RU2554735C1 - Pharmaceutical composition containing rabeprazole and method for producing it - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: pharmaceutical composition in the form of a tablet contains a core coated with a separating layer and an enteric coating. The core contains an active substance, sodium rabeprazole, and additives - calcium carbonate, lactose, starch, hydroxypropylmethyl cellulose, stearic acid salt in the amounts specified in the patent claim. What is also described is a method for producing the pharmaceutical composition of rabeprazole. The invention enables to extend the range of medical products applicable for treating gastric ulcer.

EFFECT: low in foreign impurities and having good stability.

3 cl, 3 tbl, 5 ex

Description

The invention relates to the pharmaceutical industry and medicine, namely to the production of drugs for the treatment of acid-dependent diseases, such as gastric and duodenal ulcer, gastroesophageal reflux disease (GERD), but is not limited to this [1].

The invention is a pharmaceutical composition in the form of a tablet coated with an enteric coating, consisting of the active substance rabeprazole sodium, excipients of the tablet core, separation layer and enteric coating, as well as a method for preparing it.

The main area of application of the invention is the treatment of diseases, such as:

- peptic ulcer of the duodenum in the acute stage;

- gastric ulcer in the acute stage and anastomosis ulcer;

- erosive and peptic ulcer gastroesophageal reflux disease (GERD) or reflux esophagitis;

- maintenance therapy of GERD;

- non-erosive reflux disease (NERD);

- Zollinger-Ellison syndrome or other conditions characterized by pathological hypersecretion.

As part of combination therapy with antibacterial agents:

- eradication of Helicobacter pylori in patients with peptic ulcer of the stomach and 12 duodenal ulcer or chronic gastritis;

- treatment and prevention of relapse of ulcers in patients with peptic ulcer associated with Helicobacter pylori [2].

According to the ATX classification, the A02B group “Antiulcer drugs and drugs for the treatment of gastroesophageal reflux” includes five subgroups:

- A02BA H2-histamine receptor blockers;

- A02BB Prostaglandins;

- A02BC Proton pump inhibitors (proton pump inhibitors);

- A02BD Combinations of drugs for the eradication of Helicobacter pylori;

- A02BX Other antiulcer drugs and preparations for the treatment of gastroesophageal reflux.

In practical medicine, two groups of antisecretory drugs are used: H ₂ histamine receptor blockers (ranitidine, famotidine, nizatidine, roxatidine) and proton pump inhibitors (omeprazole, lansoprazole, rabeprazole, pantoprazole, esomeprazole), which allow maintaining an optimal level of stomach pH during the day with a minimum of side effects. Proton pump inhibitors (PPIs) are the latest generation of antisecretory drugs acting directly on the proton pump of a parietal cell, irreversibly inhibiting its activity and providing a pronounced antisecretory effect regardless of the nature of the acid-stimulating factor [4].

The disadvantage of H ₂ blockers is the absence of an inhibitory effect on the secretion of hydrochloric acid caused by an increase in vagal tone, which makes them less effective in patients with traumatic brain injury or after neurosurgical interventions. The most common side effects of H ₂ blockers are: headache, dyspepsia, diarrhea. The occurrence of thrombocytopenia, arrhythmia, hypotension, etc. is more rarely observed. Antagonists of H ₂ histamine receptors are excreted by the kidneys, so their dose should be adjusted in patients with reduced creatinine clearance. H ₂ blockers interact with a wide range of drugs (opioid analgesics, anxiolytics, hypnotics, antipsychotics, antiarrhythmic drugs). Famotidine and nizatidine participate in drug interactions to a lesser extent than other representatives of the group of H ₂ blockers.

The advantages of PPI over H ₂ blockers are due to the lack of ability to cause tachyphylaxis. This can be considered as a PPI drugs with better predictability of the effect of providing more accurate control of pH, than the H ₂ -blockers.

The advantage of the PPI group compared to H ₂ -blockers is the proven clinical effectiveness in the prevention and treatment of gastrointestinal tract and gastrointestinal tract injuries due to a stronger suppression of hydrochloric acid secretion [5].

