] The resulting pellets have the target dissolution profile. If necessary, the dried pellets can be sieved and unwanted particle sizes, powders and aggregates discarded.

[0514] The obtained modified-release micropellets of doxylamine succinate were stored in 25 kg closed double-layer food and pharmaceutical grade polyethylene bags in closed high-density polyethylene drums.

[0515] 1.3.2. Preparation of multiple pyridoxine hydrochloride pellets at 25 kg scale

[0516] A. Phase Preparation

[0517] Phase 4 - Liquid coating slurry / suspension mixture for preparing inner active coating layer: A mixture of 0.850 kg (dewaxed) shellac and 3.48 kg ethanol was prepared. Then, 4.24 kg pyridoxine hydrochloride (D90 < 250 μm) was added to the mixture. The resulting 8.43 kg mixture was stirred continuously.

[0518] Phase 5 - Liquid coating slurry / suspension mixture for preparing outer coating layer: 385 g of talc (D90 < 250 μm) was added to a mixture of 68 g of Eudradil L100, 702 g of shellac, 610 g of acetone, 9.72 kg of ethanol and 68 g of purified water. The resulting 11.56 kg mixture was stirred continuously.

[0519] B. Preparation Method

[0520] - Inner active coating layer

[0521] 17.962 kg of inert cores (sugar spheres of sucrose and starch) are transferred to a coating pan, the particle size of which is such that at least 90% of the inert cores have a particle size of 600 μm to 1180 μm, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variability of no more than 100 μm in a given value of 710 μm to 1000 μm. Then, the liquid coating slurry / suspension mixture phase 4 is continuously sprayed onto the pellets, the coating pan speed is 15 rpm, the spray flow rate is 60 g / min, the negative pressure inside the coating pan is <100 Pa, the spray gun pressure is about 1.0 bar, and the open pressure is about 1.2 bar. While spraying phase 4, the pellets are continuously dried using hot air (at 38 to 42° C., with an air flow of about 100 m 3 / h) and keep the core temperature of the pellets at 21°C to 24°C. Use hot air (at 40 to 50°C, airflow of about 160m 3 / h) drying the obtained coated pellets by rotating them in a coating pan at a speed of 0 to 10 rpm for 20 minutes to obtain dried coated pellets having an inner active coating layer, wherein the inner active coating layer has an active ingredient. If necessary, the dried pellets can be sieved and unwanted particle sizes, powders and aggregates can be discarded.

[0522] - External modified release coating

[0523] Then, the coating mixture of phase 5 was continuously sprayed onto the coated active pellets obtained in the previous step, with a coating pan speed of 15 rpm, a spray flow rate of 63 g / min, a negative pressure inside the coating pan of <100 Pa, a spray gun pressure of about 1.0 bar, and an open pressure of about 1.2 bar. While spraying phase 5, the pellets were continuously dried using hot air (at 50 to 65°C, airflow of >130 m 3 / h) and maintain the core temperature of the pellets at 26°C to 30°C. Use hot air (at 45 to 55°C, airflow >120m 3 / h) drying the obtained coated pellets by rotating them in a coating pan at a rotation speed of 0 to 10 rpm for 30 minutes to obtain dried coated pellets having an inner active coating layer and an outer coating layer, with a yield of ≥93%.

[0524] The resulting pellets have the target dissolution profile. If necessary, the dried pellets can be sieved and unwanted particle sizes, powders and aggregates discarded.

[0525] The obtained modified-release micropellets of doxylamine succinate were stored in 25 kg closed double-layer food and pharmaceutical grade polyethylene bags in closed high-density polyethylene drums.

[0526] 1.4. Preparation method by discontinuous spraying of a solution and alternating addition of a solid in powder form

[0527] 1.4.1. Preparation of multiple doxylamine succinate pellets in 25 kg batches

[0528] A. Phase Preparation

[0529] Phase 1 - Powder mixture for preparation of inner active coating layer: 4.192 kg doxylamine succinate (D90 < 250 μm), 0.279 kg Aerosil 200 pharma (D90 < 250 μm) and 1.397 kg talc (D90 < 250 μm) were mixed in a coating pan.

[0530] Phase 2 - Binding solution for the preparation of the inner active coating layer: 0.419 kg of 20% w / w Povidone K30 solution in ethanol and 1.169 kg of 40% w / w (dewaxed) shellac solution in ethanol were mixed.

[0531] Phase 3 - Coating solution for preparing outer coating: 89 g of Eudragit L 100 were added to 711 g of acetone, the mixture was stirred and then 89 g of water was added to obtain a clear solution.

[0532] Phase 4 - Coating solution for preparing outer coating: Mix 2.950 g of 10% w / w Eudragit L solution in acetone, 300 g purified water and 2.937 kg of 40% w / w (dewaxed) shellac solution in ethanol.

[0533] B. Preparation Method

[0534] - Inner active coating layer

[0535] The above-mentioned amount of inert cores (sugar spheres of sucrose and starch) is transferred into the coating pan, the particle size of which is such that at least 90% of the inert cores have a particle size of 600 μm to 1180 μm and at least 90% of the pharmaceutically acceptable inert cores have a particle size variability of not more than 100 μm in a given value of 710 μm to 1000 μm. Then, the rotation is started, the coating pan rotation speed is maintained at 20 rpm during all coating steps, the negative pressure inside the coating pan is <100 Pa, while the binding solution phase 2 is sprayed discontinuously, repeating a cycle having the following sequence:

[0536] - 24 seconds to spray the bonding solution phase 2, the spray flow rate is 78g / min, the spray gun pressure is about 0.8bar, and the open pressure is about 1.0bar

[0537] -5 second pause 1

[0538] -66 seconds to add powder mixture phase 1, powder addition rate is 107 g / min

[0539] -30 second pause

[0540] - 0 seconds drying time (no drying).

[0541] The core temperature of the pellets was maintained at 21°C to 25°C. 3 / h of air flow and the resulting coated pellets are rotated in a coating pan at a speed of 0 to 5 rpm to dry the pellets at room temperature for 2 hours to obtain dried coated pellets having an inner active coating layer, the inner active coating layer having an active ingredient. If necessary, the dried pellets can be sieved and unwanted particle sizes, powders and aggregates can be discarded.

