Modified-release multiple-unit oral dosage forms of doxylamine succinate and pyridoxine hydrochloride, and methods for preparing same

Abstract

The present invention relates to a modified-release multiple-unit oral dosage form comprising: a first plurality of 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 second plurality of 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 cores of the first and second plurality of pellets is such that at least 90% of the inert cores have a particle size of 300 μm to 1700 μm as determined by analytical sieving, with a particle size variation of 200 μm or less as determined by analytical sieving. The present invention also relates to a process for its preparation and its use in therapy.

Description

[Technical Field]

[0001] This application claims the benefit of European Patent Application No. 20382227.5, filed March 25, 2020.

[0002] The present invention relates to modified-release multiple-unit oral dosage forms of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof and modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, and methods for preparing the same. [Background technology]

[0003] Doxylamine is the international nonproprietary name for (RS)-N,N-dimethyl-2-(1-phenyl-1-pyridin-2-yl-ethoxy)ethanamine, which has the CAS number 469-21-6. Doxylamine is a first-generation antihistamine that competitively, reversibly, and nonspecifically blocks H1 receptors. It is also a nonspecific antagonist that can block other receptors (e.g., central or peripheral muscarinic receptors) and has significant anticholinergic activity. Doxylamine is generally used in the form of a salt, specifically its succinate salt. (See European Pharmacopoeia 10.0. Doxylamine Hydrogen Succinate Monograph, pp. 2476-2477.) The structure of doxylamine corresponds to the following formula (I):

[0004] [ka]

[0005] Pyridoxine, also known as vitamin B6, is the international non-proprietary name for 4,5-bis(hydroxymethyl)-2-methylpyridin-3-ol, with a CAS number of 65-23-6. Pyridoxine is a water-soluble vitamin factor whose active form is pyridoxal phosphate. Pyridoxine acts as an enzyme cofactor in numerous biochemical reactions involved in the digestive breakdown of proteins and amino acids, and to a lesser extent, lipids and carbohydrates. Pyridoxine is also involved in the metabolism of unsaturated fatty acids and is a coenzyme for transaminases and decarboxylases that enable the conversion of tryptophan to nicotinic acid. Pyridoxine is commonly used in the form of a salt, specifically its hydrochloride salt. (See European Pharmacopoeia 10.0. Pyridoxine Hydrochloride Monograph, pp. 3676-3677.) The structure of pyridoxine corresponds to the following formula (II):

[0006] [ka]

[0007] Doxylamine is commonly used alone as a short-term sedative and in combination with other drugs to provide nighttime relief from allergies and colds. Doxylamine is also used in combination with the painkillers paracetamol (acetaminophen) and codeine in analgesic / sedative preparations, and is prescribed in combination with pyridoxine to prevent morning vomiting in pregnant women.

[0008] Modified release oral dosage forms of doxylamine succinate and pyridoxine hydrochloride with different pharmacokinetic and pharmacological properties have been disclosed in the state of the art.

[0009] The state of the art has disclosed several dual-release oral dosage forms of doxylamine succinate and pyridoxine hydrochloride, as well as their preparation methods.These dual-release oral dosage forms are formed by at least one immediate-release composition and at least one controlled-release composition, with each composition containing one or more active ingredients.This dosage system allows for the immediate release of one active ingredient and the controlled release of another active ingredient to be separately provided.(See International Publication WO2013 / 123569 and International Publication WO2016 / 029290).

[0010] Meanwhile, hard capsules filled with modified-release doxylamine succinate and pyridoxine hydrochloride pellets are commercially available under the name Cariban (INIBSA GINECOLOGIA: "SPC Cariban 10mg / 10mg modified-release capsules," Internet citation, March 1, 2016, available at the following URL: https: / / inibsa.com / wp-content / uploads / 2016 / 10 / En-spc-V1.pdf, retrieved 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 in pregnancy (NVP) that does not respond to traditional management. In particular, the effects of doxylamine and pyridoxine begin to be felt within 5 hours of ingestion, which is advantageous for prolonged therapeutic effects and reduced drug intake. In particular, the therapeutic effect of a multiple unit formulation is conditioned by the dissolution profile of the active ingredient from each one of the pellets and, in turn, by the uniformity between the pellets.

[0011] It is known in the state of the art that a lack of uniformity between pellets affects the dissolution profile of the active ingredient and also impairs the dosification and uniformity of these pellets in the final multiple unit oral dosage form. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] International Publication No. 2013 / 123569 [Patent Document 2] International Publication No. 2016 / 029290 [Non-patent literature]

[0013] [Non-Patent Document 1] European Pharmacopoeia Chapter 2.9.38 [Non-patent document 2] European Pharmacopoeia Monograph Doxylamine Hydrogen Succinate [Non-patent document 3] European Pharmacopoeia Pyridoxine Hydrochloride Monograph Summary of the Invention [Problem to be solved by the invention]

[0014] Therefore, from what is known in the art, it can be seen that there remains a need to provide a modified release multiple unit oral dosage form containing a plurality of uniform modified release pellets of both the active ingredients doxylamine and pyridoxine that exhibits an appropriate dissolution profile for use in therapy. [Means for solving the problem]

[0015] The inventors have discovered that the multiple unit oral dosage form of the present invention, which comprises a first plurality of modified-release pellets of the claimed doxylamine or a pharmaceutically acceptable salt thereof and a second plurality of modified-release pellets of the claimed pyridoxine or a pharmaceutically acceptable salt thereof, provides a modified release of both active ingredients for at least 8 hours after administration. The modified sustained release composition of the present invention is advantageous because it has the dual effect of providing a release immediately after administration and a prolonged release throughout the day, specifically the entire day after waking up.

[0016] Without being bound by any theory, the inventors have surprisingly found that by using pharmaceutically acceptable inert cores having a particle size of 300 μm to 1700 μm, and by having at least 90% of the pharmaceutically acceptable inert cores have a particle size variation of 200 μm or less, it is possible to obtain each of the first and second plurality of pellets having a predetermined particle size. This means that a high pellet-to-pellet uniformity of the active ingredient content is maintained without compromising the target dissolution profile. This also means that the variation in dissolution profile between different unit doses of the multiple-unit oral dosage form of the present invention is reduced. The use of the claimed pharmaceutically acceptable inert cores also means that the formation of agglomerates and / or powder mixtures is minimized.

[0017] In particular, the inventors have surprisingly observed the above-mentioned effects by using pharmaceutically acceptable inert cores having a particle size such that at least 90% of the inert cores have a particle size of 300 μm to 1700 μm, and by using pharmaceutically acceptable inert cores having a particle size such that at least 90% of the pharmaceutically acceptable inert cores have particle size variations of 150 μm or less, 100 μm or less, and 75 μm or less.

[0018] Furthermore, the high uniformity of particle size of both pellets (represented by the low particle size variation of the pharmaceutically inactive core) means that these pellets are easy to handle, allowing for high uniformity in dosing, and reducing dosing machine stuking and other problems associated with dosing (e.g., reducing the frequency of the need to readjust fill weights to within tolerances, resulting in fewer production interruptions). This means reduced machine occupancy and therefore lower costs for preparing multiple-unit dosage forms containing them.

[0019] As described above, the multiple-unit oral dosage form of the present invention includes two pellets having a high uniformity of active ingredient content. This means that each pellet has approximately the same amount of active ingredient, ensuring that the multiple-unit oral dosage form containing the 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 under- and overdosing of the active ingredients in the multiple-unit oral dosage form is minimized by using the process of the present invention.

[0020] Furthermore, the inventors have found that the process for preparing uniform batches of the multiple-unit oral dosage form of the present invention is cheaper, more robust, highly reproducible, and easier to scale up than state-of-the-art processes. Indeed, the method of the present invention makes it possible to obtain high-yield uniform batches of multiple pellets and multiple-unit oral dosage form formulations of both active ingredients without the need for intermediate sieving steps during the preparation processes of both multiple pellets to remove undesirable powdery materials and agglomerates, optionally minimizing yield losses in the final sieving step, or even carrying out the preparation processes of both multiple pellets without the need for any of these additional undesirable sieving steps. Finally, the inventors have found that this process makes it possible to prepare modified-release coatings of both multiple pellets of the present invention that exhibit target dissolution profiles.

[0021] Next, a first aspect of the present invention relates to a modified release multiple unit oral dosage form, the modified release multiple unit oral dosage form comprising: A first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, - a pharmaceutically acceptable inert nucleus, 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 anticoagulants, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; an intermediate enteric-release coating layer optionally 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; and 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-forming agents, and optionally one or more pharmaceutically acceptable excipients; a first plurality of modified release pellets comprising: a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, - a pharmaceutically acceptable inert nucleus, 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 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-forming agents, and optionally one or more pharmaceutically acceptable excipients; a second plurality of conditioning pellets, Including, The particle size of the pharmaceutically acceptable inert cores of the first and second pluralities of 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 at least 90% of the inert cores have a particle size variation of 200 μm or less, particularly 150 μm or less, particularly 100 μm or less, and particularly 75 μm or less as measured by analytical sieving.

[0022] Specifically, the present invention relates to a modified release multiple unit oral dosage form, the modified release multiple unit oral dosage form comprising: A first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, - a pharmaceutically acceptable inert nucleus, 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 anticoagulants, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; 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; and 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-forming agents, and optionally one or more pharmaceutically acceptable excipients; a first modified-release pellet comprising: a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, - a pharmaceutically acceptable inert nucleus, an inner active coating layer comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; 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-forming agents, and optionally one or more pharmaceutically acceptable excipients; a second plurality of modified release pellets comprising: Includes The particle size of the pharmaceutically acceptable inert cores of the first and second pluralities of 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 at least 90% of the inert cores have a particle size variation of 200 μm or less, particularly 150 μm or less, particularly 100 μm or less, and particularly 75 μm or less as measured by analytical sieving.

[0023] A second aspect of the present invention relates to a process for the preparation of a modified release multiple unit oral dosage form as defined in the first aspect of the present invention, the process comprising: (a1) preparing a first plurality of 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, by adding 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 cores is such that at least 90% of the inert cores have a particle size of between 300 μm and 1700 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variation of 200 μm or less, particularly 150 μm or less, particularly 100 μm or less, and particularly 75 μm or less, as measured by analytical sieving; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer by adding one or more enteric coating agents, one or more modified-release coating agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert cores 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 variation of 200 μm or less, particularly 150 μm or less, particularly 100 μm or less, and particularly 75 μm or less, as measured by analytical sieving. DETAILED DESCRIPTION OF THE INVENTION

[0024] All terms used herein in this application are to be understood in their ordinary meaning as known in the art, unless otherwise specified. Other, more specific definitions for certain terms used in this application are set forth below and are intended to be applied uniformly throughout the specification and claims, unless a definition expressly set forth elsewhere is given a broader definition.

[0025] For purposes of the present invention, any range given includes both the lower and upper endpoints of the range. Ranges and values ​​given, e.g., temperature and time, etc., are to be considered approximations unless specifically stated.

[0026] The terms "percentage by weight" or "percentage (% w / w)" have the same meaning and are used interchangeably. This term refers to the proportion of an ingredient by total weight.

[0027] As used herein, the term "about" or "around" refers to a range of values ​​of ±10% of a specified value. For example, the phrase "about 10" or "approximately 10" includes ±10% of 10, i.e., 9 to 11.

[0028] The terms "relationship" and "relationship" have the same meaning and are used interchangeably. This term is used in the present invention to refer to the relationship between the average spray flow rate of a mixture containing a coating agent and the average solids addition rate of a mixture in solid form.

[0029] 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 minitablets. They are usually delivered in hard gelatin capsules or converted into tablets.

[0030] As known in the state of the art, the term "administration" refers to the method of delivering a formulation to a desired site.The terms "oral" and "oral administration" have the same meaning and are used interchangeably.Specifically, it refers to taking a drug by swallowing or chewing.Preferably, by swallowing.

[0031] As disclosed above, the multiple-unit dosage form of the present invention contains two types of pellets. The term "pellets" refers to small particles having a substantially uniform shape and size, produced by extrusion or by coating a pharmaceutically acceptable inert core. "Small particles" refers to particles having a diameter, length, height, or width of 100 μm to 3000 μm, specifically 300 μm to 1700 μm. Small particles have a substantially uniform size if the diameter, length, height, or width of the smallest particle is at least about half the average diameter, length, height, or width of the particle, and if the diameter, length, height, or width of the largest particle is at most about twice the average diameter, length, height, or width of the particle. The terms "pellets," "spherical pellets," "beads," "beadlets," "spherical particles," "spheroids," and "microspheres" have the same meaning and are used interchangeably. The term "granules" refers to small particles obtained by a granulation process that do not have a substantially uniform shape or size. Generally, granules are not as uniform in size or shape as pellets. Granules are therefore less uniform due to their irregular surfaces, resulting in unacceptable dose uniformity and inadequate dissolution profiles. Therefore, for purposes of the present invention, the terms "pellets" and "granules" are not the same and are not interchangeable.

[0032] The terms "modified release" dosage form and "modified delivery dosage form," as well as "modified release" pellets and "modified delivery" pellets, have the same meaning and are interchangeable. Both terms should be understood as formulations or pellets that exhibit a slower release of an active agent than the release of a conventional immediate-release pharmaceutical composition administered by the same route. Generally, the term "modified release" refers to the release of an active ingredient from a pharmaceutical dosage form in a controlled, sustained, extended, or extended manner.

[0033] For purposes of the present invention, the term "modified release" refers to a multiple-unit oral dosage form that exhibits a dissolution profile according to the following: in 0.1N HCl medium (pH=1), 5% to 35% by weight of the doxylamine content is dissolved in 1 hour; then the medium is replaced with a medium of pH=4.5 (0.05M acetate buffer), and cumulatively, more than 35% to 75% by weight of the initial doxylamine content is dissolved in 4 hours; then the medium is replaced with a medium of pH=6.8 (0.05M phosphate buffer), and cumulatively, at least 75% by weight of the initial doxylamine content is dissolved in 7 hours; and In an HCl medium (pH=1), 5% to 35% by weight of the pyridoxine content is dissolved at 1 hour; then, the medium is replaced with a pH=4.5 medium (0.05M acetate buffer), and at 4 hours, more than 35% to 75% by weight of the initial pyridoxine content is dissolved cumulatively; then, the medium is replaced with a pH=6.8 medium (0.05M phosphate buffer), and at 7 hours, at least more than 75% by weight of the initial pyridoxine content is dissolved cumulatively, where the dissolution profile is measured using a suitable method. Generally, a suitable method is the USP method, for example, by using a USP Type 2 apparatus (basket) to place the composition in 900 mL of the corresponding medium / buffer at 37°C±0.5°C and 100 rpm (revolutions per minute), or by using a USP Type 3 apparatus (reciprocating cylinder) to place the composition in 250 mL of the corresponding solvent / medium at 37°C / 0.5°C and 15 dpm (dip per minute). In the present invention, the measurement of the dissolution profile of the multiple-unit oral dosage form is carried out by a USP Type 2 apparatus (basket) in which the composition is placed in 900 mL of the corresponding medium / buffer at 37°C ± 0.5°C and 100 rpm (revolutions per minute).

[0034] In one embodiment, the multiple-unit oral dosage form exhibits a dissolution profile according to the following: in 0.1N HCl medium (pH=1), 10% to 35% by weight of the doxylamine content is dissolved in 1 hour; then, the medium is replaced with a medium of pH=4.5 (0.05M acetate buffer), and 45% to 70% by weight of the initial doxylamine content is dissolved cumulatively in 4 hours; then, the medium is replaced with a medium of pH=6.8 (0.05M phosphate buffer), and 80% by weight of the initial doxylamine content is dissolved cumulatively in 7 hours; and In an HCl medium (pH=1), 10% to 35% by weight of the pyridoxine content is dissolved in 1 hour; then the medium is replaced with a medium of pH=4.5 (0.05 M acetate buffer), and 40% to 65% by weight of the initial pyridoxine content is dissolved cumulatively in 4 hours; then the medium is replaced with a medium of pH=6.8 (0.05 M phosphate buffer), and 7 hours later, at least 80% by weight of the initial pyridoxine content is dissolved cumulatively, wherein the dissolution profile is measured using an appropriate method.

[0035] In the context of the present invention, the terms "coating agent" and "film-forming coating agent" have the same meaning and are used interchangeably. Both terms should be understood as agents capable of forming a thin film on solid dosage forms or formulation intermediates such as tablets and pellets. Examples of each type of coating agent are disclosed below.

[0036] In one embodiment, the multiple unit oral dosage form of the present invention comprises a coating agent of the inner active coating layer of the first and second pluralities of pellets selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose, microcrystalline cellulose, calcium carbonate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, enzymatic hydrolyzate of carboxymethylcellulose sodium, cellaburate, cellacefate, cellulose acetate, cetyl alcohol, chitosan, coconut oil, hydrogenated, copovidone, corn syrup solids, ethylcellulose, methyl ... cellulose, ethylcellulose aqueous dispersion, ethylcellulose dispersion type B, ethylene glycol-vinyl alcohol graft copolymer, gelatin, pharmaceutical glaze, glucose solution, glyceryl behenate, glyceryl dibehenate, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, isomalt, α-lactalbumin, maltitol, maltodextrin, Eudragit® E, Eudragit® NE, Eudragit® NM, Eudragit® RL and Eudragit® RS, etc., Eudragit® (Rohm and mixtures thereof.In one embodiment, the multiple unit oral dosage form of the invention has an inner active coating layer of the first and second pluralities of pellets, wherein the coating agent is independently selected from the group consisting of polyvinylpyrrolidone, shellac, hypromellose, hydroxypropyl cellulose, microcrystalline cellulose, and mixtures thereof.

[0037] In particular, the term "modified-release coating" refers to a material capable of forming a thin film that allows a drug to be delivered at a predetermined rate and / or location over a period of time in response to the body's needs and disease. Illustrative, but non-limiting, examples of "modified-release polymers" and "delivery-modifying polymers" include polymers that provide controlled, sustained, extended, or prolonged release. Examples of modified-release coatings include, but are not limited to, acrylic polymers, cellulose and their derivatives, shellac, hydrogenated vegetable oil, hydrogenated castor oil, and mixtures thereof. Examples of suitable acrylic polymers include Eudragit® (Rohm Pharma;and methacrylic acid polymers and copolymers commercially available under the trade name of Benzyl Alcohol (Westerstadt, Germany). Examples of modified-release coating agents include, but are not limited to, alginic acid, carbomer copolymer, carbomer homopolymer, carbomer interpolymer, sodium carboxymethylcellulose, carrageenan, cerabrate, ethylcellulose, ethylcellulose aqueous dispersion, ethylcellulose dispersion type B, glyceryl monooleate, glyceryl monostearate, guar gum, hydroxypropyl betadex, hydroxypropyl cellulose, hypromellose, polyethylene oxide, shellac, sodium alginate, starch, pregelatinized, starch, pregelatinized modified, or xanthan gum. Preferably, the modified-release coating agent is shellac, particularly dewaxed shellac. Modified-release polymers include 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, glycerin, mannitol, polyethylene glycol, polyethylene glycol 3350, polyethylene glycol monoethyl ether, propylene glycol, pullulan, sorbitol, sorbitan sorbitan 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;Talc, magnesium stearate, glyceryl monostearate, behenoyl polyoxylglyceride, calcium stearate, hydrogenated castor oil, hydrogenated coconut oil, glyceryl behenate, glyceryl dibehenate, glyceryl mono- and dicaprylate, glyceryl mono- and dicaprylocaprate, glyceryl monocaprylate, glyceryl monocaprylocaprate, glyceryl monostearate, glyceryl tricaprylate, glyceryl tristearate, lauric acid, magnesium stearate, mineral oil (light), myristic acid, hydrogenated palm oil, palmitic acid, poloxamer, polyethylene glycol, polyethylene glycol 3350, polyoxyethylene 10 oleyl ether, polyoxyethylene 15 hydroxybenzoate Lubricants such as hydroxystearate, polyoxy 20 cetostearyl ether, polyoxy 35 castor oil, polyoxy 40 hydrogenated castor oil, polyoxy 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, hydrogenated vegetable oil type I, zinc stearate, and mixtures thereof may be used.

[0038] In one embodiment, the multiple unit oral dosage form of the invention is one in which the modified release coating is independently selected from the group consisting of polyvinylpyrrolidone and shellac, particularly polyvinylpyrrolidone and dewaxed shellac, and mixtures thereof.

[0039] The term "enteric-release" refers to a formulation composition or layer formulated to release an active ingredient when exposed to the characteristic conditions of the gastrointestinal tract. In one embodiment, the enteric material is pH-sensitive and is affected by changes in pH encountered in the gastrointestinal tract (pH-sensitive release). The enteric material typically remains insoluble at stomach pH, ​​allowing for subsequent release of the active ingredient in the higher pH environment of the downstream gastrointestinal tract (e.g., often the duodenum, or sometimes the colon). In another embodiment, the enteric material comprises an enzymatically degradable polymer that is degraded by bacterial enzymes present in the lower gastrointestinal tract, specifically the colon. Optionally, the unit dosage form is formulated with a pH-sensitive enteric material designed to provide release within a suitable number of hours at or above a specific pH. In various embodiments, the specific pH may 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" refers to a material capable of forming a film that allows delivery of doxylamine and pyridoxine when exposed to the characteristic conditions of the gastrointestinal tract, as defined above.Materials used in enteric-release dosage forms, for example as coatings, are well known in the art and include, but are not limited to, cellulose polymers such as hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and cellulose acetate trimellitate; cellulose polymers preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate, and / or ethyl methacrylate, and sold under the tradenames Acryl-EZE® (Colorcon, USA), Eudragit® (Rohm), including Eudragit® L30D-55 and L100-55 (soluble at pH 5.5 or above), Eudragit® L100 and L12.5 (soluble at pH 6.0 or above), Eudragit® S, S12.5, and FS30D (soluble at pH 7.0 or above as a result of a greater degree of esterification). Other methacrylic resins commercially available under the tradenames of Pharma, Westerstadt, Germany; vinyl polymers and copolymers formed from vinyl acetate, vinyl acetate phthalate, vinyl acetate-crotonic acid copolymer, and ethylene-vinyl acetate copolymer; enzymatically degradable polymers such as azopolymers; and zein. Combinations of different enteric materials may also be used. Multilayer coatings using different polymers may also be applied. The properties, manufacture, and design of enteric delivery systems are well known to those skilled in the art. In certain embodiments, 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, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate, and mixtures thereof. More specifically, it is Eudragit L®, e.g., Eudragit L100 (sold by Evonic).In one embodiment, the multiple-unit oral dosage form of the invention is one in which the enteric coating agents are independently selected from the group consisting of 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 https: / / en.wikipedia.org / wiki / Polyvinyl_acetate_phthalate In one embodiment, the multiple-unit oral dosage form of the invention is one in which the enteric coating agents are methacrylic acid-methyl methacrylate copolymer, particularly Eudragit L100.

[0040] As defined above, the multiple unit oral dosage form of the present invention comprises a first plurality of pellets comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, and a second plurality of pellets comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof.

[0041] The term "therapeutically effective amount," as used herein, refers to the amount of active ingredient per multiple unit dosage form that, when administered, is sufficient to prevent or alleviate to some extent one or more symptoms of the disease being treated. The specific dose of a compound administered according to the present invention will be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations.

[0042] As used herein, the term "pharmaceutically acceptable salts" includes any salt formed from a pharmaceutically acceptable non-toxic acid, including inorganic or organic acids. When used for therapeutic purposes, there are no limitations on the salt, except that it must be pharmaceutically acceptable. Because doxylamine and pyridoxine are basic compounds, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, among others, acetic 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. Pharmaceutically acceptable salts of doxylamine and pyridoxine can be prepared by methods known in the art. For example, they can be prepared from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts are prepared, for example, by reacting the acid or base-free forms of these compounds with a stoichiometric amount of an appropriate pharmaceutically acceptable base or acid in water or an organic solvent, or a mixture thereof. In one embodiment, a multiple-unit oral dosage form of the invention comprises a pharmaceutically acceptable salt of doxylamine and a pharmaceutically acceptable salt of pyridoxine. In one embodiment, a multiple-unit oral dosage form of the invention comprises doxylamine succinate and pyridoxine hydrochloride.

