Abstract: A method for producing a stable preparation containing nicorandil, a saturated higher aliphatic acid or a saturated higher alcohol which is solid at ordinary temperatures, and optionally, an organic acid such as fumaric acid, oxalic acid, salicylic acid, tartaric acid or glutaric acid is disclosed.Nicorandil is useful as a curative for various types of angina pectoris. However, it is unstable in humid conditions and under the compressive pressure exerted by punching operations in tablets making and, therefore, the development of a stable nicorandil preparation has been desired.
Claim: We claim:
1. A process for producing a stable nicorandilcontaining pharmaceutical composition, comprising mixing nicorandil with a protecting compound which is solid at ordinary temperatures andwhich protects nicorandil from decomposing under humid conditions selected from the group consisting of a saturated higher aliphatic acid, a saturated higher alcohol, and a mixture thereof, and formulating the mixture into a suitable dosage form.
2. The process according to claim 1 wherein said mixing is further carried out with at least one organic acid selected from the group consisting of fumaric acid, oxalic acid, salicylic acid, tartaric acid and glutaric acid.
3. The process according to claim 2 wherein the organic acid is present in an amount of at least 0.1% of the total weight of the nicorandil-containing composition.
4. The process according to claim 1 wherein the saturated higher aliphatic acid or the saturated higher alcohol or mixture thereof is present in an amount of at least 0.5% of the total weight of the nicorandil-containing composition.
5. The process according to claim 2 wherein the saturated higher aliphatic acid or the saturated higher alcohol or mixture thereof is present in an amount of at least 0.5% of the total weight of the nicorandil-containing composition.
6. The process according to claim 3 wherein the saturated higher aliphatic acid or the saturated higher alcohol or mixture thereof is present in an amount of at least 0.5% of the total weight of the nicorandil-containing composition.
7. The process according to claim 1 wherein said protecting compound comprises lauric acid, myristic acid or myristyl alcohol.
8. A process for producing a stable nicorandilcontaining pharmaceutical composition which comprises mixing nicorandil with a saturated higher aliphatic acid selected from the group consisting of palmitic acid and stearic acid or a saturatedhigher alcohol selected from the group consisting of cetyl alcohol and stearyl alcohol and formulating the mixture in a suitable dosage form.
9. A process for producing a stable nicorandilcontaining pharmaceutical composition which comprises mixing nicorandil with at least one organic acid selected from the group consisting of fumaric acid, oxalic acid, salicylic acid, tartaric acidand glutaric acid and a saturated higher aliphatic acid selected from the group consisting of palmitic acid and stearyl acid or a saturated higher alcohol selected from the group consisting of cetyl alcohol and stearyl alcohol and formulating the mixturein a suitable dosage form.
10. The process according to claim 8 wherein the saturated higher aliphatic acid is palmitic acid.
11. The process according to claim 8 wherein the saturated higher alcohol is cetyl alcohol.
12. The process according to claim 9 wherein the organic acid is glutaric acid.
13. The process according to claim 9 wherein the organic acid is present in an amount of at least 0.1% of the total weight of the nicorandil-containing preparation.
14. The process according to claim 8 wherein the saturated higher aliphatic acid or the saturated higher alcohol is present in an amount of at least 0.5% of the total weight of the nicorandil-containing preparation.
15. The process according to claim 8 wherein the saturated higher aliphatic acid is stearic acid.
16. The process according to claim 8 wherein the saturated higher alcohol is stearyl alcohol.
17. The process according to claim 14 wherein the dibasic acid is oxalic acid.
18. The process according to claim 14 wherein the dibasic acid is salicylic acid.
19. The process according to claim 14 wherein the dibasic acid is tartaric acid.
20. The process according to claim 14 wherein the dibasic acid is fumaric acid.
Description: The present invention relates to a method for producing a stable preparation of nicorandil[N-(2-hydroxyethyl)nicotinamide nitrate ester]. More particularly, the present invention relates to 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 asaturated 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 andglutaric acid.
Nicorandil has 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 cardiacfunctions (see Japanese Patent Publication No. 17463/1983 and Unexamined Published Japanese Patent Application No. 9323/1978).
Nicorandil preparations are relatively stable in the dry state but are unstable in humid conditions and must be produced and stored with special care being taken to avoid direct contact with moisture by, for example, wrapping in a completelymoistureproof package which, however, is quite expensive.
Nicorandil is also relatively stable in its crystalline form but it has been shown that if nicorandil is compressed into a tablet by routine procedures it becomes unstable and its content in the tablet is likely to experience a time-dependentdecrease. In order to avoid this problem it is conventional practice to coat the nicorandil crystal with one or more fatty or waxy substances which are solid at ordinary temperatures before compressing the same into a tablet (Unexamined publishedJapanese Patent Application No. 145659/1982). This is indeed an effective method for stabilizing nicorandil but, on the other hand, it is very expensive since not only does it require apparatus or equipment for coating the nicorandil crystal withnormally solid fatty or waxy materials but also the coating step is time-consuming.
The present inventors therefore conducted intensive studies in order to develop a method for providing a nicorandil preparation which is stable not only in humid conditions but also under the compressive pressure exerted by punching operations intablet making. Since the stability of nicorandil preparations was found to decrease as more pressure was exerted in compressing them into tablets, the present inventors noted the need to avoid the deformation of the nicorandil crystal and distortion ofits crystal lattices that would take place under compressive force. Magnesium stearate and calcium stearate are conventionally used for the purpose of reducing the friction that will occur between powder particles when they are compressed into compacts. Therefore, the inventors mixed nicorandil with progressively increasing amounts (i.e., several to ten-odd times the normally used amount) of these lubricants and compressed the mixture into tablets, which however proved to be still unsatisfactory interms of the stability of nicorandil.
Surprisingly enough, when nicorandil was mixed with a saturated higher aliphatic acid or a saturated higher alcohol which was solid at ordinary temperatures, and optionally with a certain type of organic acid, a nicorandil preparation havingremarkably improved stability could be obtained by compressing the mixture into tablets.
The present invention has been accomplished on the basis of this finding and the method it proposes is entirely different from the conventional method of coating the nicorandil crystal with a normally solid fatty or waxy material. In one aspect,the present invention relates to a method for producing a stable nicorandil preparation by mixing nicorandil with at least 0.5% (on the basis of the weight of the preparation) of a saturated higher aliphatic acid or a saturated higher alcohol which aresolid at ordinary temperatures. In another aspect, the invention relates to a method for producing a stable nicorandil preparation by mixing niorandil with at least 0.1% (on the basis of the weight of the preparation) of an organic acid and at least0.5% by weight of the preparation of a saturated higher aliphatic acid or a saturated higher alcohol which are solid at ordinary temperatures.
In addition to its ability to produce a stable nicorandil preparation, the method of the present invention has the advantage that it obviates the need to apply a coating on the nicorandil crystal and therefore that it does not require any coatingapparatus or equipment.
FIG. 1 is a graph showing the dissolution profiles of the slow release tablet of nicorandil prepared in Example 8 (- -) and of the tablet prepared in the comparative example (-o-).
