Dosage forms of prolonged action. II Chapter Technology for the manufacture of prolonged-release tablets Advantages and disadvantages of prolonged dosage forms

Prolonged tablets are tablets, the medicinal substance of which is released slowly and evenly or in several portions. These tablets allow you to provide a therapeutically effective concentration of drugs in the body for a long period of time.

The main advantages of these dosage forms are:

the possibility of reducing the frequency of reception;

the possibility of reducing the course dose;

the possibility of eliminating the irritating effect of drugs on the gastrointestinal tract;

the ability to reduce the manifestations of major side effects.

The following requirements are imposed on prolonged dosage forms:

the concentration of medicinal substances as they are released from the drug should not be subject to significant fluctuations and should be optimal in the body for a certain period of time;

excipients introduced into the dosage form must be completely excreted from the body or inactivated;

prolongation methods should be simple and affordable in execution and should not have a negative effect on the body.

The most physiologically indifferent is the method of prolongation by slowing down the absorption of medicinal substances.

2. Classification of dosage forms of prolonged action:

1) Depending on the route of administration, prolonged forms are divided into:

dosage forms of retard;

depot dosage forms ("Moditen Depot" - the frequency of administration is 15-35 days; "Klopiksol Depot" - 14-28 days);

2) Taking into account the kinetics of the process, dosage forms are distinguished:

with periodic release;

continuous;

delayed release.

Depending on the route of administration

1) Depot dosage forms- these are prolonged dosage forms for injections and implantations, which ensure the creation of a reserve of the drug in the body and its subsequent slow release.

Depot dosage forms always end up in the same environment in which they accumulate, in contrast to the changing environment of the gastrointestinal tract. The advantage is that they can be administered at longer intervals (sometimes up to a week).

In these dosage forms, the slowdown in absorption is usually achieved by the use of poorly soluble compounds of medicinal substances (salts, esters, complex compounds), chemical modification - for example, microcrystallization, placing medicinal substances in a viscous medium (oil, wax, gelatin or synthetic medium), using delivery systems - microspheres, microcapsules, liposomes.

2) Dosage forms of retard- these are prolonged dosage forms that provide the body with a supply of a medicinal substance and its subsequent slow release. These dosage forms are used primarily orally, but are sometimes used for rectal administration.

To obtain dosage forms of retard, physical and chemical methods are used:

Physical methods include coating methods for crystalline particles, granules, tablets, capsules; mixing medicinal substances with substances that slow down absorption, biotransformation and excretion; the use of insoluble bases (matrices), etc.

The release rate of the medicinal substance varies depending on the degree of grinding of the ion exchanger and on the number of its branched chains.

Depot dosage forms. Depending on the production technology, there are two main types of retard dosage forms - reservoir and matrix.

1. Tank type molds. They are a core containing a medicinal substance and a polymer (membrane) shell, which determines the release rate. The reservoir can be a single dosage form (tablet, capsule) or a medicinal microform, many of which form the final form (pellets, microcapsules).

2.Matrix type molds. They contain a polymer matrix in which the medicinal substance is distributed and very often has the form of a simple tablet.

Dosage forms of retard include enteric granules, retard dragees, enteric-coated dragees, retard and retard forte capsules, enteric-coated capsules, retard solution, rapid retard solution, retard suspension, double-layer tablets, enteric tablets, frame tablets, multilayer tablets, tablets retard, rapid retard, retard forte, retard mite and ultraretard, multiphase coated tablets, film coated tablets, etc.

2. Taking into account the kinetics of the process, dosage forms are distinguished: 1) Dosage forms with periodic release- these are prolonged dosage forms, with the introduction of which the drug substance is released into the body in portions, which essentially resembles the plasma concentrations created by the usual intake for every four hours. They provide repeated action of the drug.

In these dosage forms, one dose is separated from another by a barrier layer, which can be film, pressed or coated. Depending on its composition, the dose of the medicinal substance can be released either after a given time, regardless of the localization of the drug in the gastrointestinal tract, or at a certain time in the necessary section of the digestive tract.

So when using acid-resistant coatings, one part of the drug substance can be released in the stomach, and the other in the intestine. At the same time, the period of the general action of the drug can be extended depending on the number of doses of the medicinal substance contained in it, that is, on the number of layers of the tablet. Periodic release dosage forms include bilayer tablets and multilayer tablets.

2) Dosage forms with continuous release- these are prolonged dosage forms, when introduced into the body, the initial dose of the drug substance is released, and the remaining (maintenance) doses are released at a constant rate corresponding to the rate of elimination and ensuring the constancy of the desired therapeutic concentration. Dosage forms with a continuous, evenly extended release provide a maintenance effect of the drug. They are more effective than intermittent release forms, as they provide a constant concentration of the drug in the body at a therapeutic level without pronounced extremes, do not overload the body with excessively high concentrations.

Sustained release dosage forms include framed tablets, microformed tablets and capsules, and others.

3) Delayed release dosage forms- these are prolonged dosage forms, with the introduction of which the release of the drug substance into the body begins later and lasts longer than from the usual dosage form. They provide a delayed onset of action of the drug. Suspensions of ultralong, ultralente with insulin can serve as an example of these forms.

The method of administering drugs through the mouth (oral) for a large group of drugs is the main one. With a sufficiently reasonable choice of dosage form, it gives quite satisfactory results. The main advantages of this method are:

convenience;

Introduction.

Microencapsulation.
Conclusion.
Bibliography.

The work contains 1 file

SBEI HPE "Siberian State Medical University" of Roszdrav

Faculty of Pharmacy

Department of Pharmaceutical Technology

Baranova Svetlana Olegovna

Methods for prolonging and regulating the release and absorption of drugs from oral dosage forms.

Course work

IV year student of group 3805

Baranova S.O.

Checked:

Head cafe pharmaceutical technology

V. S. Chuchalin

Introduction.
Modified drugs.
Types of prolonged LF for oral administration
Ways of prologation of solid LF.
New solid dosage forms of prolonged action.
Microencapsulation.
Conclusion.
Bibliography.

Introduction.

the naturalness of the introduction of the drug into the body;
convenience;
sufficient dosing accuracy.

However, with all its simplicity, the oral route of administration is not without very significant drawbacks:

the difficulty (sometimes the impossibility) of using this method, for example, in pediatrics and in the unconscious state of the patient;
the influence of taste, smell, color of the drug;
the ineffectiveness of prescribing a large number of drugs (many antibiotics, enzymes, hormones, etc.);
the effect of digestive enzymes and food constituents on medicinal substances;
dependence of the absorption rate on the filling of the digestive tract;
Especially serious difficulties are encountered by the oral route of administration in case of damage to the liver and other organs of the digestive tract, violations of the processes of swallowing and diseases of the cardiovascular system with stagnation.

The main oral dosage forms are solutions, powders, tablets, capsules and pills. There are also dosage forms (for example, tablets with multilayer shells), when taking the active drug, it is released longer than usual (compared to conventional dosage forms), which allows to prolong the therapeutic effect.

Most oral medications should be taken with plenty of fluids.

Based on the shortcomings of dosage forms used by the oral route, one of the goals of pharmaceutical technology has become the improvement of drugs in order to obtain more effective, convenient to use and longer lasting. This course work will consider the methods and principles used to achieve this goal.

Modified drugs.

The most common way to take drugs is by mouth (oral administration). At the same time, the absorption of medicinal substances begins already in the stomach, but it is maximally carried out in the small intestine, which is facilitated by a significant surface of the intestine and its active blood supply. Medicinal substances are absorbed from the intestinal lumen and enter the vessels of the intestinal wall, and then into the portal vein system. Through the portal vein system, drugs enter the liver, where they can immediately undergo biotransformation. This stage of drug inactivation is defined by the term first pass metabolism. The more pronounced the presystemic metabolism of the drug, the less its amount will enter the systemic circulation. With the oral route of administration of drugs, bioavailability is determined by losses during absorption from the gastrointestinal tract and destruction during the first passage of the liver. In this regard, substances with low bioavailability should be administered orally at much higher doses than when administered intravenously or intra-arterially. We also note that with the similarity of dosage forms, differences in quality and effectiveness of different drugs based on the same active substance are largely determined by this parameter.

Currently, due to the existing shortcomings of oral drugs, LF with modified release and action have been invented.

Dosage forms with modified release - a group of dosage forms with modified, compared with the usual form, mechanism and nature of the release of medicinal substances (PM).

The concept of a drug delivery system is closely related to the concept of dosage forms with modified release.

To modify the release, methods are used:

physical (the use of substances that slow down the absorption, metabolism and excretion of drugs);
chemical (obtaining sparingly soluble salts, replacing some functional groups with others; introducing new chemical groups into the composition of the molecule of the original substance);
technological (coating with special shells, use of components with different release rates in a single dosage form, incorporation into a matrix, etc.).

Depending on the degree of control of the release process, dosage forms with controlled release and prolonged dosage forms are distinguished. Both of these groups, depending on the kinetics of the process, can be divided into dosage forms with intermittent release, continuous release, delayed release. Most modern dosage forms are in modified release versions.

Controlled release dosage forms (syn.: controlled release dosage forms, programmed release dosage forms) - a group of dosage forms with modified release, characterized by an increase in the time of entry of the drug into the biophase and its release corresponding to the real needs of the body. A release is said to be controlled if the following three conditions are met:

the type of mathematical dependence of the amount of released drug on the parameters that affect the release process is known (difference from prolonged dosage forms);
The drug is released according to a pharmacokinetically rational rate or rate program;
the release rate is not affected or only slightly affected by physiological conditions (pH and enzymatic composition of gastrointestinal fluids, etc.), so that it is determined by the properties of the system itself and can be theoretically predicted with sufficient accuracy.

If any of these conditions is not met, then the dosage form is referred to as prolonged forms. The modern nomenclature of controlled release formulations includes therapeutic systems, controlled release capsules, spansules, controlled release tablets.

Prolonged dosage forms (from lat. prolongare - lengthen, longus - long, long) - dosage forms with a modified release that provide an increase in the duration of the drug by slowing down its release.

Advantages over conventional drugs:

the possibility of reducing the frequency of reception;
the possibility of reducing the course dose;
the possibility of eliminating the irritating effect of drugs on the gastrointestinal tract;
the possibility of reducing the frequency of side effects.

The following requirements are imposed on prolonged dosage forms:

1) the concentration of the drug as it is released from the drug should not be subject to significant fluctuations and should be optimal in the body for a certain period of time;

2) excipients introduced into the dosage form must be completely eliminated from the body or inactivated;

3) prolongation methods should be simple and affordable in execution and should not have a negative effect on the body.

