Pharmaceutical composition containing rabeprazole and method for producing it

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

 

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

The invention is a pharmaceutical composition in the form of tablets, enteric coated tablets, comprising the active substance rabeprazole sodium, excipients tablet core, a separating layer and an enteric-coated membrane, and method for its preparation.

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

- peptic ulcer disease duodenal ulcer in the acute stage;

- peptic ulcer in the acute stage and ulcer anastomosis;

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

- maintenance therapy of GERD;

- non-erosive reflux disease (NERB);

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

In combination therapy with antibacterial agents:

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

- Le�ood and the prevention of recurrence of ulcers in patients with peptic ulcer disease, associated with Helicobacter pylori [2].

Classification ATC group A02B "anti-Ulcer drugs and drugs for the treatment of gastroesophageal reflux includes five subgroups:

- A02BA Blockers of H2-histamine receptors;

- A02BB Prostaglandins;

- A02BC a proton pump Inhibitor (proton pump inhibitors);

- A02BD Combinations of drugs for eradication of Helicobacter pylori.

- A02BX other antiulcer drugs and medications to treat gastroesophageal reflux.

In practical medicine, there are two groups of antisecretory drugs: H2-blockers of histamine receptors (ranitidine, famotidine, nizatidine, roxatidine) and proton pump inhibitors (omeprazole, lansoprazole, rabeprazole, pantoprazole, esomeprazole), creating the optimum pH of the stomach during the day and have minimum side effects. Proton pump inhibitors (PPIS) are the latest generation of antisecretory drugs operating directly on the proton pump of parietal cells, irreversibly inhibiting its activity and providing a pronounced antisecretory effect regardless of the nature cyclotosaurus factor [4].

A disadvantage of the H2-blocker is the lack of inhibitory effect on the secretion of hydrochloric acid caused by increased vagal tone, which makes �x less effective in patients with traumatic brain injury or after neurosurgical procedures. The most common adverse effect of H2-blockers are: headache, indigestion, diarrhea. More rarely noted the occurrence of thrombocytopenia, arrhythmia, hypotension, etc. Antagonists H2-histamine receptors are kidneys, so the dose should be adjusted in patients with reduced creatinine clearance. H2-blockers interact with a wide range of drugs (opioid analgesics, anxiolytics, hypnotics, neuroleptics, antiarrhythmics). Famotidine and nizatidine are involved in drug interactions, to a lesser extent than the other representatives of the group of H2-blockers.

The advantages of the IPP in front of H2-blockers due to the lack of ability to cause tachyphylaxis. This allows to consider the STI as drugs with better predictability effect, providing more accurate control of pH than H2-blockers.

Advantage of representatives of the group of STI than H2-blockers has proven clinical efficacy in the prevention and treatment of injuries of the gastrointestinal tract and utilities due to a stronger suppression of secretion of hydrochloric acid [5].

In General, when treating acid-related diseases STIs have a number of advantages compared to other antisecretory means, primarily blockers H2-Retz�tori histamine, due to their strong, fast, long-lasting and predictable antisecretory effect. The antisecretory effect usually requires a small dose of the drug. Drugs of this group have little to no side effects, making possible their continued use as maintenance therapy. Prolonged use of PPIS is accompanied by a low risk of developing dyspeptic disorders and drug interaction [4].

Rabeprazole is different from the structure omeprazole radicals on the pyridine and imidazole rings. The peculiarity of its chemical structure provides a more rapid inhibition of the proton pump with the ability to be activated in a fairly wide pH range. In addition, a portion of rabeprazole is metabolized by enzymatic. The bioavailability of rabeprazole is 51,8% (no change after repeated administration of the drug), the plasma protein binding is 96.3%, the maximum concentration of drug in plasma is reached after 3-4 hours after ingestion, and the half-life is 1 hour. Inhibition of gastric secretion in the application of this drug is dose-dependent. Thus, with the use of rabeprazole in the dose of 20 mg/day, the pH level on the seventh day of admission amounted to 4.2 (before treatment - 1,86, on the first day of admission -3,7), a dose of 40 mg/day - 4,7 (before treatment - 2,0, first day of admission and 4.4). According to the results of several studies eating significantly affect the pharmacokinetics of the drug. The frequency of scarring ulcers of DNA when taking rabeprazole dose of 40 mg/day after four weeks of treatment reaches 91% [4].