In accordance with the presentinvention, a composition consisting of the nicorandil crystal and a pharmaceutical vehicle such as an excipient, disintegrator, lubricant, colorant or binder is blended with at least 0.5% by weight of a saturated higher aliphatic acid or a saturatedhigher alcohol which is solid at ordinary temperatures, and optionally with at least 0.1% by weight of an organic acid, and the resulting blend is processed into a desired dosage form, such as tablet, capsule, granule or suppository, by a conventionalmethod.
Dibasic acids such as fumaric acid, oxalic acid, salicylic acid, tartaric acid and glutaric acid are particularly preferable for use as organic acids in the present invention. Particularly preferable examples of the saturated higher aliphaticacid which is solid at ordinary temperatures are palmitic acid, lauric acid, myristic acid and stearic acid. Particularly preferable examples of the saturated higher alcohol which is solid at ordinary temperatures are cetyl alcohol, myristyl alcohol andstearyl alcohol. Suitable pharmaceutical vehicles include: lactose, cornstarch, mannitol, kaolin, crystalline cellulose, carboxymethyl cellulose, crosscarmellose sodium, talc, anhydrous calcium hydrogenphosphate, calcium carbonate, calcium citrate,calcium stearate and magnesium stearate.
Among the organic acids listed above which exhibit the activity of stabilizing nicorandil, fumaric acid displays the additional advantage of enabling the production of a slow-release nicorandil preparation wherein nicorandil is slowly releasedover time.
The sustained release preparation of nicorandil may be produced by weighing predetermined amounts of nicorandil and an excipient, then mixing them, by a routine method, with at least about 10% by weight of the preparation of fumaric acid and withat least one of the saturated higher aliphatic acids or saturated higher alcohols which are solid at ordinary temperatures. To the so prepared mixed powder, a lubricant such as magnesium stearate, calcium stearate or talc is added and the mixture issubsequently compressed into tablets.
If desired, nicorandil may be formulated in troches by mixing it with the necessary ingredients and with sucrose, flavor or colorant, then compressing the mixture into a desired shape.
In order to obtain the increase in the amount of released nicorandil after the elapse of a predetermined time after administration, nicorandil may be formulated in a multi-layered tablet by laminating a nicorandil-containing layer A on a layer Bwhich is free from nicorandil, then compressing the two layers into a tablet.
Alternatively, nicorandil may be formulated in granules, capsules, or enteric granules having a coating of hydroxypropylmethyl cellulose phthalate, carboxymethylethyl cellulose, etc.
The nicorandil preparation produced by the method of the present invention has the advantage of exhibiting high stability not only in humid conditions but also when it is compressed into tablets.
The following examples are provided for the purpose of further illustrating the present invention but are in no way to be taken as limiting.
EXAMPLE 1
______________________________________ Tablet formulation (for one tablet) ______________________________________ Nicorandil 10 (mg) Stearic acid 8 Mannitol 65.7 Cornstarch 15 Methyl cellulose 0.3 Magnesium stearate 1 Total 100.0 (mg) ______________________________________
Mannitol (65.7 g), cornstarch (15 g) and methyl cellulose SM-400 (0.3 g. product of Shinetsu Chemical Industry Co., Ltd.) were mixed well in a mortar and kneaded with water. The blend was passed through a 30-mesh screen and dried at 45.degree. C. for 3 hours. The dried particles were classified by passage through a 30-mesh sieve to prepare a granulation.
Nicorandil (10 g), stearic acid that had been sieved through a 35-mesh screen (8 g), the granulation (81 g) and magnesium stearate (1 g) were mixed in a polyethylene bag, and the mixture was compressed at 2,000 kg/cm.sup.2 in die 7 mm.sup..phi.)to make tablet each weighing 100 mg.
Comparative tablets were made under the same conditions except that stearic acid was replaced by the same amount of mannitol.
Each of the two groups of tablets was divided into two subgroups. The tablets in one subgroup were vacuum-dried with P.sub.2 O.sub.5 as a desiccant) to make them substantially water-free, and the tablets in the other subgroup remainedundehydrated. All of the tablets were then put into glass bottles, screw-capped, and stored at 40.degree. C. for 3 months. The stability of the tablets was evaluated in terms of the residual amount of nicorandil as a percentage of the initial weightbefore acceleration. The results are shown in Table 1 below.
TABLE 1 ______________________________________ Residual nicorandil (%) Tablet Dried Undried ______________________________________ sample of the present invention 99.1 97.8 comparative sample 71.5 35.9 ______________________________________
EXAMPLE 2
______________________________________ Tablet formulation (for one tablet) ______________________________________ Nicorandil 10 (mg) Stearyl alcohol 10 Mannitol 72.4 Carboxymethyl 5 cellulose calcium Hydroxypropyl 1.6 cellulose Calciumstearate 1 Total 100.0 (mg) ______________________________________
Stearyl alcohol (10 g) that had been passed through a 35-mesh screen, mannitol (72.4 g), carboxymethyl cellulose calcium (5 g) and hydroxypropyl cellulose HPC-L (1.6 g, product of Nippon Soda Co., Ltd.) were mixed well in a mortar and kneadedwith water. The blend was passed through a 30-mesh screen and dried at 40.degree. C. for 5 hours. The dried particles were classified by passage through a 30-mesh sieve to prepare a granulation.
Nicorandil (10 g), the granulation (89 g) and calcium stearate (1 g) were mixed in a polyethylene bag and the mixture was compressed at 2,000 kg/cm.sup.2 in die (7 mm.sup..phi.) to make tablets each weighing 100 mg.
Comparative samples were made under the same conditions except that stearyl alcohol was replaced by the same amount of mannitol.
The two types of tablets thus prepared were subjected to a stability test as in Example 1. The results are shown in Table 2.
TABLE 2 ______________________________________ Residual nicorandil (%) Tablet Dried Undried ______________________________________ sample of the present invention 99.4 96.1 comparative sample 72.3 41.1 ______________________________________
EXAMPLE 3
______________________________________ Tablet formulation (for one tablet) ______________________________________ Nicorandil 10 (mg) Palmitic acid 3 Lactose 82 Crosscarmellose 5 sodium Total 100.0 (mg) ______________________________________
Nicorandil (10 g), palmitic acid (3 g) that had been comminicated to an average particle size 1-3 .mu.m with a micro jet mill (Model FS-4 of Seishin Kigyo K.K.), lactose (82 g) and crosscarmellose sodium (5 g, Ac-Di-Sol.RTM. of FMC Corporation)were mixed in a polyethylene bag. The mixed powder was compressed at 2,000 kg/cm.sup.2 in die (7 mm.sup..phi.) to make tablets each weighing 100 mg.
Comparative tablets were made under the same conditions except that palmitic acid was replaced by the same amount of magnesium stearate.
The two types of tablets thus prepared were subjected to a stability test as in Example 1. The results are shown in Table 3.
