KR20100007082A - Controlled-release preparation comprising nicorandil - Google Patents

Abstract

The present invention relates to a drug delivery system for controlled release oral administration of a novel angina drug, more particularly, which can be used in vivo using polysaccharides, fatty acid esters and optionally alkalizing agents as well as nicotine from the post-dose preparations. It relates to a sustained release formulation comprising nicolandil exhibiting a release pattern that can be released continuously over 12 to 24 hours.

Description

Sustained-release preparations containing nicorandil {CONTROLLED-RELEASE PREPARATION COMPRISING NICORANDIL}

The present invention relates to a sustained release preparation comprising nicolandil, and more particularly, it is possible to use it in vivo using polysaccharides, fatty acid esters and optionally an alkalizing agent, as well as to obtain nicolandil from 12 to 12. The present invention relates to a sustained release formulation comprising nicorandil that exhibits a release pattern that can be continuously released over 24 hours.

Angina is a disease that causes anemia in the heart muscle due to a temporary imbalance in the demand and supply of oxygen to the myocardium. Ischemic heart disease such as angina is increasing due to aging, stress, lack of exercise, and changes in diet. Angina is divided into three categories, stable angina, unstable angina and heterogeneous angina, depending on the severity and symptoms of symptoms. Angina is an angina that appears only when a certain level of activity is performed rather than at rest. Unstable angina refers to angina in which angina, which only appears during activity, also occurs during rest, and is more likely to transition to myocardial infarction. Heterogeneous angina is more symptomatic when resting than during activity, especially during the night or at dawn. Occurs. The treatment of angina includes nitrate, beta blocker, calcium blocker, potassium channel opener, etc. Among the conventional angina drugs, beta blocker causes bradycardia and heart failure due to cardiovascular function, and calcium blocker lowers blood pressure or impedes conduction. Nitroglycerin has long been known as a special medicine for angina, and has side effects such as lowering blood pressure, reflex tachycardia, and decreased blood flow.

Nicorandil (N- [2- (nitoxy) ethyl] -3-pyridine-carboxamide), a drug used in the present invention, has the effect of opening potassium channels and cyclic guanosine monophosphate in cells of vascular smooth muscle. Increasing cGMP) has been shown to selectively expand coronary blood vessels and have little effect on heart rate and myocardial contractility. It has been used as a treatment for various types of angina. The pharmacological action of nicorandil acts as a potassium channel opener to selectively expand blood vessels and to continuously increase blood flow. Relieves spasms by relieving blood vessel tension and has little effect on heart rate, stimulation conductivity and myocardial contractility. It is also useful for angina pectoris in patients with elderly, deep-conversion, and atrioventricular block. It is also a useful drug for angina after myocardial infarction.

Existing Nico is in the case of dill angina drug in Korea sigma agent (Sigmart ^™), the European Ikoma Morelia (Ikorel ^™), India, if Nico (Zynicor ^™) product name to 5mg 1 three times daily formulations, or 10 ~ 20mg 1 day 2 of Formulations to be administered once are commercially available.

Nicolandyl has a nitrate ester group and is unstable in an aqueous solution like other drugs having a nitrate ester group, and a series of decomposition reactions occur starting with hydration of the nitrate ester. In addition, heat causes a polymerization reaction. Hydrolysis is accelerated by three factors: increased water content, temperature, and shelf life. Due to such moisture instability of nicorandil, many researches have been conducted on the preparation and preservation methods of the preparation of the nicorandil, and the packaging method has been put into a lot of research costs, such as a complete moisture proof packaging.

In order to maintain the blood concentration of a drug over a long time, various high molecular materials are used in most of the sustained release preparations. For example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, furan, gelatin, collagen, casein, agar, ethyl cellulose, methyl cellulose, polyethylene glycol, sodium alginate, polyvinylpyrrolidone, Albumin is a representative polymer. However, there are some problems when preparing sustained release formulations using such polymeric materials. It is often the case that the water-soluble high molecular material itself has a high moisture content, the compounded drug substance is susceptible to decomposition such as hydrolysis and is not long-term preserved. In addition, the water-soluble high molecular material swells immediately, so that the drug cannot be released for a long time. In the case of nicolandil, when using a polymer having such a problem affects the stability and has a problem that can not last for the desired release time.