Famous drugs with the active substance rabeprazole sodium 10 mg and 20 mg - Pariet®", "Salesman", "Solvex®", "Harbeson", "Eflux", "Beret" in the form of tablets, enteric coated tablets.

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

The composition of the drug, for dosage 10 mg:

- active ingredient: rabeprazole sodium, 10 mg, which in terms corresponds to 9,42 mg rabeprazole, respectively;

- excipients: mannitol (mannitol) - 26,0 mg, magnesium oxide is 44.7 mg, hydroxypropyl cellulose slabosolenaja (hyprolose) - 13 mg, hydroxypropyl cellulose (hyprolose) to 4.0 mg magnesium stearate 1.0 mg, ethylcellulose - 0.7 mg, hypromellose phthalate - 8.5 mg, dezetilirovanny monoglyceride - 0,85 mg, talc and 0.80 mg, titanium dioxide (E171) and 0.43 mg, iron oxide red (E172) - 0.02 mg, Carnauba wax - 0.0015 mg, edible ink gray F6 (white shellac, iron oxide black, the dehydrated ethanol, 1-Butanol) [3].

The composition of the drug, for dosage 20 mg:

- active substances�: rabeprazole sodium, 20 mg, which corresponds in terms 18,85 mg of rabeprazole, respectively;

- excipients: mannitol (mannitol) to 40.0 mg, magnesium oxide - 63,0 mg, hydroxypropyl cellulose slabosolenaja (hyprolose) is 19.5 mg, hydroxypropyl cellulose (hyprolose) to 3.0 mg magnesium stearate 1.5 mg, ethylcellulose - 1.0 mg, hypromellose phthalate - 12,0 mg, dezetilirovanny monoglyceride - 1.2 mg, talc and 1.13 mg, titanium dioxide (E171) - 0.6 mg, iron oxide yellow - 0.07 mg, Carnauba wax - 0.02 mg, dye food red A1 (white shellac, iron oxide red, Carnauba wax, ester glyceric acid, dehydrated ethanol, 1-Butanol) [3].

The disadvantage of this drug is the education and the increase of impurities during storage, which do not possess antisecretory activity and, consequently, 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 tablets, enteric coated tablets, storage stable, consisting of the active substance rabeprazole sodium, excipients tablet core, a separating layer and an enteric-coated membrane and a method of its receipt.

The technical result of the invention is:

1. Improved stability during storage of the pharmaceutical compositing�tion, made in the form of tablets, enteric coated tablets, containing as active substance rabeprazole sodium.

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

The technical result of the invention is achieved through the development of pharmaceutical compositions in the form of tablets, enteric coated tablets, comprising the active substance rabeprazole sodium, excipients tablet core, a separating layer and an enteric-coated membrane, comprising the following components, wt.%:

- active substance:

rabeprazole sodium - 5-15

- excipients tablet core:

calcium carbonate - 15-35

lactose - 35-50

starch - 10-30

hydroxypropylmethyl cellulose is 0.5-3

salt of stearic acid - 0,5-1

total - 100% of the mass.

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

enteric-coated tablets - 8-20% wt. by weight of the tablet core

The filler in this solid dosage form is used, any pharmaceutically acceptable lactose because of its good pressuremost, cheap, and pleasant taste. The dosage of lactose - 35 to 50 wt.%, preferred dosage - 43% of the mass.

To prevent the increase of hygroscopicity of lactose in comp�in the pharmaceutical composition is injected pharmaceutically acceptable filler - calcium carbonate in the dosage of 15-35 wt.%, primarily 25% of the mass.

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

Starch performs the function of disintegrant, that is, substances that improve the dissolution of the tablet. The dosage of starch - 10-30% wt., preferably 20% by weight. As starch is used any pharmaceutically acceptable native starch, including corn starch, potato starch, wheat starch, but not limited to it.

Hydroxypropylmethyl cellulose in the pharmaceutical composition of the composition performs the function of a binder in the form of a granulating solution.

Dosage of hydroxypropylmethylcellulose - 0,5-3 wt.%, preferably 1 wt%.

