RU2411035C2 - Modified release 6-methyl-2-ethyl-hydroxypyridine succinate dosage form - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and consists in development of a new dosage of the preparation 6-methyl-2-ethyl-3-hydroxypyridine succinate providing modified release of an active substance. A unit dosage form contains 6-methyl-2-ethyl-3-hydroxypyridine succinate in amount 30.0-70.0 wt %, as a release modifier - cellulose derivatives and/or polyacrylic resins in amount 1.0-20.0 wt %, as an excipient - microcrystalline cellulose in amount 20.0-50.0 wt % and lubricants. The unit dosage form represents a tablet or a capsule consisting of a variety of small dense spheroids containing 6-methyl-2-ethyl-3-hydroxypyridine succinate as a major component. A combination of matrix and instant, coated and uncoated spheroids enables preparation of a drug in the various dosage forms with controlled release rate.

EFFECT: invention allows to produce the unit dosage forms of the preparation 6-methyl-2-ethyl-3-hydroxypyridine succinate for certain treatment regimens of various diseases.

Description

The invention relates to medicine and consists in creating a new dosage form of an existing drug 6-methyl-2-ethyl-3-hydroxypyridine succinate, providing a modified release of the active substance (from immediate, immediately after administration, to extended, for at least 12 hours )

The drug 6-methyl-2-ethyl-3-hydroxypyridine succinate (EMHPS) has found effective use in various fields of clinical medicine: neurology, psychiatry, cardiology, ophthalmology, surgery, dentistry, endocrinology, etc.

The use of EMHPS in neurology and psychiatry is due to the original spectrum of the neurotropic effects of the drug at the neuronal level (anxiolytic, anticonvulsant, antistress, cerebroprotective, antiparkinsonian, antiamnestic and anti-alcoholic properties). At the vascular level, EMHPS improves cerebral circulation, inhibits platelet aggregation, increases the antithrombogenic potential of blood, lowers total cholesterol, and has a cardioprotective and anti-atherosclerotic effect.

EMHPS is also effective in acute cerebrovascular accidents, dyscirculatory encephalopathy, vegetovascular dystonia, atherosclerotic dysfunctions of the brain, and other conditions accompanied by tissue hypoxia. The action of EMHPS is shown both prophylactic and therapeutic for these diseases.

In addition, EMHPS can be used in the treatment of various forms of coronary heart disease (CHD). It was noted that EMHPS accelerates the stabilization of angina pectoris, improves the clinical course of myocardial infarction, reduces lipoproteins in the blood, increases the antianginal effectiveness of nitrates, but does not affect the effectiveness of calcium antagonists and β-blockers. The positive effect of EMHPS on the parameters of diastolic function of the left ventricle in patients with coronary heart disease was revealed.

The high therapeutic activity of EMHPS, its ability to have a positive effect on key pathogenesis links of various diseases, the absence of significant side effects, the wide therapeutic range and low toxicity, as well as the ability to potentiate the effect of neurotropic drugs, were the basis for the development of drugs based on this substance in various forms ( injection solutions, tablets, capsules).

But, unfortunately, each dosage form is not without flaws.

Injectable forms of drugs based on EMHPS are administered intramuscularly or intravenously 1-3 times a day in a daily dose of 50-800 mg, which is a daily dose of 2.5-40 mg of active principle. Known injectable forms of EMHPS in the form of a 5% aqueous solution of EMHPS [M.D. Mashkovsky. "Medicines", 1993, part II, p.216] and in the form of a solution containing 5-6% EMHPS, 0.5-5.0% succinic acid and up to 0.2% Trilon B [RU 2205640].

The disadvantage of this method of treatment is that the injection form of EMHPS does not provide a long-term nootropic effect, is traumatic for the patient. In addition, when using EMHPS in the form of injections during course therapy (more than 30 days), a change in the spectrum of the pharmacological activity of the drug is observed, which is expressed in an increase in aggressiveness, emotional reactivity, and a decrease in antistress action [see Description of RU 2065299].

