Field of the invention

The present invention relates to pharmaceutical compositions comprising combination of 5-HT1 agonists with non-steroidal anti-inflammatory drugs (NSAIDs). More particularly, the present invention relates to pharmaceutical composition comprising sumatriptan and naproxen. The present invention also relates to a process for preparation of pharmaceutical compositions comprising sumatriptan and naproxen.

Background of the invention

Sumatriptan succinate is a selective 5-hydroxytryptamine1 (5HT1) receptor subtype agonist chemically known as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methane sulfonamide succinate and is disclosed in US 4,816,470 and US 5,037,845.

Naproxen sodium is a nonsteroidal anti-inflammatory drug chemically known as (S)-6-methoxy-a-methyl-2-naphthaleneacetic acid, sodium salt and is disclosed in US 3,904,682 and US 4,009,197.

The combination of sumatriptan and naproxen is approved for the acute treatment of migraine attacks and is currently marketed in the form of tablets under the brand name TREXIMET® in the US.

US 7,332,183 discloses a multilayer tablet for a combination of naproxen or pharmaceutically acceptable salt thereof with a triptan. The composition is formulated so that each drug is contained in separate layers located side-by-side so that each dissolves independently of the other. Thus the formulation is said to overcome difficulties associated with the poor in vivo solubility of NSAIDs in conditions of low pH found in the stomach, specifically that the slow eroding nature of NSAIDs may cause the triptan to become entrapped and thereby delay release of the triptan. The manufacturing process necessary to prepare and maintain the actives in separate layers requires specialized equipment and/or processing techniques. This adds to the time and cost for the manufacture of the product.

US 8,022,095 discloses a pharmaceutical composition useful in treating migraine headache which comprises in a unit dosage form: (a) naproxen; and (b) sumatriptan; wherein the respective amounts of sumatriptan and naproxen in said pharmaceutical composition are effective upon simultaneous administration of one or more unit dosage forms, to produce longer lasting efficacy compared to the administration of sumatriptan in the absence of naproxen or the administration of naproxen in the absence of sumatriptan; and wherein the sumatriptan is present at about 85 mg and the naproxen is present at about 500 mg.

US 2007/0184109 discloses a composition comprising a 5HT1 receptor agonist, which is sumatriptan or in combination with an NSAID, which is naproxen, wherein the 5HT1 receptor agonist and NSAID are located in discrete zones with respect to each other, wherein each zone comprises the active ingredient and optionally a carrier, and wherein the zone comprising the 5HT1 receptor agonist is formulated to ensure rapid absorption and is formulated with an effervescent couple and further discloses a multilayer tablet wherein the active agents are in separate layers or a compressed form, for example a tablet, of one active agent formulated with a powdered form of the other active agent or a tablet can be prepared by overcompression such that it would include a core of one active ingredient surrounded by an over coat of another active ingredient.

US 2008/0175897 discloses a dosage form comprising: a) a first drug, wherein said first drug is a therapeutically effective amount of a triptan or an opioid analgesic; and b) a therapeutically effective amount of a non-narcotic analgesic selected from the group consisting of: acetaminophen and an NSAID; and wherein, i) said non-narcotic analgesic is released from said unit dosage form into the gastrointestinal tract of said patient within 5 minutes after said dosage form is ingested; and ii) said triptan or opioid analgesic is either surrounded by a membrane that does not release it from said unit dosage form for at least 20 minutes after said dosage form is ingested or said triptan is formulated with components that delay its release for at least 20 minutes after said dosage form is ingested.

US 2009/0068262 discloses a method for preparing the oral dosage form comprising separately granulating each of the triptan and the NSAID, combining the separate granulates with at least one extragranular pharmaceutically acceptable excipient to form a mixture, and compacting the mixture into the oral dosage form and further discloses a method for preparing the oral dosage form comprising granulating one of the triptan or the NSAID with at least one pharmaceutically acceptable excipient to form a granulate, adding to the granulate a dry blend comprising at least the other of the triptan or the NSAID and at least one pharmaceutical^ acceptable excipient to form a mixture, and compacting the mixture into the oral dosage form.