[0542] - Intermediate enteric release coating layer

[0543] The coated active pellets obtained in the previous step were transferred to a coating pan. Then, the rotation was started, the rotation speed of the coating pan was kept at 20 rpm during this coating step, the negative pressure inside the coating pan was <100 Pa, and the coating solution phase 3 was sprayed discontinuously, repeating a cycle with the following sequence:

[0544] - Spray coating solution phase 3 for 60 seconds, spray flow rate is 46 g / min, spray gun pressure is about 1.0 bar, open air pressure is about 1.0 bar

[0545] -15 seconds of talc addition (D90 < 250 μm), powder addition rate 16.2 g / min

[0546] -15 second pause

[0547] - 45 seconds drying time (at 40 to 45°C, airflow 50m 3 / h)

[0548] The core temperature of the pellets was maintained at 19°C to 24°C. 3 / h of air flow and rotating the obtained coated pellets in a coating pan at a speed of 0 to 5 rpm to dry the pellets at room temperature for 1 hour to obtain dried coated pellets having an inner active coating layer, wherein the inner active coating layer has an active ingredient. If necessary, the dried pellets can be sieved and unwanted particle sizes, powders and aggregates can be discarded.

[0549] - External modified release coating

[0550] The coated active pellets obtained in the previous step were transferred to a coating pan. Then, the rotation was started, and the rotation speed of the coating pan was maintained at 20 rpm during this coating step, and the negative pressure inside the coating pan was <100 Pa, while the coating solution phase 4 was sprayed discontinuously, repeating a cycle with the following sequence:

[0551] - 20 seconds to spray the bonding solution phase 4, the spray flow rate is 39 g / min, the spray gun pressure is about 1.4 bar, and the open pressure is about 1.6 bar

[0552] -10 seconds of talc addition (D90 < 250 μm), powder addition rate 17 g / min

[0553] -20 second pause

[0554] - 0 seconds drying time (no drying).

[0555] The core temperature of the pellets was maintained at 24°C to 29°C. 3 / h of air flow and rotating the obtained coated pellets in a coating pan at a speed of 0 to 5 rpm to dry the pellets at 40°C to 45°C for 12 hours to obtain dried coated pellets having an inner active coating layer, wherein the inner active coating layer has an active ingredient and the yield calculated by dividing the obtained amount by the theoretical amount x 100 is equal to or greater than 93%.

[0556] The resulting pellets have the target dissolution profile. If necessary, the dried pellets can be sieved and unwanted particle sizes, powders and aggregates discarded.

[0557] The obtained modified-release micropellets of doxylamine succinate were stored in 25 kg closed double-layer food and pharmaceutical grade polyethylene bags in closed high-density polyethylene drums.

[0558] 1.4.2. Preparation of multiple pyridoxine hydrochloride pellets at 25 kg scale

[0559] A. Phase Preparation

[0560] Phase 5 - Coating solution for preparing outer coating: Mix 0.679 kg of 10% w / w Eudragit L solution in acetone, 68 g of water and 1.758 kg of 40% w / w (dewaxed) shellac solution in ethanol.

[0561] B. Preparation Method

[0562] - Inner active coating layer

[0563] The above-mentioned amount of inert cores (sugar spheres of sucrose and starch) is transferred into a coating pan, the particle size of which is such that at least 90% of the inert cores have a particle size of 600 μm to 1180 μm and at least 90% of the pharmaceutically acceptable inert cores have a particle size variability of not more than 100 μm in a given value of 710 μm to 1000 μm. Then, the rotation is started, the coating pan rotation speed is maintained at 20 rpm during all this coating step, the negative pressure inside the coating pan is <100 Pa, while 40% w / w (dewaxed) shellac ethanol solution is sprayed discontinuously, repeating a cycle having the following sequence:

[0564] -18 seconds to spray the adhesive solution phase at 56 g / min, with a spray gun pressure of about 0.8 bar and an open air pressure of about 1.0 bar

[0565] -5 second pause 1

[0566] -9 seconds to add pyridoxine hydrochloride (D90 <250μm), powder addition rate is 233g / min

[0567] -30 second pause 2

[0568] - 0 seconds drying time (no drying).

[0569] The core temperature of the pellets was maintained at 19°C to 24°C. 3 / h of air flow and the resulting coated pellets are rotated in a coating pan at a speed of 0 to 5 rpm to dry the pellets at room temperature for 2 hours to obtain dried coated pellets having an inner active coating layer, the inner active coating layer having an active ingredient. If necessary, the dried pellets can be sieved and unwanted particle sizes, powders and aggregates can be discarded.

[0570] - External modified release coating

[0571] The coated active pellets obtained in the previous step were transferred to a coating pan. Then, the rotation was started, and the rotation speed of the coating pan was maintained at 20 rpm during this coating step, and the negative pressure inside the coating pan was <100 Pa, while the coating solution phase 4 was sprayed discontinuously, repeating a cycle with the following sequence:

[0572] - 18 seconds of spraying of the adhesive solution phase 4, the spraying flow rate is 40 g / min, the spray gun pressure is about 1.4 bar, the open air pressure is about 1.6 bar

[0573] - 9 seconds to add talc (D90 < 250 μm), powder addition rate is 40 g / min

[0574] -20 second pause

[0575] - 0 seconds drying time (no drying).

[0576] The core temperature of the pellets was maintained at 23°C to 28°C. 3 / h of air flow and rotating the obtained coated pellets in a coating pan at a speed of 0 to 5 rpm to dry the pellets at 40 to 45°C for 12 hours to obtain dried coated pellets having an inner active coating layer, wherein the inner active coating layer has an active ingredient with a yield of ≥93%.

[0577] The resulting pellets have the target dissolution profile. If necessary, the dried pellets can be sieved and unwanted particle sizes, powders and aggregates discarded.

[0578] The obtained modified-release micropellets of doxylamine succinate were stored in 25 kg closed double-layer food and pharmaceutical grade polyethylene bags in closed high-density polyethylene drums.

[0579] - External modified release coating

[0580] Phase 4 was sprayed onto the coated active pellets obtained in the previous step at a flow rate of 100 g / min. While spraying the solution phase 4, talc was applied in solid form at a solid addition rate of 50 g / min, a rotation speed of 16 rpm, maintaining the core temperature of the pellets at 17°C to 22°C, and an air flow of less than 100 m 3 / h. By using>130m 3 / h of air flow and rotating the resulting coated pellets in a coating pan at a speed of 0 to 10 rpm to dry the pellets at 40 to 45°C for not less than 8 hours and up to 12 hours (yield equal to or greater than 93%).

[0581] The resulting pellets have the target dissolution profile. If necessary, the dried pellets can be sieved and unwanted particle sizes, powders and aggregates discarded.