EMGPS tablet formulations include ~ 60-80% by weight of a tablet of excipients such as starch and white clay [RU 2065299]. However, the presence of these additives does not impede the degradation of the active principle - even at the stage of manufacture, the core of the tablets turns yellow [see Description of RU 2205640].

Capsule forms of drugs based on EMHPS are characterized by a slightly lower content of excipients [RU 2145855, RU 2144822]. However, the stability of the finished dosage form is also quite low - yellowing of the capsule mass is also observed [see Description of RU 2205640]. In order to increase the stability of finished drugs containing EMHPS, it was proposed to introduce a stabilizer, succinic acid, into their composition [RU 2205640]. The preparation in the form of a powder for capsules contains 50-60% EMHPS, 20-35% cellulose, 15-20% starch, 4-6% polyvinylpyrrolidone, 0.5-5.0% succinic acid, 0.8-1.0% magnesium stearic acid, 0.6-1.1% talc and up to 0.2% Trilon B. The solid dosage form made according to this recipe is the closest analogue to the claimed invention, however, like the other previously considered, it has a fast elimination rate and after 4.7-5.0 h, EMHPS is practically not detected in the body , which is the reason for repeated use of the drug.

The multifaceted use of EMHPS requires a wide spectrum of the rate of drug release from dosage forms (from the fastest in emergency situations to the longest with long-term inpatient treatment), which directly raises the question of the need to obtain GLF with a pre-programmed release of the drug. Finished dosage forms containing EMHPS, known to date, cannot satisfy this request. Maintaining an active plasma concentration for a relatively long period of time occurs by taking large doses of dosage forms or by administering them several times a day. This approach is not suitable, since such doses can create a toxic and undesirably high drug content in the patient's body. The introduction of the drug at certain time intervals leads to the formation of a fluctuating level of the drug, the so-called peak and failure action, which in turn leads to inefficiency or failure of treatment, an increased risk of toxic side effects. Therefore, it is desirable for patients to have a constant concentration of the administered drug in the blood.

It is known that in order to achieve and maintain a constant level of active ingredients in plasma, inhibitory formulations are used in which the active ingredient is gradually released into the biological system.

The release rate from tablets or powders is determined by the solubility characteristics of the active ingredient, which, in turn, depend on the particle size, specific surface area and the interaction between the binders. Dissolution can be slowed by diffusion barriers in the core of tablets or in a film coating. Slowing down dissolution using diffusion barriers in the core is used quite often because of its technical simplicity. It is possible to use various fillers, for example, swelling agents, lipophilic substances or intermittent plastic substances as diffusion barriers. The base may be such that the release of the active ingredient occurs by diffusion of the dissolved active ingredient mainly through the pores of the tablet core and, if necessary in special cases, by diffusion through a retardant, which must have a suitable structure for this. The base may also have the property of delayed erosion, leading to a slowdown in the release of the active ingredient.

The use of hydrophilic and hydrophobic polymers as a retardant base material is well known and tested on a large number of active ingredients (for example, US 4389393; RU 2138253; RU 2212885; RU 2205007), but so far no composition has been described that is suitable would achieve the desired goals with 6-methyl-2-ethyl-3-hydroxypyridine succinate.

The behavior of a particular medical substance in combination with a moderating excipient cannot be calculated or predicted in a general way. Although the main factors affecting the release of the base from the system have been well studied, the interaction between the retarding material, on the one hand, and the active ingredient and other excipients, on the other, can have a different effect on the retarding effect.

From the foregoing, it can be seen that one cannot expect a priori the allocation of various substances with linear kinetics in the previously described systems. The kinetics of excretion should be considered as a case that can only occur with certain dosage forms of active and auxiliary substances. It is necessary to select from a large number of known pharmaceutical excipients those that are suitable for the chosen purpose, and use them in the right quantitative proportions, which should also be selected in order to obtain a base system. Such dosage forms are specifically for 6-methyl-2-ethyl-3-hydroxypyridine succinate and are contemplated by the present invention.

