Drugs ranolazine with prolonged action

 

The invention relates to the field of pharmacy and related to drug ranolazine. The invention consists in the fact. what drug ranolazine with prolonged action contains a homogeneous mixture of ranolazine and a partially neutralized pH-dependent binder to form a film, which is normally insoluble in aqueous medium with a pH below 4.5 and soluble in an aqueous environment with a pH higher than 4.5. The preparation is suitable for administration ranolazine twice a day and can be used to control the dissolution rate of ranolazine and to maintain levels of ranolazine in plasma between 350 and 7500 ng/ml Invention provides creation of dosage forms with prolonged action, while maintaining the drug for at least 24 h 2 S. and 18 C.p. f-crystals, 9 PL.

The prior art For this application claims the priority of provisional patent application U.S. registration number 60/099804, filed September 10, 1998

1. Technical field the Present invention relates to a method for oral administration of drugs of ranolazine with prolonged action (slow release) with the goal of maintaining concentrations of ranola is the U.S. 4567264, description of which is included in this application by reference, describes ranolazine, ()-N-(2,6-dimetilfenil)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl] -1-piperazineethanol, and its pharmaceutically acceptable salts, and their use in the treatment of cardiovascular disease, including arrhythmias, variant and is caused by physical exertion angina and myocardial infarction.

In U.S. patent 5506229, which is included in this description by reference, discloses the use of ranolazine and its pharmaceutically acceptable salts and esters for the treatment of tissue subjected to physical or chemical damage, including cardioplegia, hypoxic, or reperfusion damage of the heart or skeletal muscle or brain tissue, as well as for use in transplants. The usual oral and parenteral drugs, including drugs with controlled release of active compounds. In particular, in Example 7D U.S. patent 5506229 described the drug controlled release encapsulated form, containing microspheres of ranolazine and microcrystalline cellulose coated with polymers that control the release.

Currently, the preferred method pralina dosage form is compressed tablet, hard gelatin capsule filled with a powder mixture or granular material, or a soft gelatin capsule (soft gel) filled with a solution or suspension. In U.S. patent 5472707, the description of which is also incorporated by reference, describes an oral drug with a high dose, using supercooled liquid ranolazine as a fill solution for hard gelatin capsules or soft gel.

As shown in Example 3 of the application, the primary test ranolazine on people suffering from angina, were unsuccessful. In these tests was used in the preparation of ranolazine with immediate effect at the dose level of 120 mg and regimen three times a day. The results of these initial experiments did not give a clear answer, you can or cannot give ranolazine people in a quantity and manner that is effective against angina.

One of the problems with conventional oral drugs is that they are not ideally suited for ranolazine and its pharmaceutically acceptable salts, as the solubility of ranolazine relatively high at low pH values, which take place in the stomach. In addition, ranolazine also has a relatively short period of polowy the C body, what causes large and undesirable fluctuations in the concentration of ranolazine in plasma and short duration of action and forces, thus, frequent oral medication to achieve adequate treatment.

Thus, there is a need in the way of introduction of ranolazine in the form of oral dosage forms, one or two times daily, which provides a therapeutically effective concentration of ranolazine plasma in the treatment of angina in humans.

Summary of the invention In accordance with the first aspect of the present invention provides the preparation of ranolazine with prolonged action, in which a large part of the drug is active ranolien.

In accordance with another aspect of the present invention provides a method of treating people who suffer from angina or other coronary diseases, by the introduction of patient drug ranolazine with prolonged action once or twice a day.

Another object of the present invention is a method of treating a mammal having a disease state for which prescribed the introduction of ranolazine, and this method includes the introduction of one or two times a day preparatoria plasma, close to the minimum effective levels maximum without hesitation.

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

The present invention includes methods of treatment of people with cardiovascular disease, selected from arrhythmias, variant and is caused by physical exertion angina and myocardial infarction. The method comprises the administration to a human a pharmaceutical dosage form with prolonged action, containing at least 50 wt.% ranolazine, not more than two tablets per dose, to maintain levels of ranolazine plasma sick person from about 550 to 7500 ng base/ml for at least 24 hours, where the dose is given with a frequency selected from one, two or three times in 24 hours.

The invention additionally includes a method of treating a patient suffering from a cardiovascular disease selected from angina, variant and is caused by physical exertion angina and myocardial infarction. The method includes the introduction of patient pharmaceutical lekarstvennayaforma per dose, to maintain levels of ranolazine plasma sick person from about 1000 to 3900 ng base/ml for at least 24 hours, where the dose is given with a frequency selected from one or two times in 24 hours.

The present invention also includes a pharmaceutical dosage form containing at least 50 wt.% ranolazine and at least one pH-dependent binding substance, which inhibits the release of ranolazine of the dosage form with prolonged action, when this dosage form with prolonged action is exposed to the aqueous environment having a pH value of the stomach, and which contributes to the release of a therapeutically effective amount of ranolazine in an aqueous solution having a pH above about 4.5.

Detailed description of the invention "Ranolazine"predostavlyaetsyaodnim()-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-piperazineethanol, as well as their pharmaceutically acceptable salts and with whom to the concentration of free base.

The definition of "optional" and "optionally" mean that consistently describes the event or condition can occur or may not occur, and that this definition includes cases when the event or condition, and when they are absent. For example, the definition of "optional pharmaceutical excipients" indicates that described the drug may include or may not include pharmaceutical excipients other than fillers, which are specifically listed as present, and described the drug includes examples in which optional fillers, and examples in which they are missing.

