DESC:FIELD OF THE INVENTION
The present invention relates to a stable, prolonged release to solid oral pharmaceutical compositions comprising nicorandil and its pharmaceutically acceptable salts thereof and methods of preparing such pharmaceutical compositions.
BACKGROUND OF THE INVENTION
Nicorandil, the nitrate ester of N-(2-hydroxyethyl) nicotinamide, has both coronary vasodilative and coronary vasoconstriction suppressing actions and is useful as a curative for various types of angina pectoris while causing minimum effects on the dynamics of cardiovascular circulation and on cardiac functions. The oral pharmaceutical compositions of nicorandil in a solid form suitable for repeated administrations are particularly used in therapy for preventing angina attacks.

Nicorandil

In the solid crystalline state, nicorandil is stable under conditions of extreme dryness, but when it is exposed, although for short periods of time and at room temperature, even at low humidity levels, a considerable instability ensues. The hydrolysis of nicorandil is catalyzed by three factors, each influencing the others, namely, increased percentage of moisture in the product in powder state, temperature and storage period.

The progressive degradation of nicorandil results due to hydrolysis of the inorganic ester contained in the molecule, with the consequent liberation of nitric acid and N-(2-hydroxyethyl) nicotinamide, a compound that is not pharmacologically active at the considered dosages.

The degradation of nicorandil in the presence of water is so rapid that in aqueous solution at 5%, the product loses, at 60°C and pH 7 in only 12 hours, almost 20% of its titer. To the contrary, the powder in the dry state and under the same conditions does not exhibit, during the same period such qualitative and quantitative variations.

Pharmaceutical compositions of nicorandil in a solid form are generally characterized by their unsatisfactory stability, especially in the presence of moisture and other factors such as pH, temperature, light and oxygen. Particular precautions are therefore required throughout their manufacturing process and during storage, to avoid product contact with moisture and to inhibit other degradation processes which may cause significant reduction of the active ingredient content.

The stability of the pharmaceutical compositions of nicorandil in a solid form is further impaired when they are subjected to a certain degree of compression which may alter the crystalline structure of the active ingredient. It is therefore necessary to effect a proper choice of the excipients for the pharmaceutical compositions, so as to achieve a tablet formulation endowed with adequate hardness, under application of reduced compressing strength.

US 4,822,808 describes a method for producing a stable preparation containing nicorandil, at least 0.5% by weight of the preparation of a saturated higher aliphatic acid or a saturated higher alcohol which is solid at ordinary temperatures, and optionally at least 0.1% by weight of the preparation of at least one organic acid selected from the group consisting of fumaric acid, oxalic acid, salicylic acid, tartaric acid and glutaric acid.

EP 185347 describes pharmaceutical compositions of nicorandil containing a sugar, with a particle size not exceeding 10 ppm, and/or an organic acid.

However, in the pharmaceutical compositions described above, the stability of the active ingredient is still unsatisfactory. In addition, being immediate release in nature, their pharmacokinetic profile is far from being the most suitable from a therapeutical point of view, as it causes a rapid build-up of high blood concentrations of nicorandil, which may lead to high incidences of side effects such as headaches, postural hypotension, etc.

Moreover, during manufacture of the aforementioned preparations, the friction between the crystals of the product during compression is known to rupture the crystals of nicorandil and resulting in increased instability.

WO9907370 describes an oral release pharmaceutical composition in a solid form, with a modulated release of nicorandil, by combining it with a glyceride of a saturated fatty acid having a number of carbon atoms > 18 as an excipient. Although, the addition of such excipient allows reducing the compressive strength needed for tabletting, the stability of nicorandil, in such formulations, remains relatively unsatisfactory.

Various polymeric materials have been used in most of sustained-release preparations in order to keep blood levels of the drug over a long period of time, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, pullulan, gelatin, collagen, casein, agar, ethyl cellulose, methyl cellulose, polyethylene glycol, sodium alginate, polyvinylpyrrolidone, albumin, etc. However, a water-soluble polymer material itself has a high water content, thus when combined with the drug substance, such polymers may further diminish the stability of the composition.

The use of completely moisture proof materials for the packaging of the tablets proves not only relatively expensive, but also insufficient to prevent the absorption of moisture and, therefore, therefore there is a need to avoid the known degradation mechanisms of nicorandil.