With the aim of improving the fluidity of tableting granules, preventing it from adhering to the punches and the walls of the holes of the matrix as the lubricant used salt of stearic acid. As a salt of stearic acid is used, preferably but not limited to, calcium stearate or magnesium stearate, preferably with a dosage of 0.5-1% wt., preferably 1 wt%.

the Proposed combination of active substances and excipients is determined experimentally and is optimal. The result is a granulate with good processing properties in the tableting process, and the resulting tablets have properties that meet the requirements for the medicinal product, i.e. have a saleable condition with no chips or cracks and have sufficient strength.

The separation layer is applied to the tablet core by spraying a suspension, prepared from ready-mix, generally used for the production of tablets, film-coated. As a final mixture can be used Aquarius Prime (for example, Aquarius Prime BAP 218010 White), Vivacoat (e.g. Vivacoat PA-1P-000 White), é (for example, é II YS-1-7027 White), but is not limited to it.

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

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

Pills is core covered with a separating layer, covered with enteric coating.

The presence of enteric-coated shell gives the pharmaceutical composition storage stability, improves its external�s appearance and protect the proton pump inhibitor (rabeprazole sodium) from contact with acidic gastric juice.

The term "enteric-coated" in the present invention should be understood atomized on the tablet core, covered with a separating layer, a suspension, prepared from ready-mix, commonly used in the pharmaceutical industry for the preparation of enteric-coated shell, and plasticizer (preferably, but not necessarily).

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

When preparing the suspension for enteric-coated shell before adding the above prepared mixture, preferably (but not necessarily), with water softener. The plasticizer imparts ductility and hardness of the enteric shell.

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

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

The invention illustration�assured by the examples (but, not limited to, are presented in table 1.

Table 1
Examples of carrying out the invention
Name of the componentThe range of dosages of the component (%vol.) from tablet-coreThe content of the component (%vol.)
Example 1Example 2Example 3Example 4Example 5
1234567
Active substance:
Rabeprazole sodium5-15105151010
Thinking of�gateline substance tablet core:
Calcium carbonate15-3525351517,522,2
Lactose35-504349365035
Starch10-3020 (cornstarch)10 (cornstarch)30 (wheat starch)20 (cornstarch)30 (potato starch)
Hydroxypropyl methylcellulose0,5-310,531,52
Salt of stearic acid0,5-11 (magnesium stearate)0, (calcium stearate) 1 (magnesium stearate)1 (calcium stearate)0,8 (magnesium stearate)
Total - 100% of the mass.
The separation layer1-53 (é)5 (Aquarius Prime)4 (é)1 (Vivacoat)4 (é)
Enteric-coated8-2011 (10 wt%. Acryl-EZE + 1% of the mass. macrogol)8 (Aquarius Control ENA, without plasticizer)14 (11% of the mass. Acryl-EZE + 3% of the mass. triethylcitrate)20 (Aquarius Control ENA, without plasticizer)12,5 (12% of the mass. Acryl-EZE + 0,5% of the mass. propylene glycol-free)

A method of obtaining a pharmaceutical composition includes mixing of rabeprazole sodium with calcium carbonate, lactose and starch, the preparation of a 3% solution of hydroxypropylmethylcellulose, moisture 3% solution hydroxypropylmethylcellulose mixture of rabeprazole sodium, calcium carbonate, lactose and starch, wet granulation, drying, dry granulation, dusting salt of stearic acid, tabletting, cooking �angelically layer, the coating obtained tablets-cores separating layer, an enteric-coated preparation of the shell, coated tablets enteric coating.

Analyzed physico-chemical properties of the obtained samples pharmaceutical compositions according to examples 1-5.

The compressive strength was determined on the device model TVT firm ERWEKA".

Test "Dissolution", which characterizes the rate of release of active substance from the pharmaceutical composition in an environment close to the environment of the gastrointestinal tract, performed in accordance with CFC 42-0003-04.

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

The results are presented in table 2.

Table 2 also presents normative values in accordance with the requirements of the draft monograph of the enterprise, developed by JSC "tatchempharmpreparaty".

The draft monograph was developed on the basis of the existing requirements of the State Pharmacopoeia.

Thus, the normative value of the index "Dissolution" in the project FSP conforms to the value specified in the CFC 42-0003-04 "Solution": the acid stage is not more than 10% after 2 h, the buffer stage is not less than 75% (Q).

