RU2607655C1 - Method of producing dalfampridin tablets with prolonged action - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry and medicine. Method of producing dalfampridin pellets is disclosed, characterized by preparing intra-granulated mixture by screening dalfampridin together with hydroxypropyl methyl cellulose with viscosity of 80–120 MPA˙s, mixing with microcrystalline cellulose with particle size of 50–90 mcm and aerosil, compaction, mixing with magnesium stearate, it is followed by granulation of mixture by rolling, extra-granulated mixture is added to obtained granules consisting of microcrystalline cellulose with particle size of 50–90 mcm and aerosil, mixed to homogeneous state, magnesium stearate is added, tablets are pressed and coated with their shell by spraying water solution of white Opadraja till tablet weight increases by 1.0–3.0 %.

EFFECT: obtained solid shape has improved pharmacological and process characteristics.

6 cl, 1 dwg, 3 tbl, 3 ex

Description

The invention relates to the field of chemical pharmaceutical industry and medicine.

Multiple sclerosis (PC) belongs to the group of demyelinating diseases and is the most common in this category of diseases. Currently, there is a general opinion that the emergence and development of PC is due to the interaction of environmental factors - a viral infection (for example, retroviruses, measles, rubella, rubella), geographic factor, and genetically determined susceptibility.

PC is based on a universal pathological process. It consists of a complex of immunopathological and pathochemical reactions developing in immune-competent cells, cells of the nervous system.

Maintaining the working capacity of patients with demyelinating neuroimmunological diseases is one of the most important problems of public health and medical science. The whole complex of therapeutic agents for PC can be divided into two main groups - pathogenetic and symptomatic.

In recent years, significant progress has been made in the pathogenetic therapy of PC, which is aimed at preventing the destruction of brain tissue by activated cells of the immune system and toxic substances. Most of the funds in this group are:

- immunotropic drugs that affect immunoregulation, the state of the blood-brain barrier. These include:

- immunosuppressants - glucocorticosteroids (metipred), cyclosporine (sandimmune);

- immunomodulators - preparations of interferons (rebif, betaferon), synthetic origin (copaxone), enzyme preparations (wobenzym, phloenzyme, etc.), immunoglobulins (octagam).

Efficacy in patients with multiple sclerosis of all types of course has been demonstrated by tablet 4-aminopyridine (4-AR or dalfampridine) sustained (prolonged) release. The drug can be used as a monotherapy agent, or in combination with existing drugs intended for the treatment of multiple sclerosis, including immunomodulators.

Various methods are known in the art for the preparation of dalfampridine-based preparations.

US Pat. No. 5,370,879 (A), publ. 12/06/1994 discloses a method for producing a prolonged form of dalfampridine in the form of pellets in which 4-aminopyridine, talc and lactose are mixed and ground so as to obtain a uniform powder. The powder is applied to the cores from a starch-sugar mixture (0.4-5.0 mm) using a granulator and coated with a solution of 3.5% polyvinylpyrrolidone in isopropanol to form cores. Then, membranes are applied to the cores by spraying a solution consisting of: EUDRAGIT s in acetone. Pellets can be compressed into tablets.

RU 2536269 C1, publ. 12/20/2014 discloses a pharmaceutical composition for treating disorders of innervations in the form of a tablet containing Fampridine as an active principle and excipients: a substance that slows down the release selected from the group consisting of hydroxypropyl cellulose, hydroxypropyl methyl cellulose (hypromellose), methyl cellulose, hydroxyethyl cellulose, or xanthan , a binder selected from the group consisting of lactose, starch, polyvinylpyrrolidone, ethyl cellulose, polymethacrylate, waxes or mixtures thereof, sliding a component selected from the group comprising talc, magnesium stearate, calcium stearate, stearic acid or mixtures thereof in the following components, wt. %:

fampridine 70-96 release agent 3.4-23.5 binder 0.1-4.5 sliding component 0.5-2.0

The production method consists in the fact that the sifted dry powders of Ludipress® LCE, fampridine, starch 1500 and Metocel® (type K100LV CR) are mixed for 5-15 minutes at a rotation speed of the main mixer of 130-150 rpm, add magnesium stearate sifted and mixing is continued for 2-5 minutes at a speed of rotation of the main mixer of 130-150 rpm, the resulting tablet mass is tabletted on a rotary press RTM-41 M using biconvex punches with a diameter of 8 mm (deep sphere) and the coating step is carried out.

