Production of ophthalmic solutions

Ophthalmic dosage forms in industrial pharmaceutical manufacturingContents Introduction.

1. The range and structure of the eye dosage forms.

2. Requirements of the Global Fund XI. To eye dosage forms. Them
rationale and implementation.

3. Features of industrial production eye drops

4. Manufacturing technology of a dropper tube.

5. The technological process and scheme for the production of eye solutions in
tube droppers and vials.

6. Control ophthalmic solutions   on mechanical inclusions.

7. The nomenclature of eye drops produced in tube droppers and
vials. 8. Eye ointments, implementation of the requirements of the GF USSR XI edition,
nomenclature. 9. Solid dosage forms for the eyes. Their characteristics and
nomenclature. 10. The range and characteristics of film formers.
11. Production of eye films. 12. Conclusions and suggestions. 13. References.

IntroductionAssortment and structure of the eyedosage forms.In industrial production, ophthalmic dosage forms are prepared: drops, ointments, films. They stand out in a separate group in connection with the features arising from the structure and functions of the organ of vision, such as specific mechanisms of absorption, distribution and interaction of drugs with tissues and fluids of the eye, slight vulnerability of the eye, etc. With many eye diseases, permeability changes dramatically. membranes and often in the tear fluid decreases the content of lysozyme (the enzyme muromidase), which reduces the protection against exposure to microorganisms. Eye solutionsrepresented mainly by washes, lotions, eye drops and injectable preparations.

Eye drops . The term "eye drops" means a dosage form, which is an aqueous or oily solution or the thinnest suspension of drug substances for infusion into the conjunctival sac in small quantities (GF X, Article 319). To prolong the action of these substances, as directed by a doctor, methyl cellulose, sodium carboxymethyl cellulose and polyvinyl alcohol may be included in the solvent.

Eye suspensionsare the thinnest suspensions of powders of medicinal substances | in an aqueous or oily dispersion medium

Eye ointmentsare a dosage form of soft consistency, capable of forming a uniform continuous film when applied to the conjunctiva of the eye

To solid dosage formsfor the eyes include eye pills, powders and pencils.

Eye pills.This is a dosage form obtained by

pressing on tablet machines.

GGLP Ophthalmic Medicinal Films). made from a bio-soluble and compatible with the tissues of the eye polymer with medicinal substances included in its composition, are intended for the introduction of these substances into the conjunctival cavity in case of viral, bacterial, allergic and other eye diseases. HFRs, which are oval-shaped plates measuring 9.0X4.5X0.35 mm and an average weight of 0.015 g, were developed

tans in the USSR by employees of the All-Union Scientific Research Testing Institute of Medical Technology and the Moscow Scientific Research Institute of Eye Diseases named after Helmholtz Ministry of Health of the USSR (USSR copyright certificate No. 387559, 1973). The invention was patented in the UK, USA, Canada, Germany and France.

HLP have a number of significant advantages over traditional ophthalmic dosage forms such as ointments, drops, suspensions, emulsions, subconjunctival injections.

GF requirementsXied. To eye dosage forms. Their rationale and implementation.

Along with the general requirements for many finished dosage forms, they are subject to increased requirements: sterility, stability, isotonicity, lack of mechanical impurities and irritating effects, dosing accuracy. To fulfill these requirements, the production of ophthalmic dosage forms is carried out in the same way as dosage forms for injection. The most critical operations are the preparation of the solution, the filling of the vials and their capping are carried out in rooms or zones of cleanliness class A in a laminar flow of sterile air on automatic or semi-automatic lines with minimal contact with ambient air. This is especially true for aseptic

manufactured preparations not subject to thermal sterilization. Similar requirements are imposed on the quality of the starting medicinal substances and solvents. Features of industrial productioneye drops.

Analysis of the formulation of dosage forms allows us to conclude that the proportion of eye drops is approximately 9-19% of extemporaneous formulations of all drugs manufactured in pharmacies of our country [Gendrolis A. A., 1973]. Additional information has been accumulated on this subject. So, according to E.I. Panchenko (1975), V.N. Vilinbakova (1982), I.R. Tashmukhamedova (1984), R.S. Skulkova (1985), extemporal formulation of eye drops in self-supporting pharmacies over the past decade amounted to 13.2-18.4%, and in hospital pharmacies during this period 8.2-8.9% of eye drops were made [Panchenko E. I., 1983; Kuznetsova A.P., 1984]. It is important to emphasize that in the ophthalmology departments of hospitals the percentage of the production of eye drops reached 50-60 [N. Bryleva, 1984; Kuznetsova A.P., 1984].

