WO2008147245A2 - Controlled release proxodolol pharmaceutical composition - Google Patents

Abstract

The invention relates to medicine, in particular to pharmaceutic. A novel preparation exhibiting stable kinetic characteristics relating to delivery of an active substance is disclosed. The controlled release proxodolol pharmaceutical forms can be effectively and easily produced using a mixture of one or more expanding or gel-forming components, an active ingredient and a pharmaceutically acceptable filler. In the preferred embodiment, a preparation in the form of tablets containing proxodolol in a quantity of 120 mg, hypromellose and pharmaceutically acceptable fillers, for example microcristalline cellulose, calcium stearate and aerosil, is used. The novel pharmaceutical forms with a suitable proxodolol release make it possible to reduce the number of every day medications, whilst the concentration of the active ingredient remains constant within a therapeutic dose.

Description

 PHARMACEUTICAL COMPOSITION OF PROXODOLOL WITH CONTROLLED RELEASE

The present invention relates to the field of pharmacy. In particular, the invention relates to a new controlled release preparation based on the active ingredient of proxodolol or its pharmaceutically acceptable salts.

Proxodolol or butylamine hydroxypropoxyphenoxymethyl methyloxadiazole has the chemical name 5 - [2 - (3 - tert - butylamino - 2 - hydroxypropoxy) phenoxymethyl] - 3 - methyl - 1, 2, 4 - oxadiazole hydrochloride and the structural formula:

Proxodolol or butylamine hydroxypropoxyphenoxymethyl methyloxadiazole may be used in the form of a base or pharmaceutically acceptable salts. Proxodolol is a non-selective alpha and beta blocker; It has a hypotensive, antianginal and antiarrhythmic effect (refers to class II antiarrhythmics). Proxodolol is available in the form of tablets, solution for injection and eye drops. The indicated dosage forms are used according to the following indications - arterial hypertension, angina pectoris (prophylaxis), arrhythmias; compensated chronic heart failure (in the composition

SUBSTITUTE SHEET (RULE 26) combination therapy). Open - and angle-closure glaucoma, secondary glaucoma, hypertensive crisis.

For many years, proxodolol is available commercially only in the form of immediate release tablets or drops (Drug Encyclopedia 2005, p.736). The use of proxodolol in the form of eye drops is described, for example, in RF patents ЖN22173123, 2128486, 2191013. There is no information on pharmaceutical forms of proxodolol or its salts with controlled release.

Currently, it is recommended to use proxodolol orally at 10 mg 3-4 times a day, with good tolerance, the dose is gradually increased by 10-20 mg / day, to a daily dose of 80-120 mg, the maximum daily dose is 240 mg.

It is known that after oral administration of tablets, proxodolol is rapidly absorbed, reaching a maximum concentration after 0.7 hours, and is rapidly excreted (half-elimination period from the blood is 1.5 hours). An extremely low bioavailability of the drug with oral administration of tablets was noted - 3%.

There is no doubt the preparation of a pharmaceutical form with a suitable proxodolol release profile in which the number of daily doses would be reduced to only one, while the concentration of the active ingredient would remain constant within the therapeutic dose.

Retardation (delayed release of active substances), including pharmacologically active substances with a relatively short half-life in the body, allows you to get the appropriate composition of prolonged action and due to a more even level in the blood to avoid, in addition, side effects, as well as improve the accuracy of patients dosage instructions.

Controlled release dosage forms are known in the art. For example, RF patent N ° 2127587 describes a method for preparing a solid dosage form for oral administration, comprising preparing a solid substrate containing the active ingredient, preparing an aqueous dispersion of an acrylic copolymer, coating

SUBSTITUTE SHEET (RULE 26) substrate with aqueous dispersion to obtain a polymer coating. The coating provides controlled release of the active ingredient. As an acrylic copolymer, a plasticized mixture of ammonium methacrylate copolymers, which are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, is used. The coating applied to the substrate is cured at a temperature above the glass transition temperature of the plasticized mixture of acrylic copolymers for at least 24 hours.

