WO2023101620A1

WO2023101620A1 - Delayed release composition comprising doxylamine and pyridoxine

Info

Publication number: WO2023101620A1
Application number: PCT/TR2021/051318
Authority: WO
Inventors: Hatice ONCEL; Onur Pinarbasli; Feristah BILGIN; Bahar KOKSEL OZGEN; Nurdan ATILGAN; Asuman AYBEY DOGANAY; Nagehan SARRACOGLU
Original assignee: Ilko Ilac Sanayi Ve Ticaret A.S.
Priority date: 2021-11-30
Filing date: 2021-11-30
Publication date: 2023-06-08

Abstract

The present invention relates to a disintegrant free delayed release pharmaceutical tablet composition comprising doxylamine succinate and pyridoxine hydrochloride as active ingredients. It relates to a process for preparing said composition having a specific ratio of mannitol and dibasic calcium phosphate as diluent/filler providing excellent storage stability of the produced tablets.

Description

DELAYED RELEASE COMPOSITION COMPRISING DOXYLAMINE AND PYRIDOXINE

Technical field:

The present invention relates to formulate a disintegrant-free delayed release pharmaceutical tablet composition comprising doxylamine and pyridoxine, a process for the production of said formulation with tablets providing storage stability under high temperature and moisture absorption.

Prior Art:

Doxylamine succinate is a first-generation antihistamine used as a short-term sedative and hypnotic (sleep aid) or in combination formulations to provide night-time allergy and cold relief. Its chemical name is N,N-dimethyl-2-[1-phenyl-1-(2-pyridinyl)ethoxy]-, butanedioate (1 :1) with a molecular formula C17H22N2O • C₄H₆O₄. Doxylamine succinate is very soluble in water and alcohol, readily soluble in chloroform and slightly soluble in ether and benzene.

Pyridoxine hydrochloride, also known as vitamin B6, is a form of vitamin B6 found commonly in food and used as a dietary supplement. As a supplement it is used to treat and prevent pyridoxine deficiency, sideroblastic anaemia, pyridoxine-dependent epilepsy, certain metabolic disorders, side effects or complications of isoniazid use, and certain types of mushroom poisoning. Its chemical name is 5-hydroxy-6-methyl- 3,4-pyridine dimethanol hydrochloride with molecular formula CsHnNOs • HCI. Pyridoxine hydrochloride is readily soluble in water, slightly soluble in alcohol and insoluble in ether. Doxylamine succinate and pyridoxine hydrochloride are represented by chemical formulas as shown below.

Doxylamine succinate Pyridoxine hydroxide The delayed-released combination of doxylamine succinate and pyridoxine hydrochloride (10 mg each) was introduced into the market in the 1950’s to treat nausea and vomiting of pregnancy (NVP). These two components exhibited synergistic anti-nauseant effects. Doxylamine succinate (an antihistamine) and pyridoxine hydrochloride (vitamin B6) provide anti-nauseant and anti-emetic activity. The delayed action of doxylamine succinate and pyridoxine hydrochloride permits the night time dose to be effective in the morning hours, when the patient needs it most.

EP1397133B1 discloses a rapid onset formulation comprising disintegrant, preferably in form of an enterically coated tablet, for a medicament comprising a synergistic duo of active ingredients namely, doxylamine succinate and pyridoxine hydrochloride. This patent is silent for stability problems of tablets in the presence of heat and moisture.

W02013/082706A1 discloses a disintegrant-free delayed release pharmaceutical composition containing doxylamine succinate and pyridoxine hydrochloride for treatment of nausea and vomiting during pregnancy for oral administration comprising a core and an enteric coating. This patent is silent for stability problems of tablets in the presence of heat and moisture, too.

Doxylamine succinate and pyridoxine hydrochloride are currently marketed as an enteric coated tablet for delayed release under the trade name of Diclectin® (Duchesnay Inc.). In the studies conducted on the reference product, it has been observed that commercially available products have a tendency to exhibit stability problems.