[0582] The obtained modified-release micropellets of pyridoxine hydrochloride were stored in 50 kg sealed double-layer food and pharmaceutical grade polyethylene bags in sealed high-density polyethylene drums.

[0583] Using the above-mentioned procedure for preparing the plurality of first and second modified release pellets of the present invention, the particle size of the resulting doxylamine succinate pellets is such that at least 90% of the pellets have a particle size of 710 μm to 1400 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 100 μm in a given value of 850 μm to 1250 μm as measured by analytical sieving, and the particle size of the resulting pyridoxine hydrochloride pellets is such that at least 90% of the pellets have a particle size of 710 μm to 1400 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 100 μm in a given value of 850 μm to 1250 μm as measured by analytical sieving.

[0584] The same procedure mentioned above for preparing the first and second plurality of modified release pellets of the present invention can be carried out using an inert core (sugar spheres of sucrose and starch) having a particle size such that at least 90% of the inert core has a particle size of 710 μm to 1000 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert core has a particle size variability of no more than 75 μm in a given value of 800 μm to 900 μm as measured by analytical sieving. In this case, the particle size of the obtained doxylamine succinate micropellets is such that at least 90% of the micropellets have a particle size of 800 μm to 1400 μm as measured by analytical sieving, and at least 90% of the micropellets have a particle size variability of no more than 75 μm in a given value of 900 μm to 1180 μm as measured by analytical sieving, and the particle size of the obtained pyridoxine hydrochloride micropellets is such that at least 90% of the micropellets have a particle size of 800 μm to 1400 μm as measured by analytical sieving, and at least 90% of the micropellets have a particle size variability of no more than 75 μm in a given value of 900 μm to 1180 μm as measured by analytical sieving.

[0585] Capsule filling

[0586] 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 present invention as defined above were filled into each hard capsule 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.

[0587] The same procedure mentioned above for preparing capsules with about 10 mg of doxylamine succinate and about 10 mg of pyridoxine hydrochloride can be carried out by filling 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 present invention as defined above using a Bosch Zanassi E48 automatic capsule filling machine to obtain capsules containing about 20 mg of doxylamine succinate and about 20 mg of pyridoxine hydrochloride.

[0588] 2. Dissolution test

[0589] Dissolution curve

[0590] The target dissolution profile requires that both doxylamine succinate and pyridoxine hydrochloride are slightly soluble under gastric conditions and reach a major therapeutic concentration in the intestine due to their rapid dissolution rates. In particular, the preparation method of the present invention enables the acquisition of capsules filled with such modified-release pellets of doxylamine succinate and modified-release pellets of pyridoxine hydrochloride, which exhibit a dissolution profile according to which:

[0591] 5% to 35% doxylamine content by weight was dissolved in 0.1N HCl medium (pH=1) at the first hour;

[0592] Then, the medium was replaced with pH = 4.5 medium (0.05 M acetate buffer), and cumulatively greater than 35% to 75% of the initial content of doxylamine by weight was dissolved at 4 hours;

[0593] Then, the medium was replaced with pH=6.8 medium (0.05 M phosphate buffer), and at least more than 75% of the initial doxylamine content accumulated was dissolved at 7 hours;

[0594] 5% to 35% by weight of pyridoxine content dissolved in 0.1N HCl medium (pH=1) at the first hour;

[0595] Then, the medium was replaced with pH = 4.5 medium (0.05 M acetate buffer), and cumulatively greater than 35% to 75% by weight of the initial content of pyridoxine was dissolved at 4 hours;

[0596] Then, the medium was replaced with pH=6.8 medium (0.05 M phosphate buffer), and at least more than 75% of the initial pyridoxine content accumulated was dissolved at 7 hours;

[0597] Wherein the dissolution profile was measured using USP Type II apparatus (basket), the composition was placed in 900 mL of the respective medium / buffered at 37°C ± 0.5°C, 100 rpm.

[0598] Conditions of the dissolution bath

[0599] - Paddle speed: 100rpm

[0600] - Temperature of dissolution medium: 37℃±0.5℃

[0601] -Dissolution medium: hydrochloric acid 0.1N

[0602] -Container volume: 900mL

[0603] - Duration: 1 hour

[0604] -Dissolution medium: pH 4.5; 0.05M acetate buffer

[0605] -Container volume: 900mL

[0606] - Time: From 1st hour to 4th hour

[0607] -Dissolution medium: pH 6.8; 0.05M phosphate buffer

[0608] -Container volume: 900mL

[0609] - Time: From the 4th hour to the 7th hour

[0610] Chromatographic analysis conditions

[0611] - Sample preparation: Take an aliquot of about 10 ml and filter it through a 0.70 μm filter and then through another 0.22 μm filter.

[0612] -Flow rate: 1mL / min

[0613] - Column: Kromasil 100-5C18, 150 x 4.0 mm

[0614] -Phase: methanol in water

[0615] -Injection volume: 100 μL

[0616] -Excitation wavelength: 220nm

[0617] - Chromatography time: 25 minutes

[0618] - Aqueous phase: ammonium acetate buffer 0.06M pH 5.0 + 0.1% sodium hexanesulfonate (PICB6):

[0619] -gradient:

[0620]

[0621] result

[0622] The capsules of the present invention as defined above and below containing micropellets of doxylamine succinate and pyridoxine hydrochloride show a target dissolution profile. Thus, when the capsules are applied to gastric conditions, the dissolution of doxylamine succinate and pyridoxine hydrochloride is at least 5% of the total amount in 1 hour, when the capsules are applied to duodenal conditions (pH = 4.5), at least 35% of doxylamine succinate and pyridoxine hydrochloride are dissolved after 4 hours, and when the capsules are applied to colonic conditions, at least 75% of doxylamine succinate and pyridoxine hydrochloride are dissolved after 7 hours.

[0623] Packaging and stability testing

[0624] Blister:

[0625] - The capsules of the pellets of doxylamine succinate and pyridoxine hydrochloride of Examples 1.1.1 to 1.1.10 of the present invention are stable and can be stored at 25°C or below and 60% relative humidity when the primary packaging is in blisters made of PVC / PVdC (on one side of the blister) and aluminum (on the other side of the blister).

[0626] - When the primary packaging is The capsules of the micropellets of doxylamine succinate and pyridoxine hydrochloride of Examples 1.1.2, 1.1.4, 1.1.6, 1.1.8 and 1.1.10 of the present invention are stable and can be stored at 30° C. or below and 75% relative humidity when in blisters made of aluminum (on one side of the blister) and aluminum (on the other side of the blister).