The concept of "be subjected to treatment" and "treatment" refer to any treatment of a disease in a mammal, particularly human, and includes: (I) preventing the development of disease in a subject which may be predisposed to the disease but not yet diagnosed as having it; (II) inhibiting the disease, i.e., delayed in its development; or (III) the weakening of the disease, that is, his regression. The definition of "immediate action" (ND) refers to products or standard dosage forms, which are easily rescudose-intestinal tract. Usually these drugs are free, at least 90% of the active ingredient within 30 minutes after injection.

The definition of "prolonged action" (DD) refers to drugs and standard dosage forms of the present invention, which slowly and continuously dissolved and absorbed in the stomach and gastrointestinal tract over a period of approximately six hours and more. Preferred preparations with prolonged action are drugs, giving a concentration of ranolazine in the plasma, it is acceptable to introduce no more than twice a day using two or less tablets on a single administration of a medicinal product, as described below.

The concentration of ranolazine plasma mean concentration determined by analytical measuring the concentration of ranolazine not less than five people and up to ten people who took the medicine according to the same scheme. What concentration of ranolazine represents a mean value, is of great importance because of differences in concentrations of ranolazine different people, which may be due to the difference in weight, metabolism or medical conditions that may lead to the fact that odnogo of the selected blood on heparin.

Below are definitions of terms used in the description: ANOVA = analysis of variance.

ATP = adenosine triphosphate
ECG = electrocardiographic
Tpfn = tolerance test monotonous physical activity
PDG = pyruvaldehyde
Withmax= maximum concentration
Withleave= residual concentration 8 hours after drug administration for drugs in ND and 12 hours after drug administration for drugs with PD a-C of Example 2.

t/d = three times a day
d/d = twice a day
Withx= concentration at time x
Tmax= time to maximum concentration
ACCx= area under the curve through x hours or a time interval.

The above percentages, unless otherwise noted, represent weight percent. The present invention includes a pharmaceutical form of ranolazine with prolonged action, as well as methods of administration dosage forms ranolazine with prolonged action of the present invention to provide therapeutic levels of ranolazine in plasma.

The preparations of the present invention with prolonged action preferably have the form of compressed tablets containing a homogeneous mixture of lorenia of ranolazine in the aquatic environment in the range of pH values of the stomach (usually about 2) and intestines (usually about 5.5).

To obtain the prolonged action of ranolazine choose one or more pH-dependent binders to adjust the dissolution profile of the drug ranolazine so that the drug releases ranolazine slowly and continuously as the passage through the stomach and gastrointestinal tract. The ability of pH-dependent(s) binder(s) of the substance(C) to regulate the dissolution is particularly important in the drugs ranolazine with prolonged action, as the preparation with prolonged action of ranolazine that contains a sufficient number of ranolazine for administration twice a day, can cause unwanted side effects, if ranolazine is released too quickly ("reset dose").

Thus, the pH-dependent binders suitable for use in the present invention are binders that inhibit rapid drug release from tablets during her stay in the stomach (where the pH is below about 4.5), and which contribute to the release of therapeutic amounts of ranolazine from the dosage form in the lower part of the gastrointestinal tract where the pH value is usually greater than about 4.5). Many agents, have a solubility at the desired pH value. These include derivatives of phthalic acid, such as derivatives of phthalic acid, vinyl polymers and copolymers, hydroxyethylcellulose, alkylaryl, cellulose acetates, acetates hydroxyethylcellulose, ethers of cellulose, 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 may be used in combination with ranolazine to create preparations with prolonged action, 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 copolymer of methacrylic acid. Type (USP), which is a copolymer of methacrylic acid and ethyl acrylate containing from 46,0 to 50,6% links methacrylic acid). Such a copolymer is commercially available product of the firm Rohm
Pharma as Eudragit

In oral dosage forms of ranolazine with prolonged action can be used one or more pH-independent binders. It should be noted that the pH-dependent binder and agents that increase viscosity, such as hypromellose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, neutral poly(meth)acrylic esters, and so on, by themselves, do not provide the necessary control of dissolution provided by these pH-dependent binders. pH-Independent binders are present in PR is positive in the range from about 1 to 3 wt.%, and most preferably in the amount of about 2.0 wt%.

As shown in Table 1, ranolazine relatively insoluble in aqueous solutions having a pH above about 6.5, while its solubility begins to increase sharply at pH values below about 6.

The increase in the content of the pH-dependent binders in the preparation reduces the rate of release of ranolazine of the drug at pH values below 4.5, the normal pH found in the stomach. Intersolubility coating formed binder, less soluble and increases the relative rate of release at pH higher than 4.5, where the solubility of ranolazine below. The appropriate choice of the pH-dependent binder makes it possible to accelerate the release of ranolazine of the drug at pH above 4.5, while gently influencing the rate of release at low pH values. Partial neutralization of the binder contributes to the transformation of the binder in a similar latex film, which is formed around the individual granules ranolazine. Thus, the type and number of pH-dependent binder and the number of partially neutralized compositions are chosen so that lateeeee should have a number of pH-dependent binders, sufficient to obtain a preparation with prolonged action, the rate of release of ranolazine of which is regulated so that at low pH values (below about 4.5) the dissolution rate significantly slowed down. In the case of methacrylic acid copolymer, Type C, USP (EudragitL 100-55) a suitable amount of a pH-dependent binder is between 5 and 15%. the pH-dependent binder will typically contain from about 1 to 20% neutralized carboxyl groups of the methacrylic acid. However, it is preferable that the degree of neutralization was in the range from about 3 to 6%.

