How to take dispersible tablets. Viagra dispersible tablets - instructions for use

30.05.2020

Active ingredients

Levodopa
- benserazide (benserazide)

Release form, composition and packaging

Madopar "125"

Capsules hard gelatinous, size No. 2, with an opaque pinkish-flesh-colored body and an opaque light blue lid, marked "ROCHE" in black; the contents of the capsules are a fine granular powder, sometimes crumpled, of a light beige color.

Excipients: microcrystalline cellulose - 13.5 mg, talc - 6.5 mg, - 1 mg, magnesium stearate - 0.5 mg.

Capsule cap composition: dye indigo carmine (E132) - 0.01 mg, titanium dioxide (E171) - 0.5 mg, gelatin - 21 mg.
The composition of the capsule body:iron dye red oxide (E172) - 0.03 mg, titanium dioxide (E171) - 1.12 mg, gelatin - 31.2 mg.

Madopar gss "125"

Modified release capsules hard gelatinous, size No. 1, with an opaque light blue body and an opaque dark green lid, with the inscription "ROCHE" in a rusty red color; the contents of the capsules are fine granular powder, sometimes crumpled, white or slightly yellowish.

Excipients: hypromellose - 115 mg, hydrogenated vegetable oil - 30 mg, calcium hydrogen phosphate - 27.5 mg - 18 mg, povidone - 6 mg, talc - 10 mg, magnesium stearate - 5 mg.

Capsule cap composition: dye indigo carmine (E132) - 0.09 mg, iron dye yellow oxide (E172) - 0.53 mg, titanium dioxide (E171) - 0.31 mg, gelatin - 25.3 mg.
The composition of the capsule body: dye (E132) - 0.02 mg, titanium dioxide (E171) - 0.92 mg, gelatin - 38.3 mg.

30 pcs. - dark glass bottles (1) - cardboard packs.
100 pieces. - dark glass bottles (1) - cardboard packs.

Madopar fast-acting tablets (dispersible) "125"

Dispersible tablets white or off-white, cylindrical, flat on both sides, with a beveled edge, odorless or faint, slightly marble, engraved with "ROCHE 125" on one side and a fracture line on the other; tablet diameter about 11 mm, thickness about 4.2 mm.

Excipients: anhydrous citric acid - 20 mg, pregelatinized corn starch - 41.5 mg, microcrystalline cellulose - 303 mg, magnesium stearate - 7 mg.

30 pcs. - dark glass bottles (1) - cardboard packs.
100 pieces. - dark glass bottles (1) - cardboard packs.

Madopar "250"

Pills pale red with small splashes, cylindrical, flat, with a beveled edge, with a cruciform line, engraved "ROCHE" and a hexagon on one side, with a cruciform line on the other side; tablet diameter 12.6-13.4 mm, thickness 3-4 mm.

Excipients: mannitol - 103.2 mg, calcium hydrogen phosphate - 100 mg, microcrystalline cellulose - 38.6 mg, pregelatinized corn starch - 20 mg, crospovidone - 20 mg, ethyl cellulose - 3 mg, iron dye red oxide - 1.5 mg, colloidal anhydrous silicon dioxide - 1 mg, sodium docusate 0.2 mg, magnesium stearate 5.5 mg.

30 pcs. - dark glass bottles (1) - cardboard packs.
100 pieces. - dark glass bottles (1) - cardboard packs.

pharmachologic effect

Combined antiparkinsonian drug containing a precursor and inhibitor of peripheral decarboxylases.

In parkinsonism, the brain neurotransmitter dopamine is produced in the basal ganglia in insufficient quantities. Levodopa, or L-DOPA - (3,4-dihydrophenylalanine), is a metabolic precursor of dopamine and, unlike the latter, penetrates well through the BBB. After levodopa enters the central nervous system, it is converted to dopamine by aromatic acid decarboxylase.

Parkinson's disease

After oral administration, levodopa is rapidly decarboxylated to dopamine in both cerebral and extracerebral tissues. As a result most of injected levodopa does not reach the basal ganglia, and peripheral dopamine often causes adverse reactions. Therefore, it is necessary to block the extracerebral decarboxylation of levodopa. This is achieved by the simultaneous administration of levodopa and benserazide, a peripheral decarboxylase inhibitor.

Madopar is a 4: 1 combination of these substances, which is optimal and has the same efficacy as high doses of levodopa.

Fast-acting (dispersible) tablets are especially indicated for patients with dysphagia, as well as for patients requiring a faster onset of drug action.

GSS capsules - a special slow-release dosage form active substances in the stomach. The maximum concentration is 20-30% less than when taking Madopar "125" capsules and Madopar "250" tablets, and is reached 3 hours after administration.

Syndrome " restless legs"

The exact mechanism of restless legs syndrome is unknown, but the dopaminergic system plays an important role in the pathogenesis of this syndrome.

Pharmacokinetics

Suction

Capsules Madopar "125" and tablets Madopar "250".Levodopa and benserazide are absorbed mainly in the upper small intestine. C max of levodopa in plasma is reached approximately 1 hour after administration. The absolute bioavailability of levodopa averages 98% (74-112%). Madopar capsules and tablets are bioequivalent.

C max and AUC of levodopa increase in proportion to the dose (in the dose range of levodopa from 50 to 200 mg).

Food intake decreases the rate and extent of absorption of levodopa. When Madopar is prescribed after a normal meal, C max of levodopa in plasma is 30% less and is achieved later. The degree of absorption of levodopa is reduced by 15%.

Madopar fast-acting tablets (dispersible) "125". The pharmacokinetic profiles of levodopa after taking Madopar in this dosage form are similar to those after taking Madopar tablets and capsules, however, the time to reach C max tends to be shortened. The absorption parameters of fast-acting (dispersible) tablets are less variable in different patients than with conventional dosage forms.

Madopar GSS "125", kmodified release capsules.Madopar GSS "125" has different pharmacokinetic properties than conventional and dispersible forms of release. The active substances are released slowly in the stomach. C max in plasma is 20-30% less than that of conventional dosage forms, and is achieved approximately 3 hours after administration. The dynamics of plasma concentration is characterized by a longer T 1/2 than that of conventional dosage forms, which is convincing evidence of the continuous modified release of active substances. Bioavailability of Madopar GSS "125" is 50-70% of the bioavailability of capsules Madopar "125" Madopar "250" tablets and does not depend on food intake. Food intake does not affect the C max of levodopa, which is reached 5 hours after taking Madopar GSS "125".

Distribution

Levodopa crosses the BBB through a saturable transport system. Does not bind to plasma proteins, Vd is 57 liters. Levodopa's AUC cerebrospinal fluid is 12% of that in plasma.

Benserazide in therapeutic dosesah does not penetrate the BBB. It accumulates mainly in the kidneys, lungs, small intestine and liver.

Metabolism

Levodopa is metabolized by two main pathways (decarboxylation and o-methylation) and two side pathways (transamination and oxidation).

Decarboxylase aromatic amino acids converts levodopa to dopamine. The main end products of this metabolic pathway are homovanillic and dihydroxyphenylacetic acids.

COMT methylates levodopa to form 3-o-methyldopa. T 1/2 of this main metabolite from plasma is 15-17 hours, and in patients receiving therapeutic doses of Madopar, its accumulation occurs.

A decrease in the peripheral decarboxylation of levodopa when co-administered with benserazide leads to higher plasma concentrations of levodopa and 3-o-methyldopa and lower plasma concentrations of catecholamines (dopamine, noradrenaline) and phenol carboxylic acids (homovanilic acid, dihydrophenylacetic acid).

In the intestinal and liver mucosa, benserazide is hydroxylated to form trihydroxybenzylhydrazine, which is a potent inhibitor of aromatic amino acid decarboxylase.

Withdrawal

Against the background of inhibition of peripheral decarboxylase T 1/2 of levodopa is about 1.5 hours. Plasma clearance of levodopa is about 430 ml / min.

Benserazide is almost completely excreted by metabolism. Metabolites are excreted mainly in the urine - 64% and, to a lesser extent, in the feces - 24%.

Pharmacokinetics in special clinical situations

Data on the pharmacokinetics of levodopa in patients with renal and liver failure absent.

In elderly patients (65-78 years) with Parkinson's disease, T 1/2 and AUC slightly increase (by about 25%), which is not clinically significant change and no change in dosing regimen is required.

Indications

Parkinson's disease, including:

in patients with dysphagia, with akinesia in the early morning hours and in the afternoon, patients with "depletion of effect" phenomena single dose"or" increasing the latency period before the onset of the clinical effect of the drug "(Madopar" 125 "fast-acting tablets (dispersible));
in patients with any type of fluctuations in the action of levodopa, namely, "peak dose dyskinesia" and "end dose phenomenon", for example, immobility at night (Madopar GSS "125").

Restless legs syndrome:

idiopathic restless legs syndrome;
restless legs syndrome in patients with chronic renal failure on dialysis.

Contraindications

decompensated dysfunction of the endocrine system organs;
decompensated liver dysfunction;
decompensated renal dysfunction (except for patients with restless legs syndrome receiving dialysis);
diseases of cardio-vascular system in the stage of decompensation;
mental illness with a psychotic component;
angle-closure glaucoma;
simultaneous reception with non-selective MAO inhibitors, a combination of MAO type A and MAO type B inhibitors;
age under 25;
women of childbearing age who do not use reliable methods of contraception;
pregnancy;
lactation period (breastfeeding);
hypersensitivity to drug components.

Dosage

Treatment should be started gradually, individually adjusting the dose until the optimal therapeutic effect is achieved.

Capsules Madopar "125" should be swallowed whole without chewing.

Capsules Madopar GSS "125" should be swallowed whole without chewing; they must not be opened before use in order to avoid losing the modified release effect of the active substance.

Madopar "250" tablets can be crushed to facilitate swallowing.

Madopar "125" fast acting tablets (dispersible) should be dissolved in 25-50 ml of water. The tablet dissolves completely in a few minutes with the formation of a milky-white solution, which should be taken no later than 30 minutes after the tablet has dissolved. Since a precipitate can form quickly, it is recommended to stir the solution before use.

Parkinson's disease

Standard dosage regimen

Inside, not less than 30 minutes before or 1 hour after meals.

Initial therapy

On early stage for Parkinson's disease, it is recommended to start treatment with Madopar at a dose of 62.5 mg (50 mg of levodopa + 12.5 mg of benserazide 3-4 times / day). With good tolerance, the dose should be gradually increased, depending on the patient's response.

The optimal effect is usually achieved with a daily dose containing 300-800 mg of levodopa + 75-200 mg of benserazide, taken in 3 or more doses. It may take 4 to 6 weeks to achieve optimal effect. A further increase in the daily dose, if necessary, should be carried out at intervals of 1 month.

Supportive therapy

The average maintenance dose is 125 mg (100 mg levodopa + 25 mg benserazide) Madopar 3-6 times / day. The frequency of administration (at least 3 times) during the day should be distributed so as to ensure the optimal effect. To optimize the effect, it may be necessary to replace Madopar "125" in the form of conventional capsules and Madopar "250" in the form of conventional tablets with Madopar "125" fast-acting tablets (dispersible) or Madopar GSS "125".

Restless legs syndrome

The drug should be taken 1 hour before bedtime, with a small amount of food. The maximum daily dose is 500 mg Madopar (400 mg levodopa + 100 mg benserazide).

