Title of Invention	RAPID ONSET FORMULATION
Abstract	Provided herein is a novel enterically-coated pyridoxine HCI and doxylamine succinate rapid onset formulation comprising a disintegrating 5 agent such that the following dissolution profiles are satisfied when measured in 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm: (a) at least about 40% of the total pyridoxine HCI and doxylamine succinate is dissolved after 30 minutes of measurement; 10 (b) at least about 70% of the total pyridoxine HCI and doxylamine succinate is dissolved after 60 minutes of measurement; (c) at least about 80% of the total pyridoxine HCI and doxylamine succinate is dissolved after 90 minutes of measurement; (d) at about 90% of the total pyridoxine HCI and doxylamine succinate is 15 dissolved after 120 minutes of measurement. Preferably the formulation will contain a core coated with at least one enteric coating, the core comprising pyridoxine HCI, doxylamine succinate and the following non-active excipients: a filler or binder, a disintegrating agent, a lubricant, a silica flow conditioner and a stabilizing agent.

Title of Invention

RAPID ONSET FORMULATION

Abstract

Provided herein is a novel enterically-coated pyridoxine HCI and doxylamine succinate rapid onset formulation comprising a disintegrating 5 agent such that the following dissolution profiles are satisfied when measured in 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm: (a) at least about 40% of the total pyridoxine HCI and doxylamine succinate is dissolved after 30 minutes of measurement; 10 (b) at least about 70% of the total pyridoxine HCI and doxylamine succinate is dissolved after 60 minutes of measurement; (c) at least about 80% of the total pyridoxine HCI and doxylamine succinate is dissolved after 90 minutes of measurement; (d) at about 90% of the total pyridoxine HCI and doxylamine succinate is 15 dissolved after 120 minutes of measurement. Preferably the formulation will contain a core coated with at least one enteric coating, the core comprising pyridoxine HCI, doxylamine succinate and the following non-active excipients: a filler or binder, a disintegrating agent, a lubricant, a silica flow conditioner and a stabilizing agent.

