Pharmaceutical composition for oral administration based on detoxifying nucleoside with antiviral activity

 

(57) Abstract:

Usage: in medicine, for oral administration in the form of tablets or in powder form for the preparation of dispersions in liquids. The essence of the invention: pharmaceutical composition having antiviral activity, contains as active ingredient 21,31-methoxyphenoxy nucleoside selected from the group comprising 21,31-deoxyadenosine, 21,31-deoxyinosine and 21, 31-deoxyguanosine and/or their pharmaceutically acceptable salts and/or their hydrates, as well as water-insoluble antacid buffer and targeted supplements. The specified buffer system ensures the achievement of the pH in the stomach about 5 and consists of a water-insoluble antacid compounds of magnesium in combination with dihydroxyaluminum sodium at a mass ratio of 1 : (2-4) respectively or in combination with calcium carbonate at a mass ratio of the compounds of magnesium and calcium carbonate of 1 : (1.5 to 3). A mass ratio of 21,31-methoxypurine of nucleoside and specific additives in combination with the buffer system is(0,005-0,375) : (1,9-6) respectively. New pharmaceutical compositions provided tositsa to pharmaceutical compositions, providing a comfortable, pleasant to the taste dosed medications oral administration for acid-labile, dideoxy purine nucleosides such as 2',3'-dideoxyadenosine, 2', 3'-dideoxyinosine and 2',3'-dideoxyinosine. More specifically it refers to the inclusion of specific antacid buffers that provide special benefits, such as increased bioavailability, low variability in bioavailability between patients, greater convenience, reduced potential for gastrointestinal disorders and high susceptibility of the patient.

Other sources disclosed compositions containing 2',3'-dideoxyadenosine (DDA), 2',3'-dideoxyinosine (ddI) and 2',3'-dideoxyinosine (DDH) and triphosphates for the treatment of retroviral infections Mitsuya and others in the U.S. 4861759 discloses oral purpose of these dideoxyuridine nucleoside in the form of liquids or tablets containing antacid buffer agents, so that the pH of the resulting composition is a neutral range (pH6-pH8). Specific stated example is the drug of oral hyperalimentation containing 0.1 N acetate buffer with a pH of 6.8 to 7.2. Intersolubility shell tablets also disclosed as an option.

It is the purpose on an empty stomach after ingestion of antacid remedies. Obstruction of the acid-catalyzed hydrolysis of the principal tablet is important for these agents because of their potential antiviral activity is lost in their side products of hydrolysis. Attempts to improve acid stability of these acid-labile derivatives of nucleosides resulted in drugs in intersolubility shell, the inclusion of a buffer in pharmaceutical dosage form and neutralization of the gastrointestinal tract before taking the pill pretreatment commercial antacids, such as Maalox or Mylanta.

Research published Mc Gowan and others in Reviewsof Jnfections diseases, so 12, App.5 p. 5513-521 (1990) showed that for GDI the best approach for oral administration includes preparation of tablets with the selected dosage in combination with a fixed number citratestates buffer in the form of a powder mixture. This dry mixture is in foil and it works, as if shell ("LS package"), which should be mixed and diluted with liquid prior to oral administration.

Drugs, including intersolubility shell is not promising. Intersolubility shell tend to reduce the bioavailability of tablets with nucleoside and reduce the use of its clinical antiviral activity. Intersolubility drugs special susceptible to the effect of food, reducing even more bioavailability.

Citrate-phosphate buffer drugs, ddI with oral dosing is preferred clinically for long-term therapy compared with earlier liofilizirovannam dosages of medication, which also required a realignment of the component before its intravenous injection. These oral powder formulations with rebuilding components provide varying levels of ddI in combination with the same amount of buffer ingredients (about 10 g per day) regardless of the strength of the final product. Thus, drugs in any dosages have the same ability to neutralize acid. However, packets with a powder mixture is quite voluminous (about 20 g/dose) and uncomfortable - their use causes some inconvenience to the patient. Before taking medication is always required, this rebuild components, which ultimately gives a large volume of solution (20 g), which need to swallow. This salt solution can cause diarrhea, and the required dosage of about 10 g per day of soluble antacid buffers may cause systemic alkalosis, the quote of the person) infections.