Japanese Patent Application Laid-Open No. 57-145659 discloses a method of coating nicolandyl crystals with stearyl alcohol or the like in order to solve the problem of unstable and deterioration of the content over time due to tableting during tablet manufacture. Doing.

In Korean Patent Application No. 1985-0009452, the use of pulverized saccharides such as mannitol, lactose, sucrose, glucose, galactose, maltose, etc., mainly used in order to make a nicolandyl formulation stable against molding pressure and humidity is achieved. It has been reported that the stability against molding pressure and humidity have been improved, and the stability against humidity and compression molding has been markedly improved by using dibasic acids such as fumaric acid, oxalic acid, salicylic acid, tartaric acid and glutamic acid. In addition, the present invention reports that the use of pulverized saccharides and organic acids is mixed to improve the molding pressure and humidity stability.

In Korean Patent Application No. 1986-0011645, it is reported that the stability of the organic acid and the solid saturated fatty acid and saturated alcohol after mixing is greatly improved by tableting, and at least 0.1% by weight of organic acid and 0.5% by weight or more at room temperature. It has been reported that there was a stabilizing effect by mixing solid saturated fatty acids and saturated higher alcohols.

EP 0230932 describes a method of mixing the active ingredient with stearic acid and then micronizing the mixture. However, the stability of the obtained composition was not satisfactory.

Korean Patent Application No. 2007-7000276 discloses in the description that it is impossible to obtain a composition for direct compression which makes it possible to obtain a sufficiently stable tablet for a certain period of time due to the problem of inherent stability of the active ingredient. And a lubricant selected from saturated higher aliphatic acids and salts thereof or saturated higher alcohols that are solid at ambient temperature, wherein the lubricant is not micronized, but the mannitol used is 76% excess and boric. There is a problem that the released croscarmellose sodium may affect the deterioration of stability.

In Korean Patent Application No. 1986-0011644, a freeze-dried injection having excellent stability was prepared by making an injectable formulation which is hardly formulated by a conventional method into a non-liquid form by containing an inorganic acid or an organic acid and / or an alkali metal salt thereof as a stabilizer. As the inorganic acid or alkali metal salt used in the above study, phosphoric acid, carbonic acid or their alkali metal salts, preferably sodium and potassium salts, were used as the organic acid or alkali metal salt thereof, acetic acid, propionic acid, butyric acid, oxalic acid, malonic acid, succinic acid, glu Taric acid, adipic acid, etc. were used individually or in mixture of 2 or more types. However, there is a problem that inorganic acids and organic acids have a deterioration effect on their own.

Korean Patent Application No. 193-0010224 discloses a method for preparing a pharmaceutically stable nicolandyl suspension by suspending the active ingredient in a straight-chain dimethylpolysiloxane (dimethicone or simethicone) having low and medium concentrations of nicolandil and a suspension thereof. The present invention discloses a method of making a capsule filled with a hard or soft capsule.

According to the study of Radical et al. (AAPS PharmSciTech. 2006; 4 (4): article 61.), ethyl cellulose, Eudragit AL-1, Eudragit RS-100, and polyvinylpyrrolidone were dissolved in ethanol. Sustained-release tablets were prepared once daily after granules were prepared by wet granulation using matrix bases such as hydroxypropylmethylcellulose, carboxymethylcellulose, and alginate sodium. The release pattern according to the design of this prescription allowed 5.92 mg to be released within 1 hour and 3.21 mg per hour until 24 hours. According to the above study, the water-soluble matrix made by using hydroxypropylmethylcellulose alone does not effectively release nicolandil for 24 hours, and when a combination of hydroxypropylmethylcellulose and ethylcellulose is used, a sustained release system is produced. It is reported that it is more suitable for. However, the hydroxypropylmethylcellulose used in this formulation has a problem of stability and the cellulose-based excipient may have an interaction with nicolandil. In addition, since it is hydrolyzed during the dissolution test in the eluate after 24 hours, it is not a preferable design, there is a problem that the pattern is released 3 to 6mg per hour too much is released per hour.