Commercially available reference product of doxylamine succinate and pyridoxine hydrochloride enteric coated tablet has the propension of undergoing cracking on the tablet surface during the storage in the presence of heat and moisture. However, problems may occur due to cracks on the tablet surface, which can lead to premature release of the active substances from the dosage forms. The cracks formed on the tablet surface during the stability conditions cause the active substances to be released from the tablet in the acid environment, where the release of the active substance is not expected. In other words the tablets are not stable with respect to dissolution. This creates problematic situations as the expected release profiles cannot be achieved in in-vitro dissolution tests of the tablet. However, there is no prior art references dealing with problems about cracking formed in tablets and consequently effects on specific release of active substance during storage under stability conditions. The oral formulations disclosed in the prior art demand further improvements in light of the heat and moisture sensitive nature of tablets. Therefore, there is a need to develop formulation for preparing a stable combination of doxylamine succinate and pyridoxine hydrochloride delayed release tablet formulations with tablets that do not undergo cracking due to high temperature and moisture absorption and therefore provide excellent storage stability.

The present invention addresses this problem and provides a solution thereto. In this way, the present inventors have developed a disintegrant free oral tablet composition comprising doxylamine succinate and pyridoxine hydrochloride having a dissolution profile that is unaffected by the dissolution properties of the dosage form even by stability conditions.

Description of the Invention:

The present invention relates to develop a disintegrant-free tablet formulation which is less affected by unfavorable storage conditions and a method for producing the tablet.

The main object of the present invention is to develop a disintegrant-free delayed release tablet formulation comprising doxylamine succinate and pyridoxine hydrochloride that has desired stability with respect to dissolution behaviour.

The other object of the present invention is to develop a stabilized disintegrant-free formulation of doxylamine succinate and pyridoxine hydrochloride, possessing marked improvement in cracking formation over shelf life employing usage of a specific ratio of mannitol to dibasic calcium phosphate, which overcomes the drawbacks of processes recited in prior arts.

The present invention relates to produce disintegrant-free doxylamine succinate and pyridoxine hydrochloride enteric coated tablet composition maintaining specific in-vitro dissolution profiles along the stability conditions to provide desired site of release of therapeutically effective amount of therapeutic agents in the gastrointestinal track by using a certain ratio of mannitol to dibasic calcium phosphate in the formulation which overcomes the drawbacks of cracks formed in tablets.

The present invention provides a stabilized disintegrant-free doxylamine succinate and pyridoxine HCI delayed release formulation and a manufacturing process by using a specific ratio of mannitol to dibasic calcium phosphate with direct compression. According to an embodiment, the disintegrant free pharmaceutical delayed release composition comprising doxylamine and pyridoxine or pharmaceutically acceptable salts thereof, comprises mannitol and dibasic calcium phosphate in a weight ratio of between 3:1 and 1:3.

According to another embodiment, the disintegrant free pharmaceutical delayed release composition comprising doxylamine and pyridoxine or pharmaceutically acceptable salts thereof, comprises mannitol and dibasic calcium phosphate in a weight ratio of 3: 1 or less, in a weight ratio of 2: 1 or less, in a weight ratio of 1 : 1 or less, in a weight ratio of 1:2 or less, in a weight ratio of 1:3.

The present invention provides the action of two unrelated compounds. Doxylamine succinate (an antihistamine) and pyridoxine hydrochloride (vitamin B6) provide anti- nauseant and anti-emetic activity. The delayed action of the composition permits the night-time dose to be effective in the morning hours, when the patient needs it most. The Cmax of doxylamine and pyridoxine are achieved within 7.5 and 5.5 hours, respectively.

One problem of doxylamine succinate is its high hygroscopicity (tending to absorb moisture), which can lead to the need for special manufacturing conditions or the difficulty of maintaining the properties of dosage forms over a long period of time. Doxylamine succinate also suffers from the disadvantage of having incompatibility with some pharmaceutical excipients, resulting in degradation and increased impurities in the pharmaceutical preparation containing them. For these reasons, the development of oral formulations containing doxylamine succinate can be considered challenging.

Pyridoxine and its hydrochloride salt are known to be very unstable to heat and light. Therefore, it is desired to provide compositions comprising pyridoxine hydrochloride with improved stability.

Enteric coatings have been used for many years to arrest the release of the drug from orally ingestible dosage forms. Depending upon the composition and/or thickness, the enteric coatings are resistant for required periods of time before release of the therapeutic agents to the lower part of the gastrointestinal track, especially the large intestine or the colon.