TABLE 3 ______________________________________ Residual nicorandil (%) Tablet Dried Undried ______________________________________ sample of the present invention 97.3 90.6 comparative sample 75.8 56.2 ______________________________________
EXAMPLE 4
______________________________________ Tablet formulation (for one tablet) ______________________________________ Nicorandil 10 (mg) Stearic acid 16 Lactose 65 Crosscarmellose 8 sodium Cornstarch 1.0 Total 100.0 (mg) ______________________________________
Stearic acid (16 g), lactose (65 g) and crosscarmellose sodium (8 g, Ac-Di-Sol.RTM. of FMC Corporation) were mixed well in a mortar and then kneaded with 20 g of 5% cornstarch paste. The blend was sieved through a 30-mesh screen and dried at45.degree. C. for 4 hours. The dried particles were classified by passage through a 30-mesh sieve to make a granulation.
The granulation (90 g) and nicorandil (10 g) were mixed in a polyethylene bag and the mixture was compressed at 2,000 kg/cm.sup.2 in die (7 mm.sup..phi.) to make tablets each weighing 100 mg.
Three types of comparative tablets were made under the same conditions as above except that stearic acid was replaced by equal amounts of calcium stearate, hardened castor oil (Lubri Wax 101.RTM. of Freund Sangyo K.K.), and carnauba wax.
Each of the four groups of tablets was divided into two subgroups. They were put into glass bottles and stored under accelerated conditions at 50.degree. C. One set of subgroups was held for 14 days with the bottles screw-capped, whereas theother set of subgroups was held for 7 days at 50% R.H., with the bottles left open. The results of this stability test are shown in Table 4.
TABLE 4 ______________________________________ Residual nicorandil (%) 7 days in open bottles 14 days in Tablet at 50% R.H. closed bottles ______________________________________ sample stearic acid 89.9 83.6 of the invention comparative calcium 59.3 45.5 samples stearate hardened 18.2 58.3 castor oil carnauba 42.5 57.1 wax ______________________________________
EXAMPLE 5
______________________________________ Tablet formulation (for one tablet) ______________________________________ Nicorandil 10 (mg) Lactose 65.5 Stearic acid 8 Crosscarmellose 5 sodium Fumaric acid 10 Cornstarch 1 Magnesium stearate 0.5 Total 100.0 (mg) ______________________________________
Lactose (65.5 g), stearic acid (8 g) and crosscarmellose sodium (5 g, Ac-Di-Sol.RTM. of FMC Corporation) were mixed in a mortar, then kneaded with 20 g of 5% cornstarch paste. The blend was sieved through a 30-mesh screen and dried at45.degree. C. for 4 hours. The dried particles were classified by passage through a 30-mesh screen to prepare a granulation.
Nicorandil (10 g), fumaric acid (10 g), the granulation (79.5 g) and magnesium stearate (0.5 g) were mixed in a polyethylene bag.
Using a single-punch tablet machine equipped with 7-mm.sup..phi. flat-faced punches, the mixed powder was compressed for a total pressure of about 1 ton to make tablets each weighing 100 mg.
Comparative tablets were made under the same conditions except that stearic acid and fumaric acid were replaced by an equal amount of lactose.
Each of the two groups of tablets was divided into two subgroups. They were put into glass bottles and stored under accelerated conditions at 40.degree. C. One set of subgroups was held for 3 months with the bottles screw-capped, whereas theother set of subgroups was held for 3 months at 61.5% R.H., with the bottles left open. The results of this stability test are shown in Table 5.
TABLE 5 ______________________________________ Residual nicorandil (%) in open bottles Tablet in closed bottles at 61.5% R.H. ______________________________________ sample of the 98.5 97.8 present invention comparative 63.2 25.6 sample ______________________________________
EXAMPLE 6
______________________________________ Capsule formulation (for one capsule) ______________________________________ Nicorandil 10 (mg) Mannitol 40 Fumaric acid 10 Stearyl alcohol 30 Carboxymethyl 10 cellulose calcium Total 100.0 (mg) ______________________________________
Nicorandil (10 g), mannitol (40 g), fumaric acid (10 g), stearyl alcohol (30 g) and carboxymethyl cellulose calcium (10 g) were mixed in a mortar and then kneaded with 22 g of 20% ethanol. The blend was sieved through a 14-mesh screen and driedat 40.degree. C. for 6 hours. The dried particles were classified by passage through a 10-mesh screen to prepare a granulation.
The granules were filled into No. 3 capsules so that each of them would contain 100 mg of the granules.
Comparative capsules were prepared under the same conditions except that fumaric acid and stearyl alcohol were replaced by an equal amount of mannitol.
Each of the two groups of capsules was divided into two subgroups. They were put into glass bottles and stored under accelerated conditions at 40.degree. C. One set of subgroups was held for 3 months with the bottles screw-capped in thepresence of a desiccant (silica gel), whereas the other set was held for 3 months with the bottles screw-capped but in the absence of silica gel. The results of this stability test are shown in Table 6.
TABLE 6 ______________________________________ Residual nicorandil (%) Tablet with a desiccant without desiccant ______________________________________ sample of the 98.9 96.5 invention comparative sample 56.3 19.2 ______________________________________
EXAMPLE 7
______________________________________ Tablet formulation (for one tablet) ______________________________________ Nicorandil 10 (mg) Mannitol 52 Salicylic acid 5 Palmitic acid 2 Cornstarch 10 Crystalline 20 cellulose Calcium stearate 1 Total 100.0 (mg) ______________________________________
Nicorandil (10 g), mannitol (52 g), salicylic acid (5 g), palmitic acid (2 g), cornstarch (10 g), crystalline cellulose (20 g) and calcium stearate (1 g) were mixed in a polyethylene bag.
Using a single-punch tablet machine equipped with 7-mm.sup..phi. flat-faced punches, the mixed powder was compressed at 1 ton to make tablets each weighing 100 mg.
Comparative tables were made under the same conditions except that salicylic acid and palmitic acid were replaced by an equal amount of mannitol.
Each of the two groups of tablets was divided into two subgroups. They were put into glass bottles and stored under accelerated conditions at 40.degree. C. One set of subgroups was held for 3 months with the bottles screw-capped, whereas theother set of subgroups was held for 3 months at 61.5% R.H. With the bottles left open. The results of this stability test are shown in Table 7.
TABLE 7 ______________________________________ Residual nicorandil (%) in open bottles Tablet in closed bottles at 61.5% R.H. ______________________________________ sample of the 78.2 81.3 invention comparative 41.8 5.5 sample ______________________________________
EXAMPLE 8
______________________________________ Slow-release tablet formulation (for one tablet) Lower layer Upper layer ______________________________________ Nicorandil 10 (mg) -- Fumaric acid 85.5 39.8 (mg) Stearic acid 4 -- Calcium stearate 0.50.2 Total 100.0 (mg) 40.0 (mg) ______________________________________
Nicorandil (10 g), fumaric acid (85.5 g), stearic acid (4 g) and calcium stearate (0.5 g) were mixed well in a polyethylene bag to prepare a mixture (mixed powder A).