[0043] As described above, the particle size of the pharmaceutically acceptable inert cores of the first and second plurality of 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 at least 90% of the inert cores have a particle size variation of 200 μm or less, particularly 150 μm or less, particularly 100 μm or less, and particularly 75 μm or less as measured by analytical sieving. This means that the pharmaceutically acceptable inert cores of both plurality of pellets have particle size values ​​and particle size variation values ​​within the range of the present invention. This includes the fact that the particle size and particle size variation values ​​of the first plurality of pellets and the second plurality of pellets may be the same or different, and both fall within the scope of the present invention.

[0044] In one embodiment, the multiple-unit oral dosage form of the present invention comprises pharmaceutically acceptable inert cores having a particle size such that at least 90% of the inert cores have a particle size of 300 μm to 1700 μm as determined by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variation of 200 μm or less from a given value consisting of 500 μm and 1400 μm as determined by analytical sieving. In one embodiment, the multiple-unit oral dosage form of the present invention comprises pharmaceutically acceptable inert cores having a particle size such that at least 90% of the inert cores have a particle size of 300 μm to 1400 μm as determined by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variation of 150 μm or less from a given value consisting of 450 μm and 1250 μm as determined by analytical sieving. In one embodiment, the multiple-unit oral dosage form of the present invention comprises pharmaceutically acceptable inert cores having a particle size such that at least 90% of the inert cores have a particle size of 600 μm to 1180 μm as determined by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variation of 100 μm or less from a given value consisting of 710 μm and 1000 μm as determined by analytical sieving. In one embodiment, the multiple-unit oral dosage form of the present invention comprises pharmaceutically acceptable inert cores having a particle size such that at least 90% of the inert cores have a particle size of 710 μm to 1000 μm as determined by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variation of 75 μm or less from a given value consisting of 800 μm and 900 μm as determined by analytical sieving.

[0045] The term "inert core" refers to a neutral microsphere in the composition comprising at least one of the following substances: 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.

[0046] In one embodiment, the multiple-unit oral dosage form is such that the pellets in the first plurality of controlled-release pellets of doxylamine or a pharmaceutically acceptable salt thereof have a particle size distribution such that at least 90% of the pellets have a particle size distribution between 400 μm and 2000 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variation of no more than 200 μm from a given value consisting of 600 μm and 1800 μm as measured by analytical sieving. In one embodiment, the multiple-unit oral dosage form is such that the pellets in the first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof have a particle size distribution between 600 μm and 1600 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variation of no more than 150 μm from a given value consisting of 800 μm and 1400 μm as measured by analytical sieving. In one embodiment, the multiple-unit oral dosage form is such that the pellets of the first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof have a particle size distribution such that at least 90% of the pellets have a particle size distribution between 710 μm and 1400 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variation of no more than 100 μm from a given value consisting of 850 μm and 1250 μm as measured by analytical sieving. In one embodiment, the multiple-unit oral dosage form is such that the pellets of the first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof have a particle size distribution between 800 μm and 1400 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variation of no more than 75 μm from a given value consisting of 900 μm and 1180 μm as measured by analytical sieving.

[0047] In one embodiment, the multiple-unit oral dosage form is such that the pellets of the second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof have a particle size distribution such that at least 90% of the pellets have a particle size distribution between 400 μm and 2000 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variation of no more than 200 μm from a given value consisting of 600 μm and 1800 μm as measured by analytical sieving. In one embodiment, the multiple-unit oral dosage form is such that the pellets of the second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof have a particle size distribution between 600 μm and 1600 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variation of no more than 150 μm from a given value consisting of 800 μm and 1400 μm as measured by analytical sieving. In one embodiment, the multiple-unit oral dosage form is such that the pellets of the second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof have a particle size such that at least 90% of the pellets have a particle size between 710 μm and 1400 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variation of no more than 100 μm from a given value consisting of 850 μm and 1250 μm as measured by analytical sieving. In one embodiment, the multiple-unit oral dosage form is such that the pellets of the second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof have a particle size between 800 μm and 1400 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variation of no more than 75 μm from a given value consisting of 900 μm and 1180 μm as measured by analytical sieving.

[0048] In one embodiment, the multiple unit oral dosage form of the present invention comprises at least 90% of the inert cores having a particle size of 300 μm to 1700 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores having a particle size variation of 200 μm or less from a given value consisting of 500 μm and 1400 μm as measured by analytical sieving; and the particle size of the pellets of the first plurality of 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 variation of 200 μm or less from a given value consisting of 500 μm and 1400 μm as measured by analytical sieving. and a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the pellet size of the second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof has a particle size such that at least 90% of the pellets have a particle size between 400 μm and 2000 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variation of no more than 200 μm from a given value consisting of 600 μm and 1800 μm as measured by analytical sieving.

[0049] In one embodiment, the multiple unit oral dosage form of the present invention comprises at least 90% of the inert cores having a particle size of 300 μm to 1400 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores having a particle size variation of 150 μm or less from a given value consisting of 450 μm and 1250 μm as measured by analytical sieving; and the particle size of the pellets of the first plurality of 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 variation of 150 μm or less from a given value consisting of 450 μm and 1250 μm as measured by analytical sieving. the second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof has a particle size such that at least 90% of the pellets have a particle size between 600 μm and 1600 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variation of no more than 150 μm from a given value consisting of 800 μm and 1400 μm as measured by analytical sieving.

[0050] In one embodiment, the multiple unit oral dosage form of the present invention comprises at least 90% of the inert cores having a particle size of 600 μm to 1180 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores having a particle size variation of 100 μm or less from a given value consisting of 710 μm and 1000 μm as measured by analytical sieving; and the particle size of the pellets of the first plurality of 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 variation of 100 μm or less from a given value consisting of 710 μm and 1000 μm as measured by analytical sieving. the second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof has a particle size such that at least 90% of the pellets have a particle size between 710 μm and 1400 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variation of no more than 100 μm from a given value consisting of 850 μm and 1250 μm as measured by analytical sieving.

[0051] In one embodiment, the multiple unit oral dosage form of the present invention comprises at least 90% of the inert cores having a particle size of 710 μm to 1000 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores having a particle size variation of 75 μm or less from a given value consisting of 800 μm and 900 μm as measured by analytical sieving; and the particle size of the pellets of the first plurality of 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 variation of 75 μm or less from a given value consisting of 800 μm and 900 μm as measured by analytical sieving. the second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof has a particle size such that at least 90% of the pellets have a particle size between 800 μm and 1400 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variation of no more than 75 μm from a given value consisting of 900 μm and 1180 μm as measured by analytical sieving.

[0052] The particle size of the pharmaceutically acceptable inert core, pellets, active ingredient, and excipients can be measured by any method disclosed in the art. Examples of commonly used methods for measuring particle size include dynamic light scattering (DLS), which reports number-average diameter values, atomic force microscopy (AFM) or transmission electron microscopy (TEM) for measuring dried particles, laser diffraction (Laser Mastersizer, Mie theory; ISO 13320-1), and sedimentation analysis (Sedigraph-Stokes' law; ISO 13317-3) and analytical sieving. For the purposes of the present invention, the particle size of the pharmaceutically acceptable inert core as defined herein, and the first and second plurality of pellets, is preferably measured by analytical sieving, in particular as specified by the European Pharmacopoeia (see European Pharmacopoeia Chapter 2.9.38

[0053] The terms "variability" and "dispersion" have the same meaning and are used interchangeably. They refer to how spread out a data set is. Variability provides a way to describe how scattered a data set is. In particular, the term "particle size variation" refers to how spread out the particle sizes are for a given value.

[0054] The phrase "at least 90% of the (···) have a particle size between X and Y μm" means that 90% of the entire particle population have a particle size comprised of X and Y μm. For purposes of the present invention, the phrase "at least 90% of the pharmaceutically acceptable inert cores or pellets have a particle size variation of 200 μm or less" means that 90% of the population of pharmaceutically acceptable inert cores or pellets have a particle size that falls within ±200 μm of a given value. For example, for a given value of 500 μm, at least 90% of the population of pharmaceutically acceptable inert cores have a particle size between 300 μm and 700 μm (i.e., ±200 μm). The particle size variation of pharmaceutically acceptable inert cores or pellets can be measured by any method disclosed in the art. Examples of commonly used methods for measuring particle size variation include dynamic light scattering (DLS), which reports number average diameter values, atomic force microscopy (AFM) or transmission electron microscopy (TEM) for measuring dried particles, laser diffraction (Laser Mastersizer, Mie theory; ISO 13320-1), sedimentation analysis (Sedigraph-Stokes' law; ISO 13317-3), analytical sieving, and optical microscopy. For the purposes of this invention, particle size variation is defined as , minutes It is measured by analytical sieving.

[0055] In one embodiment, the multiple-unit oral dosage form is characterized in that the doxylamine or pharmaceutically acceptable salt thereof has a particle size D90 of 250 μm or less. In one embodiment, the multiple-unit oral dosage form is characterized in that the pyridoxine or pharmaceutically acceptable salt thereof has a particle size D90 of 250 μm or less. In one embodiment, the multiple-unit oral dosage form is characterized in that the doxylamine or pharmaceutically acceptable salt thereof has a particle size D90 of 250 μm or less and the pyridoxine or pharmaceutically acceptable salt thereof has a particle size D90 of 250 μm or less.

[0056] In one embodiment, the multiple-unit oral dosage form is characterized in that the particle size of one or more anti-caking agents has a D90 of 250 μm or less. In one embodiment, the multiple-unit oral dosage form is characterized in that the particle size of one or more optional pore-forming agents has a D90 of 250 μm or less.

[0057] The DX value indicates that a certain percentage of particles, X, have a weight / volume / number value below a certain limit. D90 indicates that 90% of the particles have a weight / volume / number value below a certain limit. D90 may be expressed by volume, weight, or number. For purposes of the present invention, the D90 of the active ingredients (doxylamine and pyridine) is expressed by volume. The D90 of an anticaking agent, such as talc, is expressed by weight. For example, a D90 value of 250 μm or less for doxylamine or pyridoxine means that 90% of the particles by volume have a diameter of 250 μm or less. A D90 value of 250 μm or less for talc means that 90% of the particles by weight have a diameter of 250 μm or less. DX (especially D90) can be measured using any suitable method (e.g., analytical sieving) disclosed above for measuring the particle size of the pharmaceutically acceptable inert cores, coated pellets, active ingredients, and excipients of the present invention. In particular, among the above-mentioned suitable methods, the MALVERN method (Laser Mastersizer, Mie theory; ISO 13320-1) is the 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.

[0058] In one embodiment, the multiple unit oral dosage form comprises a first plurality of pellets comprising a therapeutically effective amount of a pharmaceutically acceptable salt of doxylamine, particularly doxylamine succinate. In one embodiment, the multiple unit oral dosage form comprises a first plurality of pellets per multiple unit dosage form comprising 5 mg to 50 mg, particularly 6 mg to 40 mg, 7 mg to 30 mg, and more particularly 8 mg to 22 mg of doxylamine or a pharmaceutically acceptable salt thereof per oral dosage form. In one embodiment, the multiple unit oral dosage form comprises a first plurality of pellets per multiple unit dosage form comprising 5 mg to 50 mg, particularly 6 mg to 40 mg, 7 mg to 30 mg, and more particularly 8 mg to 22 mg of doxylamine succinate, and even more particularly 9 mg to 11 mg of doxylamine succinate per oral dosage form. In a more specific embodiment, the multiple unit oral dosage form includes a first plurality of pellets having 10 mg of doxylamine or a pharmaceutically acceptable salt thereof, particularly doxylamine succinate, per multiple unit dosage form. In another embodiment, the multiple unit oral dosage form includes a first plurality of pellets having 19 mg to 21 mg of doxylamine or a pharmaceutically acceptable salt thereof, particularly doxylamine succinate. In another more specific embodiment, the multiple unit oral dosage form includes a first plurality of pellets having 20 mg of doxylamine or a pharmaceutically acceptable salt thereof, particularly doxylamine succinate, per multiple unit dosage form.

[0059] In one embodiment, the multiple unit oral dosage form comprises a second plurality of pellets comprising a therapeutically effective amount of a pharmaceutically acceptable salt of pyridoxine, particularly pyridoxine hydrochloride. In one embodiment, the multiple unit oral dosage form comprises a second plurality of pellets comprising 5 mg to 50 mg, particularly 6 mg to 40 mg, particularly 7 mg to 30 mg, and more particularly 8 mg to 22 mg of pyridoxine or a pharmaceutically acceptable salt thereof per oral dosage form. In one embodiment, the multiple unit oral dosage form comprises a second plurality of pellets having 5 mg to 50 mg, particularly 6 mg to 40 mg, particularly 7 mg to 30 mg, more particularly 8 mg to 22 mg of pyridoxine hydrochloride, and even more particularly 9 mg to 11 mg of pyridoxine hydrochloride per oral dosage form. In a more specific embodiment, the multiple unit oral dosage form includes a second plurality of pellets having 10 mg of pyridoxine or a pharmaceutically acceptable salt thereof, particularly pyridoxine hydrochloride, per multiple unit dosage form. In another embodiment, the multiple unit oral dosage form includes a second plurality of pellets having 19 mg to 21 mg of pyridoxine or a pharmaceutically acceptable salt thereof, particularly pyridoxine hydrochloride, per multiple unit dosage form. In another more specific embodiment, the multiple unit oral dosage form includes a second plurality of pellets having 20 mg of pyridoxine or a pharmaceutically acceptable salt thereof, particularly pyridoxine hydrochloride, per multiple unit dosage form.

[0060] In one embodiment, the multiple unit oral dosage form comprises a first plurality of pellets comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, particularly doxylamine succinate, and a second plurality of pellets comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, particularly pyridoxine hydrochloride. In one embodiment, the multiple unit oral dosage form comprises a first plurality of pellets comprising 5 mg to 50 mg of doxylamine or a pharmaceutically acceptable salt thereof, particularly doxylamine succinate per multiple unit dosage form, particularly 10 mg or 20 mg of doxylamine or a pharmaceutically acceptable salt thereof, particularly doxylamine succinate per multiple unit dosage form, and a second plurality of pellets comprising 5 mg to 50 mg of pyridoxine or a pharmaceutically acceptable salt thereof, particularly pyridoxine hydrochloride per multiple unit dosage form, particularly 10 mg or 20 mg of pyridoxine or a pharmaceutically acceptable salt thereof, particularly pyridoxine hydrochloride per multiple unit dosage form. In certain embodiments, the multiple unit oral dosage form comprises a first plurality of pellets comprising 10 mg of doxylamine or a pharmaceutically acceptable salt thereof, particularly doxylamine succinate, per multiple unit dosage form, and a second plurality of pellets comprising 10 mg of pyridoxine or a pharmaceutically acceptable salt thereof, particularly pyridoxine hydrochloride, per multiple unit dosage form. In another specific embodiment, the multiple unit oral dosage form comprises a first plurality of pellets comprising 20 mg of doxylamine or a pharmaceutically acceptable salt thereof, particularly doxylamine succinate, per multiple unit dosage form, and a second plurality of pellets comprising 20 mg of pyridoxine or a pharmaceutically acceptable salt thereof, particularly pyridoxine hydrochloride, per multiple unit dosage form.

[0061] In one embodiment, the multiple unit dosage form comprises a first plurality of pellets comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, particularly doxylamine succinate, between 20 mg and 220 mg, hi one embodiment, the multiple unit dosage form comprises a first plurality of pellets comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, particularly doxylamine succinate, between 40 mg and 140 mg.

[0062] In one embodiment, the multiple unit dosage form comprises a first plurality of pellets comprising a therapeutically effective amount of about 60 mg of doxylamine or a pharmaceutically acceptable salt thereof, particularly doxylamine succinate.

[0063] In another embodiment, the multiple unit dosage form comprises a first plurality of pellets comprising a therapeutically effective amount of about 120 mg of doxylamine or a pharmaceutically acceptable salt thereof, particularly doxylamine succinate.

[0064] In one embodiment, the multiple unit dosage form comprises a second plurality of pellets comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, particularly pyridoxine hydrochloride, of 20 mg to 220 mg. In one embodiment, the multiple unit dosage form comprises a second plurality of pellets comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, particularly pyridoxine hydrochloride, of 40 to 140 mg. In one embodiment, the multiple unit dosage form comprises a second plurality of pellets comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, particularly pyridoxine hydrochloride, of about 60 mg. In another embodiment, the multiple unit dosage form comprises a second plurality of pellets comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, particularly pyridoxine hydrochloride, of about 120 mg.

[0065] In one embodiment, the multiple unit dosage form comprises a first plurality of pellets containing a therapeutically effective amount of 20 mg to 220 mg of doxylamine or a pharmaceutically acceptable salt thereof, particularly doxylamine succinate, and a second plurality of pellets containing a therapeutically effective amount of 20 mg to 220 mg of pyridoxine or a pharmaceutically acceptable salt thereof, particularly pyridoxine hydrochloride. In one embodiment, the multiple unit dosage form comprises a first plurality of pellets containing 40 mg to 140 mg, more particularly about 60 mg, containing 5 mg to 50 mg of doxylamine succinate, particularly 10 mg of doxylamine succinate, and a second plurality of pellets containing 40 mg to 140 mg, more particularly 60 mg, containing 5 mg to 50 mg of pyridoxine hydrochloride, particularly 10 mg of pyridoxine hydrochloride.

[0066] In another embodiment, the multiple unit dosage form comprises a first plurality of pellets of 40 mg to 140 mg, more specifically about 120 mg, containing 5 mg to 50 mg of doxylamine succinate, specifically 20 mg of doxylamine succinate, and a second plurality of pellets of 40 mg to 140 mg, more specifically 120 mg, containing 5 mg to 50 mg of pyridoxine hydrochloride, specifically 20 mg of pyridoxine hydrochloride.

[0067] In one embodiment, the multiple unit dosage form comprises a first plurality of pellets comprising 5 mg to 50 mg of doxylamine succinate, specifically 10 mg of doxylamine succinate, and a second plurality of pellets comprising 5 mg to 50 mg of pyridoxine hydrochloride, specifically 10 mg of pyridoxine hydrochloride. In a specific embodiment, the multiple unit dosage form comprises a first plurality of pellets comprising 10 mg of doxylamine succinate and a second plurality of pellets comprising 10 mg of pyridoxine hydrochloride.

[0068] In another embodiment, the multiple unit dosage form comprises a first plurality of pellets comprising 5 mg to 50 mg of doxylamine succinate, specifically 20 mg of doxylamine succinate, and a second plurality of pellets comprising 5 mg to 50 mg of pyridoxine hydrochloride, specifically 20 mg of pyridoxine hydrochloride. In a specific embodiment, the multiple unit dosage form comprises a first plurality of pellets comprising 20 mg of doxylamine succinate and a second plurality of pellets comprising 20 mg of pyridoxine hydrochloride.

[0069] The term "anticaking agent" refers to any pharmaceutically acceptable substance that can reduce the occurrence of surface tack and core or pellet sticking during coating, thereby improving process efficiency, coating uniformity, and appearance, preventing the formation of lumps (agglomerates), and facilitating packaging, shipping, flowability, filling into the final dosage form, and consumption. Examples of anticaking agents include, but are not limited to, calcium stearate, magnesium stearate, silica, silicates, talc, wheat flour, starch, tribasic calcium phosphate, calcium silicate, cellulose powder, magnesium oxide, magnesium silicate, magnesium trisilicate, dental silica, hydrophobic colloidal silica, colloidal silicon dioxide, sodium stearate, and mixtures thereof. In one embodiment, the multiple-unit dosage form contains one or more anticaking agents selected from the group consisting of talc and silica (colloidal silicon dioxide, particularly Aerosil), and mixtures thereof. In one embodiment, the multiple-unit dosage form contains talc as the anticaking agent. In one embodiment, a multiple unit dosage form comprises one or more anti-caking agents having a particle size distribution characterized by a D90 of 250 μm or less, specifically less than 150 μm, more specifically less than 100 μm. In one embodiment, a multiple unit dosage form comprises one or more anti-caking agents having a particle size distribution characterized by a D90 of 75 μm or less. In one embodiment, a multiple unit dosage form comprises talc as an anti-caking agent having a D90 particle diameter of less than 250 μm, specifically less than 150 μm, more specifically less than 100 μm. In one embodiment, a multiple unit dosage form comprises talc as an anti-caking agent having a D90 particle diameter of less than 75 μm.

[0070] The term "pore-forming agent" refers to any pharmaceutically acceptable substance capable of forming one or more pores in the shell / coating to allow for the controlled release of the active ingredient. The pore-forming agent can be organic or inorganic, or any combination thereof. Examples of pore-forming agents include, but are not limited to, polyethylene glycol (PEG), propylene glycol, isopropyl alcohol, glycerol, lactose, glucose, sucrose, mannitol, sorbitol, sodium chloride, potassium chloride, talc, hydroxypropyl cellulose, micronized sugar, hydroxypropylmethylcellulose (HPMC), polyvinyl alcohol, methacrylic acid copolymer, or a mixture thereof. In one embodiment, the pore-forming agent is selected from the group consisting of talc, micronized sugar, sodium chloride or potassium chloride, and a mixture thereof. As described above, the controlled-release multiple-unit oral dosage form of the present invention optionally comprises one or more pore-forming agents. In one embodiment, one or more pore-forming agents as defined above are present in the multiple-unit oral dosage form. In one embodiment, one or more pore-forming agents, as defined above, are not present in the multiple unit oral dosage form.

[0071] The term "pharmaceutically acceptable" refers to any composition, compound, or material suitable for use in pharmaceutical technology. For 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, as well as their amounts, can be easily determined by those skilled in the art according to the type of formulation to be prepared. In one embodiment, the modified-release multiple-unit dosage form of the present invention further comprises one or more binders, glidants, fillers, lubricants, wicking agents, and mixtures thereof. In one embodiment, the process comprises preparing a multiple-unit dosage form that can comprise one or more pharmaceutically acceptable excipients or carriers.

[0072] As noted above, the modified release multiple unit oral dosage forms of the present invention optionally include one or more pharmaceutically acceptable excipients or carriers. In one embodiment, the modified release multiple unit oral dosage form includes one or more pharmaceutically acceptable excipients or carriers.

[0073] In one embodiment, the multiple unit oral dosage form comprises one or more pore-forming agents as defined above and one or more pharmaceutically acceptable excipients or carriers.

[0074] The term " binder " refers to any pharmaceutically acceptable compound that has binding properties.The materials commonly used as binder include microcrystalline cellulose, polyvinylpyrrolidone (also called povidone or PVP), methylcellulose polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, L-hydroxypropyl cellulose (low-substituted), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose, carboxymethylene, carboxymethylhydroxyethyl cellulose and other cellulose derivatives, starch or modified starch, polyethylene glycol (PEG) 6000, guar gum, starch or shellac, and their mixtures. Examples of binders include acacia, agar, alginic acid, calcium carbonate, calcium lactate, sodium carboxymethylcellulose, cellulose, microcrystalline cellulose, copovidone, dextrates, dextrin, ethylcellulose, gelatin, glucose solution, glyceryl behenate, glyceryl dibehenate, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hypromellose, hypromellose acetate succinate, inulin, invert sugar, lactose monohydrate, maltodextrin, maltose, methylcellulose, hydrogenated polydextrose, polyethylene oxide, polyvinyl alcohol, and the like. These include: dimethicone (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 succinate, polyethylene glycol.

[0075] In one embodiment, the multiple unit oral dosage form is one in which the pharmaceutically acceptable excipient or carrier comprises one or more binders, preferably shellac and polyvinylpyrrolidone (PVP), and a more specific embodiment is dewaxed shellac and PVP-K30.

[0076] The term "glidant" refers to a pharmaceutically acceptable substance that improves the flow characteristics of a powder mixture in the dry state. Materials commonly used as glidants include magnesium stearate, silica (colloidal silicon dioxide, specifically Aerosil), or talc. In one embodiment, the multiple-unit dosage form is one in which the pharmaceutically acceptable excipient or carrier comprises one or more glidants, preferably colloidal silicon dioxide, and more preferably Aerosil 200 Pharma.