In addition, it was found that the most common eye drops are solutions of sulfacyl sodium, atropine sulfate, zinc sulfate with boric acid, pilocarpine hydrochloride in various concentrations, etc. Recently, many new eye drops prescriptions with vitamins and various combinations have appeared. vitamins and other medicinal substances, although in such cases it is necessary to take into account the possible antagonism of chemical compounds and their incompatibility.

Eye drops are the simplest form of drug administration for diagnosis, prevention and treatment.

eye diseases. Instillations of aqueous solutions of eye drops are simple and they are easily carried out by the patients themselves. However, the local administration of dosage forms for the eyes, especially eye drops, requires strict adherence to certain rules from the patient and medical personnel, and special requirements are imposed on the eye solutions themselves.

In domestic pharmacopeias, including the State Pharmacopoeia of the USSR IX edition, there was no special general article and in general no guidelines governing the quality and conditions of preparation of eye drops. This gap was filled only in the edition of the State Pharmacopoeia of the USSR.

However, in the light of modern advances in ophthalmology and pharmacy, the quality of eye solutions should undoubtedly meet even higher requirements, which can be formulated as follows. Eye solutions should be: sterile, isotonic, stable during storage, transparent and free of mechanical impurities, should not have toxic and irritating effects, in some cases they should have a prolonged therapeutic effect, medicinal substances   in eye solutions should have an exact concentration and show maximum biological activity, eye solutions should be dispensed in a convenient packaging for use.

Particular attention in the production of ophthalmic dosage forms should be given to the observance of the principles of sterility and isotonicity, which primarily ensure the safety of the effects of drugs on the organ of vision.

The principle of sterility:

It is known that normally the tear fluid contains a special antibiotic substance - lysozyme (according to the modern classification of enzymes - KF 3.2.1.17, called muromidase), which has the ability to lyse microorganisms that enter the conjunctiva [Bukharin O. V., Vasiliev N. V., 1974].

Gram-positive microorganisms with relatively simple cell walls with a thickness of 15-50 im, the main component of which is a large polymer, which in turn consists of two covalently bound components, are most sensitive to lysozyme. One of them is peptidoglycan (murein or mucopeptide) and forms a rigid fibrous structure that gives cells shape and strength, and also allows them to tolerate high internal osmotic pressure. Another component is teichoic acid, a substituted poly- (O-ribotol-5-phosphate), which provides a strong polarity of the cell surface. In some cases, under the influence of lysozyme, partial or complete lysis of gram-negative cultures is observed. However, the walls of gram-negative bacteria are much more complex. The various components of the wall sections form a structure 6–10 nm thick, called the outer membrane, which is a double lipid layer with hydrophobic sections inside it and hydrophilic on the surface. The main components of the outer membrane are very complex lipopolysaccharides, phospholipids (phosphatidylethanolamine, phosphatidyl glycerol), fatty acids and proteins with specialized functions. In most eye diseases, the content of lysozyme in the lacrimal fluid decreases, as a result of which the eye is not sufficiently protected from the effects of microorganisms, therefore the use of non-sterile drugs can lead to serious consequences, sometimes leading to loss of vision [A. Gendrolis, I. Deltuvene, 1976].

In this regard, the requirements for medicines for the eyes should be similar to those provided for injection solutions, and we have good reason to believe that according to the nature of the preparatory measures and the conditions of the technological process, medicines for the eyes and solutions for injection can be considered as a single whole. However, this unity is not limited.

only one technological side; as will be seen from the further material, the pharmacokinetic characteristics of drugs for the eyes also have significant similarities with those of injection solutions.

Solving microbial contamination and spoilage prevention problems medicines for eyes and solutions for injection, it becomes particularly relevant due to the fact that in these drugs, which are systems with a significant volume of the liquid phase compared to the content of active substances, favorable conditions are created for the multiplication of microorganisms. These conditions are due to both low concentrations of active substances in solutions and the presence in some cases of components that are nutrient media for microorganisms.