The most indifferent in physiological terms is the method of prolongation by slowing down the absorption of drugs. Depending on the route of administration, prolonged forms are divided into depot dosage forms and retard dosage forms. Taking into account the kinetics of the process, dosage forms are distinguished with intermittent release, continuous release, and delayed release.

Types of prolonged LF for oral administration.

Retard dosage forms (from Latin retardo - slow down, tardus - quiet, slow; synonym: retards, retarded dosage forms) - enteral prolonged dosage forms that ensure the creation of a drug reserve in the body and its subsequent slow release. They are used mainly orally; some dosage forms of retard are intended for rectal administration. The term "retard" previously also referred to prolonged injection forms of heparin and trypsin. To obtain dosage forms of retard, physical and chemical methods are usually used. Physical methods include coating methods for crystalline particles, granules, tablets, capsules; mixing drugs with substances that slow down absorption, biotransformation and excretion; the use of insoluble bases (matrices), etc. The main chemical methods are adsorption on ion exchangers and the formation of complexes.

Depending on the production technology, there are two main types of retard dosage forms - reservoir and matrix. Reservoir-type forms are a core containing a drug and a polymer (membrane) shell, which determines the release rate. The reservoir can be a single dosage form (tablet, capsule) or a medicinal microform, many of which form the final form (pellets, microcapsules, etc.). Matrix-type retard forms contain a polymer matrix in which the drug is distributed, and often have the form of a conventional tablet. Retard dosage forms include: enteric granules, retard dragees, enteric-coated dragees, retard and retard forte capsules, enteric-coated capsules, retard solution, rapid retard solution, retard suspension, double-layer tablets, enteric tablets, frame tablets, multilayer tablets, tablets retard, rapid retard, retard mite, retard forte and ultraretard; multiphase coated tablets, film coated tablets, etc.

Dosage forms with periodic release (syn.: dosage forms with multiple release, dosage forms with intermittent release) - prolonged dosage forms, when introduced into the body, the drug is released in portions, which essentially resembles the plasma concentrations created by the usual intake of tablets every 4 hours. Provide repeated action of the drug. In these dosage forms, one dose of drug is usually separated from another by a barrier layer, which can be film, pressed or coated. Depending on its composition, the drug dose can be released either after a specified time, regardless of the localization of the drug in the gastrointestinal tract, or at a certain time in the desired section of the digestive tract. So, when using acid-resistant coatings, one part of the drug can be released in the stomach, and the other part - in the intestine. At the same time, the period of the general action of the drug is extended depending on the number of doses of the drug contained in it, i.e. from the number of layers of the tablet or dragee. Dosage forms with periodic release include two-layer tablets and two-layer dragees ("duplex"), multilayer tablets.

Dosage forms with continuous release (syn.: dosage forms with prolonged release) - prolonged dosage forms, upon administration of which the initial dose of the drug is released into the body, and the remaining (maintenance) doses are released at a constant rate corresponding to the rate of elimination and ensuring the constancy of the desired therapeutic concentration . Dosage forms with a continuous, evenly extended release provide a maintenance effect of the drug. They are more effective than periodic release formulations because provide a constant concentration of drugs at a therapeutic level without pronounced extremes, do not overload the body with excessively high concentrations. Dosage forms with continuous release include frame tablets, tablets and capsules with microforms, etc.

Introduction

2. Positive and negative sides of tablets. Requirements for the manufacture of tablets

2.1 Positive and negative sides of tablets

4. Technology for the manufacture of tablets of prolonged action

4.1 Basic scheme for the manufacture of tablets

Conclusion

Bibliography

Introduction

The technology of dosage forms is the science of the natural-science and technical laws of the production process. Technology ensures the introduction of the latest and modern achievements of science.

Medicines are created from one or more parent medicines. The arsenal of drugs that modern pharmacy has is very significant and diverse. All of them by their nature are either individual chemical substances or preparations consisting of several or many substances.

Drugs or their combinations can be considered as drugs only after they have been given a certain state in accordance with their purpose, routes of administration to the body, doses and with full consideration of their physical, chemical and pharmacological properties. Such a rational state, in which drugs exhibit the necessary therapeutic or prophylactic effect and become convenient for use and storage, is called a dosage form.

The dosage form given to drugs significantly affects their therapeutic effect, affects both the speed of manifestation of the action of the medicinal substance, and equally on the rate of its excretion from the body. By using one or another dosage form, it is possible to regulate these aspects of the manifestation of drugs, achieving in some cases a rapid therapeutic effect, and in others, on the contrary, a slower and longer - prolonged action.

In view of the fact that the dosage form is an important factor in the use of drugs, when finding them, the development of a rational dosage form is an integral and final step in the introduction of each new drug into medical practice.

The technology of dosage forms widely uses the data of chemistry, physics, mathematics and medical and biological disciplines (physiology, biochemistry, etc.). Drug technology is most closely related to the disciplines of the pharmaceutical profile: pharmacognosy, pharmaceutical chemistry, as well as the organization and economics of pharmacy.

Of the medical and biological disciplines, drug technology is most associated with pharmacology, the subject of which is the study of the effect of drugs on the human body.

The medical industry is the source of most of the medicines entering the pharmacy. The priority task of the medical industry is the creation and production of new antibiotics, with special attention being paid to increasing the production of effective means for the prevention and treatment of cardiovascular diseases.

The production and range of drugs in new dosage forms (layered tablets and dragees, various capsules, special forms for children) and packages (ointments in tubes, aerosols in cylinders, packages made of polymeric and other materials, etc.) are expanding.

Currently, tablets are widely used as a dosage form of many drugs. Of the total number of factory-made finished drugs dispensed from pharmacies, up to 40% are tablets. Increasingly widespread is the preparation of tablets instead of various combinations of powders, mixtures, solutions, pills.

The tablet is one of the most common and, at first glance, well-known dosage forms, but its potential is far from being exhausted. Thanks to the achievements of domestic and foreign pharmaceutical science and industry, new technologies for producing tablets appear and their modifications are created.

1. Tablets, their characteristics and classification

Tablets (lat. tabulettae from tabula - board; medicamenta compressa, comprimata) - a solid dosage form obtained by pressing, less often - by molding powders and granules containing one or more medicinal substances with or without auxiliary components.

The first information about the possibility of pressing powders dates back to the middle of the 19th century. In our country, for the first time, the production of tablets began in 1895 at the plant of medical preparations in St. Petersburg, now the Leningrad Production Association "October". The first study on pills was the thesis of Prof. L.F. Ilyin (1900).

Tablets have the form of flat, and biconvex round, oval discs or other forms of plates. The most convenient for the manufacture, packaging and use of tablets in the form of discs, as they are easily and tightly packed. Stamps and matrices for their manufacture are simpler and cheaper. The diameter of the tablets ranges from 3 to 25 mm. Tablets with a large diameter are considered briquettes. The height of the tablets should be within 30-40% of their diameter.

Sometimes the tablets may be cylindrical. Tablets with a diameter (length) of more than 9 mm have one or two risks (notches) perpendicular to each other, allowing you to divide the tablet into two or four parts and thus change the dosage of the medicinal substance. The surface of the tablet should be smooth, uniform; identification inscriptions and symbols (marking) can be applied to the end surfaces. One tablet is usually intended for one dose.

Tablets can be intended for enteral and parenteral administration, as well as for the preparation of solutions or suspensions for oral administration, applications and injections.

Tablets are classified according to a variety of criteria.

How to receive:

pressed (actual tablets);

trituration.

By way of introduction:

oral;

vaginal;

rectal.

By the presence of the shell:

coated;

uncoated.

Depending on biopharmaceutical and pharmacokinetic properties:

with modified release.

On the basis of readiness for use:

ready-made forms;

semi-finished products for the preparation of a solution or suspension.

Depending on the purpose of drugs, the following groups of tablets are distinguished.

Oriblettae are tablets taken orally. Substances are absorbed by the mucous membrane of the stomach or intestines. Tablets are taken orally with water. Sometimes they are pre-dissolved in water. Oral tablets are the main group of tablets.

Resoriblettae are sublingual tablets. Substances are absorbed by the oral mucosa.

Implantablettae - tablets used for implantation. Designed for delayed absorption of medicinal substances in order to prolong the therapeutic effect.

Injectablettae - tablets prepared under aseptic conditions, used to obtain injectable solutions of medicinal substances.

Solublettae - tablets used for the preparation of solutions from compressed substances for various pharmaceutical purposes (rinses, douches, etc.).

Tablets for external use containing toxic substances must be stained with a solution of megillen blue, and those containing mercury dichloride with a solution of eosin.

2. Positive and negative sides of tablets. Requirements for the manufacture of tablets 2.1 Positive and negative aspects of tablets

Tablets, like other dosage forms, have positive and negative sides. The positive qualities of tablets and their production include:

1) full mechanization of the manufacturing process, providing high productivity, purity and hygiene of tablets;

2) the accuracy of dosing of medicinal substances introduced into tablets;

3) portability of tablets, providing ease of dispensing, storage and transportation of drugs;

4) preservation (relatively long) of medicinal substances in a compressed state. For insufficiently stable substances, protective shells can be applied;

5) masking of unpleasant organoleptic properties (taste, smell, coloring ability). It is achieved by imposing shells of sugar, cocoa, chocolate, etc.;

6) the possibility of combining medicinal substances that are incompatible in terms of their physicochemical properties in other dosage forms;

7) localization of the action of the medicinal substance; achieved by applying shells of a special composition, soluble mainly in an acidic (stomach) or alkaline (intestine) environment;

8) prolongation of the action of medicinal substances;

9) regulation of the sequential absorption of several medicinal substances from a tablet at certain intervals of time - the creation of multilayer tablets;

10) prevention of errors in dispensing and taking medications, achieved by pressing out inscriptions on the tablet.

Along with this, the tablets are not free from some disadvantages:

1) during storage, tablets may lose their disintegration and become cemented or, conversely, break down;

2) with tablets, substances are introduced into the body that have no therapeutic value, and sometimes cause some side effects (for example, talc irritates the mucous membrane), but it is possible to limit their amount;

3) individual drugs (for example, sodium or potassium bromide) form highly concentrated solutions in the dissolution zone, which can cause severe irritation of the mucous membranes. We can eliminate the disadvantage of this: before taking such tablets, they are crushed and dissolved in a certain amount of water;

4) not all patients, especially children, can freely swallow tablets.