Idiopathic Restless Legs Syndrome with Sleep Disorders

The starting dose is 62.5-125 mg. In case of insufficient effect, the dose of Madopar should be increased to 250 mg (200 mg of levodopa + 50 mg of benserazide).

Idiopathic Restless Legs Syndrome with Sleep and Sleep Disorders

The initial dose is 1 capsule Madopar GSS "125" and 1 capsule Madopar "125" 1 hour before bedtime. In case of insufficient effect, the dose of Madopar GSS "125" should be increased to 250 mg (2 capsules).

Idiopathic restless legs syndrome with sleep and sleep disturbances, as well as with disturbances during the day

Additionally: 1 dispersible tablet or 1 capsule Madopar "125", the maximum daily dose of Madopar is 500 mg (400 mg of levodopa and 100 mg of benserazide).

Restless legs syndrome in patients with chronic renal failure on dialysis

The drug is prescribed in a dose of 125 mg (1 dispersible tablet or 1 capsule of Madopar "125") 30 minutes before the start of dialysis.

Dosing regimen in special cases

Parkinson's disease

Madopar can be combined with other antiparkinsonian drugs. However, as treatment continues, it may be necessary to reduce the dose of other drugs or to gradually withdraw them.

Madopar "125" fast-acting tablets (dispersible) - a special dosage form for patients with dysphagia or akinesia in the early morning hours and in the afternoon or for patients with the phenomenon of "depletion of the effect of a single dose" or "increase in the latency period before the onset of the clinical effect of the drug" ...

If during the day the patient has strong motor fluctuations (the phenomenon of "depletion of the effect of a single dose", the phenomenon of "on-off"), it is recommended either more frequent intake of correspondingly smaller single doses, or - which is preferable - the use of Madopar GSS "125".

The transition to Madopar GSS "125" is best done from one day to another, starting with the morning dose. You should leave the same daily dose and regimen as when taking Madopar "125" and Madopar "250".

After 2-3 days, the dose is gradually increased by about 50%. Patients should be warned that their condition may temporarily worsen. Due to the peculiarities dosage form Madopar GSS "125" begins to operate somewhat later.

The clinical effect can be achieved faster by prescribing Madopar GSS "125" together with capsules Madopar "125" or Madopar "125" fast-acting tablets (dispersible). This may be optimal as the first morning dose, which should be slightly higher than the next dose.

The dose of Madopar GSS "125" should be selected slowly and carefully, and the interval between dose changes should be at least 2-3 days.

In patients with nighttime symptoms positive effect was achieved by gradually increasing the evening dose of Madopar GSS "125" to 250 mg (2 capsules) before bedtime.

With a pronounced effect of Madopar GSS "125" (dyskinesia), an increase in the intervals between doses is more effective than a decrease in a single dose.

If Madopar GSS "125" is not effective enough, then it is recommended to return to the previously used treatment with Madopar "125", Madopar "250" or Madopar "125" fast-acting tablets (dispersible).

With prolonged therapy, episodes of "freezing", "exhaustion" and "on-off" phenomena may appear. In episodes of "freezing", "depletion phenomenon", the drug dose is split (decreasing the single dose or shortening the interval between doses of the drug), and when the "on-off" phenomenon appears, the single dose is increased with a decrease in the number of doses. Subsequently, you can try to increase the dose again to increase the effectiveness of the treatment.

Have patients with mild renal impairment or medium gravity dose adjustment is not required. Madopar is well tolerated patients receiving hemodialysis sessions.

Restless legs syndrome

To exclude an increase in the symptoms of restless legs syndrome (early appearance during the day, increased severity and involvement of other parts of the body), the daily dose should not exceed the recommended maximum dose of Madopar - 500 mg (400 mg of levodopa + 100 mg of benserazide).

With an increase in clinical symptoms, the dose of levodopa should be reduced or levodopa should be gradually withdrawn and another therapy should be prescribed.

Side effects

From the central nervous system and peripheral nervous system: agitation, anxiety, insomnia, hallucinations, delirium, temporary disorientation (especially in elderly patients and in patients with a history of these symptoms), depression, headache, dizziness, in the later stages of treatment, sometimes - spontaneous movements (such as chorea or athetosis), episodes of "freezing", weakening of the effect by the end of the dose ("exhaustion" phenomenon), "on-off" phenomenon, severe drowsiness, episodes of sudden drowsiness, increased manifestations of the syndrome of "restless legs".

From the digestive system:nausea, vomiting, diarrhea; in some cases - loss or change in taste, dryness of the oral mucosa.

On the part of the cardiovascular system:arrhythmias, orthostatic hypotension (weakens after reducing the dose of Madopar), arterial hypertension.

From the respiratory system: rhinitis, bronchitis.

From the hematopoietic system:rarely - hemolytic anemia, transient leukopenia, thrombocytopenia.

Dermatological reactions:rarely - itching, rash.

On the part of laboratory parameters:sometimes - a transient increase in the activity of hepatic transaminases, alkaline phosphatase, an increase in gamma-glutamyl transpeptidase, an increase in blood urea nitrogen, a change in the color of urine to red, darkening on standing.

From the side of the body as a whole:anorexia.

Others:febrile infection.

Overdose

Symptoms: intensification of manifestations side effects - arrhythmia, confusion, insomnia, nausea and vomiting, pathological involuntary movements. When taking a dosage form with a modified release of active substances (Madopar GSS "125") in the stomach, the onset of symptoms may be delayed.

Treatment: symptomatic therapy - respiratory analeptics, antiarrhythmics, antipsychotics; it is necessary to monitor vital functions. When using a dosage form with a modified release of active substances (Madopar GSS "125"), further absorption of the drug should be prevented.

Drug interactions

Pharmacokinetic interaction

With the simultaneous use of trihexyphenidil (an anticholinergic drug), it reduces the rate, but not the degree of absorption of levodopa. The appointment of trihexyphenidil together with Madopar GSS "125" does not affect the pharmacokinetics of levodopa.

With the simultaneous use of antacids together with Madopar GSS, the degree of absorption of levodopa is reduced by 32%.

Ferrous sulfate reduces C max in blood plasma and the AUC value of levodopa by 30-50%; these changes in some cases are clinically significant.

Metoclopramide increases the rate of absorption of levodopa.

Levodopa does not enter into pharmacokinetic interactions with bromocriptine, amantadine, selegiline and domperidone.

Pharmacodynamic interaction

Antipsychotics, opiates and those containing reserpine suppress the action of Madopar.

If necessary, the appointment of Madopar to patients receiving irreversible non selective inhibitors MAO, from the moment you stop taking the MAO inhibitor until you start taking Madopar, at least 2 weeks should pass.

Selective type B MAO inhibitors (including selegiline, rasagiline) and type A selective MAO inhibitors (moclobemide) can be prescribed during treatment with Madopar. At the same time, it is recommended to adjust the dose of levodopa depending on the individual needs of the patient in terms of efficacy and tolerability. The combination of MAO type A and MAO type B inhibitors is equivalent to taking a non-selective MAO inhibitor, so this combination should not be administered concurrently with Madopar.

Madopar should not be administered concurrently with sympathomimetics (epinephrine, norepinephrine, isoproterenol, amphetamine), since levodopa may potentiate their action. If the simultaneous administration is still required, you should carefully monitor the state of the cardiovascular system and, if necessary, reduce the dose of sympathomimetics.

The combined use of the drug with other antiparkinsonian drugs (anticholinergic, amantadine, dopamine agonists) is possible, while not only desirable, but also undesirable effects may increase. It may be necessary to reduce the dose of Madopar or another drug.

With the simultaneous use of Madopar with a COMT inhibitor, it may be necessary to reduce the dose of Madopar. If treatment with Madopar is started, anticholinergic drugs should not be canceled abruptly, since levodopa does not begin to act immediately.

Since a patient receiving Madopar may experience fluctuations in blood pressure and arrhythmias during halothane anesthesia, Madopar should be discontinued 12-48 hours before surgical intervention.

Levodopa can interfere with the results of laboratory determination of catecholamines, creatinine, uric acid and glucose, and a false positive result of the Coombs test is possible.

In patients receiving Madopar, taking the drug at the same time as a protein-rich food may interfere with the absorption of levodopa from the gastrointestinal tract.

special instructions

For persons with increased sensitivity the development of appropriate reactions to the drug is possible.

Adverse reactions from the digestive system, possible on initial stage treatments are largely eliminated if Madopar is taken with a small amount of food or liquid, as well as with a slow increase in the dose.

Patients with open-angle glaucoma should have their intraocular pressure measured regularly because, in theory, levodopa can increase intraocular pressure.

Patients with diabetes mellitus should frequently monitor blood glucose levels and adjust the dose of hypoglycemic drugs.

If possible, Madopar should be continued as long as possible before general anesthesia, with the exception of halothane anesthesia. Since a patient receiving Madopar, during halothane anesthesia, fluctuations in blood pressure and arrhythmias may occur, Madopar should be canceled 12-48 hours before surgery. After surgery, the treatment is resumed, gradually increasing the dose to the previous level.

Madopar cannot be canceled abruptly. Abrupt withdrawal of the drug can lead to the development of neuroleptic malignant syndrome (fever, muscle stiffness, as well as possible mental changes and an increase in serum CPK), which can take a life-threatening form. If such symptoms occur, the patient should be under the supervision of a physician (if necessary, hospitalization) and receive appropriate symptomatic therapy, which may include re-prescribing Madopar after an appropriate assessment of the patient's condition.

Depression can be clinical manifestation the underlying disease (parkinsonism, restless legs syndrome) and may also occur during therapy with Madopar. Patients taking Madopar should be carefully monitored for the possible occurrence of psychiatric adverse reactions.

In some patients with Parkinson's disease, the appearance of behavioral and cognitive disorders was noted as a result of the uncontrolled use of increasing doses of the drug, despite the doctor's recommendations and a significant excess of the therapeutic doses of the drug.

Influence on the ability to drive vehicles and use mechanisms

In the event of drowsiness, sudden episodes of drowsiness, the patient should refuse to drive a car or work with machines and mechanisms. If these symptoms appear, consider reducing the dose or discontinuing therapy.

Pregnancy and lactation

Madopar is contraindicated in pregnancy and women of childbearing agewho do not use reliable methods of contraception, due to a possible violation of the development of the skeleton in the fetus.

If pregnancy occurs during treatment with Madopar, the drug should be discontinued immediately in accordance with the recommendations of the attending physician.

It is not known whether benserazide is excreted in breast milk. If it is necessary to use Madopar during lactation, breastfeeding should be discontinued, since violations of the development of the skeleton in a child cannot be ruled out.

Pediatric use

Contraindication: under 25 years of age.

Madopar "125" fast-acting tablets (dispersible) should be stored at a temperature not exceeding 25 ° C. The shelf life is 3 years.

Tablets Madopar "250" should be stored in a dry place at a temperature not exceeding 25 ° C. Shelf life is 4 years.

The drug should be kept out of the reach of children.

The field of activity (technology) to which the described invention belongs

The present invention relates to a water dispersible tablet composition that includes a therapeutically active compound.