[0077] The term "lubricant" refers to a pharmaceutically acceptable substance that prevents composition components from clumping together and adhering to tablet punches or capsule filling machines, and improves the flowability of the composition mixture.The materials that are 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 behenoyl polyoxylglyceride, calcium stearate, hydrogenated castor oil, hydrogenated coconut oil, glyceryl behenate, glyceryl dibehenate, glyceryl mono- and dicaprylate, glyceryl mono- and dicaprylocaprate, glyceryl monocaprylate, glyceryl monocaprylocaprate, glyceryl monostearate, glyceryl tricaprylate, glyceryl tristearate, lauric acid, magnesium stearate, mineral oil (light), myristic acid, hydrogenated coconut oil, palmitic acid, poloxamer, polyethylene glycol, polyethylene glycol 3350, polyoxyl 10 oleyl ether, polyoxyl 15 hydroxypropyl ether, polyoxyl 16 hydroxypropyl ether, polyoxyl 17 hydroxypropyl ether, polyoxyl 18 hydroxypropyl ether, polyoxyl 19 hydroxypropyl ether, polyoxyl 20 hydroxypropyl ether, polyoxyl 21 hydroxypropyl ether, polyoxyl 22 hydroxypropyl ether, polyoxyl 23 hydroxypropyl ether, polyoxyl 24 hydroxypropyl ether, polyoxyl 25 hydroxypropyl ether, polyoxyl 26 hydroxypropyl ether, polyoxyl 27 hydroxypropyl ether, polyoxyl 28 hydroxypropyl ether, polyoxyl 29 hydroxypropyl ether, polyoxyl 30 hydroxypropyl ether, polyoxyl 31 hydroxypropyl ether, polyoxyl 32 hydroxypropyl ether, polyoxyl 33 hydroxypropyl ether, polyoxyl 34 hydroxypropyl ether, polyoxyl 35 hydroxypropyl ether, polyoxyl 36 hydroxypropyl ether, polyoxyl 37 hydroxypropyl ether, polyoxyl 38 hydroxypropyl ether, polyoxyl 39 hydroxypropyl ether, polyoxyl 39 hydroxypropyl ether, polyoxyl 39 hydroxypropyl ether, polyoxy Lubricants include cystearate, polyoxyl 20 cetostearyl ether, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 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, hydrogenated vegetable oil type I, and zinc stearate. When the composition is a tablet, the presence of a lubricant is particularly preferred to improve the tableting process.

[0078] The terms "filler" and "diluent" have the same meaning and are used interchangeably. They refer to any pharmaceutically acceptable excipient or carrier (material) that increases the size of the composition, making it practical to produce and convenient for consumers to use. Materials commonly used as fillers include calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate, carboxymethylcellulose calcium, cellulose, cellulose products such as microcrystalline cellulose and its salts, dextrin derivatives, dextrin, 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, the multiple-unit oral dosage form is one in which the pharmaceutically acceptable excipient or carrier comprises one or more fillers, preferably sucrose, starch, or microcrystalline cellulose.Examples of fillers include amino methacrylate copolymer, ammonio methacrylate copolymer, ammonio methacrylate copolymer dispersion, calcium carbonate, dibasic calcium phosphate anhydrous, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, calcium sulfate, cerabrate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powder, cellulose acetate, corn syrup, corn syrup solids, dextrates, dextrin, dextrose, dextrose excipient, erythritol, ethyl acrylate-methyl methacrylate copolymer dispersion, fructose, invert sugar, isomalt, kaolin, alpha lactalbumin, lactitol, lactose anhydrous, lactose monohydrate, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, and mannitol. , methacrylic acid-ethyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer dispersion, methacrylic acid-methyl methacrylate copolymer, polydextrose, polyethylene glycol, polyethylene glycol 3350, polypropylene 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, powdered sugar, sugar spheres, sunflower oil, talc, trehalose, and xylitol.

[0079] The term "wicking agent" refers to a pharmaceutically acceptable material that can draw water into the porous network of the delivery device. It has the ability to physically adsorb water. The role of the wicking agent is to act as a carrier, facilitating the infiltration of water to 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, the multiple-unit oral dosage form of the present invention is one in which 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, the multiple-unit oral dosage form of the present invention is one in which the pharmaceutically acceptable excipient or carrier comprises one or more wicking agents, preferably povidone, colloidal silicon dioxide (Aerosil), or a mixture thereof.

[0080] In one embodiment, the multiple unit oral dosage form of the invention is one in which the modified-release multiple unit oral dosage form comprises a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the modified-release multiple unit oral dosage form comprising an inner active coating layer comprising 6 to 20 wt % of one or more coating agents, based on the total weight of the inner active coating layer.

[0081] In one embodiment, the multiple unit oral dosage form of the invention is one in which the modified-release multiple unit oral dosage form comprises a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the modified-release multiple unit oral dosage form comprising an inner active coating layer comprising 15 to 30 wt % of one or more anticoagulants, based on the total weight of the inner active coating layer.

[0082] In one embodiment, the multiple unit oral dosage form of the present invention comprises a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the modified-release multiple unit oral dosage form comprising an inner active coating layer comprising 6-20 wt% of one or more coating agents, based on the total weight of the inner active coating layer, 15-30 wt% of one or more anticoagulants, based on the total weight of the inner active coating layer, and optionally one or more pore-forming agents, wherein the sum of the ingredients relative to the weight of the inner active coating layer is up to 100 wt%.

[0083] In one embodiment, the multiple unit oral dosage form of the present invention is one in which the modified-release multiple unit oral dosage form comprises a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the modified-release multiple unit oral dosage form comprising an intermediate enteric-release coating layer comprising 45 to 65% by weight of one or more enteric coating agents, based on the total weight of the intermediate enteric-release coating layer.

[0084] In one embodiment, the multiple unit oral dosage form of the present invention comprises a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the modified-release multiple unit oral dosage form comprises an intermediate enteric-release coating layer comprising 35 to 55% by weight of one or more anti-caking agents, and optionally one or more pore-forming agents, based on the total weight of the intermediate enteric-release coating layer.

[0085] In one embodiment, the multiple unit oral dosage form of the present invention comprises a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the modified-release multiple unit oral dosage form comprising an intermediate enteric-release coating layer comprising 45-65 wt% of one or more enteric coating agents, based on the total weight of the intermediate enteric-release coating layer, and 35-55 wt% of one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, based on the total weight of the intermediate enteric-release coating layer, wherein the sum of the ingredients is up to 100 wt% based on the weight of the intermediate enteric-release coating layer.

[0086] In one embodiment, the multiple unit oral dosage form of the invention is one in which the modified-release multiple unit oral dosage form comprises a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the modified-release multiple unit oral dosage form comprising an outer modified-release coating layer comprising 7 to 14 wt % of one or more enteric coating agents, based on the total weight of the outer modified-release coating layer.

[0087] In one embodiment, the multiple unit oral dosage form of the present invention comprises a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the modified-release multiple unit oral dosage form comprises an outer modified-release coating layer comprising 38 to 46% by weight of one or more modified-release coating agents, based on the total weight of the outer modified-release coating layer.

[0088] In one embodiment, the multiple unit oral dosage form of the present invention comprises a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the modified-release multiple unit oral dosage form comprises an outer modified-release coating layer comprising 42-52 wt% of one or more anti-caking agents and optionally one or more pore-forming agents, based on the total weight of the outer modified-release coating layer, and the sum of the ingredients relative to the weight of the outer modified-release coating layer is up to 100 wt%.

[0089] In one embodiment, the multiple unit oral dosage form of the present invention comprises a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, the modified-release multiple unit oral dosage form comprising an outer modified-release coating layer comprising 7-14 wt% of one or more enteric coating agents, 38-46 wt% of one or more modified-release coating agents, based on the total weight of the outer modified-release coating layer, and 42-52 wt% of one or more anti-caking agents and optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, based on the total weight of the outer modified-release coating layer, wherein the sum of the ingredients relative to the weight of the outer modified-release coating layer is up to 100 wt%.

[0090] In one embodiment, the multiple unit oral dosage form of the invention is a modified release multiple unit oral dosage form comprising a first plurality of modified release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the first plurality of modified release pellets comprises: an inner active coating layer, a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof; 6 to 20 wt. % of one or more coating agents, based on the total weight of the inner active coating layer; 15% to 30% by weight of one or more anti-caking agents and optionally one or more pore formers, based on the total weight of the inner active coating layer; optionally one or more pharmaceutically acceptable excipients; Including, The sum of the components relative to the weight of the inner active coating layer is up to 100% by weight; an inner active coating layer; optionally an intermediate enteric-release coating layer, 45% to 65% by weight of one or more enteric coating agents based on 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-forming agents, based on the total weight of the intermediate enteric-release coating layer; optionally one or more pharmaceutically acceptable excipients; Including, The sum of the ingredients relative to the weight of the intermediate enteric-release coating layer is up to 100% by weight; an intermediate enteric-release coating layer; and an outer modified release coating layer, 7 to 14 wt % of one or more enteric coating agents based on the total weight of the outer modified-release coating layer; 38 to 46 wt. % of one or more modified-release coating agents based on 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-forming agents, based on the total weight of the outer modified-release coating layer; optionally one or more pharmaceutically acceptable excipients; Including, The sum of the ingredients relative to the weight of the outer modified-release coating layer is up to 100% by weight. and an outer modified release coating layer.

[0091] In one embodiment, the multiple unit oral dosage form of the present invention comprises a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the modified-release multiple unit oral dosage form comprises an inner active coating layer comprising 13-25 wt% of one or more coating agents, and optionally one or more pharmaceutically acceptable excipients, based on the total weight of the inner active coating layer, and the sum of the ingredients is up to 100 wt% based on the weight of the inner active coating layer.

[0092] In one embodiment, the multiple unit oral dosage form of the present invention is one in which the modified-release multiple unit oral dosage form comprises a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the modified-release multiple unit oral dosage form comprises an outer modified-release coating layer comprising 2 to 8 wt % of one or more enteric coating agents, based on the total weight of the outer modified-release coating layer.

[0093] In one embodiment, the multiple unit oral dosage form of the present invention comprises a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the modified-release multiple unit oral dosage form comprises an outer modified-release coating layer comprising 30 to 49% by weight of one or more modified-release coating agents, based on the total weight of the outer modified-release coating layer.

[0094] In one embodiment, the multiple unit oral dosage form of the present invention comprises a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the modified-release multiple unit oral dosage form comprises an outer modified-release coating layer comprising 46-65 wt% of one or more anti-caking agents and optionally one or more pore-forming agents, based on the total weight of the outer modified-release coating layer, and the sum of the ingredients relative to the weight of the outer modified-release coating layer is up to 100 wt%.

[0095] In one embodiment, the multiple unit oral dosage form of the present invention comprises a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the modified-release multiple unit oral dosage form comprises an outer modified-release coating layer comprising 2-8 wt% of one or more enteric coating agents, based on the total weight of the outer modified-release coating layer, 30-49 wt% of one or more modified-release coating agents, based on the total weight of the outer modified-release coating layer, and 46-65 wt% of one or more anti-caking agents and optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, based on the total weight of the outer modified-release coating layer, wherein the sum of the ingredients relative to the weight of the outer modified-release coating layer is up to 100 wt%.

[0096] In one embodiment, the multiple unit oral dosage form of the invention is a modified release multiple unit oral dosage form comprising a second plurality of modified release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the second plurality of modified release pellets comprises: an inner active coating layer, a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof; 13 to 25 wt. % of one or more coating agents, based on the total weight of the inner active coating layer; optionally one or more pharmaceutically acceptable excipients; Including, The sum of the components relative to the weight of the inner active coating layer is up to 100% by weight; an inner active coating layer; an outer modified release coating layer, 2 to 8 wt. % of one or more enteric coating agents based on the total weight of the outer modified-release coating layer; 30 to 49 wt % of one or more modified-release coating agents based on 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-forming agents, based on the total weight of the outer modified-release coating layer; optionally one or more pharmaceutically acceptable excipients; Including, The sum of the components relative to the weight of the outer modified-release coating layer is up to 100% by weight. an outer modified-release coating layer; Includes:

[0097] In one embodiment, the multiple unit oral dosage form of the invention comprises a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, and a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof; a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof comprising: a pharmaceutically acceptable inert core; an inner active coating layer, a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof; 6 to 20 wt. % of one or more coating agents, based on the total weight of the inner active coating layer; 15% to 30% by weight of one or more anti-caking agents and optionally one or more pore formers, based on the total weight of the inner active coating layer; optionally one or more pharmaceutically acceptable excipients; Including, The sum of the components relative to the weight of the inner active coating layer is up to 100% by weight; an inner active coating layer; optionally an intermediate enteric-release coating layer, 45% to 65% by weight of one or more enteric coating agents based on 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-forming agents, based on the total weight of the intermediate enteric-release coating layer; optionally one or more pharmaceutically acceptable excipients; Including, The sum of the ingredients relative to the weight of the intermediate enteric-release coating layer is up to 100% by weight. an intermediate enteric-release coating layer; and an outer modified release coating layer, 7 to 14 wt % of one or more enteric coating agents based on the total weight of the outer modified-release coating layer; 38 to 46 wt. % of one or more modified-release coating agents based on 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-forming agents, based on the total weight of the outer modified-release coating layer; optionally one or more pharmaceutically acceptable excipients; Including, The sum of the components relative to the weight of the outer modified-release coating layer is up to 100% by weight. an outer modified-release coating layer; Including, a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof; a pharmaceutically acceptable inert core; an inner active coating layer, a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof; 13 to 25 wt. % of one or more coating agents, based on the total weight of the inner active coating layer; optionally one or more pharmaceutically acceptable excipients; Including, The sum of the components relative to the weight of the inner active coating layer is up to 100% by weight; an inner active coating layer; an outer modified release coating layer, 2 to 8 wt. % of one or more enteric coating agents based on the total weight of the outer modified-release coating layer; 30 to 49 wt % of one or more modified-release coating agents based on 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-forming agents, based on the total weight of the outer modified-release coating layer; optionally one or more pharmaceutically acceptable excipients; Including, The sum of the ingredients is up to 100% by weight based on the weight of the outer modified-release coating layer; an outer modified-release coating layer; Includes:

[0098] In one embodiment, the modulated multiple unit oral dosage form of the present invention exhibits a dissolution profile according to the following: 5% to 35% by weight of the doxylamine content was dissolved in 0.1N HCl medium (pH = 1) in 1 hour. Next, the medium was replaced with a medium of pH 4.5 (0.05 M acetate buffer), and at 4 hours, at least 35% by weight to 75% by weight of the initial doxylamine content was cumulatively dissolved. Next, the medium was replaced with a medium of pH 6.8 (0.05 M phosphate buffer), and at 7 hours, at least 75% by weight of the initial doxylamine content was cumulatively dissolved, and 5% to 35% by weight of the pyridoxine content was dissolved in 0.1N HCl medium (pH = 1) in 1 hour. Next, the medium was replaced with a medium (0.05 M acetate buffer) of pH 4.5, and after 4 hours, more than 35% by weight to 75% by weight of the initial pyridoxine content was eluted. Next, the medium was replaced with a medium of pH 6.8 (0.05 M phosphate buffer), and at 7 hours, more than 75% by weight of the initial pyridoxine content was cumulatively dissolved. Here, the dissolution profile is measured using a USP Type 2 apparatus (basket) by placing the composition in 900 mL of the corresponding medium / buffer at 37° C.±0.5° C. and 100 rpm (revolutions per minute).

[0099] In one embodiment, the modulated multiple unit oral dosage form of the present invention exhibits a dissolution profile according to the following: 10% to 35% by weight of the doxylamine content was dissolved in 0.1N HCl medium (pH = 1) in 1 hour. Next, the medium was replaced with a medium of pH 4.5 (0.05 M acetate buffer), and after 4 hours, 45% to 70% by weight of the initial doxylamine content was eluted. Next, the medium was replaced with a medium of pH 6.8 (0.05 M phosphate buffer), and at 7 hours, at least 80% by weight of the initial doxylamine content was cumulatively dissolved, and 10% to 35% by weight of the pyridoxine content was dissolved in 0.1N HCl medium (pH = 1) in 1 hour. Next, the medium was replaced with a medium of pH 4.5 (0.05 M acetate buffer), and after 4 hours, 40% to 65% by weight of the initial pyridoxine content was eluted. Next, the medium was replaced with a medium (0.05 M phosphate buffer) of pH 6.8, and at 7 hours, at least 80% by weight of the initial pyridoxine content was cumulatively dissolved. Here, the dissolution profile is measured using a USP Type 2 apparatus (basket) by placing the composition in 900 mL of the corresponding medium / buffer at 37° C.±0.5° C. and 100 rpm (revolutions per minute).

[0100] As mentioned above, the dosage form of the present invention is a "multiple unit dosage form." In one embodiment, the multiple unit dosage form is a capsule filled with a plurality of first and second pellets of the present invention as subunits containing the active ingredient. In one embodiment, the multiple unit dosage form is a hard capsule.

[0101] For the purposes of the present invention, hard capsules are understood to be hard capsules suitable for use in fully automatic capsule filling machines. Generally, these capsules consist of two cylindrical halves, one of which has a larger diameter but a shorter length and is called the cap, and the other has a smaller diameter but a longer length and is called the body. In one embodiment, the multiple unit oral dosage form is a hard capsule having a capsule size of 0 to 5. In one embodiment, the multiple unit oral dosage form is a hard capsule having a capsule size of 1 to 5. In one embodiment, the multiple unit oral dosage form is a hard capsule having a capsule size of 1 to 4. In one embodiment, the multiple unit oral dosage form is a hard capsule having a capsule size of 3. In one embodiment, the multiple unit oral dosage form is a hard capsule having a capsule size of 2. In one embodiment, the multiple unit oral dosage form is a hard capsule having a capsule size of 1. In one embodiment, the multiple unit dosage form of the present invention is a hard capsule made from a material selected from the group consisting of gelatin, hydroxypropyl methylcellulose (hypromellose, HPMC), pullulan, and mixtures thereof. In one embodiment, the multiple unit dosage form of the present invention is a hard gelatin capsule. In one embodiment, the multiple unit dosage form of the present invention is a hard hydroxypropyl methylcellulose capsule.

[0102] In one embodiment, the multiple unit dosage form of the invention is a hard capsule and comprises a first plurality of modified-release pellets of 20 mg to 220 mg of doxylamine or a pharmaceutically acceptable salt thereof and a second plurality of modified-release pellets of 20 mg to 220 mg of pyridoxine or a pharmaceutically acceptable salt thereof. In one embodiment, the multiple unit dosage form of the invention is a hard capsule and comprises a first plurality of modified-release pellets of 40 mg to 140 mg of doxylamine or a pharmaceutically acceptable salt thereof and a second plurality of modified-release pellets of 40 mg to 140 mg of pyridoxine or a pharmaceutically acceptable salt thereof.

[0103] In one embodiment, the multiple unit dosage form of the present invention is a hard capsule comprising a first plurality of modified-release pellets of about 60 mg doxylamine or a pharmaceutically acceptable salt thereof and a second plurality of modified-release pellets of about 60 mg pyridoxine or a pharmaceutically acceptable salt thereof, wherein the hard capsule has a size selected from a size 2 or a size 3 or a size 4, more specifically a size 3.

[0104] In one embodiment, the multiple unit dosage form of the present invention is a hard capsule comprising a first plurality of modified-release pellets of about 120 mg doxylamine or a pharmaceutically acceptable salt thereof and a second plurality of modified-release pellets of about 120 mg pyridoxine or a pharmaceutically acceptable salt thereof, wherein the hard capsule has a size selected from size 1, 2, and 3. In one embodiment, the multiple unit dosage form of the present invention is a hard capsule comprising about 10 mg doxylamine succinate per capsule and about 10 mg pyridoxine hydrochloride per capsule, wherein 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 doxylamine succinate per capsule and about 20 mg pyridoxine hydrochloride per capsule, wherein the hard capsule has a size selected from size 1, 2, and 3.

[0105] For the purposes of the present invention, the multiple unit dosage forms of the present invention, particularly hard capsules, can be appropriately conditioned in suitable packaging. The type of packaging can be easily determined by those skilled in the art according to the type of formulation to be prepared. 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 with or without desiccants disposed in the bottle or with or without desiccants incorporated into the bottle closure system.

[0106] For the purposes of the present invention, the multiple-unit dosage forms of the present invention, particularly the hard capsules, are primarily packaged in blisters or bottles as defined above and secondarily packaged in outer boxes. Materials commonly used to make the blisters in which the multiple-unit dosage forms of the present invention, particularly the 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 (polyterephthalate), PETG (polyethylene terephthalate glycol), PCTFE (polychlorotrifluoroethylene, commercially available as polyAclar®), PVC / PE / PVdC (commercially available as AquaBa®), COC (cyclic olefin copolymer), aluminum, or combinations thereof. Materials commonly used to manufacture the bottles and associated closures or caps in which the multiple-unit dosage forms of the present invention, particularly the hard capsules, are primarily packaged are glass, aluminum, and plastic materials. Examples of plastic materials include PE (including HDPE and LDPE), PET, PP (polypropylene), PVC, PETG, PS (polystyrene), COC, and / or mixtures of two or more of these plastic materials, and / or mixtures of one or more plastic materials with additional additives. Examples of plastic material additives include binders, 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 barrier materials, such as molecular sieves such as zeolites, calcium oxide, activated carbon, calcium sulfate, calcium chloride, and silica. The desiccants can be mixed / incorporated with a suitable binder in the plastic material used to make the bottle, or placed within the bottle, or incorporated into the bottle's closure system.

[0107] The inventors have surprisingly found that the primary packaging defined above is advantageous in terms of stability. In particular, they allow storage at temperatures below 25°C and below 60% relative humidity. This is advantageous because the multiple unit dosage forms of the invention are suitable for long-term storage, even in countries of climate zones I and II (temperate and Mediterranean / subtropical countries), without the need for storage in a refrigerator, for example, and without any particular restrictions.

[0108] In one embodiment, the multiple unit dosage form of the present invention is a hard gelatin or hard HPMC (hydroxypropyl methylcellulose) capsule with a primary packaging selected from the group consisting of blisters made of any of the materials described above and plastic bottles without desiccants made of any of the plastic materials described above. These are particularly advantageous because they are stable and can be stored at or below 25°C and 60% relative humidity.

[0109] In certain embodiments, the multiple unit dosage forms of the present invention are hard gelatin or HPMC capsules that are primary packaged in blisters made of PVC / PVdC (on one side of the blister) and aluminum (on the other side of the blister), making them stable and allowing for storage at or below 25° C. and 60% relative humidity. This is advantageous because this type of blister is widely used and is easy to handle from the primary packaging manufacturing process, and therefore inexpensive.

[0110] In a specific embodiment, the multiple-unit dosage forms of the present invention are hard capsules made of gelatin or HPMC, which are primarily packaged in a plastic bottle equipped with a desiccant. These are particularly advantageous in terms of stability, allowing storage at temperatures below 30°C and below 75% relative humidity. This is advantageous because the multiple-unit dosage forms of the present invention are also suitable for long-term storage in countries in climate zones III and IV (hot-dry and hot-humid / tropical countries) without any specific restrictions (e.g., without the need for refrigeration). A further advantage is that they avoid the use of glass bottles, which are impermeable containers and can provide maximum protection against moisture, but are more fragile and heavy than plastic bottles, thus increasing costs and risks for manufacturers and users and making them much more difficult to handle from a logistical standpoint.

[0111] 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 blisters made of the materials defined above or in a plastic bottle with a desiccant as primary packaging, and is further advantageous in terms of stability, allowing storage at temperatures below 30° C. and below 75% relative humidity. This is advantageous, since the multiple unit dosage form of the present invention is also suitable for long-term storage in countries of climate zones III and IV (hot dry and hot humid / tropical countries) without any particular restrictions (e.g., without the need to store in a refrigerator).

[0112] In one embodiment, the multiple unit dosage form of the present invention is a hard HPMC capsule primarily packaged in a blister made of the material defined above, specifically AquaBa® or aluminum (on one side of the blister) and aluminum (on the other side of the blister). These are particularly advantageous because they are stable and can be stored at temperatures below 30°C and below 75% relative humidity. This is even more advantageous for users in countries in climate zones III and IV (hot dry and hot humid / tropical countries), because they not only allow storage without specific restrictions (e.g., without the need to store in a refrigerator), but also because blisters are easier to handle than bottles (e.g., they can be easily kept on hand when traveling), and because the capsules are individually protected when packaged in blisters, allowing for safer and more convenient use.

