EA044924B1 - METHOD FOR OBTAINING MULTI-ELEMENT ORAL DOSAGE FORM WITH MODIFIED RELEASE OF DOXYLAMINE SUCCINATE AND PYRIDOXINE HYDROCHLORIDE - Google Patents

Description

The present invention relates to a method for preparing a multi-element modified-release oral dosage form containing modified-release microspheres of doxylamine or a pharmaceutically acceptable salt thereof and modified-release microspheres of pyridoxine or a pharmaceutically acceptable salt thereof.

State of the art

Doxylamine has the international nonproprietary name (RS)-N,N-dimethyl-2-(1-phenyl-1pyridin-2-yl-ethoxy)ethanamine and CAS number 469-21-6. Doxylamine is a first generation antihistamine that competitively, reversibly, and nonspecifically blocks H1 receptors, and is also a nonspecific antagonist that can block other receptors, such as central or peripheral muscarinic receptors, exhibiting significant anticholinergic effects. It is usually used in the form of a salt and, in particular, in the form of the corresponding succinate salt. The structure of doxylamine corresponds to formula (I)

On the other hand, pyridoxine, also known as vitamin _B6 , has the international nonproprietary name 4,5-bis(hydroxymethyl)-2-methylpyridin-3-ol and CAS number 65-23-6. Pyridoxine is a water-soluble vitamin factor whose active form is pyridoxal phosphate. It acts as an enzymatic cofactor in numerous biochemical reactions that occur during the digestive breakdown of proteins and amino acids, as well as, to a lesser extent, lipids and carbohydrates. In addition, it takes part in the metabolism of unsaturated fatty acids, and is also a coenzyme for transaminases and decarboxylases, ensuring the conversion of tryptophan into nicotinic acid. Pyridoxine is usually used in salt form and, in particular, in the form of the corresponding hydrochloride salt. The structure of pyridoxine corresponds to formula (II)

Doxylamine is commonly used individually as a short-term sedative and in combination with other medications to counter nighttime allergies and colds. Additionally, doxylamine is used in combination with analgesics such as paracetamol (acetaminophen) and codeine as a pain reliever/sedative and is also prescribed in combination with pyridoxine to prevent morning sickness in pregnant women.

The art describes modified-release oral dosage forms of doxylamine succinate and pyridoxine hydrochloride having different pharmacokinetic and pharmacological properties.

The art describes certain oral dosage forms that release two active substances, doxylamine succinate and pyridoxine hydrochloride, as well as methods for their preparation. Said dual-active release oral dosage forms are formulated using at least one immediate release composition and at least one modified release composition, each of these compositions containing one or more active ingredients. This dosage system provides a separate immediate release of one of the active ingredients and a modified release of the other active ingredients (see documents WO 2013123569 and WO 2016029290).

On the other hand, hard capsules filled with modified-release doxylamine succinate microspheres and modified-release pyridoxine hydrochloride microspheres are commercially available under the name Cariban. Cariban capsules are used for the symptomatic treatment of nausea and vomiting. In particular, the effect of doxylamine and pyridoxine becomes noticeable within 5 hours after ingestion, which is advantageous because it provides a prolonged therapeutic effect and a reduction in the number of drug doses. However, the technique does not describe a method for obtaining such a drug.

The method used to prepare a multi-element oral dosage form (such as tablets or capsules containing varying amounts of microspheres) determines the pharmacokinetic parameters of the active ingredients as well as the therapeutic activity of the multi-element dosage form. In particular, the therapeutic effect of multi-element dosage forms is regulated by the dissolution profile of the active ingredients contained in each of the microspheres, as well as the mutual homogeneity of the microspheres.

Thus, based on what is known in the art, it can be concluded that there continues to be a need to provide a low-cost, reliable, reproducible and scalable method for producing uniform batches of a multi-element oral dosage form containing modified release microspheres of both active ingredients, representing doxylamine and pyridoxine, and exhibiting an appropriate dissolution profile for use in therapy.

The essence of the invention

We have discovered that the production method of the present invention, which includes coating by spraying onto an inert core a mixture of a modified release coating composition and simultaneously applying the active ingredient and/or blowing agent (and optionally one or more pharmaceutically acceptable excipients or carriers) in solid form at an appropriate atomization flow rate, provides uniform batches of a multi-unit oral dosage form containing modified release microspheres of both active ingredients doxylamine or the corresponding pharmaceutically acceptable salt and pyridoxine or the corresponding pharmaceutically acceptable salt, with the appropriate dissolution profile for use in therapy with a prolonged therapeutic effect.

In particular, the present inventors have discovered that the method for producing a coating of both sets of modified release microspheres according to the present invention allows for the multi-element oral dosage form thus prepared to exhibit a desired dissolution profile, which means that from 10 to 35% by weight contains doxylamine dissolves by the end of the first hour in 0.1 N HCl (pH 1);

then the medium is replaced by a medium with pH 4.5 (0.05 M acetate buffer), and by the end of the fourth hour, a total of 45 to 70% by weight of the original doxylamine content has dissolved;

the medium is then replaced by pH 6.8 medium (0.05 M phosphate buffer), and by the end of the seventh hour, a total of at least 80% of the original doxylamine content has dissolved;

from 10 to 35% by weight of pyridoxine content dissolves by the end of the first hour in 0.1 N HCl (pH 1);

then the medium is replaced by a medium with pH 4.5 (0.05 M acetate buffer), and by the end of the fourth hour, a total of 40 to 65% by weight of the initial pyridoxine content has dissolved;

the medium is then replaced by a pH 6.8 medium (0.05 M phosphate buffer) and by the end of the seventh hour, a total of at least 80% of the original pyridoxine content has dissolved, and the dissolution profile is measured using a type II device (basket) according to the pharmacopoeia USA (USP), placing the composition in 900 ml of the appropriate medium/buffer solution at 37x0.5°C and 100 rpm.

Thus, the method of producing a modified release coating of both sets of microspheres according to the present invention allows for the multi-unit oral dosage form so prepared to provide a modified sustained release of both active ingredients for at least 8 hours after administration. This is advantageous because the modified sustained release composition of the present invention produces a dual effect, including an immediate effect immediately after administration and a sustained effect during release throughout the day, in particular after a night's sleep.

Without being bound by any theory, the inventors believe that the process of the present invention allows for the production of microspheres of a uniform type without the formation of aggregates and powder mixtures, which is advantageous for achieving a desired dissolution profile.

In addition, the method according to the present invention also allows for the production of both sets of microspheres with high uniformity of active ingredient content (ie, high mutual homogeneity of microspheres). This is advantageous because it means that each microsphere contains approximately the same amount of active ingredient and thus ensures that the multiunit oral dosage form filled with these microspheres will always contain a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof and pyridoxine or a pharmaceutically acceptable salt thereof. This means that by using the method of the present invention, underdosing and overdosing of active ingredients in a multi-element oral dosage form is prevented.

Finally, the present inventors have also found that the method of the present invention is also advantageous because it is cheaper, more reliable and reproducible, and is easily scalable compared to prior art methods.

Thus, an aspect of the present invention is a method of producing a multi-element modified-release oral dosage form comprising a first plurality of modified-release microspheres of doxylamine or a pharmaceutically acceptable salt thereof, comprising an inert core, an inner active coating layer containing a therapeutically effective amount doxylamine or a pharmaceutically acceptable salt thereof, one or more coating agents and one or more blowing agents; and optionally one or more pharmaceutically acceptable excipients, an intermediate enteric coating layer comprising one or more enteric coating agents and one or more pore-forming agents, and a modified release outer coating layer containing one or more enteric coating agents, one or more coating agents modified release and one or more blowing agents; and a second plurality of modified-release microspheres of pyridoxine or a pharmaceutically acceptable salt thereof, comprising an inert core, an inner active coating layer containing a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, and one or more coating agents, and an outer modified-release coating layer comprising one or more enteric coating agents, one or more modified-release coating agents, and one or more pore-forming agents, the method comprising producing a first plurality of modified-release microspheres of doxylamine or a pharmaceutically acceptable salt thereof by coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof having an internal an active coating layer and an intermediate enteric coating layer, by simultaneously spraying a mixture containing from 2.0 to 7.5% by weight enteric coating agents and from 15.0 to 35.0% by weight modified release coating agents in a mass ratio of 5:95 to 30:70, and adding pore-forming substances in powder form, while the spray flow rate of the mixture containing coating substances ranges from 300 to 1200 mg/min per 1 kg of inert core; the rate of addition of pore-forming substances in solid form is from 75 to 500 mg/min per 1 kg of inert core; and the ratio between the rate of spraying the flow of the mixture containing coating agents and the rate of addition of blowing agents in solid form is from 90:10 to 60:40; and providing a second plurality of modified-release microspheres of pyridoxine or a pharmaceutically acceptable salt thereof by coating microspheres of pyridoxine or a pharmaceutically acceptable salt thereof having an internal active coating layer by simultaneously spraying a mixture containing from 2.0 to 7.5% by weight of enteric coating agents and from 15.0 to 35.0% by weight of modified release coating agents in a mass ratio of 5:95 to 30:70, and ranges from 75 to 500 mg/min per 1 kg of inert core; and the ratio between the spray flow rate of the mixture containing coating agents and the rate of addition of blowing agents in solid form is from 90:10 to 60:40.

Detailed Description of the Invention

All terms used in this application constituting this document, unless otherwise indicated, are to be understood in their respective ordinary meanings as known in the art. Other more specific definitions for certain terms that are used in this application are provided below and are intended to apply unambiguously throughout the text of this specification and claims, unless a specifically introduced definition provides a broader meaning.

For purposes of the present invention, any given ranges include both the lower and upper ends of the respective ranges. Ranges and values shown, such as temperature, time and other parameters, should be considered approximate unless otherwise stated.

Additionally, the terms ratio and ratio have the same meaning and are used interchangeably. This term is used in the present invention to mean that the ratio between the spray flow rate of the mixture containing coating agents and the rate of addition of blowing agents in solid form is from 90:10 to 60:40.

The method of the present invention is a method for preparing a multi-element modified-release oral dosage form containing a plurality of modified-release microspheres of doxylamine or a pharmaceutically acceptable salt thereof and modified-release microspheres of pyridoxine or a pharmaceutically acceptable salt thereof. The term multi-element dosage form is defined as a dosage form that consists of more than one element that contains an effective amount of doxylamine and pyridoxine. Typically, multiunit dosage forms are based on units such as granules, microspheres or minitablets.

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They are usually available in hard gelatin capsules or formulated into tablets. According to an embodiment, the multi-element dosage form is a hard capsule filled with microspheres as elements containing the active ingredient.