[0627] bottle:

[0628] - When the primary packaging is in a plastic bottle (containing a desiccant), the capsules of the micropellets of doxylamine succinate and pyridoxine hydrochloride of Examples 1.1.1 to 1.1.10 of the present invention are stable and can be stored at 30°C or below and 75% relative humidity.

[0629] For reasons of completeness, various aspects of the invention are listed in the following numbered clauses:

[0630] Clause 1. A modified release multiple unit oral dosage form comprising:

[0631] A plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, comprising:

[0632] - a pharmaceutically acceptable inert core;

[0633] - an inner active coating layer comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more coating agents, one or more anti-caking agents, optionally one or more pore-forming agents; and optionally one or more pharmaceutically acceptable excipients;

[0634] - optionally an intermediate enteric release coating layer comprising one or more enteric coating agents, one or more anti-caking agents, optionally one or more pore formers; and optionally one or more pharmaceutically acceptable excipients, and

[0635] - an outer modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, one or more anti-caking agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients; and

[0636] A plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, comprising:

[0637] - a pharmaceutically acceptable inert core;

[0638] - an inner active coating layer comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, one or more coating agents and optionally one or more pharmaceutically acceptable excipients; and

[0639] - an outer modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients;

[0640] in:

[0641] The particle size of the pharmaceutically acceptable inert core is such that at least 90% of the inert cores have a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert cores have a particle size variability of 200 μm, particularly a particle size variability of 150 μm, particularly a particle size variability of 100 μm, particularly a particle size variability of 75 μm, and particularly a particle size variability of 50 μm as measured by analytical sieving.

[0642] Clause 2. The modified release multiple unit oral dosage form according to clause 1, comprising:

[0643] A plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, comprising:

[0644] - a pharmaceutically acceptable inert core;

[0645] - an inner active coating layer comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more coating agents, one or more anti-caking agents, optionally one or more pore forming agents; and optionally one or more pharmaceutically acceptable excipients;

[0646] - an intermediate enteric release coating layer comprising one or more enteric coating agents, one or more anti-caking agents, optionally one or more pore formers; and optionally one or more pharmaceutically acceptable excipients, and

[0647] - an outer modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, one or more anti-caking agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients; and

[0648] A plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, comprising:

[0649] - a pharmaceutically acceptable inert core;

[0650] - an inner active coating layer comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, one or more coating agents and optionally one or more pharmaceutically acceptable excipients; and

[0651] - an outer modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients;

[0652] in:

[0653] The particle size of the pharmaceutically acceptable inert core is such that at least 90% of the inert cores have a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert cores have a particle size variability of 200 μm, particularly a particle size variability of 150 μm, particularly a particle size variability of 100 μm, particularly a particle size variability of 75 μm, and particularly a particle size variability of 50 μm as measured by analytical sieving.

[0654] Clause 3. The modified release multiple unit oral dosage form according to any one of clauses 1 or 2, wherein:

[0655] The dosage form comprises a pharmaceutically acceptable inert core having a particle size such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert core has a particle size variability of 200 μm, particularly a particle size variability of 150 μm, particularly a particle size variability of 100 μm, particularly a particle size variability of 75 μm, and more particularly a particle size variability of 50 μm as measured by analytical sieving;

[0656] In particular, the dosage form comprises a pharmaceutically acceptable inert core having a particle size such that at least 90% of the inert cores have a particle size of 300 μm to 1400 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variability of 200 μm, in particular a particle size variability of 150 μm, in particular a particle size variability of 100 μm, in particular a particle size variability of 75 μm, and more in particular a particle size variability of 50 μm as measured by analytical sieving;

[0657] In particular, the dosage form comprises a pharmaceutically acceptable inert core having a particle size such that at least 90% of the inert core has a particle size of 600 μm to 1180 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert core has a particle size variability of 150 μm, in particular a particle size variability of 100 μm, in particular a particle size variability of 75 μm, and more in particular a particle size variability of 50 μm as measured by analytical sieving;

[0658] In particular, the dosage form comprises a pharmaceutically acceptable inert core having a particle size such that at least 90% of the inert core has a particle size of 710 μm to 1000 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert core has a particle size variability of 100 μm, in particular a particle size variability of 75 μm, and more particularly a particle size variability of 50 μm as measured by analytical sieving;

[0659] In particular, the dosage form comprises a pharmaceutically acceptable inert core having a particle size such that at least 90% of the inert core has a particle size of 710 μm to 850 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert core has a particle size variability of 70 μm as measured by analytical sieving, and in particular a particle size variability of 50 μm;

[0660] In particular, the dosage form comprises a pharmaceutically acceptable inert core having a particle size such that at least 90% of the inert core has a particle size of 850 μm to 1000 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert core has a particle size variability of 70 μm as measured by analytical sieving, and in particular a particle size variability of 50 μm.

[0661] Clause 4. The modified release multiple unit oral dosage form according to any one of clauses 1 to 3, wherein:

[0662] a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof having a pellet size such that at least 90% of the pellets have a particle size of 400 μm to 1900 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of 200 μm, particularly a particle size variability of 150 μm, particularly a particle size variability of 100 μm, particularly a particle size variability of 75 μm, and more particularly a particle size variability of 50 μm as measured by analytical sieving;

[0663] and

[0664] The pellet size of the plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size of 400 μm to 1900 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of 200 μm, particularly a particle size variability of 150 μm, particularly a particle size variability of 100 μm, particularly a particle size variability of 75 μm, and more particularly a particle size variability of 50 μm as measured by analytical sieving.

[0665] Clause 5. The modified release multiple unit oral dosage form according to any one of clauses 1 to 4, wherein:

[0666] The particle size of doxylamine or a pharmaceutically acceptable salt thereof is characterized by having a D90 equal to or less than 250 μm; and the particle size of pyridoxine or a pharmaceutically acceptable salt thereof is characterized by having a D90 equal to or less than 250 μm;

[0667] Or alternatively,

[0668] The particle size of doxylamine or a pharmaceutically acceptable salt thereof is characterized by having a D90 equal to or less than 250 μm; and the particle size of pyridoxine or a pharmaceutically acceptable salt thereof is characterized by having a D90 equal to or less than 250 μm; the particle size of the one or more anti-caking agents is characterized by having a D90 equal to or less than 250 μm; and optionally, the particle size of the one or more pore forming agents is characterized by having a D90 equal to or less than 250 μm.