Recently, was published a comparative analysis of available drugs, ddI oral administration. (Hartman et al. Pharmacokinetics of 2',3'-dideoxyinosine in patients with severe human emmunodeficieney infection. II. The effects of different oral formulations and the presence of other medications", Clin. Pharmacol. Ther. 1991; 50: 278-85).

When the maximum bioavailability of any drug with a buffer ingredients of the order of 40% in the publication concludes that "have not yet found the optimal composition of the drug". Existing drugs "CF package is the best oral drug, although its use is known to cause diarrhea and/or hypokalemia some patients.

The purpose of the invention to provide improved pharmaceutical compositions of these derivative of the acid-labile nucleosides, which will make it more convenient oral assignment dosed drugs with a reduced weight, such as tablets that can be chewed and swallowed or quickly dissolve in a liquid for oral administration. Such compositions can be prepared using dosage forms of drugs in packages with a reduced weight.

Another goal is to combine the selected antacid buffers in such a way as to minimize diarrhea and/or imbalance of electrolyte and pH.

Another goal of the m The key to realizing these goals is a form with a reduced weight, the same amount of bioavailable drugs in citrate-phosphate buffer packets. It has been unexpectedly found that improved buffer system, including certain water-insoluble carbonates of aluminum or calcium in combination with water-insoluble antacids magnesium increase the bioavailability of drugs by 20-25% Sweetening and flavouring agents for inclusion in an improved drug-buffer composition will also serve to implement the goals of the invention.

The invention helps to reveal improved pharmaceutical compositions for oral purpose of the acid-labile derivatives of dideoxy purine nucleosides in the form of packets of powder with a reduced weight and convenient, palatable tablets that Joutsa. These pills also easily dispersed in liquids. The goal is successfully implemented, depending on the selection and improvement of a compatible water-insoluble antacid buffer systems, which in combination with sweetening agents, flavouring agents and other various fillers increase the bioavailability of drugs compared to predtest the key.

The invention relates to the improvement of the dosage forms oral dosage of the acid-labile derivatives of dideoxy purine nucleoside, for example, DDA, ddI, and DDH. The improvement provided through the inclusion of ingredient active substance of the drug in acidic buffer with a reduced weight, which makes a pleasant-tasting tablets that can be chewed and swallowed or easily dispersing in the corresponding non-acidic liquids and then swallow. As an option is offered in powder form with a reduced weight in the bags.

To form these acid-labile substances in the form of small chewable/dispersible tablets, pharmaceutical compositions require sufficient bioavailability at low volume and acceptable taste. It was found that the use of some insoluble antacid buffers in combination provide a buffer system that actually increases the bioavailability of drugs with reduced variability levels of the drug in humans in comparison with the known oral medications. In addition, antacid buffer system with a new combination have the best taste sensations and red eye reduction is innych agents.

Water-insoluble buffers in the use of antacid agents that can be used in fast buffer system include antacids with slight solubility in water, as well as the ones that are actually insoluble. Raman buffer system of this invention consist of mixtures of water-insoluble antacid compounds of magnesium and carbonates of alkali metals and dihydroxyaluminum or calcium carbonate. Preferred mixtures include about one part of water-insoluble antacid compounds of magnesium in combination with 2-4 parts of carbonate of alkaline metal and dihydroxyfumarate alkali metal or 1.5 to 3 parts of calcium carbonate, which is the most preferable.

Water-insoluble antacid magnesium compound can be selected from carbonate, magnesium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium phosphate (trehosnovnogo) and trisilikata magnesium, or combinations of these substances. Preferred magnesium oxide and magnesium hydroxide, and the hydroxide is most preferred. Carbonates of alkali metals and dihydroxyaluminum chiefly dihydroxyaluminum sodium and potassium, of which sodium carbonate is more preferred.