2.2 Requirements for the manufacture of tablets

There are three main requirements for tablets:

1) dosing accuracy, which refers to the correct weight of both the tablet itself and the medicinal substances included in its composition;

2) mechanical strength - tablets should not crumble and must have sufficient strength;

3) disintegration - the ability to disintegrate or dissolve within the time limits established for certain types of tablets.

Obviously, the mass subjected to tableting must have a combination of properties that ensure the fulfillment of these three requirements. Tableting itself is carried out using special presses, often referred to as tablet machines (see fig.).

The dosing accuracy depends on many conditions that must ensure the trouble-free outflow of bulk material and the filling of the matrix nest with it.

1. Dosing will be accurate if a strictly defined amount of the tablet mass is always supplied to the matrix nest during the entire tableting process. It depends on the constancy of the volume of the matrix nest, on the position of the lower punch.

2. The accuracy of dosing depends on the speed and reliability of filling the matrix nest. If, during the short residence time of the funnel, less material is poured over the matrix hole than the matrix nest can accept, the tablets will always be of a smaller mass. The required filling speed depends on the shape of the funnel and the angle of the slope, as well as on sufficient sliding of the particles of the tableting mass. This can be achieved by adding fractional substances to the material or by granulation.

3. Dosing accuracy is also due to the uniformity of the tablet mass, which is ensured by thorough mixing of medicinal and excipients and their uniform distribution in the total mass. If the mass consists of particles of different sizes, then when the hopper is shaken, the mixture is stratified: large particles remain on top, small ones fall down. This causes a change in the weight of the tablets. Sometimes delamination can be prevented by placing a small agitator in the funnel, but granulation is a more drastic measure.

Speaking about the homogeneity of the material, they also mean its uniformity in the form of particles. Particles having different shapes with the same weight will be placed in the matrix nest with different compactness, which will also affect the weight of the tablets. Alignment of the shape of the particles is achieved by the same granulation.

Mechanical strength. The strength of tablets depends on the natural (physico-chemical) and technological properties of the tableted substances, as well as on the applied pressure.

For the formation of tablets, a necessary condition is the interlocking of the particles. At the beginning of the pressing process, the tableted mass is compacted, the particles come closer together, and conditions are created for the manifestation of the forces of intermolecular and electrostatic interaction. At the first stage of pressing the material, the particles of the material approach and compact due to the displacement of the particles relative to each other, filling the voids.

At the second stage, with an increase in the pressing pressure, an intensive compaction of the material occurs due to the filling of voids and various types of deformations, which contribute to a more compact packing of particles. The deformation helps the particles to wedge each other, which increases the contact surface. At the second stage of pressing and bulk material, a compact porous body is formed, which has sufficient mechanical strength.

And, finally, at the third stage of pressing, volumetric compression of the resulting compact body occurs.

When compressing most drugs, high pressure is required, but for each tablet mass, the compression pressure must be optimal, that is, with sufficient mechanical strength, it is necessary to ensure good disintegration of the tablet.

In addition, high pressure can adversely affect tablet quality and contribute to machine wear. Water, which has a sufficient dipole moment, can often provide cohesion of particles. But water can even interfere with the binding of sparingly soluble and insoluble drugs. In this case, the addition of substances with a higher adhesive force (solutions of starch, gelatin, etc.) is required.

In the event that the natural properties of the medicinal substance cannot provide the necessary strength of tablets with direct tableting, strength is achieved by granulation. When granulating, binders are introduced into the tablet mass, with the help of which the plasticity of the medicinal substance is increased. It is very important that the amount of binders is optimal.

Disintegration Too high tablet strength affects its disintegration: the disintegration time increases, which negatively affects the quality of the tablet. With sufficient mechanical strength, it is necessary to ensure good disintegration of the tablet. Decay depends on many factors:

1) on the amount of binders. Tablets should contain as much of them as necessary to achieve the required strength;

2) on the degree of pressing: excessive pressure worsens the disintegration of the tablet;

3) on the amount of disintegrants that contribute to the disintegration of tablets;

4) on the properties of the substances included in the tablet, on their ability to dissolve in water, wet it, swell.

The selection of binding and disintegrating agents for water-insoluble medicinal substances is important. According to the physical structure, the tablets are a porous body. When they are immersed in a liquid, the latter penetrates all the capillaries penetrating the thickness of the tablet. If the tablet contains highly soluble additives, they will contribute to its rapid disintegration.

Thus, for the manufacture of accurately dosed, easily disintegrating and sufficiently strong tablets, it is necessary that:

the tablet mass, along with the main ones, contained excipients;

granulate in terms of sliding ability, uniformity and the absolute size of the grains ensured maximum dosing accuracy;

the pressure would be such that the rate of disintegration would remain normal with sufficient strength of the tablets.

3. Tablets of prolonged action

Of particular interest among prolonged dosage forms are tablets.

Prolonged tablets (synonyms - tablets with prolonged action, tablets with prolonged release) are tablets, the medicinal substance of which is released slowly and evenly or in several portions. These tablets allow you to provide a therapeutically effective concentration of drugs in the body for a long period of time.

The main advantages of these dosage forms are:

the possibility of reducing the frequency of reception;

the possibility of reducing the course dose;

the possibility of eliminating the irritating effect of drugs on the gastrointestinal tract;

the ability to reduce the manifestations of major side effects.

The following requirements are imposed on prolonged dosage forms:

the concentration of medicinal substances as they are released from the drug should not be subject to significant fluctuations and should be optimal in the body for a certain period of time;

excipients introduced into the dosage form must be completely excreted from the body or inactivated;

prolongation methods should be simple and accessible in execution and should not have a negative effect on the body.

The most physiologically indifferent is the method of prolongation by slowing down the absorption of medicinal substances. Depending on the route of administration, prolonged forms are divided into retard dosage forms and depot dosage forms. Taking into account the kinetics of the process, dosage forms are distinguished with intermittent release, continuous and delayed release. Depot dosage forms (from French depot - warehouse, set aside. Synonyms - dosage forms deposited) are prolonged dosage forms for injections and implantations, which ensure the creation of a supply of the drug in the body and its subsequent slow release.

The modern nomenclature of depot dosage forms includes:

Injection forms - oil solution, depot suspension, oil suspension, microcrystalline suspension, micronized oil suspension, insulin suspensions, injection microcapsules.

Implantation forms - depot tablets, subcutaneous tablets, subcutaneous capsules (depot capsules), intraocular films, ophthalmic and intrauterine therapeutic systems. For parenteral application and inhalation dosage forms, the term "prolonged" or more generally "modified release" is used.

Retard dosage forms (from Latin retardo - slow down, tardus - quiet, slow; synonyms - retards, retarded dosage forms) are prolonged dosage forms that provide the body with a supply of a medicinal substance and its subsequent slow release. These dosage forms are used primarily orally, but are sometimes used for rectal administration.

To obtain dosage forms of retard, physical and chemical methods are used.

The main chemical methods are adsorption on ion exchangers and formation of complexes. Substances bound to the ion exchange resin become insoluble and their release from dosage forms in the digestive tract is based solely on ion exchange. The release rate of the medicinal substance varies depending on the degree of grinding of the ion exchanger and on the number of its branched chains.

Depending on the production technology, there are two main types of retard dosage forms - reservoir and matrix.

Reservoir-type forms are a core containing a drug substance and a polymer (membrane) shell that determines the release rate. The reservoir can be a single dosage form (tablet, capsule) or a medicinal microform, many of which form the final form (pellets, microcapsules).

Matrix-type retard forms contain a polymer matrix in which the medicinal substance is distributed and very often takes the form of a simple tablet. Dosage forms of retard include enteric granules, retard dragees, enteric-coated dragees, retard and retard forte capsules, enteric-coated capsules, retard solution, rapid retard solution, retard suspension, double-layer tablets, enteric tablets, frame tablets, multilayer tablets, tablets retard, rapid retard, retard forte, retard mite and ultraretard, multiphase coated tablets, film coated tablets, etc.

Taking into account the kinetics of the process, dosage forms are distinguished with intermittent release, with continuous release and delayed release.

Intermittent release dosage forms (synonymous with intermittent release dosage forms) are sustained release dosage forms that, when administered to the body, release the drug in portions, essentially resembling the plasma concentrations generated by conventional administration every four hours. They provide repeated action of the drug.

Sustained-release dosage forms are sustained-release dosage forms that, when introduced into the body, release the initial dose of the drug, and the remaining (maintenance) doses are released at a constant rate corresponding to the rate of elimination and ensuring the constancy of the desired therapeutic concentration. Dosage forms with a continuous, evenly extended release provide a maintenance effect of the drug. They are more effective than intermittent release forms, as they provide a constant concentration of the drug in the body at a therapeutic level without pronounced extremes, do not overload the body with excessively high concentrations.

Sustained release dosage forms include framed tablets, microformed tablets and capsules, and others.

Delayed-release dosage forms are prolonged dosage forms, when introduced into the body, the release of the drug substance begins later and lasts longer than from the usual dosage form. They provide a delayed onset of action of the drug. Suspensions of ultralong, ultralente with insulin can serve as an example of these forms.

The nomenclature of prolonged tablets includes the following tablets:

implantable or depot;

retard tablets;

frame;

multilayer (repetabs);

multiphase;

tablets with ion exchangers;

"drilled" tablets;

tablets built on the principle of hydrodynamic balance,

coated tablets;

tablets, granules and dragees, the action of which is determined by the matrix or filler; implantable tablets with controlled release of a medicinal substance, etc.

Implantable tablets (syn. - implantables, depot tablets, tablets for implantation) are sterile trituration tablets with prolonged release of highly purified medicinal substances for injection under the skin. It is shaped like a very small disc or cylinder. These tablets are made without fillers. This dosage form is very common for the administration of steroid hormones. The term "pellets" is also used in foreign literature. Examples are Disulfiram, Doltard, Esperal.

Retard tablets are oral tablets with prolonged (mainly intermittent) release of medicinal substances. Usually they are microgranules of a medicinal substance surrounded by a biopolymer matrix (base). They dissolve in layers, releasing the next portion of the medicinal substance. They are obtained by pressing microcapsules with a solid core on tablet machines. As excipients, soft fats are used, which are able to prevent the destruction of the microcapsule shell during the pressing process.

There are also retard tablets with other release mechanisms - delayed, continuous and evenly extended release. Varieties of retard tablets are duplex tablets, structural tablets. These include Potassium-normin, Ketonal, Kordaflex, Tramal Pretard.

