DESC:FORM 2

THE PATENTS ACT, 1970
(SECTION 39 OF 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(SECTION 10 and RULE 13)

EXTENDED RELEASE COMPOSITION AND ITS PROCESS FOR THE PREPARATION

We, MANEESH PHARMACEUTICALS LTD,
an Indian company incorporated under Companies Act of 1956, having its registered office at Plot No. 29-33, Ancillary Industrial Plots, Govandi West, Mumbai - 400 043, Maharashtra, India.

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention also relates to an extended release single layer matrix tablet composition of doxylamine succinate and pyridoxine hydrochloride comprising immediate release blend and delayed release granules.

The present invention also relates to an extended release single layer matrix tablet composition of doxylamine succinate and pyridoxine hydrochloride comprising immediate release blend and delayed release granules, wherein immediate release portion does not involve granulation.

The present invention more specifically relates to method for the preparation of extended release single layer matrix tablet composition comprising steps of sifting, direct mixing, granulating, blending, compression and film coating.

The present invention more specifically relates to an extended release single layer matrix tablet composition of doxylamine succinate and pyridoxine hydrochloride comprising immediate release blend and delayed release granules, prepared by a process comprising steps of sifting, direct mixing, granulating, blending, compression and film coating.

BACKGROUND OF THE INVENTION
Extended release solid compositions can be in the form of tablets or capsules, wherein the release of the active ingredient is controlled by using a reservoir or a matrix system. However, extended release solid compositions suffer from certain drawbacks such as maintaining therapeutic window and bioavailability of the active medicament for 24 hours. Many of technologies have developed and being used to provide the more bioavailability of the active medicament, still facing certain problems maintaining bioavailability of the active medicament particularly for certain groups of patients, especially pregnant woman.

Pregnant women often require flexibility of dosage regimen and also requires more bioavailability by providing immediate release and extended release of medicament upto 24 hours in order to reduce frequency of taking tablets for morning sickness.

Nausea and vomiting of pregnancy, commonly known as “morning sickness,” affects approximately 80 percent of pregnant women. Nausea and vomiting in pregnancy (NVP) is common and often undertreated, in part due to fears of adverse effects of medications on the fetus during early pregnancy. The combination of doxylamine succinate and pyridoxine hydrochloride is used to treat nausea and vomiting in pregnant women whose symptoms have not improved after changing their diet or using other non-medicine treatments. Doxylamine succinate is in a class of medications called antihistamines. It works by blocking the action of certain natural substances in the body that may contribute to nausea and vomiting. Pyridoxine (vitamin B6) is a vitamin. It is given because a lack of pyridoxine in the body may also be a factor in causing nausea and vomiting during pregnancy.

Doxylamine Succinate:
Doxylamine is a first-generation antihistamine and is a potent anticholinergic agent first reported in 1949 as sleep aid with weak hypnotic and calming effects. Doxylamine acts primarily as an antagonist or inverse agonist of the histamine H1 receptor. This action is responsible for its antihistamine and sedative properties. To a lesser extent, doxylamine acts as an antagonist of the muscarinic acetylcholine receptors, an action responsible for its minor hypnotic, anticholinergic, and (at high doses) deliriant effects. Doxylamine in its succinic acid salt form in combination with vitamin B6 (pyridoxine) used to prevent morning sickness in pregnant women.

Doxylamine succinate is chemically, ethanamine, N,N-dimethyl-2-[1-phenyl-1-(2-pyridinyl)ethoxy]-, butanedioate (1:1). The empirical formula is C17H22N2O• C4H6O4 and the molecular mass is 388.46 g/mol, the structural formula is:

Doxylamine succinate is a white to creamy white powder, is an antihistamine with sedative and hypnotic properties. It is very soluble in water and alcohol, freely soluble in chloroform and very slightly soluble in ether and benzene.

Pyridoxine Hydrochloride:
Pyridoxine (also called pyridoxol) is one form of vitamin B6. Its hydrochloride salt, pyridoxine hydrochloride, is used as a vitamin B6 dietary supplement.