Thus, the subject of this invention is the development of a pharmaceutical composition containing 6-methyl-2-ethyl-3-hydroxypyridine succinate as an active ingredient and characterized by a controlled release rate. The dosage form is a tablet or capsule consisting of a plurality of small dense spheroids (coated and uncoated with a polymer coating), including 6-methyl-2-ethyl-3-hydroxypyridine succinate as a main component and excipients.

Each spheroid of 6-methyl-2-ethyl-3-hydroxypyridine succinate in accordance with this invention forms a separate element that releases the drug at a predetermined rate.

Matrix and instant coated and uncoated spheroids make it possible to manufacture the drug in various dosage forms with an adjustable release rate. They can be enclosed, for example, in hard gelatin capsules or tablets, while providing the desired dissolution profile and, accordingly, the desired plasma concentration profile and duration of action. In cases where spheroids containing 6-methyl-2-ethyl-3-hydroxypyridine succinate are tabletted, they are mixed with additives, for example, microcrystalline cellulose (MCC), starch, povidone or mixtures thereof in the form of a powder or spheroids.

Dense spheroids containing 6-methyl-2-ethyl-3-hydroxypyridine succinate have a size of 0.25-2 mm, preferably 0.35-1 mm.

The first group of spheroids (instant) contains 3-hydroxy-6-methyl-2-ethylpyridine succinate and excipients such as MCC, aerosil, magnesium stearate, HPC. The composition of the spheroids is selected so that 6-methyl-2-ethyl-3-hydroxypyridine succinate is completely released within 0.5-2 hours

The second group includes spheroids of the first group, coated with a polymer shell consisting of pH-sensitive polymers (a copolymer of methacrylic acid and methacrylic acid ester - Eudragit L and Eudragit S) and / or pH-independent polymers (Eudragit NF - methacrylic acid ester, ethyl cellulose). The polymer shell may contain plasticizers, fillers, pigments. Polymeric shell materials regulate the release of 6-methyl-2-ethyl-3-hydroxypyridine succinate for 2-8 hours

The third group of spheroids is a matrix spheroid that contains 6-methyl-2-ethyl-3-hydroxypyridine succinate, a polymer matrix, and excipients. Hydrophobic pH-independent polymers can be used as matrix-forming polymers: Eudragit RL, Eudragit NE, Eudragit RS, ethyl cellulose mixed with hydrophilic polymers (HPC, HPMC, PVP). For the claimed dosage form, the preferred hydrophobic polymer is Eudragit NE in an amount of 10.0-20.0 wt.% In a mixture with hydrophilic HPC in an amount of 2.0-6.0 wt.%. The release of 6-methyl-2-ethyl-3-hydroxypyridine succinate from the third group of spheroids occurs evenly over 5-8 hours. Any pharmaceutically acceptable excipients, diluents, binders, binders, lubricants and lubricants can be used as excipients.

The fourth group includes spheroids of the third group, coated with a polymer shell consisting of pH-sensitive polymers (a copolymer of methacrylic acid and methacrylic acid ester - Eudragit L and Eudragit S) and / or pH-independent polymers (Eudragit NF - methacrylic acid ester, ethyl cellulose). The polymer shell may contain plasticizers, fillers, pigments. The release of 6-methyl-2-ethyl-3-hydroxypyridine succinate from the fourth group of spheroids occurs evenly over 5-14 hours.

Spheroids are prepared as follows: 6-methyl-2-ethyl-3-hydroxypyridine succinate, microcrystalline cellulose and other additives, such as aerosil, magnesium stearate, are thoroughly mixed in a mixer. Then add a binder solution, for example an aqueous solution of HPC, and mix until a homogeneous plastic mass is formed. The mass is passed through an extruder to obtain an extrudate with a diameter of 0.75 mm

The wet extrudate is loaded into a “spheronizer” with a rotary disk with a diameter of 15 cm and a rotation speed of 1500 rpm. The duration of spheronization is 10 minutes. Then the spheroids are dried at a temperature of 50-60 ° C, passed through sieves, spheroids with a diameter of 0.5-0.8 mm are selected.