In general, in the treatment of acid-dependent diseases, PPIs have several advantages over other antisecretory drugs, primarily histamine H ₂ receptor blockers, due to their stronger, faster, longer-lasting and fairly predictable antisecretory effect. However, to achieve an antisecretory effect, a small dose of the drug is usually required. Medicines of this group have practically no side effects, which makes their continued use as supportive therapy possible. Long-term use of PPIs is associated with a low risk of developing dyspeptic disorders and drug interactions [4].

Rabeprazole differs from omeprazole in the structure of the radicals on the pyridine and imidazole rings. The peculiarity of its chemical structure provides faster inhibition of the proton pump due to its ability to be activated in a fairly wide pH range. In addition, part of rabeprazole is metabolized non-enzymatically. The bioavailability of rabeprazole is 51.8% (does not change after repeated administration of the drug), binding to plasma proteins is 96.3%, the maximum concentration of the drug in plasma is achieved 3-4 hours after administration, and the half-life is 1 hour. Suppression of gastric secretion when using this drug is dose dependent. So, when using rabeprazole at a dose of 20 mg / day, the pH on the seventh day of administration was 4.2 (before treatment - 1.86, on the first day of administration - 3.7), and at a dose of 40 mg / day - 4.7 (before treatment - 2.0, on the first day of admission - 4.4). According to the results of a number of studies, eating significantly affects the pharmacokinetics of the drug. The frequency of scarring of DNA ulcers when taking rabeprazole at a dose of 40 mg / day after four weeks of treatment reaches 91% [4].

Known drugs with the active substance rabeprazole sodium with a dosage of 10 mg and 20 mg are “Pariet®”, “Zolispan”, “Zulbeks®”, “Khairabesol”, “Noflux”, “Bereta” in the form of enteric coated tablets.

The closest analogue (prototype) of the present invention is the drug "Pariet®".

The composition of the drug for a dosage of 10 mg:

- active substance: rabeprazole sodium, 10 mg, which in terms of 9.42 mg of rabeprazole, respectively;

- excipients: mannitol (mannitol) - 26.0 mg, magnesium oxide - 44.7 mg, slightly substituted hydroxypropyl cellulose (hyprolose) - 13 mg, hydroxypropyl cellulose (hyprolose) - 4.0 mg, magnesium stearate - 1.0 mg, ethyl cellulose - 0.7 mg, hypromellose phthalate - 8.5 mg, diacetylated monoglyceride - 0.85 mg, talc - 0.80 mg, titanium dioxide (E171) - 0.43 mg, iron oxide red (E172) - 0.02 mg, carnauba wax - 0.0015 mg, food grade gray ink F6 (white shellac, black iron oxide, dehydrated ethanol, 1-butanol) [3].

The composition of the drug for a dosage of 20 mg:

- active substance: rabeprazole sodium, 20 mg, which in terms of 18.85 mg of rabeprazole, respectively;

- excipients: mannitol (mannitol) - 40.0 mg, magnesium oxide - 63.0 mg, slightly substituted hydroxypropyl cellulose (hyprolose) - 19.5 mg, hydroxypropyl cellulose (hyprolose) - 3.0 mg, magnesium stearate - 1.5 mg ethyl cellulose - 1.0 mg, hypromellose phthalate - 12.0 mg, diacetylated monoglyceride - 1.2 mg, talc - 1.13 mg, titanium dioxide (E171) - 0.6 mg, yellow iron oxide - 0.07 mg , carnauba wax - 0.02 mg, edible red ink A1 (white shellac, iron oxide red, carnauba wax, glyceric acid ester, ethanol dehydrated, 1-butanol) [3].

The disadvantage of this drug is the formation and increase of impurities during storage, which do not have antisecretory activity and, as a result, can reduce the activity of the active substance.

The purpose of the present invention is the development of a new pharmaceutical composition in the form of a tablet, coated with an enteric coating, storage stable, consisting of the active substance - rabeprazole sodium, excipients of the tablet core, dividing layer and enteric coating, as well as a method for its preparation.

The technical result of the invention is:

1. Improving storage stability of a pharmaceutical composition in the form of a tablet, enteric-coated, containing rabeprazole sodium as an active substance.

2. The expansion of the arsenal of drugs for the treatment of gastric ulcer.

The technical result of the invention is achieved by developing a pharmaceutical composition in the form of a tablet coated with an enteric coating, consisting of the active substance — rabeprazole sodium, excipients of the tablet core, a dividing layer and an enteric coating containing the following components, wt%:

- active substance:

rabeprazole sodium - 5-15

- excipients of the tablet core:

calcium carbonate - 15-35

lactose - 35-50

starch - 10-30

hydroxypropyl methylcellulose - 0.5-3

stearic acid salt - 0.5-1

total - 100% of the mass.

