NZ729042B2 - Plurimodal release formulation of doxylamine and pyridoxine and/or metabolites or salts thereof - Google Patents

Abstract

solid oral dosage form comprising a core comprising a doxylamine component and a pyridoxine component coated with an enteric coating is disclosed. The solid oral dosage form further comprises two active ingredient-containing coatings surrounding the enteric coating, the active ingredient-containing coatings being separated from one another by an intermediate coating, and one of the two active ingredient-containing coatings comprising a doxylamine component and being free of a pyridoxine component, and the other of the two active ingredient-containing coatings comprising a pyridoxine component and being free of doxylamine component. Uses of the solid oral dosage form for the alleviation of the symptoms of nausea and vomiting, for example in the case of nausea and vomiting of pregnancy (NVP), are also disclosed. g coatings being separated from one another by an intermediate coating, and one of the two active ingredient-containing coatings comprising a doxylamine component and being free of a pyridoxine component, and the other of the two active ingredient-containing coatings comprising a pyridoxine component and being free of doxylamine component. Uses of the solid oral dosage form for the alleviation of the symptoms of nausea and vomiting, for example in the case of nausea and vomiting of pregnancy (NVP), are also disclosed.

Description

WO 29290 PLURIMODAL RELEASE FORMULATION OF DOXYLAMINE AND PYRIDOXINE ANDIOR METABOLITES OR SALTS THEREOF TECHNICAL FIELD The present invention generally relates to dosage forms and uses and packages thereof, for example for the management of nausea and vomiting, such as for the prevention and/ortreatment of nausea and vomiting of ncy (NVP).

BACKGROUND ART Nausea and vomiting of ncy (NVP), also referred to as "morning sickness," is very common. It afflicts 50% to 80% of pregnant women with g degrees of severity.

Commonly occurring within the first 4 to 16 weeks of ncy, approximately 20% of women will continue to experience NVP for a longer period of time. Some women may suffer from NVP until the end of the pregnancy. Nausea and vomiting can have serious adverse effects. If severe enough, NVP can cause dehydration, with associated salt and vitamin imbalances. These and other effects can be harmful to the health of the woman and the well- being of her baby. In its most severe form, NVP may manifest itself as hyperemesis gravidarum, a potentially life threatening ion ing 0.5% to 2% of pregnancies, which is characterized by protracted vomiting, ng, severe dehydration, and weight loss requiring hospitalization.

The delayed release combination of doxylamine succinate/pyridoxine HCI (10 mg each), marketed in Canada under the trade-name Diclectin® and in the United States under the trade-name Diclegis®, is the only tion approved in Canada and US for the treatment of NVP. Its safety and effectiveness for the treatment of NVP is recognized by the medical community, and its safety throughout pregnancy has been long established.

Nevertheless, there is a need for the development of novel pharmaceutical dosage systems and forms, for example those having an improved pharmacokinetics profile and/or stability, for the prevention and treatment of nausea and vomiting, such as in NVP.

The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.

SUMMARY OF THE INVENTION The present invention relates to the following items 1 to 49: 1. A solid oral dosage form comprising a core comprising about 5 mg to about 40 mg of doxylamine or a salt f and about 5 mg to about 40 mg of pyridoxine or a salt f; an enteric coating surrounding said core; a first active ient-containing coating surrounding said c coating and comprising (i) about 5 mg to about 40 mg of doxylamine or a salt thereof, or (ii) about 5 mg to about 40 mg of pyridoxine or a salt thereof; and a second active ingredient-containing coating surrounding said intermediate coating and comprising (i) about 5 mg to about 40 mg of mine or a salt f, or (ii) about 5 mg to about 40 mg of pyridoxine or a salt thereof; wherein if said first active ingredient-containing coating comprises said doxylamine or salt thereof, said second active ingredient-containing coating comprises said pyridoxine or salt thereof, and if said first active ingredient-containing coating comprises said pyridoxine or salt thereof, said second active ingredient-containing coating comprises said doxylamine or salt thereof. 2. The solid oral dosage form of item 1, wherein said core comprises about 10 mg of said doxylamine or salt thereof. 3. The solid oral dosage form of item 1 or 2, wherein said core comprises doxylamine succinate. 4. The solid oral dosage form of any one of items 1 to 3, wherein said core comprises about 10 mg of said pyridoxine or salt thereof.

. The solid oral dosage form of any one of items 1 to 4, wherein said core comprises xine hydrochloride. 6. The solid oral dosage form of any one of items 1 to 5, wherein said first or second active ingredient-containing g comprises about 10 mg of said doxylamine or salt thereof. 7. The solid oral dosage form of any one of items 1 to 6, wherein said first or second active ient-containing coating ses doxylamine succinate. 8. The solid oral dosage form of any one of items 1 to 7, wherein said first or second active ingredient-containing coating comprises about 10 mg of said pyridoxine or salt thereof. 9. The solid oral dosage form of any one of items 1 to 8, wherein said first or second active ingredient-containing coating comprises pyridoxine hydrochloride. 10. The solid oral dosage form of any one of items 1 to 9, wherein said first and/or second active ingredient-containing coating comprises a film coating system 11. The solid oral dosage form of item 10, wherein said film coating system comprises a polymer and a plasticizer. 12. The solid oral dosage form of any one of items 1 to 11, wherein said core is present in an amount of about 50% to about 70% (w/w) of said solid oral dosage form. 13. The solid oral dosage form of item 12, wherein said core is present in an amount of about 55% to about 65% (w/w) of said solid oral dosage form. 14. The solid oral dosage form of any one of items 1 to 13, wherein said enteric coating is present in an amount of about 2% to about 15% (w/w) of said solid oral dosage form.

. The solid oral dosage form of item 14, wherein said enteric coating is present in an amount of about 4% to about 12% (w/w) of said solid oral dosage form. 16. The solid oral dosage form of any one of items 1 to 15, wherein said enteric coating ses an acrylic polymer or co-polymer. 17. The solid oral dosage form of item 16, wherein said acrylic polymer or co- polymer is a copolymer based on methacrylic acid and ethyl acrylate. 18. The solid oral dosage form of any one of items 1 to 17, wherein said first active ingredient-containing coating is present in an amount of about 4% to about 12% (w/w) in said solid oral dosage form. 19. The solid oral dosage form of item 18, wherein said first active ingredient- containing coating is present in an amount of about 6% to about 10% (w/w) in said solid oral dosage form. 20. The solid oral dosage form of any one of items 1 to 19, r comprising a first intermediate coating surrounding said first active ingredient-containing coating. 21. The solid oral dosage form of item 20, wherein said first intermediate coating is present in an amount of about 1% to about 4% (w/w) in said solid oral dosage form. 22. The solid oral dosage form of item 21, wherein said first ediate coating is present in an amount of about 2% to about 3% (w/w) in said solid oral dosage form. 23. The solid oral dosage form of any one of items 20 to 22, wherein said first intermediate coating comprises a film coating system. 24. The solid oral dosage form of item 23, n said film coating system comprises a polymer and a plasticizer. 25. The solid oral dosage form of any one of items 1 to 24, wherein said second active ient-containing coating is present in an amount of about 5% to about 15% (w/w) of said solid oral dosage form. 26. The solid oral dosage form of item 25, wherein said second active ingredient- containing g is present in an amount of about 8% to about 12% (w/w) of said solid oral dosage form. 27. The solid oral dosage form of any one of items 1 to 26, r comprising a second intermediate coating between said core and said c coating. 28. The solid oral dosage form of item 27, wherein said second intermediate coating is present in an amount of about 1% to about 8% (w/w) of said solid oral dosage form. 29. The solid oral dosage form of item 28, wherein said second intermediate coating is present in an amount of about 2% to about 6% (w/w) of said solid oral dosage form. 2014/050828 . The solid oral dosage form of any one of items 24 to 26, wherein said second intermediate coating comprises a film g system sing a polymer and a plasticizer. 31. The solid oral dosage form of any one of items 27 to 30, further comprising a seal coating surrounding said second active ingredient-containing coating. 32. The solid oral dosage form of item 31, wherein said seal g is present in an amount of about 2% to about 10% (w/w) of said solid oral dosage form. 33. The solid oral dosage form of item 32, wherein said seal coating is present in an amount of about 4% to about 8% (w/w) of said solid oral dosage form. 34. The solid oral dosage form of any one of items 31 to 33, wherein said seal coating comprises a film coating system.

. The solid oral dosage form of item 34, wherein said film coating system comprises a polymer and a plasticizer. 36. The solid oral dosage form of any one of items 31 to 35, further comprising a solid oral dosage form-coating agent surrounding said seal coating. 37. The solid oral dosage form of item 36, wherein said solid oral dosage form- coating agent is present in an amount of about 0.005% to about 0.5% (w/w) of said solid oral dosage form. 38. The solid oral dosage form of item 36 or 37, wherein said solid oral dosage form- coating agent comprises wax. 39. The solid oral dosage form of any one of items 1 to 38, wherein said core further comprises one or more pharmaceutically acceptable ents. 40. The solid oral dosage form of item 39, wherein said core comprises microcrystalline ose, colloidal silicon dioxide, magnesium trisilicate, croscarmellose sodium and magnesium stearate. 41. The solid oral dosage form of item 40, wherein said core comprises about 60% to about 65% (w/w) of microcrystalline cellulose, about 0.5 to about 1% (w/w) of colloidal silicon dioxide, about 16% to about 20% (wfw) of magnesium trisilicate, about 2% to about 3% (w/w) of rmellose sodium, and about 2% to about 3% (w/w) of magnesium stearate. 42. The solid oral dosage form of any one of items 1 to 41, wherein said solid oral dosage form is a . 43. The solid oral dosage form of any one of items 1 to 42, for use in ating the symptoms of nausea and vomiting of human pregnancy. 44. The solid oral dosage form of any one of items 1 to 42, for use in the manufacture of a medicament for alleviating the symptoms of nausea and vomiting of human pregnancy. 45. Use of the solid oral dosage form of any one of items 1 to 42, for alleviating the symptoms of nausea and vomiting of human pregnancy. 46. Use of the solid oral dosage form of any one of items 1 to 42, for the cture of a medicament for alleviating the symptoms of nausea and ng of human pregnancy. 47. A method for ating the symptoms of nausea and vomiting of human pregnancy, said method comprising administering the solid oral dosage form of any one of items 1 to 42 to a pregnant human female in need thereof. 48. A package comprising the solid oral dosage form of any one of items 1 to 42. 49. The package of item 48, further comprising instructions for use of said solid oral dosage form for alleviating the symptoms of nausea and vomiting of human pregnancy.

Other objects, advantages and features of the t invention will become more apparent upon reading of the following non-restrictive description of c embodiments thereof, given by way of example only.

SURE OF INVENTION The studies described herein show an ement in the degradation product profile of doxylamine succinate and pyridoxine HCI in the immediate release component of plurimodal release formulations when the two ingredients are incorporated into separate coatings.

Accordingly, in a first aspect, the present invention provides a solid oral dosage form comprising a core comprising a doxylamine component and a pyridoxine component; an enteric coating surrounding said core; a first active ient-containing coating surrounding said enteric coating and sing a doxylamine component or a pyridoxine component; and a second active ient-containing coating surrounding said intermediate g and comprising a doxylamine component or a pyridoxine component; wherein if said first active ingredient-containing coating comprises said doxylamine component, said second active ingredient-containing coating comprises said pyridoxine component, and if said first active ingredient-containing coating comprises said xine component, said second active ingredient-containing g comprises said doxylamine component.