Pyridoxine hydrochloride is a vitamin B6 analog. The chemical name for pyridoxine hydrochloride is 5-hydroxy-6-methyl-3,4­pyridinedimethanol, hydrochloride. The empirical formula is C8H11NO3•HCl and the molecular mass is 205.64 g/mol and the structural formula is:

Pyridoxine HCl is a white or practically white crystalline powder or crystals. Pyridoxine HCl is freely soluble in water, slightly soluble in alcohol and insoluble in ether. Pyridoxine is one of the compounds analog with pyridoxal and pyridoxamine that are referred to as vitamin B6. Pyridoxine HCl is used in oral vitamin supplements and injectable vitamin formulation products.

The present invention is an improvement over the prior art in that it delivers doxylamine succinate and pyridoxine hydrochloride extended release tablet composition as a single layer for the treatment of nausea and vomiting.

US Pat No. 6,340,695 B1 discloses the formulation comprising combination of doxylamine succinate and pyridoxine HCl, preferably in the form of an enterically coated tablet, a medicament comprising synergistic duo of active ingredients is useful in the treatment of nausea and vomiting, during pregnancy “NVP”, wherein the “rapid onset” formulation comprising the following non-active excipients: a filler or binder, a disintegrating agent, a lubricant, a silica flow conditioner and a stabilizing agent, wherein the formulation exhibiting a dissolution profile indicative of a rapid onset.

US Pat No. 9,089,489 B2 discloses the dual release oral dosage system comprising doxylamine or analog, derivative, prodrug, metabolite and salt thereof and pyridoxine or analog, derivative, prodrug, metabolite and salt thereof, wherein said dual release oral dosage system comprising an immediate release component and delayed release component contains one or more coating layers, wherein immediate release granules preparation involves granulation.

US Pub. No. 2014/0335176 A1 discloses the disintegrant-free delayed release doxylamine succinate and pyridoxine HCl formulation and a manufacturing process by using direct compression or dry granulation.

The combination of doxylamine succinate and pyridoxine hydrochloride available as a delayed-release tablet (releases the medication in the intestine to delay when the medication will start working) and as an extended-release (long-acting) tablet for oral use. It is usually taken on an empty stomach (at least 1 hour before or 2 hours after a meal). At first, tablet to be taken once a day at bedtime. If the symptoms of nausea and vomiting are not better, then the delayed-release tablets two or three times a day, or the extended-release tablet two times a day are prescribed.

All the prior art references discloses the doxylamine succinate and pyridoxine hydrochloride extended release single layer matrix tablets comprising immediate release granules and delayed release granules, wherein immediate release granules involve granulation step. None of the prior art references uses extended release single layer matrix tablets comprising immediate release blend involves direct mixing. Hence, inventors of the present invention provides extended release single layer matrix tablet composition of doxylamine succinate and pyridoxine hydrochloride comprising immediate release blend and delayed release granules as a single layer tablet.

OBJECTIVE OF INVENTION
One objective of the present invention is to provide an extended release single layer matrix tablet composition of doxylamine succinate and pyridoxine hydrochloride comprising immediate release blend and delayed release granules.

Another objective of the present invention is to provide an extended release single layer matrix tablet composition of doxylamine succinate and pyridoxine hydrochloride comprising immediate release blend and delayed release granules, wherein immediate release portion does not involve granulation, and prepared by direct mixing and composition further, comprises pharmaceutically acceptable excipients.

Another objective of the present invention is to provide a method for the preparation of extended release single layer matrix tablet composition comprising steps of sifting, direct mixing, granulating, blending, compression and film coating.

Another objective of the present invention is to provide extended release single layer matrix tablet composition of doxylamine succinate and pyridoxine hydrochloride comprising immediate release blend and delayed release granules, prepared by a process comprising steps of sifting, direct mixing, granulating, blending, compression and film coating.
SUMMARY OF INVENTION
One embodiment of the present invention relates to an extended release single layer matrix tablet composition of doxylamine succinate and pyridoxine hydrochloride comprising immediate release blend and delayed release granules.

Another embodiment of the present invention relates to an extended release single layer matrix tablet composition of doxylamine succinate and pyridoxine hydrochloride comprising immediate release blend and delayed release granules, wherein immediate release portion is prepared by direct mixing and said composition further comprises pharmaceutically acceptable excipients.