[0669] Clause 6. The modified release multiple unit oral dosage form according to any one of clauses 1 to 5, comprising a pharmaceutically acceptable salt of doxylamine and a pharmaceutically acceptable salt of pyridoxine; preferably comprising doxylamine succinate and pyridoxine hydrochloride.

[0670] Clause 7. The modified release multiple unit oral dosage form according to any one of clauses 1 to 6, comprising 5 mg to 50 mg of doxylamine or a pharmaceutically acceptable salt thereof per oral dosage form, and 5 mg to 50 mg of pyridoxine or a pharmaceutically acceptable salt thereof per oral dosage form.

[0671] Clause 8. A modified release multiple unit oral dosage form according to any one of clauses 1 to 7,

[0672] wherein the modified release multiple unit oral dosage form exhibits a dissolution profile according to which:

[0673] 5% to 35% doxylamine content by weight was dissolved in 0.1N HCl medium (pH=1) at the first hour;

[0674] Then, the medium was replaced with pH = 4.5 medium (0.05 M acetate buffer), and cumulatively greater than 35% to 75% of the initial content of doxylamine by weight was dissolved at 4 hours;

[0675] Then, the medium was replaced with a pH=6.8 medium (0.05 M phosphate buffer), and at least more than 75% of the initial content of doxylamine by weight was dissolved at 7 hours; and

[0676] 5% to 35% by weight of pyridoxine content dissolved in 0.1N HCl medium (pH=1) at the first hour;

[0677] Then, the medium was replaced with pH = 4.5 medium (0.05 M acetate buffer), and cumulatively greater than 35% to 75% by weight of the initial content of pyridoxine was dissolved at 4 hours;

[0678] Then, the medium was replaced with a pH=6.8 medium (0.05 M phosphate buffer), and at least more than 75% of the initial pyridoxine content by weight was dissolved at the 7th hour;

[0679] Wherein the dissolution profile was measured using a USP Type 2 apparatus (basket), the composition was placed in 900 mL of the respective medium / buffered at 37°C ± 0.5°C, 100 rpm.

[0680] Item 9. The modified release multiple unit oral dosage form according to any one of items 1 to 8 which is a capsule, in particular a hard capsule.

[0681] Clause 10. A process for preparing a modified release multiple unit oral dosage form as defined in any one of clauses 1 to 9, comprising:

[0682] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and optionally an intermediate enteric coating layer with one or more enteric coating agents, one or more modified-release coating agents, one or more anti-caking 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 core is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert core has a particle size variability of 200 μm, particularly 150 μm, particularly 100 μm, particularly 75 μm, and particularly 50 μm as measured by analytical sieving;

[0683] and

[0684] (b1) preparing a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable salt thereof having an inner active coating layer with one or more enteric coating agents, one or more modified release coating agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert core is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert core has a particle size variability of 200 μm, particularly 150 μm, particularly 100 μm, particularly 75 μm, and particularly 50 μm as measured by analytical sieving.

[0685] Clause 11. The method according to clause 10, wherein the method comprises:

[0686] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating the pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and optionally an intermediate enteric coating layer with 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 continuously or discontinuously; and

[0687] (b1) preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable salt thereof having an inner active coating layer with 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;

[0688] Or alternatively,

[0689] (a1) coating the doxylamine or pharmaceutically acceptable salt thereof pellets having an inner active coating layer and optionally an 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 simultaneously or alternately adding a mixture in powder form comprising one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients to prepare a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof; and

[0690] (b1) coating the pellets of pyridoxine or a pharmaceutically acceptable salt thereof having an 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 simultaneously or alternately adding a mixture in powder form comprising one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients to prepare a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof.

[0691] Clause 12. The method according to clause 11, comprising:

[0692] (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating the pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and optionally an intermediate enteric coating layer with one or more enteric coating agents, one or more modified-release coating agents, one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein the sum of the enteric coating agent and the modified-release coating agent in the spraying liquid mixture is 10% to 49% by weight relative to the weight of the liquid mixture; and

[0693] (b1) preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable salt thereof having an inner active coating layer with one or more enteric coating agents, one or more modified-release coating agents, one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein the sum of the enteric coating agent and the modified-release coating agent in the spraying liquid mixture is 10 to 49% by weight relative to the weight of the liquid mixture.

[0694] Clause 13. A method according to any one of clauses 11 or 12, wherein the method comprises:

[0695] (a1) coating the doxylamine or pharmaceutically acceptable salt thereof pellets having an inner active coating layer and optionally an intermediate enteric coating layer with a liquid mixture comprising 1.0 to 7.5% by weight of one or more enteric coating agents, 10.0 to 35.0% by weight of one or more modified release coating agents in a weight ratio of 5:95 to 30:70, and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a mixture in powder form comprising one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients to prepare a plurality of first modified-release pellets of doxylamine or pharmaceutically acceptable salt thereof,

[0696] wherein: the average spraying flow rate of the mixture comprising the coating is 0.30 to 5.00 g / min per kg of the pharmaceutically acceptable inert core; the average solid addition rate of the mixture in solid form is 0.05 to 1.50 g / min per kg of the pharmaceutically acceptable inert core; and the relationship between the average spraying flow rate of the mixture comprising the coating agent and the average solid addition rate of the mixture in solid form is 90:10 to 60:40, in particular 90:10 to 70:30; and

[0697] (b1) coating the pellets of pyridoxine or a pharmaceutically acceptable salt thereof having an inner active coating layer with a liquid mixture comprising 1.0 to 7.5% by weight of one or more enteric coating agents, 10.0 to 35.0% by weight of one or more modified release coating agents in a weight ratio of 5:95 to 30:70, and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a mixture in powder form comprising one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients to prepare a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof,

[0698] wherein: the average spraying flow rate of the mixture comprising the coating agent is 0.30 to 5.00 g / min per kg of the pharmaceutically acceptable inert core; the average solid addition rate of the mixture in solid form is 0.10 to 2.25 g / min per kg of the pharmaceutically acceptable inert core; and the relationship between the average spraying flow rate of the mixture comprising the coating agent and the average solid addition rate of the mixture in solid form is 90:10 to 60:40, in particular 80:20 to 60:40.