In another aspect, the present invention provides a solid oral dosage form comprising a core comprising about 5 mg to about 40 mg of doxylamine or a salt thereof and about 5 mg to about 40 mg of pyridoxine or a salt thereof; an enteric coating surrounding said core; an first active ingredient-containing coating surrounding said c coating and comprising (i) about 5 mg to about 40 mg of doxylamine or a salt thereof, or (ii) about 5 mg to about 40 mg of pyridoxine or a salt thereof; and a second active ingredient-containing coating surrounding said intermediate coating and comprising (i) about 5 mg to about 40 mg of doxylamine or a salt thereof, or (ii) about 5 mg to about 40 mg of pyridoxine or a salt thereof; wherein if said first active ingredient-containing g comprises said doxylamine or salt thereof, said second active ingredient-containing coating comprises said xine or salt thereof, and if said first active ingredient-containing coating comprises said pyridoxine or salt thereof, said second active ingredient-containing coating comprises said doxylamine or salt thereof.

In another aspect, the present invention es a solid oral dosage form (e.g., a pharmaceutical tablet) comprising a core coated with an enteric coating, the core sing a doxylamine component (doxylamine or a salt thereof such as doxylamine ate) and a pyridoxine ent (pyridoxine or a salt thereof such as pyridoxine hydrochloride), the core coated with the enteric coating being further coated with two active ingredient- containing coatings located on top of (Le. nding/covering) the enteric coating, one of the two active ingredient-containing coatings sing a doxylamine ent amine or a salt thereof such as doxylamine succinate) and being substantially free of a pyridoxine component (pyridoxine or a salt thereof such as pyridoxine hydrochloride), the other of the two active ingredient-containing coatings comprising a pyridoxine component (pyridoxine or a salt thereof such as pyridoxine hydrochloride) and being substantially free of a doxylamine component (doxylamine or a salt thereof such as doxylamine succinate). In an embodiment, the two active ingredient-containing coatings are separated from one another by an intermediate coating.

The term “about” is used herein to indicate that a value includes an inherent variation of error for the device orthe method being employed to determine the value, or encompass values close to the recited values, for example within 10% of the d values (or range of values).

The term “core” as used herein refers to the central component of the solid oral dosage form that comprises active ingredient(s) and that is coated with the different coatings defined herein. The core may further comprise one or more pharmaceutically acceptable excipients.

Further, in embodiments, one or more of the coatings described herein may r comprise one or more pharmaceutically acceptable excipients.

An "excipient," as used herein, has its normal meaning in the art and is any ingredient of an oral dosage form that is not an active ingredient (drug) itself. ents include for example binders, lubricants, diluents, fillers, thickening agents, disintegrants, cizers, coatings, barrier layer formulations, lubricants, izing agent, release-delaying agents and other components. "Pharmaceutically acceptable excipient" as used herein refers to any excipient that does not interfere with effectiveness of the biological activity of the active ingredients and that is not toxic to the subject, i.e., is a type of ent and/or is for use in an amount which is not toxic to the subject. In the case of a pregnant human female subject, the pharmaceutically acceptable excipient is also not toxic to the embryo or fetus, i.e., a pharmaceutical excipient suitable for administration to a pregnant female. Thus, in dosage forms for stration to pregnant subjects, pharmaceutically acceptable ents that have teratogenic properties and/or that are contraindicated for use in pregnancy are excluded.

Excipients are well known in the art, and the present system is not limited in these respects.

See, for example, ton's Pharmaceutical Sciences, 18th Edition, A. Gennaro, Ed., Mack Pub. Co. (Easton, Pa., 1990), Chapters 88-91. In certain embodiments, one or more formulations of the dosage form include excipients, ing for example and without limitation, one or more binders (binding agents), thickening agents, surfactants, diluents, release-delaying agents, colorants, flavoring agents, fillers, disintegrants/dissolution promoting agents, lubricants, plasticizers, silica flow conditioners, glidants, anti-caking agents, anti-tacking agents, stabilizing agents, anti-static agents, swelling agents and any combinations thereof. As those of skill would recognize, a single excipient can fulfill more than two functions at once, e.g., can act as both a binding agent and a thickening agent. As those of skill will also recognize, these terms are not necessarily ly exclusive.

Useful diluents, e.g., s, employable in the core and/or a coating of the solid oral dosage form may include, for example and without limitation, ium phosphate, calcium diphosphate, calcium carbonate, calcium sulfate, lactose, cellulose, , sodium chloride, starches, powdered sugar, colloidal silicon dioxide, titanium oxide, alumina, talc, colloidal , microcrystalline cellulose, fied micro crystalline cellulose and combinations thereof. Fillers that can add bulk to tablets with minimal drug dosage to produce s of te size and weight include croscarmellose sodium NF/EP (e.g., Ac-Di-Sol); anhydrous e NF/EP (e.g., PharmatoseT'V' DCL 21); and/or povidone USP/EP. In an embodiment, the core of the solid oral dosage form comprises a diluent or filler, preferably microcrystalline cellulose.

Binder materials employable in the core and/or a coating of the solid oral dosage form may include, for example and without limitation, starches (including corn starch and pregelatinized starch), gelatin, sugars ding sucrose, glucose, se and lactose), polyethylene glycol, povidone, waxes, and natural and synthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone, cellulosic polymers (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose, colloidal silicon dioxide NF/EP (e.g., Cab-O-SilT'V' M5P), Silicified Microcrystalline Cellulose (SMCC), e.g., Silicified rystalline cellulose NF/EP (e.g., ProsolvTM SMCC 90), and silicon dioxide, mixtures thereof, and the like), veegum, and combinations f.

Useful lubricants employable in the core and/or a coating of the solid oral dosage form may include, for example, canola oil, glyceryl palmitostearate, hydrogenated vegetable oil (type I), magnesium oxide, ium stearate, mineral oil, poloxamer, polyethylene glycol, sodium lauryl sulfate, sodium te fumarate, stearic acid, talc and, zinc stearate, glyceryl behapate, magnesium lauryl sulfate, boric acid, sodium benzoate, sodium acetate, sodium benzoate/sodium acetate (in combination), DL leucine, calcium stearate, sodium stearyl fumarate, mixtures thereof, and the like. In an embodiment, the core of the solid oral dosage form ses a lubricant, preferably magnesium stearate.

Bulking agents employable in the core and/or a coating of the solid oral dosage form may include, for example: microcrystalline cellulose, for example, AVICEL® (FMC Corp.) or EMCOCEL® (Mendell Inc.), which also has binder properties; dicalcium phosphate, for e, EMCOMPRESS® (Mendell Inc.); calcium sulfate, for example, COMPACTROL® (Mendell Inc.); and starches, for example, Starch 1500; and polyethylene glycols (CARBOWAX®).

Suitable disintegrating or dissolution promoting agents employable in the core and/or a coating of the solid oral dosage form may include, but are not limited to: starches, clays, celluloses, alginates, gums, crosslinked polymers, colloidal silicon dioxide, osmogens, mixtures thereof, and the like, such as crosslinked sodium carboxymethyl cellulose (AC-Dl-SOL®), sodium croscarmelose, sodium starch glycolate (EXPLOTAB®, PRIMO JEL®) crosslinked polyvinylpolypyrrolidone (PLASONE-XL®), sodium chloride, sucrose, lactose and mannitol. In an ment, the core of the solid oral dosage form ses a disintegrating agent, preferably sodium croscarmelose. herents and glidants able in the core and/or a coating of the solid oral dosage form may include talc, starches (e.g., cornstarch), celluloses, silicon e, sodium lauryl e, colloidal silica dioxide, and metallic stearates, among others.

Examples of silica flow conditioners include colloidal silicon dioxide, magnesium aluminum silicate and guar gum. In an ment, the core of the solid oral dosage form comprises a silica flow conditioner, preferably silicon e.

Suitable tants employable in the core and/or a coating of the solid oral dosage form e pharmaceutically acceptable non-ionic, ionic and anionic surfactants. An example of a surfactant is sodium lauryl sulfate. If desired, the pharmaceutical composition to be stered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium e, anolamine oleate, etc. If d, flavoring, coloring and/or sweetening agents may be added as well.

Examples of izing agents employable in the core and/or a coating of the solid oral dosage form include acacia, albumin, polyvinyl alcohol, c acid, bentonite, dicalcium phosphate, carboxymethylcellulose, hydroxypropylcellulose, colloidal silicon dioxide, cyclodextrins, glyceryl monostearate, hydroxypropyl methylcellulose, magnesium trisilicate, magnesium aluminum silicate, propylene glycol, propylene glycol alginate, sodium alginate, carnauba wax, xanthan gum, starch, stearate(s), stearic acid, c monoglyceride and stearyl alcohol. In an embodiment, core of the solid oral dosage form comprises a stabilizing agent, preferably magnesium trisilicate.

Optionally, a thickening agent can be added to provide the dosage form (6.9., tablet) with an accurately timed disintegration behavior. The dosage form ally egrates at a rate which is sufficiently slow to permit it to be swallowed easily, but fast enough to give an excellent suspension in water within 60 seconds. The thickening agent can be for example talc USP/EP, a natural gum, such as guar gum or gum arabic, or a cellulose derivative such as microcrystalline cellulose NF/EP (e.g., AvicelT'V' PH 102), methylcellulose, ellulose or hydroxyethylcellulose. A useful thickening agent is hydroxypropyl methylcellulose, an adjuvant which is available in various viscosity .

Similarly, suitable plasticizers employable in the core and/or a coating of the solid oral dosage form include: ated monoglycerides; these can be used as food additives; Alkyl es, used in food packagings, medical products, cosmetics and children toys; yl citrate (TEC); Acetyl triethyl e (ATEC), higher g point and lower volatility than TEC; Tributyl citrate (TBC); Acetyl tributyl citrate (ATBC), compatible with PVC and vinyl chloride copolymers; Trioctyl citrate (TOC), also used for gums and controlled release nes; Acetyl trioctyl citrate (ATOC), also used for printing ink; Trihexyl citrate (THC), compatible with PVC, also used for controlled release medicines; Acetyl yl citrate (ATHC), compatible with PVC; Butyryl trihexyl citrate (BTHC, trihexyl o-butyryl citrate), compatible with PVC; Trimethyl citrate (TMC), compatible with PVC; alkyl sulphonic acid phenyl ester, polyethylene glycol (PEG) or any combination thereof. Optionally, the plasticizer can comprise triethyl citrate NF/EP.

In an embodiment, the core comprises one or more fillers, one or more ts, one or more disintegrants and/or one or more lubricants.

In an embodiment, the core comprises microcrystalline cellulose, colloidal n dioxide, magnesium trisilicate, croscarmellose sodium and magnesium stearate. In an embodiment, the microcrystalline cellulose is present in an amount of about 60% to about 65% (w/w) of said core. In an embodiment, the colloidal silicon e is present in an amount of about 0.5 to about 1% (w/w) of said core. In an embodiment, the magnesium trisilicate is present in an amount of about 16% to about 20% (w/w) of said core. In an embodiment, the croscarmellose sodium is present in an amount of about 2% to about 3% (w/w) of said core. In an embodiment, the magnesium te is present in an amount of about 2% to about 3% (w/w) of said core.

In a further embodiment, the core comprises about 60% to about 65% (w/w) of microcrystalline cellulose, about 0.5 to about 1% (w/w) of colloidal silicon dioxide, about 16% to about 20% (w/w) of magnesium trisilicate, about 2% to about 3% (w/w) of croscarmellose sodium, and about 2% to about 3% (w/w) of magnesium stearate.