Thus, the oral formulations disclosed in the prior art demand further improvements in light of the heat and moisture sensitive nature of tablets. Also, improved stable oral formulations were yet desired to overcome the tendency of doxylamine succinate and pyridoxine hydrochloride enteric coated tablet to undesirably exhibit cracking in tablet formulations along with the above-mentioned limitations. The problems have been suggested that cracks in the coating may occur during storage conditions. These coating fractures may cause unreliable or inconsistent release of the therapeutic agent to the desired region of the gastrointestinal tract.

The term "active ingredient" or "active pharmaceutical ingredient" means any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or other animals. In the present invention, the active ingredients are doxylamine and pyridoxine or their pharmaceutically acceptable salts, esters, and solvates thereof. Especially, in the present invention the active ingredients are doxylamine succinate and pyridoxine hydrochloride.

The term “therapeutically effective amount” refers to the amount of either doxylamine and pyridoxine or salts thereof, or the combination, that is an amount sufficient to effect treatment, as defined herein, when administered to a subject in need of such treatment.

The term "disintegrant free pharmaceutical composition" refers to the pharmaceutical composition of doxylamine succinate and pyridoxine hydrochloride, which does not contain any disintegrant.

The term "delayed release pharmaceutical composition" refers to an oral pharmaceutical composition containing enteric coating which acts to resist the release of active substances in the low pH of gastric fluid, however, it allows rapid release of drug in the higher pH of the duodenum. Delayed-release pharmaceutical composition works optimally when given 4 to 6 hours prior to anticipated onset of symptoms. By this way, the active ingredients of doxylamine succinate and pyridoxine hydrochloride release at a time later than that immediately following its administration and provides plasma concentrations of the active ingredients with time within the therapeutic range of the active ingredient over a period and encompasses "prolonged release", "extended release", "modified release", "delayed release" and "sustained release" compositions.

The term "enteric coating" refers to 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 human gastric fluids, but more rapidly in human intestinal fluids. Enteric coatings consist of pH sensitive polymers, which mean the coating remains intact in the acidic environment of the stomach and then solubilizes in the more alkaline environment of the small intestine. Enteric protection for solid oral dosage forms is required to prevent gastric mucosal irritation, to protect a drug which is unstable in gastric fluids or to delay release for local release in the intestine.

The term 'stable' as used herein means the enteric coated tablet maintaining its physical and chemical properties when stored. Especially, the tablets release the therapeutically effective amounts of active ingredients doxylamine succinate and pyridoxine HCI into specific release region after production (To, initially) and during the storage conditons throughout the shelf life. When a dosage form design includes an enteric coat, the dissolution test will include two stages: an acid stage to demonstrate the integrity of the enteric coat, and a drug release phase at a higher pH. The amount released in the acid stage is commonly limited to 10% or less of the labeled content. Especially the products entail FDA dissolution methods for Doxylamine succinate/ pyridoxine HCI Extended Release Tablet. The proposed FDA dissolution method for enteric tablets requires that the product withstand agitation (paddle at 100 rpm) in the artificial gastric fluid (0.1 N hydrochloric acid, 1000 mL) at 37°C ±0.5°C, releasing less than 10% doxylamine succinate and pyridoxine hydroxide within 2 hours (120 minutes), while dissolving in paddle at 100 rpm within 30 minutes at 37°C ±0.5°C with a 0.2 M sodium phosphate buffer of pH 6.8 (1000 mL). The critical situation during dissolution is to ensure that the delayed release feature of the drug remains undissolved in the acid environment post-production and throughout the stability process. This is also considered as dissolution stability as well. The stability of the products can be determined by in-vitro dissolution studies of real time studies or during storage conditions.

The formulation of the present invention contains a core coated with an enteric coating. The core comprises the active ingredients doxylamine succinate and pyridoxine hydrochloride along with non-active excipients such as a diluent/ filler, a binder, a lubricant, and other pharmaceutically acceptable non-therapeutic agents.

The diluent/ filler employed in a composition of the present invention may be one or more compounds which are capable of providing compactibility and good flow. Suitable diluents/ fillers include, but are not limited to, lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (e.g. microcrystalline cellulose), dihydrated or anhydrous dibasic calcium phosphate, calcium carbonate, calcium sulfate, and others as known in the art. In the present invention, mannitol and dibasic calcium phosphate are preferred.