As described above, a multi-element dosage form containing two sets of microspheres can be prepared by the method according to the present invention. The term microspheres refers to small particles having approximately the same shape and size and manufactured using extrusion or layer-by-layer coating of an inert core. The term fine particle means a particle whose diameter, length, height, width or similar size is from 100 to 3000 μm, in particular from 300 to 2000 μm, more particularly from 600 to 1400 μm. Fine particles are approximately the same size if the diameter, length, height, width or similar size of the smallest particle is at least approximately half the average diameter, length, height, width or similar size of the particle and if the diameter, length, height, width or similar size the largest particle is no more than approximately twice the average diameter, length, height, width or similar particle size. In addition, the terms microsphere, spherical microparticle, bead, grain, spherical particle, spheroid and microsphere have the same meaning and are used interchangeably. The term granule refers to small particles having approximately the same shape and size and obtained by the granulation process. Typically, granules are less uniform in size or shape than microspheres. Thus, the granules have a lower degree of uniformity due to the irregular shape of their surface and create an unacceptable dosage uniformity and dissolution profile. Therefore, for the purpose of the present invention, the terms microsphere and granule are not the same and cannot be used interchangeably.

The terms modified-release dosage form and modified-delivery dosage form, as well as modified-release microsphere and modified-delivery microsphere, have the same meaning and are used interchangeably. These terms should be understood to mean a dosage form or microsphere that exhibits a delayed release of active substances than a traditional immediate release pharmaceutical composition and the same route of administration. Generally, the term modified release means that the active ingredient is released from the pharmaceutical dosage form in a controlled, sustained, extended or sustained release manner.

In the context of the present invention, the terms coating agents and film-forming agents have the same meaning and are used interchangeably. Both terms should be understood to mean a substance capable of forming a thin polymer-based coating that coats a solid dosage form such as a tablet and microsphere. Examples of each type of coating agent are described below.

In particular, the term modified release coating agent means a substance capable of forming films that provide drug delivery at a predetermined rate and/or site according to body needs and disease states over a predetermined period of time. Non-limiting examples that illustrate a modified release polymer and a modified delivery polymer are polymers that provide controlled release, sustained release, sustained release, or sustained release. Exemplary modified release coating agents include, but are not limited to, acrylic polymers, celluloses and related derivatives, shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil, and mixtures thereof. Exemplary suitable acrylic polymers include, but are not limited to, acrylic acid-methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, polyacrylic acid, polymethacrylic acid, methacrylic acid alkyl amide copolymer, polymethyl methacrylate, polymethacrylic anhydride acids, methyl methacrylate, polymethacrylate, methyl methacrylate copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, glycidyl methacrylate copolymers, shellac and mixtures thereof. The modified release polymer is selected from the group consisting of acrylic acid-methacrylic acid copolymers and shellac. Preferably the modified release polymer is shellac. Modified release polymers may be accompanied by plasticizers such as triethyl citrate (TEC), polyethylene glycol (PEG), cetyl alcohol and stearyl alcohol; surfactants such as sodium lauryl sulfate, polysorbate and poloxamer; pigments such as titanium dioxide and iron sesquioxide; lubricants such as talc, magnesium stearate or glycerol monostearate and mixtures thereof.

The term binder refers to substances that are incorporated into compositions to facilitate agglomeration of powder to form granules or microspheres during mixing with a granulating fluid such as water, water-alcohol mixtures or other solvents. Examples of binders or adhesives include, but are not limited to, microcrystalline

- 4 044924 cellulose, hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) 6000, guar gum, starch or shellac.

The term enteric means a composition or layer of a dosage form that is configured to release one or more active ingredients under the conditions of a specific part of the gastrointestinal tract. In an embodiment, the enteric material is pH sensitive and is affected by pH changes that occur in the gastrointestinal tract (pH sensitive release). Enteric material typically remains insoluble at gastric pH and then releases the active ingredient into a higher pH environment downstream in the gastrointestinal tract (eg, often in the duodenum or sometimes in the colon). In another embodiment, the enteric material comprises enzymatically degradable polymers that are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly the colon. Optionally, the multi-unit dosage form is formulated using a pH-sensitive enteric material configured to be released over approximately a predetermined period of time under conditions at or above a predetermined pH value. In various embodiments, the particular pH may be, for example, from about 4 to about 7, including about 4.5, 5, 5.5, 6, 6.5, 6.8, or 7. As used herein, the term enteric coating agent means a substance capable of forming films that allow the delivery of doxylamine and pyridoxine in the conditions of a certain part of the gastrointestinal tract, as described above. Materials used for enteric compositions, for example, as coatings, are well known in the art and include, but are not limited to, cellulose polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, methylcellulose, ethylcellulose , cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and sodium carboxymethylcellulose; polymers and copolymers of acrylic acid, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, as well as other methacrylic resins, which are commercially available under the trade name Acryl-EZE® from Colorcon (USA, Eudragit® from Rohm Pharma (Weiterstadt, Germany), including Eudragit® L30D-55 and L100-55 (soluble at pH 5.5 and above), Eudragit® L100 and L12.5 (soluble at pH 6.0 and above) , Eudragit® S, S12.5 and FS 30D (soluble at pH 7.0 and above as a result of higher degrees of esterification) and Eudragits® NE, NM, RL and RS (water insoluble polymers having varying degrees of permeability and extensibility) ; vinyl polymers and copolymers such as polyvinylpyrrolidone, vinyl acetate, vinyl acetate phthalate, vinyl acetate-crotonic acid copolymer and ethylene vinyl acetate copolymer; enzymatically degradable polymers such as azopolymers, pectin, chitosan, amizola and guar gum; zein and shellac. In addition, combinations of different enteric materials can be used. Multilayer coatings using various polymers can also be applied. The properties, manufacture and composition of enteric delivery systems are well known to those of ordinary skill in the art. In a specific embodiment, the enteric coating agent is 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, sodium alginate, cellulose acetate trimellitate, and a mixture thereof. More specifically, this substance is Eudragit L®, including, for example, Eudragit L100 (available from Evonic).

As defined above, the method of the present invention includes preparing a first plurality of microspheres that contain a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, and a second plurality of microspheres that contain a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof.

The term "therapeutically effective amount" as used herein means an amount of an active ingredient in a multiunit dosage form that, when administered, is sufficient to prevent the development or provide some relief of one or more symptoms of the disease for which the ingredient is intended to treat. The specific dose of the compound administered according to the present invention will be determined by the circumstances that arise in the case, including the compound administered, the particular condition being treated, and the like.

The term appropriate pharmaceutically acceptable salt as used herein covers any salt prepared using pharmaceutically acceptable non-toxic acids, including inorganic or organic acids. There is no restriction regarding salts, except that if used for therapeutic purposes, they must

- 5 044924 be pharmaceutically acceptable. Since doxylamine and pyridoxine are basic compounds, the salts can be prepared using pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic, methanesulfonic, phosphoric, succinic, sulfuric, tartaric or p- toluenesulfonic acid.

The preparation of the corresponding pharmaceutically acceptable doxylamine and pyridoxine salts can be accomplished by methods known in the art. For example, they can be prepared by conventional chemical methods from a starting compound that contains a basic or acidic moiety. Typically, such salts are obtained, for example, by reacting the free acid or base forms of these compounds with a stoichiometric amount of the corresponding pharmaceutically acceptable bases or acids in water or an organic solvent, or a mixture thereof.

In an embodiment, the method includes preparing a first plurality of microspheres that contain a therapeutically effective amount of a pharmaceutically acceptable doxylamine salt thereof, in particular a doxylamine succinate salt. In an embodiment, the method includes preparing a multiunit dosage form comprising a first plurality of microspheres that contain from 5 to 50 mg of doxylamine succinate per multiunit dosage form, in particular from 6 to 40 mg, from 7 to 30 mg, from 8 to 20 mg and more specifically 9 to 11 mg of doxylamine succinate. In a specific embodiment, the method includes preparing a multiunit dosage form comprising a first plurality of microspheres containing 10 mg of doxylamine succinate per multiunit dosage form. In an embodiment, the method includes preparing a second plurality of microspheres that contain a therapeutically effective amount of a pharmaceutically acceptable pyridoxine salt thereof, in particular pyridoxine hydrochloride. In an embodiment, the method includes preparing a multi-unit dosage form containing a second plurality of microspheres that contain from 5 to 50 mg of pyridoxine hydrochloride per multi-unit dosage form, in particular from 6 to 40 mg, from 7 to 30 mg, from 8 to 20 mg and more specifically 9 to 11 mg pyridoxine hydrochloride. In a specific embodiment, the method includes preparing a multiunit dosage form containing a first plurality of microspheres that contain 10 mg of pyridoxine hydrochloride per multiunit dosage form. In an embodiment, the method includes preparing a multi-unit dosage form comprising a first plurality of microspheres that contain a therapeutically effective amount of a pharmaceutically acceptable doxylamine salt thereof, in particular a doxylamine succinate salt; and a second plurality of microspheres that contain a therapeutically effective amount of a pharmaceutically acceptable pyridoxine salt thereof, in particular pyridoxine hydrochloride. In an embodiment, the method includes preparing a multiunit dosage dosage form comprising a first plurality of microspheres that contain from 5 to 50 mg of doxylamine succinate per multiunit dosage form, in particular 10 mg of doxylamine succinate per multiunit dosage form; and a second plurality of microspheres that contain from 5 to 50 mg of pyridoxine hydrochloride per multiunit dosage form, in particular 10 mg of pyridoxine hydrochloride per multiunit dosage form. In a specific embodiment, the method includes producing a first plurality of microspheres that contain 10 mg of doxylamine succinate per multiunit dosage form, and a second plurality of microspheres that contain 10 mg of pyridoxine hydrochloride per multiunit dosage form.

In an embodiment, the method includes preparing a multi-unit dosage form containing from 20 to 220 mg of a first plurality of microspheres that contain a therapeutically effective amount of a pharmaceutically acceptable doxylamine salt thereof, in particular a doxylamine succinate salt; and from 20 to 220 mg of a second plurality of microspheres that contain a therapeutically effective amount of a pharmaceutically acceptable pyridoxine salt thereof, in particular pyridoxine hydrochloride. According to an embodiment, the method comprises preparing a multi-unit dosage form containing from 20 to 220 mg, in particular 60 mg, of a first plurality of microspheres, which contain from 5 to 50 mg of doxylamine succinate, in particular 10 mg of doxylamine succinate; and from 20 to 220 mg, in particular 60 mg, of a second plurality of microspheres, which contain from 5 to 50 mg of pyridoxine hydrochloride, in particular 10 mg of pyridoxine hydrochloride. According to an embodiment, the method includes preparing a multi-unit dosage form comprising a first plurality of microspheres that contain from 5 to 50 mg of doxylamine succinate, in particular 10 mg of doxylamine succinate; and a second plurality of microspheres that contain from 5 to 50 mg of pyridoxine hydrochloride, in particular 10 mg of pyridoxine hydrochloride. According to a specific embodiment, the method includes preparing a first plurality of microspheres that contain 10 mg of doxylamine succinate and a second plurality of microspheres that contain 10 mg of pyridoxine hydrochloride.