- dividing layer of tablets - 1-5% of the mass. by weight of the tablet core

enteric coating tablets - 8-20% of the mass. by weight of the tablet core

As a filler in this solid dosage form, any pharmaceutically acceptable lactose is used because of its good compressibility, cheapness, as well as pleasant taste. The dosage of lactose is 35-50% of the mass., The preferred dosage is 43% of the mass.

To prevent an increase in the hygroscopicity of lactose, a pharmaceutically acceptable excipient, calcium carbonate, is introduced into the pharmaceutical composition in a dosage of 15-35% by weight, preferably 25% by weight.

Also, calcium carbonate in the specified pharmaceutical composition is used as an alkaline agent to increase the stability of rabeprazole sodium (the stability of rabeprazole depends on the acidity of the medium - it quickly decomposes in moderate acids and is more stable in an alkaline environment).

Starch acts as a disintegrant, that is, a substance that improves the dissolution of the tablet. The dosage of starch is 10-30 wt. -%, preferably 20% of the mass. As a starch, any pharmaceutically acceptable native starch is used, including corn starch, potato starch, but not limited to wheat starch.

Hydroxypropyl methylcellulose in the pharmaceutical composition performs the function of a binder in the form of a granulating solution.

The dosage of hydroxypropylmethyl cellulose is 0.5-3% by weight, preferably 1% by weight.

In order to increase the fluidity of the pelletized granulate, to prevent it from sticking to the punches and the walls of the holes of the matrix, a stearic acid salt is used as a lubricant. As the salt of stearic acid is used, preferably (but not limited to), calcium stearate or magnesium stearate, mainly with a dosage of 0.5-1% by weight, preferably 1% by weight.

The proposed combination of active substance and excipients is determined experimentally and is optimal. The result is a granulate that has good technological properties in the process of tabletting, and the resulting tablets have properties that meet the requirements of the drug, that is, they have a marketable appearance without chips and cracks and have sufficient strength.

The separating layer is applied to the tablet cores by spraying a suspension prepared from the finished mixture, usually used for the production of film-coated tablets. As the finished mixture, Aquarius Prime (e.g., Aquarius Prime BAP 218010 White), Vivacoat (e.g., Vivacoat PA-1P-000 White), Opadry (e.g., Opadry II YS-1-7027 White) can be used, but not limited to this.

The content of the separation layer in the pharmaceutical composition is from 1 to 5% of the mass. by weight of the tablet core, preferably 2% of the mass. by weight of the tablet core.

The separation layer prevents the interaction of rabeprazole sodium with the acidic compounds of the enteric (enteric) shell, which can lead to discoloration of rabeprazole sodium and its loss over time.

The core tablets, coated with a separation layer, are enteric coated.

The presence of an enteric coating gives the pharmaceutical composition storage stability, improves its appearance and protects the proton pump inhibitor (rabeprazole sodium) from contact with acidic gastric juice.

The term "enteric coating" in the present invention is understood to mean sprayed onto tablet cores coated with a release layer, a suspension prepared from a ready-to-use mixture commonly used in the pharmaceutical industry to prepare an enteric coating, and a plasticizer (preferably, but not required).

As a finished mixture, Aquarius Control ΕΝΑ (for example, Aquarius Control ΕΝΑ MAY 310019 Pink and Aquarius Control ΕΝΑ MAY 314037 Yellow), Acrylis (Acryl-EZE (for example Acryl-EZE 93A38076 YELLOW or Acryl-EZE 93A240008 PINK) can be used) but not limited to this.

When preparing a suspension for enteric coating, before adding the above ready-made mixture, it is preferable (but not necessary) to add a plasticizer to the water. The plasticizer gives plasticity and hardness to the enteric coating.

As the plasticizer, any pharmaceutically acceptable plasticizer is used, preferably polyethylene glycol (macrogol), triethyl citrate, propylene glycol, but not limited to.

The enteric coating in the pharmaceutical composition is 8-20% of the mass. from the tablet core, preferably 10% of the mass. from the tablet core, including (but not necessarily) a plasticizer of 0.5-3% of the mass. from the pill core.