DETAILED DESCRIPTION OF THE INVENTION

Therapeutically active compounds or drugs are often administered to patients in the form of a tablet, in the case when the drug is intended for oral administration into the body, since tablets are a particularly convenient pharmaceutical form for production, storage and use. However, in the case of the introduction of such tablets into the body of patients who may have difficulty swallowing the tablets (for example, in children or in more seriously ill patients), problems may arise, especially when taking large tablets due to large amounts of drugs which should be contained in each of the tablets. A solution to such problems would be to provide such a composition in tablet form that is dispersible in water to form a dispersion containing the drug, which can then be drunk by the patient.

Known water-dispersible tablets include foaming compositions that generate a gas that causes the tablet to disintegrate rapidly, but are expensive to manufacture and require compliance. strict rules of such production, in other known water-dispersible tablets, disintegrating agents are used, in particular microcrystalline cellulose, which is part of the dispersible tablets of the "Felden R" preparation. The authors of the present invention have tested well-known disintegrating agents (introduced both internally and externally into preformed granules), in particular sodium glycolate starch (for example, the "Explotab" preparation), structured povidone (for example, the "Kollidon CL" preparation) and structured sodium carboxymethylcellulose (eg, Starch, Avisel PH 102 and Ac-Di-Sol) in an acyclovir tablet, but they have been found to consist of a composition that does not have satisfactory water dispersibility. In addition, the authors of the present invention tested an ion exchange resin (Amberlite I RP88) as a disintegrating agent and in order to increase the wettability of the tablet with water, enhance the penetration of water into it during the dispersion process, the authors introduced surfactants [for example, sodium lauryl sulfate and sodium decusate ], but in all of them the duration of disintegration was significant.

After extensive research and research, the inventors have now found that the use of an intragranular swellable composition for making a tablet results in a tablet that has good water dispersibility, forming a dispersion that the patient can drink.

Swellable clays such as Wigham and other magnesium aluminum silicates have already been investigated and have been proposed for use as disintegrants, fillers and lubricants in the manufacture of tablets intended for swelling, and on water dispersible tablets [Rubenstein, Pharmaceutics - The Science of Dosage Form Design (1990), see disintegrators on p. 312 and 314]. Moreover, there is no suggestion that the clay would be acceptable to meet the more stringent requirements for dispersible tablets. As for the tablets for swelling, it is only necessary that the duration of their disintegration in water is less than 15 minutes and that they, when disintegrated in water, form particles that pass through a sieve with a mesh size of 2.00 mm [British Pharmacopoeia Test Standard for Swelling Tablets] ... Such long disintegration times and large particle sizes are completely unacceptable for dispersible tablets.

Even when swellable clays have been proposed as disintegrating agents for swelling tablets, they are not considered very suitable for such a field of application, because, due to their not quite white they often modify the color of the tablet and their effectiveness is inferior to the effectiveness of other disintegrating agents [Banker and Anderson - Theory and Practice of Industrial Pharmacy p. 328 (1986) and Bhargwa et al. Drug Development and Industrial Pharmacy 17 (15), 2003-2102 (1991)]. Indeed, of the ten disintegrants listed by Marshall and Rudnick in Nioderb Pharmaceutics (1990), p. 374, bentonite is the least swellable. In the above textbook references, there is no mention of how the swellable clay should be introduced, that is, introduced into the pellet or outside the pellet. In the first case, the clay should be added to the mixture from which the granulate is formed, and in the latter case, the clay should be added to the preformed granulate.

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The journal presented an overview of the following work related to swelling clays, in particular to Whigham and bentonite products as disintegrants: Way et al. J. Pharm. Sci. 55,1215 (1966); Granberg et al., J Am. Pharm. Assoc. Sci 38, 648 (1949); Gross et al. J. Am Phapm. Assoc. Sci 41,157 (1952); Firuzabadyan et al., J. Am Pharm. Assoc. Sci 43, 248 (1954); Ward et al., Drug Cosmetic Ind, 91, 35 (1962); Nair et al. J. Am. Pharm. Assoc. Sci, 46, 131 (1957) and Patel et al., Indian J. Pharm., Jan. 19. 1957 Way et al. Then compared the three varieties of Whigum products, evaluating both extragranular and intragranular addition, and concluded that "the clays were not good disintegrants in the case of wet granulation" (i.e., intragranular addition) therefore they recommended extra-granular addition. Moreover, on p. 19 in the work of employees of the company "RT Vanderbilt & Co" (manufacturer of Wigam products) entitled "Wigum - a universal component for pharmaceutical compositions", a description of the tablet composition to which the Wigum product is added after granulation (tablet NO.2) ... There is no reference in this publication to a tablet formulation to which the Wigam product is added during the granulation process.

In contrast to the above recommendations, the present inventors have found that to meet the requirements of the British Pharmacopoeia (BF) standard for dispersible tablets (currently the prescribed dispersion time is 3 minutes or less), the swellable clay, in particular the product "Whigam", should be added during the granulation process ... In the same case, when the swellable clay is added only after granulation, the dispersion time is too long to meet the requirements of the above standard.

The use of the Wigum product and other swellable clays as described above has enabled the present inventors to prepare water-dispersible tablets that contain various therapeutically active compounds. The resulting tablets can be easily dispersed in water to form a dispersion that can be easily drunk by the patient.

In accordance with the present invention, there is provided a water dispersible tablet comprising a therapeutically active compound selected from the class comprising an analgesic propionic acid derivative, a tranquilizing benzodiazepine, an activated nucleoside derivative (e.g. acyclovir), an antiprotozoan petroquinone agent, allopurinol, oxopurinol, an anticonvulsant 1,2,4-triazine derivative (e.g. lamotrigine) and trimethoprim (possibly in combination with sulfamethoxazole), together with an effective amount of a pharmaceutically acceptable swelling clay, to produce a tablet that is dispersible in water over a 3 minute period to form a dispersion capable of passing through a 710 µm sieve, which complies with the regulations for the test of dispersible tablets, as defined by British Pharmacopocia, 1988, Tau 11, p. 895.

The aforementioned therapeutically active compound used in a tablet according to the present invention is hereinafter referred to as the "active compound".

The present invention further provides a method of making a water-dispersible tablet which comprises a therapeutically active compound selected from the class comprising an analgesic propionic acid derivative, a tranquilizing benzodiazepine, an antiviral nucleoside derivative, an anti-protozoan naphthoquinone agent, allopurinol, oxopurinol, an anticonvulsant 1,2,4-triazine derivative and trimethoprim (optionally in combination with sulfamethoxazole), together with an effective amount of a pharmaceutically acceptable swellable clay, in which the above active compound is combined with the above clay to form a water-dispersible tablet that is dispersible in water for a 3 minute period of time to form a dispersion which is capable of passing through a 710 μm sieve, which corresponds to the test method for dispersible tablets as determined by the requirement according to the British Pharmacopoeia, 1988, vol. 11, p. 895.

In a preferred embodiment, the specified method includes the steps:

A) mixing in a dry fine state the active compound with an effective amount of a pharmaceutically acceptable swellable clay, optionally with the addition of one or more other pharmaceutical excipients or drug bases;

B) adding a pharmaceutically acceptable liquid in an amount sufficient to wet the dry mix;

C) granulating the resulting wet mixture to form granules;

D) drying the granules and optionally mixing these granules with other optional fillers or bases for the preparation of drugs, in particular with lubricants, glidants, flavorings or flavors and disintegrants;

E) compressing the granules to form a tablet that is dispersible in water for a 3 minute period of time to form a dispersion that is capable of passing through a 710 μm sieve that complies with the British Pharmacopoeia test for dispersible tablets.

In addition to the rate of dispersion in water, the tablet of the present invention has the added advantage of satisfying the British Pharmacopoeia (BF) test for dispersible tablets in terms of dispersion time and dispersion quality (i.e. the latter passes through sieve with a mesh size of 710 microns).

In a preferred embodiment, the dispersion time for a tablet according to the present invention should be less than 2 minutes, more preferably less than about 1.50 minutes, and most preferably less than about 1 minute.

An additional advantage of the tablets according to the present invention is that, due to the formation of a relatively fine dispersion, the dissolution time of the tablet is shortened, whereby absorption of the drug into the blood stream can occur at a significantly higher rate. In addition, the short dispersion times and the relatively fine dispersions that form the tablets of the present invention are also advantageous for swallowable tablets. In accordance with the present invention, tablets can thus be designed both for dispersion in water and for direct swallowing. Tablets which are intended to swell in accordance with the present invention should preferably be provided with a film coating that facilitates swallowing. However, the dispersion time of such film-coated tablets is increased to 5 minutes, as determined by the above BF test.

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The present invention further provides a void dispersible and film-coated tablet comprising a therapeutically active compound selected from the class comprising an analgesic propionic acid derivative, a tranquilizing benzodiazepine, an antiviral nucleoside, an antiprotozoal naphthoquinone allopurinol, oxopurinol, an anticonvulsive agent The 4-triazine derivative and trimethoprim (optionally in combination with sulfomethoxazole), together with an effective amount of a pharmaceutically acceptable swellable clay, results in a film-coated tablet that is dispersible in water to form a dispersion capable of passing through a 710 μm sieve that complies with the British Pharmacopoeia test for dispersible tablets, where the variation of the specified time period during the test is from 3 to 5 minutes. Throughout this selection, reference is made to tablets, which refer to tablets, both film-coated and non-film coated.

After passing the dispersion through a sieve with a mesh size of 710 μm, practically no residue should remain, with the exception of fragments of the undissolved coating or tablet shell, which remain on the sieve or adhere to the lower surface of the disk, if such a disk was used, and in the case when there remains any residue, it should be a soft mass without any tangible hard, unwetted core.

The distribution of particles by size in the dispersion, especially in the case when the active compound is acyclovir, is shown in table. 1, with the increase in the preference of the values \u200b\u200bbeing presented from left to right.

Such tablets can be film-coated, for example, hydroxypropyl methylcellulose, polyethylene glycol or titanium dioxide, and / or a score, and / or can be polished, for example, using polyethylene glycol 8000. In the event that the tablets are film-coated, this allows them to be simplified swallowing or chewing (i.e. tablets are acceptable for either dispersion in water or direct swallowing or chewing), but the duration of dispersion is increased.

The present invention also provides:

A) granules containing the active agent and a pharmaceutically acceptable swelling clay, suitable for use in the manufacture of a water dispersible tablet according to the present invention;

B) the use of granules as defined above in the manufacture of a water dispersible tablet according to the present invention; after granulation and before pressing, it is possible to add an additional amount of swelling clay;

C) the use of a pharmaceutically acceptable swellable clay as a dispersing agent in the manufacture of a water-dispersible tablet containing an active agent (as defined above);

D) the use in human medical therapy of a water dispersible tablet which includes an active agent (as defined above) together with an effective amount of a pharmaceutically acceptable swelling clay within the granules of the tablet.

A suitable swellable clay of the present invention is a pharmaceutically acceptable crystalline mineral compound, in particular an aluminum magnesium silicate (eg, a Wigam product).

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The therapeutic use of the tablet of the present invention includes both treatment and prophylaxis.

It has been found that the present invention can be used in a specific field of application in combination with lamotrigine due to the instability of lamotrigine over a long period of time in water. Moreover, it has been found that dispersible tablets containing lamotrigine form a finer dispersion than those tablets in which more conventional disintegrating agents are used, in particular the product "Explotab".