Thus, there exists a need to develop improved formulations of nicorandil, which would be stable for an adequate period of time, compatible with the excipients used for the formulation and, finally, preservable in conventional packaging materials, such as small glass or plastic bottles having screw caps, blister packaging or strips fabricated from thermo-sealed coupled foils of aluminum and copolymers.

SUMMARY OF THE INVENTION
The present invention relates to a stable, prolonged release composition of nicorandil. Typically, the composition comprises of nicorandil or its pharmaceutically acceptable salts and rate controlling polymer.
Further the present invention relates to a method for providing a nicorandil composition which is stable not only in humid conditions but also under the compressive pressure exerted by punching operations in tablet making.
The instant invention makes use of suitable excipients and procedures to develop a pharmaceutical composition having desired stability and dissolution profile. The various ingredients added at particular stages during the process of preparation impart to the novel formulation its desired properties.
Thus, in one aspect, the present invention provides pharmaceutical compositions having improved stability comprising 1) nicorandil or pharmaceutically acceptable salt thereof and other pharmaceutically acceptable excipients.
In another aspect, the invention provides prolonged-release pharmaceutical compositions, in solid form, for oral administration comprising 1) Nicorandil or pharmaceutically acceptable salt thereof, 2) a suitable diluent and 3) at least one rate-controlling polymer.
Further aspect of the present invention provides a method for preparing prolonged-release solid oral dosage forms, with improved stability, comprising nicorandil or pharmaceutically acceptable salt thereof and at least one rate-controlling polymer.
DESCRIPTION OF THE INVENTION
The present invention provides stable, prolonged-release oral pharmaceutical dosage forms comprising 1) nicorandil or pharmaceutically acceptable salt thereof, 2) a suitable diluent and 3) at least one rate-controlling polymer.

The term "prolonged-release ", as used herein, can be used synonymously with “extended-release” or “modified-release” or “sustained-release” or “delayed-released” or “pulsatile-release” and is understood to mean a drug dosage system in which the rate of the API release is more precisely controlled and is delivered from the dosage system at a predictable and predetermined rate within the body of a patient such that a therapeutically effective blood level, devoid of peak and trough fluctuations, over an extended period of time. This definition excludes “immediate-release” oral pharmaceutical dosage forms, which consist of pharmaceutical dosage forms which release the active drug immediately after oral administration.

As used herein, the term "nicorandil" includes the compound nicorandil, pharmaceutically acceptable salts of nicorandil, isomers, solvates, complexes and hydrates, anhydrous forms thereof, and any polymorphic or amorphous forms or combinations thereof.
As used herein, the term "stable compositions" refers to any preparation of nicorandil having sufficient stability to allow storage at a convenient temperature, such as between about 0°C and about 60°C, for a pharmaceutically acceptable duration of time. Preferably, the compositions are stable for a period of time, such as at least about one week, at least about one month, at least about three months, at least about six months, at least about one year, or at least about 2 years. Further, term "stable compositions" refers to any preparation of nicorandil that is stable against the pressure of compression and humidity.

