RU2471479C1 - Tableted pharmaceutical composition containing dexamethasone as active ingredient for oral administration, and method for preparing it - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents an oral tableted pharmaceutical composition used for oral administration and containing dexamethasone as an active ingredient, and the excipients: lactose, povidone, magnesium stearate, and differing by the fact that additionally contains the excipients: croscarmellose sodium, microcrystalline cellulose; lactose is lactose monohydrate with the ingredients taken in certain proportions, mg per one tablet.

EFFECT: invention provides high transportation durability and storage stability, and also enables reducing a number of tablets taken and side effects caused by prolonged treatment.

2 cl, 4 ex

Description

The invention relates to the field of the pharmaceutical industry and relates to new dosage forms for oral administration of glucocorticosteroids.

The problem of rheumatic diseases is currently one of the most relevant. This is evidenced by the proclamation at the initiative of the World Health Organization (WHO) of the first decade of the 21st century as the Decade of Bones and Joints (“Bone and Joint Decade, 2000-2010). Rheumatic diseases combine more than 100 different inflammatory, non-inflammatory and metabolic diseases and syndromes, manifested by pathology of the joints and periarticular soft tissues, spine, muscles, cartilage and bones, as well as systemic damage to the connective tissue. These diseases are found in people of any age, starting from childhood, but have a clear tendency to a significant, almost universal, accumulation as the population ages. The problem of these pathologies is becoming increasingly widespread in connection with the steady increase in the number of people suffering from them. Rheumatic diseases are one of the main causes of temporary disability of the working population of Russia (according to some reports, the 2nd place by cases and the 3rd by day among all causes of disability).

The main drugs for the treatment of rheumatic diseases, since the time Hench et al. (1949) on the vivid anti-inflammatory effect of cortisone are glucocorticosteroids. The drugs of this group have not only anti-inflammatory, but also immunosuppressive effects and, thus, have a versatile effect on the rheumatic process.

In addition, glucocorticosteroids are analogues of endogenous hormones produced by the adrenal cortex, which have anti-inflammatory, desensitizing, immunosuppressive, anti-shock and antitoxic effects. Due to its wide range of properties, this group of drugs is used not only for the treatment of rheumatic diseases, but also for a number of other pathologies no less important in social terms: endocrine, allergic, and malignant.

A powerful glucocorticosteroid drug is dexamethasone, a synthetic glucocorticosteroid (GCS), a methylated derivative of fluoroprednisolone. It is 25-30 times stronger than hydrocortisone and does not have mineralocorticoid activity. There are numerous studies aimed at creating new dosage forms and new formulations based on dexamethasone.

Since the administration of dexamethasone and other glucocorticosteroids is usually long-term, various systemic and local adverse reactions may develop with injection. In this regard, there is a need for forms that are effective when administered orally.

To date, tablets of dexamethasone with a dosage of 0.5 mg of Akrikhin firm (http://medi.ru/doc/12020.htm) are registered in the Russian Federation.

Decadron (Dexamethasone) oral tablets of Merck & Co., Inc. are also known. (http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=1495284d-750f-437e-8525-6834cccb78eb) containing 0.5 mg and 0.75 mg dexamethasone, and as inactive components: calcium phosphate , lactose, magnesium stearate and starch, as well as the dyes D&C Yellow 10, or FD&C Yellow 6 or FD&C Blue 1.

Diseases in which glucocorticosteroids are indicated are severe. In many cases, when the treatment involves the oral administration of a high dose of dexamethasone (up to 40 and higher mg / day), patients are forced to drink a solution for injection or eat up to 80 or more tablets of low-dose dexamethasone per day. With such modes, the incidence of ulcerogenic action increases. Oral injection of dexamethasone injections cannot guarantee a safe and effective treatment.

Anti-inflammatory steroid tablets, such as dexamethasone, containing reducing sugar and an organic acid as a stabilizer are known.

The tablets are stable for a long time, but the problem of reducing side effects is not solved (JP 62138432 (A).

Organon Laboratories Limited has attempted to create tablets with a higher dose of dexamethasone. Known tablets for the treatment of various inflammatory and autoimmune diseases containing dexamethasone 2 mg, as excipients: propylene glycol, potato starch, magnesium stearate, lactose monohydrate.

(http://www.medicines.ie/medicine/3590/SPC/Dexamethasone+2mg+tablets).

As the closest analogue, Douglas Pharmaceuticals tablets containing 4 mg of dexamethasone can be indicated as the active substance and excipients: talc, magnesium stearate, sodium glycolate starch, lactose, cornmeal and polyvinylpyrrolidone.

http://www.medsafe.govt.nz/profs/datasheet/d/Dexamethasonetab.pdf

Dexamethasone is a poorly soluble substance in water, so obtaining tablets with a high load of a drug substance with sufficient bioavailability for effective treatment is a problem.