Full Text	FORM 2 THE PATENTS ACT 1970 [39 OF 1970] THE PATENTS RULES, 2003 COMPLETE SPECIFICATION [See Section 10; rule 13] RAPID ONSET FORMULATION DUCHESNAY, INC., of 2925 Boulevard Industriel, Chomedey, Laval [Quebec] H7L 3W9, Canada. The following specification particularly describes the invention and the manner in which it is to be performed: -1- TITLE OF THE INVENTION RAPID ONSET FORMULATION BACKGROUND OF THE INVENTION 5 FIELD OF THE INVENTION The present invention relates to a rapid onset formulation, preferably in form of an enterically coated tablet, for a medicament comprising a synergistic duo of active ingredients namely, doxylamine succinate and 10 pyridoxine HCI, hereinafter referred to as "DS-P". DS-P is useful in the treatment of nausea and vomiting, especially, but not limited to, during pregnancy, hereinafter referred to as "NVP". Thus the present invention is concerned with all known and future therapeutic indications of DS-P. 15 THE PRIOR ART Pharmaceutical formulations of DS-P are known. The current formulation, commercially available in Canada under the name Diclectin (Duchesnay Inc.) comprises the following active ingredients: pyridoxine HCI and Doxylamine succinate. It additionally comprises the following excipients: 20 lactose, microcrystalline cellulose, magnesium trisilicate, silicon dioxide and magnesium stearate. Diclectin is the world's most studied drug in regard to its safety during pregnancy. Because of its excellent safety profile, Diclectin is the drug of 25 choice for the treatment of NVP. The current formulation is sugar coated and suffers from drawbacks, one of which being its delayed onset of action. However, the current formulation once ingested, can take more than 4 hours before the two active ingredients (pyridoxine HCI and doxylamine succinate) reach nearly full dissolution in the small intestines, where it is -2- absorbed. This delay is often considered too long for patients, such as women suffering from NVP, who require urgent relief of symptoms. Another drawback of the current formulation is related to patient 5 compliance. Women suffering from NVP often complain of hyper olfaction, which means that various odors and tastes can trigger nausea or vomiting problems. The smell and taste of sugar on the current sugar coated formulation as well as the use of organic solvents and phthalates in the preparation of the currently used enteric coating, bothers many pregnant 10 women to the point where the intake of the drug is essentially inhibited. The size of the currently available tablet is also problematic. A smaller size tablet would improve patient compliance since women suffering from NVP often have problems swallowing. Furthermore, a smaller tablet looks less 15 harmful than a bigger one and patients will have the impression that they are taking a lesser amount of drug. This will in turn significantly increase patient compliance. Finally, the current formulation contains lactose. This is objectionable for 20 those patients suffering from lactose intolerance. Thus, it is desirable to provide patients suffering from nausea and vomiting an improved rapid onset formulation overcoming the drawbacks of the prior art. 25 However, since DS-P is orally delivered as an enteric coated tablet, the novel oral formulation must transit through the stomach unscathed and rapidly release both active ingredients once the dosage form reaches its intended destination, namely the intestines. -3- The main challenge surmounted by the present invention was to arrive at a dosage form capable of overcoming the drawbacks of the prior art while simultaneously delivering the synergistic duo of active ingredients for rapid 5 onset. It was also important to provide a formulation exhibiting similar dissolution curves for both active ingredients so as to avoid the dissolution of one active ingredient to the detriment of the other. This was important in view of the synergistic therapeutic effect of the duo of active ingredients. 10 SUMMARY OF THE INVENTION In general terms, the invention provides a new aqueous enteric-coated formulation comprising DS-P, the formulation exhibiting a dissolution profile indicative of a rapid onset. 15 The invention also seeks to provide a pharmaceutical composition having specific in-vitro dissolution profiles indicative of rapid onset of the active ingredients. The pharmaceutical composition being suitable for simple and reproducible manufacture. 20 Further scope of applicability will become apparent from the detailed description given hereinafter. It should be understood however, that this detailed description, while indicating preferred embodiments of the invention, is given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become 25 apparent to those skilled in the art. DESCRIPTION OF THE DRAWINGS Figure 1 depicts two examples of dissolution profiles in accordance to the rapid onset formulation of the present invention in comparison to a -4- dissolution profile of the prior art formulation. The first dissolution profile (example 1) corresponds to a rapid onset formulation from which nearly 100% of both active ingredients is released within .45 minutes. The second dissolution profile (example 2) corresponds to a rapid onset formulation 5 from which approximately 95% of both active ingredients is released within 120 minutes. The last and comparative dissolution profile (prior art) corresponds to the currently available formulation from which approximately 100% of the pyridoxine HCI and approximately 90% of the doxylamine succinate is released within 240 minutes. 10 Figure 2 is a schematic flowchart of the preferred manufacturing process of a preferred formulation in accordance with the present invention. DETAILED DESCRIPTION OF THE INVENTION 15 Other objects and attendant features of the present invention will become readily appreciated, as the same becomes better understood by reference to the following detailed description of a preferred embodiment described for the purpose of illustration. 20 In a broad sense, the invention provides a rapid onset formulation comprising pyridoxine HCI and doxylamine succinate. The formulation of the present invention may be used in the human and . veterinary fields of medicine whenever symptoms of nausea and/or 25 vomiting require medical intervention. Since the formulation of the present invention is intended for medicinal purposes, then the formulation and its components should be pharmaceutically acceptable. The preferred formulation is in the form of an oral dosage form such as a tablet, pill or encapsulated beads or solution. The most preferred formulation is a tablet. -5- The tablet of the present invention is preferably capable of transiting through the stomach unscathed. To test this feature, the tablet of the present invention was tested to resist disintegration in simulated gastric fluid "SGF" for a minimum period of 1 hour. 5 In accordance with the present invention, the formulation will satisfy the following dissolution profiles when measured in 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm; preferably measured by high performance liquid chromatography: 10 (a) at least about 40% of the total amounts of each of pyridoxine HCI and doxylamine succinate are dissolved after 30 minutes of measurement; (b) at least about 70% of the total amounts of each of pyridoxine HCI and doxylamine succinate are dissolved after 60 minutes of 15 measurement; (c) at least about 80% of the total amounts of each of pyridoxine HCI and doxylamine succinate are dissolved after 90 minutes of measurement; (d) at least about 90% of the total amounts of each of pyridoxine HCI 20 and doxylamine succinate are dissolved after 120 minutes of measurement; In the present invention, any reference to dissolution profile should be construed as referring to the results of a dissolution test in which the 25 amount of pyridoxine HCI and of doxylamine succinate released is measured in 1000 ml phosphate buffer at pH 6.8 and 37°C using a USP (United States Pharmacopoeia) type 2 dissolution apparatus at 100 rpm; preferably measured by high performance liquid chromatography. -6- As used herein and in the claims, an "enteric coating" is understood to mean a coating comprising one or more layers generally resistant to disintegration in human gastric fluids, but which will disintegrate in human intestinal fluids, as well as coatings which disintegrate very slowly in 5 human gastric fluids, but more rapidly in human intestinal fluids. In a broad sense, "enteric coating" can encompass for example any seal coat placed on the compressed core of a tablet prior to the enteric coating per se as well as any finishing aesthetic coat placed on the enteric coating perse. 10 In a most preferred embodiment, the formulation of the present invention contains a core coated with an aqueous enteric coating. The core comprises the active ingredients pyridoxine HCI and doxylamine succinate along with non-active excipients such as a filler or binder, a disintegrating agent, a lubricant, a silica flow conditioner and a stabilizing agent. 