Unique synergistic characteristics of selected compounds insoluble aluminum and/or calcium carbonate of new Raman buffer systems are demonstrated by comparing the results obtained when the aluminum hydroxide is widely used antacid, was replaced with the selected aluminum/calcium component of the new buffer combinations. F hydroxide-containing buffer system has drawbacks in comparison with the high speed buffer systems, because it gives a higher acidic pH in the study of gastric secretion in vitro even when adding additional suspension of aluminum hydroxide. In contrast, the use of dihydroxyaluminum sodium carbonate or calcium carbonate, combined with an insoluble magnesium compound, provided increased over time, the pH in the desired range (pH above 5), in the study of gastric secretion in vitro, indicating more effective acid neutralization.

And, finally, the importance of the Choice of insoluble antacid buffers, including these new pharmaceutical compositions provide good ability of acid neutralization while maintaining the organoleptic properties, which minimizes the amount of sweetening and flavouring agents.

In the same way as for the citrate-phosphate buffer powders of water-insoluble antacid buffers have a constant level regardless of the dose of the drugs included in the fast pharmaceutical composition. Improved buffer system of new drugs reduce the total number of antacid and swallow them daily (about 10 g) in a known pharmaceutical forms to 3-8 g daily in forms with a reduced weight, bags or chewable dispersible tablets at recommended doses. Due to the increased bioavailability of the drug reached these pharmaceutical compositions, required less medication with a potential equivalent to the previous "CF packages". Clinically for ddI instead of dose package, as shown in the table.1, it is possible to give two tablets of improved pharmaceutical compositions.

As can be seen from the data table.1, the weight of the dose ddI can be reduced by 20-25% in the preparation in the form of a new chewable/dispersible tablets the AI of this invention contain from 5 to 150 mg of the derivative 2', 3'-dideoxyribose nucleoside, such as DDA, ddI and DDH, a tablet and from 10 to 300 mg per unit package. In these compositions is also provided a sufficient amount of an antacid buffer consisting of water-insoluble antacid compounds of magnesium in combination with carbonate of an alkali metal dihydroxyaluminum or calcium carbonate; so that adequate antacid capacity is achieved by the intake of two tablets or one bag. Can be included optionally sweetening agent, flavouring and forming fillers, and water-soluble antacid buffer. A more detailed description of the mixed water-insoluble antacid buffer systems, as well as other ingredients that can be entered in these new dideoxy nucleoside pharmaceutical compositions offered in specific variations, described below.

Another aspect of the invention relates to taste tablets for oral administration. The taste characteristics of water-insoluble antacid buffers selected for use in the invention are such that their inclusion in the data of the pharmaceutical composition facilitates goal gustatory aspect without the need of ingredients, taste mask is sorbitol or sucrose for improving taste according to certain antacid compounds, selected for the final composition. In General, if the calcium carbonate is selected as an antacid buffer component, sucrose is added little or no added. If the ingredient is dihydroxyaluminum sodium carbonate, it is desirable to add from 2 to 5 parts of sucrose on the part of aspartame.

The choice of flavouring agents may also vary depending on the specific antacid compounds. The experiments have been conducted on taste for best flavor compositions. Preferred flavors of orange, Mandarin, Grushenka. May include other pharmaceutical additives. Although traditional chewable tablets do not require a cage, it can be entered in these compositions to provide rapid disintegration in the case of appointment of dispersion, as well as to accelerate the acid neutralization after oral assignments. Can be used in commercial disintegrators, such as Polyplasolone XL and Explotab. Additives, such as silicon dioxide and lubrication, as well as magnesium stearate may also be included in pharmaceutical compositions of the invention. The use of these and other pharmaceutical excipients well known in the field of technology the Institute two chewable/dispersible tablets with the correct dosage of drugs on the tablet prescribed by a doctor, carefully razdevayutsya together or sequentially. You can drink 120 ml of non-acidic liquid, such as water. In another case, two tablets can be atomized in 30 ml of water and drink the variance. To improve the taste to the water dispersion can add the same number and twice the volume of another liquid: milk, juice. These mixed dispersion is stored for 1 h at room temperature before use. Tablets or dispersion should be taken on an empty stomach twice a day. This means at least 30 minutes before eating or 2 hours after a meal. This dosage regimen is suggested as a guideline, because physicians may deviate from this General guideline, depending on the specific treatment of the patient. Also defined and dosage that the doctor deems necessary for the patient taking into account the extent of disease, age, status, and other relevant medical parameters.