As the closest analogue, international application WO 2004082684 (A1), September 30, 2004, disclosing a prolonged tablet form of 4-aminopyridine obtained by mixing half of Methocel K100LV, Avicel PH101, Aerosil 200, micronized 4-AP and the rest of Methocel K100LV in for 15 minutes at 175 rpm, followed by the addition of magnesium stearate, mixing for 5 minutes at 100 rpm, pressing and possibly coating, such as an enteric coating.

The resulting tablets are strong, however, the tablets do not provide a sufficiently low value of variability in patients. The release profile, although it provides a prolonged effect, is not uniform.

The objective of the invention is to develop a new method for producing a solid form with improved pharmacological and technological characteristics.

The problem is solved by a method of producing a sustained-release tablet form of dalfampridine, characterized in that an intragranulatory mixture is prepared by sifting dalfampridine together with hydroxypropyl methylcellulose with a viscosity of 80-120 mPa⋅s, mixing with microcrystalline cellulose with a particle size of 50-90 microns and aerosil, compacting, mixing with magnesium stearate and granulation of the mixture by rolling, an extragranulatory mixture consisting of microcrystalline cellulose with a size of om particles of 50-90 microns and aerosil, mix until homogeneous, add magnesium stearate, compress the tablets and coat them by spraying with an 8% aqueous solution of Opadra white to achieve a tablet weight increase of 1.0-3.0%.

Dalfampridine can be used in micronized form, preferably less than 100 microns, more preferably 1-20 microns.

Intragranulatory components are preferably compacted for 20-25 minutes at 15-20 rpm.

Mixing obtained by rolling the granules and the extragranulatory mixture is preferably carried out for 3-5 minutes at 15-20 rpm.

Preferably, the particle size of hydroxypropyl methylcellulose and aerosil is about 40-60 mesh.

Effect: storage stability, high strength, reducing fluctuations in interindividual variability in patients.

The invention may be illustrated by the following embodiments.

Example 1. The formulation of the tablets, mg

Intragranular components

Dalphampridine [or micronized 4-API] 5-20 Avicel PH 101 110-120 Metocel K100LV 220-250 Aerosil 200 1-2 Magnesium stearate 0.5-1.5

Extragranular components

Avicel PH 101 16-20 Aerosil 200 1-2 Magnesium stearate 0.5-1.5 Core tablet weight 360-410

Coating components

Opadry White 3.6-12.3

The resulting tablets have an extended effect of at least 12 hours

Example 2. The production process

1. Weighed portions of APIs and excipients.

2. Screening of intragranular excipients:

- AFI and Metocel K 100 LV are sifted through an ASTM # 40 sieve

- Avicel PH 101 is sieved through ASTM # 40 sieve, Aerosil 200 Pharma is sieved through mesh # 40.

- Magnesium stearate is sieved through an ASTM # 60 sieve.

9. Pre-compacting:

- Co-sifted excipients (excluding Magnesium stearate) were placed in a 5 L double-cone mixer.

- The mixing time was 20 minutes at 15 rpm.

10. Addition of sieved Magnesium stearate to a 5 L double-cone mixer:

- Stirring was performed for 3 minutes at 15 rpm.

11. Rolling granulation:

The pre-compacted mixture was transferred to a roller press, which was put into operation in accordance with the following parameters in table 1.

The density after compaction is 0.58-0.6.

To obtain good quality granules, a hydraulic pressure of 50 bar is most preferred.

12. Screening of extragranular auxiliary components:

- Avicel PH 101 and Aerosil 200 Pharma were sieved through an ASTM # 40 sieve.

