A method of treating cardiovascular diseases

 

The invention relates to medicine, particularly cardiology, and for the treatment of cardiovascular diseases, which shows the use of the drug ranolazine. It is proposed to introduce a pharmaceutical form of ranolazine providing a prolonged release of the above medicines. The introduction should be implemented in such a way as to maintain the level of ranolazine in the blood plasma of a person within 550-7500 ng/ml For this purpose it is proposed to use, in particular, such a dosage form, which includes at measure 50 wt.% ranolazine and pH-dependent binding agent, which inhibits the release of ranolazine in the stomach. The method provides a stable therapeutic effect of the drug, increasing the efficiency of treatment for these diseases, in particular angina. 3 C. and 40 C.p. f-crystals, 9 PL.

This application sets the priority of the patent application U.S. serial number 60/099804, filed September 10, 1998

The present invention relates to a method of using dosage forms for oral administration with a slow release of ranolazine to maintain levels of ranolazine in the plasma of human blood mailki, describes ranolazine, ()-N-(2,6-dimetilfenil)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineethanol and its pharmaceutically acceptable salts, and their use for the treatment of cardiovascular disease, including arrhythmias, variant angina, angina and myocardial infarction.

U.S. patent 5506229, which is incorporated herein by reference, describes the use of ranolazine and its pharmaceutically acceptable salts and esters for the treatment of physically or chemically damaged tissues, including cardioplegia, hypoxic, or reperfusion damage of the heart or skeletal muscle or brain tissue, as well as for use in transplants. Describes the usual formulation for oral and parenteral administration, including compositions with controlled release of the active ingredient. In particular, in example 7D U.S. patent 5506229 described preparative form with controlled release of the active ingredient in the form of capsules comprising microspheres of ranolazine and microcrystalline cellulose coated with polymers that control the release.

Currently, the preferred route of administration of ranolazine and his FA form for oral administration is pressed tablet, hard gelatin capsule filled with a powder mixture or granulate, or a soft gelatin capsule (softgel), filled with the solution or suspension. U.S. patent 5472707, the description of which is incorporated herein by reference, describes oral preparative form with high doses, which uses supercooled liquid ranolazine as a solution for filling hard gelatin capsules or soft gelatin capsules.

As described in example 3, the initial test ranolazine on people suffering from angina, were unsuccessful. In these tests was used in composition with the immediate-release of ranolazine at a dose of 120 mg, which was taken three times a day. Based on the results of the initial experiments it was not clear whether it is possible to give ranolazine man in the quantity and manner that would be effective against angina.

One of the problems with conventional dosage forms is that they are not ideal for ranolazine and its pharmaceutically acceptable salts, because the solubility of ranolazine is relatively high at low pH values of the stomach. In addition, ranolazine has a relatively short is sesivany and clearance, what causes large and undesirable fluctuations in the plasma concentration of ranolazine and short duration of action, which necessitates frequent oral intake for adequate treatment.

Thus, there is a need in the way of introduction of ranolazine in the form of a dosage form for oral administration one or two times a day, which would provide a therapeutically effective concentration of ranolazine plasma for treatment of angina pectoris in humans.

The first aspect of the present invention is a composition with delayed release of ranolazine, in which the main part of the composition is active ranolazine.

Another aspect of the present invention is a method of treatment of the patient-a person suffering from angina or other coronary disorders, by introducing the indicated patient a composition with a slow release of ranolazine once or twice a day.

Another aspect of the present invention is a method of treatment of a mammal suffering from a painful condition in which shows the introduction of ranolazine, which includes the introduction of the song slow release of ranolazine of the present invention as an important levels, without peak fluctuations.

Another feature of the present invention is a method of maintaining healthy levels of ranolazine in plasma by introducing a dosage form containing ranolazine, only once or twice a day.

The present invention includes methods of treatment of the patient-a person suffering from a cardiovascular disease selected from arrhythmias, variant angina, angina stress and myocardial infarction. This method includes the introduction of pharmaceutical dosage forms with prolonged release of the active ingredient, comprising at least 50 wt.% ranolazine in not more than two tablets at a reception, patient person to maintain levels of ranolazine in the plasma of the patient is the person from about 550 to 7500 ng base/ml for at least 24 hours, and this dose is given with a frequency selected from one, two or three times within 24 hours.

The present invention also includes methods of treatment of the patient-a person suffering from a cardiovascular disease selected from arrhythmias, variant angina, angina stress and myocardial infarction. This method includes the introduction of pharmaceutical fo the azina in not more than two tablets at a reception, the patient is the person to maintain levels of ranolazine in the plasma of the patient is the person from about 1000 to 3900 ng base/ml for at least 24 hours, and this dose is given with a frequency selected from one and two times within 24 hours.

The present invention also includes a pharmaceutical dosage form comprising at least about 50 wt.% ranolazine and at least one pH-dependent binding agent, which inhibits release of ranolazine of the dosage form with prolonged release of the active ingredient when the specified dosage form with prolonged release of the active ingredient is exposed to the aqueous environment having a pH of the stomach, and which contributes to the release of therapeutic amounts of ranolazine in an aqueous solution having a pH of more than about 4.5.

"Ranolazine" represents a connection ()-N-(2,6-dimetilfenil)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl] -1-piperazineethanol or its enantiomers (R)-(+)-N-(2,6 - dimetilfenil)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl] -1-piperazineethanol and (S)-(-)-N-(2,6-dimetilfenil)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl] -1-piperazinyl what's mentioned in the description and examples are ranolazine in free base form.

"Optional", and "optional" means that the described event or circumstance may or may not take place and that the description includes instances where the event or circumstance occurs and instances in which it takes place. For example, the expression "optional pharmaceutical excipients" indicates that describes thus the composition may include or not to include pharmaceutical excipients, other than those specifically shown and described, therefore, the composition includes options that are optional fillers, and ways in which optional fillers are missing.