In conclusion, we can say that improved pharmaceutical compositions intended for oral purpose of the acid-labile, dideoxy purine nucleosides provide unexpectedly improved bioavailability of drugs, a small level of variability of the tee features enables the manufacture of bags with a reduced weight and chewable/dispersible tablets, more easy to use by patients. Is the convenience associated with using tablets, provides the advantage of compliance by the patient to therapeutic regimen. Another advantage is dispersible tablets if the patient has difficulty chewing or swallowing.

The following examples describe in detail the experimental methods and procedures for the preparation and use of pharmaceutical compositions and medicaments of the invention. Experts know that a valid modification of the methods, materials and quantities that are included in the objectives and scope of the disclosure. From the foregoing description and examples, the specialist can implement the invention in full.

Example 1. The rate of acid neutralization experimental method

This experiment was conducted to determine the rate and duration of acid neutralization and efficacy in maintaining the desired pH level. This experiment was conducted using USP apparatus II (paddle method). The tank was filled with 750 ml of purified water, USP was added and balanced to 371oC. this water was immersed calibrated probe for pH and added to 4.0 ml of 1.0 N HCl and included the paddle mixer installed on controlled samples were prepared by dissolution/dispersion of the sample in sufficient volume of water. Installed the intake/eject Harvard pump (model 940) with a 30 ml syringe filled with 0,8214 N HCl. Piston speed was regulated to supply 28 ml solution in 1 h (23 m Eq h). The test sample was introduced into the flask and immediately turn on the pump. The container with the solution was filtered purified water, USP and the volume was brought to 972 ml pH of the medium was recorded at specific intervals during 1 h

The following examples of pharmaceutical compositions and preparations use ddI /commonly known as DDI/ as a medicinal element of the acid-labile nucleosides, as ddI was approved for use in the treatment of AIDS. Other acid-labile nucleoside agents, such as DDA and DDG, can easily replace ddI in the compositions and preparations.

The pharmaceutical composition includes, as the powder mixture didanosine and buffer system, which itself consists of insoluble antacid compounds of magnesium, such as magnesium hydroxide, combined with either calcium carbonate or insoluble aluminum antacid compound, for example, dihydroxyphenylethylamine (dihydroxyaluminum sodium). Sweetening, flavouring components and the other is sodium, can also be components. These pharmaceutical compositions are then formed into oral dosage forms such as oral powder suspension or chewable/dispersible tablets.

Example 2. Dosage form suspension for oral administration (bags with reduced mass).

The preferred option didanosine powder compositions for suspension oral administration is prepared as follows.

Take the following ingredients, kg:

Didanosine 7,5

Magnesium hydroxide 14,0

Dihydroxyaluminum sodium 42,0

The dihydrate of sodium citrate to 12.0

Sucrose powder 43,0

Orange flavor 1,2

All the ingredients are placed in V-shaped drum-type mixer and mixed for 15 minutes the Mixture is passed through a Fitzmill hammer mill using 00 plate on medium speed cameras and speed of the fluid. The shredded material is again mixed in a V-mixer for 20 minutes This surround mix is then defined on drug potency and uniformity of content (278 mg of didanosine) 6.0 g weight of powder and RSD of 0.9% for 10 samples with a range 369,8 mg 381 mg (6.0 g)weight and was filled in foil packages per dose using Nazina with the following composition (depending on the strength medications).