Binders are used to impart cohesive qualities to a tablet formulation, and thus ensure that a tablet remains intact after compaction. Suitable binder materials include, but are not limited to, microcrystalline cellulose, gelatin, sugars (including sucrose, glucose, dextrose and maltodextrin), polyethylene glycol, waxes, natural and synthetic gums, polyvinylpyrrolidone, cellulosic polymers (including hydroxypropyl cellulose, hydroxypropyl methylcellulose, methyl cellulose, hydroxyethyl cellulose, and the like). In the present invention, hydroxypropyl methylcellulose is preferred.

Lubricants can be employed herein in the manufacture of certain dosage forms, and will usually be employed when producing tablets. In the present invention, a lubricant is added just before the tableting step, and is mixed with the formulation for a minimum period of time to obtain good dispersal. Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, aluminum stearate, talc, glyceryl behenate, polyethylene glycol, polyethylene oxide polymers, leucine and others as known in the art. In the present invention, magnesium stearate is preferred.

The following examples represent various embodiments of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

Example 1. Production Methods

In the formulation, the reference product produced by Duchesnay Inc. under the trademark Diclectin® was referenced. The formulation development studies started with the investigation of the physical properties, chemical properties, solubility and pharmacokinetic properties of the active ingredients, and enteric coating was applied to formulate doxylamine succinate and pyridoxine hydrochloride in such a way that it would be opened in the jejunum and ileum part of the gastrointestinal tract, where the active ingredients are absorbed.

Especially in order to prevent moisture sensitivity of active ingredients and cracks on the tablet due to moisture, direct mixing method was preferred and mannitol and dibasic calcium phosphate were used as filler-diluent. After the completion of the formulation development of the core tablets, the selection of suitable coating agents for film coating and enteric coating, coating at appropriate rates and determination of the coating process parameters, the finished product was formed.

The present invention provides a disintegrant-free delayed release pharmaceutical composition for oral administration comprising: (a) doxylamine succinate and pyridoxine hydroxide as the active pharmaceutical ingredients, (b) mannitol and dibasic calcium phosphate dihydrate as the diluent/ filler, (c) hydroxypropyl methyl cellulose as a binder, (d) magnesium stearate as a lubricant, (e) one or more film coatings and enteric coating. The excipients included in the composition are defined in international pharmacopoeias and their use in pharmaceutical products has been accepted.

The tablet composition according to present invention comprises about 1 to 10 wt.% of doxylamine succinate; about 1 to 10 wt.% of pyridoxine hydrochloride; about 20 to 68 wt.% of dibasic calcium phosphate; about 20 to 68 wt.% of mannitol; about 1 to 5 wt.% of hydroxypropylmethyl cellulose; about 0.2 to 2 wt.% magnesium stearate; and one or more film coatings and enteric coatings.

In the present invention, the process is direct compression and comprises the following steps: a) mixing doxylamine succinate, pyridoxine hydrochloride, hydroxypropylmethyl cellulose, and mannitol in a suitable blender; b) mixing the prepared mixture in a cubic mixer, c) adding magnesium stearate to prepared mixture (b) and mix, d) compressing obtained blend in step (c) using rotary tablet press, e) coating the tablets (d) with one or more film coatings and enteric coatings.

Table 1 lists six formulations (containing equivalent levels of active substances, binder and lubricant) that showing the effect of the used weight ratio of mannitol and dibasic calcium phosphate on the long term stability results of obtained enteric coated tablets. Table 1. Different weight ratio formulations tested for stability

Example 2. Dissolution Profiles

Comparative dissolution tests were conducted based on proposed FDA dissolution methods for doxylamine succinate/ pyridoxine hydrochloride extended release tablet. The proposed FDA dissolution method for enteric tablets requires that the product withstand agitation (paddle at 100 rpm) in the artificial gastric fluid (0.1 N hydrochloric acid, 1000 mL) at 37°C ±0.5°C, releasing less than 10% doxylamine succinate and pyridoxine hydroxide within 2 hours (120 minutes), while dissolving in paddle at 100 rpm within 30 minutes at 37°C ±0.5°C with a 0.2 M sodium phosphate buffer of pH 6.8 (1000 mL). The above exemplified compositions (Formulation 1-6) comprising doxylamine succinate and pyridoxine HCI were tested in vitro and they were compared with a commercial reference product Diclectin®.