As used herein, the term "diluent" refers to inert substances that may be used as a vehicle for the active agent, optionally in conjunction with other excipients, as long as the resulting formulation meets the dissolution profile desired and/or is stable. Suitable carriers or diluents illustratively include, but are not limited to, either individually or in combination, lactose, including anhydrous lactose and lactose monohydrate. Starches, including directly compressible starch, starch 1500 and hydrolyzed starches may also be used as filler as per the invention. Sugars such as sucrose, mannitol, sorbitol, xylitol, dextrose dextrin, dextran, maltodextrin and dextrose monohydrate can be employed as diluents. Further, dibasic calcium phosphate dihydrate, calcium carbonate, calcium phosphate and/or hydrogen phosphate, sulphate, confectioner's sugar, monobasic calcium sulfate monohydrate, calcium sulfate dihydrate, granular calcium lactate trihydrate, dextrates, inositol, hydrolyzed cereal solids, amylose, celluloses including microcrystalline cellulose, food grade sources of alpha and amorphous cellulose powdered cellulose, hydroxypropylcellulose (HPC) and hydroxypropyl methylcellulose (HPMC), ethyl cellulose, hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, polyvinyl acetate, gelatin, acacia gum, tragacanth, polyvinylpyrrolidone, magnesium aluminium silicate, glycine, bentonite, block co-polymers, polyvinylpyrrolidone can also be employed.
Combination of two or more diluents can be used in the dosage formulations. When used, the total amount of diluents can be up to about 99 weight percent of the total weight of the formulation; specifically about 20 to about 98 weight percent; more specifically about 25 to about 97 weight percent; and yet more specifically about 30 to about 50 weight percent. Typically, mannitol is one of the preferred diluents applied to the preparation of tablets containing humidity-sensitive substances.
As used herein, "rate controlling polymer" means an excipient in the final dosage form whose primary function is to modify the duration of release of the active drug substance from the dosage form. The “rate controlling polymer” may include hydrophobic polymers, hydrophilic polymers, or a mixture thereof.
Preferred hydrophobic polymers in this invention are glyceryl behenate, glyceryl palmitate stearate, glyceryl monostearate, polyglycolized glycerides hydrogenated vegetable oils such as hydrogenated castor oil, cetyl alcohol or mixtures thereof. A hydrophilic rate controlling polymer might be selected from the group consisting of hydroxyalkylcellulose and hydoxypropylalkylcellulose or a mixture thereof, as well as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxy-pentyl-cellulose, hydroxypropylmethylcellulose, hydroxypropylbutyl-cellulose and hydroxypropylpentylcellulose. The most preferred hydrophilic polymer is hydroxypropyl methylcellulose and is used in the amounts from 2 to 95 percentage of the total weight of the formulation, specifically from 2 to 80 percentages by weight of the formulation.
The pharmaceutical composition of the present invention, in addition to the nicorandil or pharmaceutically acceptable salt thereof, a diluent and at least one rate-controlling polymer, may contain excipients that are normally employed in such pharmaceutical compositions, the only qualification being that the excipients must not deleteriously affect the stability and intent of the pharmaceutical composition.
Examples of other excipients that can be employed include binders, disintegrant, lubricant, glidants, anti-adherents, surfactants, etc. A combination of excipients may also be used. Such excipients are known to those skilled in the art, and thus, only few representative examples for each class of excipient are mentioned herein below:
Suitable disintegrating agents illustratively include, but are not limited to, either individually or in combination croscarmellose sodium, sodium starch glycollate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl starch, starches and microcrystalline cellulose, magnesium aluminium silicate, polyacrylin potassium. Typically, microcrystalline cellulose is preferred as a disintegrant.
"Binder" or "binding agent” refers to any substance or mixture that exerts a physicochemical attractive force between molecules, and hence may be used in the formulation of a dosage form. In one embodiment of the invention, the binder or the binding agent may be mixed with other components of the composition, so that it is distributed uniformly throughout the dosage form. Binders include, but are not limited to carboxymethyl cellulose sodium, ethyl cellulose, gelatin, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch and/or combination thereof.
A lubricant and/or glidant can also be used in the dosage formulations to aid in the processing of powder materials. Exemplary lubricants include calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate, stearic acid, talc, vegetable oil, zinc stearate, and combinations thereof.