Ingredient, g:

Didanosine 0,02 0,375

Magnesium hydroxide 0,700

Dihydroxyaluminum sodium carbonate 2,100

The dihydrate sodium citrate 0,600

Sucrose powder Q. S.

Orange flavor to 0.060 Net weight of 6,000 gx< / BR>
xPackages of the prior art (CF packages) contained 20 g of powder mixture.

Example 3. Chewable/dispersible tablet for oral administration

A preferred variant of the preparation didanosine chewable/dispersible tablet is prepared as follows.

Take the following ingredients, kg:

Didanosine 2,083

Magnesium hydroxide 7,500

Dihydroxyaluminum sodium 22,500

The dihydrate sodium citrate 5,000

Aspartame 0,667

Polyplasdone XL 10 1,250

Sucrose powder 2,667

Microcrystalline cellulose pH 101 6,500

Silicon dioxide 0,525

Natural fragrance of Grushenka 0,375

Magnesium stearate (density) of 0.625

All the ingredients are placed in the V-drum-type mixer and mixed for 10 minutes the Mixture is then passed through the mill Fitzmill with knives ahead of using IB plates with an average speed cameras and average speed of supply. The shredded material is again mixed in a V-mixer b is ready ispolzuya plate with low speed and medium speed feed. Crushed slugs then passed through oscillators using a wire mesh screen 16. The obtained granules are placed in a drum V-mixer, to which is added the estimated number of stearate 0.0125 g/2,9875 g of the weight of the granules, and mixing continues for 7 minutes Then the mixture is estimated drug Potentate and homogeneous (126 mg of didanosine/3.0 g weight of granules and RSD of 1.0% per 10 samples with deadzoom 124 mg 128 mg/3.0 g of granules. The granules are compressed into tablets on a rotary tablet press D3 using a 7/8" round flat with beveled edges of the punches. Tablets are compressed to a hardness 16-24 units of force Cobb with final weight of 3.0 g/tablet.

These tablets have the following composition (depending on the strength medications).

Ingredient, g:

Didanosine 0,010 0,150

Magnesium hydroxide 0,4500

Dihydroxyaluminum sodium 1,3500

The dihydrate sodium citrate 0,3000

Aspartame 0,0400x< / BR>
Polyplasdone XL10 0,0750

Sucrose powder 0,1600

Microcrystalline cellulose pH 101 -

pH 101

Silicon dioxide 0,0375

Natural fragrance of Grushenka 0,0225

Magnesium stearate (for p is used for 150 mg tablets of didanosine

Example 4. Chewable/dispersible tablet without sodium for oral primeneniya

A preferred variant of the preparation didanosine chewable/dispersible tablet is prepared as follows.

Ingredient, kg:

Didanosine 0,300

Calcium carbonate 1,000

Magnesium hydroxide 0,500

Aspartame 0,120

Polyplasdone XL 10 0,150

Silicon dioxide 0,040

Microcrystalline cellulose 1,460

Natural orange flavor 0,100

Magnesium stearate (for seggiovia) 0.020

Magnesium stearate (tabletting) 0,010

All the ingredients are placed in the V-drum-type mixer and mixed for 10 minutes the Mixture is then passed through the mill Fitzmill with knives forward with ispolzovaniem plate with an average speed cameras and average speed of supply. The crushed material is again mixed in a V-mixer for 10 minutes the Mixture bloggerette F-press with one punch. Slugs are passed through a Fitzmill with knives forward with ispolzovaniem plate with slow speed cameras and average speed of supply. Crushed slugs then skipped through the oscillator with a wire mesh screen 16. The obtained granules are placed in a V-mixer, which is added to the calculation of the TCI F-press with one punch using 3/4" round flat with beveled edges of the punches. Tablets are compressed to a hardness 18-21 units with final weight of 1.9 g/tablet.

