DESC:PULSATILE RELEASE DOSAGE FORM OF LOSARTAN

Field of the Invention

The present invention relates to pulsatile release dosage forms of losartan, wherein said dosage forms provide pulsatile release of losartan after a predetermined lag time. It also relates to processes for the preparation of said pulsatile release dosage forms.

Background of the Invention

Pulsatile release dosage forms are gaining increasing importance for effective treatment of several disease states that show circadian rhythms in their pathophysiology. Cardiovascular diseases are one such example, asseveral functions such as blood pressure, heart rate, cardiac output, stroke volume, and blood flow are subject to circadian rhythms. For instance, capillary resistance and vascular reactivity are higher in the morning and decrease later in the day. Blood pressure is at its lowest during the sleeping period and rises steeply during the early morning hours. Therefore there is a greater risk for loss of blood pressure control and an increased chance of myocardial infarction/stroke in the early morning hours. In this instance, an ideal dosage form should allow administration at bed-time and delay the release of the drug for as many hours as is required so as to reach therapeutic blood levels in the early morning hours. This can be accomplished by administering a pulsatile release dosage form of an antihypertensive drug such as losartan, which provides the release of losartan after a predetermined lag time thereby resulting in an improved therapeutic efficacy and better patient compliance.

Losartan is a type angiotensin II receptor (type AT1) antagonist available as potassium salt. Losartan potassium is chemically designated as 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt, and is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents, including diuretics. Losartan is also indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, and for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria in patients with type 2 diabetes and a history of hypertension.

PCT Publication No. WO 03/035029 discloses a gastric retentive dosage form consisting of single polymer matrix comprising losartan and hydrophilic polymers such as hydroxypropyl methylcellulose and polyethylene oxide, wherein losartan is administered from the dosage form for a period of atleast 5 hours and atleast 40 %w/w of losartan is retained in the dosage form after 1 hour.

U.S. Publication No. 2009/0123536discloses a modified release oral pharmaceutical form of losartan comprising a plurality of losartan microunits. Said oral pharmaceutical form ensures lower variability of efficacy and of therapeutic safety of the pharmaceutical form relative to the immediate-release pharmaceutical form.

Hence, there exists a need in the art for a pulsatile release dosage form of losartan which provides release of losartan at a desired time. Therefore, the present inventors have now developed a pulsatile release dosage form of losartan, wherein the dosage form provides a pulsatile release of losartan after a predetermined lag time. Said dosage form would be administered at night (i.e. before sleep) such that it permits release of losartan during early morning hours. This would help in minimizing the target organ damage that may be caused by early morning cardiovascular events. This would also prevent any excessive reduction of blood pressure during night time.

Further, the pulsatile release dosage form of the present invention is relatively simple, easy to manufacture, and is functionally reproducible.

Summary of the Invention

The present invention relates to a pulsatile release dosage form of losartan, wherein said dosage form provides pulsatile release of losartan after a predetermined lag time. The pulsatile release dosage form of losartan comprises: (i) a core comprising losartan and one or more pharmaceutically acceptable excipients; and (ii) a coating layer over said core comprising one or more pH-dependent polymers and one or more pharmaceutically acceptable coating additives. The present invention also includes processes for the preparation of said pulsatile release dosage forms.

Detailed Description of the Invention

A first aspect of the present invention provides a pulsatile release dosage form of losartan comprising:
(i) a core comprising losartan and one or more pharmaceutically acceptable excipients; and
(ii) a coating layer over said core comprising one or more pH-dependent polymers and one or more pharmaceutically acceptable coating additives.

According to one embodiment of the present invention, there is provided a pulsatile release dosage form of losartan comprising:
(i) a core comprising losartan and one or more pharmaceutically acceptable excipients; and
(ii) a coating layer over said core comprising one or more pH-dependent polymers selected from the group consisting of hydroxypropyl methyl cellulose phthalate, Eudragit® L100, Eudragit® S 100, or combinations thereof, and one or more pharmaceutically acceptable coating additives.