Korean Patent Application No. 2000-7012646 discloses a drug subject to controlled release prepared by adding a pharmaceutically acceptable additive to one or two or more bases selected from fumaric acid, DL-tryptophan, and L-tyrosine. A release controlling agent having an inner core portion and a portion constituted by coating the drug release layer, which are prepared so that one or two or more drugs to be controlled for release using a release controlling layer free of release are released quickly or sustainedly. It is starting. The present invention has a problem in that the drug has to be dissolved and given a temperature condition in order to coat the drug layer with a prescription having a plurality of release patterns, leading to a decrease in stability of the drug during the manufacturing process.

Accordingly, the present invention overcomes the difficulty of developing nicolandyl sustained-release agent due to a short half-life of about 1 hour in vivo with nicolandil, and develops a sustained nicolandil formulation having improved stability than conventional formulations. It is a technical object of the present invention to provide a sustained release formulation comprising nicorandil which releases the drug at a controlled rate for a long time.

In order to achieve the above object, the present invention provides a sustained-release preparation containing nicorandil, polysaccharide, fatty acid ester as an active ingredient.

The present invention also provides a sustained-release preparation further comprising an alkalizing agent in addition to nicolandil, polysaccharide, fatty acid ester.

Hereinafter, the present invention will be described in more detail.

In the present invention, nicorandil may be included in the formulation in various amounts as necessary. Nicorandil in the present invention may be included, for example 5 to 50% by weight, more preferably 10 to 20% by weight relative to the total weight of the formulation.

In the present invention, as the polysaccharide, for example, corn starch, potato starch, gelatinized starch, hydroxyethyl starch which is a derivative thereof, dextrin, dextran, maltodextrin, polydextrose, alginic acid, alginic acid alkali metal salt, guar gum One or more selected from locust bean gum, xanthan gum, cyclodextrin, arabic gum, gellan gum, carrageenan, casein, tara gum, tamarind gum, tragacanth gum, gati gum, gelatin, collagen, protamine and zein However, it is not limited thereto. In the present invention, the polysaccharide is more preferably at least one selected from corn starch, potato starch, gelatinized starch, derivatives thereof hydroxyethyl starch, xanthan gum, locust bean gum, guar gum, gum arabic and carrageenan. In the present invention, the polysaccharide is included in 5 to 90% by weight, more preferably 10 to 70% by weight relative to the total weight of the formulation. In the present invention, when the polysaccharide is contained in less than 5% by weight, the release control effect may be reduced, there may be a problem in the continuous release of the drug for more than 12 hours, when contained in more than 90% by weight, the physical properties of the granules do not have good productivity problems There can be.

In the present invention, the fatty acid ester is, for example, stearyl stearate, glyceryl behenate, glyceryl monostearate, sucrose fatty acid ester, glyceryl palmitostearate, polyoxyethylene stearate, sorbitan monostearate and sorbent. One or more selected from non-elastic monopalmitates may be used, but is not limited thereto. In the present invention, the fatty acid ester is more preferably sucrose fatty acid ester or glyceryl behenate. In the present invention, the fatty acid ester includes 5 to 50% by weight, more preferably 10 to 30% by weight based on the total weight of the preparation. If the fatty acid ester is included in less than 5% by weight in the present invention may have a problem that does not affect the stability and controlled release, if contained in more than 50% by weight may have a problem that difficult to produce due to tableting disorders.

The present invention more preferably may further comprise an alkalizing agent. In the present invention, the alkalizing agent serves to improve the late hydration reaction in the acidic conditions of the polysaccharide series, it is preferable that the water content is low and insoluble in water. As the alkalizing agent, calcium carbonate, magnesium oxide, magnesium carbonate, potassium sulfate, etc. having a water content of less than 5%, more preferably less than 1% may be used, but is not limited thereto. In the present invention, the alkalizing agent is more preferably calcium carbonate. The alkalizing agent in the present invention includes 1 to 15% by weight, more preferably 2 to 10% by weight relative to the total weight of the formulation. In the present invention, when the alkalinizing agent is included in less than 1% by weight may have a problem that does not help improve the hydration reaction is insufficient effect, if contained in more than 15% by weight may have a problem in stability due to the use of more than the required amount

In addition to the above components, the sustained-release preparation of the present invention may further include excipients commonly included in the sustained-release preparation within the scope of achieving the object of the present invention, such as a mixture, a binder, a lubricant, a disintegrant, and the like. have. As the mixing agent, for example, mannitol, light silicic anhydride, calcium dihydrogen phosphate, sodium chloride and the like can be used, and as the binder, for example, cetyl alcohol, cetostearyl alcohol, stearic acid, stearyl alcohol, hydrogenated castor oil, Cured grapeseed oil and the like may be used, and as the lubricant, for example, calcium stearate, magnesium stearate, sodium stearyl fumarate and the like may be used.