Tablets have the following composition.

Ingredient quantity grams per pill

Didanosine 0,005-0,150

Calcium carbonate (light) 0,550

Magnesium hydroxide 0,250

Aspartame 0,020-to 0.060*< / BR>
Polyplasdone XL 10 0,075

Silica 0.020

Microcrystalline cellulose q.s. (at 0.730)

Natural orange flavor 0,050

Magnesium stearate (for seggiovia) 0,010

Magnesium stearate (tabletting) 0,005

The total weight of the tablet 1,900

*The amount of aspartame varies with the content of didanosine, and composition of the average force contain proportional amounts of aspartame.

Example 5. Chewable/dispersible tablet without sodium for oral administration 2

The preferred option didanosine chewable/dispersible tablets prepared following a modification of the procedure described in example 4, to obtain tablets with the following composition.

Ingredient quantity (g) per tablet

Didanosine 0,005-0,150

Calcium carbonate (light 0,550

Magnesium hydroxide 0,250

Aspartame 0,020-0,070*< / BR>
Polyplasdone XL 10 0,100

SOR is magnesium (for seggiovia) 0,015

Magnesium stearate (tabletting) 0,015

The total weight of the tablet 2,10

*The amount of aspartame varies with the content of didanosine.

Example 6. The comparative bioavailability of didanosine appointed at a dose of 375 mg in the form of a solution, chewable tablets and suspension.

Assessment of bioavailability of didanosine on two new drugs, chewable tablet and suspension compared with citrate/phosphate buffer solution was carried out on the 18 men who were seropositive for the virus of human immunodeficiency (HIV). This study was conducted for 6 persons in each of the 3 clinics using the open arbitrary triangular cross-model. Each person received one dose of didanosine 375 mg orally in the morning on an empty stomach. Between each treatment was 7-day period. For 12 h was done in serial blood, urine was collected and was done tests on intact didanosine liquid chromatography high pressure. Pharmacokinetic parameters were calculated using the inseparable ways. Average parameters are shown in table.2.

The speed of absorption and purification of these compounds are almost the same, founded the Simo on the type of drug. Assessing biological availability at 90% limit values for chews relatively citrate/phosphate buffer was 124% (106-135%) for CMAX and 116% (108-125%) for AUC/INF/. Assessing biological availability at 90% of the limit values for the suspension relative to the citrate/phosphate buffer amounted to 139% (121-154%) for CMAX and 125% (117-134%) for ABU/INF/. Based on this approach, we can say that two new drugs have greater bioavailability than the reference drug, citrate/phosphate buffer.

Example 7. The comparative bioavailability of didanosine /2', 3'-dideoxyinosine, ddI) after the appointment in the form of a solution in the form of a chewable tablet.

The bioavailability of the drug chewable tablet didanosine in comparison with a reference preparation package with citrate/phosphate buffer was determined in 24 patients-men seropositive for the virus of human immunodeficiency (HIV or VCI). Using cross-arbitrary model studies, patients in conditions of starvation were given a single 375 mg dose of oral citrate/phosphate buffer in the package or 300 mg dose of the drug in chewable tablet (administered as 2 tablets 150 mg). A week later lecesne and urine samples were analyzed for didanosine using methods liquid chromatography high pressure) UV. The sample was used for calculation of pharmacokinetic parameters using inseparable ways. Average values for the main parameters are given in table.3.

Statistically significant sequence or periodic effects were not detected for any of the parameters, if based on the results analysis of variance. Evaluation of biological availability chewable tablet didanosine compared with citrate/phosphate buffer was carried out based on two-sided tests. Estimates at 90% values for CMAX for chewable tablets in comparison with zither/phosphate buffer was 103% (95% 112% ). Corresponding values for AUC/INF/ were 87% (81% to 93%). We can conclude that the 375 mg dose of didanosine assigned in the form of citrate-phosphate buffer, equivalenta 300 mg dose of chewable tablets.