In an embodiment, the method includes preparing a multi-unit dosage form comprising a first plurality of microspheres that contain a therapeutically effective amount of a pharmaceutically acceptable doxylamine salt thereof and have a particle size of from 1 to 250 microns, in particular from 1 to 150 microns, more particularly less than 100 microns. According to an embodiment, the method is a method in which doxylamine or the corresponding salt, in particular doxylamine succinate, has a particle diameter D90 of 1 to 250 μm, in particular 1 to 150 μm, more particularly less than 100 μm.

There is a well known method for selecting size ranges or particle size fractions by sieving. One standard method for determining the particle size distribution of a particle sample is to determine the D10, D50, and D90 values. D10 is the particle diameter value such that 10% of the plurality of particles are smaller in size. D50 is the particle diameter such that 50% of the plurality of particles are smaller and 50% of the plurality of particles are larger. The D50 value is also known as the median particle diameter. D90 is the particle diameter value such that 90% of the plurality of particles are smaller in size.

In an embodiment, the method includes preparing a multi-unit dosage form comprising a first plurality of microspheres that contain a therapeutically effective amount of a pharmaceutically acceptable pyridoxine salt thereof and have a particle size equal to or less than 500 microns. According to an embodiment, the method is a method in which the pyridoxine or the corresponding salt, in particular pyridoxine hydrochloride, has a particle size of from 1 to 250 μm, in particular from 1 to 150 μm, more particularly less than 100 μm.

The particle size of the active ingredients can be measured by any method described in the prior art. Examples of methods commonly used to measure particle size include dynamic light scattering (DLS) to determine the number average particle diameter; atomic force microscopy (AFM) or transmission electron microscopy (TEM) to measure dried particles; laser diffraction using a Mastersizer laser particle analyzer and Mie theory according to ISO 13320-1; and sedimentation analysis using the Sedigraph instrument and Stokes' law according to ISO 13317-3.

The term pore-forming agent means any substance that is capable of forming one or more pores in the coating/coating to allow a modified release of the active ingredients. The blowing agent may be an organic substance, or an inorganic substance, or any suitable combination. Examples of the blowing agent include, but are not limited to, talc, polyethylene glycol (PEG), propylene glycol, isopropyl alcohol, glycerin, lactose, glucose, sucrose, mannitol, sorbitol, sodium chloride, potassium chloride, hydroxypropylcellulose, micronized sugar, hydroxypropylmethylcellulose (HPMC), polyvinyl alcohols, methacrylic acid copolymers or a mixture thereof. In an embodiment, the blowing agent is selected from the group consisting of talc, micronized sugar, sodium or potassium chloride, and a mixture thereof. According to an embodiment, the method is a method in which the blowing agent has a particle diameter D90 equal to or less than 250 μm, in particular less than 150 μm, more particularly less than 100 μm. According to a specific embodiment, the method is a method in which the blowing agent is talc having a particle diameter D90 of less than 75 microns.

The particle size of the blowing agent can be measured by any method described in the prior art. Specifically, the methods used in the present invention for measuring particle size are laser diffraction using a Mastersizer laser particle analyzer and Mie theory according to ISO 13320-1, and sedimentation analysis using a Sedigraph instrument and Stokes' law according to ISO 13317-3.

The term inert core refers to neutral microspheres that may contain one or more of the following substances: sorbitol, mannitol, sucrose, starch, microcrystalline cellulose, lactose, glucose, trehalose, maltitol or fructose. The initial size of this inert core can be between 200 and 1800 µm. In an embodiment, the inert cores are neutral microspheres containing a mixture of sucrose and starch.

In an embodiment, the method includes preparing a multi-unit dosage form that may contain one or more pharmaceutically acceptable excipients or carriers. The term pharmaceutically acceptable excipients or carriers means that the excipients or carriers are suitable for use in pharmaceutical technology for the preparation of compositions having medical use. Suitable excipients and/or carriers, as well as their amounts, can be readily determined by those skilled in the art depending on the type of composition being prepared.

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According to an embodiment of the present invention, the multi-unit modified release dosage form further comprises a binder, an alkaline agent, a glidant, a surfactant, or a mixture thereof.

As mentioned above, the method according to the present invention includes separately coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof having an active layer and an intermediate enteric coating layer, and microspheres of pyridoxine or a pharmaceutically acceptable salt thereof having an inner active coating layer, the step of applying a modified release coating includes simultaneous spraying of a mixture containing from 2.0 to 7.5% by weight enteric coating agents and from 15.0 to 35.0% by weight modified release coating agents in a mass ratio of from 5:95 to 30:70, and adding pore-forming substances in powder form, while the spray flow rate of the mixture containing coating substances ranges from 300 to 1200 mg/min per 1 kg of inert core; the rate of addition of pore-forming substances in solid form is from 75 to 500 mg/min per 1 kg of inert core, in particular from 85 to 425 mg/min per 1 kg of inert core; and the ratio between the spray flow rate of the mixture containing coating agents and the rate of addition of blowing agents in solid form is from 90:10 to 60:40. This means that the method is carried out by spraying a mixture containing coating substances and simultaneously adding ingredients that are present in powder form. According to an embodiment, the method is a method in which the mixture containing enteric coating agents and modified release coating agents as defined in accordance with the present invention has a weight ratio of from 5:95 to 30:70. In an embodiment, the method is a method as defined above, wherein the mixture contains a 1:1 ratio of methacrylic acid/methyl methacrylate copolymer (Eudragit L) as an enteric coating agent and (dewaxed) shellac as a modified release coating agent in a weight ratio of from 5:95 to 30:70, in particular from 8:92 to 20:80. According to an embodiment, the method is a method in which the spray flow rate of the mixture containing coating substances is from 300 to 1200 mg/min per 1 kg of inert core, in particular from 385 to 1000 mg/min per 1 kg of inert core.

According to an embodiment of the present invention, the method comprises separately coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof having an active layer and an intermediate enteric coating layer as defined above; wherein the method is a method in which the rate of addition of pore-forming substances in solid form is from 88 to 195 mg/min per 1 kg of inert core. According to an embodiment, the method is a method in which the ratio between the spray flow rate of the mixture containing coating agents and the rate of addition of blowing agents in solid form is from 90:10 to 60:40, in particular from 90:10 to 70:30 . In an embodiment, the method is a method in which the mixture containing from 2.5 to 7.5% enteric coating agents and from 15 to 30% modified release coating agents is a solution further containing one or more organic solvents, in in particular, in an amount of from 85 to 290 g of solvent per 1 kg of inert core, in particular from 250 to 290 g of solvent per 1 kg of inert core, more particularly from 270 to 285 g of solvent per 1 kg of inert core

According to an embodiment of the present invention, the method includes separately coating microspheres of pyridoxine or a pharmaceutically acceptable salt thereof having an internal active coating layer, the method being a method in which the rate of addition of blowing agents in solid form is from 193 to 425 mg/min per 1 kg inert core. According to an embodiment, the method is a method in which the ratio between the spray flow rate of the mixture containing coating agents and the rate of addition of blowing agents in solid form is from 90:10 to 60:40, in particular from 80:20 to 60:40. In an embodiment, the method is a method in which the mixture contains from 2.5 to 5.5% enteric coating agents and from 20 to 35% modified release coating agents and is a solution further containing one or more organic solvents, in particular , in an amount of 85 to 100 g of solvent per 1 kg of inert core, in particular 90 to 95 g of solvent per 1 kg of inert core, more particularly 280 to 290 g of solvent per 1 kg of inert core.

According to an embodiment of the present invention, the method comprises separately coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof having an active layer and an intermediate enteric coating layer as defined above, or microspheres of pyridoxine or a pharmaceutically acceptable salt thereof having an inner active coating layer, and is a method wherein the mixture containing enteric coating agents and modified release coating agents is a solution further containing one or more organic solvents selected from the group consisting of (C1- _C4 )alcohol, ( _C1 - _C4 )alkyl- CO-(C ₁ -C ₄ )alkyl, (C ₁ -C ₄ )alkyl-CO-O-(C ₁ -C ₄ )alkyl, water and mixtures thereof. Term

- 8 044924 alcohol means an alkane in which at least one hydrogen atom is replaced by a hydroxyl group and which contains the number of carbon atoms specified in the description or claims. The term alkane means a saturated, branched or linear hydrocarbon that contains the number of carbon atoms specified in the description or claims. Examples are methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol and sec-butanol. The term alkyl means a saturated linear or branched hydrocarbon chain that contains the number of carbon atoms specified in the description or claims. Examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl groups. In an embodiment, the method is a method in which the mixture containing enteric coating agents and modified release coating agents is a solution further containing one or more organic solvents selected from the group consisting of ethanol, 2-propanol, methanol, acetone, butanone, ethyl acetate, water and a mixture thereof, in particular selected from ethanol, acetone, water and a mixture thereof.

According to an embodiment of the present invention, the method includes separately coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof having an active layer and an intermediate enteric coating layer, and microspheres of pyridoxine or a pharmaceutically acceptable salt thereof having an inner active coating layer, wherein the air flow is from 0 to 20 m ³ /h per 1 kg of inert core, in particular from 0 to 4 m ³ /h per 1 kg of inert core. The air flow is controlled using an anemometer-type system for detecting air inlet, installed in the duct between the fan and the coating unit, or using another equivalent system.

According to an embodiment of the present invention, the method includes separately coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof having an active layer and an intermediate enteric coating layer, and microspheres of pyridoxine or a pharmaceutically acceptable salt thereof having an inner active coating layer, wherein the temperature in the core of the microspheres during the step coating is from 5 to 50°C, in particular from 10 to 30°C, more particularly from 15 to 25°C. This temperature is controlled using a calibrated PT100 sensor which is in direct contact with the microspheres to be coated, but can be controlled using an equivalent system.

According to an embodiment of the present invention, the method includes separately coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof having an internal active coating layer and an intermediate enteric coating layer, and microspheres of pyridoxine or a pharmaceutically acceptable salt thereof having an internal active coating layer, wherein the rotation speed is from 0 up to 50 rpm, in particular from 2 to 25 rpm, more particularly from 10 to 20 rpm, the rotation speed of the coating unit can be adjusted in any manner known from the prior art. Specifically, the method used according to the present invention is a method in which a revolution counter is used.

According to an embodiment of the present invention, the method comprises coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and an intermediate enteric coating layer; wherein the coating step includes spraying a mixture containing from 2.0 to 7.5% by weight enteric coating agents and from 15 to 35% by weight modified release coating agents; wherein the weight ratio between enteric coating agents and modified release coating agents is from 15:85 to 25:75. Specifically, the mixture contains 4 to 7% by weight of a 1:1 copolymer of methacrylic acid and methyl methacrylate (Eudragit L) as an enteric coating agent and 15 to 25% by weight of (dewaxed) shellac as a modified release coating agent in a mass ratio from 15:85 to 25:75.