Suitable surfactants illustratively include, but are not limited to, either individually or in combination ionic surfactants, such as sodium lauryl sulphate or non-ionic surfactants such as different poloxamers (polyoxyethylene and polyoxypropylene copolymers), natural or synthesized lecithins, esters of sorbitan and fatty acids (such as Span®, manufactured by Atlas Chemie), esters of polyoxyethylene sorbitan and fatty acids (such as Tween®, manufactured by Atlas Chemie), polyoxyethylated hydrogenated castor oil (such as Cremophor® manufactured by BASF), polyoxyethylene stearates (such as Brij®, manufactured by Atlas Chemie), dimethylpolysiloxane or any combination of the above mentioned surfactants.
Other conventional excipients for solid, pharmaceutical formulations include colouring agents, lakes, aromas and adsorbents may be added in the formulation according to present invention.
In another embodiment, the present invention also provides a process for the preparation of pharmaceutical composition according to present invention. All methods known in the art for preparation of such pharmaceutical compositions, suitable for moisture sensitive drug substances, could be employed for preparation of the pharmaceutical composition according to present invention. Typically, non-aqueous granulation is preferably employed in making the pharmaceutical composition according to present invention. Further direct compression method can also be utilized in making the present pharmaceutical composition.
In one embodiment of the invention, the pharmaceutical composition of the present invention is prepared by a conventional granulation method comprising:
(a) combining the diluent and rate controlling polymer with one or more excipients, to form a premix;
(b) adding premix formed in step (a) to non-aqueous binder solution to form a wet mass;
(c) drying the wet granulated mass obtained in step (b),
(d) adding Nicorandil and other extragranular excipients to granules obtained in step (c);
(e) lubricating the blend obtained in step (d); and
(f) compressing the blend of step (e) with suitable tooling punches to get a tablet.
Yet, in another embodiment, the pharmaceutical composition of the present invention is prepared by simple dry mixing method comprising:
(a) dry mixing nicorandil and all the excipients, except lubricant, to form a premix;
(b) lubricating the blend obtained in step (a); and
(c) compressing the blend of step (b) with suitable tooling punches to get a tablet.
The above disclosed processes may further include any one of the features known to a person skilled in the art. For example, the process may further, optionally include sifting of one or all ingredients and/or active agent to get the particles of suitable particle size. Typically, the dosage formulation comprises the active agent and excipients in the form of particles having a particle size distribution that allows for the ease of processing the material, for example into tablets, without segregation of the excipients. The desired particle range of active agent and excipients and other components may be obtained by processes known in the art, including granulating, screening, milling, and the like.
Drying techniques useful for drying the granulation could be any method known to the person skilled in the art. For example, drying could be achieved by spray-drying, flash drying, ring drying, tray drying, vacuum drying, microwave drying and lyophilizing.
The tablet, thus obtained, then can be, optionally, further coated with a film coating agent that may or may not contain a colorant. The film coating material is an immediate release coating material chosen to provide a coated tablet having substantially the same dissolution properties as the corresponding uncoated tablet and to improve the organoleptic properties of the tablet. An exemplary film coating material includes hydroxypropyl methyl cellulose, especially Opadry®.
The present invention is evaluated for various parameters such as stability, dissolution, etc. The tablets were stored for initial, 3 months, 6 months, 12 months at 2-8°C in a suitable pharmaceutical container. Samples of these tablets were analyzed for drug potency using a stability indicating HPLC assay method.
The stability study for the formulation obtained by the present invention indicates that the impurities such as nitrate, nicotinic acid, methyl nicotinate, 2-amino ethyl nicotinate nitrate, oxazoline and N-(2-hydroxyethyl) nicotinamide are within limits after 12 months storage. Also, the other impurities peaks are within the limit of standard values.
Evaluation of the potency for the formulation after 12 months storage demonstrates that the formulation had good stability at 2-8°C. Also, the dissolution data shows the prolonged release tablet is dissolved 35% after 2 hours and at least 80% after 8 hours.
In another embodiment of the invention, the pharmaceutical composition of the invention is prepared by a dry granulation method. In still another embodiment of the invention, the pharmaceutical composition of the invention is prepared by direct compaction method.