There is no particular limitation on the method for preparing the sustained release formulation of the present invention, and a conventional method for preparing a sustained release formulation may be applied as it is or with some modification. Sustained release formulations of the present invention are preferably prepared in tablets, for example, since nicolandil has moisture instable properties, it may be difficult to form granules with general wet granules, so that the pharmaceutical composition is mixed in a speed mixer. Then, the binding solution may be prepared by heating and melting the coalesced liquid, then slowly cooling and sizing, then tableting in a tablet press.

Sustained release preparations according to the present invention can maintain an effective blood concentration by maintaining a constant effective blood concentration, palpitations, hot flashes, systemic malaise, chest pain, lower extremity edema, headache, dizziness that are side effects of the conventional nicolandil drug Side effects such as tongue paralysis, anorexia, anorexia, constipation, abdominal pain and thrombocytopenia can be alleviated by releasing the drug in the minimally therapeutic area for a period of time.

In addition, by establishing a stabilization prescription, the problem of temperature and water instability of the existing three-time formulations can be improved, and the quality level can be significantly improved compared to the conventional formulations on the market. It is possible to take once a day from a single dose, which can increase patient compliance and increase treatment duration.

Hereinafter, the present invention will be described in detail by way of examples. However, the embodiments are only illustrative of the present invention, and the scope of the present invention is not limited thereto.

Experimental Example  One

Nicorandil is free from pharmacologically active nitric acid and N- (2-hydroxyethyl) -nicotinamide due to the hydrolysis of the inorganic esters contained in the molecule, resulting in a substantial decrease in the active ingredient and pharmacological activity. Since it is known to be degraded, an experiment was conducted to determine the suitability of each excipient prior to the study of the formulation containing nicorandil. In order to determine the excipient compatibility, each excipient and nicolandil were mixed at a ratio of 2: 1 and stored at 40 ° C / 75% RH (relative humidity).

The content of nitrate, which is a major softener produced during hydrolysis of nicorandil, was measured under the following conditions, and the results are shown in Table 1.

Column: Capcell pack C18 (250mm × 4.6mm, 5㎛ particle size)

Mobile phase: KH ₂ PO ₄ Buffer (10 mM) and Methanol (70:30, v / v)

Absorbance: 220nm

Flow rate: 1.5ml / min

As can be seen from the above results, most of nicolandil hydrated with excipients for a short period of two weeks, resulting in an increase in nitrate. In particular, it can be seen that many of the organic acids that are known to be beneficial to the stability of nicolandil show a bad result.

Experimental Example  2

Based on the results of nitrate changes at 40 ° C / 75% RH over 2 weeks of nicorandil, excipients similar to those of commercially available formulations (see Table 2 below) were included in the Japanese Pharmacopoeia after 1 month. As a result of analysis using the material analysis method, it was found that many of the flexible materials other than nitrates were increased, and the results are shown in Table 3.

The amount of change in the flexible substance was analyzed using the liquid chromatograph under the following conditions.

Column: Capcell pack C18 (250mm × 4.6mm, 5㎛ particle size)

Mobile phases: water, tetrahydrofuran, triethylamine and trifluoroacetic acid (982: 10: 5: 3)

Absorbance: 254nm

Column temperature: 25 ℃

Flow rate: 1.5ml / min

As can be seen from the results, it was found that polysaccharide-based and fatty acid ester excipients such as xanthan gum and pregelatinized starch showed better results than commercially available formulations.

Example  1 and 2 and Comparative example  1 to 4

Examples 1 to 2 and Comparative Examples 1 to 4 in order to determine the difference between the case of using only polysaccharide and the case of using a polysaccharide and fatty acid ester together and the difference between the formulation according to the present invention and a conventional commercial formulation Tablets were prepared.