Another embodiment of the present invention relates to an extended release single layer matrix tablet composition of doxylamine succinate and pyridoxine hydrochloride, wherein said composition further comprising granulating agent/enteric coating agent, antacid, disintegrants, diluents/fillers, glidant, lubricant, coating agent and other pharmaceutically acceptable excipients.

Another embodiment of the present invention relates to an extended release single layer matrix tablet composition comprising;
0.1% to 10% (w/w) of first active ingredient,
0.1% to 10% (w/w) of second active ingredient,
0.5% to 2.5% (w/w) of disintegrant,
0.5% to 5% (w/w) of glidant,
1% to 10 (w/w) of antacid,
0.5% to 3% (w/w) of lubricant,
35% to 65% (w/w) of diluent or filler,
1% to 10% (w/w) of granulating agent/enteric coating agent,
0.1% to 5% (w/w) of coating agent and
0.01% to 5% other pharmaceutically acceptable excipients.

Another embodiment of the present invention relates to an extended release single layer matrix tablet composition comprising;
0.1% to 10% (w/w) of doxylamine or its salt,
0.1% to 10% (w/w) of pyridoxine or its salt,
0.5% to 2.5% (w/w) of croscarmellose sodium,
0.5% to 5% (w/w) of silicon dioxide and
1% to 10 (w/w) magnesium trisilicate,
0.5% to 3% (w/w) of magnesium stearate,
35% to 65% (w/w) of microcrystalline cellulose and lactose monohydrate,
1% to 10% (w/w) of Acryl-Eze Aqueous Acrylic Enteric System White,
0.1% to 5% (w/w) of OPADRY Pink 85F94320, and
0.01% to 5% other pharmaceutically acceptable excipients.

Another embodiment of the present invention relates to a process for preparing extended release single layer matrix tablet composition, wherein said process comprising steps of;
1) preparing immediate release blend comprising;
(a) co-sifting of doxylamine succinate and silicon dioxide through the sieve,
(b) co-sifting of Pyridoxine HCl with the blend obtained from step a),
(c) sifting lactose monohydrate and microcrystalline cellulose through suitable sieve separately,
(d) adding sifted materials in conta blender in the following order of half quantity of materials obtained from step (c), step (b) material and remaining quantity of step (c) materials, blending for 30 minutes,
(e) sifting of croscarmellose sodium and magnesium trisilicate separately through suitable sieve, adding and blending with step (d) blended materials in conta blender for 10 minutes,
2) preparing delayed release granules comprising;
(f) co-sifting of doxylamine succinate and silicon dioxide through the sieve,
(g) co-sifting of Pyridoxine HCl with the blend obtained from step f),
(h) sifting lactose monohydrate and microcrystalline cellulose through suitable sieve separately,
(i) adding sifted materials in rapid mixer granulator/ fluidized bed processor in the following order of half quantity of materials obtained from step (h), step (g) material and remaining quantity of step (h) materials, mixing for 10 minutes,
(j) stirring purified water in mechanical stirrer by adding small quantities of Acryl-Eze aqueous enteric coating system upto 20 minutes,
(k) granulating step (i) with step (j) enteric coating solution,
(l) drying and sifting the dried granules through suitable sieve,
3) blending and compressing of immediate release blend and delayed release granules comprising;
(m) adding Blend I and Blend II into blender, mixing for 15 minutes,
(n) sifting Magnesium stearate though suitable sieve and lubricating the step (m) blend in Conta blender for 5 minutes,
(o) compressing the obtained blend from step (n) and film coating with the Opadry Pink to obtain extended release single layer matrix tablet.

DETAILED DESCRIPTION OF THE INVENTION
The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

The “active ingredients” used in the present invention can be used as pharmaceutically acceptable salts.

The pharmaceutically acceptable salts used in the present invention are doxylamine in its succinate salt form as first active ingredient and pyridoxine in its hydrochloride salt form as second active ingredient.
In a preferred embodiment, the extended release single layer tablet composition of the invention comprises first active ingredient is doxylamine succinate. The concentration of doxylamine succinate used in the extended release single layer matrix tablet composition of the invention is from 0.1% to 10%.