US 2009/0186086 discloses a compressed solid oral dosage form comprising a first layer and a second layer, wherein: the first layer comprises naproxen or a pharmaceutically acceptable salt thereof and sumatriptan or a pharmaceutically acceptable salt thereof; the second layer comprises naproxen; the ratio of the amount of naproxen present in the first layer to the amount of naproxen present in the second layer is from about 11:89 to 30:70, based on the total amount of naproxen present in the oral dosage form, and the first layer comprises substantially all of the sumatriptan present in the oral dosage form.

US 2009/0252791 discloses an inlay tablet, comprising an inner tablet and an outer tablet encompassing all but at least a portion of one surface of the inner tablet, the inner tablet comprising a first active pharmaceutical ingredient which is a triptan or a nonsteroidal anti¬inflammatory drug, and the outer tablet comprising a second active pharmaceutical ingredient which is a triptan or a nonsteroidal anti-inflammatory drug, and wherein the first and the second active pharmaceutical ingredients are not both triptans or both nonsteroidal anti¬inflammatory drugs. This patent publication also discloses a compressed layered tablet, comprising a first layer comprising substantially all of a first active pharmaceutical ingredient present in the tablet and at least 10%, but less than 90%, of the total amount of a second active pharmaceutical ingredient present in the tablet, with the balance of the second active pharmaceutical ingredient disposed in a second layer, the first and the second layers being arranged side-by-side, and wherein the first and second active pharmaceutical ingredients are triptans and nonsteroidal anti-inflammatory drugs.

US 2009/0311335 discloses a composition comprising sumatriptan and particles of NSAID having an average particle size of less than 2000 nm, and atleast surface stabilizer adsorbed on the surface thereof.
US 2010/0008986 discloses a composition comprising two active components, wherein one is naproxen and the other is sumatriptan, with a proviso that both the active components are in admixture with each other. This publication further discloses a bilayer tablet composition comprising naproxen and sumatriptan.

US 2011/0184039 discloses a composition comprising a 5-HT1 agonist; an NSAID; and a disintegrant which comprises between about 15 to about 50% w/w based on the weight of the composition.

The above prior art references disclose various approaches to improve the bioavailability of composition comprising sumatriptan and naproxen. Still, there exists a need for development of pharmaceutical composition comprising sumatriptan and naproxen which exhibit better dissolution of drugs. The inventors of the present invention have surprisingly found that pharmaceutical compositions comprising sumatriptan, naproxen and a co-processed mixture of starch and lactose shows improved/comparable stability, dissolution with respect to the marketed dosage form.

Objective of the Invention

The main objective of the present invention is to provide pharmaceutical composition comprising sumatriptan, naproxen, a co-processed mixture of starch and lactose and one or more pharmaceutically acceptable excipients.

Another objective of the present invention is to provide a pharmaceutical composition comprising sumatriptan and naproxen having improved/comparable stability and bioavailability with respect to the commercialized sumatriptan and naproxen dosage form.

Summary of the Invention

The present invention relates to pharmaceutical composition comprising sumatriptan, naproxen, a co-processed mixture of starch and lactose and one or more pharmaceutically acceptable excipients.

The present invention further relates to a process for the preparation of pharmaceutical composition comprising sumatriptan, naproxen, a co-processed mixture of starch and lactose and one or more pharmaceutically acceptable excipients.

Detailed Description of the Invention

The present invention relates to a pharmaceutical composition comprising sumatriptan and naproxen and one or more pharmaceutically acceptable excipients.

The present invention further relates to a pharmaceutical composition comprising sumatriptan, naproxen, a co-processed mixture of starch and lactose and one or more pharmaceutically acceptable excipients.

"Sumatriptan" according to the present invention includes, but not limited to, sumatriptan free base, its pharmaceutical acceptable salts, esters, ethers, solvates, hydrates, polymorphs and the like.

"Naproxen" according to the present invention includes, but not limited to, naproxen free base, its pharmaceutical acceptable salts, esters, ethers, solvates, hydrates, polymorphs and the like.