The interval of the quantitative content of rabaris�La sodium tablets, specified in the FSP project (0.009-0,011 g for dosage 10 mg calculated on the basis of the limit value of the deviation of the quantitative content of the active substance in tablets ±10% set by the global Fund XI (volume 2, General articles on dosage forms, tablets).

The normative value of the content of impurities of rabeprazole sulfone, rabeprazole sulfide, mercaptoimidazole not specified either in the CSF or in the European Pharmacopoeia. In this regard, the draft FSP prescribed normative values indicated in the scientific literature, devoted to the development of medications with active ingredient rabeprazole sodium: rabeprazole sulfone is not more than 0.5%, rabeprazole sulfide is 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 analyses of the content of impurities, conducted 6 months after the manufacture of tablets, and the analyses 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 the examples of the invention meet the requirements of the draft monograph of the enterprise, which is indicative of high quality products.

On set of physico-chemical parameters of the optimal example of this is the example 1 with the following�their components % mass.:

- active substance:

rabeprazole sodium - 10

- excipients tablet core:

calcium carbonate - 25

lactose - 43

corn starch - 20

hydroxypropyl methylcellulose - 1

magnesium stearate - 1

total - 100% of the mass.

- separation layer - 3 wt%. from tablet-core

- enteric-coated tablets - 11% of the mass. from tablet-core

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

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

The results are presented in table 3.

Table 3 shows that the developed pharmaceutical compositions have better stability compared to the medicinal drug "Pariet®".

So, if stored in specified conditions the stability of the developed pharmaceutical compositions higher than that of the original drug "Pariet®", as the quantitative content of rabeprazole sodium is reduced slightly, but kept�e impurities below than the original drug "Pariet®".

Experimental studies allow us to conclude that the technical result of the invention - increase the stability of the pharmaceutical composition containing rabeprazole sodium, made in the form of tablets, enteric coated tablets, when stored is achieved.

Developed pharmaceutical compositions allows to expand the Arsenal of drugs for the treatment of gastric ulcer.

Sources of information

1. Lazebnik L. B., D. S. Bordin, masharova A. A. Long-term therapy with proton pump inhibitors: balancing benefits and risks / L. B. Lazebnik, D. S. Bordin, A. A. masharova // Experimental and clinical gastroenterology. - 2010. - No. 9. - P. 3-8.

2. The draft instructions for use of the medicinal product for medical use "Rabeprazole tablets, enteric coated tablets" JSC "tatchempharmpreparaty".

3. The state register of medicines [Electronic resource]. - Access mode: http://www.grls.rosminzdrav.ru (21.06.14).

4. Samsonov, A. A., proton pump Inhibitors are the drugs of choice in the treatment of acid-related diseases // Farmateka. - 2007. - No. 6. - S. 10-15.

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

1. Pharmaceutical composition in the form of tablets, enteric coated tablets, comprising the active substance rabeprazole sodium, excipients tablet core, a separating layer and an enteric-coated shell, characterized in that it contains components in following ratio, wt.%:
- active substance:
rabeprazole sodium - 5-15
- excipients tablet core:
calcium carbonate - 15-35
lactose - 35-50
starch - 10-30
hydroxypropylmethyl cellulose is from 0.5 to 3
salt of stearic acid - 0,5-1
a total of 100% wt.
separating a layer from 1 to 5 wt%. from tablet-core
- enteric-coated - from 8 to 20 wt%. from the tablet core.

2. Pharmaceutical composition according to claim 1, characterized in that it contains components in following ratio, wt.%:
- active substance:
rabeprazole sodium - 10
- excipients tablet core:
calcium carbonate - 25
lactose - 43
corn starch - 20
hydroxypropyl methylcellulose - 1
magnesium stearate - 1
a total of 100% wt.
- separation layer - 3 wt%. from tablet-core
- enteric-coated - 11 wt%. from the tablet core.

3. A method of obtaining a pharmaceutical composition according to any one of claims.1-2, including the mixing of rabeprazole sodium with calcium carbon�Ohm, lactose and starch, the preparation of a 3% solution of hydroxypropylmethylcellulose, moisture 3% solution hydroxypropylmethylcellulose mixture of rabeprazole sodium, calcium carbonate, lactose and starch, wet granulation, drying, dry granulation, dusting salt of stearic acid, tableting, the preparation of the separation layer, the coating obtained tablets-cores separating layer, an enteric-coated preparation of the shell, coated tablets obtained enteric coating.