[0113] A 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. Specifically, the process comprises: (a1) preparing a first plurality of 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 by adding 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 cores is such that at least 90% of the inert cores have a particle size of between 300 μm and 1700 μm as measured by analytical sieving, and at least 90% of the inert cores have a particle size variation of 200 μm or less, particularly 150 μm or less, particularly 100 μm or less, particularly 75 μm or less, as measured by analytical sieving; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer by adding one or more enteric coating agents, one or more modified-release coating agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert cores 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 variation of 200 μm or less, particularly 150 μm or less, particularly 100 μm or less, particularly 75 μm or less, as measured by analytical sieving. As noted above, this process is less expensive, more robust, more reproducible, and easier to scale up than state-of-the-art processes. This allows for a high yield of homogenous batches of both pluralities of pellets to be obtained without significant or substantial yield loss in the sieving step, resulting in a high final yield. All of the embodiments disclosed above for the particle size and particle size variation of the pharmaceutically acceptable core and the first and second pluralities of pellets, and combinations thereof, disclosed in the first aspect of the present invention also apply to the process of the second aspect of the present invention.

[0114] In one embodiment, the process for preparing the multiple unit oral dosage form of the first aspect of the invention comprises: (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof with an inner active coating layer and optionally an intermediate enteric coating layer by continuous or discontinuous spraying of 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 with one or more pauses, and optionally drying with a continuous or discontinuous air stream; (b1) preparing a second plurality of 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 by continuous or discontinuous spraying of 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 with one or more pauses, and optionally drying with a stream of air, continuously or discontinuously.

[0115] In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by continuously spraying the liquid mixture defined above. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by continuously spraying the liquid mixture defined above and including one or more pause periods. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by continuously spraying the liquid mixture defined above, including one or more pause periods, and continuously drying with an air stream. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by continuously spraying the liquid mixture defined above, including one or more pause periods, and discontinuously drying with an air stream.

[0116] In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by discontinuously spraying the liquid mixture defined above and including one or more pause periods. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by discontinuously spraying the liquid mixture defined above and continuously drying with an air stream. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by discontinuously spraying the liquid mixture defined above and discontinuously drying with an air stream. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by discontinuously spraying the liquid mixture defined above, including one or more pause periods, and discontinuously drying with an air stream.

[0117] In one embodiment, the process for preparing the multiple unit oral dosage form of the first aspect of the invention comprises: (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof, the 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, simultaneously or alternately adding a powdered mixture comprising one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable additives, optionally with one or more pauses, and optionally drying continuously or discontinuously with an air stream; (b1) preparing a second plurality of 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 by continuous or discontinuous spraying of 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, simultaneously or alternately adding a powdered mixture comprising one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, optionally with one or more pauses, optionally with one or more pause periods, and optionally with continuous or discontinuous drying with a current of air.

[0118] In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by continuously spraying the liquid mixture defined above and simultaneously adding the mixture in powder form. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by continuously spraying the liquid mixture defined above and alternately adding the mixture in powder form. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by continuously spraying the liquid mixture defined above, simultaneously adding the mixture in powder form, and continuously drying with an air stream. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by continuously spraying the liquid mixture defined above, alternately adding the mixture in powder form, and continuously drying with an air stream. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by continuously spraying the liquid mixture defined above, alternately adding the mixture in powder form, and continuously drying with an air stream. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by continuously spraying the liquid mixture defined above, alternating with the addition of the mixture in powder form, and discontinuously drying with an air stream.

[0119] In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by discontinuously spraying the liquid mixture, simultaneously adding the mixture in powder form, and one or more pauses. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by discontinuously spraying the liquid mixture, simultaneously adding the mixture in powder form, and continuously drying with a stream of air. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by discontinuously spraying the liquid mixture, simultaneously adding the mixture in powder form, and discontinuously drying with a stream of air. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by discontinuously spraying the liquid mixture, simultaneously adding the mixture in powder form, one or more pauses, and discontinuously drying with a stream of air. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by discontinuously spraying the liquid mixture, simultaneously adding the mixture in powder form, one or more pauses, and discontinuously drying with a stream of air. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by discontinuously spraying the liquid mixture, alternately adding the mixture in powder form, and continuously drying with an airflow. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by discontinuously spraying the liquid mixture, alternately adding the mixture in powder form, and discontinuously drying with an airflow. In one embodiment, steps (a1) and (b1) of the process of the present invention are carried out by discontinuously spraying the liquid mixture, alternately adding the mixture in powder form, performing one or more pauses, and discontinuously drying with an airflow. In one embodiment, steps (a1) and (b1) of the process 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 process of the present invention are carried out by discontinuously spraying the liquid mixture and alternately adding the mixture in powder form.

[0120] For purposes of the present invention, the term "liquid mixture" refers to any mixture of one or more components defined herein, such as coatings, modified-release coatings, pharmaceutically acceptable excipients, and pharmaceutically active ingredients (pyridoxine and doxylamine), where the mixture has liquid-state behavior. The term "liquid-state behavior" refers to a mixture or substance that can flow, does not have a fixed shape, and is not a solid or gas. The mixture may be in the form of a solution or a suspension (or slurry). A solution is a type of homogeneous mixture consisting of two or more substances. In such a mixture, the solute is a substance dissolved in another substance known as the solvent. A suspension is a heterogeneous mixture containing solid particles in a liquid solvent. In fact, the solid particles do not dissolve in the liquid solvent.

[0121] The term "liquid solvent" refers to any organic and inorganic liquid solvent or mixture thereof that can dissolve compounds / components / ingredients to form a liquid solution, or any liquid that can form a suspension or slurry of one or more of the compounds / components / ingredients. The liquid solvent is preferably selected from the group of volatile liquid solvents (boiling point less than 125°C), including one or more organic liquid solvents selected from the group consisting of (C-C)alcohol, (C-C)alkyl-CO-(C-C)alkyl, (C-C)alkyl-CO-O-(C-C)alkyl, or water, or a mixture thereof. The term "alcohol" refers to an "alkane" in which at least one hydrogen atom is replaced by a hydroxyl group and contains the number of carbon atoms specified in the description or claims. The term "alkane" refers to a saturated branched or straight-chain hydrocarbon containing the number of carbon atoms specified in the description or claims. Examples include methanol, ethanol, n-propanol, iso-propanol, butanol, iso-butanol, and sec-butanol. The term "alkyl" refers to a saturated, straight or branched hydrocarbon chain containing the number of carbon atoms specified in the description or claims. Examples include, among others, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl groups. In one embodiment, the process involves a mixture comprising one or more organic solvents selected from the group consisting of ethanol, 2-propanol, methanol, acetone, butanone, ethyl acetate, water, and mixtures thereof, specifically, organic solvents selected from ethanol, acetone, water, and mixtures thereof. When used for therapeutic purposes, there are no restrictions on the liquid solvent, except that it must be pharmaceutically acceptable.

[0122] The term "mixture in powder form" refers to any individual solid compound / component / ingredient or combination thereof as defined in the present invention, which is solid and in powder form. For the purposes of the present invention, a powder form is considered to be solid in powder form if it has a D90 of 500 μm or less, preferably 250 μm or less, more preferably 150 μm or less.

[0123] The term "continuously spraying" refers to spraying continuously over time during a particular step in a process until all of the sprayed liquid is consumed. The term "discontinuously spraying" refers to spraying intermittently and periodically over time. This means spraying for some periods, stopping spraying for other periods, and repeating this "cycle" as many times as necessary until all of the sprayed liquid needed for a particular stage in the process is consumed.

[0124] The term "simultaneous addition of a mixture in powder form" refers to the simultaneous addition of a solid over time to the spraying of a liquid mixture during one step of the process. This means that when the powder mixture is added, the liquid mixture is also sprayed at the same time. The spraying can be permanent and continuous, or conversely, intermittent, but always coincides with the spraying, regardless of whether it is continuous or discontinuous spraying. The term "alternate addition of a mixture in powder form" refers to the non-simultaneous addition of a mixture of solids in powder form, which is intermittent and discontinuous, as opposed to the spraying of a liquid mixture, which is also intermittent and discontinuous, and this process is repeated periodically ("in cycles") until the addition of the solids in powder form and / or the spraying of the liquid mixture is complete.

[0125] The term "continuously drying" refers to the fact that the pellets are air-dried in the coating pan for the entire duration that the coating process is in progress, regardless of whether the spraying is continuous or discontinuous, or whether the addition of solids is simultaneous or alternating. The term "discontinuously drying" refers to the fact that the pellets are air-dried in the coating pan for only certain periods within a "cycle," regardless of whether the spraying is continuous or discontinuous, or whether the addition of solids is simultaneous or alternating.

[0126] The term "air flow" refers to a temperature between 5 and 90°C, m 3 Refers to dry airflow measured in kW / h.

[0127] The term "pause" refers to a period of time during a "cycle" that is repeated during the coating process, during which no liquid mixture is sprayed, no powdered solid mixture is added, and no airflow is used to dry. During this time, the coating pan simply rotates, mixes, and homogenizes the pellets. The term "cycle" refers to a sequence of coating processes that lasts a certain period of time, and this sequence is repeated as many times as necessary until the coating process is complete. This cycle includes a period of spraying a liquid mixture that is at least equal to or less than the cycle period, optionally a period of adding a powdered mixture that is at least equal to or less than the cycle period, optionally one or more pause periods that are shorter than the cycle period, and optionally a drying period that is at least equal to or less than the cycle period.

[0128] In one embodiment, the process for preparing the multiple unit oral dosage form of the second aspect of the invention comprises: (a1) preparing a first plurality of 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 by adding 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 particle size of the inert cores 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 variation of 200 μm or less, particularly a particle size variation of 150 μm or less, particularly a particle size variation of 100 μm or less, particularly a particle size variation of 75 μm or less as measured by analytical sieving, and the total amount of the enteric coating agent and the modified release coating agent in the spray liquid mixture is 10% to 49% by weight based on the weight of the liquid mixture; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer by adding 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 equal to or greater than the particle size of the inert core. at least 90% of the cores have a particle size of 300 μm to 1700 μm as determined by analytical sieving, and at least 90% of the inert cores have a particle size variation of 200 μm or less, particularly a particle size variation of 150 μm or less, particularly a particle size variation of 100 μm or less, particularly a particle size variation of 75 μm or less as determined by analytical sieving, and the total amount of the enteric coating agent and the modified release coating agent in the spray liquid mixture is 10% to 49% by weight based on the weight of the liquid mixture; All embodiments disclosed above for the pharmaceutically acceptable core and the particle size and particle size variation of the first and second plurality of pellets, and combinations thereof, as disclosed in the first aspect of the present invention also apply to the process of the second aspect of the present invention.

[0129] In one embodiment, the process for preparing the multiple unit oral dosage form of the first aspect of the invention comprises: (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof with an inner active coating layer and optionally an intermediate enteric coating layer by continuously or discontinuously 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 particle size of the pharmaceutically acceptable inert cores is such that at least 90% of the inert cores have a particle size of 300 μm to 1700 μm as measured by analytical sieves, and at least 90% of the inert cores have a particle size variation of 200 μm or less, particularly a particle size variation of 150 μm or less, particularly a particle size variation of 100 μm or less, and particularly a particle size variation of 75 μm or less, as measured by analytical sieves; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising 1.0 to 7.5 wt. % of one or more enteric coating agents and 10.0 to 35.0 wt. % of one or more modified-release coating agents, wherein the particle size of the pharmaceutically acceptable inert cores 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 variation of 200 μm or less, particularly a particle size variation of 150 μm or less, particularly a particle size variation of 100 μm or less, particularly a particle size variation of 75 μm or less, as measured by analytical sieving; All embodiments disclosed above for the particle size and particle size variation of the first and second pluralities of pellets, and combinations thereof, disclosed in the first aspect of the present invention also apply to the process of the second aspect of the present invention.

[0130] In one embodiment, the process for preparing the multiple unit oral dosage form of the first aspect of the invention comprises: (a1) preparing a first plurality of 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 with an inner active coating layer and optionally an intermediate enteric coating layer, wherein the weight ratio of the one or more enteric coating agents to the 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 cores 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 variation of 200 μm or less, particularly a particle size variation of 150 μm or less, particularly a particle size variation of 100 μm or less, particularly a particle size variation of 75 μm or less, as measured by analytical sieving; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer by continuously or discontinuously spraying a liquid mixture, wherein the weight ratio of the one or more enteric coating agents to the 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 cores 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 variation of 200 μm or less, particularly a particle size variation of 150 μm or less, particularly a particle size variation of 100 μm or less, particularly a particle size variation of 75 μm or less, as measured by analytical sieving; All embodiments disclosed above for the particle size and particle size variation of the first and second pluralities of pellets, and combinations thereof, disclosed in the first aspect of the present invention also apply to the process of the second aspect of the present invention.

[0131] In one embodiment, the process for preparing the multiple unit oral dosage form of the first aspect of the invention comprises: (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof with an inner active coating layer and optionally an intermediate enteric coating layer by continuously or discontinuously 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 one or more of the doxylamine or pharmaceutically acceptable salt thereof in the spray mixture are coated with an inner active coating layer and an intermediate enteric coating layer. the weight ratio of the enteric coating agent to the one or more modified release coating agents is 5:95 to 30:70, and the particle size of the pharmaceutically acceptable inert cores 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 variation of 200 μm or less, particularly a particle size variation of 150 μm or less, particularly a particle size variation of 100 μm or less, particularly a particle size variation of 75 μm or less as measured by analytical sieving; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer by continuously or discontinuously spraying a liquid mixture containing 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, the weight ratio of the one or more modified release coating agents is 5:95 to 30:70, and the particle size of the pharmaceutically acceptable inert cores 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 variation of 200 μm or less, particularly a particle size variation of 150 μm or less, particularly a particle size variation of 100 μm or less, particularly a particle size variation of 75 μm or less as measured by analytical sieving; All embodiments disclosed above for the particle size and particle size variation of the first and second pluralities of pellets, and combinations thereof, disclosed in the first aspect of the present invention also apply to the process of the second aspect of the present invention.

[0132] In one embodiment, the process for preparing the multiple unit oral dosage form of the first aspect of the invention comprises: (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the average spray flow rate of the mixture including the coating is 0.30 to 5.00 g / min per kg of pharmaceutically acceptable inert cores; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the spray average flow rate of the mixture including the coating agent is 0.30 to 5.00 g / min per kg of pharmaceutically acceptable inert cores; Includes:

[0133] In one embodiment, the process for preparing the multiple unit oral dosage form of the first aspect of the invention comprises: (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the spray topical flow rate of the mixture including the coating is 0.30 to 9.00 g / min per kg of pharmaceutically acceptable inert core; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the spray topical flow rate of the mixture including the coating is 0.30 to 9.00 g / min per kg of pharmaceutically acceptable inert core; Includes:

[0134] In one embodiment, the process for preparing the multiple unit oral dosage form of the first aspect of the invention comprises: (a1) preparing a first plurality of 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 cores; (b1) preparing a second plurality of 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 cores; Includes:

[0135] In one embodiment, the process for preparing the multiple unit oral dosage form of the first aspect of the invention comprises: (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the topical solid addition rate of the solid form mixture is 0.95 to 40 g / min per kg of pharmaceutically acceptable inert core; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the topical solid addition rate of the mixture in solid form is 0.10 to 40.00 g / min per kg of pharmaceutically acceptable inert core; Includes:

[0136] In one embodiment, the process for preparing the multiple unit oral dosage form of the first aspect of the invention comprises: (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the relationship between the average spray flow rate of the liquid mixture containing the coating agent and the average solid addition rate of the mixture in solid form is 90:10 to 60:40, particularly 90:10 to 70:30; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the relationship between the average spray flow rate of the liquid mixture containing the coating agent and the average solid addition rate of the mixture in solid form is 90:10 to 60:40, particularly 80:20 to 60:40; Includes:

[0137] In one embodiment, the process for preparing the multiple unit oral dosage form of the first aspect of the invention comprises: (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the average spray flow rate of the liquid mixture containing the coating agent is 0.30 to 5.00 g / min per kg of pharmaceutically acceptable inert cores, and the average solid addition rate of the mixture in solid form is 0.95 to 18.00 g / min per kg of pharmaceutically acceptable inert cores; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the average spray flow rate of the liquid mixture containing the coating agent is 0.30 to 5.00 g / min per kg of pharmaceutically acceptable inert cores, and 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 cores; Includes:

[0138] In one embodiment, the process for preparing the multiple unit oral dosage form of the first aspect of the invention comprises: (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the spray 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 solid form mixture is 0.95 to 40.00 g / min per kg of the inert core; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the spray 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 solid form mixture is 0.10 to 40.00 g / min per kg of the inert core; Includes:

[0139] In one embodiment, the process for preparing the multiple unit oral dosage form of the first aspect of the invention comprises: (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the average spray flow rate of the liquid mixture containing the coating agent is 0.30 to 5.00 g / min per 1 kg of pharmaceutically acceptable inert cores, the average solid addition rate of the mixture in solid form is 0.95 to 18.00 g / min per 1 kg of pharmaceutically acceptable inert cores, and the relationship between the average spray flow rate of the liquid mixture containing the coating agent and the average solid addition rate of the mixture in solid form is 90:10 to 60:40, particularly 90:10 to 70:30; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the average spray flow rate of the mixture including the coating agent is 0.30 to 5.00 g / min per kg of pharmaceutically acceptable inert cores, 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 cores, and the relationship between the average spray flow rate of the liquid mixture including the coating agent and the average solid addition rate of the mixture in solid form is 90:10 to 60:40, particularly 80:20 to 60:40; Includes:

[0140] In one embodiment, the process for preparing the multiple unit oral dosage form of the first aspect of the invention comprises: (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, wherein the spray topical flow rate of the mixture including the coating is 0.30 to 9.00 g / min per kg of pharmaceutically acceptable inert cores, and the topical solid addition rate of the mixture in solid form is 0.95 to 40.00 g / min per kg of inert cores; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the spray local flow rate of the mixture including the coating is 0.30 to 9.00 g / min per kg of pharmaceutically acceptable inert cores, and the local solid addition rate of the mixture in solid form is 0.10 to 40.00 g / min per kg of inert cores; Includes:

[0141] In one embodiment, the process for preparing the multiple unit oral dosage form of the first aspect of the invention comprises: (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof with an inner active coating layer and optionally an intermediate enteric coating layer by continuously or discontinuously spraying a liquid mixture comprising 1.0 to 7.5 wt % of one or more enteric coating agents and 10.0 to 35.0 wt % 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 powdered mixture comprising one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; the average spray flow rate of the mixture including the coating is 0.30 to 5.00 g / min per 1 kg of pharmaceutically acceptable inert cores, the average solid addition rate of the mixture in solid form is 0.05 to 1.50 g / min per 1 kg of pharmaceutically acceptable inert cores, and the relationship between the average spray flow rate of the mixture including the coating agent and the average solid addition rate of the mixture in solid form is 90:10 to 60:40, specifically 90:10 to 70:30; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising 1.0 to 7.5 wt. % of one or more enteric coating agents and 10.0 to 35.0 wt. % 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 powdered mixture comprising one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; the average spray flow rate of the mixture containing the coating agent is 0.30 to 5.00 g / min per 1 kg of pharmaceutically acceptable inert cores, the average solid addition rate of the mixture in solid form is 0.10 to 2.25 g / min per 1 kg of pharmaceutically acceptable inert cores, and the relationship between the average spray flow rate of the mixture containing the coating agent and the average solid addition rate of the mixture in solid form is 90:10 to 60:40, specifically 80:20 to 60:40; Includes:

[0142] In one embodiment, the process for preparing the multiple unit oral dosage form of the first aspect of the invention comprises: (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof with an inner active coating layer and optionally an intermediate enteric coating layer by continuously or discontinuously spraying a liquid mixture comprising 1.0 to 7.5 wt % of one or more enteric coating agents and 10.0 to 35.0 wt % 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 powdered mixture comprising one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; The local spray flow rate of the mixture containing the coating is 0.30 to 9.00 g / min per kg of pharmaceutically acceptable inert cores, and the local solid addition rate of the mixture in solid form is 0.95 to 40.00 g / min per kg of inert cores; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising 1.0 to 7.5 wt. % of one or more enteric coating agents and 10.0 to 35.0 wt. % 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 powdered mixture comprising one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; The local spray flow rate of the mixture containing the coating is 0.30 to 9.00 g / min per kg of pharmaceutically acceptable inert cores, and the local solid addition rate of the mixture in solid form is 0.10 to 40.00 g / min per kg of inert cores; Includes:

[0143] The term "average spray flow rate" refers to the average spray flow rate during a cycle, which also corresponds to the average spray flow rate of the corresponding coating step. It is understood as the result of dividing the total amount sprayed during a cycle by the time required to complete this cycle, which is the same result as dividing the total amount of liquid mixture sprayed during the coating step by the time required to complete the coating step. It is generally expressed in g / min, or in this specification, also expressed as g / min per kg of pharmaceutically acceptable inert cores. The average spray flow rate can be measured by any known method in the state of the art. In addition, the term "local spray flow rate" refers to the actual flow rate provided by the combined (total) of all sprayers in a spray gun system when the sprayers are operating (spraying), taking into account that one or more sprayers in the spray gun system operate simultaneously in parallel. The local spray flow rate can be measured by any known method in the state of the art. For the purposes of the present invention, the "local spray flow rate" is measured by prior calibration of the corresponding pump of the spray gun, for a constant pump value, by dividing the sprayed volume by the time the pump is operating, or by using a mass sensor or flow meter during the spraying period. Therefore, the difference between "spray average flow rate" and "spray local flow rate" is that the local flow rate is the actual flow rate provided by the sprayer system during operation (spraying), while the average spray flow rate is the average (g of liquid mixture sprayed per minute) during a cycle or coating process. Obviously, the average spray flow rate will be lower than the local spray flow rate when the liquid mixture is sprayed discontinuously, and will be equal to the local spray flow rate when the liquid mixture is sprayed continuously.

[0144] The term "average solid addition rate" refers to the average rate of addition of a solid mixture in powder form during a cycle, which also corresponds to the average rate of powder addition in the corresponding coating step. It is understood as the result of dividing the total amount added during the cycle by the time required to complete this cycle, which is the same result as dividing the total amount of solids / powder / mixture added during the coating step by the time required to complete the coating step, and is generally expressed in g / min, or in this document, g / min per kg of pharmaceutically acceptable inert cores. The average solid addition rate can be measured by any method known in the state of the art. The term "local solid addition rate" also refers to the actual solid addition rate provided by the corresponding powder screw feeder, or even the addition rate corresponding to the amount added by hand during the short period required for manual solid addition. The local solid addition rate can be measured by any method known in the state of the art. For the purposes of the present invention, the "local solid addition rate" is measured by prior calibration of the corresponding screw feeder or by weighing the amount of powder added by hand during the period required for local addition. Thus, the difference between "average solids addition rate" and "local solids addition rate" is that the local powder addition rate is the actual addition rate provided by the screw feeder or by manual addition (with a shovel) while powder addition is functioning, while the average powder addition rate is the average (g of powder added per minute) during the cycle or coating process. Clearly, the average powder addition rate is lower than the local powder addition rate when the liquid mixture is sprayed discontinuously and the powders are added simultaneously or alternately, and when the liquid mixture is sprayed continuously and the powders are added alternately, and is equal to the local powder addition rate only when the liquid mixture is sprayed continuously and the powders are added simultaneously.

[0145] The phrase "the relationship between the average spray flow rate of the mixture including the coating agent and the average solids addition rate" refers to the relationship between the two rates, which can be measured by dividing one by the other. Also, the phrase "the relationship between the local spray flow rate of the mixture including the coating agent and the local solids addition rate" refers to the relationship between the two rates, which can be measured by dividing one by the other.

[0146] As disclosed above, the multiple unit dosage form of the first aspect of the present invention defined above optionally comprises 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.

[0147] In one embodiment, the process of the present invention comprises preparing a multiple unit dosage form of the first aspect of the invention as defined above, comprising 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.