Repetabs are multi-coated tablets that provide repeated action of the drug substance. They consist of an outer layer with a drug that is designed to be released quickly, an inner shell with limited permeability, and a core that contains another dose of the drug.

Multilayer (layered) tablets make it possible to combine medicinal substances that are incompatible in terms of physicochemical properties, prolong the action of medicinal substances, regulate the sequence of absorption of medicinal substances at certain intervals. The popularity of multilayer tablets is increasing as equipment improves and experience is gained in their preparation and use.

Frame tablets (syn. Durula, durules tablets, matrix tablets, porous tablets, skeletal tablets, tablets with an insoluble frame) are tablets with a continuous, evenly extended release and supporting action of medicinal substances.

To obtain them, excipients are used that form a network structure (matrix) in which the medicinal substance is included. Such a tablet resembles a sponge, the pores of which are filled with a soluble substance (a mixture of a medicinal substance with a soluble filler - sugar, lactose, polyethylene oxide, etc.).

These tablets do not disintegrate in the gastrointestinal tract. Depending on the nature of the matrix, they can swell and dissolve slowly or retain their geometric shape during the entire period of stay in the body and be excreted as a porous mass, the pores of which are filled with liquid. Thus, the drug substance is released by washing out.

Dosage forms can be multi-layered. It is important that the medicinal substance is located mainly in the middle layer. Its dissolution begins from the lateral surface of the tablet, while from the upper and lower surfaces only auxiliary substances diffuse from the middle layer through the capillaries formed in the outer layers. At present, the technology for obtaining frame tablets using solid dispersed systems (Kinidin durules) is promising.

The release rate of the drug substance is determined by such factors as the nature of the excipients and the solubility of the drug substances, the ratio of drugs and matrix-forming substances, the porosity of the tablet and the method of its preparation. Auxiliary substances for the formation of matrices are divided into hydrophilic, hydrophobic, inert and inorganic.

Hydrophilic matrices - from swelling polymers (hydrocolloids): hydroxypropylC, hydroxypropylmethylC, hydroxyethylmethylC, methyl methacrylate, etc.

Hydrophobic matrices - (lipid) - from natural waxes or from synthetic mono, di - and triglycerides, hydrogenated vegetable oils, higher fatty alcohols, etc.

Inert matrices - from insoluble polymers: ethylC, polyethylene, polymethyl methacrylate, etc. To create channels in the polymer layer that is insoluble in water, water-soluble substances (PEG, PVP, lactose, pectin, etc.) are added. Washing out of the tablet frame, they create conditions for the gradual release of drug molecules.

To obtain inorganic matrices, non-toxic insoluble substances are used: Ca2HPO4, CaSO4, BaSO4, aerosil, etc.

Speystabs are tablets with a medicinal substance included in a solid fatty matrix that does not disintegrate, but slowly disperses from the surface.

Lontabs are tablets with prolonged release of medicinal substances. The core of these tablets is a mixture of medicinal substance with high molecular weight waxes. In the gastrointestinal tract, they do not disintegrate, but slowly dissolve from the surface.

One of the modern methods of prolonging the action of tablets is coating them with shells, in particular with Aqua Polish coatings. These coatings provide prolonged release of the substance. They have alkaliphilic properties, due to which the tablet is able to pass through the acidic environment of the stomach in an unchanged state. The solubilization of the coating and the release of the active substances takes place in the intestine. The release time of the substance can be controlled by adjusting the viscosity of the coating. It is also possible to set the release time of the various substances in the combined preparations.

Examples of compositions of these coatings:

Methacrylic acid / Ethyl acetate

Sodium carboxymethylcellulose

Titanium dioxide.

In another embodiment, the coating replaces sodium carboxymethyl cellulose with polyethylene glycol.

Of great interest are tablets, the prolonged action of which is determined by the matrix or filler. Prolonged release of the drug from such tablets is achieved by using an injection molding technique in which the drug is embedded in a matrix, for example by using cation or anion dependent plastics as the matrix.

The initial dose is in gastric juice-soluble epoxy resin thermoplastic, and the delayed dose is in gastric juice-insoluble copolymer. In the case of using an inert, insoluble matrix (for example, polyethylene), the drug is released from it by diffusion. Biodegradable copolymers are used: wax, ion-exchange resins; The original matrix preparation is a system consisting of a compact material that is not absorbed by the body, in which there are cavities connected to the surface by channels. The diameter of the channels is at least two times smaller than the diameter of the polymer molecule in which the active substance is located.

Tablets with ion exchangers - prolonging the action of a medicinal substance is possible by increasing its molecule due to precipitation on an ion-exchange resin. Substances bound to the ion exchange resin become insoluble, and the release of the drug in the digestive tract is based only on ion exchange.

The release rate of the medicinal substance varies depending on the degree of grinding of the ion exchanger (grains of 300-400 microns in size are more often used), as well as on the number of its branched chains. Substances that give an acid reaction (anionic), for example, derivatives of barbituric acid, bind to anion exchangers, and in tablets with alkaloids (ephedrine hydrochloride, atropine sulfate, reserpine, etc.), cation exchangers (substances with an alkaline reaction) are used. Tablets with ion exchangers maintain the level of action of the medicinal substance for 12 hours.

Some foreign firms are currently developing the so-called "drilled" tablets of prolonged action. Such tablets are formed with one or two planes on its surface and contain a water-soluble ingredient. The "drilling" of the planes in the tablets creates an additional interface between the tablets and the medium. This in turn leads to a constant release rate of the drug, since as the active substance dissolves, the release rate decreases in proportion to the decrease in the surface area of the tablet. Creating such holes and increasing them as the tablet dissolves compensates for the decrease in area of the tablet as it dissolves and keeps the dissolution rate constant. Such a tablet is coated with a substance that does not dissolve in water, but passes it through.

As the tablets move along the gastrointestinal tract, the absorption of the drug substance decreases, therefore, in order to achieve a constant rate of entry of the substance into the body for drugs that undergo resorption throughout the entire gastrointestinal tract, the release rate of the drug substance must be increased. This can be achieved by varying the depth and diameter of the "drilled" tablets, as well as changing their shape.

Long-acting tablets based on the principle of hydrodynamic balance have been created, the action of which is manifested in the stomach. These tablets are hydrodynamically balanced so that they are buoyant in the gastric juice and retain this property until the drug is completely released from them. For example, abroad they produce pills that lower the acidity of gastric juice. These tablets are two-layer, and hydrodynamically balanced in such a way that upon contact with gastric juice, the second layer acquires and retains such a density at which it floats in gastric juice and remains in it until all anti-acid compounds are completely released from the tablet.

One of the main methods for obtaining matrix carriers for tablets is compression. At the same time, a variety of polymeric materials are used as matrix materials, which eventually decompose in the body into monomers, that is, they are almost completely decomposed.

Thus, at present, in our country and abroad, various types of solid dosage forms of prolonged action are being developed and produced from simpler tablets, granules, dragees, spansules to more complex implantable tablets, tablets of the "Oros" system, therapeutic systems with self-regulation. At the same time, it should be noted that the development of sustained-release dosage forms is associated with the widespread use of new excipients, including polymeric compounds.

4. Technology for the manufacture of tablets of prolonged action 4.1 The main scheme for the manufacture of tablets

The most common are three technological schemes for obtaining tablets: using wet or dry granulation and direct compression.

The main steps in the tablet manufacturing process are as follows:

weighing, after which the raw material is sent for sifting with the help of sieves of the vibrational principle of operation;

granulation;

calibration;

pressing to obtain tablets;

packaging in blisters.

package.

Preparation of raw materials for tableting is reduced to their dissolution and hanging.

Weighing of raw materials is carried out in fume hoods with aspiration. After weighing, the raw material is sent for sifting with the help of vibrating sieves.

Mixing. The medicinal and excipients that make up the tablet mixture must be thoroughly mixed to evenly distribute them in the total mass. Obtaining a tablet mixture homogeneous in composition is a very important and rather complex technological operation. Due to the fact that the powders have different physical and chemical properties: dispersion, bulk density, moisture content, fluidity, etc. At this stage, paddle-type batch mixers are used, the shape of the blades can be different, but most often worm or z-shaped. Often also the mixing is carried out in a granulator.

Granulation. This is the process of converting a powdered material into grains of a certain size, which is necessary to improve the flowability of the tablet mixture and prevent its delamination. Granulation can be "wet" and "dry". The first type of granulation is associated with the use of liquids - solutions of excipients; in dry granulation, wetting liquids are either not used, or they are used only at one specific stage in preparing the material for tableting.

Wet granulation consists of the following operations:

grinding substances into fine powder;

moistening the powder with a solution of binders;

rubbing the resulting mass through a sieve;

drying and processing of the granulate.

Grinding. Usually, the operations of mixing and uniform moistening of a powder mixture with various granulating solutions are combined and carried out in one mixer. Sometimes mixing and granulation operations are combined in one apparatus (high-speed mixers - granulators). Mixing is provided by vigorously forced circular mixing of the particles and pushing them against each other. The mixing process to obtain a homogeneous mixture lasts 3 - 5 minutes. Then the granulating liquid is fed to the pre-mixed powder into the mixer, and the mixture is stirred for another 3-10 minutes. After the granulation process is completed, the unloading valve is opened, and with the scraper slowly rotating, the finished product is poured out. Another design of the apparatus for combining the operations of mixing and granulation is used - a centrifugal mixer - granulator.

Hydration. As binders, it is recommended to use water, alcohol, sugar syrup, gelatin solution and 5% starch paste. The required amount of binders is determined empirically for each tablet mass. In order for the powder to be granulated at all, it must be moistened to a certain extent. The adequacy of moisture is judged as follows: a small amount of mass (0.5 - 1 g) is squeezed between the thumb and forefinger: the resulting "cake" should not stick to the fingers (excessive moisture) and crumble when falling from a height of 15 - 20 cm (insufficient moisture). Humidification is carried out in a mixer with S (sigma) - shaped blades that rotate at different speeds: the front one - at a speed of 17 - 24 rpm, and the rear one - 8 - 11 rpm, the blades can rotate in the opposite direction. To empty the mixer, the body is overturned and the mass is pushed out with the help of blades.