Tablets of Examples 1 to 2 and Comparative Examples 1 to 3 were added to the pharmaceutical composition of the composition and mixed amount (one tablet equivalent) as shown in Table 4 in a speed mixer, and mixed for about 3 minutes, and then excipients corresponding to the binder solution The mixture was heated and melted as a binding liquid and then slowly cooled. The union was prepared by sizing using a sieve of a constant size and then lubricating agent and tableting using a pressure of 3-6Kp.

Comparative Example 4 was prepared in the composition of Table 2 by the method of the commercially available formulation.

Experimental Example  3

The tablets prepared in Examples 1 to 2 and Comparative Examples 1 to 4 were subjected to a dissolution test in acetate buffer solution according to the second dissolution test method (paddle method) of the Korean Pharmacopoeia General Test Method, The amount was measured at liquid chromatograph UV 252 nm, and the results are shown in Table 5 below.

As can be seen from the results of Table 5, it was found that the dissolution rate was reduced when the polysaccharide and the fatty acid ester were used together as compared with the polysaccharide alone. It has also been found that the formulations according to the invention can release nicolandil at a controlled rate for longer periods of time by delaying dissolution compared to conventional commercial formulations.

Example  3 To 8

Examples 3 to 8 were prepared in the same manner as in Examples 1 to 2 with the compositions shown in Table 6 in order to determine the change in dissolution rate according to the addition of an alkalizing agent.

Experimental Example  4

The tablets prepared in Examples 3 to 8 were eluted at pH 1.2 to determine the effect of calcium carbonate, which is an alkalizing agent, and the results are shown in Table 7 below.

As can be seen from the results of Table 7, it was confirmed that the dissolution rate was reduced by additionally including calcium carbonate. This is because the addition of an alkalizing agent such as calcium carbonate can delay the early dissolution synergistic effect by improving the hydration delay at the pH 3 or less of the polysaccharide series.

Claims (12)

Sustained release formulations comprising nicorandil, polysaccharides and fatty acid esters. The sustained release formulation of claim 1, further comprising an alkalizing agent. The method of claim 1, wherein the polysaccharide is corn starch, potato starch, gelatinized starch and derivatives thereof hydroxyethyl starch, dextrin, dextran, maltodextrin, polydextrose, alginic acid, alginic acid alkali metal salt, guar gum, One or more selected from the group consisting of locust bean gum, xanthan gum, cyclodextrin, arabic gum, gellan gum, carrageenan, casein, tara gum, tamarind gum, tragacanth gum, gati gum, gelatin, collagen, protamine and zein Sustained release formulation characterized in that. The polysaccharide according to claim 3, wherein the polysaccharide is at least one selected from the group consisting of corn starch, potato starch, gelatinized starch and derivatives thereof such as hydroxyethyl starch, xanthan gum, locust bean gum, guar gum, arabic gum and carrageenan. Sustained release formulation characterized in that.  The sustained-release preparation according to claim 1, comprising 5 to 90% by weight of polysaccharide based on the total weight of the preparation. The fatty acid ester according to claim 1, wherein the fatty acid ester is stearyl stearate, glyceryl behenate, glyceryl monostearate, sucrose fatty acid ester, glyceryl palmitostearate, polyoxyethylene stearate, sorbitan monostearate and sorbitan Sustained release formulation characterized in that at least one selected from the group consisting of monopalmitate. The sustained-release preparation according to claim 6, wherein the fatty acid ester is sucrose fatty acid ester or glyceryl behenate. The sustained-release preparation according to claim 1, comprising 5 to 50% by weight of fatty acid ester relative to the total weight of the preparation. The sustained-release preparation according to claim 2, wherein the alkalizing agent is at least one selected from the group consisting of calcium carbonate, magnesium oxide, magnesium carbonate and potassium sulfate. 10. The sustained release preparation of claim 9, wherein the alkalizing agent is calcium carbonate. The sustained-release preparation according to claim 2, wherein the water content of the alkalizing agent is within 5%. The sustained-release preparation according to claim 2, comprising an alkalizing agent in an amount of 1 to 15% by weight based on the total weight of the preparation.