The present invention is to develop a new effective oral composition with a high dose of dexamethasone and a method for its preparation.

The problem is solved by the composition of the pharmaceutical composition in the form of a tablet containing dexamethasone as an active component, and as auxiliary substances: lactose monohydrate, microcrystalline cellulose, povidone, magnesium stearate, croscarmellose sodium with the following content, mg per tablet:

dexamethasone 4.00-10.00 mg lactose monohydrate 80.00-160.00 mg microcrystalline cellulose 10.00-20.00 mg povidone 2.5-5.00 mg magnesium stearate 1.00-2.00 mg croscarmellose sodium 2.50-5.00 mg

A method of producing tablets consists in mixing dexamethasone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, adding a granulation solution obtained previously by dissolving povidone in water when heated to 35-40 ° C and stirring for 100-120 minutes, granulation is carried out at stirring with a shaking interval of 120 seconds for 37-43 minutes, drying at a temperature of 55-65 ° C to a residual moisture content of not more than 1.0-2.5%, sieve the obtained granules through a sieve with a hole diameter of 1 mm, dusting of magnesium stearate with stirring and the resulting mixture is tabletted.

The selected ratio of the components allows you to get tablets that are durable during transportation and stable during storage. The modes of the technological process provide a granulate that is homogeneous in composition and size, which increases the accuracy of dosing of the active ingredients.

The appearance on the market of high-dose dexamethasone (4-10 mg) will reduce the number of tablets consumed in doses of 0.5 mg by 10-20 times or more, which will significantly reduce the ulcerogenic effect of the drug, and increase the effectiveness of treatment. The proposed tablets are small in size with a low content of excipients, which will avoid the risk of developing allergic reactions to excipients. Since the dosage of dexamethasone is selected individually for the treatment of many diseases, taking into account the characteristics of the patient’s body, the presence of dexamethasone in several variants of high dosages seems justified and convenient for both doctors and patients. At the same time, for tablets with different dosages, it is not necessary to select their composition of excipients, that is, production is cheaper. Bioavailability and pharmacokinetic parameters do not change. The total cost of treatment using high-dose dexamethasone is significantly lower than that with the use of the drug in a dosage of 0.5 mg.

Dexamethasone in large doses has pronounced anti-inflammatory properties (especially in the treatment of diseases of the joints and dermatitis of various origins), has a pronounced immunosuppressive effect (treatment of hyperactive immune systems), is used in the treatment of cancer (lymphoma, multiple myeloma, leukemia), reduces edema spinal cord and brain (with injuries of various origins), has the ability to lower blood calcium levels (hypercalcemia).

In addition, dexamethasone tablets are indicated in the treatment of the following diseases: Addison's disease, adrenal cortex insufficiency, adrenogenital syndrome, aspiration pneumonia, asthma, acute atopic dermatitis, bursitis, cerebral edema, croup, Cushing's syndrome, herpetiform dermatitis, eczema, erythroblastopenia, gouty arthritis hay fever, hemolytic anemia, hypercalcemia, idiopathic thrombocytopenic purpura, inflammatory diseases, iridocyclitis, inflammation of the iris, keratitis, Lef syndrome EPA, meningitis, multiple sclerosis, nausea and vomiting during chemotherapy, neyrosarkaidoz, pemphigus, pulmonary tuberculosis, rheumatoid arthritis, sarcoidosis, seborrheic dermatitis, shock, synovitis, systemic lupus erythematosus, thrombocytopenia, toxic epidermal necrolysis, tuberculous meningitis, ulcerative colitis, uveitis. Can also be used to replace steroids in conditions of adrenal insufficiency.

Examples of the invention:

Example 1

Active substance: Dexamethasone 10.00 mg

excipients: lactose monohydrate (milk sugar) 158.00 mg; microcrystalline cellulose 20.00 mg; povidone 5.00 mg; magnesium stearate 2.00 mg; croscarmellose sodium 5.00 mg.

4.725 kg of povidone (polyvinylpyrrolidone) is dissolved in 42.53 kg of water at a temperature inside the reactor of 40 ° C with stirring for 120 minutes.

1.363 kg of dexamethasone, 21.33 kg of lactose monohydrate, 2.7 kg of microcrystalline cellulose, 0.675 kg of croscarmellose sodium are mixed for 30 seconds. Granulate is prepared at a frequency of shaking of bag filters, 2 Hz with a frequency of shaking of 120 seconds, for 37 minutes, dried at a temperature of 60 ° C for 15 minutes. Residual humidity - 1.0%. Calibrate the granulate by sieving through sieves with a hole diameter of 1 mm. The granules of 3, 78 kg of magnesium stearate are dusted with stirring for 20.0 minutes. Pressed tablets.