APPLICATION

List of abbreviations

AIDS (AIDS) acquired immune deficiency syndrome

ARC complex, related AIDS

the ddI dideoxyadenosine

CP sachet powder formulation of DDI with citrate/phosphate buffer, Packed in sachets

dd ATP 2',3'-dideoxyadenosine-5'-triphosphate

the ddG dideoxyinosine

ddI dideoxyinosine (DDI)

D NA desoxyribonucleic UV detector

IC50 concentration of 50% inhibition

q. s. (enough) as much as you want, i.e. to bring the weight or volume of the formulation to a certain total weight or volume

RNA ribonucleic acid

RSD relative standard deviation, a measure of the differences between samples

RT, reverse transcriptase; revertase

SD standard deviation

U. S. P. Pharmacopoeia Ssag

1. Pharmaceutical composition for oral administration in the form of tablets or in powder form for the preparation of dispersions in liquids, possessing antiviral activity, containing as active ingredient 2',3'-methoxyphenoxy nucleoside selected from the group comprising 2',3'-deoxyadenosine, 2', 3'-deoxyinosine and 2',3'-deoxyguanosine and/or their pharmaceutically acceptable salts and/or hydrates, comprising a buffer system and the target additives, characterized in that as a buffer system, it contains water-insoluble antacid buffer system, ensuring the achievement of the pH in the stomach about 5 and consisting of water-insoluble antacid compounds of magnesium in combination with dihydroxyaluminum sodium in their mass ratio 1 2 4, respectively, or in combination with mass ratio specified 2',3'-methoxypurine of nucleoside and specific additives in combination with the buffer system is 0,005 0,375 1,9 6,0 respectively.

2. The composition according to p. 1, characterized in that as the water-insoluble antacid compounds of magnesium it contains a compound selected from the group including magnesium carbonate, hydroxide, magnesium carbonate, magnesium hydroxide, magnesium oxide, trehosnovnoy phosphate of magnesium and magnesium trisilicate.

3. Composition under item 1 or 2, characterized in that as the target additives it contains one or more ingredients selected from the group comprising water-soluble antacid buffer, sweetening agent, flavoring agent, a disintegrator, a binder, pharmaceutically acceptable carriers, excipients or diluents.

4. The composition according to p. 3, characterized in that it contains 2',3'-deoxyinosine, as water-insoluble buffer system is a combination of calcium carbonate with magnesium hydroxide as the target additives, sweetening agent, flavoring agent and pharmaceutically acceptable excipients.

5. Composition in tablet form under item 1, characterized in that it contains 0,025 0,150 g of 2',3'-deoxyinosine, 1.3 to 1.4 g of dihydroxyaluminum sodium, 0.4 to 0.5 g of magnesium hydroxide, 0.3 g of sodium dehydroacetate, 0.04 - 0.06 g of aspartame, 0.16 g of sucrose, 0.075 g polyplasdone, 0.04 g dirhodium to bring the weight of the tablet up to 3 g

6. Composition in tablet form under item 1, characterized in that it contains 0,025 0,150 g of 2',3'-deoxyinosine, 0.5 to 0.6 g of calcium carbonate, 0.2 to 0.3 g of magnesium hydroxide, 0.06 g of aspartame, 0.08 g polyplasdone, 0.02 g of silicon dioxide, 0.05 g of orange flavor, 0.02 g of magnesium stearate and microcrystalline cellulose in an amount necessary to bring the mass of the tablet to 1.9 g

7. Composition in tablet form under item 1, characterized in that it contains 0,025 0,150 g of 2',3'-deoxyinosine, 0.5 to 0.6 g of calcium carbonate, 0.2 to 0.3 g of magnesium hydroxide, 0.07 g of aspartame, 0.1 g polyplasdone, 0.03 g of sorbitol, 0.05 g tangerine-orange flavor, 0.03 g of magnesium stearate and microcrystalline cellulose in an amount necessary to bring the mass of the tablet to 2.1,

 

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