15 Examples of fillers or binders include acacia, alginic acid, calcium phosphate (dibasic), carboxymethylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, dextrin, dextrates, sucrose, tylose, 20 pregelatinized starch, calcium sulfate, amylose, glycine, bentonite, maltose, sorbitol, ethylcellulose, disodium hydrogen phosphate, disodium phosphate, disodium pyrosulfite, polyvinyl alcohol, gelatin, glucose, guar gum, liquid glucose, compressible sugar, magnesium aluminum silicate, maltodextrin, polyethylene oxide, pplymethacrylates, povidone, sodium 25 alginate, tragacanth microcrystalline cellulose, starch, and zein. A most preferred filler or binder consists of microcrystalline cellulose. Examples of disintegrating agents include alginic acid, carboxymethylcellulose, carboxymethylcellulose sodium, -7- hydroxypropylcellulose (low substituted), microcrystalline cellulose, powdered cellulose, colloidal silicon dioxide, sodium croscarmellose, crospovidone, methylcellulose, polacrilin potassium, povidone, sodium alginate, sodium starch glycolate, starch, disodium disulfite, disodium 5 edathamil, disodium edetate, disodiumethylenediaminetetraacetate (EDTA) crosslinked polyvinylpyrollidines, pregelatinized starch, carboxymethyl starch, sodium carboxymethyl starch, microcrystalline cellulose. A most preferred disintegrating agent consists of sodium crosscarmelose. 10 Examples of lubricants include calcium stearate, canola oil, glyceryl palmitostearate, hydrogenated vegetable oil (type I), magnesium oxide, magnesium stearate, mineral oil, poloxamer, polyethylene glycol, sodium lauryl sulfate, sodium stearate fumarate, stearic acid, talc and, zinc stearate, glyceryl behapate, magnesium lauryl sulfate, boric acid, sodium 15 benzoate, sodium acetate, sodium benzoate/sodium acetate (in combination), DL leucine. A most preferred lubricant consists of magnesium stearate. Examples of silica flow conditioners include colloidal silicon dioxide, 20 magnesium aluminum silicate and guar gum. A most preferred silica flow conditioner consists of silicon dioxide. Examples of stabilizing agents include acacia, albumin,, polyvinyl alcohol, alginic acid, bentonite, dicalcium phosphate, carboxymethylcellulose, 25 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 -8- acid, stearic monoglyceride and stearyl alcohol. A most preferred stabilizing agent consists of magnesium trisilicate. In a preferred embodiment, the core of the new rapid onset Diclectin formulation will contain approximately about 4 to 10%, most preferably about 7% by weight of pyridoxine HCl; about 4 to10%, most preferably about 7% by weight of doxylamine succinate; about 40 to 80%, most preferably about 62% by weight of microcrystalline cellulose; about 10 to 30%, most preferably about 18% by weight of magnesium trisilicate; about 0.5 to 5%, most preferably about 1% by weight of silicon dioxide; 0.5 to 5% most preferably about 3% by weight of sodium croscarmellose and about 0.5 to 5%, most preferably about 3% by weight of magnesium stearate. -9- Example 1 The following is an example of a 145 mg Diclectin rapid onset core formulation: 5 Table 1: Core Ingredients: Ingredients Weight Mg/Tab Weight % / Tab Batch size 100 kg: Doxylamine Succinate 10.0 6.9 6.897 Pyridoxine HCl 10.0 6.9 6.897 Magnesium tnsilicate 26.4 18.2 18.207 Microcrystaliine Cellulose PH 102 90.0 62.1 62.069 Sodium Croscarmellose Type A 3.6 2.5 2.483 Magnesium Stearate 4.0 2.8 2.759 Silicon Dioxide NF 1.0 0.7 0.690 Total 1450 100 100 The core can then be enterically coated with an aqueous enteric coating which will allow the formulation to transit through the stomach relatively unscathed while allowing rapid dissolution in the intestines. -10- The coating formulation can be as follows: Table 2: Coating Formulation A Ingredients Weight Mg/Tab Weight%r ,_ Batch size 1 100kg - SerarCoat f > OpadryIM Clear YS-1-7472 4.82 3.33 3.327 Purified Water USP Total: 4.82 3.33 3.33 EstacryiiM30D Enteric Coating Solution* 39.58 27.29 27.294 Talc USP 200 Mesh 2.85 1.97 1.968 Polyethylene Glycol 400 USP 1.20 0.83 0.826 Antifoam 1520 0.12 0.08 0.081 Purified Water USP Total: 16.04 30.17 30.17 — — —™v—» —rj- —* -~-«- — _ nisliingCoaF" i OpadryIM White YS-1-7003 1.61 1.11 1.108 Purified Water USP Total: 1.61 1.11 1.11 Estacryl 30D Enteric Coating Solution contains 30% of solids. Therefore, 5 the total actual enteric coating amounts to 11.07%. Total coated tablet weight 167.47 mg. The purpose of the seal coat is to provide a smooth surface for the enteric coating, thereby avoiding mounds, pits or crevasses wherein uneven 10 amounts of enteric coating would be applied. -11- Dissolution Data The rapid onset formulation of the previous example has exhibited in-vitro dissolution profiles as shown in Table 3 below, when measured in 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at 5 100 rpm. The numerical values are expressed as percentages of dissolved active ingredient in relation to starting quantities. Table 3: Dissolution profiles Pyridoxine HCl Run 1 Run 2 Run 3 Run4 Run 5 Run 6t Avg 5 minutes 20 2 0 77 79 79 43 10 minutes 91 90 90 91 94 95 92 15 minutes 96 96 94 94 95 96 95 30 minutes 95 98 96 95 98 96 96 45 minutes 97 96 97 94 99 98 97 "^Doxylamine ^ i Succinate - Run 1 Run 2 Run 3 Run 4 "Run5 a -■" -Run 6- 5 minutes 17 2 0 70 75 76 40 10 minutes 90 87 89 89 97 96 91 15 minutes 98 97 96 92 98 97 96 30 minutes 97 98 96 94 99 97 97 45 minutes 98 96 98 92 100 99 97 10 The extremely low dissolution values obtained after 5 minutes for runs 1 to 3, can be explained by the non-disintegration of the core formulation at the 5 minute interval. -12- Example of method of manufacture . The formulation of the present invention was prepared using the ingredients shown in Table 1, above. Doxylamine succinate and silicon dioxide NF are pre-blended in a 2 cu. Ft. V-Blender. The resulting pre- 5 blend is then milled through a Quadro Co Mill, Model 196S, equipped with a 40 mesh screen. Pyridoxine HCI is also milled through a Quadro Co Mill, Model 196S, equipped with a 40 mesh screen. The milled pyridoxine HCI is then 10 combined with the doxylamine / silicon dioxide NF pre-blend and the combined mixture blended. Microcrystalline Cellulose is milled through a 40 mesh screen and split into two approximately equal portions. One portion is subsequently combined 15 in a 650L Gallay Bin with the previously formed pre-blend containing both the active ingredients, followed by the addition of the second portion. The loaded material is then blended followed by the addition of magnesium trisilicate and sodium croscarmellose. The newly formed mixture is blended. The addition of magnesium stearate followed by an additional 20 blending completes the preparation of the core formulation. The final blend is compressed in tablet form and is subsequently seal coated, enteric coated using a suitable commercially available aqueous enteric coating and top coated for aesthetics. The overall manufacturing 25 process is depicted in Figure 2. All coating steps using the ingredients of Table 2, namely, the seal coat on the core, the enteric coating and the opadry white (color coat) are -13- advantageously performed in a Vector Hi (trade-mark) coater pan equipped with a peristaltic pump. Example 2 5 The following is another example of a 146 mg Diclectin rapid onset core formulation. The formulation was manufactured along the same manufacturing methods as described above in example 1. This example demonstrates that the rapid onset feature of the formulation of the present invention was obtained with a different group of excipients. 10 Table 4: Core Ingredients: Ingredients Weight" 11 Mg/Tabf s-*1 — ._S_jjr _-. JKJ Weight % Tab Doxylamine Succinate 10.5 7.2 Pyridoxine HCI 10.5 7.2 Magnesium trisilicate 30.0 20.6 Microcrystalline Cellulose PH 102 65.0 44.5 Calcium Phosphate (Dibasic) 25.0 17.1 Magnesium Stearate 4.0 2.7 Colloidal Silicon Dioxide 1.0 0.7 Total 146.0 100 -14- The coating formulation can be. as follows: Table 5: Coating Formulation 1 Ingredients - Weight/Tablet1 (Mg)' , , 7 -i- Opadry'M White YS-1 -7003 4.38 Antifoam AF Emulsion 0.07 SuretericYAE-6-18107 16.06 Purified Water USP Opadry,M Clear YS-1-7472 . 0.73 Total coated tablet weight 167.24 mg. 5 The rapid onset formulation of the previous example has exhibited in-vitro dissolution profiles as shown in Table 6 below, when measured in 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm. The numerical values are expressed as percentages of dissolved 10 active ingredient. -15- Table 6: Dissolution profiles: Pyridoxine HCl Run 1l Run 2 Run 3 Run 4 Run 5 Run 6 Avg 15 minutes 17 13 25 31 17 22 21 30 minutes 31 28 60 63 36 43 43 45 minutes 51 45 78 80 55 60 61 60 minutes 69 64 88 89 67 72 75 75 minutes 79 76 94 94 77 81 83 90 minutes 84 84 97 97 83 87 89 105 minutes 88 89 98 99 87 90 92 120 minutes 91 93 98 98 89 92 93 /^Doxyiamirii "., Rur?1 Ruhj2,- SRurf-3' 15 minutes 16 14 22 31 47 61 32 30 minutes 31 27 64 63 38 40 44 45 minutes 47 44 75 79 58 61 61 60 minutes 71 61 90 85 68 74 75 75 minutes 76 71 96 89 81 82 82 90 minutes 85 80 101 88 83 81 86 105 minutes 92 86 103 95 93 92 93 120 minutes 93 88 101 96 96 95 95 It follows from these results that the novel formulation demonstrates a rapid onset as shown by its dissolution profile. Pyridoxine HCI presents an 5 average dissolution profile of over 90% within 120 minutes of starting the measurements. Similarly, Doxylamine succinate displays an. average dissolution profile of over 90% within 120 minutes of starting the measurements. 