According to an embodiment of the present invention, the method comprises coating microspheres of pyridoxine or a pharmaceutically acceptable salt thereof having an internal active coating layer; wherein the coating step includes spraying a mixture containing from 2.0 to 7.5% by weight enteric coating agents and from 15 to 35%, in particular from 20 to 35% modified release coating agents, the mass ratio between the enteric coating agents and modified release coating agents range from 5:95 to 30:70. Specifically, the mixture contains from 2.0 to 5% by weight of a 1:1 copolymer of methacrylic acid and methyl methacrylate (Eudragit L) as an enteric coating agent and from 25 to 35% by weight of (dewaxed) shellac as a coating agent with modified release in a mass ratio from 5:95 to 15:85.

According to an embodiment of the present invention, the method includes coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof having an internal active coating

- 9 044924 layer, and an intermediate enteric coating layer; wherein the coating step includes simultaneously spraying a mixture containing from 2.0 to 7.5% by weight enteric coating agents and from 15 to 35% by weight modified release coating agents in a mass ratio of from 5:95 to 30:70, and adding blowing substances in powder form, wherein the spray flow rate of the mixture containing coating substances is from 300 to 1200 mg/min per 1 kg of inert core, in particular from 445 to 1000 g/min per 1 kg of inert core, more specifically approximately 890 mg/min per 1 kg of microspheres; the rate of addition of pore-forming substances in solid form is from 88 to 195 mg/min per 1 kg of inert core, more specifically 178 mg/min per 1 kg of microspheres; and the ratio between the spray flow rate of the mixture containing coating agents and the rate of addition of blowing agents in solid form is from 90:10 to 70:30, in particular from 85:15 to 75:25, more particularly 83:17. This means that the method is carried out by spraying a mixture containing coating substances and simultaneously adding ingredients that are present in powder form. According to an embodiment, the method is a method in which the mixture containing enteric coating agents and modified release coating agents, as defined according to the present invention, has a weight ratio of from 10:90 to 30:70, in particular from 15:85 to 25: 75. According to an embodiment, the method is a method in which the mixture contains a copolymer of methacrylic acid and methyl methacrylate in a ratio of 1:1 (Eudragit L) as an enteric coating agent and (dewaxed) shellac as a modified release coating agent in a mass ratio of 15:85 to 25:75, in particular from 18:82 to 22:78, more specifically 20:80. According to an embodiment, the method is a method in which the spray flow rate of the mixture containing coating substances is from 300 to 1200 mg/min per 1 kg of inert core, in particular from 445 to 1000 mg/min per 1 kg of inert core, more particularly 890 mg/min per 1 kg of microspheres. According to an embodiment, the method is a method in which the rate of addition of blowing agents in solid form is from 88 to 195 mg/min per 1 kg of inert core, more particularly 178 mg/min per 1 kg of microspheres. According to an embodiment, the method is a method in which the ratio between the spray flow rate of the mixture containing coating agents and the rate of addition of blowing agents in solid form is from 85:15 to 75:25, in particular 83:17. According to an embodiment, the method is a method in which a mixture containing from 2 to 7.5% by weight of enteric coating agents as defined above, in particular a copolymer of methacrylic acid and methyl methacrylate (Eudragit L), and from 15 to 35 % by weight of modified release coating agents is a solution additionally containing one or more organic solvents, in particular the amount of solvents is from 275 to 290 g/min per 1 kg of microspheres, more specifically, 282 g per 1 kg of microspheres, at In this case, the total concentration of solvents in the mixture ranges from 72 to 78% by weight. In an embodiment, the method is a method in which the mixture comprising enteric coating agents and modified release coating agents is a solution further containing one or more organic solvents as defined above.

According to an embodiment of the present invention, the method comprises coating microspheres of pyridoxine or a pharmaceutically acceptable salt thereof having an internal active coating layer; wherein the coating step includes simultaneous spraying of a mixture containing from 2.0 to 7.5%, in particular from 2 to 5.5%, by weight of enteric coating agents and from 15 to 35% by weight of modified release coating agents in bulk ratio from 5:95 to 25:75, and the addition of pore-forming substances in powder form, while the spray flow rate of the mixture containing coating substances ranges from 385 to 850 mg/min per 1 kg of inert core; the rate of addition of pore-forming substances in solid form ranges from 193 to 425 mg/min per 1 kg of inert core; and the ratio between the spray rate of the coating agent-containing mixture flow and the rate of addition of blowing agents in solid form is from 80:20 to 60:40. This means that the method is carried out by spraying a mixture containing coating substances and simultaneously adding ingredients that are present in powder form. According to an embodiment, the method is a method in which the mixture containing enteric coating agents and modified release coating agents, as defined according to the present invention, has a weight ratio of from 5:95 to 30:70. According to an embodiment, the method is a method in which the mixture contains a copolymer of methacrylic acid and methyl methacrylate in a ratio of 1:1 (Eudragit L) as an enteric coating agent and (dewaxed) shellac as a modified release coating agent in a mass ratio of 5:95 to 25:75, in particular from 5:95 to 15:85, more specifically 9:91. According to an embodiment, the method is a method in which the spray flow rate of the mixture containing coating substances is from 385 to 850 mg/min per 1 kg of inert core, in particular 773 mg/min per 1 kg of inert core.

According to an embodiment, the method is a method in which the speed is added

- 10 044924 the concentration of pore-forming substances in solid form, in particular talc, ranges from 193 to 425 mg/min per 1 kg of inert core, in particular 387 mg/min per 1 kg of inert core. According to an embodiment, the method is a method in which the ratio between the spray flow rate of the mixture containing coating substances and the rate of addition of blowing agents in solid form is from 90:10 to 60:40, in particular from 75:25 to 65:35, more specifically 67:33. In an embodiment, the method is a method in which the mixture containing from 2.0 to 7.5% enteric coating agents and from 15 to 35% modified release coating agents is a solution further containing one or more organic solvents, in in particular, the total amount of solvents is from 90 to 95 g per 1 kg of microspheres, more particularly 93 g per 1 kg of microspheres, and the total concentration of solvents in the mixture is from 65 to 70% by weight, more particularly 68% by weight of solvents. In an embodiment, the method is a method in which the mixture comprising enteric coating agents and modified release coating agents is a solution further containing one or more organic solvents as defined above.

According to an embodiment of the present invention, the method further includes a preliminary step of coating the inert core, which separately simultaneously sprays a mixture containing from 30 to 40% by weight of one or more coating agents and adds to the powder mixture a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof. in particular doxylamine succinate, from 22 to 30% by weight of pore-forming agents and optionally one or more pharmaceutically acceptable excipients; wherein the spraying rate of the flow of the mixture containing from 30 to 40% by weight of one or more coating substances ranges from 445 to 1000 mg/min per 1 kg of inert core; the rate of addition of the mixture of solids in powder form is from 1.64 to 3.62 g/min per 1 kg of inert core; and the ratio between the spray rate of the mixture containing the coating substances and the rate of the powder mixture in solid form is from 15:85 to 25:75. According to an embodiment, the method is a method in which a mixture containing from 30 to 40% by weight of one or more coating substances is a solution additionally containing one or more organic solvents, in particular in an amount of from 60 to 70% by weight . According to an embodiment, the method is a method in which the mixture containing the coating substances is a solution further containing one or more organic solvents selected from the group consisting of ethanol, 2-propanol, methanol, acetone, butanone, ethyl acetate and water, or a mixture of them.

According to an embodiment of the present invention, the method further includes a preliminary step of coating the inert core, which involves separately simultaneously spraying a mixture containing from 30 to 40% by weight of one or more coating agents, and adding to the powder mixture a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, in particular doxylamine succinate, from 22 to 30% by weight of pore-forming agents and optionally one or more pharmaceutically acceptable excipients; wherein the spraying rate of the flow of the mixture containing from 30 to 40% by weight of one or more coating substances ranges from 445 to 1000 mg/min per 1 kg of inert core; the rate of addition of the mixture of solids in powder form is from 1.64 to 3.62 g/min per 1 kg of inert core; and the ratio between the spray rate of the mixture containing the coating substances and the rate of the powder mixture in solid form is from 15:85 to 25:75; wherein the coating agent is selected from the group consisting of polyvinylpyrrolidone, shellac, hydroxypropyl methylcellulose, hydroxypropylcellulose and microcrystalline cellulose and a mixture thereof, in particular a mixture of polyvinylpyrrolidone and shellac. In particular, a mixture containing from 30 to 40% by weight of one or more coating agents is a mixture of solid coating agents containing polyvinylpyrrolidone K30 and (dewaxed) shellac in a weight ratio of from 10:90 to 18:82 (these values are equivalent mass ratio of polyvinylpyrrolidone and shellac from 20:80 to 30:70). More specifically, a mixture of a solution of 20 wt.% polyvinylpyrrolidone K-30 in ethanol and a solution of 40 wt.% (dewaxed) shellac in ethanol is used in a weight ratio of from 20:80 to 40:60, in particular 30:70.

According to an embodiment of the present invention, the method further includes a preliminary step of coating the inert core, which involves separately simultaneously spraying a mixture containing from 30 to 40% by weight of one or more coating agents, and adding to the powder mixture a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, in particular doxylamine succinate, from 22 to 30% by weight of pore-forming agents, and optionally one or more pharmaceutically acceptable excipients; in which the spray flow rate of the mixture containing from 30 to 40% by weight of one or more coating substances is from 445 to 1000 mg/min per 1 kg of inert core; the rate of addition of the mixture of solids in powder form is from 1.64 to 3.62 g/min per 1 kg of inert core; and the relationship between the spray flow rate of the mixture containing coating substances and the powder speed

- 11 044924 co-shaped mixture in solid form is from 15:85 to 30:70. According to an embodiment, the method is a method in which the mixture containing from 30 to 40% by weight of one or more coating substances is a solution additionally containing one or more organic solvents, in particular the total amount of solvents is from 61 to 71 g per 1 kg of inert core, more specifically 66 g per 1 kg of inert core, the total concentration of solvents in the mixture being from 0 to 70% by weight. According to an embodiment, the method is a method in which the blowing agent is talc, micronized sugar, sodium or potassium chloride and a mixture thereof, in particular talc. According to an embodiment, the method is a method in which the mixture containing the coating substances is a solution further containing one or more organic solvents as defined above. According to an embodiment of the present invention, the method further includes a preliminary step of coating the inert core, which involves separately simultaneously spraying a mixture containing from 30 to 40% by weight of one or more coating agents, and adding to the powder mixture a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, in particular, doxylamine succinate, from 22 to 30% by weight of pore-forming agents, and optionally one or more pharmaceutically acceptable excipients as defined above, wherein the pharmaceutically acceptable excipient is selected from the group consisting of one or more glidants, fillers , promoting moisture absorption of substances or mixtures thereof.

The term glidant means a substance that improves the dry flow characteristics of powder mixtures. Materials commonly used as glidants are magnesium stearate, colloidal silica or talc. According to an embodiment of the present invention, the composition is a composition in which the pharmaceutically acceptable excipients or carriers include one or more glidants; preferably colloidal silica is present and preferably Aerosil 200 Pharma.