In an embodiment, the core is present in the solid oral dosage form in an amount of about 40% to about 80% or about 50% to about 70% (w/w) of the solid oral dosage form, in further embodiments in an amount of about 55% to about 65% (w/w), e.g., 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 or 65%, of the solid oral dosage form. In an embodiment, the total weight of the core is of about 100 mg to about 200 mg, in further embodiments of about 120 mg to about 180 mg, about 130 mg to about 170 mg, or about 140 to 150 mg (e.g., about 145 mg). In an embodiment, the core comprises: about 80 to about 100 mg (e.g., about 90 mg) of microcrystalline cellulose; about 5 to about 15 mg (e.g., about 10 mg) of doxylamine or a salt thereof (e.g., mine succinate); about 5 to about 15 mg (e.g., about 10 mg) of pyridoxine or a salt thereof (e.g., pyridoxine hydrochloride); about 0.5 to about 2 mg (e.g., about 1 mg) of colloidal silicon dioxide; about 20 mg to about 30 mg (e.g., about 26-27 mg) of ium trisilicate; about 3 mg to about 4 mg (e.g., about 3.5 or 3.6 mg) of croscarmellose sodium; and about 3.5 mg to about 4.5 mg (e.g., about 4 mg) of magnesium te.

The term “coating” as used herein refers to a layer or film, made of one or more suitable materials, that surrounds/covers (and preferably adheres to) an inner component of the solid oral dosage form. The coating may comprise any agent or combination of agents suitable to form a layer or film, such as polymeric materials (e.g., cellulosic-based polymers, c- based polymers, polyvinyl-based polymers. Coating materials/polymers and coating systems comprising polymer(s), plasticizers, pigments, etc. are known in the art. Examples of coating polymers and systems include the OPADRY® series of film coating system (COLORCON®), INSTACOAT® film coating systems (IDEAL CURES® PVT LTD), AQUARIUSTM film coating systems (ASHLAND®), OATTM film coating systems ®), SEPIFILMTM film coating systems (SEPP|C®), PlasACRYLTM coating systems (based on EUDRAG|T® polymers) from ®, KOLLICOATTM coating s (BASF®), SPECTRABLENDTM coating systems (SENSIENT®), VIVAPHARM® HPMC (JRS PHARMA®). In an ment, the coating ses an OPADRY® film coating system.

The term “enteric coating” is used to refer to a coating that is made from gastric resistant als (polymers), i.e. which remain substantially intact in the acidic environment of the stomach, but dissolve readily at the ed pH of the intestine (and/or in the presence of degradative enzymes that are characteristically present in the intestine). rs suitable to form enteric coating are well known in the art and include, for example, cellulosic polymers (e.g., cellulose acetate phthalate, cellulose acetate trimellitate, ose acetate succinate polymers, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate ate (hypromellose acetate succinate), carboxymethylcellulose sodium), acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl rylate (e.g., methacrylate- based polymers/copolymers (e.g., EUDRAGIT® polymers such as EUDRAGIT® L30D-55, L100-55, L-100, EUDRAGIT® S, IT® NE, RL and RS), vinyl polymers and copolymers such as polyvinyl pyrrolidone, vinyl acetate, polyvinyl acetate phthalate, vinylacetate phthalate, cetate crotonic acid copolymer, and ethylene-vinyl acetate copolymer (PVAP), enzymatically degradable polymers such as azo polymers, pectin, chitosan, amylose and guar gum; zein and c. Examples of entering coating systems include the OPADRY®, SURETERIC® or Acryl-EZE® Enteric system (COLORCON®), and SHEFFCOATTM ENT system (KERRY®). Combinations of different enteric als may also be used. Iayer coatings using ent polymers may also be applied. The properties, manufacture and design of enteric delivery systems are well known to those of ordinary skill in the art. See, e.g., Development of Biopharmaceutical Parenteral Dosage Forms (Drugs and the Pharmaceutical Sciences), by Bontempo (Publishers: a Healthcare (July 25, 1997).

In an embodiment, the enteric coating comprises an acrylic polymer or co-polymer, in a further embodiment a copolymer based on methacrylic acid and ethyl acrylate (e.g., Poly(methacylic acid-co-ethyl acrylate) 1:1, commercialized under the trade-name EUDRAGIT® L 100-55). In a further embodiment, the c coating comprises an Acryl-EZE® enteric coating system. In yet a further ment, the enteric g further comprises an antifoaming agent, for example simethicone or simethicone emulsion (e.g., Simethicone Emulsion 30% USP, KH) and a plasticizer, for example polyethylene glycol (PEG) 8000, triacetin, or yl citrate (TEC) (e.g., Triethyl Citrate NF, K). In an embodiment, the weight of the enteric g in the solid oral dosage form is about 10 to about 20 mg, in r embodiments about 14 to about 18 mg, e.g., about 16 mg. In a further embodiment, the enteric coating comprises about 0.001 to about 0.005 mg of antifoaming agent (e.g., simethicone emulsion), about 1 to about 2 mg of plasticizer (e.g., TEC) and about 14 mg to about 15 mg of c al/polymer (e.g., Acryl-EZE® enteric coating system).

The enteric coating of the solid oral dosage form described herein allows the delayed release of the active ingredients (doxylamine and pyridoxine components) comprised in the core. In an embodiment, the c coating is present in an amount of about 1% to about 20% (w/w) of said solid oral dosage form. In further embodiments, the enteric coating is present in an amount of about 2% to about 15%, about 4% to about 12% or about 4% to about 10%, for example about 4, 5, 6, 7, 8, 9, or 10% (w/w), of said solid oral dosage form.

The first active ingredient-containing coating surrounds or envelops the enteric coating and comprises eitherthe doxylamine component (e.g., doxylamine or salt thereof) orthe pyridoxine component (e.g., pyridoxine or salt thereof). In an embodiment, the first active ient-containing coating comprises the pyridoxine component, e.g., pyridoxine or salt f such as pyridoxine HCI.

The first active ingredient-containing coating may r comprise any non-enteric coating material suitable to form a layer or film, as described above. In an embodiment, the first active ingredient-containing g comprises a film coating system comprising a polymer and a plasticizer, for example an OPADRY® film coating system. The ratio of active ient to coating material in the first active ingredient-containing coating may be of about 1:4 to about 4:1, for example of about 1:3 to about 3:1 or about 1:2 to about 2:1, in further embodiments from about 1:1.5 to about 1.5:1, for example about 1:1. In an embodiment, the first active ingredient-containing coating comprises about 8 to 12 mg (e.g., about 10 mg) of pyridoxine or salt thereof such as pyridoxine HCI, and about 8 mg to about 10 mg (e.g., about 9 mg) of coating material (e.g., OPADRY® film coating).

In an embodiment, the first active ingredient-containing g is present in an amount of about 1% to about 20% (w/w) of said solid oral dosage form. In further embodiments, the first active ingredient-containing coating is present in an amount of about 2% to about 15%, about 2% to about 10%, or about 4% to about 8%, for e about 4, 5, 6, 7 or 8% (w/w), of said solid oral dosage form.

The second active ingredient-containing coating nds or ps the intermediate coating (the first and second active ingredient-containing coatings are separated by the intermediate coating) and comprises either the doxylamine component (e.g., doxylamine or salt thereof) or the pyridoxine component (e.g., pyridoxine or salt thereof), depending on whether the first active ingredient-containing coating the doxylamine component (e.g., doxylamine or salt thereof) or the pyridoxine component (e.g., pyridoxine or salt thereof). In an embodiment, the second active ingredient-containing coating comprises the doxylamine component, e.g., doxylamine or salt thereof such as doxylamine succinate.

The second active ient-containing coating may further comprise any teric coating material suitable to form a layer or film, as described above. In an embodiment, the second active ient-containing coating comprises a film coating system comprising a polymer and a plasticizer, for example an ® film coating system. The ratio of active ingredient to coating material in the second active ingredient-containing coating may be of about 1:4 to about 4:1, for example of about 1:3 to about 3:1 or about 1:2 to about 2:1, in further embodiments from about 1:1 to about 15:1, for example about 1.4 or 1.5:1. In an embodiment, the second active ient-containing coating comprises about 8 to 12 mg (6.9., about 10 mg) of doxylamine or salt f such as doxylamine succinate, and about 12 mg to about 16 mg (e.g., about 14-15 mg) of coating material (e.g., OPADRY® film coating).

In an embodiment, the second active ingredient-containing coating is present in an amount of about 2% to about 20% (w/w) of said solid oral dosage form. In further embodiments, the second active ingredient-containing coating is present in an amount of about 5% to about %, or about 8% to about 12%, for example about 8, 9, 10, 11 or 12% (w/w), of said solid oral dosage form.

In embodiments, the solid oral dosage form comprises one or more additional coatings/layers.

In an embodiment, the solid oral dosage form further comprises a first intermediate coating surrounding the first active ingredient-containing coating (i.e. between the first- and second-active ingredient-containing coatings). The intermediate coating helps forming a “seal” between the first and second active ingredient-containing coatings so as to avoid or minimize contacts/interactions between the doxylamine component (e.g., doxylamine or salt thereof) and the pyridoxine ent (e.g., pyridoxine or salt thereof) comprised in the first and second active ingredient-containing gs. The ediate g may comprise any non-enteric coating material suitable to form a layer or film between the first and second active ingredient- containing coatings, as described above. In an embodiment, the intermediate g ses a film coating system comprising a polymer and a plasticizer, for example an OPADRY® film g system. In an embodiment, the intermediate coating comprises about 5 to 6 mg of the coating al (OPADRY® film coating). In an embodiment, the intermediate coating is present in an amount of about 1% to about 10% (w/w) of said solid oral dosage form. In further embodiments, the intermediate coating is present in an amount of about 1% to about 8%, about 1% to about 5%, or about 2% to about 3 or 4%, for example about 2 or 3% (w/w), of said solid oral dosage form.

In an embodiment, the solid oral dosage form further comprises a seal coating surrounding said second active ingredient-containing coating. The seal coating may comprise any non-enteric g material suitable to form a layer or film, as bed above. In an embodiment, the seal coating ses a film coating system comprising a polymer and a plasticizer, for example an OPADRY® film coating . In an embodiment, the seal coating further comprises a dye or pigment (colorant). In an embodiment, the seal coating comprises about 11 to about 15 mg (e.g., about 13 mg) of coating material (9.9., OPADRY® film coating).

In an embodiment, the seal coating is present in said solid oral dosage form in an amount of about 1% to about 15% (w/w) of said solid oral dosage form. In r embodiments, the intermediate coating is present in an amount of about 2% to about 10%, about 4% to about 8%, for example about 4, 5, 6, 7 or 8% (w/w), of said solid oral dosage form.

In an embodiment, the solid oral dosage form further comprises a solid oral dosage form- or tablet-coating (e.g., an outer coating) surrounding the seal coating. Such coating may be used, for example, to facilitate the wing of the tablet. In an embodiment, the solid oral dosage form- ortablet-coating comprises a wax, for example Carnauba wax. In an embodiment, the solid oral dosage form- or tablet-coating comprises about 0.01 to about 0.05 mg (e.g., about 0.04 mg) of wax material (e.g., Carnauba wax).

W0 2016/029290 In an embodiment, the solid oral dosage form further comprises a second intermediate coating between the core and the enteric coating. The second intermediate coating may comprise any g material suitable to form a layer or film, as described above. In an embodiment, the second intermediate coating ses a film g system comprising a polymer and a plasticizer, for example an OPADRY® film coating system. In an embodiment, the second intermediate coating comprises about 8 mg to about 12 mg (e.g., about 9-10 mg) of coating material (e.g., OPADRY® film coating). In an embodiment, the second intermediate coating is present in an amount of about 1% to about 10% (w/w) of said solid oral dosage form.