10 -16- Example 3 (Comparative example using prior art formulation) The following is an example of the prior art Diclectin formulation. An example for a 146.2 mg tablet is provided. This example demonstrates a strikingly slower onset of dissolution in comparison to the present 5 invention. Table 7: Core Ingredients: Ingredients Weight Mg/Tab Weight % / Tab Pyridoxine HCI 11.0 7.5 Doxylamine Succinate 10.2 7.0 Lactose NF 25.0 17.1 Microcrystalline Cellulose NF 65.0 44.4 Magnesium Trisilicate 30.0 20.6 Silicon Dioxide 1.0 0.7 Magnesium Stearate 4.0 2.7 Total: 146.2 100 -17- The coating formulation is as follows: Table 8: Coating Formulation 1 -Ingredients Coating Solution No. 714 Coating Powder No. 303 CAP. solution 10% CAP. solution 5% Gelatin Solution No. 105 Dusting Powder No. 755 White Smoothing Syrup Sugar Syrup No. 111 Opalux AS-7000-B white Wax Solution No. 723 5 The current formulation of the previous example has exhibited in-vitro dissolution profiles as shown in Table 9 below, when measured in 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm. The numerical values are expressed as percentages of dissolved 10 active ingredient. -18- Table 9: Dissolution profiles: Pyridoxine HCl Run1I Run2 Run 3i Run 4 Run 5 Run 6 Avge 15 minutes 9 11 18 11 16 12 13 30 minutes 22 23 32 25 28 23 25 45 minutes 37 34 45 39 42 34 38 60 minutes 50 44 56 49 51 44 49 90 minutes 69 63 73 69 67 63 67 120 minutes 83 76 84 82 80 76 80 150 minutes 94 86 91 91 86 86 89 180 minutes 99 94 98 96 93 92 95 240 minutes 93 93 100 100 99 101 98 Run1 Run2 Run3 RUN4 Run5« Run 6 Avg 15 minutes 12 15 17 8 18 16 14 30 minutes 17 21 31 18 27 30 24 45 minutes 24 32 45 25 38 38 34 60 minutes 34 41 56 36 46 49 44 90 minutes 52 55 69 55 62 66 60 120 minutes 69 65 75 68 71 75 71 150 minutes 80 74 80 78 79 82 79 180 minutes 82 78 86 82 80 84 82 240 minutes 95 89 89 82 .80 87 87 It follows from these results that the prior art formulation, exhibits a noticeably slower dissolution pattern when compared with the novel 5 formulations. Indeed, after 90 minutes averages of only 60% doxylamine and 67% pyridoxine HCI are dissolved. A slower in-vivo dissolution profile is indicative of a delayed onset of action. The novel formulations, as depicted by examples 1 and 2, show markedly faster onset dissolution -19- profiles resulting in a rapid onset of action. The new formulations overcome most, if not all of the drawbacks associated with the prior art. The terms and descriptions used herein are preferred embodiments set 5 forth by way of illustration only, and are not intended as limitations on the many variations which those of skill in the art will recognize to be possible in practicing the present invention. It is the intention that all variants whether presently known or unknown, that do not have a direct effect upon the way the invention works, are to be covered by the following claims. -20- -AMENDED CLAIMS 1. An enterically-coated pyridoxine HCI and doxylamine succinate rapid onset formulation comprising a disintegrating agent such 5 that the following dissolution profiles are satisfied when measured in 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm: (a) at least about 40% of the total amounts of each of pyridoxine HCI and doxylamine succinate are 10 dissolved after 30 minutes of measurement; (b) at least about 70% of the total amounts of each of pyridoxine HCI and doxylamine succinate are dissolved after 60 minutes of measurement; (c) at least about 80% of the total amounts of each of 15 pyridoxine HCI and doxylamine succinate are dissolved after 90 minutes of measurement; (d) at least about 90% of the total amounts of each of pyridoxine HCI and doxylamine succinate are dissolved after 120 minutes of measurement. 20 2. An enterically-coated pyridoxine HCI and doxylamine succinate rapid onset formulation as in claim 1, wherein the following dissolution characteristics are also satisfied when measured in 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm: 25 (a) at least about 20% of the total amounts of each of pyridoxine HCI and doxylamine succinate are dissolved after 15 minutes of measurement; -21- (b) at least about 60% of the total amounts of each of pyridoxine HCl and doxylamine succinate are dissolved after 45 minutes of measurement; (c) at least about 80% of the total amounts of each of 5 pyridoxine HCI and doxylamine succinate are dissolved after 75 minutes of measurement. 3. The rapid onset formulation of claims 1 or 2, wherein at least about 40% of the total amounts of each of pyridoxine HCI and doxylamine succinate are dissolved within 5 minutes when measured in 10 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm. 4. The rapid onset formulation of claims 1 or 2, wherein said formulation contains a core coated with at feast one enteric coating, said core comprising pyridoxine HCI, doxylamine succinate and the 15 following non-active excipients: a filler or binder, a disintegrating agent, a lubricant, a silica flow conditioner and a stabilizing agent. 5. The rapid onset formulation of claim 4, wherein said filler or binder consists of microcrystalline cellulose. 6. The rapid onset formulation of claim 4, wherein said 20 disintegrating agent consists of sodium crosscarmellose. 7. The rapid onset formulation of claim 4, wherein said lubricant consists of magnesium stearate. 8. The rapid onset formulation of claim 4, wherein said silica flow conditioner consists of silicon dioxide. -22- 9. The rapid onset formulation of claim 4, wherein said stabilizing agent consists of magnesium Irisilicate. 10. The rapid onset formulation of claims 1 or 2, wherein said core comprises: 5 (a) about 4-10% by weight of pyridoxineHCI; (b) about 4-10% by weight of doxylamine succinate; (c) about 40-80% by weight of microcrystalline cellulose; (d) about 10-30% by weight of magnesium Irisilicate; (e) about 0.5-5% by weight of silicon dioxide; 10 (f) about 0.5-5% by weight of sodium croscarmellose; and (g) about 0.5-5% by weight of magnesium stearate. 11. The rapid onset formulation of claim 10, wherein said core comprises: 15 (a) about 7% by weight of pyridoxine HCI; (b) about 7% by weight of doxylamine succinate; (c) about 62% by weight of microcrystalline cellulose; (d) about 18% by weight of magnesium trisilicate; (e) about 0.7% by weight of silicon dioxide; 20 (f) about 2.5% by weight of sodium croscarmellose; and (g) about 2.8% by weight of magnesium stearate. 12. The rapid onset formulation of claim 4, wherein said at feast one enteric coating is aqueous based. 13. The rapid onset formulation of claim 12, wherein said 25 enteric coating consists of a seal coat applied to the core, an enteric coating per se applied on the seal coat and an aesthetic top coat applied on the enteric coating perse. -23- 14. The use of the rapid onset formulation of claims 1 or 2 for alleviating the symptoms of nausea and vomiting in a mammal. 15. The use of the rapid onset formulation of claims 1 or 2 for alleviating the symptoms of nausea and vomiting during human 5 pregnancy. 16. A medicament for attenuating the symptoms associated with nausea and vomiting consisting essentially of the formulation of claim 4. 17. A process for preparing the rapid onset formulation of 10 claim 4, said process comprising the steps of: • blending said doxylamine succinate and said silica flow conditioner to obtain a pre-blend; • mixing said preblend with said pyridoxine HCI to obtain an active ingredient blend; 15 • mixing said active ingredient blend v/ith said remaining non-active excipients, namely: a filler or binder, a disintegrating agent, a lubricant, and a stabilizing agent to obtain a final blend; and • tabletting and coating said final blend. 20 18. A process in accordance with claim 17 wherein said final tabletting and coating step comprises compression of said final into a tablet shape, seal coating of said tablet shape, followed by enteric coating, followed by colour coating. 19 An enterically-coated pyridoxine HCI and doxylamine succinate rapid onset formulation substantially as herein described with reference to the accompanying drawings. 20 A process for preparing the rapid onset formulation substantially as herein described with reference to the accompanying drawings. Dated this 15th day of April, 2005. -24- ABSTRACT Provided herein is a novel enterically-coated pyridoxine HCI and doxylamine succinate rapid onset formulation comprising a disintegrating 5 agent such that the following dissolution profiles are satisfied when measured in 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm: (a) at least about 40% of the total pyridoxine HCI and doxylamine succinate is dissolved after 30 minutes of measurement; 10 (b) at least about 70% of the total pyridoxine HCI and doxylamine succinate is dissolved after 60 minutes of measurement; (c) at least about 80% of the total pyridoxine HCI and doxylamine succinate is dissolved after 90 minutes of measurement; (d) at about 90% of the total pyridoxine HCI and doxylamine succinate is 15 dissolved after 120 minutes of measurement. Preferably the formulation will contain a core coated with at least one enteric coating, the core comprising pyridoxine HCI, doxylamine succinate and the following non-active excipients: a filler or binder, a disintegrating agent, a lubricant, a silica flow conditioner and a stabilizing agent.