The preparation with prolonged action may also contain pharmaceutical excipients, uniformly mixed with ranolazine and pH-dependent binder. Pharmaceutically acceptable excipients may be present, for example, a pH-independent binders or film-forming agents such as hypromellose, hydroxypropylcellulose, methylcellulose, polyvinylpyrrolidone, neutral poly(meth)acrylate esters (e.g. methyl methacrylate/ethylacrylate apochromat, gelatin, sugar, carboxymethylcellulose and other Other useful pharmaceutical excipients include diluents, such as lactose, mannitol, dry starch, microcrystalline cellulose and other similar materials; surface-active agents, such as polyoxyethylene esters sorbitan, esters sorbitan and others , as well as coloring agents and corrective taste and odor agents. Lubricants, such as talc and magnesium stearate, and other tabletiruemye excipients, can also optionally be present.

Drugs ranolazine with prolonged action of the present invention have a content of ranolazine above approximately 50 wt.% and approximately 95 wt.% or more, more preferably between about 70 and 90 weight. %, and most preferably from about 70 to 80 wt.%; the content of the pH-dependent binder is between 5 and 40%, preferably between 5 and 25%, and more preferably between 5 and 15%; the remainder of the dosage form are pH-independent binders, fillers and other optional fillers.

Particularly preferred drugs ranolazine with prolonged action of this onerownim effect of the present invention can be obtained in the following way: ranolazine, the pH-dependent binder and any optional fillers, thoroughly mix (dry mix). Mixed dry mixture then granularit in the presence of an aqueous solution of a strong base, which is dispersed in the mixed powder. The granulated material 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% miscible with water, solvents such as lower alcohols).

Received tablets containing ranolazine, can be covered with an optional film-forming agent for identification, taste masking and improve swallowing. Film-forming agent will typically be present in a quantity lying in the range between 2 and 4% based on the weight of the tablet. Suitable film-forming agents are well known in this area and these include hypromellose, cationic methacrylate copolymers (dimethylaminoethylmethacrylate/methyl-butylmethacrylate copoly prasouda agents may optionally contain colorants, plasticizers and other auxiliary ingredients.

Pressed tablets preferably have a sufficient hardness to withstand compression in 8 Cu. Tablet size will depend mainly on the number of ranolazine in the tablet. Tablets will contain from 300 to 1100 mg of free base ranolazine. Preferably the tablets will contain the amount of free base ranolazine in the range of 400-600 mg, 650-850 900-1100 mg and mg of

In order to affect the dissolution rate, the time during which the powder containing ranolazine, mixed in the wet state, is controlled. Preferably the total time of mixing of the powder, for example, the time during which the powder is exposed to sodium hydroxide solution, will be in the range from 1 to 10 minutes and preferably from 2 to 5 minutes. After granulation, the particles removed from the pellet and placed in a fluidized bed dryer for drying at approximately the 60oC.

It has been unexpectedly found that by using such methods get drugs ranolazine with prolonged action, which provide lower maximum levels of ranolazine in the plasma and is still effective concentration of the underwater base, and not in the more conventional pharmaceutically dihydrochloride of ranolazine or other salts and ether. The use of free-base provides at least one advantage: the share of ranolazine in the tablet can be increased as the molecular weight of the free base of ranolazine is only 85% of the molecular weight of the dihydrochloride of ranolazine. Thus, the delivery of an effective amount of ranolazine is achieved while limiting the physical size of a standard dosage forms.

Another advantage of drugs ranolazine with prolonged action of the present invention is that they are using the process, which essentially is used as a solvent only water and uses standard processing techniques and equipment.

Drugs ranolazine with prolonged action of the present invention can be used to treat cardiovascular disease, including arrhythmias, variant and is caused by physical exertion angina and myocardial infarction; for treatment of the tissues subjected to physical or chemical damage, including cardioplegia, hypoxic or reperfusion damage serdikauskas claudication (syndrome Charcot). Most preferably, the drug with prolonged action was used as protivoklimaktericescoe agent for a mammal, and most preferably as protivoklimaktericescoe agent for a person.

Oral drugs ranolazine with prolonged action of the present invention are inserted one, two or three times during a 24-hour period to maintain the patient's level of ranolazine in the plasma above therapeutic threshold level and below the maximum tolerated levels, approximately between 550 and 7500 ng base/ml This corresponds to the number of dihydrochloride of ranolazine lying in the range approximately from 644 to 8782 ng/ml in Addition, the timing of oral ingestion of the oral dosage form of ranolazine should be regulated to ensure that the levels of ranolazine plasma will not exceed approximately 7500 ng base/ml, and preferably so that the level of ranolazine in plasma did not exceed approximately 5000 ng base/ml, and most preferably so that it does not exceed 3800 ng base/ml In some cases it may be useful to limit the maximum level of ranolazine predpochtitelno must not fall below approximately 1000 ng/base/ml and in some cases should not fall below 1700 ng base/ml

In order to receive the preferred level of ranolazine in plasma approximately from 1000 to 3800 ng base/ml, preferably, the oral dosage form of ranolazine described in the invention was administered once or twice a day. If the drug dose to enter twice a day, preferably oral dosage forms ranolazine was injected with approximately twelve-hour intervals.