The possibility of carrying out the invention is illustrated by the examples (but not limited to) presented in table 1.

Table 1 Examples of carrying out the invention Component Name The dosage range of the component,% mass. from the pill core The content of the component,% of the mass. Example 1 Example 2 Example 3 Example 4 Example 5 one 2 3 four 5 6 7 Active substance: Rabeprazole sodium 5-15 10 5 fifteen 10 10 Excipients of the tablet core: Calcium carbonate 15-35 25 35 fifteen 17.5 22.2 Lactose 35-50 43 49 36 fifty 35 Starch 10-30 20 (corn starch) 10 (corn starch) 30 (wheat starch) 20 (corn starch) 30 (potato starch) Hydroxypropyl methylcellulose 0.5-3 one 0.5 3 1,5 2 Stearic acid salt 0.5-1 1 (magnesium stearate) 0.5 (calcium stearate) 1 (magnesium stearate) 1 (calcium stearate) 0.8 (magnesium stearate) Total - 100% of the mass. Separation layer 1-5 3 (Opadry) 5 (Aquarius Prime) 4 (Opadry) 1 (Vivacoat) 4 (Opadry) Enteric coating 8-20 11 (10% wt. Acryl-EZE + 1% wt. Macrogol) 8 (Aquarius Control ENA, without plasticizer) 14 (11% wt. Acryl-EZE + 3% wt. Triethyl citrate) 20 (Aquarius Control ENA, without plasticizer) 12.5 (12% wt. Acryl-EZE + 0.5% wt. Propylene glycol)

A method of obtaining a pharmaceutical composition includes mixing rabeprazole sodium with calcium carbonate, lactose and starch, preparing a 3% hydroxypropyl methyl cellulose solution, moistening a mixture of rabeprazole sodium, calcium carbonate, lactose and starch with a 3% hydroxypropyl methyl cellulose solution, wet granulating, drying, dry granulating, dusting with salt , tableting, preparation of a separation layer, coating of the obtained tablet cores with a separation layer, preparation of intestines orastvorimoy shell coating enteric-coated tablets.

The physicochemical properties of the obtained samples of the pharmaceutical composition according to examples 1-5 are analyzed.

Compressive strength was determined using an Erveka TVT model device.

The Dissolution test, characterizing the rate of release of the active substance from the pharmaceutical composition in a medium close to the medium of the gastrointestinal tract, was carried out in accordance with OFS 42-0003-04.

Quantitative determination of the content of rabeprazole sodium in tablets, as well as the content of impurities was determined by HPLC.

The results are presented in table 2.

Table 2 also presents the normative values of the indicators in accordance with the requirements of the draft pharmacopoeial article of the enterprise, developed by OAO Tatkhimpharmpreparaty.

This draft pharmacopoeial article was developed on the basis of current requirements of the State Pharmacopoeia.

So, the normative value of the “Dissolution” indicator in the FSP project corresponds to the normative value specified in the General Pharmacopoeia Monograph 42-0003-04 “Dissolution”: the acid stage - not more than 10% after 2 hours, the buffer stage - not less than 75% (Q).

The interval of the quantitative content of rabeprazole sodium in tablets specified in the draft FSP (from 0.009 to 0.011 g for a dosage of 10 mg) was calculated based on the limit of the deviation of the quantitative content of the active substance in tablets ± 10% established by GP XI (Volume 2, General Articles on dosage forms, tablets).

The normative values of the content of impurities of rabeprazole sulfone, rabeprazole sulfide, mercaptoimidazole are not indicated either in the Global Fund or in the European Pharmacopoeia. In this regard, the normative values specified in the scientific and technical literature on the development of drugs with the active substance rabeprazole sodium are prescribed in the FSP project: rabeprazole sulfone - not more than 0.5%, rabeprazole sulfide - not more than 0.5%, mercaptoimidazole - not more than 0.5%, the amount of unidentified impurities - not more than 1.5%.

Table 2 shows the results of analyzes of the content of impurities carried out 6 months after the manufacture of the tablets, and the analyzes were carried out after storage at a temperature of + 40 ° C and a relative humidity of 75%.

As can be seen from table 2, all examples of the invention correspond to the requirements of the draft pharmacopoeial article of the enterprise, which indicates the high quality of the products.