Additional aspects of the present invention illustrated in relation to lamotrigine are listed below:

E) granules suitable for use in the manufacture of a water dispersible compressed tablet comprising lamotrigine or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable crystalline mineral clay as a dispersing agent;

F) the use of granules as defined above in the manufacture of a water dispersible compressed tablet, where it is possible to add an additional amount of the crystalline mineral clay component after granulation and before compression;

G) the use of a pharmaceutically acceptable crystalline mineral clay as a dispersing agent in the preparation of a water dispersible compressed tablet containing lamotrigine or a pharmaceutically acceptable salt thereof;

H) a water dispersible tablet comprising lamotrigine or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable crystalline mineral clay with a lattice structure that expands upon hydration as a dispersing agent; lamotrigine or a pharmaceutically acceptable salt thereof together with mineral clay are inside the tablet in granular form;

I) A method of making a lamotrigine water-dispersible tablet, the implementation of which includes the following steps:

Dry blending finely divided lamotrigine or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable crystalline mineral clay, which may be selected from the class comprising attapulgite, smectite and montmorillonoid clays or magnesium aluminosilicate;

The possible addition of other pharmaceutical ingredients, in particular fillers (eg lactose, avisel or mannitol), disintegrants, binders and the like;

The addition of an amount of a pharmaceutically acceptable liquid sufficient to moisten the mixture;

Granulating the resulting wet mass;

Drying the granules and mixing the granules with optional lubricants, glidants, flavoring agents, disintegrating agents and the like, forming the mixture into tablets;

J) the use in human medicine of a water-dispersible compressed tablet comprising lamotrigine or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable crystalline mineral clay as a dispersing agent;

K) a method for treating a person with disorders of the central nervous system, the implementation of which provides for the introduction into the body of a water-dispersible compressed tablet comprising lamotrigine or its pharmaceutically acceptable sorrel together with a pharmaceutically acceptable crystalline mineral clay as a dispersing agent.

Particularly preferred tablets are those which contain lamotrigine as a base.

The above tablets can be used in human medicine in the treatment of disorders of the central nervous system, in particular in the treatment of epileptic seizures. They can be taken one or more times a day, for example up to five times a day, at the discretion of the attending physician and depending on the age and condition of the patient, in particular depending on the disease to be treated, the selected unit dosage and the total dose required. Acceptable daily dose for treatment epileptic seizures usually is in the range of 5 - 500 mg, more often in the range of 25 - 400 mg, in terms of the active basis.

Desirably, the physical dimensions of said tablets are such that they are dispersed before swallowing in an acceptably small volume of water. So, for example, a tablet containing 5 mg / in terms of the active basis) lamotrigine or its salt, a dose that is especially acceptable for pediatric use should be small enough to be dispersed in the volume of water that is held by a standard 5 ml medical spoon.

It is very good when the tablets of the present invention containing lamotrigine (or a salt thereof) include magnesium aluminosilicate, in particular the product "Vigam F", as a swelling clay, together with additional possible pharmaceutical excipients or drug components listed above, for example, with binding compositions , lubricating additives, fillers, disintegrating agents, and the like.

Successful results are obtained when these components are contained in such tablets in the following proportions: lamotrigine 2 - 90% by weight, more preferably 5-40% by weight; swelling clay 0.25-40 wt%, more preferably 0.25-10 wt%.

The following is a possible acceptable formulation of a dispersible tablet containing 25-200 mg lamotrigine.

Lamotrigine 30-50 wt%, more preferably 35-45 wt%.

Calcium carbonate 26 to 46 wt%, more preferably 31 to 41 wt%.

LHPC-LHII or microcrystalline cellulose (for example, Avisel PH 101) 5-30 wt.%, More preferably 5-15 wt.%.

Magnesium aluminosilicate (product "Wigum F or bentonite) 0.25-30 wt.%, More preferably 0.25-10 wt.%.

Povidone - 0.25 to 5.0 wt%, more preferably 0.5 to 2 wt%, or
Starch swelling in cold water1.0-8.0 wt.%, More preferably 2-5 wt.%.

Sodium starch glycolate 0-8 wt%, more preferably 0-5 wt%.

Magnesium stearate 0.25-2 wt%. more preferably 0.25 - 1 wt.% and, if possible, provided with a film coating of: product "Opadri" 0.1 - 2 wt. %, more preferably 0.25 - 1 wt.% polyethylene glycol 8000 - 0.1 to 0.5 wt. %, more preferably 0.1 to 0.2 wt%.

Below is a possible acceptable composition of a dispersible tablet containing 5-50 mg of lamotrigine (the concentration of the components is expressed in wt.%): Lamotrigine 3-13, preferably 5-11; lactose or calcium carbonate 50-60, preferably 53-69; microcrystalline cellulose (for example, product "Avisel PH101") or LHPC-LHII 20 - 35, more preferably 24 - 30; sodium starch glycolate 0-8, preferably 0-5; magnesium aluminosilicate (product "Wigum F" or bentonite) - 0.25 - 30, preferably 0.25 - 10; Povidone K30 0.25 - 5.0, preferably 0.5 - 2.0, or cold water-swellable starch 1.0 - 8.0, preferably 2 - 5; sodium docusate 0 - 0.5, more preferably 0.5 - 0.15; sodium saccharin 0-3, more preferably 0.5-2; magnesium stearate 0.25 - 2, preferably 0.25 - 1 and, if possible, provided with a film coating of: Opadri 0.1 - 2.0 preferably 0.25 - 1 polyethylene glycol 8000 0.1 - 0.5 , preferably 0.1 - 0.2.

As indicated above, the present invention is particularly applicable to a water dispersible tablet formulation which contains acyclovir as an active ingredient.

Acyclovir is a compound that has been shown to be potent against viruses of the herpes family, especially herpes simplex and Lerpes varicella zoster. This has been demonstrated by the outstanding therapeutic success of acyclovir. clinical condition, in particular in the treatment of genital herpes caused by the Lerpes varicella zoster virus.

In the treatment of certain diseases, in order to achieve an effective therapeutic plasma level of the drug, especially when oral administration to the body is desired, it may be necessary to administer acyclovir to the patient in relatively large doses. So, for example, in the treatment of shingles, acyclovir is recommended to be administered into the body in 800 milligram dosages five times a day. Currently, 800 mg acyclovir tablets are available, but relatively big size the pill is sometimes difficult to swallow in older patients, and such patients are particularly sensitive to herpes zoster. This problem is solved by the water dispersible tablets according to the present invention, which make it possible to administer relatively large doses of acyclovir as a dispersion for drinking by the oral route.

The water dispersibility advantages of the tablets according to the present invention containing acyclovir as the active agent are particularly surprising in view of the low water dispersibility exhibited by tablets which contain conventional disintegrating agents, in particular sodium starch glycolate, structured povidone and structured sodium carboxymethylcellulose.

However, with respect to acyclovir, the present invention is characterized by the following additional aspects:

I) a granulate comprising acyclovir together with a pharmaceutically acceptable magnesium aluminosilicate compound;

M) the use of a granulate according to e) above in the preparation of a water-dispersible tablet composition;

N) the use of magnesium aluminum silicate in the preparation of a water-dispersible tablet composition with acyclovir;

O) a water dispersible pharmaceutical tablet composition comprising acyclovir together with a pharmaceutically acceptable magnesium aluminosilicate compound;

P) a method for preparing a pharmaceutical tablet composition, the implementation of which provides for mixing acyclovir with a magnesium aluminosilicate compound and possibly one or more additional pharmaceutical excipients or drug components: granulating the resulting mixture together with a pharmaceutically acceptable liquid; drying the prepared granulate; optionally mixing the dried granulate with one or more additional pharmaceutical excipients or drug components and then compressing the dried granulate to form tablets; the liquid used in the above granulation step is preferably an aqueous liquid, for example an aqueous ethanol mixture; the finished tablets can then be film coated, for example, of hydroxypropyl methylcellulose, titanium dioxide or polyethylene glycol and, if desired, polished, for example, polyethylene glycol 8000.

It is useful when tablets according to the present invention containing acyclovir include magnesium aluminosilicate, in particular the product "Vigam F", as a swellable clay, possibly together with additional pharmaceutical excipients or drug components mentioned above, in particular with disintegrating agents, binders, fillers, lubricants and the like.

It is advantageous when the components are contained in such tablets in the following proportions: acyclovir 40-98 wt%, more preferably 75-85 wt%, swellable clay 0.5-40 wt%, more preferably 0.5-10 wt%.

The following is a possible acceptable formulation for an acyclovir dispersible tablet containing 200 - 800 mg acyclovir:

acyclovir - 70 to 90 wt%, more preferably 75 to 85 wt%;
povidone or cold water-swellable starch, 0.25-5 wt%, more preferably 0.5-2 wt%;
magnesium aluminosilicate (product "Wigham F" or bentonite) 0.5 to 30 wt.%, more preferably 0.5 to 10 wt.%;
microcrystalline cellulose (product "Avisel PH101" or LHPC-LHII) 5-25 wt.%, more preferably 5-15%;
sodium starch glucose 0-8 wt.%, more preferably 0.5 wt.%;
magnesium stearate 0.25 - 2 wt.%, more preferably 0.25 - 1.0 wt.% and, if possible, provided with a film coating of the product "Opadri" 0.1 - 2 wt.%, more preferably 0.25 - 1 , 0 wt%;
polyethylene glycol 8000 0.1 - 0.5 wt.%, more preferably 0.1 - 0.2 wt. %.

The essence of the invention is illustrated using the following examples (see table. 3-10). Examples 1 to 6 and 29 are comparative, while examples 7 to 28, 30 and 31 illustrate the processes for preparing tablets in accordance with the present invention, which contain acyclovir as an active ingredient.

In accordance with the present invention, for the purpose of illustrating that disintegration time remains constant at different tablet hardness, the composition of Example 7 was compressed with forces of approximately 8 klbs, 3629 kg (7a), 12 klbs, 5443 kg (7b) and 18 klbs, 8165 kg (7c); the results that were obtained are presented below.

Examples 32-40 illustrate the preparation of tablets according to the present invention in which the active ingredient is lamotrigine (see Tables 11 and 12).

Examples of tablet formulations including other activating agents are shown in table. thirteen.

Method of obtaining. The tablets presented in Examples 1-45 were prepared according to the following general method:

A) a dry mix was prepared using all the ingredients except Povidone (polyvinylpyrrolidone K30, sodium docusate (if applicable) and magnesium stearate;

B) povidone / polyvinylpyrrolidone K30 and sodium docusate (if it is intended to be used) were dissolved in a 50% aqueous alcoholic solution, preparing a solution for granulation;

C) the granulation solution was added to the dry mixture to prepare granules;

D) the wet granules were dried in a fluidized bed dryer;

E) the granules were then sieved through a 1000 µm sieve;

F) The dried granules were mixed with magnesium stearate and compressed to form tablets.

In the case of using aromatic (flavoring) additives, they were introduced in the above mixing step (f).

This general method is illustrated in relation to the following specific examples.

Example 8 (uncoated tablets):

A) A dry mix was prepared using all ingredients except povidone / polyvinylpyrrolidone K30 and magnesium stearate using a Diozna P100 apparatus (high shear mixer granulator) for 3 minutes;

B) povidone / polyvinylpyrrolidone K30 was dissolved in a 50% aqueous alcoholic solution to prepare a granulation solution;

C) the solution was added until an amount of approximately 300 ml was reached for each kilogram of dry mix to prepare granules. Dry mixing was carried out for about 5 minutes;

D) The wet granules were dried in an Aeromatic T3 fluid bed dryer at 70 ° C for approximately 30 minutes. The moisture content of the granules was approximately 4%;

F) The dried granules were blended with magnesium stearate using a collet blender for about 10 minutes and compressed into tablets using a Mainestri D3 rotary tablet machine that was equipped with caplet punches about 19.3 mm long and 9.0 wide. mm. The tablets were obtained by compression such that the weight of each was 1052 mg2%.