In a separate step, fumaric acid (39.8 g) and calcium stearate (0.2 g) were mixed in a polyethylene bag to prepare a mixture (mixed powder B).
Using a single-punch tablet machine equipped with 8-mm.sup..phi. flat-faced punches, mixed powder A (100 mg) was filled into the die and lightly compressed. Then, mixed powder B (40 mg) was fed on the compressed mixed powder A and compressed at1.3 tons to make slow-release tablets.
COMPARATIVE EXAMPLE
______________________________________ Slow-release tablet formulation (for one tablet) Lower layer Upper layer ______________________________________ Nicorandil 10 (mg) -- Hydroxypropyl 89.5 39.8 (mg) cellulose Calcium stearate 0.5 0.2 Total 100.0 (mg) 40.0 (mg) ______________________________________
Nicorandil (10 g), hydroxypropyl cellulose (89.5 g, HPC-L of Nippon Soda Co., Ltd.) and calcium stearate (0.5 g) were mixed well in a polyethylene bag to make a mixture (mixed powder A).
In a separate step, hydroxypropyl cellulose (39.8 g, HPC-L) and calcium stearate (0.2 g) were mixed well in a polyethylene bag to make a mixture (mixed powder B).
Using a single-punch tablet machine equipped with 8-mm.sup..phi. flat-faced punches, mixed powder A (100 mg) was filled into the dies and lightly compressed. Then, mixed powder B (40 mg) was fed on the compressed mixed powder A and compressedat 1.3 tons to make comparative slow-release tablets.
The two types of slow-release tablets were subjected to a dissolution test and the results are shown as dissolution profiles in FIG. 1. The dissolution test was conducted in 500 ml of distilled water by the method defined in JapanesePharmacopoeia, 10th Edition, Dissolution Test Method 1 (the rotary basket method) at a rotational speed of 100 rpm.
Each of the two groups of slow-release tablets was divided into two subgroups. They were put into glass bottles and stored under accelerated conditions at 50.degree. C. One set of subgroups was held for 10 days in the presence of a desiccant(silica gel) with the bottles screw-capped. The other set of subgroups was held for 5 days at 50% R.H. with the bottles left open. The results of this stability test are shown in Table 8.
TABLE 8 ______________________________________ Residual nicorandil (%) in closed bottles containing in open bottles Tablet silica gel at 50% R.H. ______________________________________ sample of the 91.3 95.6 invention comparative sample 65.4 44.5 ______________________________________
EXAMPLE 9
______________________________________ Tablet formulation (for one tablet) ______________________________________ Nicorandil 5 (mg) Lauric acid 10 Mannitol 45.5 Low-substituted 7 hydroxypropyl cellulose Hydroxypropyl cellulose 1.5 Calciumstearate 1 Total 70 (mg) ______________________________________
Lauric acid (10 g.), mannitol (45.5 g), low-substituted hydroxypropyl cellulose L-HPC LH-31 (7 g, product of Shinetsu Chemical Industry Co., Ltd.) and hydroxypropyl cellulose PHC-L (1.5 g, product of Nippon Soda Co., Ltd.) were mixed well in amortar and kneaded with water. The blend was passed through a 30-mesh screen and dried at 40.degree. C. for 5 hours. The dried particles were classifed by passage through a 30-mesh sieve to prepare a granulation.
Nicorandil (5 g), the granulation (64 g) and calcium stearate (1 g) were mixed in a polyethylene bag, and the mixture was compressed at 1,500 kg/cm.sup.2 in a die (6 mm.sup..phi.) to make tablets each weighing 70 mg.
Comparative tablets were made under the same conditions except that lauric acid was replaced with the same amount of mannitol.
Each of the two groups of tablets was divided into two subgroups. The tablets in one subgroup were vacuum-dried (with P.sub. 2O.sub. 5 as a desiccant) to make them substantially water-free, and the tablets in the other subgroup remainedundehydrated. All of the tablets were then put into glass bottles, screw-capped, and stored at 40.degree. C. for 3 months.
The stability of the tablets was evaluated in terms of the residual amount of nicorandil as a percentage of the initial weight before acceleration. The results are shown in Table 9.
TABLE 9 ______________________________________ Residual nicorandil (%) Tablet Dried Undried ______________________________________ Sample of the present 96.6 91.8 invention comparative sample 72.3 57.9 ______________________________________
EXAMPLE 10
______________________________________ Tablet formulation (for one tablet) ______________________________________ Nicorandil 10 (mg) Myristyl alcohol 10 Lactose 62 Cornstarch 15 Hydroxypropyl 2 methyl cellulose Magnesium stearate 1 Total100 (mg) ______________________________________
Myristyl alcohol (10 g), lactose (62 g), cornstarch (15 g) and hydroxypropyl methyl cellulose 60SH-50 (2 g, product of Shinetsu Chemical Industry Co., Ltd.) were mixed well in a mortar and kneaded with water. The blend was passed through a30-mesh screen and dried for 8 hours with the blend exposed to cold air. The dried particles were classified by passage through a 24-mesh sieve to prepare a granulation.
Nicorandil (10 g), the granulation (89 g) and magnesium stearate (1 g) were mixed in a polyethylene bag, and the mixture was compressed at 2,000 kg/cm.sup.2 in a die (7 mm.sup..phi.) to make tablets each weighing 100 mg.
Comparative tablets were made under the same conditions except that myristyl alcohol was replaced with the same amount of lactose.
Each of the two groups of tablets was put into glass bottles, screw-capped, and stored at 35.degree. C. for 3 months.
The stability of the tablets was evaluated in terms of the residual amount of nicorandil as a percentage of the initial weight before acceleration. The results are shown in Table 10.
TABLE 10 ______________________________________ Tablet Residual nicorandil (%) ______________________________________ sample of the present 97.1 invention comparative sample 79.8 ______________________________________
EXAMPLE 11
______________________________________ Tablet formulation (for one tablet) ______________________________________ Nicorandil 10 (mg) Myristic acid 8 Mannitol 76 Crosscarmellose sodium 5 Calcium stearate 1 Total 100 (mg) ______________________________________
Mannitol (76 g) and myristic acid (8 g) were mixed well and heated at 70.degree. C. for 15 minutes. The heated mixture was passed through a 24-mesh screen to prepare a granulation.
Nicorandil (10 g), the granulation (84 g), cross-carmellose sodium (5 g) and calcium stearate (1 g) were mixed in a polyethylene bag, and the mixture was compressed at 2,000 kg/cm.sup.2 in a die (7 mm.sup..phi.) to make tablets each weighing 100mg.
Comparative tablets were made under the same conditions except that myristic acid was replaced with the same amount of polyethylene glycol 6000.
The two types of tablets thus prepared were subjected to the same stability test as in Example 9. The results are shown in Table 11.