- Magnesium stearate was sieved through an ASTM # 60 sieve.

13. Mixing:

- Sifted auxiliary substances (except for magnesium stearate) together with pre-compacted granules were placed in a double cone mixer with a capacity of 5 l.

- The mixing time was 5 minutes at 15 rpm.

8. Lubrication:

The sieved magnesium stearate was placed in a two-cone 5-liter mixer and stirred for 3 minutes at 15 rpm.

14. Pressing:

The lower and upper punches 8 × 13 mm are mounted on a tablet press to determine the limit of the corresponding compressive strength.

The speed of the tablet press turret was set to 15-30 rpm, and the feeder for feeding in pressure mode to 20-30 rpm, the mixture was pressed further.

15. Coating:

- In a propeller-type mixer, an 8% (percent by weight) film-forming solution of Opadrai white Y - 1 - 7000 in purified water was prepared.

- The core tablets were loaded into the boiler and warmed up before starting the process.

- Upon receipt of the desired process parameters, the spraying process was started using Opadrai white solution Y - 1 - 7000, until a weight increase of 2% ± 1% (1.0-3.0%) was achieved.

Preferred process parameters:

Intake air temperature 60 ° C ± 10 ° C

Air temperature 35-55 ° C

Nozzle air pressure 1.3 kg / cm ² ± 0.5 kg / cm ²

The pressure of the exhaust air exhausted by the fan 2.0 kg / cm ² ± 0.5 kg / cm ²

Boiler rotation speed 2-8 rpm

- At the end of the spraying, the physical condition of the tablets was checked.

Example 3. The study of the solubility profile of the tablets obtained by the proposed optimized process.

The solubility study was carried out in solution with a pH of 6.8, the results are compared with the standard.

Paddle mixer 50 rpm Volume of Dissolution Medium 900 ml Rotational speed fifty Sampling interval 0.5, 1, 2, 4, 6, 8, 10 and 12 hours Standard - Original Product Fampyra

Series No. SF 14000880 according to the proposed method

Figure 1 shows the solubility profile of tablets obtained by the proposed method. The graph shows that the kinetics in individual patients (different numbers of batches of tablets obtained by the proposed method were used) differ slightly, which may indicate a low level of interindividual variability. Higher stability is confirmed by HPLC. The impurity content during long-term storage was:

Dalfampridine N-oxide No more than 0.10% 2-amino-pyridine No more than 0.30% 3-amino-pyridine No more than 0.10% Dalphampridine dimer No more than 0.10% Isonicotinic acid No more than 0.30% Isonicotinamide No more than 0.10%

Thus, the proposed method has undeniable advantages over the known and can be widely used for implementation in practice.

Claims (6)

1. A method of producing a sustained-release tablet form of dalfampridine, characterized in that an intragranulatory mixture is prepared by sifting dalfampridine together with hydroxypropyl methylcellulose with a viscosity of 80-120 mPa⋅s, mixing with microcrystalline cellulose with a particle size of 50-90 μm and aerosil, compacting, mixing with magnesium stearate, then the mixture is granulated by rolling, an extragranulatory mixture consisting of microcrystalline cellulose with a size is added to the obtained granules particles of 50-90 microns and aerosil, mix until homogeneous, add magnesium stearate, compress the tablets and coat them by spraying with an 8% aqueous solution of Opadra white to achieve a tablet weight increase of 1.0-3.0%. 2. The method according to p. 1, characterized in that the intragranulatory components are compacted for 20-25 minutes at 15-20 rpm. 3. The method according to p. 1 or 2, characterized in that the mixing obtained by rolling the granules and the extractor mixture is carried out for 3-5 minutes at 15-20 rpm 4. The method according to p. 1, characterized in that the particle size of hydroxypropyl methylcellulose and Aerosil is 40-60 mesh. 5. The method according to p. 1, characterized in that when granulating the mixture by rolling using a hydraulic pressure of 50 Bar. 6. The method according to p. 1, characterized in that dalphampridine is used in micronized form.

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