"Healing" and "treatment" refers to any treatment of a disease of a mammal, especially human, and includes: (i) prevention of disease in a subject which may be predisposed to the disease but does not yet have an established diagnosis of this disease; (ii) suppression of the disease, i.e. the suspension of its development; or (iii) facilitation of the disease, i.e. ensuring devolution of the disease.

"Immediate release" ("HB") refers to compositions or dozer the of its and absorption in the stomach or upper gastrointestinal tract. Typically, these compositions release at least 90% of the active ingredient within 30 minutes after injection.

"Prolonged release" ("PV") refers to the compositions or dosage units of the drug of the present invention, which slowly and continuously dissolved and absorbed in the stomach and gastrointestinal tract over a period of time of about six hours or more. The preferred compositions of the slow release of the active ingredient are such compositions, which provide concentration ranolazine plasma while introducing no more than twice per day in the form of two tablets or less at the reception, as described below.

The concentration of ranolazine in plasma represents the average concentration determined by analysis of the concentration of ranolazine a minimum of five and maximum of ten people receiving treatment with the same dose and the same pattern introduction. It is important that the concentration of ranolazine represents the average value of the dispersion concentration of ranolazine from person to person, which may be due to differences in weight, metabolism or painful conditions that can lead to more rapid or more melanophloia. Levels of ranolazine in plasma was determined after selection of the sample of blood in heparin.

The other definitions are used in this application terms: ANOVA - single factor analysis of variance ATP - adenosine triphosphate ECG ECG (electrocardiogram) CCT - test exercise tolerance PDG - pyruvaldehyde Cmax- the maximum concentration
Cminresidual concentration 8 hours after the introduction of HB compositions and 12 hours after the introduction of PV compositions a-C of example 2
Withx- concentration during x
Tmaxthe time to reach maximum concentration
AUCxthe area under the curve after x hours or time interval.

Percentages are given as weight percentages, unless otherwise indicated.

The present invention includes pharmaceutical form prolonged release ranolazine, and routes of administration dosage forms with prolonged release of ranolazine of the present invention to provide therapeutic levels of ranolazine in plasma.

Songs slow release of ranolazine of the present invention are preferably in the form of compressed tablets, including homoge the speed of dissolution of ranolazine in the aquatic environment as it changes the pH from the pH in the stomach (usually around 2) to a pH in the intestine (usually about 5.5).

To provide prolonged release of ranolazine choose one or more pH-dependent binding agents to control the dissolution profile of the composition of ranolazine so that the composition is released ranolazine slowly and continuously by passing the composition through the stomach and gastrointestinal tract. The effectiveness of such control dissolution pH-dependent binding agent (agents) are particularly important for the composition with slow release of ranolazine, because the composition is slow release, which contains sufficient for administration twice a day, the number of ranolazine, can cause non-directional side effects, if ranolazine is released too quickly ("reset dose").

Accordingly, the pH-dependent binding agents suitable for use in the present invention are those agents that inhibit the rapid release of drug from tablets during her stay in the stomach (where the pH is equal to or below about 4.5), and which contribute to the release of therapeutic amounts of ranolazine from the dosage form in the lower sections of the gastro-intestinal tract (where the pH is about and covering agents, have appropriate properties solubility at different pH values. These materials include derivatives of phthalic acid, such as derivatives of phthalic acid, vinyl polymers and copolymers, hydroxyethylcellulose, alkylaryl, cellulose acetates, acetates hydroxyethylcellulose, cellulose ethers, acetates alkylsalicylate and their partial esters, and polymers and copolymers of lower alkylacrylate acids and lower alkylacrylate and their partial esters.

Preferred pH-dependent binders that can be used in combination with ranolazine to create compositions with prolonged release of the active ingredient, are copolymers of methacrylic acid. The copolymers of methacrylic acid are copolymers of methacrylic acid with a neutral acrylate or methacrylate esters, such as acrylate or methacrylate. The most preferred copolymer is a methacrylic acid copolymer, type C, USP (which is a copolymer of methacrylic acid and ethyl acrylate having from 46,0% to 50.6 per units of methacrylic acid). This copolymer sold by the company Rohm Pharma as Eudragit

One or more pH-nezavisimykh binding agents can be used in oral dosage forms with prolonged release of ranolazine. It should be noted that the pH-dependent binding agents and agents that increase viscosity, such as hypromellose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate esters, etc., do not provide the desired control of dissolution provided by the listed pH-dependent binding agents. pH-independent binders are present in the compositions of the present invention in amounts of from about 1 is.

As shown in table 1, ranolazine relatively insoluble in aqueous solutions with pH above about 6.5, while the solubility begins to sharply increase when the pH is below about 6.

The increase in the content of the pH-dependent binding agent in the composition reduces the rate of release of ranolazine from the composition at a pH value below 4.5, the usual pH in the stomach. Intersolubility coating formed of the binder agent is less soluble and increases the relative rate of release at pH values higher than 4.5, in which the solubility of ranolazine below. Suitable choice of the pH-dependent binding agent allows to achieve a higher speed of release of ranolazine from the composition at pH higher than 4.5, at the same time, greatly affecting the rate of release at low pH values. Partial neutralization of the binder agent facilitates its conversion into latokartano film, which is formed around the individual granules of ranolazine. Accordingly, the type and number of pH-dependent binding agent and composition for partial neutralization are chosen in such a way as to accurately control the rate of dissolution of ranolazine of composition.

Dosage forms for the manufacture of a composition with a prolonged release of the active ingredient, from which the release of ranolazine occurs at a rate controlled so that at low pH values (below about 4.5), the dissolution rate decreases significantly. In the case of methacrylic acid copolymer, type C, USP (EudragitL 100-55), an appropriate amount of pH-dependent binding agent is from 5% to 15%. Methacrylic acid in a pH-dependent binding agent typically will be from about 1 to 20% neutralized carboxyl groups. However, preferably, if the degree of neutralization ranges from approximately 3 to 6%.

