RU2577230C1 - Method of producing capsules of fingolimod hydrochloride - Google Patents

Method of producing capsules of fingolimod hydrochloride Download PDF

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Publication number
RU2577230C1
RU2577230C1 RU2015113034/15A RU2015113034A RU2577230C1 RU 2577230 C1 RU2577230 C1 RU 2577230C1 RU 2015113034/15 A RU2015113034/15 A RU 2015113034/15A RU 2015113034 A RU2015113034 A RU 2015113034A RU 2577230 C1 RU2577230 C1 RU 2577230C1
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RU
Russia
Prior art keywords
capsules
capsule
method
fingolimod
fingolimod hydrochloride
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RU2015113034/15A
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Russian (ru)
Inventor
Иван Афанасьевич Макаров
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Общество с ограниченной ответственностью "Лонг Шенг Фарма Рус"
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Priority to RU2015113034/15A priority Critical patent/RU2577230C1/en
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Publication of RU2577230C1 publication Critical patent/RU2577230C1/en

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Abstract

FIELD: chemistry.
SUBSTANCE: invention relates to chemical-pharmaceutical industry and represents a method of producing a pharmaceutical composition in the form of capsules, consisting in the fact that is preliminarily sieved substance fingolimod hydrochloride, microcrystalline cellulose, carboxymethyl sodium and calcium stearate or magnesium stearate, mixed in weight ratio of 1:(210-215):(5-7):(1.5-2.5), respectively, to a homogeneous state and dosed mixture in the capsule.
EFFECT: invention provides higher accuracy of metering in production of capsules, stable during storage of the product.
3 cl, 1 ex

Description

The invention relates to the field of the pharmaceutical industry and the preparation of a preparation based on an S1P receptor agonist.

In neurology, a significant proportion of chronic progressive diseases. Among them - one of the most common - multiple sclerosis (PC). Multiple sclerosis (PC) is a chronic, progressive demyelinating disease that is characterized by signs of multifocal damage to the nervous system.

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. The means of this group include immunotropic drugs that affect immunoregulation, the state of the blood-brain barrier. In particular, immunosuppressants - glucocorticosteroids (metipred), cyclosporine (sandimmune), immunomodulators - interferon preparations (rebif, betaferon), synthetic origin (copaxone), enzyme preparations (wobenzym, phlogenzym, etc.), immunoglobulins (octagam).

The imperfection of immunotropic therapy of PC is largely associated with the development of numerous side effects that limit the use of drugs. For example, when using interferons, inflammatory reactions at the injection site and flu-like symptoms, as well as more rare violations of the liver and cytopenia, are common.

In September 2010, the new drug fingolimod / FTY720 was registered and approved for use in patients with PC in the USA, Europe and Russia as the first oral drug for the treatment of PC. Fingolimod is a substance isolated from the fungus Isaria sinclairii, which parasitizes on insects. Japanese researchers isolated myriocin from this fungus, acting on serine palmitoyl transferase (SPT) and inhibiting the immune system 10-100 times stronger than cyclosporin (isolated from a fungus of the same genus Cordiceps). Subsequently, Norwegian scientists synthesized a myriocin derivative - FTY720, called a fingolimod. Fingolimod, although it is a chemical derivative of myriocin, has lost activity against SPT, its target is lysophospholipid sphingosine-1-phosphate (S1P) receptors.

An analysis of the data obtained in the framework of a clinical trial of phase 3 FREEDOMS, in which 1272 people with remitting PC took part, showed that the use of fingolimod in 0.5 mg capsules for two years reduces the frequency of exacerbations by 54% compared with placebo. When taking the drug, stable remission was observed in 70% of patients (compared with 45.6% in the placebo group). According to repeated MRI, fingolimod reduced the likelihood of active foci formation, and also slowed the atrophy of nerve tissue in patients with remitting MS. In addition, the use of the drug reduced by 30% the risk of progression to disability.

Thus, obtaining highly effective drugs based on fingolimod is one of the priority tasks of researchers in this field.

The prior art patent US 5604229 (A) - 1997-02-18, which relates to a method for producing fingolimod and its preparative forms. A method for producing soft capsules by adding 300 mg of polyethylene glycol and 20 mg of polysorbate 80 to 30 mg of the active ingredient is described, followed by packing the mixture in soft capsules. Soft capsules do not provide stability during prolonged storage.

Known RF patent 2475237, according to which a method for producing a pharmaceutical composition consists in mixing a SIP receptor agonist, such as FTY720 with sugar alcohol; grind and / or granulate the mixture; and mix the milled and / or granular mixture with a sizing. The S1P receptor agonist can be finely ground and / or pre-sieved through a sieve with a mesh size of 400 to 500 μm to remove lumps. The mixing step can be carried out in any suitable mixer or mixer for, for example, 100-400 revolutions. The method may include an additional step in a hard gelatin capsule using an automatic encapsulating device. Capsules can be stained or labeled.