The term excipient means a material that is added to increase the volume of a dosage form when the active ingredient is not present in sufficient quantity. Materials commonly used as filler are lactose, sucrose, mannitol, dicalcium phosphate dihydrate, starch, cellulose and microcrystalline cellulose. According to an embodiment of the present invention, the composition is a composition in which the pharmaceutically acceptable excipients or carriers are one or more excipients; preferably sucrose, starch or microcrystalline cellulose is present.

The term moisture wicking agent means a material that has the ability to draw water into the porous structure of the delivery device. It has the ability to provide physical sorption of water. The role of the wicking agent is to act as a carrier and facilitate the flow of water to the inner surface of the kernel. Materials commonly used as wicking agents are sodium lauryl sulfate, kaolin, titanium dioxide, alumina, bentonite, magnesium aluminum silicate, povidone, and colloidal silica (Aerosil). According to an embodiment of the present invention, the composition is a composition in which the pharmaceutically acceptable excipients or carriers are one or more moisture absorption promoting substances; preferably kaolin, titanium dioxide, alumina, bentonite, magnesium aluminum silicate, povidone and colloidal silica (Aerosil). According to an embodiment of the present invention, the composition is a composition in which the pharmaceutically acceptable excipients or carriers are one or more moisture absorption promoting substances; preferably povidone or colloidal silica (Aerosil) or a mixture thereof is present.

According to an embodiment of the present invention, the method further includes a preliminary step of coating the inert core, which involves separately simultaneously spraying a mixture containing from 30 to 40% by weight of one or more coating agents, and adding to the powder mixture a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, in particular, doxylamine succinate, from 22 to 30% by weight of blowing agents, and one or more pharmaceutically acceptable excipients as defined above, wherein the spray rate of the mixture containing from 30 to 40% by weight of one or more coating agents, ranges from 445 to 1000 mg/min per 1 kg of inert core; the spray rate of the powder mixture flow is from 1.64 to 3.62 g/min per 1 kg of inert core; and the ratio between the rate of atomization of the flow of the coating agent-containing mixture and the rate of addition of the blowing agent in the solid form of the powder mixture is from 15:85 to 30:70. In an embodiment, doxylamine or a corresponding pharmaceutically acceptable salt, in particular doxylamine succinate, has a particle size equal to or less than 100 microns.

- 12 044924

According to an embodiment of the present invention, the method further includes a preliminary step of coating the inert core, which separately involves simultaneously spraying a mixture containing from 30 to 45% of one or more coating agents and adding a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, in particular the hydrochloride pyridoxine, in powder form; wherein the spray flow rate of the mixture containing from 30 to 45% of one or more coating substances, in particular 40% (dewaxed) shellac in ethanol, is from 385 to 850 mg/min per 1 kg of inert core; the rate of addition of solid powder is from 770 to 1700 mg/min per 1 kg of inert core; and the ratio between the spray flow rate of the mixture containing coating substances and the powder mixture is from 25:75 to 40:60.

According to an embodiment of the present invention, the method further includes a preliminary step of coating the inert core, which separately involves simultaneously spraying a mixture containing from 30 to 45% by weight of one or more coating agents and adding a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, in particular the hydrochloride pyridoxine, in powder form; wherein the spraying rate of the flow of the mixture containing from 30 to 45% of one or more coating substances ranges from 385 to 850 mg/min per 1 kg of inert core; the rate of addition of solid powder is from 770 to 1700 mg/min per 1 kg of inert core; and the ratio between the spray rate of the mixture containing coating substances and the rate of the powder mixture in solid form is from 25:75 to 40:60; and 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, in particular (dewaxed) shellac.

According to an embodiment of the present invention, the method further includes a preliminary step of coating the inert core, which separately involves simultaneously spraying a mixture containing from 30 to 45% by weight of one or more coating agents and adding a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, in particular, pyridoxine hydrochloride, in powder form; wherein the spraying rate of the flow of the mixture containing from 30 to 45% by weight of one or more coating substances ranges from 385 to 850 mg/min per 1 kg of inert core; the rate of addition of solid powder is from 770 to 1700 mg/min per 1 kg of inert core; and the ratio between the spray rate of the mixture containing coating substances and the rate of the powder mixture in solid form is from 25:75 to 40:60; and the weight ratio between the therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, in particular pyridoxine hydrochloride in powder form and the mixture containing coating agents is from 25:75 to 40:60, in particular the weight ratio is 1:2.

According to an embodiment of the present invention, the method further includes a preliminary step of coating the inert core, which separately involves simultaneously spraying a mixture containing from 30 to 45% by weight of one or more coating agents and adding a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, in particular the hydrochloride pyridoxine in powder form; wherein the spraying rate of the flow of the mixture containing from 30 to 45% by weight of one or more coating substances ranges from 385 to 850 mg/min per 1 kg of inert core; the rate of addition of solid powder is from 770 to 1700 mg/min per 1 kg of inert core; and the ratio between the spray rate of the mixture containing the coating agents and the rate of the powder mixture in solid form is from 25:75 to 40:60, and pyridoxine or a corresponding pharmaceutically acceptable salt, in particular pyridoxine hydrochloride, has a particle size equal to or less than than 100 microns.

According to an embodiment of the present invention, the method further includes a preliminary step of coating the inert core, which separately involves simultaneously spraying a mixture containing from 30 to 45% by weight of one or more coating agents and adding a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, wherein the mixture , containing one or more coating substances, is a solution additionally containing one or more organic solvents, in particular, the amount of solvents is from 65 to 83 g per 1 kg of microspheres, more specifically 71 g per 1 kg of microspheres, and the total concentration of solvents in the mixture is from 55 to 70% by weight, more specifically 60% by weight of solvents. According to an embodiment, the method is a method in which the mixture containing the coating substances is a solution further containing one or more organic solvents as defined above.

According to an embodiment of the present invention, the method further comprises the additional step of coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof, in particular doxylamine succinate, having an internal active coating layer by simultaneously spraying a mixture containing from 5 to 15% by weight of one or more enteric coating substances, and adding from 5.5 to 6.0 g per 1 kg of inert core powder

- 13 044924 developing substances in powder form, wherein the spray flow rate of the mixture containing from 5 to 15% by weight of one or more enteric coating substances ranges from 445 to 1000 mg/min per 1 kg of inert core; the rate of addition of the pore-forming substance in solid form is from 45 to 100 mg/min per 1 kg of inert core; and the ratio between the spray rate of the mixture containing the coating agents and the rate of addition of the blowing agent in solid form is from 87:13 to 93:7.

According to an embodiment of the present invention, the method further comprises the additional step of coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof, in particular doxylamine succinate, having an internal active coating layer by simultaneously spraying a mixture containing from 5 to 15% enteric coating agents and adding 5.5 to 6.0 g per 1 kg of an inert core of pore-forming substances in powder form; wherein the spraying rate of the flow of the mixture containing from 5 to 15% by weight of one or more enteric coating substances ranges from 445 to 1000 mg/min per 1 kg of inert core; the rate of addition of the pore-forming substance in solid form is from 45 to 100 mg/min per 1 kg of inert core; and the ratio between the spray flow rate of the mixture containing the coating agents and the rate of addition of the blowing agent in solid form is from 87:13 to 93:7 and the enteric coating agent as defined above is, in particular, a copolymer of methacrylic acid and methyl methacrylate ( Eudragit L).

According to an embodiment of the present invention, the method further comprises an additional step which includes coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof, in particular doxylamine succinate, having an internal active coating layer by simultaneously spraying a mixture containing from 5 to 15% by weight of enteric coating agents and adding from 5.5 to 6.0 g per 1 kg of an inert core of pore-forming substances in powder form; wherein the spraying rate of the flow of the mixture containing from 5 to 15% of one or more enteric coating substances ranges from 445 to 1000 mg/min per 1 kg of inert core, in particular 910 mg/min per 1 kg of inert core; the rate of addition of the pore-forming substance in solid form is from 45 to 100 mg/min per 1 kg of inert core; and the ratio between the spray flow rate of the mixture containing coating substances and the powder mixture is from 87:13 to 93:7, in particular 90:10; and the blowing agent as defined above is, in particular, talc.

According to an embodiment of the present invention, the method further comprises an additional step which includes coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof, in particular doxylamine succinate, having an internal active release coating layer by simultaneously spraying a mixture containing from 5 to 15% by weight of enteric coating agents and adding from 5.5 to 6.0 g per 1 kg of inert core, in particular 5.7 g per 1 kg of inert core, pore-forming substances in powder form, the mixture containing from 5 to 15% by weight of enteric coating substances , is a mixture additionally containing one or more organic solvents, in particular the total amount of solvents is from 48 to 55 g per 1 kg of inert core, more specifically, 51 g per 1 kg of inert core, and the total concentration of solvents in the mixture is from 85 to 95% by weight, more specifically 90% by weight, solvents. According to an embodiment, the method is a method in which the mixture containing the coating substances is a solution further containing one or more organic solvents as defined above.

According to an embodiment of the present invention, the method includes preparing a first plurality of modified release microspheres of doxylamine or a pharmaceutically acceptable salt thereof by coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and an intermediate enteric coating layer by simultaneously spraying a mixture containing from 2 .0 to 7.5% by weight of enteric coating agents and from 15.0 to 35.0% by weight of modified release coating agents in a mass ratio of 5:95 to 30:70, and adding blowing agents in powder form; in this case, the spraying rate of the flow of the mixture containing coating substances ranges from 300 to 1200 mg/min per 1 kg of inert core; the rate of addition of pore-forming substances in solid form is from 75 to 500 mg/min per 1 kg of inert core, in particular from 85 to 425 mg/min per 1 kg of inert core; and the ratio between the spray rate of the mixture containing the coating agents and the rate of addition of the blowing agents in solid form is from 90:10 to 60:40.

According to an embodiment of the present invention, the method includes preparing a first plurality of modified release microspheres of doxylamine or a pharmaceutically acceptable salt thereof by coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof having an internal active release coating layer by simultaneously spraying a mixture containing from 5 to 15% enteric coating agents , and adding from 5.5 to 6.0 g per 1 kg of inert

- 14 044924 core of pore-forming substances in powder form; wherein the spraying rate of the flow of the mixture containing from 5 to 15% by weight of one or more enteric coating substances ranges from 445 to 1000 mg/min per 1 kg of inert core; the rate of addition of the pore-forming substance in solid form is from 45 to 100 mg/min per 1 kg of inert core; and the ratio between the spray flow rate of the coating agent-containing mixture and the rate of addition of the blowing agent in solid form is from 87:13 to 93:7; and coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof having an internal active coating layer, and an intermediate enteric coating layer, by simultaneously spraying a mixture containing from 2.0 to 7.5% by weight enteric coating agents and from 15.0 to 35, 0% by weight of modified release coating agents in a mass ratio of 5:95 to 30:70, and the addition of blowing agents in powder form; in this case, the spraying rate of the flow of the mixture containing coating substances ranges from 300 to 1200 mg/min per 1 kg of inert core; the rate of addition of pore-forming substances in solid form is from 75 to 500 mg/min per 1 kg of inert core, in particular from 85 to 425 mg/min per 1 kg of inert core; and the ratio between the spray rate of the mixture containing the coating agents and the rate of addition of the blowing agents in solid form is from 90:10 to 60:40.