Composition with prolonged release of the active ingredient may also contain pharmaceutical excipients, homogeneous mixed with ranolazine and pH-dependent binding agent. Pharmaceutically acceptable excipients may include, for example, pH-independent binders or film-forming agents such as hypromellose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate esters (for example, copolymers of methyl methacrylate/ethyl acrylate sold with the trademark Eudragit

Songs slow release of ranolazine of the present invention contain ranolazine in the amount from about 50 wt.% to 95 wt.%, more preferably from about 70 wt.% up to 90 wt.% and most preferably from about 70 to 80 wt.%; pH-dependent binding agent in an amount of from 5% to 40%, preferably from 5% to 25% and more preferably from 5% to 15%; the remaining weight of the dosage form includes a pH-independent binders and other optional fillers.

Especially preferred compositions of the slow release of ranolazine see table. A.

Songs slow release of ranolazine of the present invention is made as follows.

Ranolazine and pH sasuhou the mixture was then granularit in the presence of an aqueous solution of a strong base, which is dispersed in the mixed powder. This granulate is dried, sieved, mixed with an optional lubricating agents (such as talc or magnesium stearate and pressed into tablets. Preferred aqueous solutions of strong bases are solutions of hydroxides of alkali metals such as sodium hydroxide or potassium, preferably sodium hydroxide, in water (optionally containing up to 25% mix with water, solvents such as lower alcohols).

The obtained tablets containing ranolazine, may be coated with an optional film-forming agent for the purpose of identification, taste masking, as well as to facilitate swallowing. Film-forming agent is typically present in an amount of from 2% to 4% by weight of the tablet. Suitable film-forming agents are well known in the art and include hypromellose, cationic methacrylate copolymers (copolymers of dimethylaminoethylmethacrylate/methylmetacrylate - Eudragit- Rhm Pharma), etc., These film-forming agents may optionally contain dyes, plasticizers and other added ingredients.

Presova the R tablets will depend first of all, the number of ranolazine in the tablet. These pills will contain from 300 to 1100 mg of free base ranolazine. Preferably these tablets will include the free base of ranolazine in the number of 400-600 mg, 650-850 900-1100 mg and mg of

With to affect the dissolution rate is controlled by the time during which the powder containing ranolazine, subjected to wet mixing. Preferably the total time of mixing of the powder, i.e. the time during which the powder is exposed to sodium hydroxide solution, will vary from 1 to 10 minutes and preferably from 2 to 5 minutes. After granulation, the particles are removed from the pellet and placed in a fluidized bed dryer for drying at a temperature of about 60oC.

It has been unexpectedly found that by using these methods it is possible to obtain compositions with slow release of ranolazine that provide lower peak levels of ranolazine in the plasma and at the same time, the effective concentration of ranolazine in plasma during the period of time up to 12 hours or more after the introduction, if ranolazine used in free base form, and not in the more common form of pharmaceutical salts R is et at least one advantage: the number of ranolazine in the tablet can be increased, since the molecular weight of the free base of ranolazine is only 85% of the molecular weight of ranolazine dihydrochloride. Thus, the delivery of an effective amount of ranolazine while simultaneously reducing the physical size of dosage units.

Another advantage of the compositions of the slow release of ranolazine of the present invention is that they are made by a method in which the solvent is used essentially only water and standard pharmaceutical technology and equipment.

Songs slow release of ranolazine of the present invention can be used for the treatment of cardiovascular disease, including arrhythmias, variant angina, angina and myocardial infarction; for treatment of physically or chemically damaged tissues, including cardioplegia, gipoksicescoe or reperfusion injury of the heart or skeletal muscle or brain tissue, and ischemia, and peripheral arterial disease, such as intermittent claudication. It is most preferable to use a composition with a slow release of ranolazine as antianginals/p> Songs slow release of ranolazine for oral administration is administered one, two or three times over a period of time of 24 hours with the aim of maintaining the level of ranolazine in the plasma of the patient above therapeutic threshold level and below the maximum tolerated levels, from about 550 to 7500 ng base/ml This corresponds to the number of ranolazine 2 Hcl approximately 644 ng/ml to 8782 ng/ml in Addition, it is necessary to control the time of oral administration dosage forms ranolazine for oral administration to ensure that the level of ranolazine plasma will not exceed approximately 7500 ng base/ml, and preferably, to the level of ranolazine in plasma did not exceed approximately 5000 ng base/ml, and most preferably it does not exceed 3800 ng base/ml In some cases it may be acceptable to limit the peak ranolazine in plasma more than about ng base/ml At the same time, the minimum levels of ranolazine plasma preferably should not fall below approximately 1000 ng base/ml, and in some cases should not fall below about 1700 ng base/ml

In order to achieve the preferred level of ranolazine in the plasma when the aqueous reception described herein, one or two times a day. If the dosage form is administered twice a day, preferably the dosage form of ranolazine for oral administration at intervals of approximately twelve hours.

In addition to compositions and injection dosage forms ranolazine for oral administration in such a way to control the levels of ranolazine in the plasma, it is also important to minimize the difference between the peak and the lowest levels of ranolazine in the plasma. Peak levels of ranolazine in plasma are usually achieved after approximately 30 minutes to eight hours or more after the initial reception of the dosage form inside, while low levels of ranolazine in plasma are reached approximately to the time of ingestion following scheme doses. Preferably the dosage form with prolonged release of the active ingredient of the present invention is administered such that the peak level of ranolazine was not more than 8 times more than the lowest level of ranolazine, preferably not more than 4 times the lowest level of ranolazine and most preferably not more than 2 times the lowest level of ranolazine.

The composition of the society in they minimize fluctuations in the concentration of ranolazine in the plasma, at the same time allowing the reception, at most twice a day. The composition can be entered separately or (at least initially) in combination with a composition with immediate release of the active ingredient, if it is desirable rapid achievement of a therapeutically effective concentration of ranolazine in the plasma, or by introducing a soluble compositions for intravenous administration and dosage forms for oral administration.