TABLE 11 ______________________________________ Residual nicorandil (%) Tablet Dried Undried ______________________________________ sample of the present 96.8 92.5 invention comparative sample 71.9 45.3 ______________________________________
EXAMPLE 12
______________________________________ Capsule formulation (for one capsule) ______________________________________ Nicorandil 10 (mg) Lactose 65 Fumaric acid 15 Lauric acid 10 Total 100 (mg) ______________________________________
Nicorandil (10 g), lactose (65 g), fumaric acid (15 g) and lauric acid (10 g) were mixed in a mortor and then kneaded well with water. The blend was sieved through a 14-mesh screen and dried at 40.degree. C. for 6 hours. The dried particleswere classified by passage through 10-mesh screen to prepare a granulation.
No. 3 capsules were filled with the granules so that each of them would contain 100 mg of granules.
Comparative capsules were prepared under the same conditions except that fumaric acid and lauric acid were replaced with an equal amount of lactose.
Each of these two groups of capsules was divided into two subgroups. They were put into glass bottles and stored under accelerated conditions at 40.degree. C. One set of subgroups was held for 3 months with the bottles screw-capped in thepresence of a desiccant (silica gel), whereas the other set was held for 3 months with the bottles screw-capped but in the absence of a desiccant.
The stability of the capsules was evaluated in terms of the residual amount of nicorandil as a percentage of the initial weight before acceleration. The results are shown in Table 12.
TABLE 12 ______________________________________ Residual nicorandil (%) Capsule with a desiccant without a desiccant ______________________________________ sample of the present 98.5 97.3 invention comparative sample 49.9 16.1 ______________________________________
EXAMPLE 13
______________________________________ Stabilized granule formulation (for one gram of the granules) ______________________________________ Nicorandil 100 (mg) Mannitol 700 Myristic acid 100 Salicylic acid 200 Total 1000 (mg) ______________________________________
Nicorandil (10 g), mannitol (70 g), myristic acid (10 g) and salicyclic acid (10 g) were mixed well and heated at 70.degree. C. for 15 minutes. The heated particles were sieved through a 30-mesh screen to prepare stabilized granules.
Comparative granules were prepared under the same conditions except that myristic acid was replaced with an equal amount of polyethylene glycol (6000 and salicyclic acid with an equal amount of benzoic acid).
The stability of the granules was evaluated in terms of the residual amount of nicorandil as a perl amount of benzoic acid).
The stability of the granules was evaluated in terms of the residual amount of nicorandil as a percentage of the initial weight before acceleration. The results are shown in Table 13.
TABLE 13 ______________________________________ Stabilized granule Residual nicorandil (%) ______________________________________ sample of the present 95.8 invention comparative sample 31.8 ______________________________________
2/06/2009
Nicorandil Tablets
Prescriber Criteria: Consultant Cardiologist
Consultant Physician
Clinical Indications: For the prophylaxis and treatment of unstable angina.
Conditions qualifying patients for drug:
This drug is to be used in patients suffering from unstable angina who are on triple drug
therapy, and in whom surgical procedures are not possible.
Frequency of review: At yearly intervals.
Duration of Approval: 1 year.
Consultant Physician
Clinical Indications: For the prophylaxis and treatment of unstable angina.
Conditions qualifying patients for drug:
This drug is to be used in patients suffering from unstable angina who are on triple drug
therapy, and in whom surgical procedures are not possible.
Frequency of review: At yearly intervals.
Duration of Approval: 1 year.
Nicorandil is sometimes known as Ikorel, which is its trade name
PATIENT INFORMATIONCardiac Care UnitReference No: 5350-1Issued: 08-Nov-07Valid until: 08-Nov-09Page: 1 of 2Drug Information LeafletYour GP may give you the same tablets known by a different name—the brand name.You should always check with your GP or Pharmacist if you are unsure.NicorandilThe information in this leaflet is intended for general guidance. If your doctor has givenyou different advice, follow his/her instructions.Nicorandil is sometimes known as Ikorel, which is its trade name.What is nicorandil used for?Nicorandil is used primarily for the treatment of angina in combination with other anti-anginal medications.How does it work?Nicorandil works by relaxing the muscles within the walls of the coronary arteries. Thisallows greater blood flow and hence oxygen delivery to the heart muscle reducing thelikelihood of experiencing angina pain.Possible side effects•Headache (usual within the first few days of treatment)•Dizziness as a result of low blood pressure•Flushing•Nausea and vomitingIf you experience any of the above side effects or if you have any concerns, pleaseconsult your doctor.What if I miss a dose?Try to take your nicorandil tablet the same time each day. Incorporate the administrationof your medication into your routine. If you miss your dose, do not take the tablet but waituntil the next time your medication is due. Never take a ‘double dose’.Please ensure the tablets are only taken from one strip at a time as each strip contains adesiccant or drying agent.
2/05/2009
nicorandil drug, Ikorel (nicorandil)
How does it work?
Ikorel tablets contain the active ingredient nicorandil, which is a type of medicine called a potassium-channel activator. It is used to help the heart work more easily.
The pain of angina is caused by too little oxygen reaching the heart when its workload increases, such as during exercise. This is usually a result of hardening of the arteries (atherosclerosis) that supply blood to the heart. This is also known as coronary heart disease. Nicorandil decreases the workload of the heart and also improves its blood and therefore oxygen supply.
Nicorandil works by acting on potassium channels that are found on muscle cells within the walls of blood vessels. It opens these channels, which causes the muscle cells to relax. When the muscle cells in the walls of blood vessels relax, it allows the blood vessels to widen.
Nicorandil widens the arteries that take blood from the heart to the rest of the body. This reduces the resistance within these arteries, which makes it easier for the heart to pump the blood around the body.
Nicorandil also widens the veins that return the blood to the heart. This decreases the volume of blood that returns to the heart with each heartbeat, and this makes it easier for the heart to pump that blood out again.
As a result of both these actions, the heart requires less energy to pump the blood around the body and therefore does not need as much oxygen. Nicorandil also widens the coronary arteries within the heart itself, and this increases the blood and oxygen supply to the heart muscle. Both these actions help to prevent the pain of angina.
Nicorandil is taken on regular basis to help the heart work more easily and thus prevent angina attacks. It has also been shown to reduce the risk of the complications of coronary heart disease and angina, such as heart attacks, angina that occurs at rest and death from heart disease.
What is it used for?
Angina pectoris.
Preventing the complications of coronary heart disease and angina, such as heart attack, unstable angina or death from heart disease.
Warning!
This medicine might make you feel dizzy and so may reduce your ability to drive or operate machinery safely. Do not drive or operate machinery until you know how this medicine affects you and you are sure it won't affect your performance.
If you drink alcohol while taking this medicine it might make you feel dizzy. Tell your doctor if this is the case.
This medicine may very rarely cause ulceration or bleeding in the stomach or intestines, including anal ulceration and rectal bleeding. If it occurs, the ulceration is often severe and in a few people can lead to perforation (holes appearing) in the gut. Although these types of ulcers are very rare, they usually only get better if treatment with this medicine is stopped. For this reason, it is important that you consult your doctor immediately if you experience any sign of ulceration or bleeding from the stomach or intestine, for example bleeding from the back passage, ulcers, pain, irritation or itching in the back passage, vomiting blood, or passing black/tarry/bloodstained stools. If it is decided that you should stop treatment with this medicine this should only be done under the supervision of your cardiologist, to avoid your heart condition getting worse.