In a preferred embodiment, the extended release single layer tablet composition of the invention comprises second active ingredient is pyridoxine hydrochloride. The concentration of pyridoxine hydrochloride used in the solid oral composition of the invention is from 0.1% to 10%.

Another embodiment of the present invention relates to an extended release single layer matrix tablet composition of doxylamine succinate and pyridoxine hydrochloride comprising immediate release blend and delayed release granules, wherein said immediate release blend comprising antacid, disintegrants, diluents/fillers, glidant and lubricant.

Another embodiment of the present invention relates to an extended release single layer matrix tablet composition of doxylamine succinate and pyridoxine hydrochloride comprising immediate release blend and delayed release granules, wherein said delayed release granules comprising granulating agent/enteric coating agent, diluents/fillers, glidant, lubricant and other pharmaceutically acceptable excipients.

The extended release single layer matrix tablet composition according to the present invention comprise granulating agent/enteric coating agent which includes acacia, alginic acid, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, Acryl-Eze Aqueous Acrylic Enteric System White, pregelatinized starch, calcium sulfate, amylose, glycine, bentonite, ethylcellulose, disodium pyrosulfite, polyvinyl alcohol, gelatin, glucose, guar gum, magnesium aluminum silicate, maltodextrin, polyethylene oxide, polymethacrylates, povidone, sodium alginate, tragacanth, maize starch and zein. Preferably, the granulating agent/enteric coating agent used in the extended release single layer matrix tablet composition is Acryl-Eze Aqueous Acrylic Enteric System White.

The concentration of granulating agent/enteric coating agent used in the extended release single layer matrix tablet composition of present invention is from 1% to 10% (w/w) of total weight of the composition.

The extended release single layer matrix tablet composition according to the present invention comprise antacid which includes magnesium trisilicate, calcium carbonate, sodium bicarbonate, magnesium hydroxide, aluminum hydroxide, magnesium oxide, magnesium carbonate, aluminum phosphate, magaldrate. Preferably, the antacid used in the extended release single layer matrix tablet composition is magnesium trisilicate.

The concentration of antacid used in the extended release single layer matrix tablet composition of present invention is from 1% to 10% (w/w) of total weight of the composition.

The extended release single layer matrix tablet composition according to the present invention comprise disintegrants which includes croscarmellose sodium, alginic acid, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropylcellulose (low substituted), microcrystalline cellulose, powdered cellulose, crospovidone, methylcellulose, polacrilin potassium, sodium alginate, sodium starch glycolate, starch, disodium disulfite, disodium edathamil, disodium edetate, disodiumethylenediaminetetraacetate (EDTA) crosslinked polyvinylpyrollidines, pregelatinized starch, carboxymethyl starch, sodium carboxymethyl starch, microcrystalline cellulose. Preferably, the disintegrant used in the extended release single layer matrix tablet composition is croscarmelose sodium.
The concentration of disintegrant used in the extended release single layer matrix tablet composition of present invention is from 0.5% to 2.5% (w/w) of total weight of the composition.

The extended release single layer matrix tablet composition according to the present invention comprise diluent/filler which includes cellulose or derivatives, modified cellulose, sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, cellulose acetate, hydroxypropylcellulose, lactose monohydrate, microcrystalline cellulose, dibasic calcium phosphate, sucrose, corn starch, potato starch and combinations thereof. Preferably, the diluent or filler used in the extended release single layer matrix tablet composition are lactose monohydrate and microcrystalline cellulose.

The concentration of diluent or filler used in the extended release single layer matrix tablet composition of present invention is from 35% to 65% (w/w) of total weight of the composition.

The extended release single layer matrix tablet composition according to the present invention comprise glidants which includes include silicon dioxide, calcium stearate, magnesium oxide, magnesium stearate, mineral oil, poloxamer, polyethylene glycol, sodium lauryl sulfate, sodium stearate fumarate, stearic acid, talc and, zinc stearate, glyceryl behanate, magnesium lauryl sulfate, boric acid, sodium benzoate, sodium acetate, combination of sodium benzoate and sodium acetate. Preferably, the glidant used in the extended release single layer matrix tablet composition are silicon dioxide.

The concentration of glidants used in the extended release single layer matrix tablet composition of present invention is from 0.5% to 5% (w/w) of total weight of the composition.