The following examples illustrate the present invention but should not be construed as limiting the scope of the claims.

These examples detail the methods of production of dosage forms containing ranolazine, as well as experiments performed to evaluate the effectiveness of the introduction of ranolazine. In connection with these examples, you should note the following.

(1) Oral dose of the composition with the immediate-release (HB) was given in the form of capsules or tablets dihydrochloride salt and expressed in the form of a dihydrochloride salt.

(2) Oral dose of the composition with slow release (PV) was given in pill form the base of ranolazine and were expressed as the base.

(3) When NV and PV compositeevent conversion dihydrochloride on the base is 0,854 (for example, 400 mg of the dihydrochloride x 0,854 = the equivalent of 342 mg of free base).

(4) All levels in plasma and pharmacokinetic parameters were expressed as free base.

Example 1
This example describes a method of making compositions with immediate-release (HB) ranolazine. Ranolazine the dihydrochloride (4000 g), microcrystalline cellulose (650 g), polyvinylpyrrolidone (100 g) and sodium-croscarmellose (100 g) in the form of powders were mixed to homogeneity in a mixer-granulator Fielder PMA 65, and then added enough water under stirring to obtain a granulate. This granulate was dried in a fluidized bed dryer Aeromatic Strea-5, screened and mixed with magnesium stearate (100 g). This mixture was filled hard gelatin capsules in the amount of, for example, 500 mg per capsule to obtain a dose of 400 mg ranolazine dihydrochloride (equivalent to 342 mg free base) per capsule, but you can also fill up weight from 30 to 400 mg ranolazine dihydrochloride.

Example 2
This example describes a method of making compositions with slow release (PV) ranolazine.

Composition with a slow release (PV) ranolazine, denoted as PV composition and copolymer methacrylic acid, type C (EudragitL 100-55 - Rhm Pharma) (1000 g), microcrystalline cellulose (Avicel) (100 g) (710 g) and polyvinylpyrrolidone in the form of powders were mixed to homogeneity in a mixer-granulator Fielder PMA 65. The mixture was granulated with a solution of sodium hydroxide (40 g) in water and wet weight was added 30% aqueous dispersion of a copolymer of methyl methacrylate and ethyl acrylate (EudragitNE 30 D - Rhm Pharma) (1667). The obtained granulate was dried in a fluidized bed dryer Aeromatic Strea-5, sieved and then mixed with sodium croscarmellose (100 g) and magnesium stearate (50 g). This mixture was pressed into tablets weighing 684 mg with press Manesty tableting In with the receipt of doses of the free base of ranolazine 342 mg per pill. This composition is referred to as PV composition A.

The PV of the song were made In the same way as PV composition A, except that the amount of EudragitL 100-55 was reduced to 500 g, a EudragitNE 30 D was replaced with a 40% aqueous dispersion of a copolymer mate the hm Pharma) (2,500 grams). Received (PV) composition consisted of 342 mg of the free base of ranolazine on the tablet.

The RO song free base of ranolazine (342 mg) was mixed with microcrystalline cellulose and polyvinylpyrrolidone K was granulated with water, dried and mixed with sodium croscarmellose and magnesium stearate. The mixture was pressed into tablets and put intersolubility floor.

PV composition D comprising only pH-zavisimy binder, produced by combining ranolazine (7500 g), EudragitL 100-55 (1000 g), hydroxypropylmethylcellulose (MethocelE5 - source)(200 g) and microcrystalline cellulose (Avicel) (1060 g) and mixed until homogeneous. Mixed powders were granulated with a solution of sodium hydroxide (40 g) in water (from 1900 to 2500 g). This granulate was dried and sifted, mixed with magnesium stearate (200 g) and extruded, for example, into tablets weighing 667 mg with the receipt of doses of the free base of ranolazine 500 mg per pill. These tablets were coated in the apparatus for coating cylindrical Cup 24 inches Accelacota

Phased manufacturing technology PV composition D as follows.

a) Mixing ranolazine, microcrystalline cellulose, methacrylate copolymer (type C) and hypromellose using a suitable mixer.

b) Dissolve the sodium hydroxide in purified water.

c) appropriate equipment for granulation is added slowly to the mixture a solution of sodium hydroxide with constant stirring. If necessary, add an additional aliquot of water.

d) Continue stirring to collect the whole lot in one place. If necessary, add an additional aliquot of water.

e) Dried granular mass in a fluidized bed dryer.

f) Sift the dried granules through a suitable sieve.

g) Add the sifted granules magnesium stearate and mix.

h) If required, pass the granular material through the chilsonator.

i) Press the granules into tablets using suitable equipment with predetermined dimensions.

j) is Dispersed powder OPADRY in the water and put the tape with the aid of suitable equipment for coating Sarapulov 0,002-0,003 wt.%.

Example 3
This example summarizes a study published in Circulation 90: 726-734 (1994), which showed that ranolazine was ineffective as an antianginal and antiischemic agent, if it was entered in the form of HB composition of example 1.