Full Text

FORM 2
THE PATENTS ACT 1970 [39 OF 1970]
THE PATENTS RULES, 2003 COMPLETE SPECIFICATION
[See Section 10; rule 13]
RAPID ONSET FORMULATION

DUCHESNAY, INC., of 2925 Boulevard Industriel, Chomedey, Laval [Quebec] H7L 3W9, Canada.
The following specification particularly describes the invention and the manner in which it is to be performed:

-1-
TITLE OF THE INVENTION
RAPID ONSET FORMULATION
BACKGROUND OF THE INVENTION
5
FIELD OF THE INVENTION
The present invention relates to a rapid onset formulation, preferably in form of an enterically coated tablet, for a medicament comprising a synergistic duo of active ingredients namely, doxylamine succinate and
10 pyridoxine HCI, hereinafter referred to as "DS-P". DS-P is useful in the treatment of nausea and vomiting, especially, but not limited to, during pregnancy, hereinafter referred to as "NVP". Thus the present invention is concerned with all known and future therapeutic indications of DS-P.
15 THE PRIOR ART
Pharmaceutical formulations of DS-P are known. The current formulation, commercially available in Canada under the name Diclectin (Duchesnay Inc.) comprises the following active ingredients: pyridoxine HCI and Doxylamine succinate. It additionally comprises the following excipients:
20 lactose, microcrystalline cellulose, magnesium trisilicate, silicon dioxide and magnesium stearate.
Diclectin is the world's most studied drug in regard to its safety during pregnancy. Because of its excellent safety profile, Diclectin is the drug of
25 choice for the treatment of NVP. The current formulation is sugar coated and suffers from drawbacks, one of which being its delayed onset of action. However, the current formulation once ingested, can take more than 4 hours before the two active ingredients (pyridoxine HCI and doxylamine succinate) reach nearly full dissolution in the small intestines, where it is

-2-
absorbed. This delay is often considered too long for patients, such as women suffering from NVP, who require urgent relief of symptoms.
Another drawback of the current formulation is related to patient
5 compliance. Women suffering from NVP often complain of hyper olfaction, which means that various odors and tastes can trigger nausea or vomiting problems. The smell and taste of sugar on the current sugar coated formulation as well as the use of organic solvents and phthalates in the preparation of the currently used enteric coating, bothers many pregnant
10 women to the point where the intake of the drug is essentially inhibited.
The size of the currently available tablet is also problematic. A smaller size tablet would improve patient compliance since women suffering from NVP often have problems swallowing. Furthermore, a smaller tablet looks less
15 harmful than a bigger one and patients will have the impression that they are taking a lesser amount of drug. This will in turn significantly increase patient compliance.
Finally, the current formulation contains lactose. This is objectionable for 20 those patients suffering from lactose intolerance.
Thus, it is desirable to provide patients suffering from nausea and vomiting an improved rapid onset formulation overcoming the drawbacks of the prior art.
25
However, since DS-P is orally delivered as an enteric coated tablet, the novel oral formulation must transit through the stomach unscathed and rapidly release both active ingredients once the dosage form reaches its intended destination, namely the intestines.

-3-
The main challenge surmounted by the present invention was to arrive at a dosage form capable of overcoming the drawbacks of the prior art while simultaneously delivering the synergistic duo of active ingredients for rapid
5 onset. It was also important to provide a formulation exhibiting similar dissolution curves for both active ingredients so as to avoid the dissolution of one active ingredient to the detriment of the other. This was important in view of the synergistic therapeutic effect of the duo of active ingredients.
10 SUMMARY OF THE INVENTION
In general terms, the invention provides a new aqueous enteric-coated formulation comprising DS-P, the formulation exhibiting a dissolution profile indicative of a rapid onset.
15 The invention also seeks to provide a pharmaceutical composition having specific in-vitro dissolution profiles indicative of rapid onset of the active ingredients. The pharmaceutical composition being suitable for simple and reproducible manufacture.
20 Further scope of applicability will become apparent from the detailed description given hereinafter. It should be understood however, that this detailed description, while indicating preferred embodiments of the invention, is given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become
25 apparent to those skilled in the art.
DESCRIPTION OF THE DRAWINGS
Figure 1 depicts two examples of dissolution profiles in accordance to the
rapid onset formulation of the present invention in comparison to a

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dissolution profile of the prior art formulation. The first dissolution profile (example 1) corresponds to a rapid onset formulation from which nearly 100% of both active ingredients is released within .45 minutes. The second dissolution profile (example 2) corresponds to a rapid onset formulation
5 from which approximately 95% of both active ingredients is released within 120 minutes. The last and comparative dissolution profile (prior art) corresponds to the currently available formulation from which approximately 100% of the pyridoxine HCI and approximately 90% of the doxylamine succinate is released within 240 minutes.
10
Figure 2 is a schematic flowchart of the preferred manufacturing process of a preferred formulation in accordance with the present invention.
DETAILED DESCRIPTION OF THE INVENTION
15 Other objects and attendant features of the present invention will become readily appreciated, as the same becomes better understood by reference to the following detailed description of a preferred embodiment described for the purpose of illustration.
20 In a broad sense, the invention provides a rapid onset formulation comprising pyridoxine HCI and doxylamine succinate.
The formulation of the present invention may be used in the human and . veterinary fields of medicine whenever symptoms of nausea and/or
25 vomiting require medical intervention. Since the formulation of the present invention is intended for medicinal purposes, then the formulation and its components should be pharmaceutically acceptable. The preferred formulation is in the form of an oral dosage form such as a tablet, pill or encapsulated beads or solution. The most preferred formulation is a tablet.

-5-
The tablet of the present invention is preferably capable of transiting through the stomach unscathed. To test this feature, the tablet of the present invention was tested to resist disintegration in simulated gastric fluid "SGF" for a minimum period of 1 hour.
5
In accordance with the present invention, the formulation will satisfy the
following dissolution profiles when measured in 1000 ml phosphate buffer
at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm; preferably
measured by high performance liquid chromatography:
10 (a) at least about 40% of the total amounts of each of pyridoxine HCI
and doxylamine succinate are dissolved after 30 minutes of
measurement;
(b) at least about 70% of the total amounts of each of pyridoxine HCI
and doxylamine succinate are dissolved after 60 minutes of
15 measurement;
(c) at least about 80% of the total amounts of each of pyridoxine HCI
and doxylamine succinate are dissolved after 90 minutes of
measurement;
(d) at least about 90% of the total amounts of each of pyridoxine HCI
20 and doxylamine succinate are dissolved after 120 minutes of
measurement;
In the present invention, any reference to dissolution profile should be construed as referring to the results of a dissolution test in which the
25 amount of pyridoxine HCI and of doxylamine succinate released is measured in 1000 ml phosphate buffer at pH 6.8 and 37°C using a USP (United States Pharmacopoeia) type 2 dissolution apparatus at 100 rpm; preferably measured by high performance liquid chromatography.