Such a granulate can be used for the manufacture of dispersible tablets with other doses of acyclovir, for example 200 and 400 mg, by pressing the dried granules to form tablets weighing 263 and 256 mg, respectively, using round punches with diameters of 11.0 and 8.6, respectively. mm.

Example 9 (film-coated tablet).

Steps a) to f) as described in Example 8 were repeated to obtain an uncoated tablet, which was then film-coated according to the following procedure.

For this purpose, a Mainestry Axellakot 10 film coating machine was used. The coating suspension was sprayed onto the tablet cores so that their weight gain was in the range of 0.5-1.0, observing the following acceptable parameters:

tray rotation speed - 8.5 rpm,
material consumption when spraying - 20 g / min,
inlet temperature - 75 o C,
outlet temperature - 53 o C.

Then, the film-coated tablets were polished with a Polyethylene Glycol 8000 product with an additional weight gain of 0.1-0.2%.

Examples 13 - 15. During the experiment of example 13, Acyclovir, Avisel pH101, sodium starch glycolate and Wigham F were dry blended in a mixer. After adding a sufficient volume of 50% aqueous alcohol solution (IMS), the mixture was granulated. The prepared granules were dried, mixed with magnesium stearate, and then compressed to form tablets.

Example 14. The procedure described in example 13 for the preparation of granules and the formation of tablets is carried out completely, except that the granulation of the dry mixture is carried out using Povidone in 50% aqueous solution alcohol. Molded tablets can be coated by treating the tablet with a dispersion of white Opadry in purified water and drying the coated tablets, which are then polished using a solution of polyethylene glycol 8000, USNF in 50% aqueous alcohol solution (IMS).

During the experiment of example 15, the procedure described in example 13 for the preparation of granules and the formation of tablets was repeated completely, except that the operation of granulating the dry mixture using Povidone in a 50% aqueous solution of alcohol.

Example 33:

A) A dry mix was prepared using all ingredients except Povidone / Polyvinylpyrrolidone K30 and magnesium stearate using a Morton mixer with c-blades by low speed mixing for 10 minutes;

B) povidone / porlivinylpyrrolidone K30 was dissolved in a 50% aqueous alcohol solution, prepared for granulation;

D) wet mixing was carried out for approximately 10 minutes. The wet granules were sieved through a 2000 µm sieve;

E) the wet granules were dried in an Aeromatic fluid bed dryer at 70 ° C for approximately 25 minutes;

F) then the granules were sieved through a sieve with a mesh opening of 1000 μm;

G) The dried granules were mixed with magnesium stearate using a rotary mixer Rotomixer for 5 minutes and compressed into tablets using a Meinesti D3 rotary press equipped with round punches with a diameter of 5.6 mm (normal radius of curvature) dies. Compression of the tablets was carried out in such a way that the weight of each of them was 62.55 mg2%.

In the aforementioned mixing step g), flavoring agents may be added.

To make a 50 milligram tablet, the same procedure was followed, except that in this case an 11.8 mm die was used and the tablets were compressed so that they each weigh 625.5 mg 2%.

The lamotrigated tablets can be film coated using the same procedure as described in Example 9.

Tablets made according to the above examples were then subjected to the following tests.

Tablet evaluation methods:

1. Average weight of tablets. Twenty tablets were weighed on an analytical balance and the average weight of the tablets was calculated.

2. Tensile strength of tablets (kilopounds, kf 454 kg). 5 tablets were individually tested with a Schleiniger crush tester and the average tensile strength was calculated from the results.

3. Looseness (loss in percentage). 10 tablets were accurately weighed and subjected to a 10-minute friability test using the Rocha Friability Tester. Dust was removed from the tablets, weighed again, and the weight loss due to looseness was calculated as a percentage of initial weight loss.

4. Duration of dispersive disintegration of diesel fuel (BF 1988). 6 tablets were tested according to the above BF procedure (without discs) for dispersible tablets. When this used water with a temperature of 19-21 o C.

5. The quality of dispersion. In accordance with the test procedure for the uniformity of dispersion of the RF for dispersible tablets (BF 1988, vol. 11, p. 895), two tablets were placed in 100 ml of water at a temperature of 19-21 o C and allowed to disperse. As a result, a homogeneous dispersion was obtained, which passed through a sieve with openings of 710 μm.

Granule evaluation methods:

1. Loss on drying (LRP). The residual moisture content of the pellet (RLM) was determined using a 3-4 gram sample using a Computerrek moisture analyzer set to 90 ° C and operating according to the manufacturer's procedure.

2. Weight average diameter (SVD). A 10 gram sample of granules was sieved for 2 minutes at acceptable ripple sieve amplitudes in an Allen Bradley sonic sifter according to the manufacturer's instructions. In this case, sieves with openings of 710, 500, 355, 250, 150, 106 and 53 μm were used. The SVD was calculated using a computer program from the data on the particle size distribution and the total percentage of screening.

Particle size analysis was performed using the tablet dispersion of Example 9 according to the following method.

Particle size distribution was determined using a Malvern 2600 particle analyzer as follows. The instrument was set up to analyze particles in a liquid using a magnetic stirrer. For this purpose, a lens with a focal length of 300 mm was used.

1. Disperse the tablet in 100 ml of deionized water.

2. Stir the solution for approximately 2 hours.

3. Filter or centrifuge the solution to obtain a liquid, which should be saturated with all the components that make up the tablet.

4. Disperse the second tablet in 50 ml of unsaturated liquid, holding for 3 minutes to ensure complete dispersion. Mix vigorously and sample the dispersion for 5 minutes by injecting enough liquid into the Malvern PIL cell to provide an observed value of 0.15-0.30. Analyze the sample.

Claim

1. A water-dispersible tablet formed from granules containing a pharmaceutically active compound, a pharmaceutically acceptable swellable clay and targeted additives, characterized in that it contains a compound selected from the group consisting of an analgesic propionic acid derivative that tranquilizes benzodiazepine as a pharmaceutically active compound, antiviral nucleoside derivative, naphthoquinone compound against protozoa, allopurinol, oxopurinol, anticonvulsant 1,2,4-triazine derivative, trimethoprim, trimethoprim in combination with sulfomethoxazole, pharmaceutically acceptable swelling clay is a dispersing agent and is contained inside the tablet granules in water dispersible within a 3-minute period of time with the formation of a dispersion consisting of particles with a size of less than 710 microns, and the tablet contains the indicated components in the following ratio, wt%:

The specified pharmaceutically active compound - 5 - 95
Pharmaceutically acceptable swelling clay - 0.25 - 60.0
Targeted Supplements - Rest

2. A tablet according to claim 1, characterized in that it is coated with a film membrane and is capable of dispersing in water to form a dispersion consisting of particles with a particle size of less than 710 μm.

3. A tablet according to claim 1, characterized in that it is dispersible in water over a 2 minute period.

4. Tablet according to any one of claims 1 to 3, characterized in that it is dispersible in water to form a dispersion consisting of particles, more than 50% of which have a size of less than 310 μm.

5. A tablet according to claim 4, characterized in that it is dispersible in water to form a dispersion consisting of particles, more than 70% of which are less than 310 microns in size, and more than 50% of which are less than 200 microns.

6. Tablet according to any one of claims 1 to 5, characterized in that as a pharmaceutically active compound it contains a compound selected from the group consisting of acyclovir, lamotrigine, diazepam, paracetamol, 1- (β-D-arabinofuranosyl) 5-propyl -1-yniluracil, 2-3-hydroxy-1,4-naphthoquinone, allopurinol, 3 "-azido-3" -deoxythymidine, 5-propyl-1-ynyl-1- (5-trimethylacetyl-β-D-arabinofuranosyl ) -uracil, 2- -ethylvalinate, 2 ", 3" -dideoxy-5-ethynyl-3 "-fluoruridine, 5-chloro-1- (2,3-dideoxy-3-fluoro-β-erythropentofuranosyl) -uracil, penciclovir, famciclovir, E-5- (2-bromovinyl) -1-β-arabinofuranosyluracil, dextromethorphan, pseudofedrine, acrivastin, triprolidine, guaifenesin, dihydrocodeine, codeine phosphate, and ascorbic acid.

7. Tablet according to any one of claims 1 to 6, characterized in that it contains attapulgite as a pharmaceutically acceptable swellable clay.

8. Tablet according to any one of claims 1 to 6, characterized in that it contains a clay from the montmorillonite group as a pharmaceutically acceptable swellable clay.

9. Tablet according to claim 8, characterized in that it contains smectite or bentonite or "Veegum F" clay as a clay from the montmorillonite group.

10. A tablet according to any one of claims 1 to 9, characterized in that it contains a pharmaceutically acceptable swellable clay in an amount of 0.25 to 40% by weight.

11. A tablet according to claim 10, characterized in that it contains a pharmaceutically acceptable swellable clay in an amount of 1-10% by weight.

12. Tablet according to any one of claims 1 to 11, characterized in that it contains a pharmaceutically active compound in an amount of 5 to 90 wt.%.

13. Tablet according to any one of claims 1 to 12, characterized in that it contains 5 to 90 wt.% Of a pharmaceutically active compound, 0.25 to 60 wt.% Of a pharmaceutically acceptable swelling clay, 0.1 to 5 wt.% Of a lubricant substances and targeted additives - the rest, and the lubricant is contained outside the granules.

14. A tablet according to claim 13, characterized in that it contains as target additives no more than 25 wt% of a binder, no more than 20 wt% of a disintegrating agent, no more than 95 wt% of a water-soluble filler, no more than 95% of an insoluble in the water of the filler, not more than 5 wt.% of a surfactant, not more than 10 wt.% of sweeteners, as well as dyes and flavoring (flavoring) additives.

15. Tablet according to any one of claims 1 to 14, characterized in that it contains acyclovir as a pharmaceutically active compound.

16. A tablet according to claim 15, characterized in that it contains acyclovir in an amount of 50 to 90 wt.%, And a pharmaceutically acceptable swellable clay in an amount of 0.5 to 40 wt.%.

17. Tablet according to claim 16, characterized in that it contains 200-800 mg of acyclovir.

18. Tablet according to claim 16, characterized in that it contains 70-90 wt.% Acyclovir, 0.5-30 wt.% Bentonite clay or clay "Veegum F", 0.25-5 wt.% Polyvinylpyrrolidone or starch swelling in cold water, 5 - 25 wt. % microcrystalline cellulose or low-substituted hydroxypropyl cellulose, 0.25 - 2 wt.% magnesium stearate.

19. A tablet according to claim 18, characterized in that it additionally contains not more than 8 wt.% Sodium starch glycolate.

20. A tablet according to claim 18 or 19, characterized in that it is coated with a polymer membrane from the product "Opadry" based on hydroxypropyl methylcellulose, taken in an amount of 0.1 - 2 wt.%, Or a membrane made of polyethylene glycol 8000, taken in an amount of 0, 1 - 0.5 wt%.