As a result of dissolution analysis studies performed in pH 1.2 medium for 2 hours, no release of doxylamine succinate and pyridoxine hydrochloride were observed both in test products and reference product as expected from enteric tablets. Therefore, the comparative f2 results (Table 2) belong to pH 6.8 medium followed by 2 hours pH 1.2 medium.

Table 2. The comparative dissolution f2 results of test products (Formulation 1-6) with reference products Diclectin® at pH 6.8 medium followed by 2 hours pH 1.2 medium.

Doxylamine Pyridoxine

Formulation 1 f2: 63 f2: 60

Formulation 2 f2: 70 f2: 63

Formulation 3 f2: 75 f2: 71

Formulation 4 f2: 83 f2: 81

Formulation 5 f2: 66 f2: 75

Formulation 6 f2: 74 f2: 73 Example 3. Stability Studies

The stability of a drug substance is an important factor in the manufacture of safe and effective pharmaceutical products. Stability studies are required to be submitted by any applicant seeking approval for a new pharmaceutical product. Stability study requirements are covered, for example in the United States Pharmacopea, in the Good Manufacturing Practices (GMP) as well as in FDA and ICH Guidelines. Stability issues can be caused by environmental factors such as humidity, temperature and the like. The physical and chemical stability may be tested in conventional manner, e.g. the doxylamine succinate - pyridoxine hydrochloride delayed release tablets may be tested as such by measurement of dissolution and assay for active substances, degradation products, and appearance.

Physical stability means that the formulation is totally unchanged throughout its shelflife and has not suffered any changes by way of appearance, organoleptic properties (color, odor and taste), hardness, brittleness, particle size etc. Also, physical stability affects pharmaceutical elegance, drug content uniformity and drug release rate. The general appearance of a tablet, its visual identity and overall elegance is essential for consumer acceptance and lot-to-lot uniformity, general tablet-to-tablet uniformity, and for monitoring trouble free manufacturing. The control of general appearance of tablets involves the measurements of a number of tablet’s size, shape, color, presence or absence of an odor, taste, surface texture, physical flaws and consistency, and legibility of any identifying markings.

Studies on the stability of and under which conditions doxylamine succinate and pyridoxine hydrochloride molecules undergo degradation are present in the literature and in these, both active substances are said to decompose to some degradation products when exposed to heat, light or oxidation. In particular, pyridoxine hydrochloride is shown to be a highly sensitive molecule as it undergoes degradation up to 30% when exposed to oxidation, heat or light.

In order to examine the physical and chemical stability of the products, stability studies were conducted under the guideline of ICH Q1A (R2) stability testing of new drug substances and drug products assessed at different conditions (40°C±2°C & 75%±5% Relative humidity, 30°C±2°C & 65%±5% RH, 25°C±2°C & 60±5%).

In the accelerated condition stability (40°C±2°C, 75% RH), according to the study results of the reference product it was observed that the degradation product of the pyridoxine hydrochloride active substance increased significantly and cracks formed in the tablets. These results describe the physical and chemical unstability of the reference product at high temperature.

Short term comparative stability data of the compositions of the present invention (Formulation 1 - 6) at high temperature are given in Table 3.

Table 3. Comparative stability results

After 3 months at 40C stability condition

Dissolution

Product Appearance

Acid stage Buffer stage

Formulation 1 Cracks occurred Not suitable X*

Formulation 2 Suitable/ No crack Suitable Suitable

Formulation 3 Suitable/ No crack Suitable Suitable

Formulation 4 Suitable/ No crack Suitable Suitable

Formulation 5 Suitable/ No crack Suitable Suitable

Formulation 6 Suitable/ No crack Suitable Suitable

*Since the tablets showed high release in acid medium, dissolution study in base medium was not carried out.

Influence on dissolution stability of the proposed invention was showed in Table 2. In vitro dissolution test is generally applicable in order to test whether the composition is stable with respect to dissolution profile. From the results given in the Table 3, it shows the relationships between the ratio of mannitol and dibasic calcim phosphate with crack formation and consequently the in vitro dissolution after stability conditions.

According to the results obtained in the accelerated condition studies, Formulation 4 was selected for further studies. The comparative in-vitro dissoluton profile of the present invention (Formulation 4) and reference product (Diclectin®) was given at Figure 1 which belongs to pH 6.8 medium followed by 2 hours pH 1.2 medium (no release of doxylamine succinate and pyridoxine hydrochloride were observed in pH 1.2 medium for 2 hours). Long-term stability tests were performed on Formulation 4 and the results were given at Table 4. Table 4. Long term Stability results of Formulation 4

After After After

Specification 3 months 12 months 36 months at 40C at 30C at 25C

Appearance No cracks should be Suitable Suitable Suitable occurred.