Rubbing (proper granulation). Granulation is carried out by rubbing the resulting mass through a sieve of 3 - 5 mm (No. 20, 40 and 50). Punching sieves made of stainless steel, brass or bronze are used. The use of woven wire sieves is not allowed in order to avoid falling into the tablet mass of wire fragments. Rubbing is carried out with the help of special rubbing machines - granulators. The granulated mass is poured into a vertical perforated cylinder and wiped through the holes with the help of springy blades.

Drying and processing of granules. The resulting ranulas are scattered in a thin layer on pallets and sometimes dried in air at room temperature, but more often at a temperature of 30 - 40? C in drying cabinets or drying rooms. Residual moisture in granules should not exceed 2%.

Compared with drying in drying cabinets, which are inefficient and in which the duration of drying reaches 20 - 24 hours, drying of granules in a fluidized (fluidized) bed is considered more promising. Its main advantages are: high intensity of the process; reduction of specific energy costs; full automation of the process.

But the pinnacle of technical perfection and the most promising is the apparatus in which the operations of mixing, granulating, drying and dusting are combined. These are the well-known devices SG-30 and SG-60, developed by the Leningrad NPO Progress.

If the wet granulation operations are carried out in separate apparatuses, the drying of the granules is followed by the dry granulation operation. After drying, the granulate is not a uniform mass and often contains lumps of sticky granules. Therefore, the granulate is re-entered into the masher. After that, the resulting dust is sifted from the granulate.

Since the granules obtained after dry granulation have a rough surface, which makes it difficult to spill them out of the hopper during tableting, and in addition, the granules can stick to the matrix and punches of the tablet press, which causes, in addition to weight loss, flaws in the tablets, resorted to to the operation of "dusting" the granulate. This operation is carried out by free application of finely divided substances on the surface of the granules. Sliding and disintegrating agents are introduced into the tablet mass by dusting.

dry granulation. In some cases, if the drug substance decomposes in the presence of water, dry granulation is resorted to. To do this, briquettes are pressed from the powder, which are then ground to obtain grits. After sifting from dust, the grains are tableted. At present, dry granulation is understood as a method in which a powdered material is subjected to an initial compaction (compression) and a granulate is obtained, which is then tableted - a secondary compaction. During the initial compaction, dry adhesives (MC, CMC, PEO) are introduced into the mass, which provide adhesion of particles of both hydrophilic and hydrophobic substances under pressure. Proven suitability for dry granulation of PEO in combination with starch and talc. When using one PEO, the mass sticks to the punches.

Pressing (actual tableting). This is the process of forming tablets from granular or powdered material under pressure. In modern pharmaceutical production, tableting is carried out on special presses - rotary tablet machines (RTM). Pressing on tablet machines is carried out by a press tool consisting of a matrix and two punches.

The technological cycle of tableting on the RTM consists of a number of successive operations: dosing of the material, pressing (formation of a tablet), its ejection and dropping. All of the above operations are carried out automatically one after the other with the help of appropriate actuators.

Direct pressing. This is a process of pressing non-granular powders. Direct pressing eliminates 3-4 technological steps and thus has an advantage over tableting with pre-granulation of powders. However, despite the apparent advantages, direct compression is slowly being introduced into production.

This is due to the fact that for the productive operation of tablet machines, the pressed material must have optimal technological characteristics (flowability, compressibility, moisture content, etc.). Only a small number of non-granular powders have such characteristics - sodium chloride, potassium iodide, sodium and ammonium bromide, hexomethylenetetramine, bromamphor and other substances that have isometric shapes of particles of approximately the same particle size distribution, not containing a large amount of fine fractions. They are well pressed.

One of the methods for preparing medicinal substances for direct compression is directional crystallization - they achieve the production of a tableting substance in crystals of a given flowability, compressibility and moisture content by means of special crystallization conditions. Acetylsalicylic acid and ascorbic acid are obtained by this method.

The widespread use of direct pressing can be ensured by increasing the flowability of non-granular powders, high-quality mixing of dry medicinal and excipients, and reducing the tendency of substances to separate.

Dedusting. To remove dust fractions from the surface of the tablets coming out of the press, dust removers are used. The tablets pass through a rotating perforated drum and are cleaned of dust, which is sucked off by a vacuum cleaner.

After the production of tablets, the stage of their packaging in blisters on blister machines and packaging follows. In large industries, blister and carton machines (the latter also include a false machine and a marker) are combined into a single technological cycle. Manufacturers of blister machines complete their machines with additional equipment and deliver the finished line to the customer. In low-productivity and pilot productions, it is possible to perform a number of operations manually, in connection with this, this paper provides examples of the possibility of purchasing individual items of equipment.

4.2 Features of the technology for the manufacture of prolonged-release tablets

With the help of multilayer tablets, it is possible to achieve a prolongation of the action of the drug. If there are different medicinal substances in the layers of the tablet, then their action will manifest itself differentially, sequentially, in the order of the dissolution of the layers.

For the production of multilayer tablets, cyclic tablet machines with multiple filling are used. The machines can carry out triple spreading, performed with different granulates. Medicinal substances intended for different layers are fed into the feeder of the machine from a separate hopper. A new medicinal substance is poured into the matrix in turn, and the lower punch falls lower and lower. Each medicinal substance has its own color, and their action is manifested sequentially, in the order of the dissolution of the layers. To obtain layered tablets, various foreign companies produce special RTM models, in particular, the company "W. Fette" (Germany).

Dry pressing also made it possible to separate incompatible substances by placing one medicinal substance in the core and the other in the shell. Resistance to the action of gastric juice can be given by adding to the shell-forming granulate a 20% solution of cellulose acetate.

In these tablets, the layers of the medicinal substance alternate with layers of the excipient, which prevent the release of the active substance until it is destroyed under the influence of various factors of the gastrointestinal tract (pH, enzymes, temperature, etc.).

A variety of multilayer tablets of prolonged action are tablets that are pressed from granules having a coating of various thicknesses, which determines their prolonging effect. Such tablets can be compressed from particles of a medicinal substance coated with polymeric materials, or from granules, the coating of which differs not in its thickness, but in the time and degree of destruction under the influence of various factors of the gastrointestinal tract. In such cases, fatty acid coatings with different melting points are used.

Very original are multilayer tablets containing microcapsules with a medicinal substance in the medial layer, and alginates, methylcarboxycellulose, starch in the outer layer that protects the microcapsules from damage during pressing.

Skeleton tablets can be obtained by simply compressing drugs and excipients that form the skeleton. They can also be multi-layered, for example three-layered, with the medicinal substance predominantly in the middle layer. Its dissolution begins from the side surface of the tablet, while only excipients (for example, lactose, sodium chloride) diffuse from large surfaces (upper and lower). After a certain time, diffusion of the medicinal substance from the middle layer begins through the capillaries formed in the outer layers.

For the production of tablets and granules with ion exchangers, various fillers are used, which, as they break down, release the medicinal substance. So, as a filler for granules of prolonged action, a mixture of a substrate with an enzyme is proposed. The core contains the active component, which is coated. The drug shell contains a pharmacologically acceptable, water-insoluble, film-forming micromolecular component and a water-soluble blowing agent (cellulose ethers, acrylic resins and other materials). The creation of tablets of this type makes it possible to release macromolecules of active substances from them within a week.

This dosage form is obtained by incorporating (incorporating) the medicinal substance into a network structure (matrix) of insoluble excipients, or into a matrix of hydrophilic substances that do not form a high viscosity gel. The material for the "skeleton" are inorganic compounds - barium sulfate, gypsum, calcium phosphate, titanium dioxide and organic - polyethylene, polyvinyl chloride, aluminum soap. Skeletal tablets can be obtained by simply compressing the drugs that form the skeleton.

Coating of tablets. The application of shells has the following goals: to give the tablets a beautiful appearance, increase their mechanical strength, hide an unpleasant taste, smell, protect against environmental influences (light, moisture, atmospheric oxygen), localize or prolong the action of the medicinal substance, protect the mucous membranes of the esophagus and stomach from the damaging effects of the drug.

Coatings applied to tablets can be divided into 3 groups: coated, film and pressed. Enteric coatings localize the drug in the intestine, prolonging its action. AcetylphthalylC, metaphthalylC, polyvinyl acetate phthalate, dextrin, lactose, mannitol, sorbitol, shellac phthalates (natural HMS) are used to obtain coatings. To obtain a film, these substances are used in the form of solutions in ethanol, isopropanol, ethyl acetate, toluene and other solvents, CFI (Moscow). Petersburg) developed a technology for coating tablets with an aqueous ammonia solution of shellac and acetylphthalylC. To improve the mechanical properties of the films, a plasticizer is added to them.

Often the release of the drug substance from the tablets is prolonged by coating them with a polymer shell. For this purpose, various acrylic resins are used along with nitrocellulose, polysiloxane, vinylpyrrolidone, vinyl acetate, carboxymethyl cellulose with carboxymethyl starch, polyvinyl acetate and ethyl cellulose. Using a polymer and a plasticizer to cover prolonged tablets, it is possible to select their quantity in such a way that the drug substance will be released from a given dosage form at a programmed rate.

However, when using them, it must be remembered that in this case, manifestations of biological incompatibility of implants, toxicity phenomena are possible; when they are inserted or removed, surgical intervention associated with pain is necessary. Their significant cost and complexity of the manufacturing process are also important. In addition, it is necessary to apply special security measures to prevent leakage of medicinal substances during the introduction of these systems.

Often, the process of microencapsulation is used to prolong dosage forms.

Microencapsulation is the process of encapsulating microscopic particles of solid, liquid or gaseous medicinal substances. Most often, microcapsules with a size of 100 to 500 microns are used. Particle size< 1 мкм называют нанокапсулами. Частицы с жидким и газообразным веществом имеют шарообразную форму, с твердыми частичками - неправильной формы.

Possibilities of microencapsulation:

a) protection of unstable drugs from environmental influences (vitamins, antibiotics, enzymes, vaccines, sera, etc.);

b) masking the taste of bitter and nauseating drugs;

c) release of medicinal substances in the desired area of the gastrointestinal tract (enteric-soluble microcapsules);

d) prolonged action. A mixture of microcapsules, differing in size, thickness and nature of the shell, placed in one capsule, ensures the maintenance of a certain level of the drug in the body and an effective therapeutic effect for a long time;

e) combination in one place of drugs that are incompatible with each other in pure form (use of separating coatings);

f) "transformation" of liquids and gases into a pseudo-solid state, that is, into a loose mass consisting of microcapsules with a hard shell filled with liquid or gaseous medicinal substances.