21. Tablet according to claim 18, characterized in that it contains 75-85 wt.% Acyclovir, 0.5-10 wt.% Bentonite clay or clay "Veegum F", 0.5-2 wt.% Polyvinylpyrrolidone or starch , swelling in cold water, 5 - 15 wt. % microcrystalline cellulose or low-substituted hydroxypropyl cellulose, 0.25 - 2 wt.% magnesium stearate.

22. A tablet according to claim 21, characterized in that it additionally contains not more than 5% by weight of sodium starch glycolate.

23. A tablet according to claim 21 or 22, characterized in that it is coated with a film membrane made of the Opadry product based on hydroxypropyl methylcellulose, taken in an amount of 0.25-1 wt%, or a membrane made of polyethylene glycol 8000, taken in an amount of 0.1 - 0.2 wt.%.

24. A tablet according to any one of claims 1 to 9, characterized in that it contains acyclovir as a pharmaceutically active compound in an amount of 750 to 850 mg with a total tablet weight of 1000 to 1200 mg.

25. A tablet according to claim 24, characterized in that it contains a pharmaceutically acceptable swellable clay in an amount of 40-120 mg.

26. A tablet according to any one of claims 1 to 14, characterized in that it contains lamotrigine as a pharmaceutically active compound.

27. A tablet according to claim 26, characterized in that it contains lamotrigine in an amount of 2 to 90 wt.%, And a pharmaceutically acceptable swelling clay in an amount of 0.25 to 40 wt.%.

28. A tablet according to claim 27, characterized in that it contains 25-200 mg of lamotrigine.

29. A tablet according to claim 27, characterized in that it contains 30-50 wt.% Lamotrigine, 0.25-30 wt.% Bentonite clay or clay "Veegum F", 26-46 wt.% Calcium carbonate, 5 - 30 wt.% Microcrystalline cellulose or low-substituted hydroxypropyl cellulose, 1-8 wt.% Polyvinylpyrrolidone or starch, swellable in cold water, 0.25-2 wt.% Magnesium stearate.

30. A tablet according to claim 29, characterized in that it additionally contains not more than 8% by weight of sodium starch glycolate.

31. A tablet according to claim 29 or 30, characterized in that it is coated with a film membrane of the Opadry product based on hydroxypropyl methylcellulose, taken in an amount of 0.25-1 wt%, or a membrane of polyethylene glycol 8000, taken in an amount of 0, 1 - 0.5 wt%.

32. Tablet according to claim 29, characterized in that it contains 35-45 wt.% Lamotrigine, 0.25-10 wt.% Bentonite clay or clay "Veegum F", 31-41 wt.% Calcium carbonate, 5 - 15 wt.% Microcrystalline cellulose or low-substituted hydroxypropyl cellulose, 2-5 wt.% Polyvinylpyrrolidone or starch, swellable in cold water, 0.25-1 wt.% Magnesium stearate.

33. A tablet according to claim 32, characterized in that it additionally contains not more than 5 wt% sodium starch glycolate.

34. A tablet according to claim 32 or 33, characterized in that it is coated with a film membrane of the Opadry product based on hydroxypropyl methylcellulose, taken in an amount of 0.25-1 wt%, or a membrane of polyethylene glycol 8000, taken in an amount of 0, 1 - 0.2 wt.%.

35. A tablet according to claim 27, characterized in that it contains 5-50 mg of lamotrigine.

36. A tablet according to claim 27, characterized in that it contains 3-13 wt.% Lamotrigine, 50-60 wt.% Lactose or calcium carbonate, 20-35 wt.% Microcrystalline cellulose or low-substituted hydroxypropyl cellulose, 0.25-30 wt.% bentonite clay or clay "Veegum F", 1 - 8 wt.% polyvinylpyrrolidone or starch, swellable in cold water, 0.25 - 2 wt.% magnesium stearate.

37. A tablet according to claim 36, characterized in that it additionally contains no more than 8 wt% sodium starch glycolate, no more than 0.5 wt% sodium docusate and no more than 3 wt% sodium saccharin.

38. A tablet according to claim 36 or 37, characterized in that it is coated with a polymeric film membrane from the Opadry product based on hydroxypropyl methylcellulose, taken in an amount of 0.1-2 wt%, or a membrane made of polyethylene glycol 8000, taken in an amount of 0 , 1 - 0.5 wt%.

39. A tablet according to claim 36, characterized in that it contains 5-11 wt.% Lamotrigine, 53-59 wt.% Lactose or calcium carbonate, 24-30 wt.% Microcrystalline cellulose or low-substituted hydroxypropyl cellulose, 0.25-10 wt.% bentonite clay or clay "Veegum F", 2 - 5 wt.% polyvinylpyrrolidone or starch, swellable in cold water, 0.25 - 1 wt.% magnesium stearate.

40. A tablet according to claim 39, characterized in that it additionally contains not more than 5 wt.% Sodium starch glycolate, 0.15 - 0.5 wt.% Sodium docusate, 0.5 - 2 wt.% Sodium saccharin.

41. A tablet according to claim 39 or 40, characterized in that it is coated with a polymer film membrane from the Opadry product based on hydroxypropyl methylcellulose, taken in an amount of 0.25-1 wt%, or a membrane made of polyethylene glycol 8000, taken in an amount of 0 , 1 - 0.2 wt%.

42. A method for preparing a water-dispersible tablet, comprising mixing in finely divided form a pharmaceutically active compound with target additives and a pharmaceutically acceptable swellable clay, adding a pharmaceutically acceptable liquid in an amount sufficient to moisten the dry mixture, granulating the resulting wet mixture to obtain granules, drying the granules, mixing these granules with targeted additives and compressing the granules to form a tablet, characterized in that the components according to claim 1 are used, a pharmaceutically acceptable swelling clay is contained within the granules of the obtained tablet, which is capable of dispersing in water for a 3-minute period of time to form a dispersion, consisting of particles less than 710 microns in size.

43. Granules for water-dispersible tablets containing a pharmaceutically active compound, a pharmaceutically acceptable swelling clay and targeted additives, characterized in that they contain components according to any one of claims. 1 to 41, and the pharmaceutically acceptable swelling clay is contained within the granules.

44. The use of a pharmaceutically acceptable swellable clay as a dispersing agent in a water-dispersible tablet according to any one of claims 1 to 41.

Inventor Name: Christina Elzbieta Filden
Name of the patentee: Dze Wellcam Foundation Limited (GB)
Date of commencement of validity of the patent: 1992.01.29

Flemoxin is a generic drug of one of the most popular antibiotics in the world -. The original drug was developed by British pharmacists in the 60s of the last century. Amoxicillin appeared on the pharmaceutical market in the early 70s.

Amoxicillin is undoubtedly one of the safest broad-spectrum antibacterial drugs. According to some reports, this penicillin antibiotic is almost the most prescribed medicine in pediatrics. Almost every reputable pharmaceutical company considers it its duty to release its own "Amoxicillin". The Japanese corporation Astellas Pharma also succeeded in this business, developing Flemoxin.

Flemoxin solutab stands out against the monotonous background of Amoxicillins due to its release form. After all, the drug is produced in the form of dispersible tablets, which have a lot of advantages over the pills we are used to.

In this article we will try to understand how Flemoxin differs from analogues, as well as clarify the positive aspects of the drug. And we will not bypass negative qualities, which, of course, are also present.

Astellas Pharma: new life for antibiotics

Astellas Pharma is the largest Japanese pharmaceutical concern. It appeared in 2005 through the merger of two well-known Japanese companies: Fujisawa Pharmaceutical Co and Yamanouchi Pharmaceutical Co.

Today Astellas Pharma works in different areas of medicine, creating both original drugsand analogues of well-known brands. The company also manufactures several antibiotics that have become widely known for their dispersible formulation.

Each of these drugs has an additional word in the name indicating a special form - solutab. Dispersible drugs include:

cephalosporin antibiotic Ceforal solutab;
Unidox solutab, widely known in Russia;
Wilprafen solutab;
Flemoxin Solutab and Flemoklav Solutab are two related drugs containing Amoxicillin as an active ingredient.

I would like to note that Flemoxin solutab is registered only in Germany, Iceland, Portugal and the CIS countries.

\u003e\u003e Recommended: if you are interested effective methods getting rid of chronic rhinitis, pharyngitis, tonsillitis, bronchitis and persistent colds, then be sure to look at this site page after reading this article. Information based on personal experience author and helped many people, we hope it will help you too. Now we return to the article.<<

Flemoxin solutab: composition of the drug

Flemoxin contains, as you already understood, the only active ingredient - Amoxicillin - in the form of a stable compound (trihydrate).

The active ingredient of the drug is perindopril. Prestarium belongs to a group of medicines that inhibit the activity of an enzyme that converts angiotensin 1 into an active vasoconstrictor factor - angiotensin 2. Due to the expansion of peripheral vessels against the background of taking this drug, pressure decreases, manifestations of myocardial and cerebral ischemia decrease, and heart function is restored.

The drug helps to control the level of blood pressure, maintaining it at the recommended values, and also reduces the load on the heart muscle by expanding the peripheral vessels. These properties of the Prestarium have found application in the treatment of such diseases:

in violation of the blood supply to the brain;
preventing the progression of myocardial ischemia, reducing the likelihood;
insufficiency of blood circulation and prevention of its decompensation;
to reduce the risk of complications.

The decision to correct treatment and transfer patients to taking pills with a higher content of perindopril is made by the doctor 2 to 4 weeks after the start of therapy. The maximum dose is 10 mg, it can be used for a long time to reduce the risk of complications of hypertension, myocardial ischemia and brain.

Possible adverse drug reactions

Most often, such undesirable effects are noted when applied:

Most of these manifestations occur due to an excessive drop in pressure, in such cases the drug is discontinued. Another reason, because of which it is necessary to suspend therapy, is a persistent dry cough, characteristic of almost all drugs from the ACE inhibitors group.

Application during pregnancy

In connection with the possible danger to the health of the unborn child, Prestarium is not prescribed during the preparation period for pregnancy, and if it nevertheless occurred during treatment, then it should be canceled as soon as possible. If the therapy is continued at a later date, the ossification of the skull and kidney function may be disturbed in the newborn. Because of the risk of hypotension, these infants should be monitored by a pediatrician for the first year of life.

Therefore, most often for pregnant women, Prestarium is replaced with medicines with proven safety, the same rule applies during lactation, especially if the baby was born prematurely or with low weight. Since there is no sufficient confirmation of the possibility of prescribing to children under 18, it cannot be recommended to them.

Watch the video about the drug Prestarium from high blood pressure:

The cost of the drug

In the pharmacy chain, perindopril arginine is presented, produced by the French company Servier under the name Prestarium A in dosages of 5 and 10 mg in one tablet. For a package containing 30 pieces, on average you need to pay:

Analogs

There are no analogues of Prestarium A completely identical in chemical composition, the composition of drugs identical in pharmacological action contains perindopril, but in the form of a different salt, therefore their dosage is different (instead of 5 and 10 mg, the tablet contains 4 and 8).

Perindopril trade names:

Prenesa,
Koverx,
Parnavel,
Pyristar,
Arentopres,
Hypernik,
Promepril,
Stoppress,
Perineva.

The drug Lozap from pressure helps in many cases. However, pills should not be taken if you have certain medical conditions. When should you choose Lozap, and when Lozap plus?