Then part of the spheroids (or all) is coated with a mixture in the form of a solution in an organic solvent or an aqueous dispersion of the polymer.

For each group of obtained spheroids, a dissolution profile is determined and, based on the data obtained, the necessary ratio of spheroids in the finished dosage form is calculated to achieve the desired dissolution profile.

The dissolution profile is obtained using the USP 2 (USP apparatus 2): volume of dissolution medium 900 ml; stirrer rotation speed of 50 rpm; bath temperature 37 ± 0.5 ° C. Dissolution medium 0.1 N Hcl ^0- for 2 hours, the rest of the time - phosphate buffer, pH 6.8.

In addition, in order to obtain a pharmaceutical composition containing 6-methyl-2-ethyl-3-hydroxypyridine succinate as an active ingredient and characterized by a modified release rate of the active substance, it is proposed to obtain a tablet of 6-methyl-2-ethyl-3-hydroxypyridine succinate by the method direct pressing with certain selected ratios of components:

6-methyl-2-ethyl-3-hydroxypyridine succinate in an amount of 30.0-70.0 wt.%, Release modifier in an amount of 1.0-20.0 wt.%, Filler microcrystalline cellulose in an amount of 20.0- 50.0 wt.%, Moving substances. In this case, cellulose ethers such as methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose are used as a retarding agent (release modifier).

We give specific examples of the invention.

Example 1. The preparation of instant spheroids.

The composition of the spheroids, wt.%:

6-Methyl-2-ethyl-3-hydroxypyridine succinate - 60.0%

MCC - 32.0%

GOC - 4.0%

Aerosil - 2.0%

Magnesium Stearate - 1.0%

Succinic acid - 1.0%

Microcrystalline cellulose (MCC), hydroxypropyl cellulose (HPC) or hydroxypropyl methyl cellulose (HPMC), aerosil, magnesium stearic and succinic acid (mixture A) are mixed in a container. Then 6-methyl-2-ethyl-3-hydroxypyridine succinate was added and stirred (mixture B). Mixture B is loaded into the mixer, water is added and mixed for 5 minutes. The finished extrudate is loaded into a spheronizer. The spheronization time is 2-5 minutes. The finished spherical granules are air dried 24 hours, then placed for 24 hours in an oven (40 ° C).

Dissolution of instant spheroids:

Time min 0 fifteen thirty 45 60 75 Amount, % 0 70.12 101.0 101.0 101.0 102.0

The dissolution profile of instant spheroids is shown in FIG.

Example 2. The preparation of spheroids on a matrix basis.

The composition of the spheroids, wt.%:

6-Methyl-2-ethyl-3-hydroxypyridine succinate - 50.0%

MCC-27.0%

HPC-4.0%

Aerosil - 2.0%

Magnesium Stearate - 1.0%

Succinic acid - 1.0%

Eudragit NE 30D - 15.0%

The technology for producing matrix-based spheroids is similar to Example 1, using the dispersion Eudragit NE 30D.

Dissolution of spheroids:

Time hour 0 one 2 four 8 12 Amount, % 0 50.21 70.11 85,10 101.0 101.0

The dissolution profile of spheroids is shown in FIG.

Example 3. Coating of a pH-independent polymer on instant spheroids.

The spheroids prepared according to Example 1 are coated with a membrane that regulates the release of the active substance. The coating is carried out in an apparatus for spheronization. The coating solution contains Eudragit NE 30D (pH independent polymer) as a film former.

Dissolution of spheroids coated with a membrane that regulates the release of the active substance:

Time hour 0 one 2 four 8 12 Amount, % 0 20.11 35.13 55.21 85.14 100.0

Release coating technology: the spheroids are poured into the spheronizer, the warm air is turned on (incoming air temperature should be 41-43 ° C), then the coating solution is sprayed through the nozzle. In order to avoid adhesion of the spheroids during coating to the spheroids, talc is added during the process.