The extended release single layer matrix tablet composition according to the present invention comprise lubricant which include magnesium oxide, grades of magnesium stearate, calcium stearate, hydrogenated castor oil, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate. Preferably, the lubricant used in the extended release single layer matrix tablet composition is grades of magnesium stearate.

The concentration of lubricant used in the extended release single layer matrix tablet composition of present invention is from 0.5% to 3% (w/w) of total weight of the composition.

The extended release single layer matrix tablet composition according to the present invention comprise coating agent which includes polyvinyl acetate polymer, OPADRY Pink 85F94320, acrylic resin, polymers or coplymers of acrylic acid, methyl acrylate, ethyl acrylate, methacrylic acid, methyl methacrylate, ethyl methacrylate and the like which may contain quaternary ammonium groups such as ammonio (meth)acrylate copolymers. Preferred examples are copolymers of ethyl acrylate, methyl methacrylate and trimethylammonioethyl methacrylate chloride. Such an acrylic polymer is available under the name Eudragit RS which is a water-insoluble copolymer (poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1, manufactured by Rh6m Pharma, Germany) e.g. in form of organic-based polymeric solutions or aqueous-based polymeric dispersions thereof which may be used for coating, for example Eudragit RS 30D. Another acrylic polymer may be Eudragit RL which consists of the same components as Eudragit RS but has a different molar ratio (Eudragit RL: poly(ethylacrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride; 1:2:0.2) e.g. in form of organic-based polymeric solutions or aqueous-based polymeric dispersions thereof, for example Eudragit RL 30D. Preferably, the coating agent used in the extended release single layer matrix tablet composition is OPADRY Pink 85F94320.

The concentration of coating agent used in the extended release single layer matrix tablet composition of present invention is from 0.1% to 5% (w/w) of total weight of the composition.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Example 1
Sr.No. Ingredients mg/Tablet
Blend I (Immediate Release Blend)
1 Doxylamine Succinate 10
2 Pyridoxine HCl 10
3 Lactose Monohydrate (DC) 15.1
4 Microcrystalline cellulose (Avicel PH 102) 74.9
5 Croscarmellose Sodium 3.6
6 Magnesium Trisilicate 26.4
7 Silicon dioxide 1
Blend I weight 141
Blend II (Delayed Release Granules)
1 Doxylamine Succinate 10
2 Pyridoxine HCl 10
3 Lactose Monohydrate 15
4 Microcrystalline cellulose (Avicel PH 101) 46
5 Silicon dioxide 1

Granulation
6 Acryl-Eze Aqueous Acrylic Enteric System 16
93O18509 White
7 Purified Water q.s
Blend II weight 98
Final Lubrication
8 Magnesium Stearate 6
Final Tablet weight (core) 245
Film Coating (15% solids)
9 OPADRY Pink 85F94320 5
10 Purified Water q.s
FINAL TABLET WEIGHT 250

Manufacturing procedure:
Blend I (Immediate Release Blend)
1. Dispense the ingredients of the core tablets,
2. Co-sift Doxylamine succinate and Silicon dioxide through suitable sieve,
3. Co-sift Pyridoxine HCl with the step 2 sifted materials through suitable sieve,
4. Sift Lactose Monohydrate and MCC through suitable sieve separately,
5. Add the sifted materials in Conta blender in the following order: Half quantity of Diluents (Lactose Monohydrate and MCC), step 3 material and remaining quantity of Diluents, blend the materials for 30 mins at 12 rpm,
6. Sift Magnesium trisilicate and Croscarmellose sodium separately through suitable sieve and blend with step 5 blended materials in Conta blender at 12 rpm for 10 mins.
Blend II (Delayed Release Granules)
1. Dispense the ingredients of the core tablets,
2. Co-sift Doxylamine succinate and Silicon dioxide through suitable sieve,
3. Co-sift Pyridoxine HCl with the step 2 sifted materials through suitable sieve,
4. Sift Lactose Monohydrate and MCC through suitable sieve separately,
5. Add the sifted materials in RMG/FBP in the following order: Half quantity of Diluents (Lactose Monohydrate and MCC), step 3 material and remaining quantity of Diluents & mix for 10 minutes,
6. Dispense Acryl-Eze Aqueous Enteric Coating System and Purified water. Stir Purified water using Mechanical stirrer and add small quantities of Acryl-Eze Aqueous Enteric Coating System to it,
7. Continue the stirring for about 20 minutes,
8. Granulate step 5 with step 7 enteric coating solution at inlet temp.50°C.
9. Dry at inlet temperature 50°C till get desired LOD.
10. Sift dried granules through suitable sieve.
Blending of Blend I and Blend II
1. Add Immediate Release blend from step 6 and Delayed Release Granules from step 11 in to suitable blender and mix for 15 minutes at 12 rpm,
2. Sift Magnesium stearate though suitable sieve and lubricate the step 1 blend in Conta blender at 12 rpm for 5 mins.
Compression
1.Compress the lubricated blend using suitable punch (round, standard concave punches plain on both sides).
Film Coating
1.Dispense Opadry Pink 85F94320 and Purified water,
2.Stir Purified water using Mechanical stirrer and add small quantities of Opadry Clear 02O190000 to it,
3.Continue the stirring for about 45 minutes,
4.Coat the tablets in Tablet coating machine with the dispersion till the required weight gain is achieved. Stir the dispersion continuously using suitable stirrer during the coating operation.