[0148] In one embodiment, the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric-release coating layer, and then the process comprises separately: (a2) a prior step of coating pellets of doxylamine or a pharmaceutically acceptable salt thereof with an inner active coating layer by continuous or discontinuous spraying of a liquid mixture comprising one or more enteric coating agents and, optionally, one or more pharmaceutically acceptable excipients; (b2) a prior step of coating the pharmaceutically acceptable inert core by continuous or discontinuous spraying of 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; Further includes:

[0149] In one embodiment, the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric-release coating layer, and then the process comprises separately: (a2) a prior step of coating pellets of doxylamine or a pharmaceutically acceptable salt thereof with an inner active coating layer by continuous or discontinuous spraying of 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 anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; (b2) a prior step of coating the pharmaceutically acceptable inert core by continuous or discontinuous spraying of a liquid mixture containing 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; Further includes:

[0150] In one embodiment, the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric-release coating layer, and then the process comprises separately: (a2) a preliminary step of coating pellets of doxylamine or a pharmaceutically acceptable salt thereof with 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 a solid mixture containing one or more anticaking agents and, optionally, one or more pore-forming agents and, optionally, one or more pharmaceutically acceptable excipients, 5.0 to 6.5 g per kg of pharmaceutically acceptable inert cores; (b2) a prior step of coating the 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; Further includes:

[0151] In one embodiment, the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric-release coating layer, and then the process comprises separately: (a2) a step prior to coating pellets of doxylamine or a pharmaceutically acceptable salt thereof with an inner active coating layer by continuously or discontinuously spraying a liquid mixture containing one or more enteric coating agents and, optionally, one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a solid form mixture containing one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein the average spray flow rate of the mixture containing the enteric coating agents is 0.30 to 3.00 g / min per kg of pharmaceutically acceptable inert cores; (b2) a prior step of coating the pharmaceutically acceptable inert cores by continuously or discontinuously spraying a liquid mixture containing 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 solid form and, optionally, the pharmaceutically acceptable excipients, wherein the average spray flow rate of the mixture containing the coating agent is 0.30 to 4.50 g / min per kg of the pharmaceutically acceptable inert cores; Further includes:

[0152] In one embodiment, the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric-release coating layer, and then the process comprises separately: (a2) a step prior to coating pellets of doxylamine or a pharmaceutically acceptable salt thereof with 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 anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein the topical spray flow rate of the mixture comprising the enteric coating agents is 0.3 to 8.0 g / min per kg of pharmaceutically acceptable inert cores; (b2) a prior step of coating the pharmaceutically acceptable inert cores by continuously or discontinuously spraying a liquid mixture containing 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 containing the coating agent is 0.30 to 9.0 g / min per kg of the pharmaceutically acceptable inert cores; Further includes:

[0153] In one embodiment, the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric-release coating layer, and then the process comprises separately: (a2) a step prior to coating pellets of doxylamine or a pharmaceutically acceptable salt thereof with 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 anticaking 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 cores; (b2) a step prior to coating the pharmaceutically acceptable inert cores by continuously or discontinuously spraying a liquid mixture containing 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 solid addition rate of the powder is 0.50 to 9.0 g / min per kg of the pharmaceutically acceptable inert cores; Further includes:

[0154] In one embodiment, the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric-release coating layer, and then the process comprises separately: (a2) a step prior to coating pellets of doxylamine or a pharmaceutically acceptable salt thereof with 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 anticaking 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 cores; (b2) a step prior to coating the pharmaceutically acceptable inert cores by continuously or discontinuously spraying a liquid mixture containing 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 solid addition rate of the powder is 0.95 to 40.0 g / min per kg of the pharmaceutically acceptable inert cores; Further includes:

[0155] In one embodiment, the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric-release coating layer, and then the process comprises: (a2) a step prior to coating pellets of doxylamine or a pharmaceutically acceptable salt thereof with 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 anticaking agents, optionally one or more pore-forming agents, and, optionally, one or more pharmaceutically acceptable excipients, wherein the relationship between the average spray flow rate of the mixture comprising the coating agents and the average solid addition rate of the solid form mixture is 85:15 to 95:5; (b2) a step prior to coating the pharmaceutically acceptable inert cores by continuously or discontinuously spraying a liquid mixture containing 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 spray flow rate of the mixture containing the coating agent and the average solid addition rate is 25:75 to 40:60; Further includes:

[0156] In one embodiment, the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric-release coating layer, and then the process comprises separately: (a2) a step prior to coating pellets of doxylamine or a pharmaceutically acceptable salt thereof with 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 anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein the average spray rate of the mixture comprising the enteric coating agents is 0.30 to 3.00 g / min per kg of pharmaceutically acceptable inert cores, the average solid addition rate of the mixture in the solid form is 0.025 to 0.40 g / min per kg of pharmaceutically acceptable inert cores, and the relationship between the average spray flow rate of the mixture comprising the coating agents and the average solid addition rate of the mixture in the solid form is 85:15 to 95:5; (b2) a prior step of coating pharmaceutically acceptable inert cores by spraying a liquid mixture containing 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, the pharmaceutically acceptable excipients, wherein the average spray flow rate of the mixture containing the coating agent is 0.30 to 4.50 g / min per kg of pharmaceutically acceptable inert cores, the average solids addition rate of the powder is 0.50 to 9.0 g / min per kg of pharmaceutically acceptable inert cores, and the relationship between the average spray flow rate of the mixture containing the coating agent and the average solids addition rate is 25:75 to 40:60; Further includes:

[0157] In one embodiment, the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric-release coating layer, and then the process comprises separately: (a2) a step prior to coating pellets of doxylamine or a pharmaceutically acceptable salt thereof with 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 anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein the local spray flow rate of the mixture comprising the enteric coating agents is 0.3 to 8.0 g / min per kg of pharmaceutically acceptable inert cores, and the local solid addition rate of the solid form mixture is 0.025 to 40.0 g / min per kg of pharmaceutically acceptable inert cores; (b2) a prior step of coating the pharmaceutically acceptable inert cores by continuously or discontinuously spraying a liquid mixture containing 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 containing the coating agent is 0.30 to 9.0 g / min per kg of the pharmaceutically acceptable inert cores, and the local solid addition rate of the powder is 0.95 to 40.0 g / min per kg of the pharmaceutically acceptable inert cores; Further includes:

[0158] In one embodiment, the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric-release coating layer, and then the process comprises: (a2) 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 a powdered mixture of a solid mixture containing, per 1 kg of pharmaceutically acceptable inert cores, one or more anticaking agents, optionally one or more pore-forming agents, and, optionally, one or more pharmaceutically acceptable excipients, in an amount of 5.0 to 6.5 g. a step prior to coating pellets of silamine or a pharmaceutically acceptable salt thereof, wherein the average spray flow rate of the mixture containing an enteric coating agent is 0.30 to 3.00 g / min per 1 kg of pharmaceutically acceptable inert cores, the average solid addition rate of the mixture in solid form is 0.025 to 0.400 g / min per 1 kg of pharmaceutically acceptable inert cores, and the relationship between the average spray flow rate of the mixture containing a coating agent and the average solid addition rate of the mixture in solid form is 85:15 to 95:5; (b2) a prior step of coating pharmaceutically acceptable inert cores 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 spray flow rate of the mixture containing the coating agent is 0.30 to 4.50 g / min per kg of pharmaceutically acceptable inert cores, the average solid addition rate of the powder is 0.50 to 9.0 g / min per kg of pharmaceutically acceptable inert cores, and the relationship between the average spray flow rate of the mixture containing the coating agent and the average solid addition rate is 25:75 to 40:60; Further includes:

[0159] In one embodiment, the multiple unit dosage form of the first aspect of the invention as defined above comprises an intermediate enteric-release coating layer, and then the process comprises separately: (a2) a step prior to coating pellets of doxylamine or a pharmaceutically acceptable salt thereof with 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 powder form mixture of a solid form mixture containing one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients per 1 kg of pharmaceutically acceptable inert cores, wherein the local spray flow rate of the mixture containing the enteric coating agents is 0.3 to 8.0 g / min per 1 kg of pharmaceutically acceptable inert cores, and the local solid addition rate of the solid form mixture is 0.025 to 40.0 g / min per 1 kg of pharmaceutically acceptable inert cores; (b2) a prior step of coating the pharmaceutically acceptable inert cores 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 local spray flow rate of the mixture containing the coating agent is 0.30 to 9.0 g / min per kg of the pharmaceutically acceptable inert cores, and the local solid addition rate of the powder is 0.95 to 40.0 g / min per kg of the pharmaceutically acceptable inert cores; Further includes:

[0160] In one embodiment, the process of the present invention comprises preparing a multiple unit dosage form of the first aspect of the present invention as defined above, which does not comprise an intermediate enteric-release coating layer comprising one or more enteric coating agents, one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients. In one embodiment, the multiple unit dosage form of the first aspect of the present invention as defined above does not comprise an intermediate enteric-release coating layer, and the process further comprises performing step (b2) as defined above. All embodiments disclosed above for step (b2) of the process for preparing a multiple unit dosage form of the present invention comprising an intermediate enteric-release coating layer also apply to the process for preparing a multiple unit dosage form that does not comprise an intermediate enteric-release coating layer.

[0161] In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention as defined above further comprises a prior step (a3) ​​of coating the pharmaceutically acceptable inert core by continuous or discontinuous spraying of 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.

[0162] In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention as defined above further comprises a prior step (a3) ​​of coating the pharmaceutically acceptable inert core by continuous or discontinuous spraying of a liquid mixture comprising one or more coating agents and, optionally, one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a powdered mixture 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.

[0163] In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention as defined above further comprises a prior step (a3) ​​of coating the pharmaceutically acceptable inert core by continuous or discontinuous spraying of 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.

[0164] In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention defined above further comprises a prior step (a3) ​​of coating the pharmaceutically acceptable inert cores 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 powdered mixture 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 spray flow rate of the mixture comprising the coating agents is 0.30 to 4.50 g / min per kg of the pharmaceutically acceptable inert cores.

[0165] In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention defined above further comprises a prior step (a3) ​​of coating the pharmaceutically acceptable inert cores by continuously or discontinuously spraying a liquid mixture comprising one or more coating agents and, optionally, pharmaceutically acceptable excipients, and simultaneously or alternately adding a powdered mixture 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 spray flow rate of the mixture comprising the coating agents is 0.30 to 9.0 g / min per kg of the pharmaceutically acceptable inert cores.

[0166] In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention defined above further comprises a step (a3) ​​prior to coating the pharmaceutically acceptable inert cores 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 powdered mixture 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 powdered mixture is 0.95 to 18.0 g / min per kg of pharmaceutically acceptable inert cores.

[0167] In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention defined above further comprises a prior step (a3) ​​of coating the pharmaceutically acceptable inert cores 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 powdered mixture 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 solid addition rate of the powdered mixture is 0.95 to 40.0 g / min per kg of the pharmaceutically acceptable inert cores.

[0168] In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention defined above further comprises a prior step (a3) ​​of coating the pharmaceutically acceptable inert cores 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 powdered mixture 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 relationship between the average spray flow rate of the mixture comprising the coating agents and the average solid addition rate of the mixture in powdered form is 15:85 to 30:70.

[0169] In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention defined above further comprises a prior step (a3) ​​of coating the pharmaceutically acceptable inert cores 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 powder-form mixture comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein the average spray flow rate of the mixture comprising the coating agents is 0.30 to 4.50 g / min per kg of the pharmaceutically acceptable inert cores, and the average solid addition rate of the mixture in powder form is 0.95 to 18.0 g / min per kg of the pharmaceutically acceptable inert cores, specifically, the relationship between the average spray flow rate of the mixture comprising the coating agents and the average solid addition rate of the mixture in powder form is 15:85 to 30:70.

[0170] In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention defined above further comprises a prior step (a3) ​​of coating the pharmaceutically acceptable inert cores 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 spray flow rate of the mixture comprising the coating agents is 0.30 to 9.0 g / min per kg of the pharmaceutically acceptable inert cores, and the local solid addition rate of the mixture in powder form is 0.95 to 40.0 g / min per kg of the pharmaceutically acceptable inert cores.

[0171] In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention as defined above comprises 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 a powdered mixture 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. and (b) simultaneously or alternately adding the above-mentioned components to the pharmaceutically acceptable inert cores, wherein the average spray flow rate of the mixture containing the coating agent is 0.30 to 4.50 g / min per 1 kg of the pharmaceutically acceptable inert cores, the average solid addition rate of the mixture in powder form is 0.95 to 18.0 g / min per 1 kg of the pharmaceutically acceptable inert cores, and the relationship between the average spray 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.

[0172] In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention defined above further comprises a prior step (a3) ​​of coating the pharmaceutically acceptable inert cores by continuously or discontinuously spraying a liquid mixture comprising 15% by weight 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% by weight 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 local spray flow rate of the mixture comprising the coating agents is 0.30 to 9.0 g / min per kg of pharmaceutically acceptable inert cores, 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 cores.

[0173] In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention comprises preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof by carrying out steps (a2) and (a1) as defined above. In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention comprises preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating a pharmaceutically acceptable inert core by carrying out steps (a3), (a2), and (a1) as defined above. In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention comprises preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof by carrying out steps (a3) ​​and (a1) as defined above.

[0174] In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention comprises preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating a pharmaceutically acceptable inert core, which comprises carrying out (b2) and (b1).

[0175] In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention comprises, separately, preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof by carrying out steps (a2) and (a1) as defined above, and preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating a pharmaceutically acceptable inert core by carrying out steps (b2) and (b1).

[0176] In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention comprises, separately, preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating a pharmaceutically acceptable inert core by carrying out steps (a3), (a2) and (a1) as defined above, and preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating a pharmaceutically acceptable inert core by carrying out steps (b2) and (b1).

[0177] In one embodiment, the process for preparing the multiple-unit oral dosage form of the first aspect of the present invention comprises, separately, preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating a pharmaceutically acceptable inert core by carrying out steps (a3) ​​and (a1) as defined above, and preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating a pharmaceutically acceptable inert core by carrying out steps (b2) and (b1).

[0178] In one embodiment, each of the coating steps of the process of the present invention is carried out at an air temperature of 5° C. to 80° C., specifically 20° C. to 70° C., more specifically 25° C. to 65° C., and even more specifically 25° C. to 55° C. In one embodiment, each of the coating steps of the process of the present invention is carried out at an air temperature of 0 to 20 ml per kg of pharmaceutically acceptable inert cores. 3 / h airflow, specifically 0-6 m per kg of pharmaceutically acceptable inert nuclei 3 / h. The airflow is controlled using an anemometer-type air inlet detection system. In one embodiment, each of the coating steps of the process of the present invention is carried out at an air temperature of 5°C to 80°C and an airflow of 0 to 20 m / kg of pharmaceutically acceptable inert cores. 3 / h airflow.

[0179] In one embodiment, each coating step of the process of the present invention comprises spraying a mixture of one or more enteric coating agents and one or more modified-release coating agents as defined above, specifically, the enteric coating is a methacrylic acid-methyl methacrylate copolymer and the modified-release coating is shellac. In one embodiment, each coating step of the process of the present invention comprises spraying a mixture of one or more enteric coating agents and one or more modified-release coating agents, specifically, the enteric coating is a methacrylic acid-methyl methacrylate copolymer, specifically, methacrylic acid-methyl methacrylate copolymer (1:1) (Eudragit L), and the modified-release coating is shellac. In one embodiment, each coating step of the process of the present invention comprises a spray mixture comprising one or more enteric coating agents and one or more modified-release coating agents in a weight ratio of 5:95 to 30:70, particularly 8:92 to 20:80, where the enteric coating agent is methacrylic acid-methyl methacrylate copolymer, particularly methacrylic acid-methyl methacrylate copolymer (1:1) (Eudragit L), and the modified-release coating agent is shellac.

[0180] In one embodiment, the coating step of step (a1) of the process of the present invention, which comprises a spray mixture comprising one or more enteric coating agents and one or more modified-release coating agents, comprises 4 to 7 wt. % of an enteric coating agent, specifically methacrylic acid-methyl methacrylate copolymer (1:1) (Eudragit L), and 15 to 25 wt. % of a modified-release coating agent, specifically (dewaxed) shellac. In one embodiment, the coating step of step (a1) of the process of the present invention, which comprises a spray mixture comprising one or more enteric coating agents and one or more modified-release coating agents, comprises 4 to 7 wt. % of an enteric coating agent, specifically methacrylic acid-methyl methacrylate copolymer (1:1) (Eudragit L), and 15 to 25 wt. % of a modified-release coating agent, specifically (dewaxed) shellac, in a weight ratio of 15:85 to 30:70. In one embodiment, in the coating step of step (b1) of the process of the present invention, which comprises a spray mixture containing 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 the enteric coating agent and 10 to 35%, specifically 20 to 35%, of the modified-release coating agent. In one embodiment, in the coating step of step (b1) of the process of the present invention, which comprises a spray mixture containing 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 the enteric coating agent and 10 to 35%, specifically 20 to 35%, of the modified-release coating agent, in a weight ratio of 5:95 to 15:85.

[0181] In one embodiment, the coating step of step (b1) of the process of the present invention, which comprises a spray mixture comprising one or more enteric coating agents and one or more modified-release coating agents, comprises 2.0 to 7.5 wt. % methacrylic acid-methyl methacrylate copolymer (1:1) (Eudragit L) as the enteric coating agent and 10 to 35 wt. % (dewaxed) shellac as the modified-release coating agent. In one embodiment, the coating step of step (b1) of the process of the present invention, which comprises a spray mixture comprising one or more enteric coating agents and one or more modified-release coating agents, comprises 2.0 to 7.5 wt. % methacrylic acid-methyl methacrylate copolymer (1:1) (Eudragit L) as the enteric coating agent and 10 to 35 wt. % (dewaxed) shellac as the modified-release coating agent, in a weight ratio of 5:95 to 15:85.

[0182] In one embodiment, in coating step (a3) ​​of the process of the present invention, the coating agent is selected from the group consisting of polyvinylpyrrolidone, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, and microcrystalline cellulose, and mixtures thereof, specifically a mixture of polyvinylpyrrolidone and shellac. In one embodiment, in coating step (a3) ​​of the process of the present invention, the coating agent is a mixture of polyvinylpyrrolidone, specifically K30, and shellac in a weight ratio of 20:80 to 30:70. In one embodiment, in coating step (a3) ​​of the process of the present invention, the spray mixture comprises 30 to 40 wt.% of one or more coating agents as defined above. In a specific embodiment, the spray mixture in coating step (a3) ​​comprises 30 to 40 wt.% of a mixture of polyvinylpyrrolidone K30 and (dewaxed) shellac, and the polyvinylpyrrolidone and shellac in a weight ratio of 20:80 to 30:70. In certain embodiments, the spray mixture in coating step (a3) ​​comprises one or more organic solvents as defined above and below, specifically, the mixture comprises a solvent concentration of 0 to 70 wt. %. In certain embodiments, the spray mixture in coating step (a3) ​​is a 20% ethanol solution of polyvinylpyrrolidone K-30 and a 40% w / w ethanol solution of (dewaxed) shellac in a weight ratio of 20:80 to 40:60, specifically 30:70.

[0183] In one embodiment, in coating step (b2) of the process of the present invention, the spray mixture comprises 20 to 45% of one or more coating agents. In one embodiment, in coating step (b2) of the process of the present invention, the coating agent is selected from the group consisting of microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), shellac, polyethylene glycol (PEG) 6000, guar gum, and starch, specifically (dewaxed) shellac, especially shellac. In a specific embodiment, the spray mixture in coating step (b2) comprises 30% to 45% by weight of (dewaxed) shellac. In a specific embodiment, the spray mixture in coating step (b2) comprises one or more organic solvents as defined above and below, especially ethanol.

[0184] In one embodiment, in coating step (a2) of the process of the present invention, the enteric coating agent is as defined above and below, in particular methacrylic acid-methyl methacrylate copolymer (Eudragit L). In one embodiment, in coating step (b2) of the process of the present invention, the spray mixture comprises 5-15 wt. % of one or more enteric coating agents.

[0185] In one embodiment, in coating step (a2) of the process of the present invention, the spray mixture contains 5 to 15% by weight of one or more enteric coating agents, and the process includes adding 5.0 to 6.5 g of an anti-caking agent in powder form per 1 kg of pharmaceutically acceptable inert cores. In a specific embodiment, the spray mixture in coating step (a2) contains one or more organic solvents as defined above and below, specifically acetone, or a mixture of acetone, ethanol, and water. In a specific embodiment, the spray mixture in coating step (a2) contains one or more solvents in a concentration of 85% to 95% by weight, more specifically 90% by weight.

[0186] In one embodiment, in each of coating steps (a1) and (b1) of the process of the present invention, which comprises a spray mixture containing a coating agent, the spray mixture further comprises one or more organic solvents as defined above in an amount of 85 to 1200 g of solvent per 1 kg of pharmaceutically acceptable inert cores, specifically in an amount of 85 to 650 g of solvent per 1 kg of pharmaceutically acceptable inert cores. In one embodiment, in each of coating steps (a1) and (b1), which comprises a spray mixture containing a coating agent, the spray mixture further comprises one or more organic solvents as defined above in an amount of 270 to 285 g of solvent per 1 kg of pharmaceutically acceptable inert cores for (a1), and in an amount of 85 to 100 g of solvent per 1 kg of pharmaceutically acceptable inert cores for (b1).

[0187] In one embodiment, each of the coating steps of the process of the present invention is performed at a rate of 0 to 20 ml per kg of pharmaceutically acceptable inert cores. 3 / h airflow, specifically 0-6 m per kg of pharmaceutically acceptable inert nuclei 3 / h airflow.

[0188] In one embodiment, in each coating step of the process of the present invention, the temperature of the inert core of the pellet during the coating step is between 5° C. and 50° C., specifically between 10° C. and 30° C. In one embodiment, in each coating step of the process of the present invention, the temperature of the inert core of the pellet during the coating step is between 19° C. and 30° C. Temperature is controlled using a calibrated PT100 sensor in direct contact with the pellet being coated, but can be controlled using an equivalent system.

[0189] In one embodiment, in each of the spraying steps (a1), (a2), (a3), (b1) and (b2), the liquid mixture is sprayed at an atomizer atomizing pressure of 0.6 to 2.2 bar and an open pattern pressure of 0.6 to 2.5 bar.

[0190] The coating step of the process of the second aspect of the present invention can be carried out by any known method disclosed in the state of the art. In one embodiment, the coating step is carried out by a method selected from the group consisting of 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 reduced pressure 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 reduced pressure inside the pan coating is 0 to 100 Pa.

[0191] In one embodiment, the process of the present invention is one in which one or more of the coating steps is carried out in the absence of a drying step.

[0192] In one embodiment, the process of the present invention is one in which one or more of the coating steps further comprises one or more drying steps. In one embodiment, the process of the present invention further comprises an additional step (inter-coating drying step) of separately drying each of the plurality of pellets obtained after preparing each coating layer. This refers to the first plurality of pellets after preparing the inner active coating layer, the intermediate enteric-release coating layer, and the outer modified-release coating layer, and the second plurality of pellets after preparing the inner active coating layer and / or the outer modified-release coating layer.

[0193] In one embodiment, each drying step of the process of the present invention is carried out at a temperature between 15° C. and 60° C., specifically between 25° C. and 45° C. ... For a period of time appropriate to have the amount of each solvent less than 5000 ppm, the drying step is carried out at a temperature between 15° C. and 60° C., specifically between 25° C. and 45° C. 3 In one embodiment, each of the drying steps of the process of the present invention is carried out at a temperature of 15°C to 60°C, and 1 m for a period of time suitable to have an amount of each solvent less than 5000 ppm. 3 It is carried out with an airflow of at least / (h per kg of inert nuclei).

[0194] In certain embodiments, the inter-coating drying step is carried out at a temperature of 15°C to 45°C and at a rate of 1 ml per kg of pharmaceutically acceptable inert cores. 3 In a specific embodiment, the drying step of the outer coating of both plurality of pellets is carried out for at least 1 hour at an airflow of more than 2 ml / kg of pharmaceutically acceptable inert cores for a period of 8 hours to 12 hours, specifically at a temperature of 15°C to 60°C, preferably 25°C to 50°C, more specifically at a temperature of 40°C to 45°C. 3 / h.

[0195] In certain embodiments, the drying step of the process of the present invention is carried out in any suitable equipment, particularly in a coating pan at a speed of 0-10 rpm.

[0196] In one embodiment, the coating step of the process of the present invention is carried out in a coating pan at a rotation speed of 0 to 50 rpm, specifically 2 to 25 rpm, more specifically 10 to 2 rpm. The rotation pan speed can be controlled by any method known in the art. In particular, the method used in the present invention is by using a rotation counter.

[0197] In one embodiment, the process of the present invention further comprises one or more additional steps of separately sieving each of the plurality of pellets obtained in each of the coating steps if agglomeration of the powder into granules is observed. In one embodiment, the process of the present invention further comprises one or more additional steps of separately sieving a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof 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 / or a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof comprising a pharmaceutically acceptable inert core, an inner active coating layer, and an outer modified-release coating layer.