[0699] Clause 14. The method according to any one of clauses 10 to 13, wherein the method further comprises a separate preceding step of:

[0700] Optionally (a2) coating the pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients; and

[0701] (b2) coating a pharmaceutically acceptable inert core by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients;

[0702] Or alternatively,

[0703] Optionally (a2) coating the micropellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a mixture of a solid form comprising one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients; and

[0704] (b2) coating a pharmaceutically acceptable inert core 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 a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof in powder form and optionally one or more pharmaceutically acceptable excipients.

[0705] Clause 15. The method according to clause 14, wherein the method comprises:

[0706] Optionally (a2) coating the pellets of doxylamine or its pharmaceutically acceptable salt having an inner active coating layer by continuously or discontinuously spraying a liquid mixture containing 5 to 15% by weight of one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding 5.0 to 6.5 g of a mixture in powder form containing one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients per kg of a pharmaceutically acceptable inert core of the mixture in solid form; wherein: the average spraying flow rate of the mixture containing the enteric coating agent is 0.30 to 3.00 g / min per kg of the pharmaceutically acceptable inert core, the average solid addition rate of the mixture in solid form is 0.025 to 0.400 g / min per kg of the pharmaceutically acceptable inert core, and the relationship between the average spraying flow rate of the mixture containing the coating agent and the average solid addition rate of the mixture in solid form is 85:15 to 95:5; and

[0707] (b2) coating a pharmaceutically acceptable inert core by simultaneously or alternately spraying a liquid mixture containing 20% ​​to 45% by weight of one or more coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof in powder form and optionally one or more pharmaceutically acceptable excipients; wherein: the average spraying flow rate of the mixture containing the coating agent is 0.30 to 4.50 g / min per Kg of pharmaceutically acceptable inert core, the average solid addition rate of the powder is 0.50 to 9.00 g / min per Kg of pharmaceutically acceptable inert core, and the relationship between the average spraying flow rate of the mixture containing the coating agent and the average solid addition rate is 25:75 to 40:60.

[0708] Clause 16. The method according to any one of clauses 14 or 15, wherein the method further comprises an additional step, the additional step comprising:

[0709] (a3) coating a pharmaceutically acceptable inert core by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients;

[0710] Or alternatively,

[0711] (a3) coating a pharmaceutically acceptable inert core 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 a mixture in powder form comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients.

[0712] Clause 17. The method according to clause 16, wherein the method comprises:

[0713] (a3) coating a pharmaceutically acceptable inert core by continuously or discontinuously spraying a liquid mixture comprising 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 a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, 18 to 36% by weight of one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients;

[0714] Wherein: the average spraying flow rate of the mixture containing the coating agent is 0.30 to 4.50 g / min per Kg of pharmaceutically acceptable inert core; the average solid addition rate of the mixture in powder form is 0.95 to 18.00 g / min per Kg of pharmaceutically acceptable inert core; and the relationship between the average spraying flow rate of the mixture containing the coating agent and the average solid addition rate of the mixture in powder form is 15:85 to 30:70.

[0715] Item 18. A method according to any one of items 10 to 17, wherein in each spraying step (a1), (a2), (a3), (b1) and (b2), the liquid mixture is sprayed at a spray gun atomization pressure of 0.6 to 2.2 bar and an open air pressure of 0.6 to 2.5 bar.

[0716] Reference List

[0717] 1. WO2013123569

[0718] 2. WO2016029290

[0719] 3. European Pharmacopoeia Chapter 2.9.38

[0720] 4. European Pharmacopoeia Monograph on Doxylamine Hydrogen Succinate

[0721] 5. European Pharmacopoeia Monograph on Pyridoxine Hydrochloride

Claims

1. A modified release multiple unit oral dosage form comprising: A plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, comprising: - a pharmaceutically acceptable inert core; - an inner active coating layer comprising 5 mg to 50 mg of doxylamine or a pharmaceutically acceptable salt thereof per oral dosage form, one or more coating agents, one or more anti-caking agents, optionally one or more pore-forming agents; and optionally one or more pharmaceutically acceptable excipients; the coating agent is selected from polyvinylpyrrolidone, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, microcrystalline cellulose and mixtures thereof; the anti-caking agent is selected from talc, silicon dioxide and mixtures thereof; the pore-forming agent is selected from talc, micronized sugar, sodium chloride or potassium chloride and mixtures thereof; the inner active coating layer comprises 6 to 20% by weight of the coating agent relative to the total weight of the inner active coating layer, and 15 to 30% by weight of the anti-caking agent relative to the total weight of the inner active coating layer; - optionally an intermediate enteric-release coating layer comprising one or more enteric coating agents, one or more anti-caking agents, optionally one or more pore-forming agents; and optionally one or more pharmaceutically acceptable excipients, the enteric coating agent being selected from copolymers of methacrylic acid and methyl methacrylate, copolymers of methacrylic acid and methyl acrylate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate and mixtures thereof; the anti-caking agent being selected from talc, silicon dioxide and mixtures thereof; the pore-forming agent being selected from talc, micronized sugar, sodium chloride or potassium chloride and mixtures thereof; the intermediate enteric-release coating layer comprising 45 to 65% by weight of the enteric coating agent relative to the total weight of the intermediate enteric-release coating layer, and 35 to 55% by weight of the anti-caking agent relative to the total weight of the intermediate enteric-release coating layer, and - an outer modified release coating layer, which comprises one or more enteric coating agents, one or more modified release coating agents, one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients; the enteric coating agent is selected from the copolymer of methacrylic acid and methyl methacrylate, the copolymer of methacrylic acid and methyl acrylate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate and mixtures thereof; the modified release coating agent is selected from the copolymer of polyvinyl acetate phthalate, polyvinyl acetate phthalate, polyvinyl acetate trimellitate and mixtures thereof; vinylpyrrolidone, shellac and mixtures thereof; the anti-caking agent is selected from talc, silicon dioxide and mixtures thereof; the pore-forming agent is selected from talc, micronized sugar, sodium chloride or potassium chloride and mixtures thereof; the outer modified-release coating layer comprises 7 to 14% by weight of the enteric coating agent relative to the total weight of the outer modified-release coating layer, 38 to 46% by weight of the modified-release coating agent relative to the total weight of the outer modified-release coating layer, and 42 to 52% by weight of the anti-caking agent relative to the total weight of the outer modified-release coating layer; and A plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, comprising: - a pharmaceutically acceptable inert core; - an inner active coating layer comprising 5 mg to 50 mg of pyridoxine or a pharmaceutically acceptable salt thereof per oral dosage form, one or more coating agents and optionally one or more pharmaceutically acceptable excipients; the coating agent is selected from polyvinylpyrrolidone, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, microcrystalline cellulose and mixtures thereof; the inner active coating layer comprises 13 to 25% by weight of the coating agent relative to the total weight of the inner active coating layer; and - an outer modified release coating layer comprising one or more enteric coating agents, one or more modified release coating agents, optionally one or more pore formers and optionally one or more pharmaceutically acceptable excipients; the enteric coating agent is selected from the group consisting of copolymers of methacrylic acid and methyl methacrylate, copolymers of methacrylic acid and methyl acrylate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate and mixtures thereof; the modified release coating agent is selected from the group consisting of polyvinyl pyrrolidone, shellac and mixtures thereof; the pore former is selected from the group consisting of talc, micronized sugar, sodium chloride or potassium chloride and mixtures thereof; the outer modified release coating layer comprises 2 to 8% by weight of the enteric coating agent relative to the total weight of the outer modified release coating layer, and 30 to 49% by weight of the modified release coating agent relative to the total weight of the outer modified release coating layer; in: the particle size of the pharmaceutically acceptable inert core of the first and second plurality of pellets is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert core has a particle size variability of no more than 200 μm within a given value of 500 μm to 1400 μm as measured by analytical sieving; Herein, particle size variability means that from a given value, at least 90% of the pharmaceutically acceptable inert cores of the first and second plurality of micropellets have a particle size of ±200 μm of the given value.