In further embodiments, the second intermediate g is present in an amount of about 1% to about 8%, about 2% to about 6%, for example about 2, 3, 4, 5 or 6% (w/w), of said solid oral dosage form.

The solid oral dosage form may further comprise one or more additional gs (in addition to those defined ) or ingredients (excipients).

The term “doxylamine component” (or “doxylamine compound”) as used herein refers to mine, doxylamine analogs, derivatives, gs, metabolites and/or salts. The term oxine component” (or “pyridoxine compound”) as used herein refers to pyridoxine, pyridoxine analogs, derivatives, prodrugs, metabolites and/or salts.

The term “analog” or “derivative” as used herein refers to a different compound having a structure similar to that of the “parent” compound (e.g., doxylamine or pyridoxine) but differing from the parent compound in structure (e.g., replacement of one or more atoms by an atom of a different element, presence or absence of a particular group, etc.). An analog/derivative lly exhibits an overall biological effect that is similar to that of the t” compound but may differ in one or more physicochemical andfor pharmacokinetic properties (potency, stability, lity, absorption, in vivo half-life, in vivo distribution, etc.).

“Prodrug” as used herein refers to a compound for administration (which is e.g., in an inactive, or significantly less active form) in a form that, following administration, undergoes chemical conversion by metabolic processes to be transformed into a compound to effect the desired pharmacological activity (e.g., to become an active, or more active, pharmacological “Metabolite” as used herein refers to a compound resulting from a biochemical conversion of a first compound by metabolic processes/pathways in vivo. A metabolite may differ in one or more physicochemical and/or pharmacokinetic properties (potency, stability, solubility, absorption, in vivo half-life, in vivo distribution, etc.) as compared to the first compound (which may be a prodrug or an active agent). If its structure is known, such a metabolite can be prepared in vitro and administered directly to a subject to exert a ical . A given metabolite may itself be metabolized through lic processes/pathways, WO 29290 thus resulting in one or more further metabolites that may differ in more or more physico- chemical and/or pharmacokinetic properties as compared to the “first” metabolite.

In an embodiment, the pyridoxine component is a compound of formula I, / R1 \N (I) wherein R1 is a hydroxyl (OH) or phosphate (PO42 or HPO4' or H2PO4) group; and R2 is CHZOH, CHO, or CH2NH2 or a pharmaceutically acceptable ester of said compound of formula I, or a pharmaceutically acceptable salt f. 1O As used herein the term "pharmaceutically acceptable salt" refers to a salt of a compound (an active ingredient) that retains the biological activity ofthe parent compound, and which is not biologically or otherwise undesirable, i.e., is a type of salt and/or is for use in an amount which is not toxic to the subject. In the case of a pregnant human female subject, the pharmaceutically acceptable salt is in concentrations that is not toxic to the embryo or fetus, (i.e., a pharmaceutical salt which is able for administration to a pregnant female) and not contraindicated for use in human pregnancy. Thus, in dosage forms for stration to pregnant subjects, pharmaceutically able salts that have teratogenic properties are excluded. ceutically able acid addition salts may be prepared from inorganic and organic acids. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methane sulfonate, nicotinate, 2—naphthalene sulfonate, oxalate, palmitoate, pectinate, fate, 3-phenylpropionate, picrate, pivalate, nate, succinate, tartrate, anate, ate, glutamate, bicarbonate, p—toluenesulfonate, and undecanoate. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, ene-sulfonic acid, salicylic acid, and the like.

Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include, for example, an inorganic acid, e.g., hydrochloric acid, hydrobromic acid, sulphuric acid, and phosphoric acid, and an organic acid, e.g., oxalic acid, maleic acid, succinic acid, and citric acid. In an ment, the pharmaceutically acceptable salt of doxylamine is doxylamine succinate. In an embodiment, the pharmaceutically acceptable salt of pyridoxine is pyridoxine hydrochloride oxine HCI).

In an embodiment, the core and the first or second active ingredient-containing gs comprise the same doxylamine, analog thereof, tive thereof, prodrug thereof, metabolite thereof or salt thereof (or the same combination of mine, analog thereof, derivative thereof, prodrug thereof, metabolite thereof and/or salt thereof). In another embodiment, the core and the first or second active ingredient-containing coatings comprise ent doxylamine, analog thereof, derivative thereof, prodrug thereof, metabolite thereof or salt thereof (or a different combination of doxylamine, analog thereof, derivative thereof, prodrug thereof, metabolite thereof and/or salt thereof). In an embodiment, the core and/or the first or second active ingredient-containing coatings se only one of doxylamine, an analog thereof, a derivative thereof, a prodrug thereof, a metabolite thereof or a salt thereof. In an embodiment, the core and/or the first or second active ingredient-containing coatings comprise doxylamine succinate.

In an embodiment, the mentioned core and/or first or second active ingredient- containing coatings comprise pyridoxine (PYR) and/or a further medicinal ingredient, such as one or more metabolites of PYR, such as pyridoxine phosphate (PYP), pyridoxal (PYL), pyridoxal 5-phosphate (PLP), pyridoxamine (PYM), pyridoxamine 5-phosphate (PMP), and/or one or more pharmaceutically acceptable salts of PYR, PYP, PYL, PLP, PYM and/or PMP. In an embodiment, the core and/or the first or second active ingredient-containing coatinsg se pyridoxal (in addition to one or more of (i) doxylamine, (ii) an analog thereof, (iii) a derivative thereof, (iv) a prodrug thereof, (v) a metabolite thereof and (vi) a salt of any of (i)-(v)).

Pyridoxine analogs, derivatives, prodrugs, metabolites and salts include, for example, pharmaceutically acceptable esters or amines of pyridoxine, xine hydrochloride, xine phosphate, pyridoxal, pyridoxal phosphate, pyridoxal calcium phosphate, pyridoxal hydrochloride, pyridoxamine, or pyridoxamine dihydrochloride. In an embodiment, the pharmaceutically acceptable salt of pyridoxine is pyridoxine hydrochloride. In an embodiment, the core and the first or second active ingredient-containing coatings comprise the same pyridoxine, metabolite thereof or salt thereof (or the same combination of pyridoxine, lite thereof and/or salt thereof), and in a further embodiment the core and the first or second active ient-containing coatings comprises pyridoxine or a salt thereof, preferably pyridoxine hloride. In another embodiment, the core and the first or second active ingredientcontaining coatings comprise a different pyridoxine, prodrug, metabolite f or salt thereof (or a different combination of xine, g thereof and/or lite thereof and/or salt thereof).

In an embodiment, the core comprises pyridoxine hydrochloride and doxylamine succinate, the second active ient-containing coating comprises doxylamine ate and the first active ingredient-containing coating comprises pyridoxine hloride.

The solid oral dosage form comprises a delayed released component, comprising the core and the enteric coating (and optionally the second intermediate coating), and an ate release component, sing the first and second active ingredient-containing coatings and the first intermediate coating (and optionally the seal coating, and the solid oral dosage form- coating .

The term iate release component" or "immediate release composition" as used herein refers to a component/composition of a dosage form that is formulated to release substantially all the active ingredients in a relatively short period on administration with no enhanced, delayed or extended release effect. In some embodiments, the relatively short period can be, for example, within about 0.1 to about 2 hours, e.g., about 10, 15, 20, 30, 40, 60, 90 or 120 minutes. In some embodiments, the immediate release ent releases a majority of the active ient(s), e.g., at least about 50%, 60%, 70%, 80%, 90%, 95% or 99% of active ingredient(s) from within the dosage form within such a relatively short period after administration. For example, about 80% of the drug can be released within about 30 or 40 minutes after administration, as measured by standard dissolution assays such as those described herein. In an embodiment, the immediate release composition is for effecting release substantially (at least about 90, 91, 92, 93, 94, 95, 96, 97, 98 or 99% is released) within the stomach.

The term "delayed release component" or ed release composition" as used herein refers to a component/composition of a dosage form that is formulated so as to have zero or relatively low release of the active ients during a period after administration to the subject. The period is typically in the range of about 0.5 to 12 hours, for example in the range of about 1 or 2 hours to about 6, 7, 8 or 9 hours, such as about 1, 2, 3, 4, 5, 6, 7, 8, or 9 hours. In embodiments, the delayed release begins after a period that is from about 2 hours to about 3 hours, or from about 3 hours to about 4 hours, or from about 4 hours to about 5 hours, or from about 5 hours to about 6 hours, after administration. In an embodiment, the delayed release composition is for effecting release substantially within the intestine, i.e., so that there is no or substantially no (less than about 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1%) release in the stomach.

In an embodiment, although the delayed release component from the dosage form commences to ve at a later time point than the immediate release component, once release begins, the release n of the delayed release component is similar to the pattern of the immediate release component, described above. For example, a relatively short burst duration, for example less than 60 minutes, for instance less than about 50, 40, 30, 20, 15, 10, or 5 minutes, may be teristic of both immediate release and delayed-burst release.

The immediate release and delayed release compositions result in two tial releases of the active ingredients, the first release occurring relatively soon after administration and the second release coming later. The time period between the first immediate e of the active ingredients and the subsequent delayed release of the active ingredients can be referred to as the "release interval". In dosage forms of the invention, the release interval can generally be in the range of about 0.5 to 12 hours, for example in the range of about 1 or 2 hours to about 6, 7, 8 or 9 hours, such as about 1, 2, 3, 4, 5, 6, 7, 8, or 9 hours. In embodiments, the delayed release begins after a period that is from about 2 hours to about 3 hours, or from about 3 hours to about 4 hours, or from about 4 hours to about 5 hours, or from about 5 hours to about 6 hours. Optionally, the delayed release is timed to occur at a time when the dosage form is found in the small intestine in g and/or fed subjects. The immediate release of active ingredients can for example occur within about 1 hour after administration, for example within about 30 minutes or within about 15 minutes. In an embodiment, the release rate of the doxylamine component is substantially similar (i.e., the difference is less than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1%) to that of the pyridoxine component (in either one of, or both, the immediate and delayed release ents). In an embodiment, the release rate of the doxylamine component is different than that of the pyridoxine component (in either one of, or both, the immediate and delayed release compositions).

The release interval can be determined in vitro or in vivo. Although the plasma concentration of a drug can lag behind the actual time of release in the GI tract, the e interval can be approximately determined in vivo as the time interval between the Cmax (i.e., the maximum plasma concentration) of the active ingredients achieved by the immediate release component and the Cmax of the active ingredients achieved by the delayed release ent.

Alternatively, the release interval can be red through the increased plasma concentration of the active ients caused by delayed e following immediate release, compared to that achieved by only the immediate release of the active ingredients.

Release can also be assessed using commonly used in vitro dissolution assays.

Generally an in vitro dissolution assay is carried out by placing the dosage form(s) (e.g., tablet(s)) in a known volume of dissolution medium in a container with a suitable stirring device.

An aliquot of the medium is withdrawn at various times and analyzed for dissolved active substance to determine the rate of dissolution. In one approach, the dosage form (e.g., tablet) is placed into a vessel of a United States Pharmacopeia ution apparatus ll (Paddles) containing 900 ml dissolution medium at 37°C. The paddle speed is 50, 75 or 100 RPM.

Independent measurements are made for at least three (3) s, e.g., 6 s. The dissolution medium can be a neutral dissolution medium such as 50 mM potassium phosphate buffer, pH 7.2 ("neutral conditions") or water or an acidic medium such as 50 mM potassium (or sodium) acetate , at pH 4.5. Typically a unit dose form is added to the vessel and dissolution is started. At specified times, e.g., 5, 10, 15, 20, 30, 45 or 60 minutes, an t (e.g., 2 ml) of medium is withdrawn and the amount of active ingredient in solution is determined using routine ical methods (e.g., HPLC).