In this study involved patients with stable angina pectoris. Taking any previously these patients antianginal medications were stopped under medical supervision. Three hundred and nineteen patients received placebo blind method over a period of time up to 18 days, and 318 stopped exercise because of pain of moderate severity, had signs of myocardial ischemia (ST segment depression1 mm) and were randomized into one of four groups and received: ranolazine2hcl 30 mg three times a day (n= 81); ranolazine2hcl 60 mg three times daily (n=81); ranolazine2hcl 120 mg three times daily (n=78) and placebo three times daily (n=79). After a dose of 30, 60 and 120 mg three times per day average peak concentration of free base ranolazine in plasma within 1 hour after the dose was 94, 219 and 510 ng/ml, respectively, while the average low concentrat oinoi blind phase tests the load with symptomatic limitation was repeated after 1 hour test (peak concentration) and 8 hours (test at lower concentrations) after administration of the test drug. The total value of the total duration of exercise (FROM the middle) was 5.90.2 minutes for the placebo group and 6.40,3, 5,9of 0.3 and 6.60.2 minutes for groups receiving ranolazine at a dose of 30, 60 and 120 mg, respectively (P= NS). After 4 weeks of double-blind therapy compared with baseline values within 1 hour after administration of the test drug (peak effect) the total duration of exercise (FROM the middle) has increased by 0.450.2 minutes in the placebo group and 0.3of 0.2 to 0.60.2 and 0.50.2 minutes in the groups receiving ranolazine at a dose of 30, 60 and 120 mg, respectively (placebo compared with ranolazine, P=NS). The time elapsed before the appearance of ST depression of 1 mm compared to the baseline condition was the same in all four groups and after 4 weeks of treatment in each group was significantly increased by the same amounts through 1 hour after administration of the test drug. Similar changes were observed in relation to time of onset of symptoms of angina. Eight hours after injection (eff is the teli, associated with load in the placebo group and the groups receiving ranolazine, was not observed. In comparison with the initial values of the number of angina attacks per week and the number and duration of ischemic episodes 48 hours of monitoring by the method of Holter significantly decreased by the same magnitude in the placebo group and the groups receiving ranolazine.

These results show that treatment with ranolazine2hcl at a dose of 30, 60 and 120 mg three times a day showed no advantage over placebo. This study also showed favorable effects of similar doses of ranolazine both myocardial ischemia and stamina to physical exertion or in respect of strokes within the daily life of patients suffering from angina.

Example 4
In this example evaluated the safety and antiischemic effects of high levels of ranolazine in plasma by a large group of patients suffering from angina, and duration of any effects during chronic administration of the same doses of modes of reception twice and three times a day. In this example, patients with chronic stable angina who were amenable to treatment obychnyj, 400 mg twice daily and 400 mg three times a day in the form of HB composition of example 1. The load parameters and the concentration of free base ranolazine evaluated at the peak and the lowest levels in plasma.

Methods
The study included phase double-blind, randomized treatment with placebo-control with 4 treatments (placebo, ranolazine2hcl 400 mg twice a day, ranolazine2hcl 267 mg three times a day and ranolazine2hcl 400 mg three times a day), 4 sequences of treatment and 5 periods of double-blind treatment in an extended period of Latin squares methods involving pre-screened patients who were amenable to treatment known antianginal drugs and had a stable time of exercise.

Patients (men) with chronic stable angina lasting at least 3 months, which were amenable to treatment with conventional antianginal drugs were considered as candidates for participation in the study. In addition, patients were required to have electrocardiographic (ECG) evidence of presence induced by exercise ischemia based on the Hori is agenie 3 consecutive cardiac complexes during the exercise test, sample ECG that does not hinder the interpretation of changes in the ST segment. This last criterion is particularly excluded patients with left ventricular hypertrophy, early stimulation, conduction disturbances or pacemaker. Other exclusion criteria included unstable angina or myocardial infarction within the preceding period of 3 months, heart failure class III or IV, by definition, New York Heart Association, significant valvular or congenital heart disease that were not skorrigirovanna, need digoxin or therapy with long-acting nitrates, labile diabetes or other serious conditions that could cause confusion in the assessment of patients in follow up.

These modes immediate introduction of the composition of ranolazine2hcl with release (267 mg three times daily, 400 mg twice daily 400 mg three times daily) and placebo was carried out during the phase of treatment.

Patients took one capsule, containing 267 mg or 400 mg of ranolazine dihydrochloride or placebo in 8:00, 16:00, 20:00 and 12:00 noon. All capsules outwardly look the same. Patients randomized to participate in 1 of 4 consistently the Yali during the fifth 1-week period.

For selection of patients receiving conventional antianginal medication, carried out a screening test exercise tolerance (CCT-1) using the Bruce Protocol modified according to the method of Sheffield. If the time of onset of symptoms of angina was3, but13 minutes, antianginal drug was cancelled and started treatment with a blind introduction of a placebo. After 1-2 weeks, the patients again underwent CCT (CCT-2). If the time of onset of symptoms of angina was reduced to 1 minute in comparison with the CCT-1, the patient was qualified as past the first qualifying CCT. If reducing the time of onset of symptoms of angina was not1 minute, you can cancel the second antianginal medication and repeat the sequence described above. If necessary, you can cancel the third antianginal drug in accordance with this procedure with the purpose of qualification of the patient. Long-acting nitrates have always been abolished first; beta-blockers and calcium antagonists can be cancelled at any order in patients not receiving long-acting nitrates. After passing the onset of symptoms of angina should be within the15% of the value recorded during CCT-2. In addition, each qualifying CCT must have had ECG signs of ischemia (horizontal or colonista ST segment depression1 mm over 3 consecutive cardiac complexes). The study included patients that met these criteria.

After each weekly period, the patients again underwent CCT in a special laboratory at least 1 hour after a light Breakfast. This CCT was defined as the lowest CCT; lower CCT for each patient was performed at the same time of day. After completing the lower CCT patient blindly received the following scheme the dose from the blister pack, which was used during a given week. Another CCT was performed within 1 hour after a dose of the drug. This CCT was defined as the maximum CCT. Blood samples were collected
on the lower phase (approximately 8 hours after taking the drug) and the peak phase (1 hour after taking the drug). Other routine laboratory tests were regularly monitored throughout the study.

Blood pressure (sphygmomanometer cuff) and heart rate were monitored before all of EM is CCE maximal exercise and during the recovery period (every minute for 4 minutes, then every 5 minutes until the return of indicators at the level of the original values). Heart rate was recorded continuously and removed the standard 12-lead ECGs immediately prior to the exercise, when the patient is standing on the treadmill, and at the end of each stage of exercise, at the maximum tolerable load, and at the end of the exercise.