Use with caution in
People with a low volume of circulating blood (hypovolaemia), for example due to blood loss or dehydration.
People with fluid in the lungs (pulmonary oedema).
People taking medicines to treat high blood pressure (see end of factsheet for more information).
Not to be used in
Failure of the heart to maintain adequate circulation of blood (cardiogenic shock).
Left-sided heart failure (left ventricular failure with low filling pressures).
Low blood pressure (hypotension).
Breastfeeding.
This medicine is not recommended for children.
This medicine should not be used if you are allergic to one or any of its ingredients. Please inform your doctor or pharmacist if you have previously experienced such an allergy.
If you feel you have experienced an allergic reaction, stop using this medicine and inform your doctor or pharmacist immediately.
Pregnancy and breastfeeding
Certain medicines should not be used during pregnancy or breastfeeding. However, other medicines may be safely used in pregnancy or breastfeeding providing the benefits to the mother outweigh the risks to the unborn baby. Always inform your doctor if you are pregnant or planning a pregnancy, before using any medicine.
The safety of this medicine during pregnancy has not been established. The manufacturer therefore advises that it should not be used during pregnancy unless there is no safer alternative. Seek medical advice from your doctor.
It is not known if this medicine passes into breast milk. For this reason, it should not be used by breastfeeding mothers. Women who need treatment with this medicine should not breastfeed. Seek medical advice from your doctor.
Side effects
Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated with this medicine. Just because a side effect is stated here does not mean that all people using this medicine will experience that or any side effect.
Very common (affects more than 1 in 10 people)
Headache, particularly in the first few days of treatment, but this usually disappears with time.
Common (affects between 1 in 10 and 1 in 100 people)
Dizziness.
Nausea and vomiting.
Increased blood flow to the skin (flushing).
Feeling of weakness.
Uncommon (affects between 1 in 100 and 1 in 1000 people)
Increased heart rate at high doses.
Low blood pressure at high doses.
Mouth ulcers.
Rare (affects between 1 in 1000 and 1 in 10,000 people)
Rash.
Abnormal liver function.
Pain in the muscles.
Persistant mouth ulcers that may be severe.
Very rare (affects less than 1 in 10,000 people)
Swelling of the lips and tongue (allergic reaction called angieodema - seek medical attention straight away if you experience these symptoms).
Ulceration and bleeding in the stomach or intestine, including anal ulceration or bleeding from the rectum (see warning above).
The side effects listed above may not include all of the side effects reported by the medicine's manufacturer.
For more information about any other possible risks associated with this medicine, please read the information provided with the medicine or consult your doctor or pharmacist.
How can this medicine affect other medicines?
It is important to tell your doctor or pharmacist what medicines you are already taking, including those bought without a prescription and herbal medicines, before you start treatment with this medicine. Similarly, check with your doctor or pharmacist before taking any new medicines while taking this one, to ensure that the combination is safe.
This medicine must not be used in combination with any of the following medicines that are used to treat erectile dysfunction (impotence):
sildenafil (Viagra)
tadalafil (Cialis)
vardenafil (Levitra).
This is because the combination of these medicines and nicorandil can cause a dangerous drop in blood pressure.
If this medicine is taken with any of the following medicines, the combination might cause your blood pressure to drop. If your blood pressure falls too low it might make you feel dizzy, in which case lie down until the feeling passes. You should let your doctor know if you feel dizzy while taking this medicine with any of those listed below, in case your doses need adjusting:
other medicines that widen the blood vessels (eg alpha-blockers, nitrates, calcium channel blockers, minoxidil, hydralazine)
medicines to treat high blood pressure (antihypertensives)
medicines that can decrease blood pressure as a side effect (eg tricyclic antidepressants, sedatives).
Other medicines containing the same active ingredient
There are currently no other medicines available in the UK that contain nicorandil as the active ingredient.
Ikorel tablets contain the active ingredient nicorandil, which is a type of medicine called a potassium-channel activator. It is used to help the heart work more easily.
The pain of angina is caused by too little oxygen reaching the heart when its workload increases, such as during exercise. This is usually a result of hardening of the arteries (atherosclerosis) that supply blood to the heart. This is also known as coronary heart disease. Nicorandil decreases the workload of the heart and also improves its blood and therefore oxygen supply.
Nicorandil works by acting on potassium channels that are found on muscle cells within the walls of blood vessels. It opens these channels, which causes the muscle cells to relax. When the muscle cells in the walls of blood vessels relax, it allows the blood vessels to widen.
Nicorandil widens the arteries that take blood from the heart to the rest of the body. This reduces the resistance within these arteries, which makes it easier for the heart to pump the blood around the body.
Nicorandil also widens the veins that return the blood to the heart. This decreases the volume of blood that returns to the heart with each heartbeat, and this makes it easier for the heart to pump that blood out again.
As a result of both these actions, the heart requires less energy to pump the blood around the body and therefore does not need as much oxygen. Nicorandil also widens the coronary arteries within the heart itself, and this increases the blood and oxygen supply to the heart muscle. Both these actions help to prevent the pain of angina.
Nicorandil is taken on regular basis to help the heart work more easily and thus prevent angina attacks. It has also been shown to reduce the risk of the complications of coronary heart disease and angina, such as heart attacks, angina that occurs at rest and death from heart disease.
What is it used for?
Angina pectoris.
Preventing the complications of coronary heart disease and angina, such as heart attack, unstable angina or death from heart disease.
Warning!
This medicine might make you feel dizzy and so may reduce your ability to drive or operate machinery safely. Do not drive or operate machinery until you know how this medicine affects you and you are sure it won't affect your performance.
If you drink alcohol while taking this medicine it might make you feel dizzy. Tell your doctor if this is the case.
This medicine may very rarely cause ulceration or bleeding in the stomach or intestines, including anal ulceration and rectal bleeding. If it occurs, the ulceration is often severe and in a few people can lead to perforation (holes appearing) in the gut. Although these types of ulcers are very rare, they usually only get better if treatment with this medicine is stopped. For this reason, it is important that you consult your doctor immediately if you experience any sign of ulceration or bleeding from the stomach or intestine, for example bleeding from the back passage, ulcers, pain, irritation or itching in the back passage, vomiting blood, or passing black/tarry/bloodstained stools. If it is decided that you should stop treatment with this medicine this should only be done under the supervision of your cardiologist, to avoid your heart condition getting worse.
Use with caution in
People with a low volume of circulating blood (hypovolaemia), for example due to blood loss or dehydration.
People with fluid in the lungs (pulmonary oedema).
People taking medicines to treat high blood pressure (see end of factsheet for more information).
Not to be used in
Failure of the heart to maintain adequate circulation of blood (cardiogenic shock).
Left-sided heart failure (left ventricular failure with low filling pressures).
Low blood pressure (hypotension).
Breastfeeding.
This medicine is not recommended for children.