By way of example, immediate release and/or delayed release of drugs from the dosage form can be monitored using Apparatus II (Paddles) as described in US.

Pharmacopeia, where the dissolution is conducted by placing one dosage form into each of six vessels ning 900 ml of release media with temperature at 37°C and speed of 100 rpm.

Optionally, the release media of 0.1N Hydrochloric acid (pH 1.2 or 4.5) is used for stage 1 for 2 hours, and 0.2M tribasic sodium phosphate buffer adjusted to pH6.8 is used for stage 2 (Buffer stage) at 5, 10,15, 20, 30, 45, 60, 90 and 120 minutes and assayed for drug content by HPLC.

Further, various media for in vitro dissolution assays (e.g., simulated c fluid (SGF), simulated intestinal fluid (SIF), ns to simulate fed or fasting conditions (FeSSGF or FeSSIF for fed conditions, FaSSGF or FaSSIF for fasting ions), etc.) are well known in the art.

In an embodiment, the solid oral dosage form is monolithic in nature, e.g., in the form of a . Monolithic unit dosage forms may vary in shape and may be, for example, round, ovoid, oblong, cylindrical (e.g., disk shaped) or any other geometric shape, for example rectilinear. For example, the solid oral dosage form can have a disk or ovoid shape, or a shape like a flattened disk or torpedo. The edges can be beveled or rounded.

The active ingredients may iently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in for example Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association of one or more active ients with any additional excipients. In general, the dosage forms are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then shaping the product. In an embodiment, the solid oral dosage form is in tablet form. Various methods of preparation of tablets are well known to one of ordinary skill in the art. See, e.g., Pharmaceutical Dosage Forms: Tablets, Third Edition, by Larry L. Augsburger and Stephen W. Hoag (publisher: Informa Healthcare; December 15, 2007). These methods e direct compression and granulation (e.g., wet or dry orquid-bed).

The pellets can be made by, for example, simple granulation such as wet granulation or dry ation, followed by sieving; extrusion and rization (spheronization); anulation; or any agglomeration process that results in a pellet of reasonable size and robustness. For extrusion and marumerization, the drug and other additives are granulated by addition of a binder solution. The wet mass is passed through an extruder equipped with a certain size , and the extrudates are spheronized in a rizer. The resulting pellets are dried and sieved for further applications. One may also use high-shear granulation, wherein the drug and other additives are dry-mixed and then the e is wetted by addition of a binder solution in a high shear-granulator/mixer. The granules are kneaded after wetting by the combined s of mixing and milling. The resulting granules or pellets are dried and sieved for further applications. Alternatively, the immediate release beadlets or pellets are prepared by solution or sion layering, whereby a solution or dispersion of the active ingredients, with or without a binder and optionally an anti-tacking agent such as talc, is sprayed onto a core or starting seed (either prepared or a commercially available t) in a fluid bed processor or other suitable equipment. The cores or starting seeds can be, for example, sugar spheres or spheres made from microcrystalline cellulose. The active ingredients, thus, are coated on the surface of the starting seeds. The active ients may also be layered onto the active ingredients-containing pellets described above, if desired. Following drug layering, the resulting active ingredients-loaded pellets are dried for further applications. A protective layer, or overcoating, may be desired to ensure that the active ingredients-loaded pellets do not aggregate during processing or upon e. The protective coating layer may be applied immediately outside the core, either an active ingredients-containing core or an active ingredients-layered core, by tional coating techniques such as pan coating or fluid bed coating using solutions of polymers in water or suitable organic solvents or by using aqueous polymer dispersions. Coating s such as OPADRY®, OPADRY ll® CON®) and corresponding color and colorless grades from COLORCON® can be used to protect the pellets from being tacky and provide colors to the product. Different anhydride-based polymers (e.g., sebacic/fumaric copolymers such as SPHEROMERT'VI l or SPHEROMERT'VI II from SPHERICS, Inc.) may also be used as tive layer. The core (coated or uncoated with a protective g layer) is then successively coated with the layers/coatings d , e.g., according to the method described in the Examples below.

Dosages may be adjusted to provide the optimum prophylactic/therapeutic response, via administration of a prophylactically or therapeutically effective amount of the active agent(s).

A prophylactically or therapeutically effective amount is one in which any toxic or detrimental effects of the active agents amine and/or pyridoxine component(s)) are outweighed by the lactic or eutic beneficial effects. For administration to a pregnant human female subject, the effective amount of the active agents is such that it is not toxic to the embryo or fetus.

In an embodiment, the solid oral dosage form comprises about 40 mg or less (e.g., about 35, 30, 25, 20, 15 mg or less) of the doxylamine component, in embodiments between about 10, 11, 12,13, 14, 15 to about 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 mg. In an embodiment, the oral dosage form comprises about 20 mg of the doxylamine component (e.g., doxylamine succinate).

In an embodiment, the amount of the doxylamine component, e.g., doxylamine or salt thereof, in the core is from about 5 to about 40 mg, in further embodiments from about 5 to about 30 mg, from about 5 to about 25 mg, from about 5 to about 20 mg, or from about 5 to about 15 mg, for example about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 mg. The amount of the doxylamine component, e.g., doxylamine or salt f, in the first or second active ingredient- containing coating is from about 5 to about 40 mg, in further embodiments from about 5 to about mg, from about 5 to about 25 mg, from about 5 to about 20 mg, or from about 5 to about 15 mg, for example about 5, 5, 7, 8, 9, 1o, 11, 12, 13, 14 or 15 mg, preferably about 10 mg.

In an embodiment, the solid oral dosage form comprises about 40 mg or less (e.g., about 35, 30, 25, 20, 15 mg or less) of the pyridoxine component, in embodiments between about 10, 11, 12,13, 14, 15 to about 16, 17, 18, 19, 20,21, 22, 23, 24, 25,26, 27, 28,29 or 30 mg. In an embodiment, the oral dosage form comprises about 20 mg of the pyridoxine component (e.g., pyridoxine hydrochloride).

The amount of the pyridoxine component, e.g., pyridoxine or salt thereof, in the core is from about 5 to about 40 mg, in further embodiments from about 5 to about 30 mg, from about 5 to about 25 mg, from about 5 to about 20 mg, or from about 5 to about 15 mg, for e about 5, 6, 7, 8, 9, 10, 11,12, 13, 14 or 15 mg, preferably about 10 mg.

The amount of the pyridoxine ent, e.g., pyridoxine or salt thereof, in the first or second active ingredient-containing coating is from about 5 to about 40 mg, in further embodiments from about 5 to about 30 mg, from about 5 to about 25 mg, from about 5 to about mg, or from about 5 to about 15 mg, for example about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 mg, ably about 10 mg.

In an ment, the total weight of the solid oral dosage form is from about 200 mg to about 300 mg, in further embodiment from about 200 mg to about 250 mg or about 220 mg to about 240 mg, for example about 230 mg to about 235 mg.

In an embodiment, the solid oral dosage form ses: a core comprising: about 80 to about 100 mg (e.g., about 90 mg) of microcrystalline cellulose; about 5 to about 15 mg (e.g., about 10 mg) of doxylamine or a salt thereof (e.g., doxylamine succinate); about 5 to about 15 mg (e.g., about 10 mg) of pyridoxine or a salt thereof (e.g., pyridoxine hydrochloride); about 0.5 to about 2 mg (e.g., about 1 mg) of colloidal silicon dioxide; about 20 mg to about 30 mg (e.g., about 26-27 mg) of magnesium trisilicate; about 3 mg to about 4 mg (e.g., about 3.5 or 3.6 mg) of croscarmellose sodium; and about 3.5 mg to about 4.5 mg (e.g., about 4 mg) of magnesium stearate; an c g comprising about 0.001 to about 0.005 mg of antifoaming agent (e.g., simethicone emulsion), about 1 to about 2 mg of plasticizer (e.g., TEC) and about 14 mg to about 15 mg of enteric material/polymer (e.g., Acryl-EZE® enteric coating system); a first active ient-containing coating comprising about 8 to 12 mg (e.g., about 10 mg) of pyridoxine or salt thereof such as pyridoxine HCI, and about 8 mg to about 10 mg (e.g., about 9 mg) of coating material (e.g., OPADRY® film coating); a first intermediate coating comprises about 5 to 6 mg of a coating al (OPADRY® film coating); a second active ingredient-containing coating sing about 8 to 12 mg (e.g., about mg) of doxylamine or salt thereof such as doxylamine succinate, and about 12 mg to about 16 mg (6.9., about 14-15 mg) of coating material (6.9., OPADRY® film g); a second intermediate coating (between the core and the enteric coating) comprising about 8 mg to about 12 mg (e.g., about 9-10 mg) of coating al (e.g., OPADRY® film coating); a seal coating (surrounding the second active ingredient-containing coating) comprising about 11 to about 15 mg (e.g., about 13 mg) of coating material (6.9., OPADRY® film coating); a solid oral dosage form- ortablet-coating comprises about 0.01 to about 0.05 mg (e.g., about 0.04 mg) of wax material (e.g., Carnauba wax).

In an embodiment, the stability of the solid oral dosage form is preferably such that: . the total amount of related substances (degradation products) of the pyridoxine or salt thereof (e.g., pyridoxine hydrochloride) in the solid oral dosage form kept at 40°C and 75% relative humidity is about 2% or less after 1, 2, 3 or 6 months; 0 the total amount of related nces (degradation products) of the doxylamine or salt thereof (e.g., doxylamine succinate) in the solid oral dosage form kept at 40°C and 75% relative ty is about 2% or less after 1, 2, 3 or 6 months; . the total amount of related substances dation products) of the pyridoxine or salt thereof (e.g., pyridoxine hydrochloride) in the solid oral dosage form kept at 25°C and 60% relative humidity is about 2% or less after 1, 2, 3 or 6 months; . the total amount of related substances (degradation products) of the doxylamine or salt thereof (e.g., doxylamine ate) in the solid oral dosage form kept at °C and 60% relative humidity is about 2% or less after 1, 2, 3 or 6 months; . the amount of each unknown related substances (degradation products) in the solid oral dosage form kept at 40°C and 75% ve humidity is about 0.2% or less after 1, 2, 3 or 6 months; and/or . the amount of each unknown related substances (degradation products) in the solid oral dosage form kept at 25°C and 60% relative humidity is about 0.2% or less after 1, 2, 3 or 6 months.

In another , the present invention provides a method for alleviating the symptoms of nausea and ng in a mammal, said method comprising administering an effective amount of the above-mentioned solid oral dosage form to a mammal in need thereof.

In another aspect, the present invention provides a method for alleviating the symptoms of nausea and vomiting of human pregnancy (NVP), the method comprising administering an effective amount of the above-mentioned solid oral dosage form to a pregnant human female in need thereof.

In another aspect, the present invention provides a use of the above-mentioned solid oral dosage form for alleviating the symptoms of nausea and vomiting in a mammal.

In another aspect, the present ion provides a use of the above-mentioned solid oral dosage form for alleviating the symptoms of NVP.

In another aspect, the present invention provides a use of the above-mentioned solid oral dosage form for the ation of a medicament for alleviating the symptoms of nausea and vomiting in a mammal.

In another aspect, the present invention provides a use of the above-mentioned solid oral dosage form for the preparation of a medicament for alleviating the symptoms of NVP.

In another aspect, the present invention es the above-mentioned solid oral dosage form for use in alleviating the symptoms of nausea and ng in a mammal.

In another aspect, the present invention es the above-mentioned solid oral dosage form for use in the preparation of a medicament for alleviating the symptoms of NVP.