In addition to the preparation and introduction of oral dosage forms ranolazine with prolonged action of the present invention in a way that regulates the levels of ranolazine in the plasma, it is also important to minimize the difference between the maximum and residual levels of ranolazine in the plasma. The maximum levels of ranolazine in plasma are usually achieved in approximately 30 minutes - 8 hours or more after ingestion of the dosage form, while the residual levels of ranolazine in plasma are reached approximately to the time of swallowing following the regimen dosage forms. Preferably, the dosage form with prolonged action of the present invention was administered in a way that creates maximum level of ranolazine not more than 8 Veni, and most preferably not more than 2 times greater than the residual level of ranolazine.

Drugs ranolazine with prolonged action of the present invention provide a therapeutic advantage minimized differences in the concentrations of ranolazine in the plasma, allowing in most cases, the introduction of twice a day. The drug can be introduced separately or (at least initially) in combination with the drug, immediate action if you want quick achieve therapeutically effective concentrations in the plasma, or by using soluble drugs IV and oral dosage forms.

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

EXAMPLES
In these examples, the described methods of manufacture of the dosage forms ranolazine, as well as the experiments conducted to assess the effectiveness of the introduction of ranolazine and efficiency. For all these Examples, it should be noted that:
(1) Oral dose of the drug with immediate effect (OD) was given in the form of capsules or tablets dihydrochloride and presented based on the dihydrochloride.

(2) Oral dose of the drug with prolongiro the/p> (3) When compared in the same study drugs with ND and PD dose is expressed based on both the base and the dihydrochloride. The conversion factor dihydrochloride on the base is 0,854 (for example, 400 mg of the dihydrochloride x 0,854=342 mg equivalent of free base).

(4) plasma Concentrations and pharmacokinetic parameters expressed in terms of concentrations of free base.

EXAMPLE 1
This Example describes a method of obtaining drugs ranolazine with immediate effect (ND). Powders dihydrochloride of ranolazine (4000 g), microcrystalline cellulose (650 g), polyvinylpyrrolidone (100 g) and sodium salt croscarmellose (100 g) are thoroughly mixed together in the mixer-granulator Fielder PMA 65 and then with stirring, add enough water to form a granular material. The granulated material is dried in a fluidized bed dryer Aeromatic Strea-5, sieved and mixed with magnesium stearate (100 g). The mixture is filled hard gelatin capsules to weight, for example, 500 mg of ranolazine the capsule to achieve a dose of 400 mg of the dihydrochloride of ranolazine (equivalent to 342 g of free base ranolazine) to capsule, but filling and to aseparate of ranolazine with prolonged action (POA).

Drug ranolazine with prolonged action (POA), which is represented as a Drug-PD and containing pH-dependent and pH-independent binders, obtained by mixing powders of Ranolazine (2500 g), methacrylic acid copolymer, Type C (EudragitL 100-55 - Rohm Pharma) (1000 g), microcrystalline cellulose (Avicel) (100 g) (710 g) and polyvinylpyrrolidone, which are thoroughly mixed in the mixer-granulator Fielder PMA 65. The mixture granularit using sodium hydroxide solution (40 g) in water and the wet mass is added a 30% aqueous dispersion of a copolymer of methyl methacrylate/acrylate (EudragitNE 30D - Rohm Pharma) (1667). The obtained granules are dried in a fluidized bed dryer Aeromatic Strea-5, sieved and mixed with the sodium salt croscarmellose (100 g) and magnesium stearate (50 g). The mixture is pressed into tablets weighing 684 mg with teletrauma Manesty machines, receiving a dose of the free base of ranolazine per tablet 342 mg of This drug is designated as a Drug-PD A.

Drug-DD To get in the same way as the drug-DD A, except that the amount of EudragitNE 30 replace 40% aqueous dispersion of a copolymer of methyl methacrylate/acrylate (EudragitNE 40 D - Rohm Pharma) (2,500 grams). The resulting drug-DD contains 342 mg of the free base of ranolazine on one tablet.

To obtain drug-PD With free base of ranolazine (342 mg) is mixed with microcrystalline cellulose and polyvinylpyrrolidine K, granularit with water, dried and mixed with the sodium salt croscarmellose and magnesium stearate. The mixture is pressed into tablets and cover intersolubility the floor.

Drug-PD D containing only the pH-dependent binder, obtained by thorough mixing of ranolazine
(7500 g), EudragitL 100-55 (1000 g), hydroxypropylmethyl-cellulose (MethocelE5 - source) (200 g) and microcrystalline cellulose (Avicel) (1060 g). Mixed powders granularit using sodium hydroxide solution (40 g) in water (1900-2500 g). The granulated product is dried and sieved, mixed with magnesium stearate (200 g) and pressed, for example, into tablets weighing 667 mg, receiving a dose of free oncescu plate machine for coating Accelacotasolution covering film OPADRY to the increased weight of 2-4%. Solutions covering film OPADRY different colors are commercial products Colorcon, West Point, PA.

Stepwise method for producing Drug-PD D:
a) Mix with each other ranolazine, microcrystalline cellulose, methacrylate copolymer (Type C) and hypromellose using a suitable mixer.

b) Dissolving sodium hydroxide in purified water.

C) Using the right equipment for granulating, slowly add to the mixture with constant stirring a solution of sodium hydroxide. If necessary, add an additional aliquot of water.

g) Continue mixing to achieve additional joins mass. Add, if necessary, another aliquot of water.

d) Drying the granular material in a fluidized bed dryer.

e) Sift the dried granules through a suitable mill.

g) Add magnesium stearate to the sifted granules and mix with each other.