According to an embodiment of the present invention, the method includes preparing a first plurality of modified release microspheres of doxylamine or a pharmaceutically acceptable salt thereof by separately coating an inert core by simultaneously spraying a mixture containing from 30 to 40% by weight of one or more coating agents and adding a powder mixture of a therapeutically effective an amount of doxylamine or a pharmaceutically acceptable salt thereof, from 22 to 30% by weight of pore-forming agents and optionally one or more pharmaceutically acceptable excipients; wherein the spraying rate of the flow of the mixture containing from 30 to 40% by weight of one or more coating substances ranges from 445 to 1000 mg/min per 1 kg of inert core; the rate of addition of the mixture of solids in powder form is from 1.64 to 3.62 g/min per 1 kg of inert core; and the ratio between the spray rate of the mixture containing coating substances and the rate of the powder mixture in solid form is from 15:85 to 25:75;

coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof having an internal active coating layer by simultaneously spraying a mixture containing from 5 to 15% enteric coating substances and adding from 5.5 to 6.0 g per 1 kg of an inert core of pore-forming substances in powder form form; wherein the spraying rate of the flow of the mixture containing from 5 to 15% by weight of one or more enteric coating substances ranges from 445 to 1000 mg/min per 1 kg of inert core; the rate of addition of the pore-forming substance in solid form is from 45 to 100 mg/min per 1 kg of inert core; and the ratio between the spray flow rate of the coating agent-containing mixture and the rate of addition of the blowing agent in solid form is from 87:13 to 93:7; and coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof having an internal active coating layer, and an intermediate enteric coating layer, by simultaneously spraying a mixture containing from 2.0 to 7.5% by weight enteric coating agents and from 15.0 to 35, 0% by weight of modified release coating agents in a mass ratio of 5:95 to 30:70, and the addition of blowing agents in powder form; in this case, the spraying rate of the flow of the mixture containing coating substances ranges from 300 to 1200 mg/min per 1 kg of inert core; the rate of addition of pore-forming substances in solid form is from 75 to 500 mg/min per 1 kg of inert core, in particular from 85 to 425 mg/min per 1 kg of inert core; and the ratio between the spray flow rate of the mixture containing coating agents and the rate of addition of blowing agents in solid form is from 90:10 to 60:40.

According to an embodiment of the present invention, the method includes preparing a second plurality of modified release microspheres of pyridoxine or a pharmaceutically acceptable salt thereof by coating the microspheres of pyridoxine or a pharmaceutically acceptable salt thereof, in particular doxylamine succinate, having an internal active coating layer, by simultaneous spraying simultaneous spraying of a mixture containing from 2.0 to 7.5% by weight enteric coating agents and from 15.0 to 35.0% by weight modified release coating agents in a mass ratio of 5:95 to 30:70, and the addition of blowing agents in powder form ; in this case, the spraying rate of the flow of the mixture containing coating substances ranges from 300 to 1200 mg/min per 1 kg of inert core; the rate of addition of pore-forming substances in solid form is from 75 to 500 mg/min per 1 kg of inert core, in particular from 85 to 425 mg/min per 1 kg of inert core; and the ratio between the spray rate of the mixture containing the coating agents and the rate of addition of the blowing agents in solid form is from 90:10 to 60:40.

According to an embodiment of the present invention, the method includes preparing a second plurality of modified-release microspheres of pyridoxine or pharmaceutically

- 15 044924 acceptable salt by separately coating the inert core by simultaneously spraying a mixture containing from 30 to 45% of one or more coating substances and adding a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof in powder form; wherein the spraying rate of the flow of the mixture containing from 30 to 45% of one or more coating substances ranges from 385 to 850 mg/min per 1 kg of inert core; the rate of addition of solid powder is from 770 to 1700 mg/min per 1 kg of inert core; and the ratio between the spray flow rate of the mixture containing coating substances and the powder mixture is from 25:75 to 40:60; and coating microspheres of pyridoxine or a pharmaceutically acceptable salt thereof, in particular doxylamine succinate, having an internal active coating layer by simultaneously spraying a mixture containing from 2.0 to 7.5% by weight of enteric coating agents and from 15.0 to 35, 0% by weight of modified release coating agents in a mass ratio of 5:95 to 30:70, and the addition of blowing agents in powder form; in this case, the spraying rate of the flow of the mixture containing coating substances ranges from 300 to 1200 mg/min per 1 kg of inert core; the rate of addition of pore-forming substances in solid form is from 75 to 500 mg/min per 1 kg of inert core, in particular from 85 to 425 mg/min per 1 kg of inert core; and the ratio between the spray flow rate of the mixture containing coating agents and the rate of addition of blowing agents in solid form is from 90:10 to 60:40.

According to an embodiment, each of the coating steps occurs at a temperature ranging from 10 to 30°C, in particular from 15 to 25°C, more particularly from 17 to 22°C.

According to an embodiment, each of the coating steps occurs at an air flow of from 0 to 20 m ³ /h per 1 kg of inert core, in particular from 0 to 4 m ³ /h per 1 kg of inert core. The air flow is controlled using an anemometer-type system to detect air inlet, installed in the duct between the fan and the coating unit, or other equivalent system.

According to an embodiment of the present invention, the method further comprises one or more additional steps of separately drying each of the plurality of microspheres produced in each coating step to remove solvents and moisture; and optionally another additional step of sieving a plurality of microspheres if agglomeration of the powder to form granules is observed. According to an embodiment, the drying steps take place at a temperature ranging from 20 to 60°C, preferably from 25 to 45°C.

In a specific embodiment, the drying steps between coating steps occur for at least one hour at a temperature of 15 to 45° C., a coater speed of 0 to 10 rpm, and an air flow of more than 1 m ³ /h per 1 kg of inert core.

According to a specific embodiment, the step of drying the outer coating of the microspheres occurs for no less than 8 hours and no more than 12 hours at a temperature of from 15 to 60°C, preferably from 25 to 50°C, more particularly from 40 to 45°C , a coating unit speed of 0 to 10 rpm and an air flow of more than 1 m ³ /h per 1 kg of inert core.

According to an embodiment of the present invention, the method further includes one or more additional steps of sifting a plurality of microspheres until the sieving results in a size of equal to or greater than 500 μm to equal to or less than 1500 μm, in particular equal to or greater than 500 μm. being more than 600 µm to equal to or being less than 1320 µm, more particularly from being equal to or being more than 710 µm to equal to or being less than 1180 µm.

In an embodiment, the method is a method wherein the multi-unit modified-release oral dosage form exhibits a dissolution profile such that 10 to 35% by weight of the doxylamine content is dissolved by the end of the first hour in 0.1 N HCl (pH 1);

then the medium is replaced by a medium with pH 4.5 (0.05 M acetate buffer), and by the end of the fourth hour, a total of 45 to 70% by weight of the original doxylamine content has dissolved;

the medium is then replaced by pH 6.8 medium (0.05 M phosphate buffer), and by the end of the seventh hour, a total of at least 80% of the original doxylamine content has dissolved;

from 10 to 35% by weight of pyridoxine content dissolves by the end of the first hour in 0.1 N HCl (pH 1);

then the medium is replaced by a medium with pH 4.5 (0.05 M acetate buffer), and by the end of the fourth hour, a total of 40 to 65% by weight of the initial pyridoxine content has dissolved;

- 16 044924 the medium is then replaced by a medium with a pH of 6.8 (0.05 M phosphate buffer), and by the end of the seventh hour at least 80% of the original pyridoxine content has dissolved in total, the dissolution profile being measured using a device (basket) of the type II according to the United States Pharmacopoeia (USP), placing the composition in 900 ml of the appropriate medium/buffer solution at 37 ± 0.5 ° C and 100 rpm.

According to an embodiment of the present invention, there is provided a method wherein the multi-element modified-release oral dosage form comprises a first plurality of modified-release microspheres of doxylamine or a pharmaceutically acceptable salt thereof containing an inert core, an inner active coating layer containing a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof. salts, from 7 to 11% by weight of one or more coating agents and from 20 to 28% by weight of one or more blowing agents; and optionally one or more pharmaceutically acceptable excipients, an intermediate enteric coating layer comprising from 45 to 65% by weight of one or more enteric coating agents and from 55 to 35% by weight of one or more pore-forming agents, and a modified release outer coating layer containing from 8 to 14% by weight of one or more enteric coating agents, from 38 to 46% by weight of one or more modified release coating agents, and from 42 to 52% by weight of one or more pore-forming agents; and a second plurality of modified-release microspheres of pyridoxine or a pharmaceutically acceptable salt thereof, comprising an inert core, an inner active coating layer containing a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, and from 14 to 20% by weight of one or more coating agents, and an outer a modified release coating layer comprising 2 to 6% by weight of one or more enteric coating agents, 30 to 45% by weight of one or more modified release coating agents, and 50 to 65% by weight of one or more pore-forming agents.

According to an embodiment of the present invention, the method further includes the further step of encapsulating a first plurality of microspheres of doxylamine or a pharmaceutically acceptable salt thereof and a second plurality of microspheres of pyridoxine or a pharmaceutically acceptable salt thereof in capsules, particularly hard capsules.

The encapsulation step can be carried out by methods known in the art.

Throughout the specification and claims of the present invention, the word include and its variations are not intended to exclude other technical features, additives, components or steps. Additionally, the word include covers the meaning of consist of. Additional objects, advantages and features of the present invention will become apparent to those skilled in the art upon reading the present description or may be learned by practice of the present invention. The following examples are provided by way of illustration and are not intended to limit the present invention. Moreover, the present invention extends to all possible combinations of the specific and preferred embodiments that are described herein.

Examples

1. A method for preparing capsules containing microspheres of doxylamine succinate and pyridoxine hydrochloride according to the present invention.

1.1. Quantitative composition of the hard capsule.

The amount of each ingredient per capsule is determined as follows.

Ingredient Amount per capsule (mg) Function Active Ingredients Doxylamine succinate 10.0 Active Ingredient Pyridoxine hydrochloride 10.0 Active Ingredient Excipients Sugar balls 79.5 Inert core

- 17 044924

Shellac (dewaxed) 7.6 Coating substance Polyvinylpyrrolidone (povidone K-30) 0.2 Coating substance Talc 9.5 Pore-forming agent Copolymer of methacrylic acid and methyl methacrylate (1:1) (Eudragit L) 1.1 Enteric coating agent Anhydrous colloidal silica (Aerosil) 0.7 Anti-caking and slip-promoting agent Hard gelatin capsule ^ω 48 Number of doses per package Weight of capsule filler 118.6 Total capsule weight 166.6

⁽¹⁾ Gelatin capsule contains 0.0211% FD&C Indigotine Blue 2 (E132), 0.01% Quinoline Yellow (E104), 1.8% Titanium Dioxide (E171) and up to 100% gelatin.