Retardation of pharmaceutically active substances can also be achieved through the formation of special granules. Such particles contain a sugar-based core, the therapeutic material can be incorporated directly into it, or sprayed on top, or distributed differently over the surface of the particle. The particles are then coated with a suitable coating material, such as wax or varnish. The release of therapeutic material upon coating failure is controlled by adjusting the coating thickness or coating composition. Examples of therapeutic formulations of collapsible particles are disclosed in US Pat. No. 3,939,259. These formulations are prepared by placing a portion of the uncoated particles containing a therapeutically active material in a rotating vat and contacting the particles with a sufficient amount of a coating solution, namely a zein shellac solution , for coating granules. The coating operation is repeated until the zein-alkali coating reaches a suitable thickness in order to prevent destruction during a selected period of time after ingestion. Groups of particles with different coatings intended for disintegration at different times are combined into capsules or tablets, thereby producing modified release therapeutic preparations of the active ingredient.

The disadvantage of these drug delivery systems is the high cost of their manufacture. In addition, since proxodolol is a readily soluble substance, conventional retardation systems do not provide a dosage form that meets modern

SUBSTITUTE SHEET (RULE 26) requirements. The release rate of the active substance depends on the ionic strength. A change in ionic strength can even lead to the so-called dose dumping. In this case, the entire amount of the active substance is released in a very short time, which can lead to undesirable and even dangerous high levels of the active substance in the blood.

Surprisingly, it has been found that controlled-release proxodolol dosage forms can be prepared efficiently and conveniently using a mixture of one or more swelling or gelling components, an active ingredient and a pharmaceutically acceptable excipient. The drug provides immediate release of part of the dose of the active substance necessary to create a therapeutic effect, the rest is released for a long time.

The objective of the invention is the creation of an effective dosage form with controlled release, with stable kinetic indicators of delivery of the active substance and allowing to maintain the stability of proxodolol over a long shelf life.

Thus, the present invention provides controlled release compositions comprising: a) an active ingredient consisting of proxodolol or a pharmaceutically acceptable salt thereof; b) at least one swellable or gelling component; c) suitable excipients.

Examples of suitable swelling or gelling agents include: polyvinylpyrrolidone, polyethylene oxide, polymers or copolymers of acrylic acid, polyethylene glycols, alginates, cellulose and derivatives (ethers and salts). Hydroxypropyl cellulose, in particular hypromellose (METNOCEL®) or hypromellose (BENECEL® MP 824), is particularly preferred.

In addition, conventional excipients commonly used in the preparation of oral solid pharmaceutical forms may be added to the preparation. Examples of these fillers include glide

SUBSTITUTE SHEET (RULE 26) substances, disintegrants, binders, diluents, colorants and the like. In particular, the following substances can be used: dextrin, lactose, microcrystalline cellulose, calcium stearate, silicon dioxide, sucrose, glucose, sodium chloride, starch, sodium bicarbonate, crospovidone, magnesium stearate, water, silica gel, sodium chloride, talc, glycine, polyethylene oxide , aerosil, gelatin, mannitol, sorbitol, titanium dioxide.

A significant advantage of the proposed composition is the ability to prepare solid dosage forms using conventional and inexpensive methods. For example, tabletting after preliminary wet granulation. After this, the tablets can be film-coated by conventional methods. For film coating, in particular, Opadray II can be used: polyvinyl alcohol, macrogol, titanium dioxide E 171, talc.

The invention is illustrated by the following examples.

Example 1

Composition per tablet proxodolol 120 mg

Proxodolol - 0.12 g

(FSP 42-0067-2253-02)

Microcrystalline cellulose - 0.0685 g

(FS 42-3728-99 or EUR.Ph.)

Hypromellose (METNOSEL®) - 0.0015 g

(Nd 42-12399-04 or EUR.Ph.)

Hypromellose VENECEL® MP-824 - 0.055 g

(EUR.Ph.)

Colloidal silicon dioxide (Aerosil) - 0.0025 g

(GOST 14922-77 or TU U 24.1-31695418-002-2003, Eur.Ph.) Calcium stearate - 0.0025 g

(TU 2432-003-48602470-99 or Еur.Рh.)

The mass of the tablet core: 0.25 g

Opadry II 85 F (white) (ND 42-14219-06) - 0.007 g

SUBSTITUTE SHEET (RULE 26) Coated tablet weight: 0.257 g

Example 2

Comparison of the bioavailability of controlled-release proxodolol tablets and standard proxodolol.