A known method for producing a solid oral pharmaceutical composition is that weighed portions of an S1P receptor agonist (or a pharmaceutically acceptable salt of an S1P receptor agonist); sifting through a sieve the crushed portion of an S1P receptor agonist (or a pharmaceutically acceptable salt of an S1P receptor agonist), as well as a portion of a lubricant and starch, or a pharmaceutically acceptable starch derivative; mixed in a mixer, weighed portions of the S1P receptor agonist and starch; add to the mixer a portion of a lubricant for dusting; fill capsules or compress the mixture into tablets (RF application 2012157310).

As the closest analogue, patent RU 2487703 C2 can be mentioned, which describes a composition in the form of a hard gelatin capsule comprising an S1P receptor modulator and microcrystalline cellulose in the absence of aldit. The possibility of obtaining soft capsules is also mentioned. The method for producing the pharmaceutical composition according to claim 29, which consists in mixing the S1P receptor modulator with microcrystalline cellulose, for example, Avicel®, in grinding the mixture, and in mixing the ground mixture with a sizing agent, for example, magnesium stearate, calcium stearate, sodium stearyl fumarate, colloidal hydroxide silicon or talc. Other fillers may be added.

We have found that known methods do not provide high metering accuracy in the industrial production of capsules.

An object of the present invention is to provide an effective and convenient form of fingolimod.

The problem is solved in a new way to obtain a pharmaceutical composition in the form of capsules, which consists in the fact that pre-sieved substances of fingolimod hydrochloride, microcrystalline cellulose, sodium carboxymethyl starch and calcium stearate or magnesium stearate are mixed in a mass ratio of 1: (210-215) :( 5-7 ) :( 1.5-2.5), respectively, to a homogeneous state and dose the mixture into capsules.

Then, the capsules can be packaged in blister strip packaging from a film of combined polyvinyl chloride / polyvinylidene chloride on one side and aluminum foil of the FGPL A5T brand on the other. Using this package allows you to further stabilize the capsules during storage.

Effect: increasing the accuracy of dosing.

The technical result is achieved by the selected composition of excipients and the ratio of components in the production.

The possibility of carrying out the invention can be demonstrated by the following example.

Example 1

Screening Raw Material

The series of ingredients obtained from the warehouse must correspond to the series indicated on the chemical analytical sheet. OKK laboratories. Upon receipt of raw materials, it is necessary to pay attention to the integrity of the packaging, the appearance, uniformity of the raw materials, the absence of impurities

Received from the warehouse in containers - 0.010 kg of fingolimod hydrochloride, 2.143 kg of microcrystalline cellulose, 0.061 kg of sodium carboxymethyl starch, 0.018 kg of calcium stearate are sieved on a vibrating screen with mesh No. 38 according to OCT 17-46-82. The sifting of the powders is carried out separately, cleaning the sieve after each type of raw material. The resulting screenings in the receiving containers are passed to the stage of TP 3 to obtain the mass for encapsulation. Screenings are collected in OP-2-11 and sent to the dump.

Mixing ingredients

Before starting work, check the serviceability of grounding, the purity of the V-mixer-duster and the capacity for the capsule mass.

The sifted ingredients are loaded from the containers into the mixer. Close the mixer lid tightly and turn on the mixer for 5 minutes.

The OKC controller takes a sample for analysis (Kx TP 3.2.2.). After analysis for quantitative content, the mixture is transferred to the operation "Encapsulation" to fill the capsules.

Encapsulation

A label is attached to the hopper of the capsule machine indicating the capsule preparation and the average weight of the contents of the capsule (0.125 g), series number.

The following parameters are set on the control panel:

The name of the drug, the date of encapsulation, the rate of encapsulation is 10 thousand drops / hour. The size of the capsules is number 3.

The mass for encapsulation is poured into the hopper and proceed to the test filling. After setting the mass of the contents of the capsule is checked for quality indicators: appearance, average weight of the capsule and its contents, deviation from the average weight, disintegration, dissolution.

The average weight of the capsules is determined by weighing 20 capsules on an electronic balance KP 9-2 every 60 minutes. Each capsule is opened, carefully emptied and the empty capsule is weighed.

For encapsulation, commercial capsules are used. An example would be the composition of a hard gelatin capsule: titanium dioxide (El71), quinoline yellow (E104), dye "sunset" yellow (E110), methyl parahydroxybenzoate, ropyl parahydroxybenzoate, acetic acid, gelatin. Another example may be the composition: titanium dioxide (E171), quinoline yellow (E104), dye "sunset" yellow (E110), gelatin.