A co-processed mixture of starch and lactose according to the present invention is a mixture comprising starch and lactose in different proportions. One of the commercially available co-processed mixture of starch and lactose is Starlac®. Starlac® is a spray-dried compound consisting of 85% alpha-lactose monohydrate and 15% maize starch dry matter. The advantages of using Starlac® are better compressibility, good flowability, improved disintegration which results in improved dissolution of the drugs. Since, naproxen is poorly soluble in water, the use of Starlac® in the composition comprising sumatriptan and naproxen results in improved dissolution of naproxen.

"Pharmaceutically acceptable excipient/s" are the components added to pharmaceutical formulation to facilitate manufacture, enhance stability, control release, enhance product characteristics, enhance bioavailability, enhance patient acceptability, etc. Pharmaceutically acceptable excipients includes, but not limited to, diluents/fillers, binders, disintegrants, sugars, base components, lubricants, glidants, compression aids, colors, sweeteners, preservatives, surfactants, suspending agents, dispersing agents, film formers, flavors, printing inks, etc.

Binders hold the ingredients in the composition together. Exemplary binders include, but not limited to, cellulose and its derivatives including, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose and hydroxyethyl cellulose, carboxymethyl cellulose; starch and its derivatives; hydrocolloids; sugars; polyvinyl pyrrolidone, copovidone, methacrylic acid copolymers and combinations comprising one or more of the foregoing binders. The binder may be used in the range of 1-40%, preferably 1-20% by weight of the dosage form.

Diluents increase the bulk of the composition. Diluents according to the present invention include, but not limited to, sugars such as lactose, sucrose, dextrose; sugar alcohols such as mannitol, sorbitol, xylitol, lactitol; Microcelac® (co-processed mixture of microcrystalline cellulose and lactose), starch, corn starch, modified starches, pregelatinized starch, dibasic calcium phosphate, tribasic calcium phosphate, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and the like or combinations thereof. The diluent may be used in the range of 5-95%, preferably 10-70% by weight of the dosage form.

Disintegrants according to the present invention include, but not limited to, water swellable substances, for example, cellulose and its derivatives including low-substituted hydroxypropyl cellulose; cross-linked polyvinylpyrrolidone; cross-linked sodium carboxymethylcellulose, cross-linked calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxy methylcellulose, microcrystalline cellulose; sodium starch glycolate; ion-exchange resins; starch and modified starches including pregelatinized starch; formalin-casein; alginates, gums, and combinations comprising one or more of the foregoing water swellable substances. The disintegrant may be used in the range of 1-30%, preferably 1-20% by weight of the dosage form.

Base components according to the present invention include, but not limited to, an alkali metal or alkaline earth metal carbonate or bicarbonate, such as sodium bicarbonate, potassium bicarbonate, magnesium carbonate or calcium carbonate and the like or combination thereof. The base component may be used in the range of 1-20%, preferably 1-10% by weight of the dosage form.

Surfactants are compounds which are capable of improving the wetting of the drug and/or enhancing the dissolution. The surfactants can be selected from hydrophilic surfactants or lipophilic surfactants or mixtures thereof. The surfactants can be anionic, nonionic, cationic, and zwitterionic surfactants. Surfactants according to the present invention include, but not limited to, polyoxyethylene alkylaryl ethers such as polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether; polyethylene glycol fatty acid esters such as PEG monolaurate, PEG dilaurate, Polyethylene glycol 660 12- hydroxyl Stearate or Polyoxyl 15 hydroxystearate (Solutol HS 15), PEG distearate, PEG dioleate; polyoxyethylene sorbitan fatty acid ester such as polysorbate 40, polysorbate 60, polysorbate 80; sorbitan fatty acid mono esters such as sorbitan monolaurate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene castor oil derivates such as polyoxyl castor oil, polyoxyl hydrogenated castor oil, sodium lauryl sulphate, monooleate, monolaurate, monopalmitate, monostearate, sodium dioctyl sulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, cremophore RH 40, and the like or combinations thereof. The surfactant may be used in the range of 0.001-5% by weight of the dosage form.