Should be between D:101.0% D: 98.3% D: 98.8%

Assay y 95.0% - 105.0% P: 99.2% P: 102.5% P: 97.0%

Acid medium:

Max. 10% release D: 0% D: 0% D: 0% after 120 minutes

°%

Dissolution

Buffer medium:

Min. 75% release D: 89% D: 100% D: 97% after 30 minutes P: 88% P:97% P: 96%

*D for Doxylamine & P for Pyridoxine

Example 4. Bioequivalence study

As per USFDA guideline titled "Bioavailability and Bioequivalence Studies for Orally Administered Drug Products — General Considerations" Bioequivalence is defined as: "the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study."

The tablets produced with the present invention (Formulation 4) have been found to be bioequivalent to reference product Diclectin® with the bioequivalence study conducted in normal, healthy, adult, female subjects under fasting condition.

FIGURES:

Figure 1. In-vitro dissolution profiles of Test product - Formulation 4 (Doxylamine succinate and Pyridoxine hydrochloride Delayed Release Tablet) and reference product (Diclectin®) performed in pH 6.8 medium followed by 2 hours pH 1.2 medium (no release of doxylamine succinate and pyridoxine hydrochloride were observed in pH 1.2 medium for 2 hours); a) for Doxylamine and b) for Pyridoxine.

Claims

1. A pharmaceutical delayed release composition comprising doxylamine and pyridoxine or pharmaceutically acceptable salts thereof, wherein said composition is free of disintegrant and comprising mannitol and dibasic calcium phosphate in a weight ratio of between 3:1 and 1 : 3.

2. The pharmaceutical composition according to claim 1 , wherein said composition comprises mannitol and dibasic calcium phosphate in a weight ratio of 3:1 or less.

3. The pharmaceutical composition according to claim 1 , wherein said composition comprises mannitol and dibasic calcium phosphate in a weight ratio of 2:1 or less.

4. The pharmaceutical composition according to claim 1 , wherein said composition comprises mannitol and dibasic calcium phosphate in a weight ratio of 1:1 or less.

5. The pharmaceutical composition according to claim 1 , wherein said composition comprises mannitol and dibasic calcium phosphate in a weight ratio of 1:2 or less.

6. The pharmaceutical composition according to claim 1 , wherein said composition comprises mannitol and dibasic calcium phosphate in a weight ratio of 1:3.

7. The pharmaceutical composition according to claim 1, wherein said composition comprises doxylamine succinate.

8. The pharmaceutical composition according to claim 1 , wherein said composition comprises pyridoxine hydrochloride.

9. The pharmaceutical composition according to claim 1, wherein said composition is prepared by direct compression.

10. The pharmaceutical composition according to claim 1 , wherein said composition comprises a tablet core with an enteric coating.

11. The pharmaceutical composition according to claim 1 , wherein said composition comprises tablet core having active ingredients and a diluent/ filler, a binder, a lubricant, and other pharmaceutically acceptable non-therapeutic agents.

12. The pharmaceutical composition according to claim 11 , wherein said composition comprises mannitol and dibasic calcium phosphate dihydrate as the diluent/ filler.

13. The pharmaceutical composition according to claim 12, wherein said composition comprises 20 to 68 wt.% of dibasic calcium phosphate; and 20 to 68 wt.% of mannitol.

14. The pharmaceutical composition according to claim 11 , wherein said composition comprises hydroxypropyl methyl cellulose as a binder.

15. The pharmaceutical composition according to claim 11 , wherein said composition comprises magnesium stearate as a lubricant.

16. The pharmaceutical composition according to claim 11 , wherein said composition is prepared by the following steps: a) mix doxylamine succinate, pyridoxine HCI, hydroxypropylmethyl cellulose, and mannitol in a suitable blender; b) mix the prepared mixture in a cubic mixer, c) add magnesium stearate to prepared mixture (b) and mix, d) compress obtained blend in step (c) using rotary tablet press, e) coat the tablets obtained in step (d) with one or more film coatings and enteric coatings.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein said composition is used for the treatment of nausea and vomiting during pregnancy.