The pharmaceutical compositions of the invention may be in the form of a capsule, caplet, powder, disc or tablet. In one embodiment of the invention, the compositions of the invention are presented as tablet.

The following non-limiting examples illustrate further aspects of the invention.
EXAMPLES:
Table 1: Example 1 for preparation of nicorandil 10 mg tablet
Sr. No. Name of Ingredients Quantity/ Tablet (mg)
Dry Mix
1 Mannitol 23.00
2 Hydrogenated Castor Oil 18.00
3 Hypromellose 45.00
Binder
4 Hypromellose 4.50
5 Hydrogenated Castor Oil 2.00
6 Isopropyl Alcohol Q.S.
7 Methylene Chloride Q.S.
Prelubricant
8 Nicorandil 10.80
9 Mannitol 23.70
10 Stearic Acid 10.00
Lubricant
11 Magnesium Stearate 3.00
Total weight of uncoated tablet 140.00

Procedure: Solution of hypromellose in isopropyl alcohol and hydrogenated castor oil in methylene chloride was mixed to obtain a clear binder solution. Premix comprising sifted mannitol, hydrogenated castor oil and hypromellose was added to the binder solution and granulated in rapid mixer granulator till endpoint granulation. Granules were dried in rapid fluid bed dryer and mixed with nicorandil and mannitol in a double cone blender. The mixture was lubricated with magnesium stearate and compressed into tablets using suitable tooling. The said formulation was then evaluated for various parameters and results are summarised in Table 2 & Table 3.
Table 2: Stability Data at storage condition 2 to 8°C of Example 1
Particulars Limit Initial 3 months 6 months 12 months
Nitrate NMT 2.5% 0.1 0.2 0.84 0.74
Nicotinic acid NMT 0.5% BDL BDL BDL BDL
Methyl nicotinate NMT 0.5% BDL BDL BDL BDL
2-amino ethyl nicotinate nitrate NMT 1.5% BDL BDL BDL BDL
Oxazoline NMT 1.5% BDL BDL BDL BDL
N-(2-hydroxyethyl) nicotinamide NMT 0.5% BDL BDL BDL BDL
Any other secondary peak NMT 0.5% 0.21 0.24 0.27 0.32
All other secondary peak NMT1.0% 0.31 0.38 0.37 0.41
Total secondary Peak NMT 6.0% 0.31 0.46 0.40 0.41
% Assay 90 to 110 105.0 103.1 98.7 99.8
BDL: Below the limit
Table 2 reports stability data for tablets made according to Example 1. The tablets were stored for initial, 3 months, 6 months, 12 months at 2-8°C in a suitable pharmaceutical container. Samples of these tablets were analyzed for drug potency using a stability indicating HPLC assay method. Evaluation of the potency for these tablets (i.e. percentage label claim of nicorandil in the tablet) after 12 months storage demonstrates that the formulation described in Example 1 yields a product which gives good stability at 2 to 8°C

Table 3: Dissolution data of example 1

Time point (min) Limit % Dissolution
30 10 to 40% 21
120 35 to 75 % 54
480 NLT 80% 97

In accordance with an embodiment of the invention, the tablet releases not less than about 80% nicorandil after 480 minutes when measured using dissolution apparatus II (paddle method), 100 rpm (while the USP indicates 50 rpm), pH 7.2 phosphate buffer, 37°C, according to IP reference standard.
Table 4: Example 2 for preparation of nicorandil tablet
Sr. No. Name of Ingredients Quantity/ Tablet (mg)
1 Nicorandil 10.80
2 Mannitol 62.20
3 Hypromellose 50.00
4 Stearic Acid 10.00
5 Colloidal Silicon Dioxide 2.00
6 Magnesium Stearate 5.00
Total weight of uncoated tablet 140 .00

Procedure: All the ingredients, except magnesium stearate, were sifted and mixed in a double cone blender. The mixture was then lubricated with magnesium stearate and compressed into tablets using suitable tooling. Stability and dissolution studies performed of example 2, shows significantly stability in various condition.

,CLAIMS:1. A stable, prolonged release pharmaceutical composition comprising nicorandil or its pharmaceutically acceptable salts.

2. The stable, prolonged release pharmaceutical composition as claimed in claim 1, comprising nicorandil and rate-controlling polymer.

3. The stable, prolonged release pharmaceutical composition as claimed in claim 2, wherein the rate controlling polymer is selected from the group comprising hydrophobic polymers, hydrophilic polymers, and/or a mixture thereof.

4. The stable, prolonged release pharmaceutical composition as claimed in claim 3, wherein the hydrophobic rate controlling polymer is selected from group comprising glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, polyglycolized glycerides hydrogenated castor oil, cetyl alcohol or mixtures thereof.

5. The stable, prolonged release pharmaceutical composition as claimed in claim 3, wherein the hydrophilic rate controlling polymer is selected from group comprising cellulose polymers and its derivatives.

6. The stable, prolonged release pharmaceutical composition as claimed in claim 5, wherein the cellulosic hydrophilic rate controlling polymer is hydroxypropyl methyl cellulose.

7. The stable, prolonged release pharmaceutical composition as claimed in claim 6, wherein hydroxypropyl methyl cellulose in an amount ranging from 2 to 80% of the total weight of composition.

8. The stable, prolonged release pharmaceutical composition as claimed in claim 1, wherein the nitrate impurity observed after storage of tablet at 2 to 8 0C is less than 2.5% w/w.

9. The stable, prolonged release pharmaceutical composition as claimed in claim 1, wherein dissolution of prolonged release tablet is 35% after 2 hours and at least 80% after 8 hours.

10. The process for preparation of stable, prolonged release composition of nicorandil comprising the steps of:
(a) mixing diluent and rate controlling polymer with one or more excipients, to form a premix;
(b) adding premix of step (a) to non-aqueous binder solution to form a wet mass;
(c) drying the wet granulated mass obtained in step (b),
(d) adding nicorandil and other extragranular excipients to granules obtained in step (c);
(e) lubricating the blend obtained in step (d); and
(f) compressing the blend of step (e) with suitable tooling punches to get a tablet.