Lubricants and glidants aids in the processing of powder materials. Exemplary lubricants include, but not limited to, calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate, and combinations comprising one or more of the foregoing lubricants. The lubricant may be used in the range of 0.01-5%, preferably 0.1-2% by weight of the dosage form. Exemplary glidants include, but not limited to, talc, silicon dioxide, silicic acid, cornstarch and the like. The glidant may be used in the range of 0.01-5%, preferably 0.1-2% by weight of the dosage form.

Dosage form according to the present invention can be selected from the group comprising tablets, capsules, minitablets and the like or combinations thereof, preferably in the form of tablet and more preferably in the form of mono-layered tablets.

The dosage form according to the present invention may be prepared by any method known in the art such as wet granulation, dry granulation or direct compression and melt granulation.

The dosage form according to the present invention may be uncoated or optionally coated with film coating/moisture barrier coating composition.

Film coating composition includes one or more polymeric carriers along with one or more pharmaceutically acceptable excipients such as plasticizer, opacifier, anti-sticking agent, colorants, sugars, pore forming agent, surfactants and the like.

In another embodiment, the amount of sumatriptan used may be in the range from about 5 to about 200 mg.

In another embodiment, the amount of naproxen used may be in the range from about 5 to about 1500 mg.

In a preferred embodiment, the present invention relates to a pharmaceutical composition comprising:

(a) naproxen sodium granules comprising naproxen, 1-20% by weight of disintegrant selected from cross-linked polyvinyl pyrrolidone; cross-linked sodium carboxymethyl cellulose, 1- 20% by weight of binder selected from polyvinyl pyrrolidone, hydroxypropyl cellulose and one or more pharmaceutically acceptable excipients,

(b) sumatriptan succinate granules comprising sumatriptan succinate, 5-40% by weight of diluent selected from dibasic calcium phosphate, microcrystalline cellulose and silicified microcrystalline cellulose, 1-20% by weight of disintegrant selected from cross-linked polyvinyl pyrrolidone; cross-linked sodium carboxymethyl cellulose, 1-20% by weight of binder selected from polyvinyl pyrrolidone, hydroxypropyl cellulose and one or more pharmaceutically acceptable excipients, and

(c) extragranular excipients comprising co-processed mixture of starch and lactose, 1-10% by weight of base component selected from sodium bicarbonate and potassium bicarbonate, 5-40% by weight of diluent selected from dibasic calcium phosphate, microcrystalline cellulose and silicified microcrystalline cellulose, 1-20% by weight of disintegrant selected from cross-linked polyvinyl pyrrolidone; cross-linked sodium carboxymethyl cellulose and 0.1-2% by weight of glidant selected from talc and silicon dioxide, 0.1-2% by weight of lubricant selected from magnesium stearate and sodium stearyl fumarate.

In a preferred embodiment, the present invention relates a process for the preparation of pharmaceutical composition comprising sumatriptan, naproxen, a co-processed mixture of starch and lactose comprising the steps of:

(a) preparing granules comprising naproxen sodium and one or more pharmaceutically acceptable excipients separately,

(b) preparing granules of sumatriptan succinate and one or more pharmaceutically acceptable excipients separately,

(c) blending the naproxen sodium granules and sumatriptan succinate granules with a co-processed mixture of starch and lactose and one or more pharmaceutically acceptable excipients,

(d) processing the blend into a suitable dosage form. "% by weight" according to the present invention is calculated based on the total weight of dosage form.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Example 1:

The processing steps involved in manufacturing sumatriptan and naproxen tablets are given below:

fi) Preparation of Naproxen sodium granules:

a) Naproxen sodium and croscarmellose sodium were co-sifted and blended,

b) binder solution was prepared by dispersing povidone 30 and croscarmellose sodium in purified water,

c) the blend of step (a) was granulated with the binder solution of step (b) and the wet mass was dried and sifted,