In another aspect, the present invention provides the above-mentioned solid oral dosage form for use in the preparation of a medicament for alleviating the symptoms of nausea and vomiting in a mammal.

In another aspect, the present invention es the above-mentioned solid oral dosage form for use in alleviating the symptoms of NVP.

In another aspect, the present invention provides the above-mentioned solid oral dosage form for use as a medicament In another aspect, the present invention provides a package or kit for alleviating the symptoms of nausea and vomiting in a mammal, the package comprising the above-mentioned solid oral dosage form. In an embodiment, the package r comprises instructions for using the solid oral dosage form for alleviating the symptoms of nausea and vomiting in a mammal.

The package may further comprise one or more containers.

In another , the present ion provides a package for alleviating the ms of nausea and vomiting of human ncy (NVP), the kit comprising the above- mentioned solid oral dosage form. In an embodiment, the e further ses instructions for using the solid oral dosage form for alleviating the symptoms of NVP. The package may further comprise one or more containers.

In an embodiment, the package comprises solid oral dosage forms identified to be taken at different times of the day. For example, the package may comprise a first solid oral dosage form comprising an tor (shape, color, markings, etc.) that it has to be taken at a certain time of the day (9.9., in the evening, 9.9., at about 10 PM), and a second solid oral dosage form comprising an tion (shape, color, markings, etc.) that it has to be taken at another time of the day (9.9., in the morning, e.g., at about 10 AM).

In another ment, the package comprises instructions for using the solid oral dosage form according to the following le: a first solid oral dosage form in the evening (e.g., at about 10 PM) and a second solid oral dosage form in the morning (e.g., at about 10 AM). The first and second solid oral dosage forms may be the same or different. In an embodiment, the first and second solid oral dosage forms are cal.

In an embodiment, the package further comprises a container in which the above- ned solid oral dosage forms are packaged.

In an embodiment, the package comprises a solid oral dosage form bearing a pregnancy-friendly indicia to cally confirm the ratogenic aspect of said dosage form. Examples of such pregnancy-friendly indicia are bed in PCT publication No.

WO/2004/004694. In an embodiment, the indicia is the shape of a graphical illustration of a pregnant woman applied to the dosage form itself or to the container/package.

As used herein, the terms "subject" or "patient" are taken to mean warm blooded animals such as mammals, for e, cats, dogs, mice, guinea pigs, horses, bovine cows, sheep and humans. In an embodiment, the subject is a mammal, and more particularly a female. In a further embodiment, the above-mentioned subject is a human. In yet a further embodiment, the subject is a human female, and more particularly a pregnant human female.

MODE(S) FOR CARRYING OUT THE INVENTION The present invention is illustrated in further details by the following non-limiting examples.

Example 1: Stability of enteric coated tablets of doxylamine succinate and pyridoxine HCI Drug product formulation.

Table 1 presents core composition of delayed enteric coated s lot lNG-028.

Table 1: Lot lNG-028 enteric-coated Core Tablet Composition Ingredient Name mgltab Croscarmellose Sodium P9?” 0003 lear coat Purified water USP Opadry clear 472 Purified water USP Simethicone Emulsion 30% USP, Trieth l Citrate NF AcryI-EZETM Clear Seal coating.

The c-coated core tablets lot INC-028 of Table 1 were coated for an average weight gain of2.67%, and were renamed L148—02010 SC 20 mg using materials in Table 2.

Table 2: Seal Coat Com osition Formulation for L148—02010 SC 20 m . % solid USP Water 93.400 0.00%* PIasAcryI T20TM (20%) C00174 0.600 0.12% Hypromellose 10056/10 6'000 RM® HPMC E5 100.000 6.12% *: removed during coating and drying ses Immediate release layer g.

A target immediate release (IR) composed of 10 mg of mine succinate and 10 mg of Pyridoxine HCI was applied on the seal coated tablet lot L148—02010 SC 20 mg, which were renamed lot L148—02010A bimodal FCT IR & DR 40 mg. The actual average amount of both active pharmaceutical ingredients (APls) (doxylamine succinate and pyridoxine HCI) applied per one tablet was 26.2 mg, included overage. The composition of the IR layer coat is presented in Table 3.

Table 3: IR La er Coat Com osition Formulation for L148—0201OA Bimodal FCT IR & DR 40 mg 0 .

Ingredient Lot (% wlw) £34: USP Water N/A 78.1 0.00%* Dox lamine succinate 1045 5.0 5.00% Pyridoxine HCI 11MP039 5.0 5.00% Hypromellose (Vivapharm HPMC 10056/10 6.00% PlasAcryl T20 000174 5.9 1.18% (20%), 17.18% *: removed during coating and drying processes Finishing coating.

The Diclectin FCT bimodal IR & DR 40 mg lot L148—02010A was then over layer coated with an average weight of 1.4% weight gain from a 5% (w/w) of aqueous suspension of OPADRY® YS18027-A white lot TSO60604. Finally, a finishing layer of 0.1% of Carnauba Wax powder lot 14613 was applied on the tablets.

Stability program.

An R&D stability study was initiated for the coated Diclectin bimodal tablets IR & DR 40 mg lot 2010A for up to a 12-month period under long term (25°C/60% relative humidity (RH)), and a 6 month period under rated (40°C/75%RH) ions to evaluate stability results of new drug products.

The tablets were packaged in 60 cc round white opaque high density polyethylene (HDPE) bottles (Lot C00139, Drug Plastic & Glass Co.) and induction sealed with polypropylene caps child resistant (Lot 000137, Drug Plastic & Glass Co.). The bottles were then placed in controlled nment chambers.

The following methods were used: . Visual observation for Appearance; 0 Assay and d Substances. Assay and ation products (Related Substances) for doxylamine succinate and Pyridoxine HCI was determined using High Performance Liquid Chromatography (HPLC) equipped with UV detector. The HPLC column used was an lnertsilTM ODSZ, (150 x 4.6 mm, 5 um), flow 1.0 mL/min. It was performed under gradient at 291 nm for 0-10 min. and 261 nm for 10—45 min. The typical retention is . 6 minutes for Pyridoxine HCI and 28 minutes for Doxylamine succinate.

. Dissolution. Acid stage: 100 rpm paddle, 900 mL 0.1N HCI; and Buffer stage: 100 rpm , 900 mL Phosphate buffer pH 6.8: Non USP buffer preparation: 0.2M Na3PO4: 0.1N HCI 1:3, pH 6.8).

Tables 4A and 48 present ble ity results of samples stored under accelerated (Table 4A) and long term (Table 4B) stability conditions up to 6 months. t uniformity values at T=0 showed acceptable variability. ND = not detected; NA = not applicable (not tested); RRT = relative retention time; %LC = % Label Claim; RSD = relative standard deviation and AV = acceptable value.

Table 4A: it Results at T=0 T=1 T=2 and T=6 months at 40°C/75% RH _~m_ L140-02010A-1R-0R maim— IR 1010 —DR 1010 FCT Dose strength oPyrIdoxme HCI 20 mglamine succinate 20 mo —_—P ridoxiDne HCI Time Off-white round tablet with mottled s-ecks Off-white round tablet with d s-ecks Appearance m Off white- brownish round bIconvex tablets (Organoleptic) m Not tested %LC %LCBContent BContent 113- 3 107- 3 1082 101. 3 Uniformity of Dosage Unit NRC-988 107.5 110.0 102.8 104.0 (/° Labe'C'a'm)o . 1115 109.6 1058 105.8 <USP<905> AV: Acceptable value 103_2 515) m- RSVD 1.7 13 -n T= 0 108.4 % 105.0% 1 month 106.9 % 108.7 % Assay Diluent pH 6.8 [30%m 105.2 % 107.3 % Methanol m 100.9 % 106.1 % Total: 0.12%area Largest impurity:0.12%area Total. 0.08%area_ ” RRT 1.44 o Largest impurity:0.08%area Related Substances u RRT 1.04 ' ' Total: 1.16% area Largest impurity:0.75%area Total: 0.45% area 0 RRT 1.44 t impurity:0.30%area " RRT 0-56 Total: 0.98% area Total: 0.87% area Largest impurity:0.71% Largest impurity:0.33% area area 0 RRT 1.44 at RRT 0.57 %area Total 0.98 Total: 1.88%area Total: 0.59%area .

Largest impurity:0.20%area Lar1ge22to/Ingpeuarlty.. ' ° u RRT 1.44 D @ RRT 0.56 % area - ND 1-44 Total .E- 1.88 T”.“e % LC T”.“° % LC (mm.) (min.) Dissolution IR Acid Stage Time % LC Time % LC (mm.) (min.) 900 ml 0.1N HCI s at 100 rpm T”.“e % LC T".“e % LC (mm.) (min.) Dissolution DR Buffer Stage (following exposure to acid stage) 900 ml Phosphate Buffer pH 6.81 Paddles at 100 rpm ——-———-I-=I=-I Non USP buffer preparation: 0.2M Na3PO4: 0.1N HCI 1:3, pH 6.8 Table 4B: Stabilit Results at T=0 T=1 T=2 and T=6 months at 25°C/60%RH m L148-02010A-IR-DR Formulation IR (10/10) —DR(10/10) FCT xine HCI 20 mg Dose strength Doxylamine succinate 20 mg —_—Pridoxine HCI Time Off-white round tablet with mottled s-ecks Appearance m Off white-greyish round biconvex tablets (Organoleptic) m Not tested %LC %LCBContent BContent 113- 3 107- 3 108.2 101. 3 mity of 110.6 109.0 106.4 103. 9 Dosage Unit 111 .4 108. 9 107.2 105. 7 NPLC-988 (% Label Claim) llllg 1332 18:: lg??? (USP <905> 107.3 101.3 AV :Acceptable value 113.3 108.2 R—SVD 1.7 RSD —108.4% —:- 105.0% Assay Diluent pH 6.8 [30%m 108.6 % 107.5 % Methanol m 108.1 % 107.1 % Total: 0.12%area Largest impurity:0.12%area Total: 0.08%area n RRT 1.44 Largest impurity:0.08%area " RRT 1-04 Related Substances Total: 0.08% area Total: 0.36% area t Impurlty.0.08A). . _ o Largest impurity:0.18% area area u RRT 1.44 RRT 1‘08 2014/050828 1.44 0.1% 1.08 0.08 Total: 0.59%area Largest impurity:0.20%area ND » RRT 1.44 —-E- T”.“e % LC T”.“e % LC (mm.) (min.) Dissolution IR _120— _120 ““3““ m—— 900 ml01NHCl T'me T'me Paddles at 100 rpm % LC % LC (min. ) (min. ) months Buffer Stage (min. ) (min.) wing exposure _— _— to acid stage) m—— 900 ml Phosphate Timie Time Buffer pH 6.81 % LC % LC (m.n ) Padd'es at 100 rpm —m=- —— Non USP buffer preparation: 0.2M NasPO4: 0.1N HCI 1:3, pH 6.8 Summary ofresults At T = 1 month, no significant changes were observed for appearance, assay and dissolution tests. An increase in related substances was ed for both doxylamine succinate and xine hydrochloride under accelerated conditions, but was more prominent for Pyridoxine HCI (1.16% vs. 0.45% for Doxylamine succinate).

At T = 2 months, under accelerated conditions (40°C!75%RH), the appearance of tablets became off-white sh but the assay and the dissolution results for both APls remained unchanged. Between 1 month and 2 months, the total related substances of Doxylamine succinate doubled from 0.45% to 0.98%, and the total related substances of Pyridoxine HCI slightly decreased from 1.16% down to 0.87%.