The study was taken 6 rabbits of the breed "chinchilla" weighing 2.5-W) kg obtained from the nursery of the Academy of Medical Sciences of the Russian Federation. The animals were kept under stationary conditions with natural light and a standard diet (feed, water). 20 hours before the start of the experiment, animals were deprived of food. Used tablets of proxodolol with controlled release of 0.12 g (prolonged), composition per tablet (g): Proxodolol 0.1200

Metocel YKM Premium 0.0810 Microcrystalline cellulose 0.0636 Calcium stearate 0.0027 Aerosil 0.0027

Tablet weight: 0.27 g.

As a comparison drug used proxodolol tablets of 0.04 g, composition per tablet (g): Proxodolol 0.0400

Milk sugar 0.0770 Potato starch 0.0165 Sugar 0.0150

Calcium stearic acid 0.0015 Tablet weight: 0.150.

Compared preparations were given once at a dose of 43.6 mg / kg, intragastrically. Tests of drugs were carried out according to an open, randomized and cross-sectional scheme. Each rabbit alternately received the test drug (one 120 mg tablet) and the comparison drug (3 tablets of 40 mg) once. The time interval between taking medications is

10 days.

SUBSTITUTE SHEET (RULE 26) Sample selection. Blood samples in a volume of 1.5 ml were taken from the ear vein of rabbits in polypropylene tubes before use of the drug (zero sample) and 0.25, 0.5, 0.67, 1, 1.5, 2, 3, 4 (6, 8, 24, 30) hours after administration proxodolol (prolonged proxodolol). After centrifugation at 14 TWQ. 0.5 ml of serum were taken rpm, frozen and stored until analysis at a temperature of -20 ⁰ C.

High-performance liquid chromatography was used to determine unchanged proxodolol. Rhepomepeh Column (LUNA) Ci _8, 5 mm (250x4,6 mm). The eluent is 25% acetonitrile / 75% solution of the following composition: 176 mg of sodium pentyl sulfonate (as a counter-ion) per 1 liter of distilled water, adjusted to pH 3 with phosphoric acid. The flow rate is 1 ml / min. The volume of injected sample (injector Rheodeup, loop) - 50 μl. UV detector at a wavelength of 272 nm. The exit time of proxodolol from the chromatographic column is 6.5 minutes.

The method of extracting the drug. 100 μl of 2.5 N NaOH was added to 500 μl of blood serum, 4 ml of chloroform was extracted with vigorous shaking. After centrifugation, the organic layer was separated and evaporated to dryness under a stream of nitrogen. The residue was dissolved with shaking in 100 μl of sodium pentyl sulfonate solution (pH 3), 50 μl was introduced into the chromatographic column. The recovery of proxodolol from serum was 80%. The detection limit is 0.03 μg / ml serum.

The results of the study. In order to assess the bioavailability of the studied dosage forms, the concentrations of unchanged proxodolol in rabbit blood serum were determined and the main pharmacokinetic parameters were calculated that quantitatively characterize the relative degree of absorption of the active substance (f), the area under the concentration-time pharmacokinetic curves (AUC _O - h) the time to reach the maximum concentration (Tmax.) and the value of the maximum concentrations (Smake). The assessment of parameter (f) - the relative degree of absorption - was calculated as the ratio of the areas AUC ₀ - _Oo under the pharmacokinetic curves with the introduction of test and reference

SUBSTITUTE SHEET (RULE 26) preparations. Tables 1 and 2 show the concentrations of proxodolol (μg / ml) in the blood serum of rabbits when taking the compared dosage forms, calculated average values, standard errors and confidence (95%) intervals.

Concentrations of proxodolol (μg / ml) when using proxodolol tablets prolonged at a dose of 43.6 mg / kg

Table 1

Concentrations of proxodolol (μg / ml) when using standard proxodolol tablets at a dose of 43.6 mg / kg

table 2

SUBSTITUTE SHEET (RULE 26)

Table 3 and 4 show the main pharmacokinetic parameters of Smake, Tmax, MRT, AUC, etc., calculated from concentration curves, reflecting the degree, absorption rate and elimination of the drug when using the compared dosage forms of proxodolol. Pharmacokinetic parameters of prolonged proxodolol

Table 3

Pharmacokinetic parameters of proxodolol (comparison drug)

Table 4

SUBSTITUTE SHEET (RULE 26)

In order to assess the bioavailability of proxodolol, the maximum concentrations (Smake), the time of its achievement (Tmax), the average retention times of the drug in the body (MRT), the areas under the pharmacokinetic curves (AUC) and the Smake / AUC ratio were compared.