2. The modified release multiple unit oral dosage form according to claim 1, wherein the first modified release pellets of the plurality of doxylamine or a pharmaceutically acceptable salt thereof comprise an intermediate enteric release coating layer, the intermediate enteric release coating layer comprising one or more enteric coating agents, one or more anti-caking agents, optionally one or more pore forming agents; and optionally one or more pharmaceutically acceptable excipients.

3. The modified release multiple unit oral dosage form of claim 1, wherein: The dosage form comprises a pharmaceutically acceptable inert core of a plurality of first and second micropellets, the particle size of the inert core being such that at least 90% of the inert core has a particle size of 300 μm to 1400 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert core has a particle size variability of no more than 150 μm in a given value of 450 μm to 1250 μm as measured by analytical sieving; wherein the particle size variability means that from a given value, at least 90% of the pharmaceutically acceptable inert core of the plurality of first and second micropellets has a particle size of ±150 μm of the given value.

4. The modified release multiple unit oral dosage form of claim 1, wherein: The plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof have a pellet size such that at least 90% of the pellets have a particle size of 400 μm to 2000 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 200 μm in a given value of 600 μm to 1800 μm as measured by analytical sieving; wherein the particle size variability means that from a given value, at least 90% of the plurality of first modified-release pellets have a particle size of ±200 μm of the given value; and The pellet particle size of the plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size of 400 μm to 2000 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variability of no more than 200 μm in a given value of 600 μm to 1800 μm as measured by analytical sieving; wherein the particle size variability means that from a given value, at least 90% of the plurality of second modified-release pellets have a particle size of ±200 μm of the given value.

5. The modified release multiple unit oral dosage form of claim 1, wherein: The particle size of doxylamine or a pharmaceutically acceptable salt thereof is characterized by having a D90 equal to or less than 250 μm; and the particle size of pyridoxine or a pharmaceutically acceptable salt thereof is characterized by having a D90 equal to or less than 250 μm; Or alternatively, doxylamine or a pharmaceutically acceptable salt thereof having a particle size characterized by having a D90 equal to or less than 250 μm; and pyridoxine or a pharmaceutically acceptable salt thereof having a particle size characterized by having a D90 equal to or less than 250 μm; the particle size of the one or more anti-caking agents having a particle size characterized by having a D90 equal to or less than 250 μm; in: The D90 of the particle size of doxylamine or a pharmaceutically acceptable salt thereof is expressed by volume; the D90 of the particle size of pyridoxine or a pharmaceutically acceptable salt thereof is expressed by volume; and the D90 of the particle size of the anti-caking agent is expressed by weight.

6. The modified release multiple unit oral dosage form of claim 1, comprising a pharmaceutically acceptable salt of doxylamine and a pharmaceutically acceptable salt of pyridoxine.

7. The modified release multiple unit oral dosage form of claim 6, comprising doxylamine succinate and pyridoxine hydrochloride.

8. The modified release multiple unit oral dosage form of claim 1, comprising: 10 mg to 20 mg of doxylamine or a pharmaceutically acceptable salt thereof per oral dosage form, and 10 mg to 20 mg of pyridoxine or a pharmaceutically acceptable salt thereof per oral dosage form.

9. The modified release multiple unit oral dosage form according to claim 1, wherein the modified release multiple unit oral dosage form exhibits a dissolution profile according to which: 5% to 35% doxylamine content by weight dissolved in 0.1N HCl medium pH=1 at hour 1; Then, the medium was replaced with pH = 4.5 medium 0.05 M acetate buffer, and cumulatively greater than 35% to 75% of the initial content of doxylamine by weight was dissolved at 4 hours; Then, the medium was replaced with a pH=6.8 medium 0.05 M phosphate buffer, and at least more than 75% of the initial doxylamine content by weight was dissolved at 7 hours; and 5% to 35% by weight of pyridoxine content dissolved in 0.1N HCl medium pH=1 at hour 1; Then, the medium was replaced with pH = 4.5 medium 0.05 M acetate buffer, and cumulatively greater than 35% to 75% by weight of the initial content of pyridoxine was dissolved at 4 hours; Then, the medium was replaced with a pH=6.8 medium 0.05 M phosphate buffer, and at least more than 75% of the initial pyridoxine content by weight was dissolved at the 7th hour; Wherein the dissolution profile was measured using USP Type 2 Apparatus Basket, the composition was placed in 900 mL of the respective medium / buffered at 37°C ± 0.5°C, 100 rpm.

10. The modified release multiple unit oral dosage form of claim 1 which is a capsule.

11. The modified release multiple unit oral dosage form of claim 10 which is a hard capsule.

12. The modified release multiple unit oral dosage form according to claim 11, which is a hard capsule selected from the group consisting of a hard gelatin capsule and a hard hydroxypropylmethylcellulose capsule.