This medicine should not be used if you are allergic to one or any of its ingredients. Please inform your doctor or pharmacist if you have previously experienced such an allergy.
If you feel you have experienced an allergic reaction, stop using this medicine and inform your doctor or pharmacist immediately.
Pregnancy and breastfeeding
Certain medicines should not be used during pregnancy or breastfeeding. However, other medicines may be safely used in pregnancy or breastfeeding providing the benefits to the mother outweigh the risks to the unborn baby. Always inform your doctor if you are pregnant or planning a pregnancy, before using any medicine.
The safety of this medicine during pregnancy has not been established. The manufacturer therefore advises that it should not be used during pregnancy unless there is no safer alternative. Seek medical advice from your doctor.
It is not known if this medicine passes into breast milk. For this reason, it should not be used by breastfeeding mothers. Women who need treatment with this medicine should not breastfeed. Seek medical advice from your doctor.
Side effects
Medicines and their possible side effects can affect individual people in different ways. The following are some of the side effects that are known to be associated with this medicine. Just because a side effect is stated here does not mean that all people using this medicine will experience that or any side effect.
Very common (affects more than 1 in 10 people)
Headache, particularly in the first few days of treatment, but this usually disappears with time.
Common (affects between 1 in 10 and 1 in 100 people)
Dizziness.
Nausea and vomiting.
Increased blood flow to the skin (flushing).
Feeling of weakness.
Uncommon (affects between 1 in 100 and 1 in 1000 people)
Increased heart rate at high doses.
Low blood pressure at high doses.
Mouth ulcers.
Rare (affects between 1 in 1000 and 1 in 10,000 people)
Rash.
Abnormal liver function.
Pain in the muscles.
Persistant mouth ulcers that may be severe.
Very rare (affects less than 1 in 10,000 people)
Swelling of the lips and tongue (allergic reaction called angieodema - seek medical attention straight away if you experience these symptoms).
Ulceration and bleeding in the stomach or intestine, including anal ulceration or bleeding from the rectum (see warning above).
The side effects listed above may not include all of the side effects reported by the medicine's manufacturer.
For more information about any other possible risks associated with this medicine, please read the information provided with the medicine or consult your doctor or pharmacist.
How can this medicine affect other medicines?
It is important to tell your doctor or pharmacist what medicines you are already taking, including those bought without a prescription and herbal medicines, before you start treatment with this medicine. Similarly, check with your doctor or pharmacist before taking any new medicines while taking this one, to ensure that the combination is safe.
This medicine must not be used in combination with any of the following medicines that are used to treat erectile dysfunction (impotence):
sildenafil (Viagra)
tadalafil (Cialis)
vardenafil (Levitra).
This is because the combination of these medicines and nicorandil can cause a dangerous drop in blood pressure.
If this medicine is taken with any of the following medicines, the combination might cause your blood pressure to drop. If your blood pressure falls too low it might make you feel dizzy, in which case lie down until the feeling passes. You should let your doctor know if you feel dizzy while taking this medicine with any of those listed below, in case your doses need adjusting:
other medicines that widen the blood vessels (eg alpha-blockers, nitrates, calcium channel blockers, minoxidil, hydralazine)
medicines to treat high blood pressure (antihypertensives)
medicines that can decrease blood pressure as a side effect (eg tricyclic antidepressants, sedatives).
Other medicines containing the same active ingredient
There are currently no other medicines available in the UK that contain nicorandil as the active ingredient.
Nicorandil
Nicorandil is a drug used to treat angina. It is marketed under the trade names Ikorel (in the United Kingdom, Australia and most of Europe), Dancor (in Switzerland), Zynicor (in India), Aprior (in the Philippines) and Sigmart (in Japan, South Korea and Taiwan). Nicorandil is not available in the United States.
[edit] Mechanism of action
Nicorandil acts by relaxing the smooth muscle of the blood vessels, especially those of the venous system. It does this through two methods. Firstly, by activating potassium channels, and secondly by donating nitric oxide to activate the enzyme guanylate cyclase. Guanylate cyclase causes activation of GMP leading to both arterial and venous vasodilatation. As it is selective for vascular potassium channels, it has no significant action on cardiac contractility and conduction.
Although it can dilate the coronary vessels of a healthy individual, its effects on the coronary vessels of someone with ischaemic heart disease will be little as they will already be completely dilated. Instead, it dilates the venous system, reducing preload and the work of the heart.
[edit] Side effects
Common side effects include flushing, palpitation, weakness, headache, mouth ulcers, nausea and vomiting. More recently peri-anal, ileal and peri-stomal ulceration has been reported as a side effect. Anal ulceration is now included in the British National Formulary as a reported side effect.
[edit] References
Kukovetz WR et al (1992). Molecular mechanism of action of nicorandil. Journal of Cardiovascular Pharmacology 20 Suppl.3:S1–S7.
Tripathi, K.D. Essentials of Medical Pharmacology, chapter 37, page 499.
[edit] Mechanism of action
Nicorandil acts by relaxing the smooth muscle of the blood vessels, especially those of the venous system. It does this through two methods. Firstly, by activating potassium channels, and secondly by donating nitric oxide to activate the enzyme guanylate cyclase. Guanylate cyclase causes activation of GMP leading to both arterial and venous vasodilatation. As it is selective for vascular potassium channels, it has no significant action on cardiac contractility and conduction.
Although it can dilate the coronary vessels of a healthy individual, its effects on the coronary vessels of someone with ischaemic heart disease will be little as they will already be completely dilated. Instead, it dilates the venous system, reducing preload and the work of the heart.
[edit] Side effects
Common side effects include flushing, palpitation, weakness, headache, mouth ulcers, nausea and vomiting. More recently peri-anal, ileal and peri-stomal ulceration has been reported as a side effect. Anal ulceration is now included in the British National Formulary as a reported side effect.
[edit] References
Kukovetz WR et al (1992). Molecular mechanism of action of nicorandil. Journal of Cardiovascular Pharmacology 20 Suppl.3:S1–S7.
Tripathi, K.D. Essentials of Medical Pharmacology, chapter 37, page 499.
Important information about all medicines
Keep all medicines out of the sight and reach of children.
Make sure that the person prescribing this medicine knows about any other medicines that you are taking. This includes medicines you buy and herbal and homeopathic medicines.
If you buy any medicines check with a pharmacist that they are safe to take with your other medicines.
Before taking this medicine tell your doctor if you have ever had an allergic reaction after taking any medicine.
Never take more than the prescribed dose. If you suspect that you or someone else has taken an overdose of this medicine go to the accident and emergency department of your local hospital at once. Take the container with you, even if it is empty.
If you are having any treatment like an operation or dental treatment tell the person carrying out the treatment which medicines you are taking.
Always read the printed information leaflet that comes with your medicine.
This medicine is for you. Never give it to other people even if their condition appears to be the same as yours.
Never keep out of date or unwanted medicines. Take them to your local pharmacy which will dispose of them for you.
If you have any questions about this medicine ask your pharmacist.