A number of medicinal substances are produced in the form of microcapsules: vitamins, antibiotics, anti-inflammatory, diuretic, cardiovascular, anti-asthma, antitussive, sleeping pills, anti-tuberculosis, etc.

Microencapsulation opens up interesting possibilities with a number of drugs that cannot be realized in conventional dosage forms. An example is the use of nitroglycerin in microcapsules. Conventional nitroglycerin in sublingual tablets or drops (on a piece of sugar) has a short period of action. Microencapsulated nitroglycerin has the ability to be released in the body for a long time.

There are methods of microencapsulation: physical, physico-chemical, chemical.

Physical methods. Physical methods for microencapsulation are numerous. These include drageeing, spraying, spraying in a fluidized bed, dispersion in immiscible liquids, extrusion methods, electrostatic method, etc. The essence of all these methods is the mechanical coating of solid or liquid particles of medicinal substances. The use of one or another method is carried out depending on whether the "core" (the contents of the microcapsule) is a solid or liquid substance.

spray method. For microencapsulation of solids that must first be reduced to fine suspensions. The size of the obtained microcapsules is 30 - 50 microns.

The method of dispersion in immiscible liquids is used for microencapsulation of liquid substances. The size of the obtained microcapsules is 100 - 150 microns. Here the drip method can be used. The heated emulsion of the oily drug solution stabilized with gelatin (O/B type emulsion) is dispersed in the cooled liquid paraffin using a stirrer. As a result of cooling, the smallest droplets are covered with a rapidly gelatinous shell. The frozen balls are separated from the liquid paraffin, washed with an organic solvent and dried.

Method of "spraying" in a fluidized bed. In devices such as SP-30 and SG-30. The method is applicable to solid medicinal substances. The solid cores are liquefied with a stream of air and a solution of a film-forming substance is “sprayed” onto them using a nozzle. Solidification of liquid shells occurs as a result of the evaporation of the solvent.

extrusion method. Under the influence of centrifugal force, the particles of medicinal substances (solid or liquid), passing through the film of the film-forming solution, are covered by it, forming a microcapsule.

Solutions of substances with significant surface tension (gelatin, sodium alginate, polyvinyl alcohol, etc.)

Physical and chemical methods. Based on phase separation, they make it possible to encapsulate a substance in any state of aggregation and obtain microcapsules of different sizes and film properties. Physicochemical methods use the phenomenon of coacervation.

Coacervation - the formation in a solution of high-molecular compounds of droplets enriched with a dissolved substance.

As a result of coacervation, a two-phase system is formed due to delamination. One phase is a solution of a macromolecular compound in a solvent, the other is a solution of a solvent in a macromolecular substance.

A solution richer in macromolecular substance is often released in the form of coacervate droplets - coacervate drops, which is associated with the transition from complete mixing to limited solubility. A decrease in solubility is facilitated by a change in such system parameters as temperature, pH, concentration, etc.

Coacervation during the interaction of a polymer solution and a low molecular weight substance is called simple. It is based on the physico-chemical mechanism of sticking together, "raking into a heap" of dissolved molecules and separating water from them with the help of water-removing agents. Coacervation during the interaction of two polymers is called complex, and the formation of complex coacervates is accompanied by the interaction between (+) and (-) charges of molecules.

The method of coacervation is as follows. First, in a dispersion medium (polymer solution), the cores of future microcapsules are obtained by dispersion. The continuous phase is, as a rule, an aqueous solution of the polymer (gelatin, carboxymethyl cellulose, polyvinyl alcohol, etc.), but sometimes it can also be a non-aqueous solution. When conditions are created under which the solubility of the polymer decreases, coacervate drops of this polymer are released from the solution, which are deposited around the nuclei, forming the initial liquid layer, the so-called embryonic membrane. Then there is a gradual hardening of the shell, achieved using various physico-chemical methods.

Hard shells make it possible to separate the microcapsules from the dispersion medium and prevent the penetration of the core substance to the outside.

Chemical methods. These methods are based on polymerization and polycondensation reactions at the interface between two immiscible liquids (water - oil). To obtain microcapsules by this method, first the drug substance is dissolved in oil, and then the monomer (for example, methyl methacrylate) and the corresponding polymerization reaction catalyst (for example, benzoyl peroxide). The resulting solution is heated for 15 - 20 minutes at t=55 °C and poured into an aqueous solution of the emulsifier. An M/B type emulsion is formed which is held to complete the polymerization for 4 hours. The resulting polymethyl methacrylate, insoluble in oil, forms a shell around the droplets of the latter. The resulting microcapsules are separated by filtration or centrifugation, washed and dried.

Apparatus for drying tablet mixtures in a fluidized bed SP-30

Designed for drying powdery materials and tablet granulates that do not contain organic solvents and pyrophoric impurities in the pharmaceutical, food, chemical industries.

When drying multicomponent mixtures, mixing is carried out directly in the apparatus. In dryers of the SP type, it is possible to carry out dusting of tablet mixtures before tableting.

Specifications

How it works: The air flow sucked into the dryer by the fan is heated in the calorific unit, passes through the air filter and is directed under the mesh bottom of the product tank. Passing through the holes in the bottom, the air brings the granulate into suspension. Humidified air is removed from the working area of the dryer through a bag filter, the dry product remains in the tank. After drying, the product is transported in a trolley for further processing.

Conclusion

According to the forecast, at the beginning of the 21st century, significant progress should be expected in the development of new drugs containing new substances, as well as using new systems for administration and delivery to the human body with their programmed distribution.

Thus, not only a wide range of medicinal substances, but also the variety of their dosage forms will allow for effective pharmacotherapy, taking into account the nature of the disease.

It should also be noted the need to study and use in pharmaceutical technology the latest achievements in colloid chemistry and chemical technology, physical and chemical mechanics, colloidal chemistry of polymers, new methods of dispersion, drying, extraction, and the use of non-stoichiometric compounds.

It is quite obvious that the solution of these and other issues facing pharmacy will require the development of new production technologies and methods for the analysis of drugs, the use of new criteria for evaluating their effectiveness, as well as studying the possibilities of implementation in practical pharmacy and medicine.

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Manufacture of new drugs. Such an approach to this problem is qualitatively new in pharmaceutical practice and, obviously, will open up new possibilities in the complex process of creating and using drugs. 2. Ways to improve traditional medicines When developing new medicines with already known effects, attempts are made to...

In the clinic. The rate of dissolution of anhydrous forms of caffeine, theophylline, glutethimide is much higher than their solvate forms. Conversely, the solvate forms of fluorocortisone and succinylfathiazole dissolve more readily than their non-solvate forms. Hydrocortisone tributyl acetate in the form of monoethanol solvate is absorbed 4 times faster than its anhydrous counterpart. Using one or another polymorphic form of a medicinal substance, ...

Registration number: LP 001351-161014
Trade name of the drug: EGILOK® S
International non-proprietary name: metoprolol
Dosage form: prolonged-release film-coated tablets
Compound: 1 tablet contains: active ingredient: 23.75 mg, 47.5 mg, 95 mg or 190 mg metoprolol succinate, which corresponds to 25 mg, 50 mg, 100 mg or 200 mg of metoprolol tartrate, respectively; excipients: microcrystalline cellulose 73.9/147.8/295.6/591.2 mg, methylcellulose 11.87/23.75/47.5/95 mg, glycerol 0.24/0.48/0.95 /1.9 mg, corn starch 1.94/3.87/7.75/15.5 mg, ethylcellulose 11.43/22.85/45.7/91.4 mg, magnesium stearate 1.87/3 .75/7.5/15 mg. Tablet shell (Sepifilm LP 770 white) 3.75 / 7.5 / 15 / 30 mg: microcrystalline cellulose (5-15%), hypromellose (60-70%), stearic acid (8-12%), titanium dioxide ( E-171) (10-20%),
Description: White, oval, biconvex, film-coated tablets, scored on both sides.

Pharmacological group: selective beta1-blocker
ATX code: C07AB02

PHARMACOLOGICAL PROPERTIES

Pharmacodynamics
Metoprolol is a β1-adrenergic blocker that blocks β1 receptors at doses significantly lower than those required to block β2 receptors.
Metoprolol has a slight membrane-stabilizing effect and does not show partial agonist activity.
Metoprolol reduces or inhibits the agonistic effect that catecholamines, which are released during nervous and physical stress, have on cardiac activity. This means that metoprolol has the ability to prevent an increase in heart rate (HR), minute volume and an increase in cardiac contractility, as well as an increase in blood pressure (BP) caused by a sharp release of catecholamines.
Unlike conventional tableted dosage forms of selective blockers (including metoprolol tartrate), when using the long-acting metoprolol succinate drug, a constant concentration of the drug in the blood plasma is observed and a stable clinical effect (β1-blockade) is provided for more than 24 hours. Due to the absence of significant maximum plasma concentrations, the drug is characterized by a higher β1-selectivity compared to conventional tablet forms of metoprolol. In addition, the potential risk of side effects observed at maximum plasma concentrations of the drug, such as bradycardia and weakness in the legs when walking, is greatly reduced. Patients with symptoms of obstructive pulmonary disease, if necessary, can be prescribed long-acting metoprolol succinate in combination with β2-agonists. When used together with β2-agonists, metoprolol succinate of prolonged action in therapeutic doses has a lesser effect on bronchodilation caused by β2-agonists than non-selective β-blockers. Metoprolol, to a lesser extent than non-selective β-blockers, affects insulin production and carbohydrate metabolism. The effect of the drug on the cardiovascular system under conditions of hypoglycemia is much less pronounced compared to non-selective β-blockers.
The use of the drug in hypertension leads to a significant decrease in blood pressure for more than 24 hours, both in the supine and standing position, and during exercise. At the beginning of therapy with metoprolol, an increase in vascular resistance is noted. However, with prolonged use, a decrease in blood pressure is possible due to a decrease in vascular resistance with a constant cardiac output.
Pharmacokinetics
Each tablet of metoprolol succinate of prolonged action contains a large number of microgranules (pellets) that allow controlled release of metoprolol succinate. Outside, each microgranule (pellet) is covered with a polymer shell, which allows for controlled release of the drug.
The action of prolonged tablets comes quickly. In the gastrointestinal tract (GIT), the tablet is disintegrated into separate microgranules (pellets), which act as independent units and provide a uniform controlled release of metoprolol (zero order kinetics) for more than 20 hours. The release rate of the active substance depends on the acidity of the medium. The duration of the therapeutic effect after taking the drug in the dosage form of a prolonged-release tablet is more than 24 hours. The half-life of free metoprolol is on average 3.5-7 hours,
The drug is completely absorbed after oral administration. Systemic bioavailability after oral administration of a single dose is approximately 30-40%. Metoprolol undergoes oxidative metabolism in the liver. The three main metabolites of metoprolol did not show a clinically significant β-blocking effect. About 5% of the oral dose is excreted unchanged by the kidneys, the rest of the drug is excreted as metabolites. Communication with blood plasma proteins is low, approximately 5-10%.