According to the set of physical and chemical indicators, the optimal example is Example 1 with the following composition of components,% mass .:

- active substance:

rabeprazole sodium - 10

- excipients of the tablet core:

calcium carbonate - 25

lactose - 43

corn starch - 20

hydroxypropyl methylcellulose - 1

magnesium stearate - 1

total - 100% of the mass.

- separation layer - 3% of the mass. from the pill core

- enteric coating tablets - 11% of the mass. from the pill core

Experimental studies were conducted to compare storage stability of the invention (examples 1-5) with the drug “Pariet®” (in examples 1-5 and the drug “Pariet®”, the dosage of rabeprazole sodium is 10 mg).

For the reliability of the study, the analyzes were carried out under the same conditions - 1.5 years after the manufacture of the tablets when stored at a temperature of 25 ± 2 ° C and a relative humidity of 65 ± 5 ° C.

The results of the analyzes are presented in table 3.

From table 3 it follows that the developed pharmaceutical compositions have better stability compared to the drug "Pariet®".

So, when stored under the specified conditions, the stability of the developed pharmaceutical compositions is higher than that of the original Pariet® drug, since the quantitative content of rabeprazole sodium is reduced slightly, and the content of impurities is lower than that of the original Pariet® drug.

The conducted experimental studies allow us to conclude that the technical result of the invention is to increase the stability of the pharmaceutical composition containing rabeprazole sodium, made in the form of a tablet, coated with an enteric coating, during storage is achieved.

Developed pharmaceutical compositions can expand the arsenal of drugs for the treatment of gastric ulcer.

Information sources

1. Lazebnik LB, Bordin DS, Masharova A.A. Long-term therapy with proton pump inhibitors: a balance of benefits and risks / L.B. Lazebnik, D.S. Bordin, A.A. Masharova // Experimental and clinical gastroenterology. - 2010. - No. 9. - S. 3-8.

2. Draft instructions for the use of a medicinal product for medical use, "Rabeprazole enteric-coated tablets" of OAO Tatkhimpharmpreparaty.

3. The state register of medicines [Electronic resource]. - Access mode: http://www.grls.rosminzdrav.ru (accessed June 21, 2014).

4. Samsonov A.A. Proton pump inhibitors are the drugs of choice in the treatment of acid-dependent diseases // Farmateka. - 2007. - No. 6. - S. 10-15.

5. Nikoda VV, Khartukova N.E. The use of proton pump inhibitors in intensive care and resuscitation / V.V. Nikoda, N.E. Khartukova // Farmateka. - 2008. - No. 13. - S. 10-16.

Claims (3)

1. The pharmaceutical composition in the form of a tablet, coated with an enteric coating, consisting of the active substance - rabeprazole sodium, excipients of the tablet core, separating layer and enteric coating, characterized in that it contains components in the following proportions, wt.%:
- active substance:
rabeprazole sodium - 5-15
- excipients of the tablet core:
calcium carbonate - 15-35
lactose - 35-50
starch - 10-30
hydroxypropyl methylcellulose - 0.5-3
stearic acid salt - 0.5-1
total - 100% wt.
- separation layer - from 1 to 5% wt. from the pill core
- enteric coating - from 8 to 20% wt. from the pill core. 2. The pharmaceutical composition according to claim 1, characterized in that it contains components in the following proportions,% wt .:
- active substance:
rabeprazole sodium - 10
- excipients of the tablet core:
calcium carbonate - 25
lactose - 43
corn starch - 20
hydroxypropyl methylcellulose - 1
magnesium stearate - 1
total - 100% wt.
- separation layer - 3% wt. from the pill core
- enteric coating - 11% wt. from the pill core. 3. A method of obtaining a pharmaceutical composition according to any one of claims 1 to 2, comprising mixing rabeprazole sodium with calcium carbonate, lactose and starch, preparing a 3% solution of hydroxypropyl methyl cellulose, moistening a mixture of rabeprazole sodium, calcium carbonate, lactose and starch with a 3% solution of hydroxypropyl methyl cellulose, wet granulation, drying, dry granulation, dusting with stearic acid salt, tabletting, preparation of a separation layer, coating of the obtained tablet cores with a separation layer preparation of an enteric coating, coating of the resulting tablets with an enteric coating.