Make sure that the person prescribing this medicine knows about any other medicines that you are taking. This includes medicines you buy and herbal and homeopathic medicines.
If you buy any medicines check with a pharmacist that they are safe to take with your other medicines.
Before taking this medicine tell your doctor if you have ever had an allergic reaction after taking any medicine.
Never take more than the prescribed dose. If you suspect that you or someone else has taken an overdose of this medicine go to the accident and emergency department of your local hospital at once. Take the container with you, even if it is empty.
If you are having any treatment like an operation or dental treatment tell the person carrying out the treatment which medicines you are taking.
Always read the printed information leaflet that comes with your medicine.
This medicine is for you. Never give it to other people even if their condition appears to be the same as yours.
Never keep out of date or unwanted medicines. Take them to your local pharmacy which will dispose of them for you.
If you have any questions about this medicine ask your pharmacist.
How to store nicorandil
Keep all medicines out of the reach and sight of children.
Do not transfer tablets from the blister packs into other containers because they will degrade very quickly.
Once you have taken a tablet from a blister pack, the pack should be used within 30 days because the tablets will slowly degrade.
Store in a cool, dry place, away from direct heat and light.
Do not transfer tablets from the blister packs into other containers because they will degrade very quickly.
Once you have taken a tablet from a blister pack, the pack should be used within 30 days because the tablets will slowly degrade.
Store in a cool, dry place, away from direct heat and light.
Can nicorandil cause problems?
Along with their useful effects all medicines can cause unwanted side effects which usually improve as your body adjusts to the new medicine. Speak with your doctor or pharmacist if any of the following side effects continue or become troublesome.
Common side-effects What can I do if I experience this
Headache Ask your pharmacist to recommend a suitable pain-killer. If this continues or becomes a problem speak to your doctor
Feeling or being sick This may get better once your body has adjusted to the new medicine
Dizziness Nicorandil may cause dizziness, you should not drive or operate machinery for the first few days after beginning treatment to see if you are affected
Weakness If this continues speak with your doctor
Flushing (redness of the face) If this is troublesome, speak to your doctor
If you experience any other symptoms which you think may be due to this medicine, discuss them with your pharmacist or doctor.
Common side-effects What can I do if I experience this
Headache Ask your pharmacist to recommend a suitable pain-killer. If this continues or becomes a problem speak to your doctor
Feeling or being sick This may get better once your body has adjusted to the new medicine
Dizziness Nicorandil may cause dizziness, you should not drive or operate machinery for the first few days after beginning treatment to see if you are affected
Weakness If this continues speak with your doctor
Flushing (redness of the face) If this is troublesome, speak to your doctor
If you experience any other symptoms which you think may be due to this medicine, discuss them with your pharmacist or doctor.
Getting the most from your treatment
Keep your regular appointments with your doctor so your progress can be checked.
It is best not to drink alcohol while you are taking these tablets as nicorandil may cause you to feel dizzy particularly at the start of your treatment. Drinking alcohol will increase this dizziness.
It is best not to drink alcohol while you are taking these tablets as nicorandil may cause you to feel dizzy particularly at the start of your treatment. Drinking alcohol will increase this dizziness.
How to take nicorandil
Take these tablets exactly as your doctor has told you to. Swallow the tablets whole with a drink of water.
Before beginning treatment, read the manufacturer's printed information leaflet.
If you miss a dose of this medicine take it as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and continue taking it at the usual times. Do not take two doses at the same time to make up.
Do not stop taking nicorandil without speaking to your doctor first because this can cause angina attacks.
Nicorandil is for you. Never give it to others, even if their condition appears to be the same as yours.
Before beginning treatment, read the manufacturer's printed information leaflet.
If you miss a dose of this medicine take it as soon as you remember. However, if it is almost time for your next dose, skip the missed dose and continue taking it at the usual times. Do not take two doses at the same time to make up.
Do not stop taking nicorandil without speaking to your doctor first because this can cause angina attacks.
Nicorandil is for you. Never give it to others, even if their condition appears to be the same as yours.
Before taking nicorandil
Before taking nicorandil make sure your doctor or pharmacist knows:
If you are pregnant, trying for a baby or breast-feeding.
If you suffer from hypotension (low blood pressure).
If you have recently suffered from a heart attack.
If you have any other heart conditions.
If you suffer from lung problems.
If you suffer from mouth ulcers.
If you have ever had an allergic reaction to this or any other medicine.
If you are taking any other medicines, including those available to buy without a prescription, herbal and complementary medicines.
If you are pregnant, trying for a baby or breast-feeding.
If you suffer from hypotension (low blood pressure).
If you have recently suffered from a heart attack.
If you have any other heart conditions.
If you suffer from lung problems.
If you suffer from mouth ulcers.
If you have ever had an allergic reaction to this or any other medicine.
If you are taking any other medicines, including those available to buy without a prescription, herbal and complementary medicines.
About nicorandil
About nicorandil
Type of medicine Potassium channel activator
Used for Angina (chest pain)
Also called Ikorel®
Available as Tablets
Angina occurs when the heart muscles do not receive enough oxygen. Nicorandil works by relaxing blood vessels and increasing the supply of blood and oxygen to the heart while reducing its work load.
Type of medicine Potassium channel activator
Used for Angina (chest pain)
Also called Ikorel®
Available as Tablets
Angina occurs when the heart muscles do not receive enough oxygen. Nicorandil works by relaxing blood vessels and increasing the supply of blood and oxygen to the heart while reducing its work load.
nicorandil - hydroxypropy release matrix tablets of nicorandil: Formulation and in vitro evaluation
The objective of the present study was to develop once-daily sustained-release matrix tablets of nicorandil, a novel potassium channel opener used in cardiovascular diseases. The tablets were prepared by the wet granulation method. Ethanolic solutions of ethylcellulose (EC), Eudragit RL-100, Eudragit RS-100, and polyvinylpyrrolidone were used as granulating agents along with hydrophilic matrix materials like hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose, and sodium alginate. The granules were evaluated for angle of repose, bulk density, compressibility index, total porosity, and drug content. The tablets were subjected to thickness, diameter, weight variation test, drug content, hardness, friability, and in vitro release studies. The granules showed satisfactory flow properties, compressibility, and drug content. All the tablet formulations showed acceptable pharmacotechnical properties and complied with in-house specifications for tested parameters. According to the theoretical release profile calculation, a oncedaily sustained-release formulation should release 5.92 mg of nicorandil in 1 hour, like conventional tablets, and 3.21 mg per hour up to 24 hours. The results of dissolution studies indicated that formulation F-I (drug-to-HPMC, 1∶4; ethanol as granulating agent) could extend the drug release up to 24 hours. In the further formulation development process, F-IX (drug-to-HPMC, 1∶4; EC 4% wt/vol as granulating agent), the most successful formulation of the study, exhibited satisfactory drug release in the initial hours, and the total release pattern was very close to the theoretical release profile. All the formulations (except F-IX) exhibited diffusion-dominated drug release. The mechanism of drug release from F-IX was diffusion coupled with erosion.
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