C) Skip granular material through the ultrasonic device with cooling (chilsonator), if necessary.

and to Compress granules in toshok OPADRY in water and apply a film coating using a properly adjusted equipment for applying coatings to normal 2-4 wt.%.

l) to be Polished with the use of Carnauba wax using conventional level 0,002-0,003 wt.%.

EXAMPLE 3
In this experiment, the empirical results of the study published in Circulation 90: 726-734 (1994), who showed that ranolazine ineffective as protivoklimaktericescoe agent and anti-ischemic agent, when it is used in the Medication-ND of Example 1.

The study involved patients with stable angina. The reception of any prior drugs against angina stopped under medical supervision. Three hundred and nineteen patients received single-blind placebo for up to 18 days and 318 stopped exercise because of angina moderate, had signs of myocardial ischemia1-mm decrease in ST segment) and were randomly distributed into one of four experimental groups, which were introduced: ranolazine.2HCl, 30 mg, three times daily (n=81); ranolazine.2HCl, 60 mg, three times daily (n=81); ranolazine.2HCl, 120 mg, three times daily (n=78); and placebo, three times daily (n=79). After doses of 30, 60 and 120 mg three times daily average maximum concentration of free base ranolazine in plasma within 1 hour after the dose was appropriate alali respectively 18, 37 and 90 ng/ml

After 4 weeks of double-blind phase of the study limited the symptoms tests tolerance monotonous physical activity were repeated after 1 hour (test at maximum concentration) and 8 hours (test at a residual concentration) after the introduction of the investigational drug. The total duration of physical activity at the ground state (cf. square error) was 5.90.2 minutes for the group receiving placebo, and 6.40,3, 5,9of 0.3 and 6.60.2 minutes respectively for groups who ranolazine at doses of 30, 60 and 120 mg (P=ND - not reliably). After 4 weeks of double-blind treatment in comparison with the basic values after 1 hour after administration of study medication (maximum effect) the total duration of physical activity (cf. square error) increased by 0.450.2 minutes in the placebo group, and 0.3of 0.2 to 0.60.2 and 0.50.2 minutes respectively for groups receiving ranolazine at doses of 30, 60 and 120 mg (placebo relative ranolazine, P=NS). Oia in each group were increased significantly at similar values after 1 hour after drug administration. Similar changes were observed for time to onset of angina. 8 hours after drug administration (residual effect) no differences in total duration of exercise or any other physical variables were observed between the groups receiving placebo and treated groups ranolazine. Compared with the basic values of the number of angina attacks per week, and number and duration of acute ischaemic attacks for 48 hours during Holter monitoring was reduced substantially similar in magnitude in the placebo group, and the groups who ranolazine.

The results show that treatment with ranolazine.2HCl at doses of 30, 60 and 120 mg in the scheme "three times a day" is not superior to placebo. The study also showed no positive effect of the same doses of ranolazine or myocardial ischemia, either in physical activity or angina in the daily activities of patients with angina.

EXAMPLE 4
In this example, a large group of patients with angina assess the safety and anti-ischemic actions of high concentrations of ranolazine in plasma, and also determined the duration of any of affecto the tion constant angina, that easily respond to conventional drugs against angina were treated using three schemes the introduction of ranolazine.2HCl: 267 mg three times daily, 400 mg twice daily and 400 mg three times a day in the form of Drugs-ND of Example 1. Test settings on physical activity and the concentration of free base ranolazine determine when the maximum and residual plasma concentrations.

Ways
The study includes a double-blind, placebo-controlled, with a random sample phase of treatment with 4 courses of treatment (placebo; ranolazine. 2HCl, 400 mg, twice a day; ranolazine.2HCl, 267 mg, three times a day; and ranolazine. 2HCl, 400 mg, three times a day), 4 treatment sequences and 5 double-blind periods of treatment with long-term planning period of experience of the Latin square on pre-prepared for study patients, which easily react to known treatment of angina and have sustained duration of physical exercise.

Candidates for study are patients with chronic ongoing angina lasting at least 3 months, which respond to the usual treatment of angina. In addition, bulgarization or deviating down the decrease in ST-segment1 mm, which is held for 3 consecutive reductions in test time for physical activity, and electrocardiogram interpretation which do not interfere with changes ST-segment. The last criterion is actually excludes patients with left ventricular hypertrophy, predopredeniem, conduction disturbances or pacemaker rhythm. Other exclusionary criteria are unstable angina or myocardial infarction within the preceding three months, heart failure, attributable to the new York heart Association Class III or IV, significant heart valve disease or congenital heart valve disease, which was not fixed, need digoxin or treatment long acting nitrates, labile diabetes or other serious conditions that could confuse subsequent evaluation.

These schemes introduce ranolazine.2HCl with immediate effect (267 mg three times daily, 400 mg twice daily 400 mg three times daily) and placebo conduct during the phase of treatment. Ill give one capsule containing or 267 mg or 400 mg of the dihydrochloride of ranolazine, or placebo at 8:00am, 4:00pm, 8: 00pm and 12:00am. All capsules are identical in Vnesh in each of the sequences. Each treatment is given for one week when the same treatment is repeated during the fifth week period.