 

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5 cl, 3 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmaceutical industry, and describes a tabletted oral dosage form containing desloratadine in an amount of 3 to 15%, processing additives and a pharmaceutically acceptable excipient. The processing additives consist of sodium croscarmellose, magnesium stearate and povidone. The excipient represents a mixture of lactose disaccharide and microcrystalline cellulose polysaccharide in ratio from 2:1 to 8:1. Lactose and microcrystalline cellulose have an average particle size from 30 to 200 mcm. Producing the table involves granulating desloratadine, lactose and microcrystalline cellulose.

EFFECT: invention provides reducing granulate compression force, increasing process capability and maintaining the high quality of the tablets.

9 cl, 4 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to a pharmaceutical composition containing a compound presented by formula (I) , wherein R1 represents a hydrogen atom, C1-6 alkyl group or C3-8 cycloalkyl group; while R2 represents a hydrogen atom or a methoxyl group, or its pharmaceutically acceptable salt, or solvate; and alkaline earth carbonate, wherein the content of the compound presented by formula (I), or its salt or solvate makes 0.25 to 50 wt %, and the content of alkaline earth carbonate makes 1 to 60 wt % in relation to total weight of the composition, respectively.

EFFECT: composition exhibits excellent solubility; it is storage-stable or even long-term storage-stable, and applicable as a preventive or therapeutic agent for treating a tumour.

10 cl, 7 dwg, 10 tbl, 19 ex

FIELD: medicine.

SUBSTANCE: invention provides a solid hypolipidemic dosage form containing rosuvastatin or its pharmaceutically acceptable salt in an amount of 3 to 15%, processing additives and a pharmaceutically acceptable excipient containing microcrystalline cellulose, lactose monohydrate, polyvinylpyrrolidone and croscarmellose sodium. The above excipient represents granulate in an amount of 79 to 95 wt % of the dosage form containing absorbed moisture within the range of 0.5% to 1.5%. What is also described is a method for preparing the dosage form.

EFFECT: uniform distribution of the active substance and storage stability of the dosage form of rosuvastatin.

11 cl, 3 tbl

FIELD: medicine.

SUBSTANCE: pharmaceutical composition for treating joint and bone tissue diseases contains a combination of active substances consisting of the glucosamine sulphate salt, chondroitin sulphate sodium salt, ibuprofen as a non-steroidal anti-inflammatory agent, additives from excipients and processing additives, wherein the additives optionally contain vitamins and a calcium-containing excipient. The group of inventions also concerns a method for preparing the above pharmaceutical composition.

EFFECT: enhancing the therapeutic effect of the pharmaceutical composition in relation to the common knowledge without increasing the number and severity of its side effects.

8 cl, 1 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of encapsulating fenbendazole. Said method is characterised by that fenbendazole is dissolved in dioxane or dimethyl sulphoxide or dimethyl formamide, then dispersed in a mixture of sodium carboxymethyl cellulose and tetrachloromethane in the presence of E472c, followed by addition of methyl carbinol and water, filtering and drying the obtained suspension of microcapsules.

EFFECT: invention provides a simple and fast process of producing microcapsules and increases mass output.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of encapsulating fenbendazole. Said method is characterised by that fenbendazole is dissolved in dioxane or dimethyl sulphoxide or dimethyl formamide, then dispersed in a mixture of sodium carboxymethyl cellulose and toluene in the presence of E472c, followed by addition of methyl carbinol and distilled water, and filtering and drying the obtained suspension of microcapsules.

EFFECT: invention provides a simple and fast process of producing microcapsules and increases mass output.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to encapsulation. A method of producing lithium chloride microcapsules in a sodium alginate envelope comprises: adding a suspension of lithium chloride in benzene to a suspension of sodium alginate in butanol in the presence of an E472c preparation while stirring at 1200 rps; the lithium chloride and said polymer are taken in weight ratio of 1:1 or 1:3; adding chloroform; and filtering and drying the obtained suspension of microcapsules. The process of producing the microcapsules is carried out at room temperature for 10 minutes.

EFFECT: method provides a simple and fast process of producing microcapsules and increases mass output.

3 dwg, 3 ex

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