Average time burden on the treadmill for 3 different load modes of interest, while receiving placebo and different doses and regimen of administration of ranolazine (ranolazine - placebo) for all patients at the peak and lower phase are summarized in table 2.

Peak concentrations of ranolazine in the plasma of all ischemic parameters CCT compared with placebo increased, and, most notably, before the arrival of ST depression of 1 mm In the analysis of data on all patients, the increase in time to onset of symptoms of angina compared with placebo ranged from 0.32 to 0.39 minutes (p0.01) and the time until ST depression of 1 mm ranged from 0.28 to 0.41 minutes (p0,02) for each of the modes of reception of ranolazine and all modes in combination. The total duration of physical control who were noted for each of the modes of reception of ranolazine. When conducting portocarero analysis of each of the 3 CCT parameters was increased (p0,01) for all modes ranolazine in combination. All of the individual modes ranolazine significantly increased the time until ST depression of 1 mm, and an unreliable trend similar orientation and proportions were observed for time to onset of symptoms of angina and duration of exercise. In General, the results portocarero analysis, except for the severity of the effect was slightly larger in comparison with the results of monotherapy.

At lower concentrations in plasma ranolazine influenced CCT options to a lesser extent. The results for all patients and the results oprotocol analyses were relatively constant with a tendency to increase the time of exercise. However, just before the arrival of ST depression of 1 mm for all modes ranolazine in combination with the analysis of data on all patients reached statistical significance.

Taking into account a more pronounced increase of parameters of physical activity observed in monotherapy ranolazine, was analyzed the responses ranolazine in patients receiving different sourikova concentrations ranolazine, when the effects of improving time exercises were the most distinct. Because long-acting nitrates were cancelled in the first place during the qualifying phase with one program, no patient included in the double-blind treatment, did not receive long-acting nitrates. Among patients for whom data were obtained for peak efficiency, 34% (107/312) received beta-blockers during the double-blind treatment and 24% (75/312) received calcium antagonists.

The parameters of the exercise test was improved when peak concentrations ranolazine (ranolazine placebo) regardless of whether they received beta-blockers or not. These improvements were somewhat greater in 205 patients not receiving beta-blockers, compared with 107 patients who received beta-blockers. However, the difference between the results for patients who received beta-blockers, and patients not receiving beta-blockers, did not reach statistical significance for any of the parameters of physical activity. In patients not receiving beta-blockers, all parameters of physical activity was significantly improved when using each of the 3 modes ranolazine, as well as in alocasia beta-blockers. Comparative analysis of data on physical activity was obtained for patients taking calcium antagonists, and for patients who were not taking calcium antagonists, gave similar results.

Table 3 summarizes the average peak and the lowest concentrations of ranolazine plasma-based ranolazine dihydrochloride for all patients by sex and for each of the treatment regimens.

Average peak concentrations of ranolazine in plasma ranged from 1346 to 2128 ng free base of ranolazine on ml regimen 400 mg three times daily was associated with higher concentrations of ranolazine in the plasma. Average lowest concentration ranolazine in plasma ranged from 235 to 514 ng per ml Average peak concentrations of ranolazine in plasma were slightly higher in women than men, but lower concentrations in the plasma of differences by gender were not.

Peak concentrations of ranolazine plasma statistically significant differences between any of the modes of reception of ranolazine and placebo for the double product was not observed. Similarly, when lower concentrations of ranolazine plasma statistically significant differences between the 3 modes ranolazine and placebo in Portocolom analysis for dual productrating is an effective antianginal and antiischemic connection for patients with chronic stable angina. Peak concentrations in the plasma of all three used the reception mode ranolazine increased the time of onset of symptoms of angina and duration of exercise and the time of occurrence of ST-segment depression of 1 mm on average grew by approximately 0.33 minutes compared to placebo. Improvement of the parameters of physical activity was observed in the present study not only in patients receiving concomitant antianginal therapy (e.g., beta-blockers and calcium antagonists), but also in the subgroup of patients who received only ranolazine as monotherapy. These latter patients, the effect of treatment, it seems, was somewhat more pronounced. This suggests that ranolazine may also be suitable as monotherapy for patients with chronic stable angina.

Hemodynamic studies have shown that the improvement of parameters of physical load at peak concentrations ranolazine in plasma was not associated with changes in blood pressure or heart rate. Nejmodernejsi the mechanism of action of ranolazine thus, in Surv.

Most importantly, the authors present invention has documented that the antianginal and antiischemic effects of the drug immediate-release of ranolazine was not maintained during the interval between doses. Despite the fact that the time of occurrence of ST-segment depression 1 mm ischemic type was significantly increased and trends in the same direction was observed for the other parameters CCT, this effect was minimal at lower concentrations ranolazine in the plasma. The average peak concentration of free base ranolazine in plasma ranged from 1346 to 2128 ng per ml, while the average low plasma concentrations ranged from 235 to 514 ng per ml. it is evident that higher average levels of ranolazine in plasma observed at the peak, associated with clinically significant antianginal and antiischemic effects, while the lowest concentrations do not have the specified action.

Based on the results of the present experiment it was found that the threshold concentration of free base ranolazine plasma to provide anti-ischemic actions identified during the UCT is, in all likelihood, magnitude above priborov or above the threshold value during the whole interval between dose to ensure antianginal and antiischemic activity during physical exertion throughout this interval.

Ranolazine was well tolerated at those concentrations in plasma, which was achieved in this study. The frequency of adverse effects in different modes ranolazine and placebo did not differ and were not observed associated with the action of the medicinal product change in ECG intervals or complex morphology. In addition, no statistically significant changes in concentrations of glucose in the blood, the levels of lipids or functional hepatic tests, suggesting that the metabolic effects of ranolazine not affect the systemic regulation of glucose or lipid metabolism.

Ranolazine improves the physical parameters of the load, without detectable effects on the heart rate and blood pressure in patients with chronic stable angina. In all probability threshold concentration ranolazine plasma above about 550 ng per ml should be obtained to identify these antianginal and antiischemic effects. Ranolazine good transfer is PCIe treatment of ischemia justifies further studies using higher doses of the drug slow release of ranolazine.