To prepare a study for patients receiving conventional medicines, angina, pass the qualifying test monotonous physical load (test on exercise tolerance, cpfn-1) using the technique of Bruce, modified Sheffield. If the time to onset of angina is3, but13 minutes, medicine to treat angina reject and begin treatment with single-blind placebo. After 1-2 weeks, the patients again pass the test exercise tolerance (tpfn-2). If the time to onset of angina reduced to 1 minute in comparison with tppn-1, the patient is considered able to withstand the first qualification test of physical activity. If the decrease in time to onset of angina is > 1 min, the second cure angina can be rejected and repeated the sequence described above. If necessary, the third cure angina can be rejected in accordance with this methodology is appropriate for the patient order. Long-term action is m order in the case of patients not receiving long-acting nitrates. After successful completion of the first qualifying patient test exercise tolerance (tpfn-2) have a second qualifying test (tpfn-3), in which the time to onset of angina should be within the15% of the time observed in tpfn-1. In addition, each of successfully tpfn must have electrocardiographic evidence of ischaemia (1 mm horizontal or leaning down lower ST-segment within 3 consecutive beats). Patients who meet these criteria, participated in the study.

After each weekly period, patients were sent to the laboratory for evaluation of physical parameters in the morning at least 1 hour after a light Breakfast, to conduct a test on exercise tolerance. This condition simulates tpfn at a residual concentration; tpfn when the residual concentration is carried out in one time of day for each patient. After tpfn at a residual concentration of the patient receives the next scheduled dose blind medication from the blister pack to be used this week. Another tpfn conduct krovi selected when the residual (approximately 8 hours after drug administration) and at the maximum (within 1 hour after drug administration) concentration. During the whole study regularly other standard laboratory tests.

Blood pressure (using a cuff for measuring pressure and heart rate check before all tpfn, during tpfn during the last minute of each stage of the test, at the beginning of a stroke, at the point of maximum exercise, and during recovery (every minute for 4 minutes, then every 5 minutes as long as the value will not return to the base value). Heart rate monitor constantly and standard ECG with 12 leads, write directly to the physical load of the patient, monotonous physical exercises at the end of each stage of exercise, at the maximum tolerated exercise and after exercise.

Average time values with monotonous physical exercises for 3 physical variables studied while receiving placebo and with different schemes of doses of ranolazine (ranolazine-placebo) for all patients at the maximum and residual concentrations are summarized below in Table 2.

At maximum concentrations of ranolazine plasma all tpfn-ishemic is Nigeria ST-segment. In the analysis for all patients, the increase in time to onset of angina compared with placebo lies in the range from 0.32 to 0.39 minutes (p0.01) and the time until the beginning of the 1-mm decrease ST-segment lies in the range from 0.28 to 0.41 minutes (p0,02) for each of the 3 schemes the introduction of ranolazine and all the merged schema. Also the total duration of physical activity increases significantly in the case of all the merged schemes and noted trends in the same direction and magnitude for each schema drug administration. In the analysis according to the recipe each of the 3 parameters tpfn was prolonged (p0.01) in the case of all of the combined regimen of administration of ranolazine. All individual doses of ranolazine significantly prolonged the time to 1-mm decrease in ST-segment and minor trends in the same direction and ratios found for time to onset of angina and duration of physical exercise. In General, the results of the analysis according to the recipe, except for the magnitude of the eect, as it turned out, somewhat higher than the results obtained when alone.

If residual concentrations in plasma ranolazine has less influence on the parameters of the test pereosnastku, showing a tendency to increase the time of exercise. But only time to 1-mm decrease ST-segment for all of the combined regimen of administration of ranolazine in the analysis for all patients has statistical significance.

Due to the explicit parameters increases physical activity observed with monotherapy using ranolazine analyzed response ranolazine among patients receiving different related protivoklimaktericescoe medicines. Such post-hoc analyses conducted on the data with the maximum concentration of ranolazine, when the effect of improving time physical activity most obvious. As a long-acting nitrates were rejected the first during the single blind qualification phase, no patient treated with long-acting nitrates, did not get the double-blind treatment. Of the patients who had the maximum performance data, 34% (107/312) patients received beta-blockers during the double-blind treatment and 24% (75/312) received calcium antagonists.

The test parameters on physical activity was improved at maximum concentrations of ranolazine (ranolazine placebo), regardless of whether accepted or did not accept patients is compared with 107 patients who took beta-blockers. But the differences between patients taking beta-blockers, and patients who were not taking them, did not reach statistical significance in the case of any option exercise. Patients who were not taking beta-blockers, all parameters of physical activity were significantly better at each of the 3 schemes the introduction of ranolazine and also for all of the combined regimen of administration of ranolazine. Similar trends are observed in fewer patients taking beta-blockers. Analysis of data on physical activity for patients taking calcium antagonists compared with patients not treated with calcium antagonists, leads to the same conclusions.

In the following Table 3 summarizes the data on maximum and residual concentrations ranolazine in plasma based on di-hydrochloride ranolazine on all patients by gender and for each schema drug administration.

The average values of maximum concentrations in plasma are in the range from 1346 to 2128 ng/ml based on the free base of ranolazine. The scheme is the introduction of 400 mg three times daily is associated with the highest concentrations of ranolazine in the plasma. Average values of residual concentrations in plasma between the than men, but the difference in values of residual concentrations in plasma based on gender is missing.

At maximum concentrations of ranolazine in plasma no statistically significant difference between any of the schemes dose of ranolazine and placebo in the case of the double product. Similarly, when the residual concentrations of ranolazine in the plasma there is no statistically significant difference between the 3 schemes the introduction of ranolazine and placebo in the analysis according to the recipe when standing or maximum exercise double product.