Indications for use

Arterial hypertension.
Angina.
Stable chronic heart failure with the presence of clinical manifestations (II-IV functional class (FC) according to the NYHA classification) and impaired systolic function of the left ventricle (as an adjunct therapy to the main treatment of chronic heart failure).
Decreased mortality and re-infarction rates after the acute phase of myocardial infarction.
Cardiac arrhythmias, including supraventricular tachycardia, decreased ventricular rate in atrial fibrillation and ventricular extrasystoles.
Functional disorders of cardiac activity, accompanied by tachycardia.
Prevention of migraine attacks.

Contraindications

Hypersensitivity to metoprolol, other components of the drug or other β-blockers.
Atrioventricular block II and III degree, heart failure in the stage of decompensation, patients receiving long-term or course therapy with inotropic agents and acting on beta-adrenergic receptors, clinically significant sinus bradycardia (heart rate less than 50 beats / min), sick sinus syndrome, cardiogenic shock, severe peripheral circulatory disorders with the threat of gangrene, arterial hypotension (systolic blood pressure less than 90 mm Hg), pheochromocytoma without concomitant use of alpha-blockers.
Suspicion of acute myocardial infarction with heart rate less than 45 beats / min, PQ interval more than 0.24 seconds, systolic blood pressure less than 100 mm Hg.
Simultaneous use of monoamine oxidase (MAO) inhibitors (with the exception of MAO-B inhibitors).
Intravenous administration of blockers of "slow" calcium channels such as verapamil.
Age up to 18 years (efficacy and safety not established).

Carefully: atrioventricular block I degree, Prinzmetal's angina, bronchial asthma, chronic obstructive pulmonary disease, diabetes mellitus, severe renal failure, severe liver failure, metabolic acidosis, simultaneous use with cardiac glycosides, myasthenia gravis, pheochromocytoma (with simultaneous use of alpha-blockers), thyrotoxicosis, depression, psoriasis, obliterating peripheral vascular disease ("intermittent" claudication, Raynaud's syndrome), old age.

Use during pregnancy and during breastfeeding

Since well-controlled studies on the use of metoprolol during pregnancy have not been conducted, the use of the drug EGILOK® S in the treatment of pregnant women is possible only if the benefit to the mother outweighs the risks to the embryo / fetus.
Like other antihypertensive drugs, β-blockers can cause side effects, such as bradycardia in the fetus, newborns, or children who are breastfed. The amount of metoprolol excreted in breast milk and the β-blocking effect in a breastfed child (when the mother takes metoprolol in therapeutic doses) are insignificant. Despite the fact that in children who are breastfed, when prescribing therapeutic doses of the drug, the risk of developing side effects is low (the exception is children with metabolic disorders), it is necessary to carefully monitor the appearance of signs of blockade of beta-adrenergic receptors in them.

Dosage and administration

EGILOC® S is intended for daily use once a day, it is recommended to take the drug in the morning. EGILOK® C tablet should be swallowed with liquid. Tablets (or tablets divided in half) should not be chewed or crushed. Eating does not affect the bioavailability of the drug. When selecting a dose, it is necessary to avoid the development of bradycardia.
Arterial hypertension
50-100 mg once a day. If necessary, the dose can be increased to 200 mg per day or another antihypertensive agent can be added, preferably a diuretic and a slow calcium channel blocker (CCB). The maximum daily dose for hypertension is 200 mg / day.
angina pectoris
100-200 mg EGILOK® C once a day. If necessary, another antianginal drug may be added to therapy.
Stable chronic heart failure with the presence of clinical manifestations and impaired systolic function of the left ventricle
Patients must be in the stage of stable chronic heart failure without exacerbations during the last 6 weeks and without changes in the main therapy during the last 2 weeks.
Therapy of chronic heart failure with beta-blockers can sometimes lead to a temporary worsening of CHF. In some cases, it is possible to continue therapy or reduce the dose, in some cases it may be necessary to discontinue the drug.
Stable chronic heart failure, functional class II
The recommended initial dose of EGILOK® C for the first 2 weeks is 25 mg once a day. After 2 weeks of therapy, the dose can be increased to 50 mg once a day, and then can be doubled every 2 weeks.
The maintenance dose for long-term treatment is 200 mg of EGILOK® C once a day.
Stable chronic heart failure, III-IV functional class
The recommended initial dose for the first 2 weeks is 12.5 mg of EGILOC® C (1/2 tablet of 25 mg) once a day. The dose is selected individually. During the period of increasing the dose, the patient should be monitored, since in some patients the symptoms of chronic heart failure may progress.
After 1-2 weeks, the dose can be increased to 25 mg of EGILOK® C once a day. Then after 2 weeks the dose can be increased to 50 mg once a day. For patients who tolerate the drug well, the dose can be doubled every 2 weeks until a maximum dose of 200 mg of EGILOC® C is reached once a day. In case of arterial hypotension and / or bradycardia, it may be necessary to adjust the doses of the main therapy or reduce the dose of EGILOK® S. Arterial hypotension at the beginning of therapy does not necessarily indicate that a given dose of EGILOK® S will not be tolerated during further long-term treatment. However, increasing the dose is possible only after stabilization of the patient's condition. Monitoring of kidney function may be required.
Heart rhythm disorders
100-200 mg once a day.
Supportive care after myocardial infarction
The target dose is 100-200 mg / day, in one (or two) doses.
Functional disorders of cardiac activity, accompanied by tachycardia
100 mg once a day. If necessary, the dose can be increased to 200 mg per day.
Prevention of migraine attacks
100-200 mg once a day.
Impaired kidney function
There is no need to adjust the dose in patients with impaired renal function.
Impaired liver function
Usually, due to the low degree of binding to plasma proteins, dose adjustment of the drug is not required. However, in severe hepatic impairment (in patients with severe liver cirrhosis or portocaval anastomosis), a dose reduction may be required.
Elderly age
There is no need to adjust the dose in elderly patients.

Side effect

The drug is well tolerated by patients, side effects are mostly mild and reversible.
The following criteria were used to assess the incidence of cases: very often (> 10%), often (1-9.9%), infrequently (0.1-0.9%), rarely (0.01-0.09%) and very rarely (<0,01 %).
The cardiovascular system: often - bradycardia, orthostatic hypotension (very rarely accompanied by fainting), cold extremities, palpitations; infrequently - peripheral edema, pain in the region of the heart, temporary increase in symptoms of heart failure, AV blockade of the first degree; cardiogenic shock in patients with acute myocardial infarction; rarely - other cardiac conduction disorders, arrhythmias; very rarely - gangrene in patients with previous severe peripheral circulatory disorders,
Central nervous system: very often - increased fatigue; often - dizziness, headache; infrequently - paresthesia, convulsions, depression, weakening of attention, drowsiness or insomnia, nightmares; rarely - increased nervous excitability, anxiety, impotence / sexual dysfunction; very rarely - amnesia / memory impairment, depression, hallucinations.
Gastrointestinal tract: often - nausea, pain in the abdomen, diarrhea, constipation; infrequently - vomiting; rarely - dryness of the oral mucosa.
Liver: rarely - abnormal liver function; very rarely - hepatitis.
Skin covers: infrequently - rash (in the form of urticaria), increased sweating; rarely - hair loss; very rarely - photosensitivity, exacerbation of the course of psoriasis.
Respiratory system: often - shortness of breath with physical effort; infrequently - bronchospasm; rarely - rhinitis.
Sense organs: rarely - visual disturbances, dryness and / or irritation of the eyes, conjunctivitis; very rarely - ringing in the ears, taste disturbances.
From the musculoskeletal system: very rarely - arthralgia.
Metabolism: infrequently - an increase in body weight.
Blood: very rarely - thrombocytopenia.

Overdose

Symptoms: with an overdose of metoprolol, the most serious symptoms are from the cardiovascular system, however, sometimes, especially in children and adolescents, symptoms from the central nervous system and suppression of pulmonary function, bradycardia, AV blockade of I-III degree, asystole, a pronounced decrease in blood pressure, weak peripheral perfusion, heart failure, cardiogenic shock; depression of lung function, apnea, as well as increased fatigue, impaired consciousness, loss of consciousness, tremor, convulsions, increased sweating, paresthesia, bronchospasm, nausea, vomiting, esophageal spasm is possible, hypoglycemia (especially in children) or hyperglycemia, hyperkalemia; impaired renal function; transient myasthenic syndrome; concomitant use of alcohol, antihypertensive drugs, quinidine or barbiturates may worsen the patient's condition. The first signs of an overdose can be observed 20 minutes - 2 hours after taking the drug.
Treatment: the appointment of activated charcoal, if necessary, gastric lavage.
Atropine (0.25–0.5 mg IV for adults, 10–20 mcg/kg for children) should be given before gastric lavage (due to the risk of vagus nerve stimulation). If necessary, maintain airway patency (intubation) and adequate ventilation of the lungs. Replenishment of circulating blood volume and infusion of glucose. ECG control. Atropine 1.0-2.0 mg IV, if necessary, repeat the introduction (especially in the case of vagal symptoms). In the case of (suppression) of myocardial depression, infusion administration of dobutamine or dopamine is indicated. Glucagon 50-150 mcg / kg IV with an interval of 1 min can also be used. In some cases, adding epinephrine (adrenaline) to therapy may be effective. With arrhythmia and an extensive ventricular (QRS) complex, a 0.9% solution of sodium chloride or sodium bicarbonate is infused. It is possible to set up an artificial pacemaker. Cardiac arrest due to an overdose may require resuscitation for several hours. Terbutaline can be used to relieve bronchospasm (by injection or by inhalation). Symptomatic treatment is carried out.