A second aspect of the present invention provides a pulsatile release dosage form of losartan comprising:
(i) a core comprising losartan and one or more pharmaceutically acceptable excipients; and
(ii) a coating layer over said core comprising one or more pH-dependent polymers and one or more pharmaceutically acceptable coating additives
wherein the core further comprises one or more rate-controlling polymers.

According to one embodiment of the present invention, there is provided a pulsatile release dosage form of losartan comprising:
(i) a core comprising losartan and one or more pharmaceutically acceptable excipients; and
(ii) a coating layer over said core comprising one or more pH-dependent polymers selected from the group consisting of hydroxypropyl methyl cellulose phthalate, Eudragit® L100, Eudragit® S 100, or combinations thereof, and one or more pharmaceutically acceptable coating additives
wherein the core further comprises hydroxypropyl methyl cellulose.

A third aspect of the present invention provides a process for the preparation of a pulsatile release dosage form of losartan, wherein the process comprises the steps of:
(a) blending/granulating losartan and one or more pharmaceutically acceptable excipients, and optionally one or more rate-controlling polymers;
(b) compressing the blends/granules of step (a) into a tablet core using appropriate tooling;
(c) dissolving or dispersing one or more pH-dependent polymers and one or more pharmaceutically acceptable coating additives in a suitable solvent; and
(d) applying the coating composition of step (c) over the tablet core of step (b) to form the pulsatile release dosage form.

A fourth aspect of the present invention provides a process for the preparation of a pulsatile release dosage form of losartan, wherein the process comprises the steps of:
(a) blending/granulating losartan and one or more pharmaceutically acceptable excipients, and optionally one or more rate-controlling polymers;
(b) filling the blends/granules of step (a) into a suitable sized capsule to form a capsule core;
(c) dissolving or dispersing one or more pH-dependent polymers and one or more pharmaceutically acceptable coating additives in a suitable solvent; and
(d) applying the coating composition of step (c) over the capsule core of step (b) to form the pulsatile release dosage form.

The term “pulsatile release dosage form” as used herein, refers to a dosage form designed such that, upon administration of the dosage form, there is a release of either some or all of the losartan after a predetermined lag time. For instance, the pulsatile release dosage form of the present invention may be administered at bedtime, such that it permits delivery of losartan at the time of awakening or a few hours before awakening for the effective treatment or prevention of early morning cardiovascular events.

The term “core”, as used herein, refers to tablets, capsules, granules, caplets, spheroids, and pellets, preferably tablets and capsules.

The coating layer comprising the pH-dependent polymer delays the release of losartan for a predetermined time, i.e. lag time, after which either someor all of the losartan is released. The lag time is controlled by the amount and type of pH-dependent polymer used in the coating as well as the thickness of the coating layer.

Further, when one or more rate-controlling polymers are incorporated in the core of said pulsatile release dosage form, some of the losartan would be released as a pulse after a predetermined lag time, and the remaining amount of losartan would be released continuously over a prolonged period of time, thereby rendering extended release benefits.

The term “losartan” as used herein means losartan, as well as its pharmaceutically acceptable salts, polymorphs, hydrates, solvates, and prodrugs. The preferred salt of losartan is losartan potassium.

The pulsatile release dosage form of the present invention may additionally comprise one or more diuretics. Diuretics are selected from the group consisting of hydrochlorothiazide, chlorthalidone, chlorothiazide, bendroflumethiazide, hydroflumethiazide, methyclothiazide, metolazone, polythiazide, trichlormethiazide, bumetanide, furosemide, amiloride, spironolactone, triamterene, or combinations thereof.

The term “pH-dependent polymer” as used herein, means any polymer that dissolves/disperses at a specified pH and is intended to delay the release of losartan based on the pH of the gastro-intestinal tract. The pH-dependent polymer is selected from the group consisting of esters of cellulose and its derivatives such as cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate; shellac; pH-sensitive methacrylic acid-methacrylate copolymers such as Eudragit®L100, Eudragit®S100, and Eudragit®L30D;or combinations thereof. These polymers may be used as a dry powder or as an aqueous dispersion.