Example 5
I. Comparison of HB song and PV compositions in vitro
HB composition made as described in example 1, and PV compositions made as described in examples 2A-2C, was tested in the tester for USP dissolution Apparatus 2 with 900 ml of 0.1 M hydrochloric acid as a solvent fluid to simulate dissolution in the stomach.

Tabular data (see tab.4) show that while HB composition is completely dissolved not more than 0.5 hours (as expected for the composition with the immediate-release), PV compositions a, b and C showed a prolonged dissolution at low pH value, as it is desirable for the composition with prolonged release of the active ingredient.

II. Comparison of HB song and PV compositions in vivo
A single dose of HB composition made as described in example 1, and PV compositions a and b, produced as described in example 2, was introduced eleven healthy volunteers and measured the concentration of free base ranolazine in plasma after 0, 20, 40, 60, 90 and 120 minutes, every hour up to six hours, two times per hour for up to eighteen hours and 24 hours after injection (only for PV compositions). The results are presented in table 5.

Example 6
This example describes in detail a cross-sectional study using a single rising doses, which evaluated the safety and pharmacokinetic profile of a single oral dose PV composition base ranolazine described in example 2D. The study involved people who were divided into three groups. Group 1 received 500, 750 and 1000 mg of the composition with a slow release of ranolazine. Group 2 received 1250 and 1750 mg songs with slow release of ranolazine. Group 3 received 1500 and 2000 mg songs with slow release of ranolazine. Each group were also randomised phase placebo. Average pharmacokinetic parameters after a single oral dose of the composition with a slow release of ranolazine presented in detail in table 6.

The pharmacokinetic results are presented in table 6, indicate that ranolazine was slowly released from the PV of the composition, and further the absorption of ranolazine was limited by the dissolution rate. This resulted in prolonged concentration profiles of lekarstvennyy in plasma was observed after 4-6 hours after taking the dose. Within doses of 500-2000 mg averagemaxand AUC0-30hincreased approximately in proportion to dose, although it appears that there was some deviation from proportionality in group 2.

Example 7
This example describes in detail a double-blind, crossover, placebo-controlled study on human volunteers using multiple rising doses, which was conducted to assess dosing twice a day. Six participants received within 4 days composition with a slow release of ranolazine made as described in example 2D, at a dose of 500, 750 and 1000 mg twice a day, and then received a morning dose on day 5. The pharmacokinetic results are presented in table 7.

According to table 7 ranolazine was slowly released from the PV of the composition, and further pharmacokinetic parameters were limited by the dissolution rate. This resulted in enhanced concentration profiles of the drug in the plasma depending on time, which was observed at all dose levels, with peak plasma levels were observed within 2 to 4 hours after the dose.

These results indicate that useful levels of ranolazine plasma is canivet safety and tolerability of introducing songs free base of racemic ranolazine as in example 2D. Determined individual and average concentrations of racemic ranolazine and its enantiomers, (R)-(+)-N-(2,6-dimetilfenil)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl] -1-piperazineethanol and (S)-(-)-N-(2,6-dimetilfenil)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl] -1-piperazineethanol, in the plasma of human blood.

This study was carried out using increasing doses of dosage forms with prolonged release of ranolazine. Before the introduction of doses at certain intervals during and after administration of doses were taken blood samples for analysis ranolazine, as well as throughout the study watched blood pressure, heart rate, ECG and symptoms. Summary data were analyzed after each phase before moving to the next phase of this study.

Were included in the study and in full force completed the study and were available for analysis of pharmacokinetic parameters and safety of eight subjects healthy male volunteers aged 18 to 40 years. These subjects were given doses of different types of free base ranolazine in the form of a slow release tablets, including tablets 500 mg and 750 mg, or p is receiving standard oral doses of 1500 and 2000 mg

During each phase: one dose twice a day for four days with a single dose on day 5. On day 5, each volunteer underwent determination of the full pharmacokinetic profile, including blood pressure (BP) and heart rate in the supine position and standing, ECG data, adverse effects, biochemical and hematological parameters, and urine tests.

Tested steady state for each level doses using48hWithCand CCand logarithmically transformed data by analyzing covariance and by testing, significantly if different from 0, the coefficient for time (adopted by the reliability of p<0,05). These tests were performed using two-sided t-test with the assessment of the variability in the results of univariate analysis of variance (ANOVA). Steady state was evaluated by comparing mean values for C48hWithCand CCusing mixed-effects ANOVA and untransformed and log-transformed data. For analysis of hemodynamic effects compared averages in the treatment of pre-dose on day 1 and data on day 5 in all treatment regimens through doctor is anasto and 95% confidence intervals. For multiple comparisons below were not used.

Average pharmacokinetic parameters of free base ranolazine on day 5 and standard deviation are presented in detail in table 8. Sustainable levels of free base ranolazine in plasma appears to be achieved by the 4th day. During the interval between receptions of doses has been a slow rise to maximum levels, with values of tmaxfrom 1 to 6 h after the dose. After that, the levels fell slowly with small fluctuations during the intervals between receptions of doses. It seems that on the pharmacokinetic parameters of (+)R and (-)S-enantiomers of ranolazine after multiple dosing using PV composition differences are not observed.

Some participants standing symptoms were too pronounced to complete the measurements HELL, when using doses of ranolazine 1500 mg (n=3 out of 8) and 2000 mg (n=2 of 8), usually within 2-6 hours after taking the dose. Statistically significant decrease in orthostatic systolic blood pressure was noted on day 5 when using doses of 1500 mg (-9,8 mm RT.article; 4 hours after the dose) and 2000 mg (-8,4 mm RT.article; 6 hours after the dose). Despite the fact that the character seems adverse, more often met when receiving ranolazine.