Assessment of appearance is made on the basis of examination with the naked eye of 50-100 capsules. Capsules should not have jagged places, the correct shape, the surface should be smooth and uniform.

Disintegration of the capsules is determined at the beginning of encapsulation and during operation, but at least 2 times per shift.

Suitable capsules are poured into a container with a label that indicates the name of the drug, series number, capsule weight, operator name and capsule manufacturing date. Substandard capsules that do not correspond to HF XI in appearance, weight, etc., are collected in a separate container and transferred for disposal.

Capsule analysis and rejection

The OCC controller from the finished capsules takes an average sample for analysis, which is recorded in a special journal (Kx TP 4.1.). Capsules are subjected to quality control according to GF XI, v.2 and FSP. If finimolimod capsules 0.5 mg are in compliance with the requirements of ND, they are transferred to the operation UMO 5 “Packaging”

Filling and packaging of capsules in blisters

Packing capsules in blister strip packaging from a film of combined polyvinyl chloride / polyvinylidene chloride on one side and aluminum foil of the FGPL A5T brand on the other.

Set the temperature values of the preheating plates and the welding roller:

- upper and lower preheating plate 115 ° C

- welding roller 187 ° C

The temperature reaches the set value within 10 minutes.

The PVC / PVDC film from the feed drum is fed to the forming plates through the bypass roller and the rod. The foil from the feed drum passes through the bypass roller, the upper non-drive hot roll and enters the gluing with PVC / PVDC. A PVC / PVDC film with molded cells is fed to the machine table, where the cells are filled with capsules coming from a vibrating feeder with a capsule dedusting system through the stacking unit. On the table, automatic control of filling the cells with capsules is carried out. The top non-driven hot roll presses the foil to the PVC / PVDC with the filled cells and glues it. The glued web, enveloping the rocking roller and the bypass roller, is fed by a lingering mechanism to the marking press and then to the die cutting die.

Weight control during dosing showed that the deviation of the average weight of the capsules obtained by the claimed method is less than 3.5%, of the capsules of the prototype 7%.

Claims (3)

1. A method of obtaining a pharmaceutical composition in the form of capsules, which consists in the fact that pre-sifted substances of fingolimod hydrochloride, microcrystalline cellulose, sodium carboxymethyl starch and calcium stearate or magnesium stearate are mixed in a mass ratio of 1: (210-215) :( 5-7) : (1.5-2.5), respectively, to a homogeneous state and the mixture is metered into capsules.
2. The method according to p. 1, characterized in that the substances are sieved through a vibrating screen with mesh No. 38.
3. The method according to p. 1, characterized in that the capsules are Packed in blister strip packaging from a film of combined polyvinyl chloride / polyvinylidene chloride on the one hand and aluminum foil grade FGPL A5T on the other hand.
RU2015113034/15A 2015-04-09 2015-04-09 Method of producing capsules of fingolimod hydrochloride RU2577230C1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011131368A2 (en) * 2010-04-22 2011-10-27 Ratiopharm Gmbh A method of preparing an oral dosage form comprising fingolimod
WO2013019872A1 (en) * 2011-08-01 2013-02-07 Teva Pharmaceutical Industries Ltd. Process for preparing pharmaceutical compositions comprising fingolimod
RU2475237C2 (en) * 2003-04-08 2013-02-20 Новартис Аг Oral pharmaceutical composition
RU2487703C2 (en) * 2006-09-26 2013-07-20 Новартис Аг Pharmaceutical compositions containing s1p receptor modulator
RU2506949C1 (en) * 2012-06-13 2014-02-20 Открытое акционерное общество "Новосибхимфарм" Pharmaceutical composition of sip receptor agonist for treating demyeliniating diseases

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2475237C2 (en) * 2003-04-08 2013-02-20 Новартис Аг Oral pharmaceutical composition
RU2487703C2 (en) * 2006-09-26 2013-07-20 Новартис Аг Pharmaceutical compositions containing s1p receptor modulator
WO2011131368A2 (en) * 2010-04-22 2011-10-27 Ratiopharm Gmbh A method of preparing an oral dosage form comprising fingolimod
WO2013019872A1 (en) * 2011-08-01 2013-02-07 Teva Pharmaceutical Industries Ltd. Process for preparing pharmaceutical compositions comprising fingolimod
RU2506949C1 (en) * 2012-06-13 2014-02-20 Открытое акционерное общество "Новосибхимфарм" Pharmaceutical composition of sip receptor agonist for treating demyeliniating diseases

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Effective date: 20170410