-6-
As used herein and in the claims, an "enteric coating" is understood to mean a coating comprising one or more layers generally resistant to disintegration in human gastric fluids, but which will disintegrate in human intestinal fluids, as well as coatings which disintegrate very slowly in
5 human gastric fluids, but more rapidly in human intestinal fluids. In a broad sense, "enteric coating" can encompass for example any seal coat placed on the compressed core of a tablet prior to the enteric coating per se as well as any finishing aesthetic coat placed on the enteric coating perse.
10 In a most preferred embodiment, the formulation of the present invention contains a core coated with an aqueous enteric coating. The core comprises the active ingredients pyridoxine HCI and doxylamine succinate along with non-active excipients such as a filler or binder, a disintegrating agent, a lubricant, a silica flow conditioner and a stabilizing agent.
15
Examples of fillers or binders include acacia, alginic acid, calcium
phosphate (dibasic), carboxymethylcellulose, carboxymethylcellulose
sodium, hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, dextrin, dextrates, sucrose, tylose,
20 pregelatinized starch, calcium sulfate, amylose, glycine, bentonite, maltose, sorbitol, ethylcellulose, disodium hydrogen phosphate, disodium phosphate, disodium pyrosulfite, polyvinyl alcohol, gelatin, glucose, guar gum, liquid glucose, compressible sugar, magnesium aluminum silicate, maltodextrin, polyethylene oxide, pplymethacrylates, povidone, sodium
25 alginate, tragacanth microcrystalline cellulose, starch, and zein. A most preferred filler or binder consists of microcrystalline cellulose.
Examples of disintegrating agents include alginic acid,
carboxymethylcellulose, carboxymethylcellulose sodium,

-7-
hydroxypropylcellulose (low substituted), microcrystalline cellulose, powdered cellulose, colloidal silicon dioxide, sodium croscarmellose, crospovidone, methylcellulose, polacrilin potassium, povidone, sodium alginate, sodium starch glycolate, starch, disodium disulfite, disodium
5 edathamil, disodium edetate, disodiumethylenediaminetetraacetate (EDTA) crosslinked polyvinylpyrollidines, pregelatinized starch, carboxymethyl starch, sodium carboxymethyl starch, microcrystalline cellulose. A most preferred disintegrating agent consists of sodium crosscarmelose.
10 Examples of lubricants include calcium stearate, canola oil, glyceryl palmitostearate, hydrogenated vegetable oil (type I), magnesium oxide, magnesium stearate, mineral oil, poloxamer, polyethylene glycol, sodium lauryl sulfate, sodium stearate fumarate, stearic acid, talc and, zinc stearate, glyceryl behapate, magnesium lauryl sulfate, boric acid, sodium
15 benzoate, sodium acetate, sodium benzoate/sodium acetate (in combination), DL leucine. A most preferred lubricant consists of magnesium stearate.
Examples of silica flow conditioners include colloidal silicon dioxide,
20 magnesium aluminum silicate and guar gum. A most preferred silica flow conditioner consists of silicon dioxide.
Examples of stabilizing agents include acacia, albumin,, polyvinyl alcohol, alginic acid, bentonite, dicalcium phosphate, carboxymethylcellulose,
25 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

-8-
acid, stearic monoglyceride and stearyl alcohol. A most preferred stabilizing agent consists of magnesium trisilicate.
In a preferred embodiment, the core of the new rapid onset Diclectin formulation will contain approximately about 4 to 10%, most preferably about 7% by weight of pyridoxine HCl; about 4 to10%, most preferably about 7% by weight of doxylamine succinate; about 40 to 80%, most preferably about 62% by weight of microcrystalline cellulose; about 10 to 30%, most preferably about 18% by weight of magnesium trisilicate; about 0.5 to 5%, most preferably about 1% by weight of silicon dioxide; 0.5 to 5% most preferably about 3% by weight of sodium croscarmellose and about 0.5 to 5%, most preferably about 3% by weight of magnesium stearate.

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Example 1
The following is an example of a 145 mg Diclectin rapid onset core formulation:
5 Table 1: Core Ingredients:

Ingredients Weight Mg/Tab Weight % / Tab Batch size 100 kg:
Doxylamine Succinate 10.0 6.9 6.897
Pyridoxine HCl 10.0 6.9 6.897
Magnesium tnsilicate 26.4 18.2 18.207
Microcrystaliine Cellulose PH 102 90.0 62.1 62.069
Sodium Croscarmellose Type A 3.6 2.5 2.483
Magnesium Stearate 4.0 2.8 2.759
Silicon Dioxide NF 1.0 0.7 0.690
Total 1450 100 100
The core can then be enterically coated with an aqueous enteric coating which will allow the formulation to transit through the stomach relatively unscathed while allowing rapid dissolution in the intestines.

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The coating formulation can be as follows:
Table 2: Coating Formulation

A Ingredients Weight Mg/Tab Weight*%r ,_ Batch size 1 100kg -
SerarCoat f * >
OpadryIM Clear YS-1-7472 4.82 3.33 3.327
Purified Water USP
Total: 4.82 3.33 3.33

EstacryiiM30D Enteric Coating Solution* 39.58 27.29 27.294
Talc USP 200 Mesh 2.85 1.97 1.968
Polyethylene Glycol 400 USP 1.20 0.83 0.826
Antifoam 1520 0.12 0.08 0.081
Purified Water USP
Total: 16.04 30.17 30.17
— — —™v—» —rj- —* -~-«- — _ nisliing*CoaF" i
OpadryIM White YS-1-7003 1.61 1.11 1.108
Purified Water USP
Total: 1.61 1.11 1.11
*Estacryl 30D Enteric Coating Solution contains 30% of solids. Therefore,
5 the total actual enteric coating amounts to 11.07%. Total coated tablet weight 167.47 mg.
The purpose of the seal coat is to provide a smooth surface for the enteric coating, thereby avoiding mounds, pits or crevasses wherein uneven
10 amounts of enteric coating would be applied.

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Dissolution Data
The rapid onset formulation of the previous example has exhibited in-vitro dissolution profiles as shown in Table 3 below, when measured in 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at
5 100 rpm. The numerical values are expressed as percentages of dissolved active ingredient in relation to starting quantities.
Table 3: Dissolution profiles

Pyridoxine HCl Run 1 Run 2 Run 3 Run4 Run 5 Run 6t Avg
5 minutes 20 2 0 77 79 79 43
10 minutes 91 90 90 91 94 95 92
15 minutes 96 96 94 94 95 96 95
30 minutes 95 98 96 95 98 96 96
45 minutes 97 96 97 94 99 98 97
"^Doxylamine ^ i Succinate - Run 1 *Run 2 Run 3 Run 4 "Run5 a -■" -Run 6- 5 minutes 17 2 0 70 75 76 40
10 minutes 90 87 89 89 97 96 91
15 minutes 98 97 96 92 98 97 96
30 minutes 97 98 96 94 99 97 97
45 minutes 98 96 98 92 100 99 97
10 The extremely low dissolution values obtained after 5 minutes for runs 1 to 3, can be explained by the non-disintegration of the core formulation at the 5 minute interval.