The diuretic Indapamide, the indications for the use of which are quite extensive, is drunk once a day. The properties of the medicine help to remove excess fluid. For long-term use, the retard form is selected. Before starting the appointment, it is better to know the contraindications.

The drug Vinpocetine is very common, the use of which is prescribed after heart attacks, to maintain good blood circulation in the brain. The drug comes in several forms, including tablets.

With VSD, Tonginal is often prescribed, the use of which helps to normalize blood pressure, vascular tone. The instructions for the drug indicate that only drops are possible, tablets are not available today. It can be difficult to find analogues of a medicine.

Madopar ® fast-acting tablets (dispersible) "125"

Madopar ® "125"

in dark glass bottles 30 or 100 pcs.; in a pack of cardboard 1 bottle.

Madopar ® "250"

in dark glass bottles 30 or 100 pcs.; in a pack of cardboard 1 bottle.

Madopar ® GSS "125"

in dark glass bottles 30 or 100 pcs.; in a pack of cardboard 1 bottle.

Description of the dosage form

Dispersible tablets: cylindrical, flat on both sides with a beveled edge, white or off-white, odorless or low odor, slightly marbled, engraved with "ROCHE 125" on one side of the tablet and a fracture line on the other side. Tablet diameter - about 11 mm; thickness - about 4.2 mm.

Capsules: hard gelatinous; body - pinkish-flesh-colored, opaque; the lid is light blue, opaque; the capsule is marked "ROCHE" in black. The contents of the capsules are a fine granular powder, sometimes crumpled, of a light beige color, with a subtle odor.

Pills: cylindrical, flat with a beveled edge, pale red in color with small blotches, with a faint smell; on one side of the tablet there is a cruciform line, engraving "ROCHE" and a hexagon; on the other - a cruciform risk. Tablet diameter - 12.6-13.4 mm; thickness - 3-4 mm.

Modified Release Capsules: hard gelatinous; body - light blue, opaque; the lid is dark green, opaque; the capsule is marked "ROCHE" in rusty red ink. The contents of the capsules are fine granular powder, sometimes crumpled, white or slightly yellowish, with a subtle odor.

pharmachologic effect

pharmachologic effect - antiparkinsonian.

Pharmacodynamics

Combined remedy for the treatment of Parkinson's disease and restless legs syndrome.

Parkinson's disease. Dopamine, which is a neurotransmitter in the brain, is produced in the basal ganglia in patients with Parkinson's disease in insufficient quantities. Levodopa or L-DOPA (3,4-dihydrophenylalanine) is the metabolic precursor of dopamine. Unlike dopamine, levodopa penetrates well through the BBB. After levodopa enters the central nervous system, it is converted to dopamine by aromatic amino acid decarboxylase.

Replacement therapy is carried out by prescribing levodopa - the direct metabolic precursor of dopamine - since the latter poorly penetrates the BBB.

After oral administration, levodopa is rapidly decarboxylated to dopamine in both cerebral and extracerebral tissues. As a result, most of the levodopa administered does not reach the basal ganglia, and peripheral dopamine often causes side effects. Therefore, it is necessary to block the extracerebral decarboxylation of levodopa. This is achieved by the simultaneous administration of levodopa and benserazide, a peripheral decarboxylase inhibitor.

Madopar ® is a combination of these substances in an optimal ratio of 4: 1 and is as effective as large doses of levodopa.

Restless legs syndrome. The exact mechanism of action is unknown, but the dopaminergic system plays an important role in the pathogenesis of this syndrome.

Pharmacokinetics

Suction

Capsules Madopar ® "125" and tablets Madopar ® "250"

Levodopa is mainly absorbed in the upper small intestine. The time to reach C max of levodopa is 1 hour after taking capsules or tablets.

Capsules and tablets are bioequivalent.

C max of levodopa in plasma and the degree of absorption of levodopa (AUC) increase in proportion to the dose (in the dose range of levodopa from 50 to 200 mg).

Food intake decreases the rate and extent of absorption of levodopa. When capsules or tablets are prescribed after a meal, the C max of levodopa in plasma decreases by 30% and is reached later. The degree of absorption of levodopa is reduced by 15%. The absolute bioavailability of levodopa in Madopar ® "125" capsules and Madopar ® "250" tablets is 98% (from 74 to 112%).

Madopar ® fast-acting tablets (dispersible) "125"

Pharmacokinetic profiles of levodopa after taking dispersible tablets are similar to those after taking Madopar ® "125" capsules or Madopar ® "250" tablets, but the time to reach C max tends to decrease. Patient absorption parameters for dispersible tablets are less variable.

Madopar ® GSS "125", capsules with modified release of the active substance

Madopar ® GSS "125" has different pharmacokinetic properties than the above-mentioned forms of release. The active substances are released slowly in the stomach. C max in plasma is 20-30% less than that of conventional dosage forms, and is achieved 3 hours after administration. The dynamics of plasma concentration is characterized by a longer period of "half-life" (the period of time during which the concentration in plasma exceeds or is equal to half of the maximum) than that of Madopar ® "125" capsules and Madopar ® "250" tablets, which indicates continuous modified release. ... Bioavailability of Madopar ® GSS "125" is 50-70% of the bioavailability of Madopar ® "125" capsules and Madopar ® "250" tablets and does not depend on food intake. Food intake does not affect the C max of levodopa, which is reached later, 5 hours after taking Madopar ® GSS "125".

Distribution

Levodopa passes through the BBB via a saturable transport system. It does not bind to plasma proteins. The volume of distribution is 57 liters. AUC for levodopa in cerebrospinal fluid is 12% of that in plasma.

Benserazide in therapeutic doses does not penetrate the BBB. It accumulates mainly in the kidneys, lungs, small intestine, and liver.

Metabolism

Levodopa is metabolized by two main pathways (decarboxylation and o-methylation) and two additional pathways (transamination and oxidation).

Aromatic amino acid decarboxylase converts levodopa to dopamine. The main end products of this metabolic pathway are homovanillic and dihydroxyphenylacetic acids.

Catechol-o-methyl-transferase methylates levodopa to form 3-o-methyldopa. T 1/2 of this main metabolite from plasma is 15-17 hours, and in patients taking therapeutic doses of Madopar, its accumulation occurs.

In the intestinal mucosa and liver, benserazide is hydroxylated to form trihydroxybenzylhydrazine. This metabolite is a potent inhibitor of aromatic amino acid decarboxylase.

Withdrawal

With peripheral inhibition of decarboxylase T 1/2 of levodopa - 1.5 hours. Clearance of levodopa from plasma is approximately 430 ml / min.

Benserazide is almost completely eliminated by metabolism. Metabolites are excreted mainly in the urine (64%) and to a lesser extent in the feces (24%).

Pharmacokinetics in special patient groups

Patients with renal and hepatic impairment. There are no data on the pharmacokinetics of levodopa in patients with renal and hepatic impairment.

Senile patients (65-78 years old). In elderly patients (65-78 years old) with Parkinson's disease, T 1/2 and AUC of levodopa increase by 25%, which is not a clinically significant change and does not affect the dosage regimen.

Indications for Madopar ® fast-acting tablets (dispersible) "125"

parkinson's disease:

Madopar ® fast-acting tablets (dispersible) "125" - a special dosage form for patients with dysphagia and akinesia in the early morning hours and in the afternoon, or with the phenomenon of "depletion of the effect of a single dose" or "increase in the latency period before the onset of the clinical effect of the drug" ;

Madopar ® GSS "125" is indicated for all types of fluctuations in the action of levodopa (namely: "dyskinesia of the peak dose" and "the phenomenon of the end of the dose", for example, immobility at night);

restless legs syndrome, including idiopathic syndrome and restless legs syndrome in patients with chronic renal failure on dialysis.

Contraindications

hypersensitivity to levodopa, benserazide or any other component of the drug;

decompensated dysfunctions of endocrine organs, liver or kidneys (except for patients with restless legs syndrome receiving dialysis);

diseases of the cardiovascular system in the stage of decompensation;

mental illness with a psychotic component;

angle-closure glaucoma;

in combination with non-selective MAO inhibitors or a combination of MAO-A and MAO-B inhibitors;

age under 25;

pregnancy;

lactation period;

women of childbearing age who do not use reliable methods of contraception (see "Pregnancy and the period of breastfeeding").

Application during pregnancy and lactation

Madopar ® is absolutely contraindicated in pregnancy and women of childbearing age who do not use reliable methods of contraception, due to a possible violation of the development of the skeleton in the fetus.

If pregnancy occurs during treatment, the drug should be discontinued in accordance with the recommendations of the attending physician.

If you need to take Madopar® during lactation, you should stop breastfeeding, due to the lack of reliable data on the penetration of benserazide into breast milk. The danger of incorrect skeletal development in a newborn cannot be ruled out.

Side effects

From the blood system: rare cases of hemolytic anemia, transient leukopenia, thrombocytopenia. In patients taking levodopa for a long time, it is recommended to periodically monitor the blood count, liver and kidney function.

From the digestive tract: anorexia, nausea, vomiting, diarrhea, isolated cases of loss or change in taste, dryness of the oral mucosa.

From the skin: rarely - itching, rash.

On the part of the cardiovascular system: arrhythmias, orthostatic hypotension (weakened after a dose reduction of Madopar ®), arterial hypertension.

On the part of the nervous system and mental sphere: agitation, anxiety, insomnia, hallucinations, delusions, temporary disorientation (especially in elderly patients and patients with a history of these symptoms), depression, headache, dizziness, in the later stages of treatment, sometimes - spontaneous movements (such as chorea or athetosis ), episodes of "freezing", weakening of the effect by the end of the dose period (the phenomenon of "exhaustion"), the phenomenon of "on-off", severe drowsiness, episodes of sudden drowsiness, increased manifestations of the syndrome of "restless legs".

From the side of the body as a whole: febrile infection, rhinitis, bronchitis.

Laboratory indicators: sometimes - a transient increase in the activity of hepatic transaminases and alkaline phosphatase, an increase in blood urea nitrogen, a change in the color of urine to red, darkening when standing.

Interaction

Pharmacokinetic interaction

Trihexyphenidil (anticholinergic drug) reduces the rate, but not the extent of absorption of levodopa. The appointment of trihexyphenidil together with Madopar ® GSS "125" does not affect other parameters of the pharmacokinetics of levodopa.

Antacids reduce the degree of absorption of levodopa by 32% when administered with Madopar ® GSS "125".

Ferrous sulfate reduces C max and AUC of levodopa in plasma by 30-50%, which is a clinically significant change in some patients.

Metoclopramide increases the rate of absorption of levodopa.

Levodopa does not enter into pharmacokinetic interactions with bromocriptine, amantadine, selegiline and domperidone.

Pharmacodynamic interaction

Antipsychotics, opiates, and antihypertensive drugs containing reserpine, inhibit the effect of Madopar ®.

MAO inhibitors. If Madopar ® is prescribed to patients receiving irreversible non-selective MAO inhibitors, then at least 2 weeks should elapse from stopping the MAO inhibitor to the beginning of Madopar ® administration (see "Contraindications"). However, selective MAO-B inhibitors (such as selegiline or rasagiline) and selective MAO-A inhibitors (such as moclobemide) can be prescribed to patients taking Madopar®. At the same time, it is recommended to adjust the dose of levodopa depending on the individual needs of the patient in terms of efficacy and tolerability. The combination of MAO-A and MAO-B inhibitors is equivalent to taking a non-selective MAO inhibitor, therefore, such a combination should not be administered simultaneously with Madopar®.