[0198] In one embodiment, the process of the present invention comprises one or more additional sieving steps as defined above until 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 variation of 200 μm or less as measured by analytical sieving, particularly a particle size variation of 150 μm or less, particularly a particle size variation of 100 μm or less, more particularly a particle size variation of 75 μm or less; and the particle size of the pellets of the first plurality of 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 the particle size of the pellets of the second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size variation of 400 μm to 2000 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size variation of 200 μm or less, particularly a particle size variation of 150 μm or less, particularly a particle size variation of 100 μm or less, more particularly a particle size variation of 75 μm or less, as measured by analytical sieving. All embodiments disclosed above for the particle size and particle size variation of the pharmaceutically acceptable core and the first and second plurality of pellets, and combinations thereof, as disclosed in the first aspect of the present invention also apply to the process of the second aspect of the present invention.

[0199] In one embodiment, when the multiple-unit oral dosage form is a hard capsule, the process of the present invention further comprises the additional step of filling the hard capsule with a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof and a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof. The capsule filling process can be carried out using known methods disclosed in the state of the 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 Bosch, IMA Zanasi, Dott Bonapace, and MG2 machines. In the present invention, the filling of the hard capsule is carried out using an automatic filling machine using intermittent motion. In one embodiment, when the multiple-unit oral dosage form is a hard capsule, the process of the present invention further comprises the additional step of filling the hard capsule, including individually and separately filling the first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof and the second plurality of 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 process of the present invention further comprises the additional step of filling the hard capsule, comprising first filling the capsule body with a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, and then filling the capsule body with a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, or vice versa, and attaching a capsule cap onto the capsule body. In one embodiment, when the multiple unit oral dosage form is a hard capsule, the process of the present invention further comprises the additional step of filling the hard capsule, comprising filling a combination of a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof and a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof.

[0200] The use of the first and second plurality of pellets disclosed in the present invention allows for the accuracy of the individual amount of each of the plurality of pellets filled into a capsule to be within ±5% by weight of the theoretical fill weight or less. For purposes of the present invention, the term "theoretical fill weight" refers to a target fill weight calculated based on the actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride to ensure a theoretical content of X mg of doxylamine succinate (X is, for example, 10.0 or 20.0 mg) and Y mg of pyridoxine hydrochloride (Y is, for example, 10.0 or 20.0 mg) per capsule, which can be measured by a suitable balance.

[0201] In one embodiment, when the multiple unit oral dosage form is a hard capsule, the step of filling the capsule includes adding one or more pharmaceutically acceptable excipients. Examples of suitable pharmaceutically acceptable excipients for use in the step of filling the capsule are selected from lubricants, fillers, diluents, flow agents, and anti-caking agents, or mixtures thereof.

[0202] In one embodiment, when the multiple unit oral dosage form is a hard capsule, the process further includes the additional step of filling the capsule with a first plurality of pellets comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof and a second plurality of pellets comprising a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, specifically having 5 mg to 50 mg of doxylamine succinate per capsule and 5 mg to 50 mg of pyridoxine hydrochloride per capsule.

[0203] All embodiments disclosed above and below for the multiple unit oral dosage form of the first aspect of the invention also apply to the process for its preparation of the second aspect of the invention.

[0204] The multiple-unit oral dosage form of the first aspect of the present invention may be defined by its preparation process 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 process of the present invention is considered to be part of the present invention. For the purposes of the present invention, the terms "obtainable", "obtained" and equivalent expressions are used interchangeably, and in each case the term "obtainable" encompasses the term "obtained".

[0205] All the embodiments disclosed above for the multiple unit oral dosage form of the first aspect of the present invention and the preparation process thereof also apply to the multiple unit oral dosage form of the present invention obtainable by the preparation process.

[0206] Finally, the present invention also relates to a multiple unit oral dosage form of the first aspect of the present invention for use in therapy. Specifically, the multiple unit oral dosage form of the first aspect of the present invention for use in the symptomatic treatment of nausea and vomiting. In one embodiment, the multiple unit oral dosage form of the first aspect of the present invention for use in the symptomatic treatment of nausea and vomiting (NVP) associated with pregnancy. In one embodiment, the multiple unit oral dosage form of the first aspect of the present invention for use in the symptomatic treatment of nausea and vomiting associated with tumor therapy, such as chemotherapy or radiotherapy. This aspect may also be configured as the use of a multiple unit oral dosage form of the first aspect of the present invention as defined above for the preparation of a medicament for the symptomatic treatment of nausea and vomiting. Also relates to a method of preventing and / or treating a mammal suffering from or susceptible to nausea and vomiting, the method comprising administering to said mammal a multiple unit oral dosage form of the first aspect of the present invention as defined above. In one embodiment, the nausea and vomiting is associated with pregnant women (NVP) or with oncology treatment, e.g., chemotherapy or radiation therapy. All of the embodiments disclosed above for the multiple unit oral dosage form of the first aspect of the invention also apply to the multiple unit oral dosage form of the first aspect of the invention as defined by its use.

[0207] Throughout the description and claims, the word "comprise" and variations of this word are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word "comprise" encompasses the term "consisting of." Additional objects, advantages, and features of the present invention will become apparent to those skilled in the art upon examination of this specification or may be learned by practice of the present invention. The following examples are provided by way of illustration and are not intended to be limiting of the present invention. Furthermore, the present invention includes all possible combinations of the specific and preferred embodiments described herein. [Example]

[0208] General Considerations D90 measurements of the active ingredients (doxylamine and pyridoxine) were performed using the Malvern method (Laser Mastersizer, Mie Theory, ISO 13320-1).

[0209] The D90 value of doxylamine or a pharmaceutically acceptable salt was measured using the Malvern method (Laser Mastersisizer, Mie theory; ISO 13320-1) under the following main operating parameters: Sample, dispersion medium 250 mg, 5 mL Isopar G + 5% w / w lecithin Ultrasonic time: 20 seconds Dispersant (volume) Isopar G (approx. 100 mL) Cleaning medium (volume) Acetone (approx. 50 mL), toluene (approx. 50 mL) and Isopar G (approximately 50 mL) Particle refractive index 1.52 Particle absorption 0.1 Dispersant refractive index 1.42 General Purpose Analysis Model - Normal Sensitivity Particle shape irregular Repeat the measurement three times for each aliquot. 10 seconds delay between measurements Sample measurement time: 15 seconds Background measurement time: 15 seconds Absorbance range 15~30% Suspension stirring speed: 2500±10rpm

[0210] The samples were measured using the following procedure. Procedure: Sample vials were subjected to a standard mixing cycle in a BioGrant PTR-30 rotary mixer. Approximately 250 mg of sample was transferred to a 10 mL vial and 5 mL of a 5% w / w solution of lecithin in Isopar G was added. The suspension was sonicated for 20 seconds using a Bandelin Sonopuls HD3100 equipped with an ultrasonic probe (MS72 tip, 20% intensity). Under continuous rotation (2500 rpm), the sample suspension was added to the measurement medium (approximately 100 mL of Isopar G) until the absorbance reached 15-30%. Measurements were taken immediately after sample addition and 3 minutes later to ensure dispersion stability. Each result is the average of three consecutive measurements of 15,000 swipes. The above procedure was performed three times.

[0211] - The determination of the D90 value of pyridoxine or a pharmaceutically acceptable salt thereof was carried out using the Malvern method (Laser Mastersisizer, Mie theory; ISO 13320-1) under the following main operating parameters: Sample, dispersion medium: 70-100 mg, 10 mL toluene Ultrasonic time: 20 seconds Dispersant (volume) Toluene (approximately 100 mL) Washing medium (volume): acetone (approx. 50 mL) twice, toluene (approx. 50 mL) Particle refractive index 1.52 Particle absorption 0.1 Dispersant refractive index 1.49 General Purpose Analysis Model - Normal Sensitivity Particle shape irregular Repeat the measurement three times for each aliquot. 10 seconds delay between measurements Sample measurement time: 15 seconds Background measurement time: 15 seconds Absorbance range 15~30% Suspension stirring speed: 2500±10rpm

[0212] The samples were measured using the following procedure. Procedure: Sample vials were subjected to a standard mixing cycle in a BioGrant PTR-30 rotary mixer. Approximately 70–250 mg of sample was transferred to a 20 mL vial and 10 mL of toluene was added. The suspension was sonicated for 20 seconds using a Bandelin Sonopuls HD3100 equipped with an ultrasonic probe (MS72 tip, 20% intensity). Under continuous rotation (2500 rpm), the sample suspension was added to the measurement medium (approximately 100 mL of toluene) until an absorbance value of 15–30% was reached. The sample vial was rinsed with approximately 5 mL of toluene. Measurements were taken immediately after sample addition and 3 minutes later to ensure dispersion stability. Each result is the average of three consecutive measurements of 15,000 swipes. The above procedure was performed three times.

[0213] 1. Capsules of doxylamine succinate and pyridoxine hydrochloride pellets of the present invention 1.1 Quantitative composition per hard capsule The amount of each ingredient per capsule is as follows: 1.1.1 Hard gelatin capsules containing 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride The hard gelatin capsules filled with doxylamine succinate and pyridoxine hydrochloride pellets of the present invention are obtained starting from inert cores having a particle size such that at least 90% of the inert cores have a particle size of 300 μm to 1700 μm as determined by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variation of 200 μm or less as determined by analytical sieving.

[0214] [Table 1]

[0215] (1) At least 90% of the inert cores have a particle size between 300 μm and 1700 μm, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variation of 200 μm or less from a given value consisting of 500 μm and 1400 μm as determined by analytical sieving. (2) Based on the actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride, calculate an actual target fill weight of 60 mg + / - 10% to ensure a theoretical content of 10.0 mg doxylamine succinate and 10.0 mg pyridoxine hydrochloride per capsule. (3) 48mg + / - 10%, based on capsule supplier's specifications

[0216] 1.1.2 Hard HPMC capsules containing 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride The hard HPMC capsules filled with doxylamine succinate and pyridoxine hydrochloride pellets of the present invention are obtained starting from inert cores having a particle size such that at least 90% of the inert cores have a particle size of 300 μm to 1700 μm as determined by analytical sieving, and at least 90% of the inert cores have a particle size variation of 200 μm or less as determined by analytical sieving.

[0217] [Table 2]

[0218] (1) At least 90% of the inert cores have a particle size between 300 μm and 1700 μm, and at least 90% of the inert cores have a particle size variation of 200 μm or less from a given value consisting of 500 μm and 1400 μm as determined by analytical sieving. (2) Based on the actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride, calculate an actual target fill weight of 60 mg + / - 10% to ensure a theoretical content of 10.0 mg doxylamine succinate and 10.0 mg pyridoxine hydrochloride per capsule. (3) 47mg + / - 10%, based on capsule supplier's specifications (4) HPMC (hydroxypropyl methylcellulose or hypromellose)

[0219] 1.1.3 Hard gelatin capsules containing 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride The hard gelatin capsules filled with doxylamine succinate and pyridoxine hydrochloride pellets of the present invention are obtained starting from inert cores having a particle size such that at least 90% of the inert cores have a particle size of 600 μm to 1180 μm as determined by analytical sieving, and at least 90% of the inert cores have a particle size variation of 100 μm or less as determined by analytical sieving.

[0220] [Table 3]

[0221] (1) At least 90% of the inert cores have a particle size between 600 μm and 1180 μm, and at least 90% of the inert cores have a particle size variation of 100 μm or less from a given value consisting of 710 μm and 1000 μm as determined by analytical sieving. (2) Based on the actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride, calculate an actual target fill weight of 60 mg + / - 10% to ensure a theoretical content of 10.0 mg doxylamine succinate and 10.0 mg pyridoxine hydrochloride per capsule. (3) 48mg + / - 10%, based on capsule supplier's specifications

[0222] 1.1.4 Hard HPMC capsules containing 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride The hard HPMC capsules filled with doxylamine succinate and pyridoxine hydrochloride pellets of the present invention are obtained starting from inert cores having a particle size such that at least 90% of the inert cores have a particle size of 600 μm to 1180 μm as determined by analytical sieving, and at least 90% of the inert cores have a particle size variation of 100 μm or less as determined by analytical sieving.

[0223] [Table 4]

[0224] (1) At least 90% of the inert cores have a particle size between 600 μm and 1180 μm, and at least 90% of the inert cores have a particle size variation of 100 μm or less from a given value consisting of 710 μm and 1000 μm as determined by analytical sieving. (2) Based on the actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride, calculate an actual target fill weight of 60 mg + / - 10% to ensure a theoretical content of 10.0 mg doxylamine succinate and 10.0 mg pyridoxine hydrochloride per capsule. (3) 47mg + / - 10%, based on capsule supplier's specifications (4) HPMC (hydroxypropyl methylcellulose or hypromellose)

[0225] 1.1.5 Hard gelatin capsules containing 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride The hard gelatin capsules filled with doxylamine succinate and pyridoxine hydrochloride pellets of the present invention are obtained starting from inert cores having a particle size such that at least 90% of the inert cores have a particle size of 710 μm to 1000 μm as determined by analytical sieving, and at least 90% of the inert cores have a particle size variation of 75 μm or less as determined by analytical sieving.

[0226] [Table 5]

[0227] (1) At least 90% of the inert cores have a particle size between 710 μm and 1000 μm, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variation of 75 μm or less from a given value consisting of 800 μm and 900 μm as determined by analytical sieving. (2) Based on the actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride, calculate an actual target fill weight of 60 mg + / - 10% to ensure a theoretical content of 10.0 mg doxylamine succinate and 10.0 mg pyridoxine hydrochloride per capsule. (3) 48 mg + / - 10%, based on capsule supplier's specifications.

[0228] 1.1.6 Hard HPMC capsules containing 10 mg doxylamine succinate and 10 mg pyridoxine hydrochloride The hard HPMC capsules filled with doxylamine succinate and pyridoxine hydrochloride pellets of the present invention are obtained starting from inert cores having a particle size such that at least 90% of the inert cores have a particle size of 710 μm to 1000 μm as determined by analytical sieving, and at least 90% of the inert cores have a particle size variation of 75 μm or less as determined by analytical sieving.

[0229] [Table 6]

[0230] (1) At least 90% of the inert cores have a particle size between 710 μm and 1000 μm, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variation of 75 μm or less from a given value consisting of 800 μm and 900 μm as determined by analytical sieving. (2) Based on the actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride, calculate an actual target fill weight of 60 mg + / - 10% to ensure a theoretical content of 10.0 mg doxylamine succinate and 10.0 mg pyridoxine hydrochloride per capsule. (3) 47mg + / - 10%, based on capsule supplier's specifications (4) HPMC (hydroxypropyl methylcellulose or hypromellose)

[0231] 1.1.7 Hard gelatin capsules containing 20 mg doxylamine succinate and 20 mg pyridoxine hydrochloride The hard gelatin capsules filled with doxylamine succinate and pyridoxine hydrochloride pellets of the present invention are obtained starting from inert cores having a particle size such that at least 90% of the inert cores have a particle size of 600 μm to 1180 μm as determined by analytical sieving, and at least 90% of the inert cores have a particle size variation of 100 μm or less as determined by analytical sieving.

[0232] [Table 7]

[0233] (1) At least 90% of the inert cores have a particle size between 600 μm and 1180 μm, and at least 90% of the inert cores have a particle size variation of 100 μm or less from a given value consisting of 710 μm and 1000 μm as determined by analytical sieving. (2) Based on the actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride, calculate an actual target fill weight of 120 mg + / - 10% to ensure a theoretical content of 20.0 mg doxylamine succinate and 20.0 mg pyridoxine hydrochloride per capsule. (3) 61 mg + / - 10%, based on capsule supplier's specifications

[0234] 1.1.8 Hard HPMC capsules containing 20 mg doxylamine succinate and 20 mg pyridoxine hydrochloride The hard HPMC capsules filled with doxylamine succinate and pyridoxine hydrochloride pellets of the present invention are obtained starting from inert cores having a particle size such that at least 90% of the inert cores have a particle size of 600 μm to 1180 μm as determined by analytical sieving, and at least 90% of the inert cores have a particle size variation of 100 μm or less as determined by analytical sieving.

[0235] [Table 8]

[0236] (1) At least 90% of the inert cores have a particle size between 600 μm and 1180 μm, and at least 90% of the inert cores have a particle size variation of 100 μm or less from a given value consisting of 710 μm and 1000 μm as determined by analytical sieving. (2) Based on the actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride, calculate an actual target fill weight of 120 mg + / - 10% to ensure a theoretical content of 20.0 mg doxylamine succinate and 20.0 mg pyridoxine hydrochloride per capsule. (3) 61 mg + / - 10%, based on capsule supplier's specifications (4) HPMC (hydroxypropyl methylcellulose or hypromellose)

[0237] 1.1.9 Hard gelatin capsules containing 20 mg doxylamine succinate and 20 mg pyridoxine hydrochloride The hard gelatin capsules filled with doxylamine succinate and pyridoxine hydrochloride pellets of the present invention are obtained starting from inert cores having a particle size such that at least 90% of the inert cores have a particle size of 600 μm to 1180 μm as determined by analytical sieving, and at least 90% of the inert cores have a particle size variation of 100 μm or less as determined by analytical sieving.

[0238] [Table 9]

[0239] (1) At least 90% of the inert cores have a particle size between 600 μm and 1180 μm, and at least 90% of the inert cores have a particle size variation of 100 μm or less from a given value consisting of 710 μm and 1000 μm as determined by analytical sieving. (2) Based on the actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride, calculate an actual target fill weight of 120 mg + / - 10% to ensure a theoretical content of 20.0 mg doxylamine succinate and 20.0 mg pyridoxine hydrochloride per capsule. (3) 76mg + / - 10%, based on capsule supplier's specifications

[0240] 1.1.10 Hard HPMC capsules containing 20 mg doxylamine succinate and 20 mg pyridoxine hydrochloride The hard HPMC capsules filled with doxylamine succinate and pyridoxine hydrochloride pellets of the present invention are obtained starting from inert cores having a particle size such that at least 90% of the inert cores have a particle size of 600 μm to 1180 μm as determined by analytical sieving, and at least 90% of the inert cores have a particle size variation of 100 μm or less as determined by analytical sieving.

[0241] [Table 10]

[0242] (1) At least 90% of the inert cores have a particle size between 600 μm and 1180 μm, and at least 90% of the inert cores have a particle size variation of 100 μm or less from a given value consisting of 710 μm and 1000 μm as determined by analytical sieving. (2) Based on the actual potency of the pellets in doxylamine succinate or pyridoxine hydrochloride, calculate an actual target fill weight of 120 mg + / - 10% to ensure a theoretical content of 20.0 mg doxylamine succinate and 20.0 mg pyridoxine hydrochloride per capsule. (3) 76mg + / - 10%, based on capsule supplier's specifications (4) HPMC (hydroxypropyl methylcellulose or hypromellose)

[0243] Dissolution Profile The doxylamine succinate and pyridoxine hydrochloride pellet capsules of the present invention in Examples 1.1.1 to 1.1.10 exhibit a dissolution profile in accordance with the target dissolution profile measured using a USP Type 2 apparatus (basket), as shown below, when the compositions are placed in 900 mL of the corresponding vehicle / buffer at 37°C ± 0.5°C and 100 rpm (revolutions per minute).

[0244] 1.2 Quantitative composition per pellet 1.2.1 A composition of doxylamine succinate pellets of the present invention, obtained starting from inert cores having a particle size such that at least 90% of the inert cores have a particle size between 600 μm and 1180 μm, with at least 90% of the inert cores having a particle size variation of 100 μm or less from a given value comprised between 710 μm and 1000 μm, the composition comprising a doxylamine succinate active ingredient having a particle size characterized by a D90 of 250 μm or less, and a talc anticaking agent having a particle size characterized by a D90 of 250 μm or less.

[0245] The amounts of each ingredient per batch of about 25 Kg or about 180 Kg of doxylamine succinate pellets are as follows:

[0246] [Table 11]

[0247] (*) If necessary, purified water or ethanol can be added as a processing aid to facilitate obtaining the enteric-release coating solution.

[0248] The resulting doxylamine succinate pellets have a particle size such that at least 90% of the pellets have a particle size between 710 μm and 1400 μm as determined by analytical sieving, and at least 90% of the pellets have a particle size variation of 100 μm or less from a given value consisting of 850 μm and 1250 μm as determined by analytical sieving. The uniformity of the pellet particle size and the pellet-to-pellet uniformity of active ingredient content makes the pellets easier to handle, allows for greater uniformity in dosing, and ensures the desired active ingredient content and desired dissolution profile as described in the examples above.

[0249] 1.2.2 Composition of pyridoxine hydrochloride pellets of the present invention, obtained starting from inert cores having a particle size such that at least 90% of the inert cores have a particle size between 600 μm and 1180 μm, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variation of not more than 100 μm from a given value comprised between 710 μm and 1000 μm, the composition comprising a pyridoxine hydrochloride active ingredient having a particle size characterized by a D90 of not more than 250 μm, and a talc anticaking agent having a particle size characterized by a D90 of not more than 250 μm.

[0250] The amounts of each ingredient per batch of about 25 Kg or about 180 Kg of pyridoxine hydrochloride pellets are as follows:

[0251] [Table 12]

[0252] (*) If necessary, purified water or ethanol can be added as a processing aid to facilitate obtaining the enteric-release coating solution.

[0253] The resulting pyridoxine hydrochloride pellets have a particle size such that at least 90% of the pellets have a particle size between 710 μm and 1400 μm as determined by analytical sieving, and at least 90% of the pellets have a particle size variation of 100 μm or less from a given value consisting of 850 μm and 1250 μm as determined by analytical sieving. The uniformity of the pellet particle size and the pellet-to-pellet uniformity of the active ingredient content makes the pellets easier to handle, allows for high uniformity in dosing, and ensures the desired active ingredient content and desired dissolution profile as described in the examples above.

[0254] 1.3 Preparation process by continuous atomization of liquid slurry / suspension 1.3.1 Preparation of 25 kg scale batches of doxylamine succinate pellets A. Phase Preparation Liquid coating slurry / suspension mixture for preparation of Phase 1 - 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. 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) was then added to this mixture. The resulting 10.7 kg mixture was continuously stirred. Liquid coating slurry / suspension mixture for the preparation of the second phase—intermediate coating layer: A mixture of 89 g of Eudradil L100, 1064 g of acetone, 133 g of purified water, and 45 g of talc (D90<250 μm) was prepared. The resulting mixture (1.331 kg) was continuously stirred. Liquid coating slurry / suspension mixture for preparation of the third phase—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 mixture (22.04 kg) was continuously stirred.

[0255] B. Preparation Process -Inner active coating layer 15.625 kg of inert cores (sucrose and starch sugar spheres) with particle sizes such that at least 90% of the inert cores had a particle size between 600 μm and 1180 μm, and at least 90% of the pharmaceutically acceptable inert cores had a particle size variation of 100 μm or less from the given values ​​consisting of 710 μm and 1000 μm, were transferred to a coating pan. Next, the liquid coating slurry / suspension mixture Phase 1 was continuously sprayed onto the pellets at a coating pan rotation speed of 15 rpm, a spray flow rate of 65 g / min, a vacuum of less than 100 Pa inside the coating pan, an atomizer pressure of approximately 1.0 bar, and an open pattern pressure of approximately 1.2 bar. While spraying Phase 1, hot air (approximately 100 m at 30-35°C) was simultaneously blown onto the pellets. 3The pellets were continuously dried using an airflow of 1000 rpm (1000 rpm / h) to maintain the core temperature of the pellets at 22°C to 26°C. The coated pellets thus obtained were dried at speeds of 0 and 10 rpm and at a temperature of approximately 160 m. 3 The pellets were dried at 35-50°C for 10 minutes by rotating them in a coating pan with an airflow of 1 / h, to obtain dried coated pellets with an inner active coating layer containing the active ingredient. If necessary, the dried pellets can be sieved to discard undesired particle size, powder, and agglomerates.