At T = 2 months for samples under long term stability conditions (25°C/60%RH), the total related substances of Pyridoxine HCI increased from 0.12% to 0.36%. A slight change in ance to off-white greyish tablets was observed.

At T = 6 months, there was no noticeable change observed under both stability conditions evaluated for the assay. However, in one hand, while the total related substances of Pyridoxine HCl ued to decrease when compared to T = 1 months under rated ions (from 1.16% down to 0.59% area), it appeared that heat and humidity had a icant impact in increasing the related substances of Doxylamine succinate from 0.45% up to 1.88% area with time. On the other hand and in long term ity conditions, while the xine HCl presented a moderate raise of related substances (0.59% when compared to 0.12% area at T = 0), the Doxylamine succinate proved to be vely stable up to 6 months with NMT 0.08% area of total related substances.

The results above showed that the degradation product profile of Doxylamine succinate and xine HCI did not follow an expected e compared to ntial volume of historical data from Diclectin®/Diclegis®, indicating that the coating process used for the ation of this formulation is not acceptable.

Example 2: Analytical testing of Doxylamine ate and Pyridoxine HCI coating solutions To investigate the unexpected results of Example 1, considering stability of the 2 APls (doxylamine succinate and xine hydrochloride) in the core tablet of Diclectin®/Diclegis®, the hypothesis was that the possible drug-drug interaction in the coating solution. Therefore various coating solutions with different API combination at different pH were prepared and tested. For each test, assay and degradation product analyses were performed under the following stability conditions: 24 hrs and 48 hrs at ambient temperature, 4 days at 40°C and 2 hours at 50°C.

Test 1 (Coating Suspension A): coating solution used forthe formulations of Example 1 (doxylamine succinate 50 mg/g + pyridoxine HCI 50 mg/g).

Test 2 (Coating Suspension B): doxylamine succinate 5O mg/g + pyridoxine HCl 50 mg/g with pH lowered to 2.5.

Test 3 (Coating Suspension C): doxylamine succinate 5O mg/g + pyridoxine HCl 50 mg/g with pH raised to 12.3.

Test 4 (Coating Suspension D): doxylamine succinate 64 mg/g + pyridoxine HCl 64 mg/g in water.

Test 5 (Coating Suspension E): pyridoxine HCI 50 mg/g only in water.

Test 6 (Coating Suspension F): doxylamine succinate 5O mg/g only in water.

All sample solutions were prepared by dissolving 0.5 g of the suspension or solution in 100 ml of diluent (0.1% phosphoric acid in water) and filtered. The results of the tests are depicted in Tables 5A to SF.

Table 5A: Stability results for coating suspension A “L148-02 g Suspension Sus ension A Coating Suspension As oerformulation of Examle 1 Pyridoxine HCI 50 mg/g Dose strength Dox lamine succinate 50 mn/ White suspension T: 24 hrs Light pink colored suspensron, _ , T = 48 hrs Light pink colored suspension Appearance ambient 4 days at Light tan colored suspension 40°C Tan d suspension Pyridoxine HCI Doxylamine succinate 104.3 % 105.3 % (52.2 mg/g) (52.6 mg/g) 105.7 % 106.9 % T: 24 hrs Assay - (528 mg/g) (53.4 mg/g) 104.2 % 105.0 % (% Label T = 48 hrs Claim) (52.1 mg/g) (52.5 mg/g) 4 days at 103.5 % 105.0 % 40°C (51.7 mg/ml) (52.5 mg/ml) 2 hours 105.3 % 105.5 % 50°C (52.7 mg/ml) (53.3 mg/ml) Suii'fa‘fifies 4 days at (% Label No peaks L: 0.05% 40°C Claim) No peaks 2: 0.05% Table 58: Stability results for g suspension B L148-02 Coating Suspension Sus-ension B Coating Suspension H lowered to 2.5 Pyridoxine HCI 50 mg/g Dose strength Dox lamine succinate 50 moo/ White suspension T: 24 hrs White suspension ambient T: 48 hrs White suspension 4 days at White suspension 40°C 2 hours White suspension 50°C mine succinate 100.5 % 101.0% 50.3 moo/ 50.5 moo/ T: 24 hrs 102.1 % 102.6 % ambient (51.1 mg/g) (51.3 mg/g) Assay (% Label T = 48 hrs 100.1 % 100.4 % Claim) ambient (50.1 mg/g) (50.2 mg/g) 4 days at 101.7 % 102.2 % 40°C (50.8 mg/ml) (51.1 mg/ml) 2 hours 101.1 % 101.8% 50°C (50.6 mg/ml) (50.9 mg/ml) No peaks :2 0.05% No peaks 3: 0.05% T: 2‘17 hrs No peaks 33 0.05% No peaks L: 0.05% ambient T = 4? hrs No peaks 1: 0.05% No peaks 3:“ 0.05% Related ambient Substances (% Label 4 days at Claim) No peaks :3 0.05% 40°C No peaks '5 0.05% Table 5C: Stability results for coating suspension C L148-02 Coating Suspension sion C Coating Suspension oH raised to 12.3 Dose strength Pyridoxine HCI 50 mg/g —Doxylamine succinate 50 mg/g Pale yellow suspension T: 24 hrs Pale yellow sion ambient Appearance T = 48 hrs Pale yellow suspension ambient 4 days at 40°C Pale yellow suspension 2 hours 50°C Pale yellow suspension —PyridoxineHCI ooxylammemmaet 93.5 % 94.0 % 46.8 moo/ 47.0 moo/ T= 24 hrs 94.4 % 95-2 % Assay ambient (47-2 mg/g) (47-6 mg/g) (% L_abe| T = 48 hrs 92.6 % 93.2 % Claim) ambient (45-3 mg/g) (466 mg/g) o 94.0 % 95.4 % 4 days at 40 C (47.0 mg/g) (477 mg/g) 94.1 % 94.1 % 2 hours 50 Co (47.0 mg/ml) (47.1 mg/ml) 1 peak No peaks '3 0.05% 0.06% @ RRT 0.74 1 peak No peaks 13 0.05% 0.12% @ RRT 0.74 Related Su bstances 1 peak (% Label No peaks 13 0.05% 0.14% Claim) @ RRT 0.74 1 peak 4 days at 40°C No peaks :3 0.05% 0.22% @ RRT 0.72 RRT % LC 0.72 0.20 2 hours 50°C No peaks 33 0.05% 1.04 0.08 Total 0.28 Table 5D: Stability results for coating suspension D L148-02 Solution Sample Solution D Formulation Solution in Water, pH 4.4 Pyridoxine HCI 64 mg/g Dose strength Dox lamine ate 64 moo/ Clear solution Appearance T: 24 hrs Solution wnth precnpitate_ _ _ _ WO 29290 T = 48 hrs Solution With prec1pitate. . . . ambient 4 days at 40°C Pale amber, clear solution 2 hours 50°C Pale amber, clear solution oxine HCI Doxylamine succinate 98.5 % 99.1 % 63.1 moo/ 63.5 moo/ T: 24 hrs 107.5 % 99.9 % Assay ambient (58-8 mg/g) (53-9 mg/g) (% Label T = 48 hrs 98.1 % 99.7 % Claim) ambient (62.8 mg/g) (63.8 mg/g) 86.6 %1 87.5 %1 4 days at 40 Co 55.4 m/ml 62.4 m/ml 103.0 % 99.7 % 2 hours 50 C0 65.9 m/ml 54.1 mo/ml No peaks 33 0.05% No peaks L: 0.05% T: 24 hrs No peaks :3 0.05% No peaks 2: 0.05% ambient Related Substances 48.3 hrs No peaks 12 0.05% No peaks 3: 0.05% ambient (% Label Claim) 4 days at 40°C No peaks L: 0.05% RRT % LC 1'22 0'07 2 hours 50°C No peaks L: 0.05% Total 0.13 Table 5E: Stability results for coating suspension E L148-02 Solution Solution E Solution in Water, pH 2.8 P ridoxine HCI onl Dose stren-th Pyridoxine HCI 50 mg/g T=0 Clear solution T: 24 hrs Clear solution Appearance T = 48 hrs Clear solution ambient 4 days at Clear solution 40°C -2 hours Clear solution. 50°C —Pyridoxine HCI Doxylamine succinaet 98.3 % T: 24 hrs 1oo_7 % ambient' (50.3 mg g)/ Assay (% Label T = 48 hrs 100.1 % Claim) ambient (50.1 mg/g) 4 days at 100.8 % (504 mg/ml) 2 hours 100.6 % 50°C (50.3 mg/ml) No peaks :3 0.05% N/A T: 2‘? hrs No peaks :3 0.05% N/A Related ambient Substances (% Label 45.5 hrs No peaks ;_~=- 0.05% N/A ambient Claim) 4 3331?" No peaks :2 0.05% N/A 2 hours No peaks a 0.05%.

Table 5F: Stability results for coating sion F L148-02 Solution Solution F Solution in Water, pH 5.0 Do lamine succinate onl Dose strength Doxylamine succinate 50 mg/g T=O Clear on T: 24 hrs Clear on ambient T=48 hrs Clear solution Appearance ambient 4 days at Clear solution 40°C Clear solution Pyridoxine HCI Doxylamine succinate 99.1 % (49.6 mg/g) (% Label T: 24 hrs 98.5 % ambient (49.2 mg/g) 4 days at 100.7 % 40°C (50.4 mg/ml) 2 hours 101.4 % T: 24 hrs N/A No peaks L: 0.05% Related ambient Substances T: 48 hrs (% Label No peaks :3 0.05% ambient Claim) 2 hours . o The results from these tests indicate that when doxylamine and pyridoxine are er in on, degradation products are present for pyridoxine and/or doxylamine, showing drug- drug interaction in all solutions.

Example 3: Analytical testing ofa ation comprising doxylamine succinate and pyridoxine HCI in separate layers/coatings To overcome the issue noted above, new prototype formulations were prepared, in which the active ingredients (doxylamine succinate and pyridoxine HCI) were added as individual ons and added as successive coats with a protective coat in between. The ype formulations were prepared with the successive addition of the following layers coating the c—coated core tablet (lot lNG-028, Table 1): Layer 1: seal coat (3%), Layer 2: pyridoxine HCI 37.5 g/batch solution, Layer 3: seal coat (3%), Layer 4: doxylamine succinate 40 g/ batch, Layer 5: Opadry white over layer (6%), Layer 6: carnauba wax (0.1%).

The first lot of these prototypes (lot 02016A) was put in stability testing under long term (25°C!60%RH) and accelerated (40°C/75%RH) conditions. The results from the stability studies are depicted in Tables 6A to 6D.

Table 6A: ity Results for Pyridoxine HCI at T=0, T=1, T=2, T=3 and T=6 months at %RH RRT Levels 0 month 1 month 2 months 3 months 6 months 00-29 0-30 ———— 00-32 0323 ———— 034-035 073-075 00-83 00-85———W 0.87-0.89———— 11-22 1.28-1.30 1.41-1.44 1.49-1.52 Total “m—m RTT = relative retention time LOQ = limit ofquantification Table SB: Stabilit Results for P ridoxine HCI at T=O T=3 and T=6 months at 25°C/60%RH 0.30 0.31—0.32 0.84-0.85 0.87-0.89 1.15 1.28-1.30 11-44 1.49-1.52 Total mm— Table 6C: it Results for Do lamine succinate at T=0 T=1 T=2 T=3 and T=6 months at 40°C/75% RH RRT mumm— 00-60 070-072 00-74 00-79———— 0.81-0.82———— 0.82-0.83 0.85-0.86 0.91 0.96-0.97 1.03-1.05 2014/050828 1.04—1.05 1.08 0.03 0.04 0.06 0.06 0.09 | Total 0.2 0.4 0.45 0.59 | 1.21 Table 6D: Stability Results for Doxylamine succinate at T=0, T=3 and T=6 months at °C!60%RH ———m —-Emm The above results under accelerated and long term conditions clearly show that after 6 months the amounts of related substances in the formulations remain at an acceptable level using the improved coating process.