Interaction with other drugs

Metoprolol is a substrate of the CYP2D6 isoenzyme, and therefore, drugs that inhibit the CYP2D6 isoenzyme (quinidine, terbinafine, paroxetine, fluoxetine, sertraline, celecoxib, propafenone and diphenhydramine) may affect the plasma concentration of metoprolol.
The co-administration of EGILOK® S with the following medicinal products should be avoided:
Barbituric acid derivatives: barbiturates (the study was conducted with pentobarbital) increase the metabolism of metoprolol, due to the induction of enzymes.
Propafenone: when prescribing propafenone to four patients treated with metoprolol, there was an increase in the plasma concentration of metoprolol by 2-5 times, while two patients had side effects characteristic of metoprolol. Probably, the interaction is due to inhibition by propafenone, like quinidine, of the metabolism of metoprolol through the cytochrome P450 system of the CYP2D6 isoenzyme. Taking into account the fact that propafenone has the properties of a β-blocker, the co-administration of metoprolol and propafenone is not recommended,
Verapamil: the combination of β-blockers (atenolol, propranolol and pindolol) and verapamil can cause bradycardia and lead to a decrease in blood pressure. Verapamil and β-blockers have a complementary inhibitory effect on atrioventricular conduction and sinus node function.
The combination of EGILOK® S with the following drugs may require dose adjustment:
Amiodarone: The combined use of amiodarone and metoprolol can lead to severe sinus bradycardia. Given the extremely long half-life of amiodarone (50 days), the potential for interactions long after amiodarone withdrawal should be taken into account.
Class I antiarrhythmic drugs: Class I antiarrhythmics and β-blockers can lead to a summation of negative inotropic effect, which can lead to serious hemodynamic side effects in patients with impaired left ventricular function. This combination should also be avoided in patients with sick sinus syndrome and impaired AV conduction.
The interaction is described on the example of disopyramide.
Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs weaken the antihypertensive effect of β-blockers. This interaction has been documented for indomethacin. Probably, the described interaction will not be observed when interacting with sulindac. Negative interactions have been noted in studies with diclofenac.
Diphenhydramine: Diphenhydramine reduces the metabolism of metoprolol to α-hydroxymetoprolol by 2.5 times. At the same time, there is an increase in the action of metoprolol.
Diltiazem: Diltiazem and β-blockers mutually reinforce the inhibitory effect on AV conduction and sinus node function. When metoprolol was combined with diltiazem, there were cases of severe bradycardia.
Epinephrine: 10 cases of severe arterial hypertension and bradycardia have been reported in patients taking non-selective β-blockers (including pindolol and propranolol) and receiving epinephrine. The interaction was also noted in the group of healthy volunteers. It is assumed that similar reactions can be observed when using epinephrine in conjunction with local anesthetics in case of accidental entry into the vascular bed. It is assumed that this risk is much lower with the use of cardioselective β-blockers.
Phenylpropanolamine: Phenylpropanolamine (norephedrine) in a single dose of 50 mg can cause an increase in diastolic blood pressure to pathological values in healthy volunteers. Propranolol mainly prevents the increase in blood pressure caused by phenylpropanolamine. However, β-blockers may cause paradoxical hypertension reactions in patients receiving high doses of phenylpropanolamine. Several cases of hypertensive crisis have been reported while taking phenylpropanolamine.
Quinidine: Quinidine inhibits the metabolism of metoprolol in a special group of patients with rapid hydroxylation (approximately 90% of the population in Sweden), causing mainly a significant increase in the plasma concentration of metoprolol and an increase in β-blockade. It is believed that such an interaction is also characteristic of other β-blockers, in the metabolism of which cytochrome P450 of the CYP2B6 isoenzyme is involved.
Clonidine: Hypertensive reactions with abrupt withdrawal of clonidine may be aggravated by the combined use of β-blockers. When used together, if clonidine is discontinued, discontinuation of β-blockers should begin a few days before clonidine is discontinued.
Rifampicin: Rifampicin may increase the metabolism of metoprolol, decreasing the plasma concentration of metoprolol.
Patients simultaneously taking metoprolol and other β-blockers (in the dosage form of eye drops) or monoamine oxidase inhibitors (MAOIs) should be closely monitored. Against the background of taking β-blockers, inhalation anesthetics increase the cardiodepressive effect. Against the background of taking β-blockers, patients receiving oral hypoglycemic agents may require dose adjustment of the latter.
The plasma concentration of metoprolol may increase when taking cimetidine or hydralazine.
Cardiac glycosides, when used together with β-blockers, can increase the time of atrioventricular conduction and cause bradycardia.

special instructions

Patients taking β-blockers should not be given intravenous calcium channel blockers such as verapamil.
Patients with obstructive pulmonary disease are not recommended to prescribe β-blockers. In case of poor tolerance of other antihypertensive drugs or their ineffectiveness, metoprolol can be prescribed, since it is a selective drug. It is necessary to prescribe the minimum effective dose, if necessary, it is possible to prescribe a β2-agonist.
It is not recommended to prescribe non-selective β-blockers to patients with Prinzmetal's angina. Selective β-blockers should be used with caution in this group of patients.
When using β2-blockers, the risk of their effect on carbohydrate metabolism or the possibility of masking the symptoms of hypoglycemia is much less than when using non-selective β-blockers.
In patients with chronic heart failure in the stage of decompensation, it is necessary to achieve the stage of compensation both before and during treatment with EGILOK® S.
Very rarely, patients with impaired AV conduction may worsen (possible outcome - AV blockade). If bradycardia develops during treatment, the dose of EGILOK® C should be reduced or the drug should be gradually discontinued.
Metoprolol may worsen the symptoms of peripheral circulatory disorders, mainly due to a decrease in blood pressure.
Caution should be exercised when prescribing the drug to patients with severe renal insufficiency, with metabolic acidosis, co-administration with cardiac glycosides.
In patients taking β-blockers, anaphylactic shock is more severe. The use of adrenaline in therapeutic doses does not always lead to the desired clinical effect while taking metoprolol.
Patients with pheochromocytoma should be given an alpha-adrenergic blocker in parallel with EGILOK® C.
In the case of surgery, the anesthesiologist should be informed that the patient is taking EGILOC® S. Patients who are to undergo surgery should not stop treatment with β-blockers,
Clinical trial data on efficacy and safety in patients with severe stable heart failure (NYHA class IV) are limited.
Patients with symptoms of heart failure in combination with acute myocardial infarction and unstable angina pectoris were excluded from studies on the basis of which indications were determined for the appointment. The efficacy and safety of the drug for this group of patients has not been described. Use in heart failure in the stage of decompensation is contraindicated.
Abrupt withdrawal of a β-blocker may lead to an increase in CHF symptoms and an increased risk of myocardial infarction and sudden death, especially in high-risk patients, and therefore should be avoided. If it is necessary to discontinue the drug, it should be carried out gradually, over at least 2 weeks, with a two-fold reduction in the dose of the drug at each stage, until the final dose of 12.5 mg (1/2 tablet of 25 mg) is reached, which should be taken at least 4 days before the complete withdrawal of the drug. If symptoms appear, a slower withdrawal regimen is recommended.

Influence on the ability to drive vehicles

Care must be taken when driving vehicles and engaging in potentially hazardous activities that require increased concentration of attention, due to the risk of dizziness and increased fatigue when using the drug EGILOK® S.

RELEASE FORM
Long-acting film-coated tablets 25 mg, 50 mg, 100 mg, 200 mg. 10 tablets in a PVC/PE/PVDC//aluminum foil blister. 3 or 10 blisters with instructions for use in a cardboard box.

BEST BEFORE DATE
3 years. Do not use the drug after the expiration date.

STORAGE CONDITIONS
At a temperature not higher than 30 °C. Keep out of the reach of children.

HOLIDAY CONDITIONS
Released by prescription.

REGISTRATION AUTHORIZATION HOLDER
CJSC "Pharmaceutical plant EGIS", 1106 Budapest, st. Keresturi 30-38, HUNGARY
Phone: (36-1) 803-5555;

Introduction

Currently, the issue of creating prolonged dosage forms that can provide a long-term effect of the drug with a simultaneous decrease in its daily dose is becoming more relevant. Preparations of this type ensure the maintenance of a constant concentration of the active substance in the blood without peak fluctuations.

Prolonged dosage forms can reduce the frequency of drug administration, and, consequently, reduce the incidence and severity of possible adverse drug reactions. Reducing the frequency of drug intake creates certain conveniences for both medical staff in clinics and for those patients who are treated on an outpatient basis, significantly increasing their compliance, which is very important, especially when using drugs for the treatment of chronic diseases.

General characteristics of prolonged dosage forms

Prolonged dosage forms (from lat. Prolongare - lengthen) are dosage forms with a modified release. Due to the slowing down of the release of the medicinal substance, an increase in the duration of its action is provided. The main advantages of these dosage forms are:

the possibility of reducing the frequency of reception;

the possibility of reducing the course dose;

the possibility of eliminating the irritating effect of the drug on the gastrointestinal tract;

the ability to reduce the manifestations of major side effects.

There are various technological principles for achieving prolonged action of solid dosage forms. The modern pharmaceutical industry provides for the use of special dosage forms that provide a prolonged action of drugs, the main of which are the following:

1) varieties of tablets for oral use:

coated tablets, slow release;

coated tablets, prolonged action;

coated tablets, soluble in the intestine, prolonged action;

modified release tablets;

2) varieties of capsules for oral use:

sustained-release modified-release capsules;

capsules with microspheres;

spansules.

3) dosage forms for implantation:

tablets for implantation;

capsules for implantation (pellets);

implants;

TTS - transdermal therapeutic systems;

injectable dosage forms of prolonged action;

suspensions of medicinal substances for parenteral administration.

Requirements for prolonged LF

The following requirements are imposed on prolonged dosage forms:

The concentration of drugs as they are released from the drug should not be subject to significant fluctuations and should be optimal in the body for a certain period of time;

Excipients introduced into the dosage form must be completely excreted from the body or inactivated;

Prolongation methods should be simple and accessible in execution and should not have a negative effect on the body. The most physiologically indifferent is the method of prolongation by slowing down the absorption of the drug.

Technological methods of drug prolongation:

· Increasing the viscosity of the dispersion medium (the conclusion of the medicinal substance in the gel).

As a gel for prolonged medications, IUD solutions of various concentrations are more often used: microcrystalline cellulose (MC), carboxymethylcellulose (CMC) and sodium CMC (1%), polyvinyl pyrrolidone (PVP), collagen, etc.

The conclusion of the medicinal substance in film shells.

· Introduction of polymers directly into the dosage form.

The polymers methylcellulose (soluble MC) and chitosan do not dissolve in biological fluids themselves, and at the same time, the films obtained from their solutions slowly swell and gradually dissolve, releasing the medicinal substances introduced into them, which allows creating a prolonged effect.