-12-
Example of method of manufacture
. The formulation of the present invention was prepared using the
ingredients shown in Table 1, above. Doxylamine succinate and silicon
dioxide NF are pre-blended in a 2 cu. Ft. V-Blender. The resulting pre-
5 blend is then milled through a Quadro Co Mill, Model 196S, equipped with
a 40 mesh screen.
Pyridoxine HCI is also milled through a Quadro Co Mill, Model 196S, equipped with a 40 mesh screen. The milled pyridoxine HCI is then
10 combined with the doxylamine / silicon dioxide NF pre-blend and the combined mixture blended.
Microcrystalline Cellulose is milled through a 40 mesh screen and split into two approximately equal portions. One portion is subsequently combined
15 in a 650L Gallay Bin with the previously formed pre-blend containing both the active ingredients, followed by the addition of the second portion. The loaded material is then blended followed by the addition of magnesium trisilicate and sodium croscarmellose. The newly formed mixture is blended. The addition of magnesium stearate followed by an additional
20 blending completes the preparation of the core formulation.
The final blend is compressed in tablet form and is subsequently seal coated, enteric coated using a suitable commercially available aqueous enteric coating and top coated for aesthetics. The overall manufacturing
25 process is depicted in Figure 2.
All coating steps using the ingredients of Table 2, namely, the seal coat on the core, the enteric coating and the opadry white (color coat) are

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advantageously performed in a Vector Hi (trade-mark) coater pan equipped with a peristaltic pump.
Example 2
5 The following is another example of a 146 mg Diclectin rapid onset core formulation. The formulation was manufactured along the same manufacturing methods as described above in example 1. This example demonstrates that the rapid onset feature of the formulation of the present invention was obtained with a different group of excipients.
10
Table 4: Core Ingredients:

Ingredients Weight" *11 Mg/Tabf s-*1 — ._S_jjr _-. JKJ Weight % Tab
Doxylamine Succinate 10.5 7.2
Pyridoxine HCI 10.5 7.2
Magnesium trisilicate 30.0 20.6
Microcrystalline Cellulose PH 102 65.0 44.5
Calcium Phosphate (Dibasic) 25.0 17.1
Magnesium Stearate 4.0 2.7
Colloidal Silicon Dioxide 1.0 0.7
Total 146.0 100

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The coating formulation can be. as follows: Table 5: Coating Formulation

1 Ingredients - Weight/Tablet1 (Mg)' , , 7 -i-
Opadry'M White YS-1 -7003 4.38
Antifoam AF Emulsion 0.07
SuretericYAE-6-18107 16.06
Purified Water USP
Opadry,M Clear YS-1-7472 . 0.73
Total coated tablet weight 167.24 mg. 5
The rapid onset formulation of the previous example has exhibited in-vitro dissolution profiles as shown in Table 6 below, when measured in 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm. The numerical values are expressed as percentages of dissolved
10 active ingredient.

-15-
Table 6: Dissolution profiles:

Pyridoxine HCl Run 1l Run 2 Run 3 Run 4 Run 5 Run 6 Avg
15 minutes 17 13 25 31 17 22 21
30 minutes 31 28 60 63 36 43 43
45 minutes 51 45 78 80 55 60 61
60 minutes 69 64 88 89 67 72 75
75 minutes 79 76 94 94 77 81 83
90 minutes 84 84 97 97 83 87 89
105 minutes 88 89 98 99 87 90 92
120 minutes 91 93 98 98 89 92 93
/^Doxyiamirii "., Rur?1 Ruhj2,- SRurf-3' 15 minutes 16 14 22 31 47 61 32
30 minutes 31 27 64 63 38 40 44
45 minutes 47 44 75 79 58 61 61
60 minutes 71 61 90 85 68 74 75
75 minutes 76 71 96 89 81 82 82
90 minutes 85 80 101 88 83 81 86
105 minutes 92 86 103 95 93 92 93
120 minutes 93 88 101 96 96 95 95
It follows from these results that the novel formulation demonstrates a rapid onset as shown by its dissolution profile. Pyridoxine HCI presents an
5 average dissolution profile of over 90% within 120 minutes of starting the measurements. Similarly, Doxylamine succinate displays an. average dissolution profile of over 90% within 120 minutes of starting the measurements.
10

-16-
Example 3 (Comparative example using prior art formulation)
The following is an example of the prior art Diclectin formulation. An example for a 146.2 mg tablet is provided. This example demonstrates a strikingly slower onset of dissolution in comparison to the present
5 invention.
Table 7: Core Ingredients:

Ingredients Weight Mg/Tab Weight % / Tab
Pyridoxine HCI 11.0 7.5
Doxylamine Succinate 10.2 7.0
Lactose NF 25.0 17.1
Microcrystalline Cellulose NF 65.0 44.4
Magnesium Trisilicate 30.0 20.6
Silicon Dioxide 1.0 0.7
Magnesium Stearate 4.0 2.7
Total: 146.2 100

-17-
The coating formulation is as follows: Table 8: Coating Formulation

1 -Ingredients
Coating Solution No. 714
Coating Powder No. 303
CAP. solution 10%
CAP. solution 5%
Gelatin Solution No. 105
Dusting Powder No. 755
White Smoothing Syrup
Sugar Syrup No. 111
Opalux AS-7000-B white
Wax Solution No. 723
5
The current formulation of the previous example has exhibited in-vitro dissolution profiles as shown in Table 9 below, when measured in 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm. The numerical values are expressed as percentages of dissolved
10 active ingredient.

-18-
Table 9: Dissolution profiles:

Pyridoxine HCl Run1I Run2 Run 3i Run 4 Run 5 Run 6 Avge
15 minutes 9 11 18 11 16 12 13
30 minutes 22 23 32 25 28 23 25
45 minutes 37 34 45 39 42 34 38
60 minutes 50 44 56 49 51 44 49
90 minutes 69 63 73 69 67 63 67
120 minutes 83 76 84 82 80 76 80
150 minutes 94 86 91 91 86 86 89
180 minutes 99 94 98 96 93 92 95
240 minutes 93 93 100 100 99 101 98
Run1 Run2 Run3 RUN4 Run5« Run 6 Avg
15 minutes 12 15 17 8 18 16 14
30 minutes 17 21 31 18 27 30 24
45 minutes 24 32 45 25 38 38 34
60 minutes 34 41 56 36 46 49 44
90 minutes 52 55 69 55 62 66 60
120 minutes 69 65 75 68 71 75 71
150 minutes 80 74 80 78 79 82 79
180 minutes 82 78 86 82 80 84 82
240 minutes 95 89 89 82 .80 87 87
It follows from these results that the prior art formulation, exhibits a noticeably slower dissolution pattern when compared with the novel
5 formulations. Indeed, after 90 minutes averages of only 60% doxylamine and 67% pyridoxine HCI are dissolved. A slower in-vivo dissolution profile is indicative of a delayed onset of action. The novel formulations, as depicted by examples 1 and 2, show markedly faster onset dissolution

-19-
profiles resulting in a rapid onset of action. The new formulations overcome most, if not all of the drawbacks associated with the prior art.
The terms and descriptions used herein are preferred embodiments set
5 forth by way of illustration only, and are not intended as limitations on the many variations which those of skill in the art will recognize to be possible in practicing the present invention. It is the intention that all variants whether presently known or unknown, that do not have a direct effect upon the way the invention works, are to be covered by the following claims.