Claims

1. A method of treating a person suffering from a cardiovascular disease selected from arrhythmias, variant angina, angina stress and myocardial infarction, by introducing a pharmaceutical dosage form with prolonged release of the active ingredient, comprising at least 50 wt.% ranolazine in not more than two tablets at a reception person to maintain levels of base ranolazine in plasma from approximately 550 to 7500 ng/mg for at least 24 h, and this dose is injected with a frequency selected from one, two or three times within 24 hours

2. The method according to p. 1, in which the dosage form slow release includes at least one pH-dependent binder; and specified pH-dependent binding agent inhibits release of ranolazine of the dosage form, when it is exposed to the aqueous environment having a pH of the stomach and the pH-dependent binder contributes to the release of therapeutic amounts of ranolazine in an aqueous solution having a pH higher than 4.5.

3. The method according to p. 2, where rn-soviershenno form is administered to a person with a frequency selected from one and two times within 24 hours

5. The method according to p. 1, in which the pharmaceutical dosage form is administered to a person with two doses within 24 h, and each dose consists of two tablets.

6. The method according to p. 1, in which the pharmaceutical dosage form comprises from 50 to 95 wt.% ranolazine.

7. The method according to p. 1, in which the pharmaceutical dosage form includes from 70 to 80 wt.% ranolazine.

8. The method according to p. 2, in which the pH-dependent binder is chosen from copolymers of methacrylic acid phthalate of hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose, phthalate cellulose acetate, polyvinyl acetate phthalate, phthalate of polyvinylpyrrolidone and mixtures thereof.

9. The method according to p. 2, in which the pH-dependent binder is a copolymer of methacrylic acid.

10. The method according to p. 9, in which the methacrylic acid copolymer is a copolymer of methacrylic acid type With USP.

11. The method according to p. 2, in which 5-12 wt.% pH-dependent binding agent are methacrylic acid copolymer type C USP.

12. The method according to p. 1, in which 10 wt.% pH-dependent binding agent present copolymer metacrilato acid type C USP.

13. The method according to p. 1, in which farmatsevticheskii binding agent selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, poly(meth)acrylate esters, polyvinylpyrrolidone and mixtures thereof.

15. The method according to p. 13, in which the pH-independent binding agent is hypromellose.

16. The method according to p. 15, in which the pharmaceutical dosage form contains from 1 to 3 wt.% hydroxypropylmethylcellulose.

17. The method according to p. 15, in which the pharmaceutical dosage form comprises 2 wt.% hydroxypropylmethylcellulose.

18. The method according to one of paragraphs. 1, 6-17, in which the level of ranolazine in plasma is in the range 1000 - 5000 ng/ml

19. The method according to one of paragraphs. 1, 6-17, in which the level of ranolazine in plasma is in the range 1000 - 3800 ng/ml

20. The method according to one of paragraphs. 1, 6-17, in which the level of ranolazine in plasma is in the range 550 - 5000 ng/ml

21. The method according to one of paragraphs. 1, 6-17, in which the level of ranolazine in plasma is in the range 550 - 3800 ng/ml

22. The method according to one of paragraphs. 1, 6-17, in which the level of ranolazine in plasma is in the range 1000 - 2800 ng/ml

23. The method according to one of paragraphs. 1, 6-17, in which the level of ranolazine in the blood plasma of the patient is within the 1700 3900 ng/ml

24. The method according to one of paragraphs. 1, 6-17, in which governmental form includes 650-850 mg ranolazine.

26. The method according to p. 24, in which the dosage form includes 900-1100 mg ranolazine.

27. The method according to p. 25, in which dosage form comprises a 400 - 600 mg ranolazine.

28. The method according to one of paragraphs.22-27, in which the ratio of the maximum and minimum levels of ranolazine in plasma is less than 4:1 within 24 hours

29. The method according to one of paragraphs.23-27, in which the ratio of the maximum and minimum levels of ranolazine in plasma is less than 3:1 for 24 hours

30. The method according to p. 24 or 28, in which the ratio of the maximum and minimum levels of ranolazine in plasma is less than 2:1 within 24 hours

31. A method of treating a person suffering from a cardiovascular disease selected from arrhythmias, variant angina, angina stress and myocardial infarction, by introducing a pharmaceutical dosage form comprising ranolazine to maintain levels of base ranolazine in plasma from 550 to 7500 ng/ml for at least 24 hours

32. A method for the treatment of variant angina or angina stress in humans, including the introduction of the specified person of pharmaceutical dosage forms with prolonged-release formulation comprising at least 50 wt.% nanolanguage agent.

33. The method according to p. 32, in which the pharmaceutical dosage form is administered in an amount of not more than two tablets per dose.

34. The method according to p. 33, in which the pharmaceutical dosage form is administered once, twice or three times within 24 hours

35. The method according to p. 32, in which the pharmaceutical dosage form is administered with such frequency that the ratio of the maximum and minimum levels of ranolazine in plasma was less than 4:1 within 24 hours

36. The method according to p. 32, in which the pharmaceutical dosage form is administered with such frequency that the ratio of the maximum and minimum levels of ranolazine in plasma is less than 3:1 for 24 hours

37. The method according to p. 32, in which the pharmaceutical dosage form includes a number of ranolazine sufficient to maintain the levels of base ranolazine in plasma from 550 to 7500 mn/mg within 24 hours

38. The method according to p. 32, in which the pharmaceutical dosage form includes from 70 to 80 wt.% ranolazine.

39. The method according to p. 38, in which the pharmaceutical dosage form includes from 5 to 12.5 wt.% pH-dependent binding agents.

40. The method according to p. 39, in which the pH-dependent agent is at least one copolymer of methacrylic acid.<

42. The method according to p. 41, in which the pH-independent binding agent is hypromellose.

43. The method according to p. 42, in which each tablet contains from 350 to 800 mg ranolazine.

Priority items:
10.09.1998 on PP.1-17, 20-21, 23-43
27.05.1999 on PP.18, 19 and 22.

 

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