[0256] -Intermediate coating layer The second phase liquid mixture was continuously sprayed onto the coated active pellets obtained in the previous step with a coating pan rotation speed of 15 rpm at a spray flow rate of 20 g / min, a vacuum inside the coating pan of less than 100 Pa, an atomizer pressure of about 1.0 bar, and an open pattern pressure of about 1.2 bar. While spraying the second phase, hot air (100 m at 30-35°C) was blown simultaneously. 3 The pellets were continuously dried using an airflow of less than 1 / h (less than 1 / h) and maintaining the pellet core temperature at 24°C to 28°C. The resulting coated pellets were dried at speeds of 0 rpm and 10 rpm for approximately 160 min. 3 The pellets were dried at 35-50°C for 30 minutes by rotating them in the coating pan with an airflow of 1 / h to obtain dried coated pellets having an inner active coating layer and a middle coating layer.

[0257] -Outer modified release coating layer Next, the third-phase coating mixture was continuously sprayed onto the bilayer pellets obtained in the previous step at a coating pan rotation speed of 15 rpm, a spray flow rate of 75 g / min, a vacuum inside the coating pan of less than 100 Pa, an atomizer pressure of approximately 1.0 bar, and an open pattern pressure of approximately 1.2 bar. While spraying the third phase, hot air (140 m at 45-50°C) was blown simultaneously. 3The pellets were continuously dried using an airflow of more than 1000 rpm (more than 1000 rpm) to maintain the pellet core temperature at 25°C to 29°C. The resulting coated pellets were dried at speeds of 0 rpm and 10 rpm for approximately 160 min. 3 The pellets were dried at about 50°C for 30 minutes by continuing to rotate in the coating pan with an air flow of 1 / h to obtain dried coated pellets having an inner active coating layer, a middle coating layer and an outer coating layer.

[0258] The pellets thus obtained have the target dissolution profile. If desired, the dried pellets can be sieved to discard undesirable particle sizes, powders and agglomerates.

[0259] The doxylamine succinate modified-release pellets thus obtained were stored in 25 kg sealed double FDA-approved polyethylene bags in sealed high density polyethylene drums.

[0260] 1.3.2. Preparation of 25 kg scale batches of pyridoxine hydrochloride pellets A. Phase Preparation Liquid coating slurry / suspension mixture for preparation of Phase 4 - inner active coating layer: A mixture of 0.850 kg (dewaxed) shellac and 3.48 kg ethanol was prepared. To this mixture was then added 4.24 kg pyridoxine hydrochloride (D90<250 μm). The resulting 8.43 kg mixture was continuously stirred. Liquid coating slurry / suspension mixture for preparation of Phase 5 - outer coating layer: 385 g of talc (D90<250 μm) was added to a mixture of 68 g of Eudragil L100, 702 g of shellac, 610 g of acetone, 9.72 kg of ethanol, and 68 g of purified water. The resulting mixture (11.56 kg) was continuously stirred.

[0261] B. Preparation Process -Inner active coating layer 17.962 kg of inert cores (sucrose and starch sugar spheres) with particle sizes such that at least 90% of the inert cores had a particle size between 600 μm and 1180 μm, and at least 90% of the pharmaceutically acceptable inert cores had a particle size variation of 100 μm or less from the given values ​​consisting of 710 μm and 1000 μm, were transferred to a coating pan. Next, the liquid coating slurry / suspension mixture Phase 4 was continuously sprayed onto the pellets at a coating pan rotation speed of 15 rpm, a spray flow rate of 60 g / min, a vacuum of less than 100 Pa inside the coating pan, an atomizer pressure of approximately 1.0 bar, and an open pattern pressure of approximately 1.2 bar. While spraying Phase 4, hot air (approximately 100 m at 38-42°C) was simultaneously blown onto the pellets. 3 The pellets were continuously dried using an airflow of approximately 160 m / h (approximately 160 m / h) by maintaining the core temperature of the pellets at 21°C to 24°C. The resulting coated pellets were continuously rotated in a coating pan at rotation speeds consisting of 0 rpm and 10 rpm. 3 The pellets were then dried at 40-50°C for 20 minutes at 1000 kJ / h airflow to obtain dried coated pellets with an inner active coating layer containing the active ingredient. If necessary, the dried pellets can be sieved to discard undesired particle sizes, powders, and agglomerates.

[0262] -Outer modified release coating layer Next, the fifth phase coating mixture was continuously sprayed onto the coated active pellets obtained in the previous step at a coating pan rotation speed of 15 rpm, a spray flow rate of 63 g / min, a vacuum inside the coating pan of less than 100 Pa, an atomizer pressure of approximately 1.0 bar, and an open pattern pressure of approximately 1.2 bar. While spraying the fifth phase, hot air (130 m at 50-65°C) was blown simultaneously. 3 The pellets were continuously dried using hot air (120 m at 45-55°C) with an airflow of more than 1000 rpm, maintaining the core temperature of the pellets at 26-30°C. The resulting coated pellets were continuously rotated in a coating pan at rotation speeds consisting of 0 rpm and 10 rpm. 3The pellets were dried at an airflow of more than 1000 kJ / h for 30 minutes to obtain dried coated pellets having an inner active coating layer and an outer coating layer in a yield of more than 93%.

[0263] The pellets thus obtained have the target dissolution profile. If desired, the dried pellets can be sieved to discard undesirable particle sizes, powders and agglomerates.

[0264] The doxylamine succinate modified-release pellets thus obtained were stored in 25 kg sealed double FDA-approved polyethylene bags in sealed high density polyethylene drums.

[0265] 1.4. A preparation process by discontinuous spraying of a solution and alternating addition of a powdered solid 1.4.1. Preparation of 25 kg scale batches of doxylamine succinate pellets A. Phase Preparation Powder mixture for preparation of Phase 1 - inner active coating layer: In a coating pan, 4.192 kg of doxylamine succinate (D90<250 μm), 0.279 kg of Aerosil 200 pharma (D90<250 μm), and 1.397 kg of talc (D90<250 μm) were mixed. Binder solution for preparation of Phase 2 - inner active coating layer: 0.419 kg of povidone K30 20% w / w ethanol solution and 1.169 kg of (dewaxed) shellac 40% w / w ethanol solution were mixed. Coating solution for preparation of third phase - outer coating: 89 g of Eudragit L100 was added to 711 g of acetone, the mixture was stirred, and then 89 g of water was added to obtain a clear solution. Coating solution for preparation of phase 4 - outer coating: 2.950 g of Eudragit L 10% w / w solution in acetone, 300 g of purified water and 2.937 kg of (dewaxed) shellac 40% w / w solution in ethanol were mixed.

[0266] B. Preparation Process -Inner active coating layer The above-mentioned amount of inert cores (spherical sugars of sucrose and starch) having particle sizes such that at least 90% of the inert cores have a particle size between 600 μm and 1180 μm, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variation of 100 μm or less from the given values ​​consisting of 710 μm and 1000 μm, was transferred to a coating pan. Rotation was then started, and the second phase of binder solution was sprayed discontinuously in a repeated cycle in the following sequence, while maintaining a coating pan rotation speed of 20 rpm and a vacuum inside the coating pan of less than 100 Pa throughout this coating process. - spraying the binder solution second phase for 24 seconds at a spray rate of 78 g / min, an atomizer pressure of about 0.8 bar and an open pattern pressure of about 1.0 bar. -5 second pause 1 - Addition of powder mixture phase 1 at a powder addition rate of 107 g / min for 66 seconds -30 second pause -0 seconds drying time (no drying).

[0267] The core temperature of the pellets was maintained at 21° C. to 25° C. The coated pellets thus obtained were heated at speeds comprised of 0 and 5 rpm for approximately 50 min. 3 The pellets were dried at room temperature for 2 hours by rotating in a coating pan with an air flow of more than 1 / h to obtain dried coated pellets with an inner active coating layer having the active ingredient. If necessary, the dried pellets can be sieved to discard undesired particle sizes, powders, and agglomerates.

[0268] -Middle enteric-release coating layer The coated active pellets obtained in the previous step were transferred to a coating pan, and then rotation was initiated to spray the third phase of the coating solution discontinuously in the following cycles, while maintaining a coating pan rotation speed of 20 rpm and a vacuum pressure of less than 100 Pa inside the coating pan during this coating step. - spraying the binder solution third phase for 60 seconds at a spray rate of 46 g / min, an atomizer pressure of about 1.0 bar and an open pattern pressure of about 1.0 bar. -Addition of talc (D90<250μm) at a powder addition rate of 16.2g / min for 15 seconds -15 second pause -45 seconds drying time (air flow 50m 3 / h, 40-45℃)

[0269] The core temperature of the pellets was maintained at 19° C. to 24° C. The coated pellets thus obtained were heated at speeds comprised of 0 and 5 rpm for approximately 50 min. 3 The pellets were dried at room temperature for 1 hour by rotating in a coating pan with an air flow of more than 1 / h to obtain dried coated pellets with an inner active coating layer having the active ingredient. If necessary, the dried pellets can be sieved to discard undesired particle sizes, powders, and agglomerates.

[0270] -Outer modified release coating layer The coated active pellets obtained in the previous step were transferred to a coating pan, and then rotation was initiated, and the fourth phase of the coating solution was sprayed discontinuously in cycles in the following sequence, while maintaining a coating pan rotation speed of 20 rpm and a vacuum pressure inside the coating pan of less than 100 Pa during this coating step. - spraying the binder solution fourth phase for 20 seconds at a spray rate of 39 g / min, an atomizer pressure of about 1.4 bar and an open pattern pressure of about 1.6 bar. -Addition of talc (D90<250μm) at a powder addition rate of 17g / min for 10 seconds -20 second pause -0 seconds drying time (no drying).

[0271] The core temperature of the pellets was maintained at 24° C. to 29° C. The coated pellets thus obtained were then heated at speeds consisting of 0 rpm and 5 rpm for 80 min. 3The pellets were rotated in a coating pan with an airflow of more than 1000 kJ / h and dried at 40-45°C for 12 hours to obtain dried coated pellets with an inner active coating layer containing the active ingredient in a yield of 93% or more, calculated by dividing the obtained amount by the theoretical amount x 100.

[0272] The pellets thus obtained have the target dissolution profile. If desired, the dried pellets can be sieved to discard undesirable particle sizes, powders and agglomerates.

[0273] The doxylamine succinate modified-release pellets thus obtained were stored in 25 kg sealed double FDA-approved polyethylene bags in sealed high density polyethylene drums.

[0274] 1.4.2. Preparation of 25 kg scale batches of pyridoxine hydrochloride pellets A. Phase Preparation Phase 5 - Coating solution for preparation of outer coating: 0.679 kg of Eudragit L 10% w / w solution in acetone, 68 g of water and 1.758 kg of (dewaxed) shellac 40% w / w solution in ethanol were mixed.

[0275] B. Preparation Process -Inner active coating layer The above-mentioned amount of inert cores (spherical sugars of sucrose and starch) having particle sizes such that at least 90% of the inert cores have a particle size between 600 μm and 1180 μm, and at least 90% of the pharmaceutically acceptable inert cores have a particle size variation of 100 μm or less from the given values ​​consisting of 710 μm and 1000 μm, was transferred to a coating pan. Rotation was then started, and (dewaxed) shellac 40% w / w ethanol solution was sprayed discontinuously in cycles in the following sequence, while maintaining a coating pan rotation speed of 20 rpm and a vacuum of less than 100 Pa inside the coating pan throughout this coating process. - spraying the binder solution second phase for 18 seconds at 56 g / min, atomizer pressure of about 0.8 bar and open pattern pressure of about 1.0 bar. -5 second pause 1 -Addition of pyridoxine hydrochloride (D90<250μm) at a powder addition rate of 233g / min for 9 seconds -30 second pause 2 -0 seconds drying time (no drying).

[0276] The core temperature of the pellets was maintained at 19° C. to 24° C. The coated pellets thus obtained were heated at speeds comprised of 0 and 5 rpm for approximately 50 min. 3 The pellets were dried at room temperature for 2 hours by rotating in a coating pan with an air flow of more than 1 / h to obtain dried coated pellets with an inner active coating layer having the active ingredient. If necessary, the dried pellets can be sieved to discard undesired particle sizes, powders, and agglomerates.

[0277] -Outer modified release coating layer The coated active pellets obtained in the previous step were transferred to a coating pan, and then rotation was initiated, and the fourth phase of the coating solution was sprayed discontinuously in cycles in the following sequence, while maintaining a coating pan rotation speed of 20 rpm and a vacuum pressure inside the coating pan of less than 100 Pa during this coating step. - spraying the binder solution fourth phase for 18 seconds at a spray rate of 40 g / min, an atomizer pressure of about 1.4 bar and an open pattern pressure of about 1.6 bar. -Addition of talc (D90<250μm) at a powder addition rate of 40g / min for 9 seconds -20 second pause -0 seconds drying time (no drying).

[0278] The core temperature of the pellets was maintained at 23° C. to 28° C. The coated pellets thus obtained were then heated at speeds consisting of 0 rpm and 5 rpm for 50 min. 3The pellets were rotated in a coating pan with an airflow of more than 1 / h and dried at 40-45°C for 12 hours to obtain dried coated pellets with an inner active coating layer containing the active ingredient in a yield of more than 93%.

[0279] The pellets thus obtained have the target dissolution profile. If desired, the dried pellets can be sieved to discard undesirable particle sizes, powders and agglomerates.

[0280] The doxylamine succinate modified-release pellets thus obtained were stored in 25 kg sealed double FDA-approved polyethylene bags in sealed high density polyethylene drums.

[0281] -Outer modified release coating layer The fourth phase was sprayed onto the coated active pellets obtained in the previous step at a flow rate of 100 g / min. While spraying the fourth phase of the solution, the core temperature of the pellets was kept at 17°C to 22°C, and the airflow was kept at 100 m / s. 3 Talc was added in solid form at a solid addition rate of 50 g / min and a rotation speed of 16 rpm, while maintaining the temperature below 100°C / h. The resulting coated pellets were rotated in the coating pan for 130 min at speeds consisting of 0 rpm and 10 rpm. 3 The mixture was dried at 40-45°C for 8 hours or more and up to 12 hours at a rate of 1 / h with continuous rotation and an airflow of over 1 / h (yield of 93% or more).

[0282] The pellets thus obtained have the target dissolution profile. If desired, the dried pellets can be sieved to discard undesirable particle sizes, powders and agglomerates.

[0283] The pyridoxine hydrochloride modified release pellets thus obtained were stored in 50 kg sealed double FDA grade polyethylene bags in sealed high density polyethylene drums.

[0284] The above-described process for preparing the first and second plurality of modified-release pellets of the present invention results in doxylamine succinate pellets having a particle size such that at least 90% of the pellets have a particle size between 710 μm and 1400 μm as measured by analytical sieving, with at least 90% of the pellets having a particle size variation of no more than 100 μm from a given value consisting of 850 μm and 1250 μm as measured by analytical sieving, and the pyridoxine hydrochloride pellets having a particle size such that at least 90% of the pellets have a particle size between 710 μm and 1400 μm as measured by analytical sieving, with at least 90% of the pellets having a particle size variation of no more than 100 μm from a given value consisting of 850 μm and 1250 μm as measured by analytical sieving.

[0285] The same procedures described above for preparing the first and second plurality of modified-release pellets of the present invention can be carried out using inert cores (sucrose and starch sugar spheres), but with at least 90% of the inert cores having a particle size of 710 μm to 1000 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores having a particle size variation of 75 μm or less for a given value of 800 μm to 900 μm as measured by analytical sieving. In this case, the resulting doxylamine succinate pellets have a particle size such that at least 90% of the pellets have a particle size between 800 μm and 1400 μm as determined by analytical sieving, with at least 90% of the pellets having a particle size variation of not more than 75 μm from a given value consisting of 900 μm and 1180 μm as determined by analytical sieving, and the resulting pyridoxine hydrochloride pellets have a particle size such that at least 90% of the pellets have a particle size between 800 μm and 1400 μm as determined by analytical sieving, with at least 90% of the pellets having a particle size variation of not more than 75 μm from a given value consisting of 900 μm and 1180 μm as determined by analytical sieving.

[0286] Capsule filling Each hard capsule was filled with about 60 mg of doxylamine succinate modified-release pellets of the present invention as defined above and about 60 mg of pyridoxine hydrochloride modified-release pellets using a Bosch Zanassi E48 automatic capsule filling machine to yield capsules containing about 10 mg of doxylamine succinate and about 10 mg of pyridoxine hydrochloride.

[0287] The same procedure described above for preparing capsules having about 10 mg of doxylamine succinate and about 10 mg of pyridoxine hydrochloride can be carried out using a Bosch Zanassi E48 automatic capsule filling machine by filling capsules with about 120 mg of modified-release pellets of doxylamine succinate and about 120 mg of modified-release pellets of pyridoxine hydrochloride of the present invention to obtain capsules containing about 20 mg of doxylamine succinate and about 20 mg of pyridoxine hydrochloride.

[0288] 2.Dissolution test Dissolution Profile The target dissolution profile requires that both doxylamine succinate and pyridoxine hydrochloride dissolve poorly under gastric conditions and that primary therapeutic concentrations are achieved in the intestinal tract due to their rapid dissolution rates. In particular, the preparation method of the present invention makes it possible to obtain capsules filled with such modified-release pellets of doxylamine succinate and modified-release pellets of pyridoxine hydrochloride, which capsules exhibit a dissolution profile according to the following: 5% to 35% by weight of the doxylamine content was dissolved in 0.1N HCl medium (pH = 1) in 1 hour. Next, the medium was replaced with a medium of pH 4.5 (0.05 M acetate buffer), and after 4 hours, more than 35% to 75% by weight of the initial doxylamine content was eluted. Next, the medium was replaced with a medium of pH 6.8 (0.05 M phosphate buffer), and at 7 hours, more than 75% of the initial doxylamine content was cumulatively dissolved, and 5% to 35% by weight of the pyridoxine content was dissolved in 0.1N HCl medium (pH = 1) in 1 hour. Next, the medium was replaced with a medium (0.05 M acetate buffer) of pH 4.5, and after 4 hours, more than 35% by weight to 75% by weight of the initial pyridoxine content was eluted. Next, the medium was replaced with a medium of pH 6.8 (0.05 M phosphate buffer), and at 7 hours, more than 75% of the initial pyridoxine content was eluted cumulatively. Here, the dissolution profile is measured using a USP Type II apparatus (basket) by placing the composition in 900 mL of the corresponding medium / buffer at 37° C.±0.5° C. and 100 rpm.

[0289] Dissolution tank conditions Paddle speed: 100 rpm ·Elution medium temperature: 37℃±0.5℃ Dissolution medium: 0.1N hydrochloric acid ·Container volume: 900mL Duration: 1 hour Dissolution medium: pH 4.5; 0.05M acetate buffer ·Container volume: 900mL Time: 1st to 4th period Dissolution medium: pH 6.8; 0.05M phosphate buffer ·Container volume: 900mL Time: 4th to 7th period

[0290] Chromatographic analysis conditions Sample preparation: Take an aliquot of approximately 10 ml and filter it through a 0.70 μm membrane filter, then another 0.22 μm membrane filter. ·Flow rate: 1mL / min Column: Kromasil 100-5 C18, 150 x 4.0 mm Phase: Methanol / water ·Injection volume: 100μL Excitation wavelength: 220nm Chromatography time: 25 minutes Aqueous phase: ammonium acetate buffer (0.06 M, pH 5.0) + 0.1% sodium hexanesulfonate (PICB6) Gradient

[0291] [Table 13]

[0292] result The capsules of the present invention, as defined above and below, containing pellets of doxylamine succinate and pyridoxine hydrochloride, exhibit target dissolution profiles such that when placed under gastric conditions, at least 5% of both doxylamine succinate and pyridoxine hydrochloride dissolves in one hour, when placed under duodenal conditions (pH=4.5) at least 35% of doxylamine succinate and pyridoxine hydrochloride dissolves after four hours, and when placed under colonic conditions at least 75% of doxylamine succinate and pyridoxine hydrochloride dissolves after seven hours.

[0293] Packaging and Stability Testing Blister: The inventive doxylamine succinate and pyridoxine hydrochloride pellet capsules of Examples 1.1.1 to 1.1.10 are stable when primary packaged in blisters made of PVC / PVdC (one side of the blister) and aluminum (the other side of the blister), allowing storage at or below 25°C and 60% relative humidity. When primary packaged in blisters made of AquaBa® or aluminum (on one side of the blister) and aluminum (on the other side of the blister), the doxylamine succinate and pyridoxine hydrochloride pellet capsules of Examples 1.1.2, 1.1.4, 1.1.6, 1.1.8 and 1.1.10 are stable, allowing storage at or below 30°C and 75% relative humidity.

[0294] bottle: The doxylamine succinate and pyridoxine hydrochloride pellet capsules of the present invention in Examples 1.1.1 to 1.1.10 are stable when primary packaged in a plastic bottle containing a desiccant, allowing storage at temperatures below 30°C and below 75% relative humidity.

[0295] For completeness, various aspects of the present invention are described in detail in the following numbered clauses.

[0296] Clause 1. A modified release multiple unit oral dosage form comprising: A first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, - a pharmaceutically acceptable inert nucleus, 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 anticoagulants, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; an optional 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; and 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-forming agents, and optionally one or more pharmaceutically acceptable excipients; a first plurality of modified release pellets comprising: a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, - a pharmaceutically acceptable inert nucleus, an inner active coating layer comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; 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-forming agents, and optionally one or more pharmaceutically acceptable excipients; a second plurality of modified release pellets comprising: Including, Here, the particle size of the pharmaceutically acceptable inert cores 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 By analytical sifting A modified release multiple unit oral dosage form having a measured particle size variation of 200 μm, particularly a particle size variation of 150 μm, particularly a particle size variation of 100 μm, particularly a particle size variation of 75 μm, particularly a particle size variation of 50 μm.

[0297] Article 2. A first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, - a pharmaceutically acceptable inert nucleus, 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 anticoagulants, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; 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; and 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-forming agents, and optionally one or more pharmaceutically acceptable excipients; a first plurality of modified release pellets comprising: a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, - a pharmaceutically acceptable inert nucleus, an inner active coating layer comprising a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more coating agents, and optionally one or more pharmaceutically acceptable excipients; 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-forming agents, and optionally one or more pharmaceutically acceptable excipients; a second plurality of modified release pellets comprising: Including, Here, the particle size of the pharmaceutically acceptable inert cores 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 By analytical sifting 2. The modified release multiple unit oral dosage form according to clause 1, wherein the dosage form has a measured particle size variation of 200 μm, particularly a particle size variation of 150 μm, particularly a particle size variation of 100 μm, particularly a particle size variation of 75 μm, particularly a particle size variation of 50 μm.

[0298] Article 3. The dosage form comprises at least 90% of the inert cores having a particle size of 300 μm to 1700 μm as determined by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores By analytical sifting a pharmaceutically acceptable inert core having a particle size such that it has a measured particle size variation of 200 μm, particularly a particle size variation of 150 μm, particularly a particle size variation of 100 μm, particularly a particle size variation of 75 μm, more particularly a particle size variation of 50 μm; Specifically, the dosage form has at least 90% of the inert cores having a particle size of 300 μm to 1400 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores By analytical sifting a pharmaceutically acceptable inert core having a particle size such that it has a measured particle size variation of 200 μm, particularly a particle size variation of 150 μm, particularly a particle size variation of 100 μm, particularly a particle size variation of 75 μm, more particularly a particle size variation of 50 μm; Specifically, the dosage form has at least 90% of the inert cores having a particle size of 600 μm to 1180 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores By analytical sifting a pharmaceutically acceptable inert core having a particle size such that it has a measured particle size variation of 150 μm, particularly a particle size variation of 100 μm, particularly a particle size variation of 75 μm, more particularly a particle size variation of 50 μm; Specifically, the dosage form has at least 90% of the inert cores having a particle size of 710 μm to 1000 μm as determined by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores By analytical sifting a pharmaceutically acceptable inert core having a particle size such that it has a measured particle size variation of 100 μm, particularly a particle size variation of 75 μm, more particularly a particle size variation of 50 μm; Specifically, the dosage form has at least 90% of the inert cores having a particle size of 710 μm to 850 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores By analytical sifting a pharmaceutically acceptable inert core having a particle size such that it has a measured particle size variation of 70 μm, and in particular a particle size variation of 50 μm; Specifically, the dosage form has at least 90% of the inert cores having a particle size of 850 μm to 1000 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores By analytical sifting 3. A modified release multiple unit oral dosage form according to clause 1 or 2, comprising a pharmaceutically acceptable inert core having a particle size such that it has a measured particle size variation of 70 μm, in particular a particle size variation of 50 μm.