1.2. Quantitative composition of many microspheres.

1.2.1. Composition of doxylamine succinate microspheres.

The amount of each ingredient per batch of approximately 180 kg of doxylamine succinate microspheres is determined as follows.

Microsphere layer Ingredients Function Quantity in per batch (kg) Core Sugar balls made from sucrose and starch Inert core 112,564 Inner active coating layer Doxylamine succinate Active Ingredient 30,200 Talc Pore-forming substance 10,067 Anhydrous colloidal silica (Aerosil 200 Pharma) Anti-caking and slip-promoting agent 2,013

- 18 044924

Polyvinylpyrrolidone (20% solution in ethanol, povidone K-30) Coating solution 3,020 Shellac (dewaxed, 40% solution in ethanol) Coating solution 8,419 Intermediate enteric layer Talc Pore-forming substance 0.641 Copolymer of methacrylic acid and methyl methacrylate (1:1) (EudragitL, 10% solution in acetone) Mixture enteric coating substances 6,406 Modified release outer layer Copolymer of methacrylic acid and methyl methacrylate (1:1) (EudragitL, 10% solution in acetone) Mixture enteric coating substances 21,155 Shellac (dewaxed, 40% solution in ethanol) Modified release coating solution 21,156 Talc Pore-forming substance 9.425 Total dry weight: 180.14

1.2.2. Composition of pyridoxine hydrochloride microspheres.

The amount of each ingredient per batch of approximately 180 kg of pyridoxine hydrochloride microspheres is determined as follows.

- 19 044924

Microsphere layer Ingredients Function Quantity in per batch (kg) Core Sugar balls made from sucrose and starch Inert core 129.285 Inner active coating layer Pyridoxine hydrochloride Active Ingredient 30,600 Shellac (dewaxed, 40% solution in ethanol) Coating solution 15,300 Modified release outer layer Copolymer of methacrylic acid and methyl methacrylate (1:1) (Eudragit L, 10% solution in acetone) Mixture enteric coating substances 4,896 Shellac (dewaxed, 40% solution in ethanol) Modified release coating solution 12,677 Talc Pore-forming substance 8,743 Total dry weight: 180.31

1.3. Method of production by applying powder.

1.3.1. A variety of doxylamine succinate microspheres.

A. Obtaining phases.

Phase 1 - powder mixture to form the inner active coating layer: Doxylamine succinate, Aerosil 200 Pharma and talc in the above quantities were mixed in a coating unit.

Phase 2 - Binder solution to produce the inner active coating layer: Povidone K30 (20% solution in ethanol) and (dewaxed) shellac 40% in ethanol were mixed in the above quantities.

Phase 3 - solution of coating agent to obtain the outer coating: (dewaxed) shellac (40% solution in ethanol) and Eudragit L (10% solution in acetone) were mixed in the quantities indicated above.

B. Method of obtaining.

Internal active cover layer.

The sugar beads were placed in the coater and then the binder solution (phase 2) was sprayed onto the sugar beads while the coater was kept rotating at a spray flow rate of 100 g/min. In the phase 2 spray process, the powder mixture (phase 1) was applied (in solid form) to the sugar beads at a solid addition rate of 370 g/min. The atomization step was carried out at a rotation speed of 16 rpm, maintaining the microsphere core temperature at 17 to 22° C. and the air flow at less than 100 m ³ /h.

The coated microspheres thus obtained were dried for at least 2 hours at room temperature while continuing to rotate them in the coating apparatus at a speed of 0 to 10 rpm and an air flow of more than 130 m ³ /h, obtaining dried coated microspheres with an inner active coating layer containing the active ingredient. If necessary, you can sift the dried microspheres and discard particles, powders and aggregates that have undesirable sizes.

Intermediate enteric coating layer.

The coated active microspheres obtained in the previous step were sprayed with a mixture of Eudragit L (10% solution in acetone) at a spray flow rate of 100 g/min per 1 kg of inert core. In the Eudragit spraying process, talc in solid form was applied to microspheres, floor

- 20 044924 tea microspheres containing an internal active coating layer and an intermediate enteric coating layer, at a solids addition rate of 10 g/min and a rotation speed of 16 rpm, maintaining the microsphere core temperature between 17 and 22° C and an air flow of less than 100 m ³ /h. The resulting coated microspheres were dried for at least one hour at room temperature while continuing to rotate them in the coating apparatus at a speed of between 0 and 10 rpm and an air flow of more than 130 m ³ /h.

Modified release outer coating layer.

Phase 3 was then sprayed onto the bilayer coated microspheres obtained in the previous step at a spray flow rate of 100 g/min. In the phase 3 spray process, talc was applied in solid form at a solid addition rate of 20 g/min and a rotation speed of 16 rpm, maintaining a microsphere core temperature of 17 to 22°C and an air flow of less than 100 m ³ /h. The resulting coated microspheres were dried for at least 8 hours and up to 12 hours at a temperature of 40 to 45°C, while continuing to rotate in the coating unit at a speed of 0 to 10 rpm, with an air flow of more than 130 m ³ /h.

The microspheres obtained in this way have a given dissolution profile. If necessary, the dried microspheres can be sieved to discard undesirable sized particles, powders and aggregates.

Modified release doxylamine succinate microspheres obtained in this manner were stored in 50 kg units in sealed double-layer food and pharmaceutical polyethylene bags inside sealed high-density polyethylene drums.

1.3.2. Many microspheres of pyridoxine hydrochloride.

A. Obtaining phases.

Phase 4 - coating solution to obtain the outer coating: (dewaxed) shellac (40% solution in ethanol) and Eudragit L (10% solution in acetone) were mixed in the above quantities.

B. Method of receipt.

Internal active cover layer.

The sugar balls were placed in a coating machine and then a (dewaxed) shellac solution (40% ethanol solution) was sprayed onto the sugar balls while maintaining a rotation speed of 16 rpm and a spray flow rate of 100 g/min at coating installation. In a process of spraying a 40% solution of (dewaxed) shellac in ethanol, solid pyridoxine hydrochloride was applied to the sugar beads at a solids addition rate of 200 g/min, maintaining a microsphere core temperature of 17 to 22°C and an air flow of less than 100 m ³ /h.

The coated microspheres thus obtained were dried for at least 2 hours at room temperature while continuing to rotate them in the coating apparatus at a speed of from 0 to 10 rpm with an air flow of more than 130 m ³ /h, producing dried coated microspheres with an inner active coating layer containing the active ingredient. If necessary, the dried microspheres can be sieved to discard undesirable sized particles, powders and aggregates.

Modified release outer coating layer.

On the coated active microspheres obtained in the previous step, phase 4 was sprayed at a flow rate of 100 g/min. During the spraying process of solution phase 4, talc in solid form was applied at a solid addition rate of 50 g/min and a rotation speed of 16 rpm, maintaining the microsphere core temperature at 17°C to 22°C and the air flow , amounting to less than 100 m ³ /h. The resulting coated microspheres were dried for at least 8 hours and up to 12 hours at a temperature of 40 to 45°C, while continuing to rotate them in the coating unit at a speed of 0 to 10 rpm, with an air flow of more than 130 m ³ /h.

The coated microspheres obtained in this way have a given dissolution profile. If necessary, the dried microspheres can be sieved to discard undesirable sized particles, powders and aggregates.

The modified hydrochloride release microspheres obtained in this manner were stored in 50 kg units in sealed double-layer food and pharmaceutical polyethylene bags inside sealed high-density polyethylene drums.

Filling capsules.

Each hard capsule was filled with 60 mg of doxylamine succinate modified release microspheres and 60 mg of pyridoxine hydrochloride modified release microspheres according to the present invention as defined above using a Bosch Zanussi E48 automatic capsule filling machine.

- 21 044924

2. Dissolution study.

Dissolution profile.

The predetermined dissolution profile requires that doxylamine succinate and pyridoxine hydrochloride dissolve to a small extent under gastric conditions so that the main therapeutic concentration is achieved in the intestinal tract due to the high dissolution rate. In particular, the production method according to the present invention allows for the production of capsules filled with such microspheres with modified release of doxylamine succinate and microspheres with modified release of pyridoxine hydrochloride, and these capsules exhibit a dissolution profile whereby from 10 to 35% by weight of the doxylamine content is dissolved by the end of the first hours in 0.1 N HCl (pH 1);

then the medium is replaced by a medium with pH 4.5 (0.05 M acetate buffer), and by the end of the fourth hour, a total of 45 to 70% by weight of the original doxylamine content has dissolved;

the medium is then replaced by pH 6.8 medium (0.05 M phosphate buffer), and by the end of the seventh hour, a total of at least 80% of the original doxylamine content has dissolved;

from 10 to 35% by weight of pyridoxine content dissolves by the end of the first hour in 0.1 N HCl (pH 1);

then the medium is replaced by a medium with pH 4.5 (0.05 M acetate buffer), and by the end of the fourth hour, a total of 40 to 65% by weight of the initial pyridoxine content has dissolved; and then the medium is replaced by pH 6.8 medium (0.05 M phosphate buffer), and by the end of the seventh hour, a total of at least 80% of the original pyridoxine content has dissolved, the dissolution profile being measured using a Type II basket according to United States Pharmacopeia (USP) by placing the composition in 900 ml of the appropriate medium/buffer solution at 37 ± 0.5 ° C and 100 rpm.

Conditions in the dissolution bath.

Stirrer speed: 100 rpm.

Temperature of the dissolving medium: 37±0.5°C.

Dissolving medium: 0.1 N hydrochloric acid solution.

Tank volume: 900 ml.

Time: 1 hour

Solvent medium: pH 4.5; 0.05 M acetate buffer.

Tank volume: 900 ml.

Time: from 1 to 4 hours.

Solvent medium: pH 6.8; 0.05 M phosphate buffer.

Tank volume: 900 ml.

Time: from 4 to 7 hours.

Conditions for chromatographic analysis.

Sample preparation: Take an aliquot of approximately 10 ml and filter it through a 0.70 µm membrane filter and then filter it through another 0.22 µm membrane filter.

Flow rate: 1 ml/min.

Column: Kromasil 100-5 C18, 150±4.0 mm.

Phases: methanol in water.

Injection volume: 100 µl.

Excitation wavelength: 220 nm.

Chromatography time: 25 min.

Aqueous phase: buffer pH 5.0 - solution of 0.06 M ammonium acetate + 0.1% sodium hexanesulfonate (PICB6)).

Gradient.

Time (min) Methanol (%) Aqueous phase (%) 0 20 80 4 32.5 80 8 100 50 13 100 50 17 20 80 25 20 80

Results.

Dissolution profile of a capsule according to the present invention, which contains microspheres of doxylamine succinate and pyridoxine hydrochloride.