The core of the present invention comprises one or more pharmaceutically acceptable excipients that are routinely used in pharmaceutical dosage forms and are selected from the group consisting of fillers, binders, disintegrants, lubricants/glidants, or combinations thereof.

Suitable fillers are selected from the group consisting of lactose, glucose, corn starch, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulphate, starch, pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, lactitol, mannitol, sorbitol, or combinations thereof.

Suitable binders are selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose sodium, acacia, guar gum, alginic acid, acrylic acid polymer, dextrin, maltodextrin, magnesium aluminum silicate, polymethacrylates, polyvinylpyrrolidone, copolymer of polyvinylpyrrolidone, gelatin, starch,or combinations thereof.

Suitable disintegrants are selected from the group consisting of crospovidone, croscarmellose sodium, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, magnesium aluminum silicate, sodium alginate, sodium starch glycolate, starch, mannitol, alginic acid, or combinations thereof.

Suitable lubricants/glidants are selected from the group consisting of colloidal silicon dioxide, talc, stearic acid, magnesium stearate, zinc stearate, calcium stearate, hydrogenated castor oil, polyethylene glycol, polyvinyl alcohol, sodium benzoate, sodium stearyl fumarate, magnesium oxide, poloxamer, sodium lauryl sulphate, polyoxyethylene monostearate, cocoa butter, mineral oil, polysaccharides, or combinations thereof.

The coating of the present invention comprises one or more pharmaceutically acceptable coating additives selected from the group consisting of plasticizers, opacifiers, anti-tacking agents, coloring agents, or combinations thereof.

Suitable plasticizers are selected from the group consisting of triethylcitrate, dibutylsebacate, triacetin, acetylated triacetin, tributylcitrate, glyceryltributyrate, diacetylatedmonoglyceride, rapeseed oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin, sorbitol, diethyloxalate, diethyl phthalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, or combinations thereof.

Suitable opacifiers are selected from the group consisting of titanium dioxide, manganese dioxide, iron oxide, silicon dioxide, or combinations thereof.

Suitable anti-tacking agents are selected from the group consisting of talc, magnesium stearate, calcium stearate, stearic acid, silica, glycerylmonostearate, or combinations thereof.

Suitable coloring agents are selected from the group consisting of FD&C (Federal Food, Drug and Cosmetic Act) approved coloring agents; natural coloring agents; natural juice concentrates; pigments such as iron oxide, titanium dioxide, and zinc oxide; or combinations thereof.
Examples of solvents used for granulation and coating include ethanol, water, methylene chloride, isopropyl alcohol, acetone, methanol, or combinations thereof.

The term “rate-controlling polymer” as used herein refers to the agent that helps to control the release of losartan from the core. The rate-controlling polymers are selected from the group consisting of cellulose derivatives such as hydroxypropyl methylcellulose of various grades such as Methocel® K15MCR, hydroxypropyl cellulose, carboxymethyl cellulose, and ethyl cellulose; polysaccharides such as alginate, xanthan, carrageenan, and starch; acrylic acid polymers such as carbomer, polymethacrylate, poly(hydroxy ethyl methacrylate), poly(methyl methacrylate), and poly(hydroxy ethyl methacrylate-co methyl methacrylate); polyethylene oxides and co-polymers thereof; polypropylene and co-polymers thereof; or combinations thereof.

The core can be prepared by usual blending or granulating techniques and the resultant blends/granules can be formulated into a tablet using a conventional tabletting process, or filled into a capsule of a suitable size using any conventional process.

Coating may be performed by applying the coating composition as a solution/suspension/blend using any conventional coating technique known in the art such as spray coating in a conventional coating pan, fluidized bed processor, dip coating, or compression coating. The percentage of the coating build-up shall be varied depending on the required lag time.

The following examples represent various embodiments according to 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.