The results of this study confirm that ranolazine is effective protivoateroskleroticheskim and anti-ischemic connection for patients with chronic ongoing angina. At maximum concentrations in plasma used three schemes of ranolazine increased the time to onset of angina and duration of physical activity, and time to 1-mm decrease ST-segment average approximately 0.33 minutes compared to the time observed in the case of placebo. Improving physical parameters observed in this study, not only in patients receiving concomitant treatment of angina (for example, beta-locationlogic patients therapeutic effect, as it turned out, was slightly higher in value. This confirms the fact that ranolazine can also be used in monotherapy in patients with chronic ongoing angina.

Hemodynamic findings indicate that the improvement of the physical parameters at maximum concentrations of ranolazine in the plasma are not associated with changes in blood pressure or heart rate. Nejmodernejsi the mechanism of action of ranolazine, therefore, differs from the mechanism of action of other protivoateroskleroticheskim drugs that are currently found clinical application.

Most importantly, we have documented that protivoklimaktericescoe and anti-ischemic action of the studied drug ranolazine immediate action is not preserved during the whole interval between doses of the drug. Although time before lowering ischemic ST segment type is greatly extended and trends similar trends were observed for the test parameters on the physical load, the effect was minimal when the residual concentrations of ranolazine in the plasma. Average concentrations of the free base of ranolazine plasma lie in the interval for the ng/ml It is obvious that the higher average concentrations in plasma observed at the maximum value, associated with significant clinical protivoateroskleroticheskim and anti-ischemic effects, whereas the concentrations observed at the minimum level, no such connection.

Based on the results of this experiment we can conclude that the threshold concentration of free base ranolazine plasma for the manifestation of anti-ischemic activity determined during the test exercise tolerance, apparently, is about 550 ng/ml in Addition, it is likely that the concentration of ranolazine in the plasma must be maintained near or above the threshold value during the whole interval between doses of a medicinal product, to ensure protivoklimaktericescoe and anti-ischemic activity during exercise in all this interval.

Ranolazine well tolerated at concentrations in plasma are achieved in the present study. On degree of negative effects there are no differences between the schemes introduction ranolazine and placebo and not marked associated with medication changes in ECG intervals or integrated the s on lipid and liver function, that confirms the fact that the metabolic effects of ranolazine does not apply to systemic glucose regulation and lipid metabolism.

Ranolazine improves physical parameters without significant effect on heart rate and blood pressure of the patient constant chronic angina. Probably that should be achieved threshold concentration ranolazine in plasma approximately 550 ng/ml, in order to detect such protivoklimaktericescoe and anti-ischemic effects. Ranolazine well tolerated in a wide range of concentrations in plasma. Justified additional research using large doses of the drug with prolonged action, to fully appreciate a new perspective on metabolism in the treatment of ischemia.

EXAMPLE 5
I. Comparison of in vitro Drug with ND and Drugs with PD
Drug OD, prepared in accordance with Example 1, and Preparations with PD, prepared according to Examples 2A-2C, tested on the device for the study of the USP dissolution Apparatus 2 with 900 ml of 0.1 M hydrochloric acid as a solvent fluid to simulate dissolution in the stomach.

The results in Table 4 show that the Drug with ND in the m), Drugs with DD, and have a longer dissolution at low pH value, which is desirable for preparations with prolonged action.

II. Comparison of in vivo Drug with ND and Drugs with PD
Single dose of the Drug with the nm, prepared in accordance with Example 1, and Preparations with PD a and b, prepared in accordance with Example 2, were given eleven healthy volunteers, and the concentration of ranolazine in their plasma was measured after 0, 20, 40, 60, 90 and 120 minutes, every hour up to 6 hours, every two hours to eighteen hours and twenty-four hours after injection (only for products with DD). The results are presented below in Table 5.

From Table 5 it is clear that Drugs-DD a, b and C of the present invention have a solubility, which makes them acceptable for introduction of ranolazine twice a day.

EXAMPLE 6
In this Example, described planned with overlapping study of single ascending doses in which to evaluate the safety and pharmacokinetic profile of oral single dose of the Drug with DD free base of ranolazine Example 2D. People are divided into three groups. Group 1 receives 500, 750 and 1000 mg ranolazine-PD. Group 2 receives 1250 and 1750 mg renalase what Borkou. Average pharmacokinetic parameters after oral single doses of ranolazine-PD are presented below in Table 6.

The pharmacokinetic results are presented in Table 6, show that ranolazine slowly released from the drug with PD and therefore the absorption of ranolazine limited by the dissolution rate. This leads to prolonged profiles (concentration of drug in plasma)/time observed at all dose levels with the maximum concentrations in plasma after 4-6 hours after administration of the dose. In doses ranging from 500 to 2000 mg average values WithmaxACC0-30hour increase approximately in proportion to dose, although it turned out that there are some deviations from proportionality in Group 2.

EXAMPLE 7
In this example, the described double-blind placebo controlled planned with overlapping research on volunteers multiple ascending dose to assess drug administration twice a day. Six people were given 4 days of drug ranolazine with PD, prepared according to Example 2D, at doses of 500, 750 and 1000 mg twice a day, followed by a morning dose on day 5. The pharmacokinetic results are presented below in Table 7.

In SOA is limited by the dissolution rate. This leads to extended profiles (concentration of drug in plasma)/time to maximum plasma levels observed within 2 to 4 hours after a dose.