(ii) Preparation of sumatriptan succinate granules:

a) Sumatriptan succinate, dibasic calcium phosphate and colloidal silicon dioxide were sifted and blended,

b) binder solution was prepared by dispersing povidone 30 in purified water,

c) the blend of step (a) was granulated with the binder solution of step (b) and the wet mass was dried and sifted,

d) the granules of step (c) were blended with Starlac®, silicified microcrystalline cellulose,
crospovidone, sodium bicarbonate, colloidal silicon dioxide and talc,

(iii) Preparation of tablets:

a) the prepared naproxen sodium granules and sumatriptan succinate granules were blended together,

b) the blend of step (a) was lubricated with magnesium stearate and compressed into tablets.
Example 2:

The composition given in Example 2 was prepared using the similar procedure described in Example 1.
Dissolution data: The tablets of naproxen and sumatriptan succinate prepared according to Example-1 of the present invention were subjected to dissolution studies using 900 ml of pH 6.8 Phosphate buffer as dissolution medium in USP II apparatus at 75 rpm. The dissolution data is given in Table 1.

Table-1

We Claim:

1. A pharmaceutical composition comprising sumatriptan, naproxen, a co-processed mixture of starch and lactose and one or more pharmaceutically acceptable excipients.

2. The composition as claimed in claim 1, wherein one or more pharmaceutically acceptable excipients are selected from diluent, binder, disintegrant, base component, glidant and lubricant.

3. The composition as claimed in claim 2, wherein the diluent is selected from group consisting of dibasic calcium phosphate, lactose, sucrose, mannitol, powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose and combinations thereof.

4. The composition as claimed in claim 2, wherein the disintegrant is selected from group consisting of cross-linked polyvinyl pyrrolidone; cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, sodium starch glycolate and combinations thereof.

5. The composition as claimed in claim 2, wherein the binder is selected from the group consisting of polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, sugars and combinations thereof.

6. The composition as claimed in claim 2, wherein the base component is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate and combinations thereof.

7. The composition as claimed in claim 2, wherein the glidant is selected from the group consisting of talc, silicon dioxide, silicic acid, cornstarch and combinations thereof.

8. The composition as claimed in claim 2, wherein the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, glycerol behenate, sodium stearyl fumarate, stearic acid, talc and combinations thereof.

9. A process for the preparation of pharmaceutical composition comprising sumatriptan, naproxen, a co-processed mixture of starch and lactose comprising the steps of:

(a) preparing granules comprising naproxen sodium and one or more pharmaceutically acceptable excipients separately,

(b) preparing granules of sumatriptan succinate and one or more pharmaceutically acceptable excipients separately,

(c) blending the naproxen sodium granules and sumatriptan succinate granules with a co-processed mixture of starch and lactose and one or more pharmaceutically acceptable excipients,

(d) processing the blend into a suitable dosage form.

10. A pharmaceutical composition comprising:

(a) naproxen sodium granules comprising naproxen, 1-20% by weight of disintegrant selected from cross-linked polyvinyl pyrrolidone; cross-linked sodium carboxymethyl cellulose, 1- 20% by weight of binder selected from polyvinyl pyrrolidone, hydroxypropyl cellulose and one or more pharmaceutically acceptable excipients,

(b) sumatriptan succinate granules comprising sumatriptan succinate, 5-40% by weight of diluent selected from dibasic calcium phosphate, microcrystalline cellulose and silicified microcrystalline cellulose, 1-20% by weight of disintegrant selected from cross-linked polyvinyl pyrrolidone; cross-linked sodium carboxymethyl cellulose, 1-20% by weight of binder selected from polyvinyl pyrrolidone, hydroxypropyl cellulose and one or more pharmaceutically acceptable excipients, and

(c) extragranular excipients comprising co-processed mixture of starch and lactose, 1-10% by weight of base component selected from sodium bicarbonate and potassium bicarbonate, 5-40% by weight of diluent selected from dibasic calcium phosphate, microcrystalline cellulose and silicified microcrystalline cellulose, 1-20% by weight of disintegrant selected from cross-linked polyvinyl pyrrolidone; cross-linked sodium carboxymethyl cellulose and 0.1-2% by weight of glidant selected from talc and silicon dioxide, 0.1-2% by weight of lubricant selected from magnesium stearate and sodium stearyl fumarate.