EXAMPLES
Example 1
Ingredients Quantity (mg/tablet)
Example 1
Core
Losartan potassium 100.00
Mannitol 42.00
Microcrystalline cellulose 60.00
Hydroxypropyl methyl cellulose 42.00
Croscarmellose sodium 50.00
Colloidal silicon dioxide 3.00
Magnesium stearate 3.00
Core weight 300.00
Coating layer
Hydroxypropyl methyl cellulose phthalate 36.00
Dibutyl sebacate 3.60
Talc 3.39
Titanium dioxide 2.01
Ethanol q.s.
Purified water q.s.
Coating Weight 45.00
Total weight 345.00

Procedure:
Core:
1. Losartan potassium, mannitol, microcrystalline cellulose, hydroxypropyl methyl cellulose, croscarmellose sodium, and colloidal silicon dioxide were sifted through a suitable mesh and blended.
2. Magnesium stearate was mixed with the blend of step 1.
3. The resultant blend of step 2 was compressed into a tablet using appropriate tooling.
Coating layer:
4. Hydroxypropyl methyl cellulose phthalate and dibutylsebacate were dissolved in a mixture of ethanol and purified water.
5. Talc and titanium dioxide were dispersed into the solution of step 4.
6. The tablets of step 3 were coated in a pan coating machine using the coating solution of step 5 to form the pulsatile release dosage form.

In-Vitro Studies:

The tablets prepared according to Example 1 were subjected to dissolution studies in 900 mL of 0.1N HCl (acid stage) and pH 6.8 phosphate buffer (buffer stage)using a USP type II apparatus with a paddle speed at 50 rpm.

No drug release was observedfor2 hours in0.1N HCl (acid stage).The result of drug release in pH 6.8 phosphate buffer (buffer stage)is represented in Table 1 below.

Table 1: Percentage (%) of In-Vitro Drug Release in USP Type II Apparatus (Media: 900 mL of pH 6.8 phosphate buffer at 50 rpm)

Time (hours) Drug dissolved (Percent w/w)
0.5 11
1 33
2 78
4 99

Examples 2-4
Ingredients Quantity (mg/tablet)
Example 2 Example 3 Example 4
Core
Losartan potassium 100.00 100.00 100.00
Lactose 42.00 42.00 42.00
Microcrystalline cellulose 60.00 60.00 60.00
Hydroxypropyl methyl cellulose 50.00 50.00 50.00
Crospovidone 42.00 42.00 42.00
Colloidal silicon dioxide 3.00 3.00 3.00
Magnesium stearate 3.00 3.00 3.00
Core weight 300.00 300.00 300.00
Coating layer
Hydroxypropyl methyl cellulose phthalate 36.00 - -
Eudragit® L100 - 36.00 -
Eudragit® S100 - - 36.00
Dibutyl sebacate 3.60 3.60 3.60
Talc 3.39 3.39 3.39
Titanium dioxide 2.01 2.01 2.01
Ethanol q.s. q.s. q.s.
Purified water q.s. q.s. q.s.
Coating Weight 45.00 45.00 45.00
Total weight 345.00 345.00 345.00

Procedure:
Core:
1. Losartan potassium, lactose, microcrystalline cellulose, hydroxypropyl methyl cellulose, crospovidone, and colloidal silicon dioxide were sifted through a suitable mesh and blended.
2. Magnesium stearate was mixed with the blend of step 1.
3. The resultant blend of step 2 was compressed into a tablet using appropriate tooling.
Coating layer:
4. Hydroxypropyl methyl cellulose phthalate/Eudragit® L100/Eudragit® S100 and dibutylsebacate were dissolved in a mixture of ethanol and purified water.
5. Talc and titanium dioxide were dispersed into the solution of step 4.
6. The tablets of step 3 were coated in a pan coating machine using the coating solution of step 5 to form the pulsatile release dosage form.
Examples 5-6
Ingredients Quantity (mg/tablet)
Example 5 Example 6
Core
Losartan potassium 100.00 100.00
Lactose 22.00 22.00
Methocel® K15MCR 80.00 80.00
Hydroxypropyl methyl cellulose 42.00 42.00
Microcrystalline cellulose 50.00 50.00
Colloidal silicon dioxide 3.00 3.00
Magnesium stearate 3.00 3.00
Core weight 300.00 300.00
Coating Layer
Hydroxypropyl methyl cellulose phthalate 24.00 36.00
Dibutyl sebacate 2.40 3.60
Talc 2.26 3.39
Titanium dioxide 1.34 2.01
Ethanol q.s. q.s.
Purified water q.s. q.s.
Coating weight 30.00 45.00
Total weight 330.00 345.00