From the tables 1 and 2 it can be seen that the concentration profile of proxodolol when using prolonged-release tablets (with controlled release) is significantly different from the pharmacokinetic curve obtained when using proxodolol tablets. So, the maximum concentration (Smake) of proxodolol is recorded after 0.73 hours from the moment of administration of proxodolol, for a prolonged form - after 1.5 hours. At the same time, the average Smake value for proxodolol is 0.87 μg / ml, for the prolonged form - 0.51 μg / ml.

The mean retention time (MRT) parameter was 3.2 and 17.2 hours, respectively. Significant differences are also observed in the AUC parameter, which reflects the degree of absorption. For the tested tablets (prolonged dosage form), AUC _0-∞ is 5.15, for the comparison drug - 1.82 mcg / ml / hour. The ratios of the values of the maximum concentrations to the areas under the Smaks / AUS pharmacokinetic curve (parameter reflecting the absorption rate) for the test and reference tablets are 0.122 and 0.635 h, respectively, ¹ i.e., the absorption rate of the reference drug is higher than that of prolonged form.

Relative bioavailability, calculated as the ratio of the areas under the concentration-time pharmacokinetic curves (AUC), at

SUBSTITUTE SHEET (RULE 26) the use of proxodolol prolonged and proxodolol tablets was:

AUC Proxodolol Prolong. f = x 100 = 303%,

AUC Proxodolol i.e. when using the dosage form of proxodolol with a modified release, the degree of absorption of the drug increases by 3 times.

It should be noted that when using a prolonged form of proxodolol on the pharmacokinetic curve, a time range (9-24 hours) with a rather slow drop in blood concentration is distinguished. Thus, proxodolol from a prolonged dosage form is characterized by a slower absorption from the gastrointestinal tract (with a decrease in maximum concentrations), a significant increase in the degree of absorption and a prolongation of the circulation period of the drug in the bloodstream (14.8 versus 2.4 hours).

Example 3

Preparation of tablets (composition according to example 1).

Proxodolol is thoroughly mixed with microcrystalline cellulose, moistened with an aqueous solution of hypromellose (METNOCEL®), granulated, dried granulate at a temperature of 5O ⁰ C, dry granulation is carried out. Then, dusting is carried out with Benecel, then Aerosil and calcium stearate. Tableting is carried out on biconvex punches d = 9 mm (deep sphere). The weight of the tablet core is 0.25 g. The obtained tablet core is transferred for coating on the coator. Use Opadray II (series 85) (ND 42-14219-06): polyvinyl alcohol, macrogol, titanium dioxide E 171, talc. The coating is carried out until a tablet with a shell weighing 0.257 g.

Example 4

Other embodiments of the invention are illustrated in table 5.

Table 5.

SUBSTITUTE SHEET (RULE 26)

Example 5

The study of adrenergic blocking activity.

In rats, proxodolol when administered orally at a dose of 50 mg / kg (dose corresponding to an ED50 2 hours after administration) provides an effective blockade of beta-adrenergic receptors (blocking the positive chronotropic and depressant effects of isoproterenol by at least 25%) for 8 hours. In this regard, a comparative study of beta-adrenergic blocking activity and duration of action of controlled-release proxodolol tablets (120 mg each), conventional tablets (40 mg each) and the substance of the drug was carried out when used in ze 150 mg / kg. Several groups of awake male rats weighing 300-400 g (3-10 animals each) were injected into the stomach (via a probe) the studied drugs (in the form of tablets or 1 ml of an aqueous solution of the substance proxodolol), or a solvent (control) for 2 or 24 h before anesthesia caused by sodium ethaminol (40-50 mg / kg intraperitoneally) followed by tracheotomy, catheter insertion and into the external jugular vein (for a single injection of 1 μg / kg of isoproterenol for each animal for 20-30 s). Heart rate was recorded using a tachometer. After administration of isoproterenol, the maximum increase in heart rate in the control and after administration of the studied drugs was determined (on the Rikadenki R-10 recorder). The presence of βl-adrenergic blocking activity (in the studied drugs) was indicated by a decrease in the positive

SUBSTITUTE SHEET (RULE 26) the chronotropic effect of isoproterenol. It was found that 2 hours after oral administration of proxodolol tablets of 120 mg, ordinary tablets of 40 mg and the substance of the drug in the same dose (150 mg / kg), the positive chronotropic effect of isoproterenol is blocked on average, respectively, by 92.65 and 100% and 24 hours after the administration of the studied drugs by 69.27 and 23%

Thus, among the studied preparations, only the claimed proxodolol preparation provides an effective blockade of beta-adrenergic receptors within 24 hours after its administration, which gives reason to attribute it to long-acting beta-blockers.