-20-
-AMENDED CLAIMS
1. An enterically-coated pyridoxine HCI and doxylamine
succinate rapid onset formulation comprising a disintegrating agent such
5 that the following dissolution profiles are satisfied when measured in 1000
ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus
at 100 rpm:
(a) at least about 40% of the total amounts of each of
pyridoxine HCI and doxylamine succinate are
10 dissolved after 30 minutes of measurement;
(b) at least about 70% of the total amounts of each of
pyridoxine HCI and doxylamine succinate are
dissolved after 60 minutes of measurement;
(c) at least about 80% of the total amounts of each of
15 pyridoxine HCI and doxylamine succinate are
dissolved after 90 minutes of measurement;
(d) at least about 90% of the total amounts of each of
pyridoxine HCI and doxylamine succinate are
dissolved after 120 minutes of measurement.
20 2. An enterically-coated pyridoxine HCI and doxylamine
succinate rapid onset formulation as in claim 1, wherein the following
dissolution characteristics are also satisfied when measured in 1000 ml
phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at
100 rpm:
25 (a) at least about 20% of the total amounts of each of
pyridoxine HCI and doxylamine succinate are dissolved after 15 minutes of measurement;

-21-
(b) at least about 60% of the total amounts of each of pyridoxine HCl and doxylamine succinate are dissolved after 45 minutes of measurement;
(c) at least about 80% of the total amounts of each of
5 pyridoxine HCI and doxylamine succinate are
dissolved after 75 minutes of measurement.
3. The rapid onset formulation of claims 1 or 2, wherein
at least about 40% of the total amounts of each of pyridoxine HCI and
doxylamine succinate are dissolved within 5 minutes when measured in
10 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm.
4. The rapid onset formulation of claims 1 or 2, wherein
said formulation contains a core coated with at feast one enteric coating,
said core comprising pyridoxine HCI, doxylamine succinate and the
15 following non-active excipients: a filler or binder, a disintegrating agent, a lubricant, a silica flow conditioner and a stabilizing agent.
5. The rapid onset formulation of claim 4, wherein said
filler or binder consists of microcrystalline cellulose.
6. The rapid onset formulation of claim 4, wherein said
20 disintegrating agent consists of sodium crosscarmellose.
7. The rapid onset formulation of claim 4, wherein said lubricant consists of magnesium stearate.
8. The rapid onset formulation of claim 4, wherein said silica flow conditioner consists of silicon dioxide.

-22-
9. The rapid onset formulation of claim 4, wherein said stabilizing agent consists of magnesium Irisilicate.
10. The rapid onset formulation of claims 1 or 2, wherein said core comprises:
5 (a) about 4-10% by weight of pyridoxineHCI;
(b) about 4-10% by weight of doxylamine succinate;
(c) about 40-80% by weight of microcrystalline cellulose;
(d) about 10-30% by weight of magnesium Irisilicate;
(e) about 0.5-5% by weight of silicon dioxide;
10 (f) about 0.5-5% by weight of sodium croscarmellose;
and (g) about 0.5-5% by weight of magnesium stearate.
11. The rapid onset formulation of claim 10, wherein said
core comprises:
15 (a) about 7% by weight of pyridoxine HCI;
(b) about 7% by weight of doxylamine succinate;
(c) about 62% by weight of microcrystalline cellulose;
(d) about 18% by weight of magnesium trisilicate;
(e) about 0.7% by weight of silicon dioxide;
20 (f) about 2.5% by weight of sodium croscarmellose; and
(g) about 2.8% by weight of magnesium stearate.
12. The rapid onset formulation of claim 4, wherein said
at feast one enteric coating is aqueous based.
13. The rapid onset formulation of claim 12, wherein said
25 enteric coating consists of a seal coat applied to the core, an enteric
coating per se applied on the seal coat and an aesthetic top coat applied on the enteric coating perse.

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14. The use of the rapid onset formulation of claims 1 or 2 for alleviating the symptoms of nausea and vomiting in a mammal.
15. The use of the rapid onset formulation of claims 1 or 2 for alleviating the symptoms of nausea and vomiting during human
5 pregnancy.
16. A medicament for attenuating the symptoms
associated with nausea and vomiting consisting essentially of the
formulation of claim 4.
17. A process for preparing the rapid onset formulation of
10 claim 4, said process comprising the steps of:
• blending said doxylamine succinate and said silica flow conditioner to obtain a pre-blend;
• mixing said preblend with said pyridoxine HCI to obtain an active ingredient blend;
15 • mixing said active ingredient blend v/ith said
remaining non-active excipients, namely: a filler or binder, a disintegrating agent, a lubricant, and a stabilizing agent to obtain a final blend; and
• tabletting and coating said final blend.
20 18. A process in accordance with claim 17 wherein said
final tabletting and coating step comprises compression of said final into a tablet shape, seal coating of said tablet shape, followed by enteric coating, followed by colour coating.

19 An enterically-coated pyridoxine HCI and doxylamine succinate rapid onset formulation substantially as herein described with reference to the accompanying drawings.
20 A process for preparing the rapid onset formulation substantially as herein described with reference to the accompanying drawings.
Dated this 15th day of April, 2005.

-24-
ABSTRACT
Provided herein is a novel enterically-coated pyridoxine HCI and doxylamine succinate rapid onset formulation comprising a disintegrating
5 agent such that the following dissolution profiles are satisfied when measured in 1000 ml phosphate buffer at pH 6.8 and 37°C in a type 2 dissolution apparatus at 100 rpm:
(a) at least about 40% of the total pyridoxine HCI and doxylamine succinate is dissolved after 30 minutes of measurement;
10 (b) at least about 70% of the total pyridoxine HCI and doxylamine succinate is dissolved after 60 minutes of measurement;
(c) at least about 80% of the total pyridoxine HCI and doxylamine
succinate is dissolved after 90 minutes of measurement;
(d) at about 90% of the total pyridoxine HCI and doxylamine succinate is
15 dissolved after 120 minutes of measurement.
Preferably the formulation will contain a core coated with at least one enteric coating, the core comprising pyridoxine HCI, doxylamine succinate and the following non-active excipients: a filler or binder, a disintegrating agent, a lubricant, a silica flow conditioner and a stabilizing agent.

RAPID ONSET FORMULATION

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