Example 2

Composition per 1 tablet: Dexamethasone 4.00 mg

excipients: lactose monohydrate (milk sugar) 80.00 mg; microcrystalline cellulose 10.00 mg; povidone 2.50 mg; magnesium stearate 1.00 mg; croscarmellose sodium 2.50 mg.

The process of obtaining a pharmaceutical composition is carried out analogously to example 1, but the preliminary dissolution of povidone in water is carried out at 35 ° C, granulation is carried out for 43 minutes, drying at 65 ° C to a residual moisture content of not more than 2.5%.

Example 3

Active substance: Dexamethasone 8.00 mg

excipients: lactose monohydrate (milk sugar) 160.00 mg; microcrystalline cellulose 20.00 mg; povidone 5.00 mg; magnesium stearate 2.00 mg; croscarmellose sodium 5.00 mg.

The process of obtaining a pharmaceutical composition is carried out analogously to example 1, but the preliminary dissolution of povidone in water is carried out at 37 ° C, granulation is carried out for 40 minutes, drying at 55 ° C to a residual moisture content of not more than 1.5%.

Description:

4 mg and 8 mg tablets:

Tablets are white or almost white, round flat-cylindrical, with a notch on one side and a chamfer on both sides.

10 mg tablets:

Tablets are white or almost white, round biconvex, with a risk on one side.

Example 4

Pharmacokinetics

The studies were conducted on volunteers who received 4 mg, 8 mg and 10 mg tablets according to the scheme with a randomized, balanced, based on a single dose, with two cycles of treatment with two drugs, with two periods, a cross-sectional study. Blood samples were taken from them at regular intervals of 15 minutes, starting from 15 minutes after administration and then up to 24 hours.

The results of the study:

After oral administration, dexamethasone is rapidly and completely absorbed, the time to reach maximum plasma concentration (TCmax) is on average 1-1.5 hours. Communication with plasma proteins is 70%. Penetrates into the tissue fluid through the blood-brain barrier. It is metabolized mainly in the liver, as well as in tissues. Inactive metabolites are excreted mainly by the kidneys in the form of glucuronides and sulfates, a small part in the form of unconjugated metabolites and unchanged dexamethasone. 60-65% of the administered dose is excreted in the first 24 hours with urine. The biological half-life is 190-210 minutes.

Thus, the onset of action and the residual amount for a long time indicates the effectiveness of the drug.

In a bioavailability study, data were obtained that tablets with a dose of 8 mg are bioequivalent to a parenteral solution with a concentration of 4 mg / ml. The relative bioavailability is 96-105%.

Dosage and administration.

Inside, in individually selected doses, the value of which is determined by the type of disease, the degree of its activity and the nature of the patient's response. An average of 0.75 mg - 15 mg per day. If necessary, up to 40 mg per day. Dosage regimen 3-4 times a day.

After achieving a therapeutic effect, the dose is usually gradually reduced (usually by 0.5 mg in 3 days) to a maintenance dose of 2-4.5 mg / day. The duration of the use of dexamethasone depends on the nature of the pathological process and the effectiveness of treatment and ranges from several days to several months or more. Treatment is stopped gradually.

The study of the strength and stability of the tablets during storage:

Roche freezer was used to measure abrasion resistance

using the following procedure. Pre-weighed tablets were placed in a freezer. The freezer consists of a plastic chamber that rotates at a speed of 25 rpm, dropping tablets from a distance of 6 inches at each revolution. The tablets rotate in the freezer for at least 4 minutes. After completion of the test, the tablets are blown and reweighed. % abrasion resistance was 97%.

Shelf life was determined by accelerated aging.

The proposed composition of the media provides a storage period of at least 3 years.

Claims (2)

1. The pharmaceutical composition is in the form of tablets for oral administration, containing dexamethasone as an active ingredient, and as excipients: lactose, povidone, magnesium stearate, characterized in that it additionally contains croscarmellose sodium, microcrystalline cellulose as auxiliary substances, and as lactose - lactose monohydrate in the following ingredients in mg per tablet:
dexamethasone 4.00-10.00 lactose monohydrate 80.00-160.00 microcrystalline cellulose 10.00-20.00 povidone 2.5-5.00 magnesium stearate 1.00-2.00 croscarmellose sodium 2,50-5,00 2. The method of obtaining the pharmaceutical composition according to claim 1, characterized in that dexamethasone, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium are mixed, a granulating solution obtained previously by dissolving povidone in water when heated to 35-40 ° C and stirring for 100 is added -120 min, granulation is carried out with stirring with a frequency of shaking 120 s for 37-43 min, drying at a temperature of 55-65 ° C to a residual moisture content of not more than 1.0-2.5%, the granules obtained are sieved through a sieve with a diameter of versts of 1 mm, dust them with magnesium stearate with stirring and tablet the mixture.