13. A method for preparing a modified release multiple unit oral dosage form according to any one of claims 1 to 12, comprising: (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and optionally an intermediate enteric coating layer with one or more enteric coating agents, one or more modified-release coating agents, one or more anti-caking 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 core is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert core has a particle size variability of no more than 200 μm as measured by analytical sieving; and (b1) preparing a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable salt thereof having an inner active coating layer with one or more enteric coating agents, one or more modified release coating agents, optionally one or more pore formers, and optionally one or more pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert core is such that at least 90% of the inert core has a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the inert core has a particle size variability of no more than 200 μm as measured by analytical sieving; The method further comprises the separate preceding steps of: Optionally (a2) coating the pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients; and (b2) coating a pharmaceutically acceptable inert core by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients; Or alternatively, Optionally (a2) coating the micropellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a mixture of a solid form comprising one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients; and (b2) coating a pharmaceutically acceptable inert core 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 a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients in powder form; The method further comprises additional steps, the additional steps comprising: (a3) coating a pharmaceutically acceptable inert core by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents, a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients; Or alternatively, (a3) coating a pharmaceutically acceptable inert core 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 a mixture in powder form comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients.

14. The method according to claim 13, wherein the method comprises: (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating the pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and optionally an intermediate enteric coating layer with 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 continuously or discontinuously; and (b1) preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable salt thereof having an inner active coating layer with 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; Or alternatively, (a1) coating the doxylamine or pharmaceutically acceptable salt thereof pellets having an inner active coating layer and optionally an 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 simultaneously or alternately adding a mixture in powder form comprising one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients to prepare a plurality of first modified release pellets of doxylamine or pharmaceutically acceptable salt thereof; and (b1) coating the pellets of pyridoxine or a pharmaceutically acceptable salt thereof having an 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 simultaneously or alternately adding a mixture in powder form comprising one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients to prepare a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof.

15. The method according to claim 14, comprising: (a1) preparing a plurality of first modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating the pellets of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and optionally an intermediate enteric coating layer with one or more enteric coating agents, one or more modified-release coating agents, one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the sum of the enteric coating agent and the modified-release coating agent in the spraying liquid mixture is 10% to 49% by weight relative to the weight of the liquid mixture; and (b1) preparing a plurality of second modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating the pellets of pyridoxine or a pharmaceutically acceptable salt thereof having an inner active coating layer with one or more enteric coating agents, one or more modified-release coating agents, one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein: the sum of the enteric coating agent and the modified-release coating agent in the spraying liquid mixture is 10 to 49% by weight relative to the weight of the liquid mixture.

16. The method according to any one of claims 14 or 15, wherein the method comprises: (a1) coating the doxylamine or pharmaceutically acceptable salt thereof pellets having an inner active coating layer and optionally an intermediate enteric coating layer with a liquid mixture comprising 1.0 to 7.5% by weight of one or more enteric coating agents, 10.0 to 35.0% by weight of one or more modified release coating agents in a weight ratio of 5:95 to 30:70, and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a mixture in powder form comprising one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients to prepare a plurality of first modified-release pellets of doxylamine or pharmaceutically acceptable salt thereof, wherein: the average spraying flow rate of the mixture comprising the coating is 0.30 to 5.00 g / min per kg of the pharmaceutically acceptable inert core; the average solid addition rate of the mixture in solid form is 0.05 to 1.50 g / min per kg of the pharmaceutically acceptable inert core; and the relationship between the average spraying flow rate of the mixture comprising the coating agent and the average solid addition rate of the mixture in solid form is 90:10 to 60:40; and (b1) coating the pellets of pyridoxine or a pharmaceutically acceptable salt thereof having an inner active coating layer with a liquid mixture comprising 1.0 to 7.5% by weight of one or more enteric coating agents, 10.0 to 35.0% by weight of one or more modified release coating agents in a weight ratio of 5:95 to 30:70, and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a mixture in powder form comprising one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients to prepare a plurality of second modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein: the average spraying flow rate of the mixture comprising the coating agent is 0.30 to 5.00 g / min per kg of the pharmaceutically acceptable inert core; the average solid addition rate of the mixture in solid form is 0.10 to 2.25 g / min per kg of the pharmaceutically acceptable inert core; and the relationship between the average spraying flow rate of the mixture comprising the coating agent and the average solid addition rate of the mixture in solid form is 90:10 to 60:

40.

17. The method according to claim 13, wherein the method comprises: Optionally (a2) coating the pellets of doxylamine or its pharmaceutically acceptable salt having an inner active coating layer by continuously or discontinuously spraying a liquid mixture containing 5 to 15% by weight of one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding 5.0 to 6.5 g of a mixture in powder form containing one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients per kg of a pharmaceutically acceptable inert core of the mixture in solid form; wherein: the average spraying flow rate of the mixture containing the enteric coating agent is 0.30 to 3.00 g / min per kg of the pharmaceutically acceptable inert core; the average solid addition rate of the mixture in solid form is 0.025 to 0.400 g / min per Kg of the pharmaceutically acceptable inert core; and the relationship between the average spraying flow rate of the mixture containing the coating agent and the average solid addition rate of the mixture in solid form is 85:15 to 95:5; and (b2) coating a pharmaceutically acceptable inert core by simultaneously or alternately spraying a liquid mixture containing 20% ​​to 45% by weight of one or more coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof in powder form and optionally one or more pharmaceutically acceptable excipients; wherein: the average spraying flow rate of the mixture containing the coating agent is 0.30 to 4.50 g / min per Kg of pharmaceutically acceptable inert core; the average solid addition rate of the powder is 0.50 to 9.00 g / min per Kg of pharmaceutically acceptable inert core; and the relationship between the average spraying flow rate of the mixture containing the coating agent and the average solid addition rate is 25:75 to 40:

60.

18. The method according to claim 13, wherein the method comprises: (a3) coating a pharmaceutically acceptable inert core by continuously or discontinuously spraying a liquid mixture comprising 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 a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, 18 to 36% by weight of one or more anti-caking agents, optionally one or more pore-forming agents and optionally one or more pharmaceutically acceptable excipients; Wherein: the average spraying flow rate of the mixture containing the coating agent is 0.30 to 4.50 g / min per Kg of pharmaceutically acceptable inert core; the average solid addition rate of the mixture in powder form is 0.95 to 18.00 g / min per Kg of pharmaceutically acceptable inert core; and the relationship between the average spraying flow rate of the mixture containing the coating agent and the average solid addition rate of the mixture in powder form is 15:85 to 30:

70.

19. The method according to claim 13, wherein in each of the spraying steps (a1), (a2), (a3), (b1) and (b2), the liquid mixture is sprayed at a spray gun atomization pressure of 0.6 to 2.2 bar and an open air pressure of 0.6 to 2.5 bar.

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