The dissolution profile of spheroids is shown in FIG.

Example 4. Coating of a pH-sensitive polymer on instant spheroids.

The obtained dried spheroids according to example 1 are coated with a coating of a pH-sensitive polymer that regulates the release of the drug. The spheroids are coated using a spheronizer with a 30% aqueous dispersion of Eudragit L30D-55 or alcohol Eudragit L 100-55. Triethyl citrate is used as a plasticizer. Talc is used to prevent adhesion of spheroids.

Dissolution of protective coated spheroids:

Time hour 0 one 2 four 8 12 Amount, % 0 3.12 8.20 101.0 102.0 103.0

Release coating technology: the spheroids are poured into the spheronizer, the warm air is turned on (incoming air temperature should be 41-43 ° C), then the coating solution is sprayed through the nozzle. If the spheroids stick together during the coating process, talc is added.

The dissolution profile of the coated spheroids is shown in FIG.

Example 5. Coating of a pH-independent polymer on spheroids prepared on a matrix basis.

The spheroids prepared according to example 2 are coated with a regulating release of the active substance. The coating is carried out in an apparatus for spheronization. The coating solution contains Eudragit NE 30D (pH independent polymer) as a film former.

Dissolution of coated spheroids prepared on a matrix basis:

Time hour 0 one 2 four 8 12 Amount, % 0 9.12 18.19 35.11 65.21 95.33

Release coating technology: spheroids fall asleep in a rotary apparatus. Turn on the supply of warm air (incoming air temperature should be 41-43 ° C). Then, a coating solution is sprayed through the nozzle. If the spheroids stick together during the coating process, talc is added.

The dissolution profile of the coated spheroids is shown in FIG.

Example 6. Coating of a pH-sensitive polymer on spheroids prepared on a matrix basis.

The obtained dried spheroids according to example 2 are coated with a coating of a pH-sensitive polymer that regulates the release of the drug. The spheroids are coated using a spheronizer with a 30% aqueous dispersion of Eudragit L30D-55 or alcohol Eudragit L 100-55. Triethyl citrate is used as a plasticizer. Talc is used to prevent adhesion of spheroids.

Dissolution of coated spheroids prepared on a matrix basis:

Time hour 0 one 2 four 8 12 Amount, % 0 2,33 3.14 70.21 85.18 95.11

The technology of applying a protective shell: spheroids fall asleep in a rotary apparatus, turn on the supply of warm air (incoming air temperature should be 41-43 ° C), then a coating solution is sprayed through the nozzle. If the spheroids stick together during the coating process, talc is added.

The dissolution profile of the coated spheroids is shown in FIG. 6.

Example 7. Preparation of tablets (uncoated) from spheroids. It is necessary to make a tablet with an average theoretical dissolution profile:

Time hour 0 one 2 four 8 12 Amount, % 0 50.00 64.00 76.00 92.00 100.00

The required amount of spheroids, mg per tablet:

Matrix Based Spheroids Coated matrix spheroids Instant spheroids 279.82 121.59 82.16

The obtained spheroids according to examples 1, 2, 5 are compressed into tablets by a method known per se.

The dissolution profile of the obtained tablets:

Time hour 0 one 2 four 8 12 Amount, % 0 50.23 63.58 76.08 92.30 99.62

The dissolution profile of the obtained tablets is shown in Fig.7 and 8.

Example 8. The preparation of tablets from spheroids and coating, regulating the release of the obtained tablets.

It is necessary to make a tablet with an average theoretical dissolution profile:

Time hour 0 one 2 four 8 12 Amount, % 0 18.00 33.00 56.00 84.00 100.00

The required amount of spheroids, mg per tablet:

Matrix Based Spheroids Coated matrix spheroids Instant spheroids 132.39 367.61 0.00

The obtained spheroids according to examples 2, 5 are compressed into tablets by a method known per se. The resulting tablets were coated with a release-regulating coating of 6-methyl-2-ethyl-3-hydroxypyridine succinate containing HPC. The technology for coating tablets is similar to the technology for coating the shell of spheroids. Dissolution of coated tablets:

Time hour 0 one 2 four 8 12 Amount, % 0 20.00 31.94 48.35 74.69 96.83

The dissolution profile of tablets coated with a film regulating the release of the active substance is shown in FIGS. 9 and 10.