Example 2
Sr.No. Ingredients mg/Tablet
Blend I (Immediate Release Blend)
1 Doxylamine Succinate 10
2 Pyridoxine HCl 10
3 Lactose Monohydrate (DC) 31.1
4 Microcrystalline cellulose (Avicel PH 102) 71
5 Croscarmellose Sodium 2
6 Magnesium Trisilicate 16.4
7 Silicon dioxide 0.5
Blend I weight 141
Blend II (Delayed Release Granules)
1 Doxylamine Succinate 10
2 Pyridoxine HCl 10
3 Lactose Monohydrate 28.5
4 Microcrystalline cellulose (Avicel PH 101) 39
5 Silicon dioxide 0.5
Granulation
6 Acryl-Eze Aqueous Acrylic Enteric System 10

93O18509 White
7 Purified Water q.s
Blend II weight 98.0
Final Lubrication
8 Magnesium Stearate 5
Final Tablet weight (core) 244
Film Coating (15% solids)
9 OPADRY Pink 85F94320 6
10 Purified Water q.s
FINAL TABLET WEIGHT 250

Example 3
Sr.No. Ingredients mg/Tablet
Blend I (Immediate Release Blend)
1 Doxylamine Succinate 10
2 Pyridoxine HCl 10
3 Lactose Monohydrate (DC) 8.5
4 Microcrystalline cellulose (Avicel PH 102) 84.9
5 Croscarmellose Sodium 5.2
6 Magnesium Trisilicate 20.4
7 Silicon dioxide 2
Blend I weight 141
Blend II (Delayed Release Granules)
1 Doxylamine Succinate 10
2 Pyridoxine HCl 10
3 Lactose Monohydrate 5
4 Microcrystalline cellulose (Avicel PH 101) 51
5 Silicon dioxide 2
Granulation
6 Acryl-Eze Aqueous Acrylic Enteric System 20
93O18509 White
7 Purified Water qs
Blend II weight 98.0
Final Lubrication
8 Magnesium Stearate 7
Final Tablet weight (core) 246
Film Coating (15% solids)
9 OPADRY Pink 85F94320 4
10 Purified Water q.s
FINAL TABLET WEIGHT 250

Compositions of examples 2-3 were also prepared using the similar method used for the preparation of example 1 composition.

Dissolution data

Comparative Dissolution Bonjesta (RLD Product) Vs. Example 1 composition is as given below:

Dissolution Data Dissolution Parameters: 1000mL, 0.1N HCl for 2 hrs followed by 0.2M Sodium Phosphate Buffer pH 6.8 for 45 minutes, 1000 ml,100 rpm, Paddle, 37°C
API Doxylamine Succinate Doxylamine Succinate
Product/Batch details Bonjesta (RLD ) Example 1 composition
Time points % Drug Release
(cumulative release) % Drug Release
(cumulative release
Minutes 0.1N HCl 0.1N HCl
0 0 0
5 23 25
10 35 37
15 40 44
20 41 46
30 44 49
45 46 49
60 47 51
120 49 54
F2
Minutes pH6.8 Sodium Phosphate Buffer pH6.8 Sodium Phosphate Buffer
125 56 56
130 97 100
135 99 104
140 99 105
150 100 106
165 101 107
Recovery 101 108