SUBSTITUTE SHEET (RULE 26)

Claims

Claim 1. A controlled-release pharmaceutical composition containing an active substance and a carrier, characterized in that it contains an effective amount of proxodolol or a pharmaceutically acceptable salt thereof as an active substance, and a mixture of a swellable or gel-forming component and a pharmacologically acceptable excipient as a carrier. 2. The pharmaceutical composition according to claim 1, characterized in that it contains polyvinylpyrrolidone, acrylic acid polymers, polyethylene glycols, alginates, carbomer, amylopectin, agar-agar, tragacanth, cellulose, cellulose derivatives or a mixture of these substances as a swelling or gelling component. 3. The pharmaceutical composition according to claim 2, characterized in that, as cellulose derivatives, it contains hydroxypropyl cellulose, in particular hypromellose. 4. The pharmaceutical composition according to claim 2, characterized in that as a pharmacologically acceptable excipient, it contains at least one substance selected from the group: dextrin, lactose, microcrystalline cellulose, calcium stearate, silicon dioxide, sucrose, glucose, sodium chloride, starch, sodium bicarbonate, crospovidone, magnesium stearate, silica gel, sodium chloride, talc, glycine, polyethylene oxide, gelatin, mannitol, sorbitol, titanium dioxide. 5. The pharmaceutical composition according to any one of paragraphs. 1-4, characterized in that it contains the following number of components (mass%) Proxodolol 10-80 Swelling or gelling component 5-60 Pharmacologically acceptable excipient 6. The pharmaceutical composition according to claim 5, characterized in that it contains the following number of components (mass%) Proxodolol 10-80 SUBSTITUTE SHEET (RULE 26) Hypromellose 10-55 Pharmacologically acceptable excipient 7. The pharmaceutical composition according to any one of paragraphs. 1-4, characterized in that it contains the following number of components per unit dose (g) Proxodolol 0.04-0.25 Swelling or gelling component 0.03-0.1 Pharmacologically acceptable excipient 0.01-0.2 8. The pharmaceutical composition according to claim 7, characterized in that it contains the following number of components per unit dose (g). Proxodolol 0.04-0.25 Hypromellose 0.03-0.1 Pharmacologically acceptable excipient 0.01- 0.2 9. The pharmaceutical composition according to claim 8, characterized in that it contains the following number of components per unit dose (g). Proxodolol 0.04-0.25 Hypromellose 0.03-0.1 Microcrystalline cellulose 0.03-0.1 Silicon Colloidal Dioxide 0.001-0.005 Calcium Stearate 0.001-0.005 10. The pharmaceutical composition according to p. 9, characterized in that it contains the following number of components per unit dose (g) Proxodolol 0.12 Hypromellose 0.0565-0.081 Microcrystalline cellulose 0.0636-0.0685 Colloidal silicon dioxide 0 , 0025-0.0027 Calcium stearate 0.0025-0.0027 11. The pharmaceutical composition according to p. 10, characterized in that it contains the following number of components per unit dose (g). Proxodolol 0.12 Hypromellose 0.0565 SUBSTITUTE SHEET (RULE 26) Microcrystalline cellulose 0.0685 Silicon Colloidal Dioxide 0.0025 Calcium Stearate 0.0025 12. The pharmaceutical composition according to any one of paragraphs. 1-11, characterized in that it is additionally coated. 13. The pharmaceutical composition according to any one of paragraphs. 5-6, characterized in that it is additionally coated with a shell containing Opadry in an amount of 1-5 wt%. 14. The pharmaceutical composition according to any one of paragraphs. 7-11, characterized in that it is additionally coated with a shell containing Opadry in an amount of 0.005-0.01 g, preferably 0.007 g SUBSTITUTE SHEET (RULE 26)