Sympathomimetics (epinephrine, norepinephrine, isoproterenol, amphetamine). Madopar® should not be administered concurrently with sympathomimetics, since levodopa may potentiate their action. If simultaneous administration is still required, careful monitoring of the state of the cardiovascular system and, if necessary, reducing the dose of sympathomimetics is very important.

Antiparkinsonian drugs. The combined use of the drug with other antiparkinsonian drugs (anticholinergics, amantadine, dopamine agonists) is possible, however, this can enhance not only desirable, but also undesirable effects. You may need to reduce the dose of Madopar or another drug. If a catechol-o-methyltransferase inhibitor (COMT) is added to treatment, a dose reduction of Madopar® may be required. When starting therapy with Madopar ®, anticholinergic drugs should not be abruptly canceled, since levodopa does not begin to act immediately.

Levodopa may affect on the results of laboratory determination of catecholamines, creatinine, uric acid and glucose, a false positive result of the Coombs test is possible.

In patients receiving Madopar, taking the drug at the same time as food rich in proteins may interfere with the absorption of levodopa from the gastrointestinal tract.

General anesthesia with halothane. Taking Madopar ® should be canceled 12-48 hours before surgery, since a patient receiving Madopar ® may experience fluctuations in blood pressure and arrhythmia during halothane anesthesia.

Method of administration and dosage

Inside, not less than 30 minutes before or 1 hour after meals.

Capsules (Madopar ® "125" or Madopar ® GSS "125") should be swallowed whole without chewing. Capsules Madopar ® GSS "125" must not be opened before use, otherwise the effect of the modified release of the active substance is lost.

Tablets (Madopar ® "250") can be crushed to facilitate swallowing.

Dispersible tablets (Madopar ® fast-acting tablets (dispersible) "125") must be dissolved in 1/4 cup of water (25-50 ml); the tablet dissolves completely after a few minutes with the formation of a milky-white suspension, which should be taken no later than 30 minutes after the tablet has dissolved. Since a precipitate can form quickly, it is recommended to stir the solution before use.

Parkinson's disease

Standard dosage regimen

Treatment should be started gradually, individually adjusting the dose to the optimal effect.

Initial therapy

At an early stage of Parkinson's disease, it is recommended to start treatment with Madopar ® with 62.5 mg (50 mg levodopa + 12.5 mg benserazide) 3-4 times a day. If the initial dosage regimen is tolerated, the dose should be slowly increased depending on the patient's response.

The optimal effect is usually achieved with a daily dose of 300-800 mg of levodopa + 75-200 mg of benserazide taken in 3 or more divided doses. It may take 4 to 6 weeks to achieve optimal effect. If it is necessary to further increase the daily dose, this should be done at intervals of 1 month.

Supportive care

The average maintenance dose is 125 mg (100 mg levodopa + 25 mg benserazide) 3-6 times a day. The number of doses (at least 3) and their distribution throughout the day should provide an optimal effect.

To optimize the effect, you can replace Madopar ® "125" capsules and Madopar ® "250" tablets with Madopar ® fast-acting tablets (dispersible) or Madopar ® GSS "125" capsules.

Restless legs syndrome

The maximum allowable dose is 500 mg / day Madopar ® (400 mg of levodopa + 100 mg of benserazide). 1 hour before bedtime, with a little food.

Idiopathic Restless Legs Syndrome with Sleep Disorders

Initial dose: 62.5 mg (50 mg levodopa + 12.5 mg benserazide) -125 mg (100 mg levodopa + 25 mg benserazide) Madopar ®. In case of insufficient effect, the dose should be increased to 250 mg (200 mg of levodopa + 50 mg of benserazide) Madopar ®.

Idiopathic Restless Legs Syndrome with Sleep and Sleep Disorders

Initial dose: 1 caps. Madopar ® GSS "125" and 1 cap. Madopar ® "125" 1 hour before bedtime. In case of insufficient effect, it is recommended to increase the dose of Madopar ® GSS "125" to 250 mg (2 capsules).

Idiopathic restless legs syndrome with sleep and sleep disturbances, as well as with disturbances during the day

Additionally: 1 tab. dispersible or 1 caps. Madopar ® "125", the maximum permissible daily dose is 500 mg (400 mg of levodopa + 100 mg of benserazide).

Restless legs syndrome in patients with chronic renal failure on dialysis

125 mg Madopar ® (1 tablet. Dispersible or 1 capsule. Madopar ® "125") 30 minutes before the start of dialysis.

Dosing in special cases

Parkinson's disease

Madopar ® can be combined with other antiparkinsonian drugs; as treatment continues, it may be necessary to reduce the dose of other drugs or to gradually withdraw them.

Madopar ® fast-acting tablets (dispersible) "125" - a special dosage form for patients with dysphagia or akinesia in the early morning hours and in the afternoon, or with the phenomenon of "depletion of the effect of a single dose" or "increase in the latency period before the onset of the clinical effect of the drug" ...

If during the day the patient has pronounced motor fluctuations (the phenomenon of "depletion of the effect of a single dose", the phenomenon of "on-off"), it is recommended either more frequent intake of correspondingly smaller single doses, or - which is preferable - the use of Madopar ® GSS "125".

It is best to start the transition to Madopar ® GSS "125" with the morning dose, keeping the daily dose and regimen for Madopar ® "125" or Madopar ® "250".

After 2-3 days, the dose is gradually increased by about 50%. The patient should be warned that his condition may temporarily worsen. Due to its pharmacological properties, Madopar ® GSS "125" begins to act somewhat later. The clinical effect can be achieved faster by prescribing Madopar ® GSS "125" together with Madopar ® "125" capsules or dispersible tablets. This can be especially helpful in the case of the first morning dose, which should be slightly higher than the next. The individual dose of Madopar ® GSS "125" should be selected slowly and carefully, and the interval between dose changes should be at least 2-3 days.

In patients with nocturnal symptoms, it was possible to achieve a positive effect by gradually increasing the evening dose of Madopar ® GSS "125" to 250 mg (2 capsules) before going to bed.

To eliminate the pronounced effect of Madopar ® GSS "125" (dyskinesia), it is more effective to increase the intervals between doses than to reduce a single dose.

If Madopar ® GSS "125" is not effective enough even in a daily dose corresponding to 1500 mg of levodopa, it is recommended to return to the previous treatment with Madopar ® "125", Madopar ® "250" and Madopar ® fast-acting tablets (dispersible) "125".

In patients with mild to moderate renal insufficiency, dose adjustment is not required.

Madopar ® is well tolerated by patients receiving hemodialysis sessions.

With prolonged therapy, episodes of "freezing", "exhaustion", and "on-off" phenomena may appear. In episodes of "freezing" and "exhaustion", they resort to splitting the dose of the drug (decreasing the single dose or shortening the interval between doses of the drug), and when the phenomenon of "on-off" appears, increasing the single dose while reducing the number of doses. Later, you can try to increase the dose again to enhance the effect of the treatment.

Restless legs syndrome

To exclude an increase in the symptoms of restless legs syndrome (early appearance during the day, increased severity and involvement of other parts of the body), the daily dose should not exceed the recommended maximum dose - 500 mg (400 mg of levodopa + 100 mg of benserazide) Madopar ®.

With an increase in clinical symptoms, the dose of levodopa should be reduced or levodopa should be gradually canceled and another therapy should be prescribed.

Overdose

Symptoms: on the part of the cardiovascular system - arrhythmias; mental sphere - confusion, insomnia; from the digestive tract - nausea and vomiting; pathological involuntary movements (mentioned in the section "Side effects", but in a more pronounced form).

When taking capsules with modified release (Madopar ® GSS "125"), the onset of symptoms of overdose may occur later due to the slow absorption of active substances in the stomach.

Treatment: it is necessary to control vital functions; symptomatic therapy - the appointment of respiratory analeptics, antiarrhythmic drugs, in appropriate cases - neuroleptics.

When using a dosage form with modified release of active substances (Madopar ® GSS "125"), further absorption of the drug should be prevented.

special instructions

Individuals with hypersensitivity to the drug may develop appropriate reactions.

Side effects from the gastrointestinal tract, which are possible at the initial stage of treatment, can be largely eliminated if Madopar is taken with a small amount of food or liquid, as well as if the dose is increased slowly.

During treatment, it is necessary to monitor the function of the liver and kidneys, the blood count.

Patients with diabetes need to frequently monitor blood glucose levels and adjust the dose of hypoglycemic drugs.

If it is necessary to perform a surgical intervention with general anesthesia, Madopar® therapy should be continued until the operation, with the exception of general anesthesia with halothane. Since a patient receiving Madopar® may experience fluctuations in blood pressure and arrhythmia during halothane anesthesia, Madopar® should be canceled 12-48 hours before surgery. After surgery, treatment is resumed, gradually increasing the dose to the previous level.

Madopar ® should not be canceled abruptly. Abrupt withdrawal of the drug can lead to "neuroleptic malignant syndrome" (fever, muscle stiffness, as well as possible mental changes and an increase in serum creatine phosphokinase), which can take a life-threatening form. If such symptoms occur, the patient should be under medical supervision (if necessary, he should be hospitalized) and receive appropriate symptomatic therapy. It may include re-appointment of Madopar® after an appropriate assessment of the patient's condition.

Depression can be both a clinical manifestation of the underlying disease (parkinsonism, "restless legs" syndrome), and may occur during therapy with Madopar®. The patient should be closely monitored for possible psychiatric adverse reactions.

Possibility of drug dependence and abuse

Impact on driving vehicles and working with machines and mechanisms

If drowsiness occurs, incl. sudden episodes of drowsiness, you should refuse to drive a car or work with machines and mechanisms. If these symptoms appear, consider reducing the dose or discontinuing therapy.

Storage conditions of the drug Madopar ® fast-acting tablets (dispersible) "125"

At a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life of the drug Madopar ® fast-acting tablets (dispersible) "125"

modified release capsules 100 mg + 25 mg 100 mg + 25 - 3 years.

dispersible tablets 100 mg + 25 mg 100 mg + 25 - 3 years.

tablets 200 mg + 50 mg 200 mg + 50 - 4 years.

capsules 100 mg + 25 mg 100 mg + 25 - 3 years.

Do not use after the expiration date printed on the package.

How to take dispersible tablets. Viagra dispersible tablets - instructions for use

Active ingredients

Release form, composition and packaging

pharmachologic effect

Pharmacokinetics

Indications

Contraindications

Dosage

Side effects

Overdose

Drug interactions

special instructions

Pregnancy and lactation

Pediatric use

The field of activity (technology) to which the described invention belongs

DETAILED DESCRIPTION OF THE INVENTION

Claim

Astellas Pharma: new life for antibiotics

Flemoxin solutab: composition of the drug

Possible adverse drug reactions

Application during pregnancy

The cost of the drug

Analogs

Description of the dosage form

pharmachologic effect

Pharmacodynamics

Pharmacokinetics

Indications for Madopar ® fast-acting tablets (dispersible) "125"

Contraindications

Application during pregnancy and lactation

Side effects

Interaction

Method of administration and dosage

Overdose

special instructions

Storage conditions of the drug Madopar ® fast-acting tablets (dispersible) "125"

Shelf life of the drug Madopar ® fast-acting tablets (dispersible) "125"

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