Example 9. Preparation of gelatin capsules containing spheroids. It is necessary to make a capsule with an average theoretical dissolution profile:

Time hour 0 one 2 four 8 12 Amount, % 0 33.33 48.00 61.33 84.00 100.00

The required amount of spheroids, mg per capsule:

Matrix Based Spheroids Coated matrix spheroids Instant spheroids 350.31 356.86 35.70

The obtained spheroids according to examples 1, 2, 5 are packaged in capsules in a manner known per se.

Capsule Dissolution:

Time hour 0 one 2 four 8 12 Amount, % 0 33.56 47.17 62.22 83.97 98.30

The dissolution profile of the resulting capsules is shown in FIGS. 11 and 12.

Example 10. The preparation of tablets with a modified nature of the release of the active substance by direct compression.

The composition of the tablets, wt.%:

6-Methyl-2-ethyl-3-hydroxypyridine succinate - 60.0%

MCC-13.5%

GPMC-20.0%

PVP-2.5%

Aerosil - 2.0%

Magnesium Stearate - 1.0%

Succinic acid - 1.0%

Preparation technology: MCC, HPMC, PVP, Aerosil, magnesium stearate and succinic acid are thoroughly mixed in the container. Then add 6-methyl-2-ethyl-3-hydroxypyridine succinate, mix until smooth and compress the tablets.

Dissolution of tablets obtained by direct compression:

Time min 0 one 2 four 8 12 16 Amount, % 0 18.2 30.12 40.86 62.3 79.6 96.4

The dissolution profile of the tablets is shown in FIG. 13.

Claims (10)

1. A pharmaceutical composition containing 6-methyl-2-ethyl-3-hydroxypyridine succinate as an active ingredient, characterized in that it is an oral dosage form with a modified release form of 6-methyl-2-ethyl-3-hydroxypyridine succinate taken in an amount of 30.0-70.0 wt.%, while it contains cellulose derivatives and / or polyacrylic resins in an amount of 1.0-20.0 wt.% as a release modifier, and microcrystalline cellulose in an amount of 20 as a filler , 0-50.0 wt.% And moving substances state. 2. The pharmaceutical composition according to claim 1, characterized in that it is made of at least one group of spheroids having a diameter of 0.25-2.0 mm 3. The pharmaceutical composition according to claim 2, characterized in that hydroxypropyl methyl cellulose, methyl cellulose and / or cellulose ethers are used as a release modifier. 4. The pharmaceutical composition according to claim 2, characterized in that Eudragit NE 30D, or Eudragit RS, or Eudragit RL, or mixtures thereof, are used as a release modifier. 5. The pharmaceutical composition according to claim 2, characterized in that the spheroids are coated or uncoated with a protective coating regulating the release of the active substance consisting of Eudragit L and / or Eudragit RS and / or Eudragit RL and / or Eudragit NE 30D, talc and triethyl citrate. 6. The pharmaceutical composition according to claim 2, characterized in that the spheroids in the desired ratio are packaged in tablets. 7. The pharmaceutical composition according to claim 2, characterized in that the spheroids in the required ratio are packaged in capsules. 8. The pharmaceutical composition according to claim 6, characterized in that the resulting tablets are coated with a polymer shell that regulates the release of the active substance, consisting of Eudragit L, and / or Eudragit RS, and / or Eudragit RL, and / or Eudragit NE 30D, talc and triethyl citrate. 9. The pharmaceutical composition according to claim 1, characterized in that it is obtained in the form of a tablet by direct compression. 10. The pharmaceutical composition according to claim 9, characterized in that methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose are used as a release modifier.

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