Dissolution Data Dissolution Parameters: 1000mL, 0.1N HCl for 2 hrs followed by 0.2M Sodium Phosphate Buffer pH 6.8 for 45 minutes, 1000 ml,100 rpm, Paddle, 37°C
API Pyridoxine HCl Pyridoxine HCl
Product/Batch details Bonjesta RLD Example 1 composition
Time points % Drug Release
(cumulative release) % Drug Release
(cumulative release
Minutes 0.1N HCl 0.1N HCl
0 0 0
5 3 2
10 16 16
15 28 30
20 35 39
30 43 47
45 47 51
60 48 52
120 52 55
Minutes pH6.8 Sodium Phosphate Buffer pH6.8 Sodium Phosphate Buffer
125 57 56
130 99 102
135 101 105
140 101 106
150 102 108
165 103 109
Recovery 102 109

Stability data for example 1 composition
Accelerated stability studies were conducted for the composition of the example 1 as given in the below table
Storage Condition 40 °C ± 2 °C / 75 % RH ± 5% RH
Initial 3 Month 6 Month
Description: Pink coloured, biconvex round shaped film coated tablets Complies Complies Complies
Water Content Not more than 8.0 % 6.4 5.8 6.1
Dissolution (by UV) For Acid Stage (0.1N HCl)
Doxylamine Succinate Between 35% - 60% in 120 mins 51 53 56
Pyridoxine HCl Between 35% - 60% in 120 mins 52 50 54
Dissolution (by UV) For Buffer Stage
pH 6.8
Doxylamine Succinate Not Less Than 75% (Q) in 45 mins 101 98 98
Pyridoxine HCl Not Less Than 75% (Q) in 45 mins 108 100 99
Assay (by HPLC)
Doxylamine Succinate 90.0% - 110% of labeled amount 97.7 101.4 98.3
Pyridoxine HCl NLT 90.0% of labeled amount 102.7 100.5 101.7

,CLAIMS:WE CLAIM:

1. An extended release single layer matrix tablet composition of doxylamine succinate and pyridoxine hydrochloride comprising immediate release blend and delayed release granules, wherein immediate release portion is prepared by direct mixing and said composition further comprises pharmaceutically acceptable excipients.

2. The extended release single layer matrix tablet composition as claimed in claim 1, wherein said excipients are granulating agent/enteric coating agent, antacid, disintegrants, diluents/fillers, glidant, anti-adherent, lubricant, coating agent.

3. The extended release single layer matrix tablet composition as claimed in claim 2, wherein said granulating agent/enteric coating agent selected from acacia, alginic acid, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, acryl-eze aqueous acrylic enteric system white, pregelatinized starch, calcium sulfate, amylose, glycine, bentonite, ethylcellulose, disodium pyrosulfite, polyvinyl alcohol, gelatin, glucose, guar gum, magnesium aluminum silicate, maltodextrin, polyethylene oxide, polymethacrylates, povidone, sodium alginate, tragacanth, maize starch and zein.

4. The extended release single layer matrix tablet composition as claimed in claim 2, wherein said antacid is selected from magnesium trisilicate, calcium carbonate, sodium bicarbonate, magnesium hydroxide, aluminum hydroxide, magnesium oxide, magnesium carbonate, aluminum phosphate, magaldrate.

5. The extended release single layer matrix tablet composition as claimed in claim 2, wherein said disintegrants are selected from croscarmellose sodium, alginic acid, carboxymethylcellulose, carboxymethylcellulose sodium, hydroxypropylcellulose (low substituted), microcrystalline cellulose, powdered cellulose, crospovidone, methylcellulose, sodium starch glycolate, starch, crosslinked polyvinylpyrollidines, pregelatinized starch, carboxymethyl starch, sodium carboxymethyl starch, microcrystalline cellulose.