Procedure:
Core:
1. Losartan potassium, lactose, Methocel® K15MCR, hydroxypropyl methyl cellulose, microcrystalline cellulose and colloidal silicon dioxide are sifted through a suitable mesh and blended.
2. Magnesium stearate is mixed with the blend of step 1.
3. The resultant blend of step 2 is compressed into a tablet using appropriate tooling.
Coating layer:
4. Hydroxypropyl methyl cellulose phthalate and dibutylsebacate are dissolved in a mixture of ethanol and purified water.
5. Talc and titanium dioxide are dispersed into the solution of step 4.
6. The tablets of step 3 are coated in a pan coating machine using the coating solution of step 5 to form the pulsatile release dosage form.

CLAIMS:WE CLAIM:
1. A pulsatile release dosage form of losartan comprising:
(i) a core comprising losartan and one or more pharmaceutically acceptable excipients; and
(ii) a coating layer over said core comprising one or more pH-dependent polymers and one or more pharmaceutically acceptable coating additives.

2. The pulsatile release dosage form of claim 1, wherein the pH-dependent polymer is selected from the group consisting of esters of cellulose and its derivatives, polyvinyl acetate polymers, shellac, pH- sensitive methacrylic acid-methacrylate copolymers, or combinations thereof.

3. The pulsatile release dosage form of claim 1, wherein the pH-dependent polymer is selected from the group consisting of hydroxypropyl methyl cellulose phthalate, Eudragit® L 100, Eudragit® S 100, or combinations thereof, and one or more pharmaceutically acceptable coating additives

4. The pulsatile release dosage form of claim 1, wherein the pharmaceutically acceptable excipients are selected from the group consisting of fillers, binders, disintegrants, lubricants/glidants, or combinations thereof.

5. The pulsatile release dosage form of claim 1, wherein the pharmaceutically acceptable coating additives are selected from the group consisting of plasticizers, opacifiers, anti-tacking agents, coloring agents, or combinations thereof. The pulsatile release dosage form of claim 1, wherein the core further comprises one or more rate-controlling polymers.

6. The pulsatile release dosage form of claim 5, wherein the rate-controlling polymer is selected from the group consisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, ethyl cellulose, polysaccharides, acrylic acid polymer, polymethacrylate, poly(hydroxy ethyl methacrylate), poly(methyl methacrylate), poly(hydroxy ethyl methacrylate-co methyl methacrylate), polyethylene oxides and co-polymers thereof, polypropylene and co-polymers thereof, or combinations thereof.

7. The pulsatile release dosage form of claim 1, wherein the core is selected from the group consisting of tablets, capsules, granules, caplets, spheroids, and pellets.

8. The pulsatile release dosage form of claim 7, wherein the core is a tablet. The pulsatile release dosage form of claim 8, wherein the core is a capsule.

9. A process for the preparation of pulsatile release dosage form of claim 9, wherein the process comprises the steps of:
(a) blending/granulating losartan and one or more pharmaceutically acceptable excipients, and optionally one or more rate-controlling polymers;
(b) compressing the blends/granules of step (a) into a tablet core using appropriate tooling;
(c) dissolving or dispersing one or more pH-dependent polymers and one or more pharmaceutically acceptable coating additives in a suitable solvent; and
(d) applying the coating composition of step (c) over the tablet core of step (b) to form the pulsatile release dosage form.

10. A process for the preparation of a pulsatile release dosage form of claim 10, wherein the process comprises the steps of:
(a) blending/granulating losartan and one or more pharmaceutically acceptable excipients, and optionally one or more rate-controlling polymers;
(b) filling the blends/granules of step (a) into a suitable sized capsule to form a capsule core;
(c) dissolving or dispersing one or more pH-dependent polymers and one or more pharmaceutically acceptable coating additives in a suitable solvent; and
(d) applying the coating composition of step (c) over the capsule core of step (b) to form the pulsatile release dosage form.