Example 4: ation of Tablet Cores Tablets cores were produced as using the ingredients shown in Table 7.

Table 7 Ingredients_ Weight per batch* Weight per tablet (kg) (mg) Microcrystallme. cellulose 102 mine Succinate USP 10.345 10.0 3 Collondal Silicon Dioxide 1.035 1.0 Pyridoxine HCI 10.345 10.0 Magnesium trlsllicate USP 27.31 26.4 Croscarmellose sodium 3.724 3.6 2.000 Magnesium stearate non-bovine 4.0 2.136 * Batch size: 1 034 462 tablets 1. First, ient 1A was processed using a QuadroTM Comil U10 with 024R screen and collected. 2. Then, ingredients 2, 3 and 4 were mixed together. This mixture was then processed using the ComilTM U10 and added to ingredient 1A. 3. Ingredient 1B was processed using the ComilTM U10 and added to the e obtained step 2. The new mixture thus produced was then mixed. 4. Ingredients 5 and 6 were mixed together and then added to the mixture ed in step 3. The new mixture thus produced was then mixed.

. Ingredient 7A was added to the mixture obtained in step 4. The new mixture thus produced was then mixed. 6. The e obtained in step 5 was then compacted with a sTM Mini- Pactor with grooved rollers and 1000 micron mesh screen. 7. The compacted material was then collected and mixed with ingredient 7B.

Compressed tablets were then produced using a ManestyTM Diamon Unipress press equipped with 5/16” round standard concave, plain upper and lower punches. The target hardness was 7 kp. e 5: Tablet Coating The tablet cores of Example 4 were coated as described below. Table 8 shows the name of the s coats and their ingredients.

Table 8 Weight per Weight per Ingredients batch" tablet (kg) ("19) Diclectin 10mg - uncoated cores (from Example 4 above) Clear Coat #1 and #2 OpaolryTM Clear 020190000 9.631 Enteric Coat 4 Simethicone Emulsion 30% USP, KH n-II——— Clear Coat with Pyridoxine HCI 7 Sterile purified water 89. 88 “ Opadry Clear 020190000 9.356 2014/050828 “Pyridoxine HCI 10.375 10.03 Clear Coat #3 OpaciryTM Clear 020190000 5.877 Clear Coat with Doxylamine Succinate Sterile purified water 114.9 _ Opadry Clear 020190000 14.868 14.37 Doxylamine succinate USP 10.354 10.01 Pink Coat Sterile ed water 63.0 - 16 OpadryTM N Pink 85F94320 11.122 13.17 17 Carnauba wax powder NF 0.030 .04 Total weight of coated tablets 232.6 * Batch size: 689 655 s Table 9 shows the names and ingredients of the coating solutions and suspensions that were prepared forthe coating process.

Table 9 Ingredients Solution/Suspension (no. from Table 8) Clear Coating on #1 and #2 1 and 2 Enteric Coating Suspension 3, 4, 5, and 6 CIearChatingSolutiorHfl—mandfl Pink Coating Suspension 15 and 16 Table 10 shows the order in which the coats were applied on the tablet cores, the target weight gain for each coating step, and which coating solution/suspension was used to produce which coating. Coating was carried out using a 48 inches Accela CotaT'V' equipped with half-moon 4 inches shield and baffles.

Table 10 m—Solution/Suspension Target weight -——— Clear Coat with Pyridoxine Clear Coating on with Pyridoxine 4 1 1.2 HCI HCI Clear Coat #3 Clear Coating Solution #3 3.0 Clear Coat with Clear Coating Solution with 12.5 Doxylamine Succinate Doxylamine Succinate Pink Coat Pink Coating sion “ Then, the s were waxed with ingredient no. 17 (carnauba wax powder) in a pan coater.

Although the present invention has been described hereinabove by way of specific embodiments thereof, it can be modified, t departing from the nature of the subject invention as defined in the ed . The scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole. In the claims, the word "comprising" is used as an open-ended term, substantially equivalent to the phrase "including, but not limited to". The singular forms "a", "an" and "the" include corresponding plural references unless the context clearly dictates othenivise.

Claims (46)

WHAT IS CLAIMED IS:

1. A solid oral dosage form sing a core comprising 5 mg to 40 mg of doxylamine or a salt thereof and 5 mg to 40 mg of pyridoxine or a salt thereof; an enteric coating surrounding said core; a first active ingredient-containing coating surrounding said enteric coating and comprising (i) 5 mg to 40 mg of doxylamine or a salt thereof, or (ii) 5 mg to 40 mg of pyridoxine or a salt f; and a second active ingredient-containing coating surrounding said intermediate coating and comprising (i) 5 mg to 40 mg of doxylamine or a salt thereof, or (ii) 5 mg to 40 mg of xine or a salt thereof; wherein if said first active ingredient-containing coating comprises said doxylamine or salt thereof, said second active ingredient-containing coating comprises said pyridoxine or salt thereof, and if said first active ingredient-containing coating comprises said xine or salt thereof, said second active ingredient-containing coating comprises said doxylamine or salt thereof.

2. The solid oral dosage form of claim 1, wherein said core comprises 10 mg of said doxylamine or salt thereof.

3. The solid oral dosage form of claim 1 or 2, wherein said core comprises doxylamine ate.

4. The solid oral dosage form of any one of claims 1 to 3, wherein said core ses 10 mg of said pyridoxine or salt thereof.

5. The solid oral dosage form of any one of claims 1 to 4, wherein said core comprises pyridoxine hydrochloride.

6. The solid oral dosage form of any one of claims 1 to 5, wherein said first or second active ingredient-containing g comprises 10 mg of said doxylamine or salt thereof.

7. The solid oral dosage form of any one of claims 1 to 6, wherein said first or second active ingredient-containing coating comprises doxylamine succinate.

8. The solid oral dosage form of any one of claims 1 to 7, wherein said first or second active ingredient-containing coating comprises 10 mg of said pyridoxine or salt thereof.

9. The solid oral dosage form of any one of claims 1 to 8, wherein said first or second active ingredient-containing coating comprises pyridoxine hydrochloride.

10. The solid oral dosage form of any one of claims 1 to 9, wherein said first and/or second active ingredient-containing coating comprises a film coating system.

11. The solid oral dosage form of claim 10, wherein said film coating system comprises a r and a plasticizer.

12. The solid oral dosage form of any one of claims 1 to 11, wherein said core is present in an amount of 50% to 70% (w/w) of said solid oral dosage form.

13. The solid oral dosage form of claim 12, wherein said core is present in an amount of 55% to 65% (w/w) of said solid oral dosage form.

14. The solid oral dosage form of any one of claims 1 to 13, wherein said enteric coating is present in an amount of 2% to 15% (w/w) of said solid oral dosage form.

15. The solid oral dosage form of claim 14, wherein said enteric coating is t in an amount of 4% to 12% (w/w) of said solid oral dosage form.

16. The solid oral dosage form of any one of claims 1 to 15, wherein said enteric coating comprises an acrylic polymer or co-polymer.

17. The solid oral dosage form of claim 16, wherein said acrylic polymer or co-polymer is a copolymer based on methacrylic acid and ethyl acrylate.

18. The solid oral dosage form of any one of claims 1 to 17, wherein said first active ingredientcontaining coating is present in an amount of 4% to 12% (w/w) in said solid oral dosage form.

19. The solid oral dosage form of claim 18, n said first active ingredient-containing g is present in an amount of 6% to 10% (w/w) in said solid oral dosage form.

20. The solid oral dosage form of any one of claims 1 to 19, further comprising a first intermediate coating surrounding said first active ingredient-containing coating.

21. The solid oral dosage form of claim 20, n said first intermediate coating is present in an amount of 1% to 4% (w/w) in said solid oral dosage form.

22. The solid oral dosage form of claim 21, wherein said first intermediate coating is present in an amount of 2% to 3% (w/w) in said solid oral dosage form.

23. The solid oral dosage form of any one of claims 20 to 22, wherein said first intermediate g comprises a film coating system.

24. The solid oral dosage form of claim 23, n said film coating system comprises a r and a plasticizer.

25. The solid oral dosage form of any one of claims 1 to 24, wherein said second active ingredient-containing coating is present in an amount of 5% to 15% (w/w) of said solid oral dosage form.

26. The solid oral dosage form of claim 25, wherein said second active ingredient-containing coating is present in an amount of 8% to 12% (w/w) of said solid oral dosage form.

27. The solid oral dosage form of any one of claims 1 to 26, further comprising a second intermediate coating between said core and said enteric coating.

28. The solid oral dosage form of claim 27, wherein said second intermediate coating is present in an amount of 1% to 8% (w/w) of said solid oral dosage form.

29. The solid oral dosage form of claim 28, wherein said second intermediate g is present in an amount of 2% to 6% (w/w) of said solid oral dosage form.

30. The solid oral dosage form of any one of claims 24 to 26, wherein said second intermediate coating comprises a film coating system comprising a polymer and a plasticizer.

31. The solid oral dosage form of any one of claims 27 to 30, further comprising a seal coating surrounding said second active ingredient-containing coating.

32. The solid oral dosage form of claim 31, wherein said seal coating is present in an amount of 2% to 10% (w/w) of said solid oral dosage form.

33. The solid oral dosage form of claim 32, n said seal coating is present in an amount of 4% to 8% (w/w) of said solid oral dosage form.

34. The solid oral dosage form of any one of claims 31 to 33, wherein said seal coating ses a film coating system.

35. The solid oral dosage form of claim 34, wherein said film coating system comprises a polymer and a plasticizer.

36. The solid oral dosage form of any one of claims 31 to 35, further comprising a solid oral dosage form-coating agent surrounding said seal coating.

37. The solid oral dosage form of claim 36, wherein said solid oral dosage oating agent is present in an amount of 0.005% to 0.5% (w/w) of said solid oral dosage form.

38. The solid oral dosage form of claim 36 or 37, wherein said solid oral dosage form-coating agent comprises wax.

39. The solid oral dosage form of any one of claims 1 to 38, wherein said core further comprises one or more pharmaceutically acceptable excipients.

40. The solid oral dosage form of claim 39, wherein said core comprises microcrystalline cellulose, colloidal n dioxide, magnesium trisilicate, croscarmellose sodium and magnesium stearate.

41. The solid oral dosage form of claim 40, wherein said core comprises 60% to 65% (w/w) of microcrystalline cellulose, 0.5 to 1% (w/w) of colloidal silicon dioxide, 16% to 20% (w/w) of ium trisilicate, 2% to 3% (w/w) of croscarmellose sodium, and 2% to 3% (w/w) of magnesium stearate.

42. The solid oral dosage form of any one of claims 1 to 41, wherein said solid oral dosage form is a tablet.

43. The solid oral dosage form of any one of claims 1 to 42, for use in alleviating the symptoms of nausea and vomiting of human pregnancy.

44. The solid oral dosage form of any one of claims 1 to 42, for use in the manufacture of a medicament for alleviating the symptoms of nausea and vomiting of human pregnancy.

45. A e comprising the solid oral dosage form of any one of claims 1 to 42.

46. The package of claim 45, further comprising ctions for use of said solid oral dosage form for alleviating the symptoms of nausea and vomiting of human pregnancy.