[0299] Article 4. The particle size of the first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size between 400 μm and 1900 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size between 400 μm and 1900 μm as measured by analytical sieving. By analytical siftingThe particle size dispersion measured is 200 μm, particularly 150 μm, particularly 100 μm, particularly 75 μm, more particularly 50 μm, The particle size of the second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof is such that at least 90% of the pellets have a particle size between 400 μm and 1900 μm as measured by analytical sieving, and at least 90% of the pellets have a particle size between 400 μm and 1900 μm as measured by analytical sieving. By analytical sifting The particle size variation measured is 200 μm, particularly 150 μm, particularly 100 μm, particularly 75 μm, more particularly 50 μm, 4. The modified release multiple unit oral dosage form according to any one of clauses 1 to 3.

[0300] Article 5. The particle size of the doxylamine or its pharmaceutically acceptable salt is characterized by having a D90 of 250 μm or less, and the particle size of the pyridoxine or its pharmaceutically acceptable salt is characterized by having a D90 of 250 μm or less; or alternatively, the particle size of the doxylamine or pharmaceutically acceptable salt thereof is characterized by having a D90 of 250 μm or less; the particle size of the pyridoxine or pharmaceutically acceptable salt thereof is characterized by having a D90 of 250 μm or less; the particle size of the one or more anticoagulants is characterized by having a D90 of 250 μm or less; and optionally the particle size of the one or more pore-forming agents is characterized by having a D90 of 250 μm or less; 5. The modified release multiple unit oral dosage form according to any one of clauses 1 to 4.

[0301] Clause 6. A 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 doxylamine succinate and pyridoxine hydrochloride.

[0302] Clause 7. The modified-release multiple-unit oral dosage form of any 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.

[0303] Article 8. A modified release multiple unit oral dosage form comprising: 5% to 35% by weight of the doxylamine content was dissolved in 0.1N HCl medium (pH = 1) in 1 hour. Next, the medium was replaced with a medium of pH 4.5 (0.05 M acetate buffer), and after 4 hours, more than 35% to 75% by weight of the initial doxylamine content was eluted. Next, the medium was replaced with a medium of pH 6.8 (0.05 M phosphate buffer), and at 7 hours, more than 75% by weight of the initial doxylamine content was cumulatively dissolved. 5% to 35% by weight of the pyridoxine content was dissolved in 0.1N HCl medium (pH = 1) in 1 hour. Next, the medium was replaced with a medium (0.05 M acetate buffer) of pH 4.5, and after 4 hours, more than 35% by weight to 75% by weight of the initial pyridoxine content was eluted. Next, the medium was replaced with a medium of pH 6.8 (0.05 M phosphate buffer), and at 7 hours, more than 75% by weight of the initial pyridoxine content was cumulatively dissolved. The dissolution profile is shown: 8. The modified release multiple unit oral dosage form according to any of clauses 1 to 7, wherein the dissolution profile is measured using a USP Type 2 apparatus (basket) by placing the composition in 900 mL of the corresponding medium / buffer at 37°C ± 0.5°C and 100 rpm.

[0304] Clause 9. A modified release multiple unit oral dosage form according to any one of clauses 1 to 8, which is a capsule, in particular a hard capsule.

[0305] Article 10. (a1) preparing a first plurality of 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 by adding 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 cores is such that at least 90% of the inert cores have a particle size of between 300 μm and 1700 μm as measured by analytical sieving, and at least 90% of the inert cores are By analytical sifting such that the particle size variation measured is 200 μm, particularly 150 μm, particularly 100 μm, particularly 75 μm, particularly 50 μm; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer by adding one or more enteric coating agents, one or more modified-release coating agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert cores is such that at least 90% of the inert cores have a particle size of between 300 μm and 1700 μm as measured by analytical sieving, and at least 90% of the inert cores are By analytical sifting such that the particle size variation measured is 200 μm, particularly 150 μm, particularly 100 μm, particularly 75 μm, particularly 50 μm; 10. A process for preparing a modified release multiple unit oral dosage form as defined in any of clauses 1 to 9, comprising:

[0306] Article 11. (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating the pellets of doxylamine or a pharmaceutically acceptable salt thereof with 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; (b1) preparing a second plurality of 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 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; or alternatively, (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof, the 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 powdered mixture comprising one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable additives; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof 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 coating the pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer by simultaneously or alternately adding a powdered mixture comprising one or more anti-caking agents, optionally one or more pore-forming agents, and optionally pharmaceutically acceptable excipients.

[0307] Article 12. (a1) preparing a first plurality of 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, by adding 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 total amount of the enteric coating agent and the modified-release coating agent in the spray liquid mixture is 10% to 49% by weight based on the weight of the liquid mixture; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer by adding 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 total amount of the enteric coating agents and the modified-release coating agents in the spray liquid mixture is 10% to 49% by weight based on the weight of the liquid mixture; 12. The process described in clause 11, including:

[0308] Article 13. (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating pellets of doxylamine or a pharmaceutically acceptable salt thereof with an inner active coating layer and optionally an intermediate enteric coating layer by continuously or discontinuously spraying a liquid mixture comprising 1.0 to 7.5 wt % of one or more enteric coating agents and 10.0 to 35.0 wt % 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 powdered mixture comprising one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; the average spray flow rate of the mixture containing the coating is 0.30 to 5.00 g / min per 1 kg of pharmaceutically acceptable inert cores, the average solid addition rate of the mixture in solid form is 0.05 to 1.50 g / min per 1 kg of pharmaceutically acceptable inert cores, and the relationship between the average spray flow rate of the mixture containing the coating agent and the average solid addition rate of the mixture in solid form is 90:10 to 60:40, particularly 90:10 to 70:30; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising 1.0 to 7.5 wt. % of one or more enteric coating agents and 10.0 to 35.0 wt. % 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 powdered mixture comprising one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; the average spray flow rate of the mixture containing the coating agent is 0.30 to 5.00 g / min per 1 kg of pharmaceutically acceptable inert cores, the average solid addition rate of the mixture in solid form is 0.10 to 2.25 g / min per 1 kg of pharmaceutically acceptable inert cores, and the relationship between the average spray flow rate of the mixture containing the coating agent and the average solid addition rate of the mixture in solid form is 90:10 to 60:40, particularly 90:10 to 70:30; 13. The process according to clause 11 or 12, comprising:

[0309] Article 14. The process may be carried out separately. Optionally, a prior step of (a2) coating the pellets of doxylamine or a pharmaceutically acceptable salt thereof with an inner active coating layer by continuous or discontinuous spraying of a liquid mixture comprising one or more enteric coating agents and, optionally, one or more pharmaceutically acceptable excipients; (b2) a prior step of 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 pyridoxine or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients; or alternatively, a prior step of optionally (a2) coating the pellets of doxylamine or a pharmaceutically acceptable salt thereof with an inner active coating layer by continuous or discontinuous spraying of 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; (b2) a prior step of coating the pharmaceutically acceptable inert core by continuous or discontinuous spraying of a liquid mixture containing 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; 14. The process of any of clauses 10 to 13, further comprising:

[0310] Article 15. Optionally (a2) spraying continuously or discontinuously 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 a powdered mixture of a solid mixture containing one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, in an amount of 5.0 to 6.5 g per kg of pharmaceutically acceptable inert cores. and pellets of doxylamine or a pharmaceutically acceptable salt thereof having an enteric coating layer, wherein the average spray rate of the mixture including the enteric coating agent is 0.30 to 3.00 g / min per 1 kg of pharmaceutically acceptable inert cores, the average solid addition rate of the mixture in solid form is 0.025 to 0.400 g / min per 1 kg of pharmaceutically acceptable inert cores, and the relationship between the average spray flow rate of the mixture including the coating agent and the average solid addition rate of the mixture in solid form is 85:15 to 95:5. (b2) A pharmaceutically acceptable inert core, produced 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 spray flow rate of the mixture containing the coating agent is 0.30 to 4.50 g / min per 1 kg of the pharmaceutically acceptable inert core, the average solid addition rate of the powder is 0.50 to 9.0 g / min per 1 kg of the pharmaceutically acceptable inert core, and the relationship between the average spray flow rate of the mixture containing the coating agent and the average solid addition rate is 25:75 to 40:60. 14. The process described in clause 14, including:

[0311] Article 16. The process (a3) an additional step of 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; or alternatively, (a3) an additional step of coating the pharmaceutically acceptable inert core by continuously or discontinuously spraying a liquid mixture containing one or more coating agents and, optionally, one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a powdered mixture containing a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more anticoagulants, optionally one or more pore-forming agents, and, optionally, one or more pharmaceutically acceptable excipients. 16. The process of clause 14 or 15, further comprising:

[0312] Article 17. (a3) coating a pharmaceutically acceptable inert core by continuously or discontinuously spraying a liquid mixture containing 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 powdered mixture containing 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, a step in which the average spray flow rate of the mixture containing the coating agent is 0.30 to 4.50 g / min per 1 kg of pharmaceutically acceptable inert cores, the average solid addition rate of the mixture in powder form is 0.95 to 18.00 g / min per 1 kg of pharmaceutically acceptable inert cores, and the relationship between the average spray 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; 16. The process described in clause 16, comprising:

[0313] Clause 18. The process of any of clauses 10 to 17, wherein in each of the spraying steps (a1), (a2), (a3), (b1) and (b2), the liquid mixture is sprayed at an atomizer atomizing pressure of 0.6 to 2.2 bar and an open pattern pressure of 0.6 to 2.5 bar.

Claims

1. 1. A modified release multiple unit oral dosage form comprising: A first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof, comprising: - a pharmaceutically acceptable inert core, 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-coagulating agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; an optional 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; and 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-forming agents, and optionally one or more pharmaceutically acceptable excipients; a first plurality of modified release pellets comprising: a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof, - a pharmaceutically acceptable inert core, 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 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-forming agents, and optionally one or more pharmaceutically acceptable excipients; a second plurality of modified release pellets comprising: Including, the particle size of the pharmaceutically acceptable inert cores of the first and second pluralities of 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 at least 90% of the inert cores have a particle size variation of 200 μm or less from a given value consisting of 500 μm and 1400 μm as measured by analytical sieving; wherein the particle size variation means that from a given value, at least 90% of the pharmaceutically acceptable inert cores of the first and second plurality of pellets have particle sizes that fall within ±200 μm of the given value, a modified release multiple unit oral dosage form.

2. 2. The modified-release multiple-unit oral dosage form of claim 1, wherein the first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof comprises 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 pharmaceutically acceptable excipients.

3. 3. The modified release multiple unit oral dosage form of claim 1, wherein the dosage form comprises pharmaceutically acceptable inert cores of the first and second plurality of pellets 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 variation of 150 μm or less from a given value consisting of 450 μm and 1250 μm as measured by analytical sieving, wherein the particle size variation means that from the given value, at least 90% of the pharmaceutically acceptable inert cores of the first and second plurality of pellets have a particle size included within ±150 μm from the given value.

4. A modified-release multiple-unit oral dosage form as described in claim 3, wherein the dosage form comprises pharmaceutically acceptable inert cores of the first and second pluralities of pellets, at least 90% of the inert cores having a particle size of 600 μm to 1180 μm as measured by analytical sieving, and at least 90% of the pharmaceutically acceptable inert cores having a particle size variation of 100 μm or less from a given value consisting of 710 μm and 1000 μm as measured by analytical sieving, wherein the particle size variation means that, from the given value, at least 90% of the pharmaceutically acceptable inert cores of the first and second pluralities of pellets have a particle size included within ±100 μm of the given value.

5. A modified-release multiple-unit oral dosage form as described in claim 4, wherein the dosage form comprises pharmaceutically acceptable inert cores of the first and second pluralities of pellets, at least 90% of which 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 variation of 75 μm or less from a given value consisting of 800 μm and 900 μm as measured by analytical sieving, wherein the particle size variation means that, from the given value, at least 90% of the pharmaceutically acceptable inert cores of the first and second pluralities of pellets have a particle size included within ±75 μm of the given value.

6. the particle size of the first plurality of 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 variation of 200 μm or less from a given value consisting of 600 μm and 1800 μm as measured by analytical sieving, wherein the particle size variation from the given value means that at least 90% of the first plurality of modified-release pellets have a particle size comprised within ±200 μm of the given value; and, the particle size of the second plurality of 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 variation of 200 μm or less from a given value consisting of 600 μm and 1800 μm as measured by analytical sieving, wherein the particle size variation from the given value means that at least 90% of the second plurality of modified-release pellets have a particle size comprised within ±200 μm of the given value; The modified release multiple unit oral dosage form according to any one of claims 1 to 5.

7. A modified-release multiple-unit oral dosage form as described in claim 6, wherein the particle size of the first plurality of 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 variation of 150 μm or less from a given value consisting of 800 μm and 1400 μm as measured by analytical sieving, wherein the particle size variation means that, from the given value, at least 90% of the first plurality of modified-release pellets have a particle size included within ±150 μm of the given value.

8. A modified-release multiple-unit oral dosage form as described in claim 7, wherein the particle size of the first plurality of 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 variation of 100 μm or less from a given value consisting of 850 μm and 1250 μm as measured by analytical sieving, wherein the particle size variation means that from the given value, at least 90% of the first plurality of modified-release pellets have a particle size included within ±100 μm of the given value.

9. A modified-release multiple-unit oral dosage form as described in claim 8, wherein the particle size of the first plurality of 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 variation of 75 μm or less from a given value consisting of 900 μm and 1180 μm as measured by analytical sieving, wherein the particle size variation means that, from the given value, at least 90% of the first plurality of modified-release pellets have a particle size included within ±75 μm of the given value.

10. The modified-release multiple-unit oral dosage form of claim 6, wherein the particle size of the second plurality of 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 variation of 150 μm or less from a given value consisting of 800 μm and 1400 μm as measured by analytical sieving, wherein the particle size variation means that, from the given value, at least 90% of the second plurality of modified-release pellets have a particle size comprised within ±150 μm of the given value.

11. The modified-release multiple-unit oral dosage form of claim 10, wherein the particle size of the second plurality of 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 variation of 100 μm or less from a given value consisting of 850 μm and 1250 μm as measured by analytical sieving, wherein the particle size variation means that from the given value, at least 90% of the second plurality of modified-release pellets have a particle size comprised within ±100 μm of the given value.

12. The modified-release multiple-unit oral dosage form of claim 11, wherein the particle size of the second plurality of 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 variation of 75 μm or less from a given value consisting of 900 μm and 1180 μm as measured by analytical sieving, wherein the particle size variation means that, from the given value, at least 90% of the second plurality of modified-release pellets have a particle size included within ±75 μm of the given value.

13. the particle size of doxylamine or a pharmaceutically acceptable salt thereof is characterized by having a D90 of 250 μm or less, and the particle size of pyridoxine or a pharmaceutically acceptable salt thereof is characterized by having a D90 of 250 μm or less; or alternatively, the particle size of doxylamine or a pharmaceutically acceptable salt thereof is characterized by a D90 of 250 μm or less; the particle size of pyridoxine or a pharmaceutically acceptable salt thereof is characterized by a D90 of 250 μm or less; the particle size of one or more anti-coagulants is characterized by a D90 of 250 μm or less; and optionally the particle size of one or more pore-forming agents is characterized by a D90 of 250 μm or less; wherein the particle size D90 of doxylamine or a pharmaceutically acceptable salt thereof is expressed by volume, the particle size D90 of pyridoxine or a pharmaceutically acceptable salt thereof is expressed by volume, and the particle size D90 of the anticoagulant is expressed by weight. The modified release multiple unit oral dosage form according to any one of claims 1 to 12.

14. 14. The modified release multiple unit oral dosage form of any one of claims 1 to 13, comprising a pharmaceutically acceptable salt of doxylamine and a pharmaceutically acceptable salt of pyridoxine.

15. A modified-release multiple-unit oral dosage form as described in claim 14, wherein the pharmaceutically acceptable salt of doxylamine and the pharmaceutically acceptable salt of pyridoxine are doxylamine succinate and pyridoxine hydrochloride.

16. 16. The modified release multiple unit oral dosage form of any one of claims 1 to 15, 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.

17. A modified-release multiple-unit oral dosage form as described in claim 16, 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.

18. The modified release multiple unit oral dosage form comprises: 5% to 35% by weight of the doxylamine content is dissolved in 0.1 N HCl medium (pH = 1) at 1 hour; Next, the medium was replaced with a medium of pH 4.5 (0.05 M acetate buffer), and at 4 hours, more than 35% by weight to 75% by weight of the initial doxylamine content was eluted cumulatively. Next, the medium was replaced with a medium of pH 6.8 (0.05 M phosphate buffer), and at 7 hours, at least 75% by weight of the initial doxylamine content was cumulatively dissolved, and 5% to 35% by weight of the pyridoxine content is dissolved in 0.1 N HCl medium (pH=1) at 1 hour; Next, the medium was replaced with a medium of pH 4.5 (0.05 M acetate buffer), and at 4 hours, more than 35% by weight to 75% by weight of the initial pyridoxine content was eluted cumulatively. Next, the medium is replaced with a medium of pH 6.8 (0.05 M phosphate buffer), and at 7 hours, at least 75% by weight of the initial pyridoxine content is eluted cumulatively. The dissolution profile is shown:

18. The modified release multiple unit oral dosage form according to any one of claims 1 to 17, wherein the dissolution profile is measured using a USP Type 2 apparatus (basket) by placing the composition in 900 mL of the corresponding medium / buffer at 37°C ± 0.5°C and 100 rpm.

19. 19. The modified release multiple unit oral dosage form according to any one of claims 1 to 18, which is a capsule.

20. The modified-release multiple-unit oral dosage form of claim 19, wherein the capsule is a hard capsule.

21. The modified-release multiple-unit oral dosage form of claim 20, wherein the hard capsule is selected from the group consisting of a hard gelatin capsule and a hard hydroxypropyl methylcellulose capsule.

22. (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating the doxylamine or pharmaceutically acceptable salt thereof pellets having an inner active coating layer and optionally an intermediate enteric coating layer by adding 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 cores 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 variation of 200 μm or less as measured by analytical sieving; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer by adding one or more enteric coating agents, one or more modified-release coating agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, wherein the particle size of the pharmaceutically acceptable inert cores 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 variation of 200 μm or less as measured by analytical sieving; A process for preparing the modified release multiple unit oral dosage form of any one of claims 1 to 21, comprising:

23. (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating the pellets of doxylamine or a pharmaceutically acceptable salt thereof with an inner active coating layer and optionally an intermediate enteric coating layer by continuous or discontinuous spraying of 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; (b1) preparing a second plurality of 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 by continuous or discontinuous spraying of 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; Including, or alternatively, (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating said pellets with 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 powdered mixture comprising one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable additives; (b1) preparing a second plurality of 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 by continuous or discontinuous spraying of 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 powdered mixture comprising one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; 23. The process of claim 22, comprising:

24. (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating said pellets of doxylamine or a pharmaceutically acceptable salt thereof with an inner active coating layer and optionally an intermediate enteric coating layer by adding 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 total amount of the enteric coating agents and the modified-release coating agents in the spray liquid mixture is 10% to 49% by weight based on the weight of the liquid mixture; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating said pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer by adding 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 total amount of said enteric coating agents and said modified-release coating agents in the spray liquid mixture is 10% to 49% by weight based on the weight of said liquid mixture; 24. The process of claim 23, comprising:

25. (a1) preparing a first plurality of modified-release pellets of doxylamine or a pharmaceutically acceptable salt thereof by coating said pellets with an inner active coating layer and optionally an intermediate enteric coating layer by continuously or discontinuously spraying a liquid mixture comprising 1.0 to 7.5 wt % of one or more enteric coating agents and 10.0 to 35.0 wt % 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 powdered mixture comprising one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; the average spray flow rate of the mixture including the coating is 0.30 to 5.00 g / min per kg of pharmaceutically acceptable inert cores, the average solid addition rate of the mixture in solid form is 0.05 to 1.50 g / min per kg of pharmaceutically acceptable inert cores, and the relationship between the average spray flow rate of the mixture including the coating agent and the average solid addition rate of the mixture in solid form is 90:10 to 60:40; (b1) preparing a second plurality of modified-release pellets of pyridoxine or a pharmaceutically acceptable salt thereof by coating said pellets of pyridoxine or a pharmaceutically acceptable salt thereof with an inner active coating layer by continuously or discontinuously spraying a liquid mixture comprising 1.0 to 7.5 wt. % of one or more enteric coating agents and 10.0 to 35.0 wt. % 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 powdered mixture comprising one or more anti-caking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; the average spray flow rate of the mixture containing the coating agent is 0.30 to 5.00 g / min per kg of pharmaceutically acceptable inert cores, 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 cores, and the relationship between the average spray flow rate of the mixture containing the coating agent and the average solid addition rate of the mixture in solid form is 90:10 to 60:40; 25. The process of claim 23 or 24, comprising:

26. The process described in claim 25, wherein the relationship between the average spray flow rate of the mixture containing the coating agent in step (a1) and the average solid addition rate of the mixture in solid form is 90:10 to 70:

30.

27. ​​The process described in claim 25, wherein the relationship between the average spray flow rate of the mixture containing the coating agent in step (b1) and the average solid addition rate of the mixture in solid form is 80:20 to 60:

40.

28. The process separately comprises: Optionally, a prior step of (a2) coating the pellets of doxylamine or a pharmaceutically acceptable salt thereof with an inner active coating layer by continuous or discontinuous spraying of a liquid mixture comprising one or more enteric coating agents and, optionally, one or more pharmaceutically acceptable excipients; (b2) a prior step of 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 pyridoxine or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients; or alternatively, Optionally, a prior step of (a2) coating the pellets of doxylamine or a pharmaceutically acceptable salt thereof with an inner active coating layer by continuous or discontinuous spraying of 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; (b2) a prior step of coating the pharmaceutically acceptable inert core by continuous or discontinuous spraying of a liquid mixture containing 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; The process of any one of claims 22 to 25, further comprising:

29. Optionally, (a2) forming an inner active coating by continuously or discontinuously spraying a liquid mixture comprising 5-15% by weight of one or more enteric coating agents and optionally one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding 5.0-6.5 g of a powder form mixture per 1 kg of pharmaceutically acceptable inert cores in a solid form comprising one or more anticaking agents, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients. doxylamine or a pharmaceutically acceptable salt thereof pellets having a coating layer, wherein the average spray flow rate of the mixture including the enteric coating agent is 0.30 to 3.00 g / min per kg of pharmaceutically acceptable inert cores, the average solid addition rate of the mixture in solid form is 0.025 to 0.400 g / min per kg of pharmaceutically acceptable inert cores, and the relationship between the average spray flow rate of the mixture including the coating agent and the average solid addition rate of the mixture in solid form is 85:15 to 95:5; (b2) A pharmaceutically acceptable inert core obtained 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 in powder form and, optionally, one or more pharmaceutically acceptable excipients, wherein the average spray flow rate of the mixture comprising the coating agent is 0.30 to 4.50 g / min per kg of the pharmaceutically acceptable inert core, the average solid addition rate of the powder is 0.50 to 9.0 g / min per kg of the pharmaceutically acceptable inert core, and the relationship between the average spray flow rate of the mixture comprising the coating agent and the average solid addition rate is 25:75 to 40:60; 29. The process of claim 28, comprising:

30. (b3) 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; or alternatively, (a3) Coating a pharmaceutically acceptable inert core by continuously or discontinuously spraying a liquid mixture containing one or more coating agents and, optionally, one or more pharmaceutically acceptable excipients, and simultaneously or alternately adding a powdered mixture containing a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more anticoagulants, optionally one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients.

30. The process of claim 28 or 29, further comprising an additional step comprising:

31. (a3) coating a pharmaceutically acceptable inert core by continuously or discontinuously spraying a liquid mixture containing 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 powdered mixture containing 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, 31. The process according to claim 30, comprising a step in which the average spray flow rate of the mixture containing the coating agent is 0.30 to 4.50 g / min per kg of pharmaceutically acceptable inert cores, 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 cores, and the relationship between the average spray 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.

32. 32. The process of any one of claims 22 to 31, wherein in each of the spraying steps (a1), (a2), (a3), (b1) and (b2), the liquid mixture is sprayed at an atomizer atomizing pressure of 0.6 to 2.2 bar and an open pattern pressure of 0.6 to 2.5 bar.

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