The results show that useful levels of ranolazine in plasma can be achieved by injection with PD on the regimen twice a day.

EXAMPLE 8
In this Example, assess the safety and tolerability of administration of racemic free base of ranolazine Example 2D. Also identified 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.

The study was conducted using increasing doses of the dosage forms ranolazine with prolonged action. Before and at intervals during and after the period of drug administration take blood samples to assess the content of ranolazine and the whole experience check blood pressure, heart rate, ECG and symptoms. Aggregated data are reviewed after each phase before the next phase isciii the study and were available for conducting pharmacokinetic analysis and safety assessment. Each person received doses of different types of free base ranolazine in the form of tablets with prolonged action, including tablets, 500 and 750 mg or with matched placebo as needed (h mg plus h mg) to obtain the standard oral dose of 1500 and 2000 mg

At each phase: one dose twice a day for four days with a single dose on day 5. On the 5th day of each volunteer was assessed full pharmacokinetic profile, including blood pressure in the supine position and a vertical position (KD) and heart rate, ECG, adverse effects, clinical biochemistry and Hematology results, the results of urine.

Stable phase estimate for each level doses using C48hWith72hand C96hand logarithmically transformed data by covariance analysis and evaluation, significantly if different coefficient for time (defined as p<0,05) from 0. Such studies are conducted using bilateral t-analysis to account for the deviation from the ANOVA models. Stable stage is also assessed by comparing the values of C48hWith72hand C96h

Mean values and standard deviations of pharmacokinetic parameters of free base ranolazine on day 5 is detailed below in Table 8, and figures showing the average values of the profiles in the plasma. Sustainable levels of free base ranolazine in the plasma, as it turns out, are achieved on day 4. In the interval between the introduction of drugs is a slow rise to maximum levels with the maximum values of tmaxsituated in the interval from 1 to 6 hours after a dose of medication. The levels are then slowly lowered, giving a small degree of fluctuations of the concentrations in plasma in the interval between the introduction of the medication. It turned out that there were no differences in pharmacokinetic parameters (+)R and (-)S-enantiomers of ranolazine after repeated administration of the drug with PD.

In some of the=3 of 8) and 2000 mg (n=2 8), usually 2-6 hours after drug administration. A statistically significant decrease in orthostatic systolic KD observed on day 5 at the dose of 1500 mg (-9,8 mm RT.art., 4 hours after drug administration) and at the dose of 2000 mg (-8,4 mm RT. art, 6 hours after drug administration). Although the models of adverse events similar to the reception and ranolazine and placebo, headache, dizziness, and stuffy nose were more common symptoms in the case of ranolazine.


Claims

1. Pharmaceutical dosage form containing at least about 50 weight. % ranolazine and at least one pH-dependent binding substance, which inhibits the release of ranolazine of the dosage form with prolonged action, when the dosage form with prolonged action is exposed to the aqueous environment having a pH value of the stomach, and helps to release therapeutic amounts of ranolazine in an aqueous solution having a pH above about 4.5.

2. Pharmaceutical dosage form under item 1, characterized in that it includes not more than two tablets per dose.

3. Pharmaceutical dosage form under item 2 different practical dosage form under item 2, characterized in that the pharmaceutical dosage form contains about 70-80 wt.% ranolazine.

5. Pharmaceutical dosage form under item 1, characterized in that 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.

6. Pharmaceutical dosage form under item 1, characterized in that the pH-dependent binder is a copolymer of methacrylic acid.

7. The pharmaceutical dosage form according to p. 6, characterized in that the copolymer of methacrylic acid is methacrylic acid copolymer type C (USP).

8. The pharmaceutical dosage form according to p. 6, characterized in that the pharmaceutical dosage form includes about 5-12 wt.% of methacrylic acid copolymer type C (USP).

9. The pharmaceutical dosage form according to p. 6, characterized in that the pharmaceutical dosage form comprises about 10 wt.% copolymer of methacrylic acid.

10. Pharmaceutical dosage form under item 1, otlichatsa.

11. The pharmaceutical dosage form according to p. 10, characterized in that the pH-independent binding substance selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, poly(meth)acrylate esters, polyvinylpyrrolidone and mixtures thereof.

12. The pharmaceutical dosage form according to p. 10, characterized in that the pH-independent binding agent is hypromellose.

13. The pharmaceutical dosage form according to p. 12, wherein the pharmaceutical dosage form contains about 1-3 wt.% hydroxypropylmethylcellulose.

14. The pharmaceutical dosage form according to p. 12, wherein the pharmaceutical dosage form contains about 2 wt.% hydroxypropylmethylcellulose.

15. Pharmaceutical dosage form under item 1, characterized in that the dosage form contains approximately 650-850 mg ranolazine.

16. Pharmaceutical dosage form under item 1, characterized in that the dosage form contains approximately 900-1100 mg ranolazine.

17. Pharmaceutical dosage form under item 1, characterized in that the dosage form contains approximately 400-600 mg ranolazine.

18. Pharmaceutical latestgeneration dosage form under item 2, characterized in that the pharmaceutical dosage form is compressed tablet.

20. Molded tablet containing about 70-80 wt.% ranolazine, at least one pH-dependent binder selected from methacrylic acid phthalate of hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose, phthalate cellulose acetate, polyvinyl acetate phthalate, phthalate of polyvinylpyrrolidone and mixtures thereof, and at least one pH independent binder, when pressed tablet contains approximately 350-800 mg ranolazine.

 

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