6. The extended release single layer matrix tablet composition as claimed in claim 2, wherein said diluents/fillers selected from cellulose or derivatives, modified cellulose, sodium carboxymethyl cellulose, ethyl cellulose hydroxymethyl cellulose, cellulose acetate, hydroxypropylcellulose, lactose monohydrate, microcrystalline cellulose, dibasic calcium phosphate, sucrose, corn starch, potato starch and combinations thereof.

7. The extended release single layer matrix tablet composition as claimed in claim 2, wherein said glidants which includes include silicon dioxide, calcium stearate, magnesium oxide, magnesium stearate, mineral oil, poloxamer, polyethylene glycol, sodium lauryl sulfate, sodium stearate fumarate, stearic acid, talc and, zinc stearate, glyceryl behanate, magnesium lauryl sulfate, boric acid, sodium benzoate, sodium acetate, combination of sodium benzoate and sodium acetate. Preferably, the glidant used in the extended release single layer matrix tablet composition are silicon dioxide.

8. The extended release single layer matrix tablet composition as claimed in claim 2, wherein said lubricant is selected from magnesium oxide, grades of magnesium stearate, calcium stearate, hydrogenated castor oil, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate.

9. The extended release single layer matrix tablet composition as claimed in claim 2, wherein said coating agent selected from polyvinyl acetate polymer, OPADRY Pink 85F94320, acrylic resin, polymers or coplymers of acrylic acid, methyl acrylate, ethyl acrylate, methacrylic acid, methyl methacrylate, ethyl methacrylate and the like which may contain quaternary ammonium groups such as ammonio (meth)acrylate copolymers.

10. An extended release single layer matrix tablet composition comprising;
0.1% to 10% (w/w) of doxylamine or its salt,
0.1% to 10% (w/w) of pyridoxine or its salt,
0.5% to 2.5% (w/w) of croscarmellose sodium,
0.5% to 5% (w/w) of silicon dioxide and
1% to 10 (w/w) magnesium trisilicate,
0.5% to 3% (w/w) of magnesium stearate,
35% to 65% (w/w) of microcrystalline cellulose and lactose monohydrate,
1% to 10% (w/w) of Acryl-Eze Aqueous Acrylic Enteric System White,
0.1% to 5% (w/w) of OPADRY Pink 85F94320, and
0.01% to 5% other pharmaceutically acceptable excipients.

11. A process for preparing extended release single layer matrix tablet composition, wherein said process comprising steps of;
1) preparing immediate release blend comprising;
(a) co-sifting of doxylamine succinate and silicon dioxide through the sieve,
(b) co-sifting of Pyridoxine HCl with the blend obtained from step a),
(c) sifting lactose monohydrate and microcrystalline cellulose through suitable sieve separately,
(d) adding sifted materials in conta blender in the following order of half quantity of materials obtained from step (c), step (b) material and remaining quantity of step (c) materials, blending for 30 minutes,
(e) sifting of croscarmellose sodium and magnesium trisilicate separately through suitable sieve, adding and blending with step (d) blended materials in conta blender for 10 minutes,
2) preparing delayed release granules comprising;
(f) co-sifting of doxylamine succinate and silicon dioxide through the sieve,
(g) co-sifting of Pyridoxine HCl with the blend obtained from step f),
(h) sifting lactose monohydrate and microcrystalline cellulose through suitable sieve separately,
(i) adding sifted materials in rapid mixer granulator/ fluidized bed processor in the following order of half quantity of materials obtained from step (h), step (g) material and remaining quantity of step (h) materials, mixing for 10 minutes,
(j) stirring purified water in mechanical stirrer by adding small quantities of Acryl-Eze aqueous enteric coating system upto 20 minutes,
(k) granulating step (i) with step (j) enteric coating solution,
(l) drying and sifting the dried granules through suitable sieve,
3) blending and compressing of immediate release blend and delayed release granules comprising;
(m) adding Blend I and Blend II into blender, mixing for 15 minutes,
(n) sifting Magnesium stearate though suitable sieve and lubricating the step (m) blend in Conta blender for 5 minutes,
(o) compressing the obtained blend from step (n) and film coating with the Opadry Pink to obtain extended release single layer matrix tablet.

Dated this Twenty Third (23rd) day of June, 2021

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883