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Claims (16)

pH Time (h) Dissolved doxylamine succinate(%) Dissolved pyridoxine hydrochloride(%) 1 0.5 from 9.3 1 22.3 16.5 4.5 2 38.7 33.0 3 47.6 44.0 4 54.9 52.8 6.8 5 84.6 74.4 6 93.8 90.2 7 97.2 97.8 The dissolution profile that is described above shows that the capsules according to the present invention have the desired dissolution profile. Thus, the dissolution of doxylamine succinate and pyridoxine hydrochloride after their joint administration in the stomach is at least 10% of the total amount within one hour, and at least 40% of the doxylamine succinate and pyridoxine hydrochloride are dissolved within 4 hours after administration in the duodenum colon (pH 4.5) and dissolves at least 80% of doxylamine succinate and pyridoxine hydrochloride within 7 hours after administration under colonic conditions. List of cited literature 1. WO 2013/123569. 2. WO 2016/029290. CLAIM 1. A method of producing a multi-element modified-release oral dosage form containing a first plurality of modified-release microspheres of doxylamine or a pharmaceutically acceptable salt thereof, containing an inert core, an inner active coating layer containing a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, one or more coating agents and one or more pore-forming agents, an intermediate enteric coating layer containing one or more enteric coating agents and one or more pore-forming agents, and a modified release outer coating layer containing one or more enteric coating agents, one or more coating agents with modified release and one or more pore-forming agents; and a second plurality of modified release microspheres of pyridoxine or a pharmaceutically acceptable salt thereof, comprising an inert core, an inner active coating layer containing a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, and one or more coating agents; and a modified release outer coating layer comprising one or more enteric coating agents, one or more modified release coating agents, and one or more blowing agents; wherein the method includes preparing a first plurality of modified release microspheres of doxylamine or a pharmaceutically acceptable salt thereof by coating microspheres of doxylamine or a pharmaceutically acceptable salt thereof having an inner active coating layer and an intermediate enteric coating layer by simultaneously spraying a mixture containing from 2.0 to 7, 5% by weight enteric coating agents and from 15.0 to 35.0% by weight modified release coating agents in a mass ratio of 5:95 to 30:70, and adding blowing agents in powder form, while the spray flow rate of the mixture , containing coating substances, ranges from 300 to 1200 mg/min per 1 kg of inert core; the rate of addition of pore-forming substances in solid form is from 75 to 500 mg/min per 1 kg of inert core; and the ratio between the rate of spraying the flow of the mixture containing coating agents and the rate of addition of blowing agents in solid form is from 90:10 to 60:40; and producing a second plurality of modified release microspheres of pyridoxine or a pharmaceutically acceptable salt thereof by coating the microspheres with pyridoxine or pharmaceuticals thereof - 23 044924 commercially acceptable salt having an internal active coating layer, by simultaneously spraying a mixture containing from 2.0 to 7.5% by weight enteric coating agents and from 15.0 to 35.0% by weight modified release coating agents in a mass ratio from 5:95 to 30:70, and adding pore-forming substances in powder form, while the spraying rate of the mixture containing coating substances is from 300 to 1200 mg/min per 1 kg of inert core; the rate of addition of pore-forming substances in solid form is from 75 to 500 mg/min per 1 kg of inert core; and the ratio between the spray flow rate of the mixture containing coating agents and the rate of addition of blowing agents in solid form is from 90:10 to 60:40. 2. The method of claim 1, wherein the inner active coating layer of the first plurality of modified release microspheres further comprises one or more pharmaceutically acceptable excipients. 3. The method of claim 1, wherein the method comprises preparing a first plurality of modified-release microspheres of doxylamine or a pharmaceutically acceptable salt thereof as defined in claim 1, wherein the rate of addition of solid form pore-forming agents is from 88 to 195 mg/min per 1 kg of inert core; and obtaining a second plurality of modified release microspheres of pyridoxine or a pharmaceutically acceptable salt thereof as defined in claim 1, wherein the rate of addition of solid form blowing agents is from 193 to 425 mg/min per 1 kg of inert core. 4. The method according to any one of claims 1 to 3, wherein the method includes obtaining a first plurality of microspheres with modified release of doxylamine or a pharmaceutically acceptable salt thereof, as defined in claim 1, wherein the relationship between the spray flow rate of the mixture containing coating substances and the speed addition of pore-forming substances in solid form is from 90:10 to 60:40; and providing a second plurality of modified-release microspheres of pyridoxine or a pharmaceutically acceptable salt thereof as defined in claim 1, wherein the ratio between the spray flow rate of the mixture containing coating agents and the rate of addition of blowing agents in solid form is from 90:10 to 60: 40. 5. The method according to any one of claims 1 to 4, wherein the mixture contains from 2.5 to 5.5% by weight of enteric coating agents and from 18 to 30% by weight of modified release coating agents. 6. The method according to any one of claims 1 to 5, the method further comprising a preliminary coating step in which microspheres of doxylamine or a pharmaceutically acceptable salt thereof having an internal active coating layer are separately coated by simultaneously spraying a mixture containing from 5 to 15% enteric coating agents, and adding from 5.5 to 6.0 g per 1 kg of an inert core of pore-forming substances in powder form, while the spray flow rate of the mixture containing from 5 to 15% by weight of one or more enteric coating agents is from 445 to 1000 mg/min per 1 kg of inert core; the rate of addition of the pore-forming substance in solid form is from 45 to 100 mg/min per 1 kg of inert core; and the ratio between the spray flow rate of the coating agent-containing mixture and the rate of addition of the blowing agent in solid form is from 87:13 to 93:7; and coating the inert core by simultaneously spraying a mixture containing from 30 to 45% of one or more coating agents and adding a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof in powder form, the spray flow rate of the mixture containing from 30 to 45% of one or more more coating substances, ranges from 385 to 850 mg/min per 1 kg of inert core; the rate of addition of solid powder is from 770 to 1700 mg/min per 1 kg of inert core; and the ratio between the spray flow rate of the mixture containing coating substances and the powder mixture is from 25:75 to 40:60. 7. The method according to any one of claims 1 to 6, wherein the particle size of doxylamine or a pharmaceutically acceptable salt thereof and pyridoxine or a pharmaceutically acceptable salt thereof is from 1 to 250 μm. 8. The method according to any one of claims 1 to 7, wherein the method further comprises the further step of coating the inert core by simultaneously spraying a mixture containing from 30 to 40% by weight of one or more coating agents and adding a therapeutically effective amount of the powder mixture doxylamine or a pharmaceutically acceptable salt thereof, from 22 to 30% by weight of blowing agents and optionally one or more pharmaceutically acceptable excipients, wherein the spray flow rate of the mixture containing from 30 to 40% by weight of one or more coating agents is from 445 to 1000 mg/min per 1 kg of inert core; the rate of addition of the powder mixture in solid form is from 1.64 to 3.62 g/min per 1 kg of inert core; and the ratio between the spray flow rate of the mixture containing coating agents and the addition rate of the powder mixture in solid form is from 15:85 to 25:75. 9. The method according to any one of claims 1 to 8, in which the pore-forming substance has a particle size of - 24 044924 1 to 250 µm. 10. The method according to any one of claims 1 to 9, wherein the multi-unit modified-release oral dosage form contains doxylamine succinate and pyridoxine hydrochloride. 11. The method according to any one of claims 1 to 10, wherein the multi-unit modified-release oral dosage form is a hard capsule containing from 5 to 50 mg of doxylamine succinate per capsule and from 5 to 50 mg of pyridoxine hydrochloride per capsule. 12. The method according to any one of claims 1 to 11, in which the coating substances of the inner active coating layer of doxylamine microspheres or a pharmaceutically acceptable salt thereof are selected from the group consisting of polyvinylpyrrolidone, shellac, hypromellose, hydroxypropylcellulose, microcrystalline cellulose and a mixture thereof; or alternatively, the blowing agent is selected from the group consisting of talc, micronized sugar, sodium or potassium chloride, and a mixture thereof. 13. The method according to any one of claims 1 to 12, in which the enteric coating agent is selected from the group consisting of a copolymer of methacrylic acid and methyl methacrylate, a copolymer of methacrylic acid and methyl acrylate, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, sodium alginate, cellulose acetate trimellitate and mixture thereof. 14. The method according to any one of claims 1 to 13, wherein the method further includes the additional step of separately drying each of the plurality of microspheres obtained at each coating stage, the drying step being carried out at a temperature of from 15 to 60°C and an air flow of more than 1 m ³ /h per 1 kg of inert core for an appropriate period of time until the content is less than 5000 ppm of each of the solvents used in the method. 15. The method according to any one of claims 1 to 14, wherein the multi-unit modified-release oral dosage form exhibits a dissolution profile such that 10 to 35% by weight of the doxylamine content dissolves by the end of the first hour in 0.1 N HCl ( pH 1); then the medium is replaced by a medium with pH 4.5 (0.05 M acetate buffer), and by the end of the fourth hour, a total of 45 to 70% by weight of the original doxylamine content has dissolved; the medium is then replaced by pH 6.8 medium (0.05 M phosphate buffer), and by the end of the seventh hour, a total of at least 80% of the original doxylamine content has dissolved; by the end of the first hour in a medium of 0.1 N HCl (pH 1), from 10 to 35% by weight of the pyridoxine content is dissolved; then the medium is replaced by a medium with pH 4.5 (0.05 M acetate buffer), and by the end of the fourth hour, a total of 40 to 65% by weight of the initial pyridoxine content has dissolved; the medium is then replaced by a pH 6.8 medium (0.05 M phosphate buffer) and by the end of the seventh hour, a total of at least 80% of the original pyridoxine content has dissolved, and the dissolution profile is measured using a type II device (basket) according to the pharmacopoeia USA (USP), placing the composition in 900 ml of the appropriate medium/buffer solution at 37 ± 0.5 ° C and 100 rpm. 16. The method according to any one of claims 1 to 15, wherein the multi-element modified-release oral dosage form comprises a first plurality of modified-release microspheres of doxylamine or a pharmaceutically acceptable salt thereof containing an inert core, an inner active coating layer containing a therapeutically effective amount of doxylamine or a pharmaceutically acceptable salt thereof, from 7 to 11% by weight of one or more coating agents and from 20 to 28% by weight of one or more pore-forming agents, and optionally one or more pharmaceutically acceptable excipients, an intermediate enteric coating layer containing from 45 to 65% by weight of one or more enteric coating agents and from 55 to 35% by weight of one or more pore-forming agents, and a modified release outer coating layer containing from 8 to 14% by weight of one or more enteric coating agents, from 38 to 46% by weight of one or more modified release coating agents and 42 to 52% by weight of one or more blowing agents; and a second plurality of modified release microspheres of pyridoxine or a pharmaceutically acceptable salt thereof, comprising an inert core, an inner active coating layer containing a therapeutically effective amount of pyridoxine or a pharmaceutically acceptable salt thereof, and from 14 to 20% by weight of one or more coating agents; And - 25 044924 a modified release outer coating layer containing from 2 to 6% by weight of one or more enteric coating agents, from 30 to 45% by weight of one or more modified release coating agents and from 50 to 65% by weight of one or more more pore-forming substances. ^gj) Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2