The degree of risk of seeding of drugs depends on many factors, for example, the presence of pathogenic microflora, the nature of the decomposition products of the drug due to exposure to developing microorganisms that initiate a wide variety of reactions (oxidation, reduction, polymerization, etc.). Microbial infection pharmaceuticals   can take place at all stages of their preparation, storage, transportation and use, although in the vast majority of cases the vegetative microflora is represented by saprophytic forms. Nevertheless, its presence is unacceptable not only from a sanitary and hygienic point of view, but also from the standpoint of preserving the chemical stability of drugs, since the seeding by microorganisms accelerates the decomposition of drugs under the action of bacterial enzymes and leads to their deterioration. Therefore, aseptic conditions for the preparation of ophthalmic dosage forms become important, which is emphasized by many experts. However, such conditions do not yet guarantee complete protection of solutions (including eye drops) from microbial contamination [Besedina I.V. et al., 1981], and the term “sterilization” itself, which appeared at the turn of the 19th and 20th centuries. and meaning

“Collateralization” is also quite relative. It implies either the destruction of microorganisms in solution (or in a substance of a different aggregate state), or the removal of microorganisms (and other contaminants), in particular bacterial vital products, from sterilization objects [Rabinskiy B. Ya., 1981]. In the first case, this is achieved by using methods of thermal, chemical or radiation treatment of the object, in the second - by centrifugation, filtering, flocculation, the use of static electricity, etc.

In order to prevent microbial contamination and spoilage of ophthalmic drugs, various methods are used in the industry that make it possible to obtain the appropriate medicine under strictly aseptic conditions, and in the future, to increase sterility guarantees, sterilize this drug using technology that ensures stability. Modern production currently has such technical capabilities that completely exclude the contact of the manufactured medicine with sources of potential contamination by microorganisms, for example, with the hands of a person, and allows the release of drugs in an air-free environment, in an airless space or inert gas environment.

Compliance with strict aseptic rules is equally a prerequisite for the work of pharmacies and pharmaceutical companies that produce ophthalmic medicines, including those that are further sterilized, since this process does not release the drug from dead organisms or from toxins secreted by them, many of which are stable at high temperatures.

The role of aseptics in the manufacture of ophthalmic drugs that are not subject to heat treatment, powders containing thermolabile drugs, emulsions and suspensions, in which the processes of recrystallization sharply increase upon heating, especially increase.

flocculation and coalescence. In these cases, compliance with aseptic rules is the only way to ensure the proper quality of drugs produced.

In practice, this is achieved by the fact that thermolabile substances suspended under aseptic conditions are dissolved in a previously sterilized solvent or ointment base in a sterile container, adding preservatives and stabilizers if necessary. These manipulations are carried out in special sterile shops, blocks, boxes.

To date, intensive research has been carried out in the development of issues related to the sterilization of drugs for the eyes. B.V. Nazarov (1972), summarizing the available experience in the manufacture of eye drops in pharmacy conditions, gives the following classification of drugs used in the composition of eye drops according to their stability during sterilization.

I. Medicinal substances, aqueous solutions of which withstand sterilization at a temperature of 100 ° C for 30 minutes without the addition of stabilizers:

A group of substances from which eye drops can be prepared in a combined solvent (aqueous solution of boric acid 1.9% and chloramphenicol 0.2%). On this solvent (pH 5.0), you can prepare eye drops with substances that have an acidic reaction. It withstands sterilization at a temperature of 100 C for 30 minutes. It is used for the production of the following eye drops (storage periods are indicated subject to the availability of sealed packaging.

To make a stable solution, we can hardly recommend

the methodology approved by the Pharmacological Committee of the Ministry of Health of the USSR. To 1 liter of a 20-30% solution of sulfacyl sodium prepared in freshly distilled water, 0.5% sodium metabisulfite solution and 18 ml of IN sodium hydroxide solution are added. The resulting solution was sterilized at a temperature of 100 ° C for 30 minutes In sealed packaging (penicillin vials), this solution remains stable for 1 year. The addition of sodium hydroxide solution is necessary in order to prevent the precipitation of a crystalline precipitate, which is a white streptocide, during storage.

Ethyl morphine 1.2 and 3%

It can be made in water for injection, 0.1% sodium metabisulfite solution is added as a stabilizer, and 0.7% sodium chloride solution for isotonicity. The solutions are sterilized at a temperature of 100 ° C for 30 minutes.

Research on the possibility of sterilizing eye drops by autoclaving in pharmacies was carried out by L. V. Polyakova et al. (1977). The following solutions used in the ophthalmic practice of Belarus were the objects of study:

To prepare solutions of eye drops used sterile distilled water, the work was carried out under aseptic conditions. As substances providing isotonicity, sodium chloride or boric acid was used. The ethylmorphine hydrochloride solution was stabilized by the addition of sodium metabisulfite. The prepared solutions were packaged in NS-1 brand penicillin vials, corked with rubber stoppers for break-in using metal caps and sterilized in an autoclave at a temperature of 119–121 ° С (0.1–1.1 atm) for 8 min.

The most stable during sterilization and storage were solutions of amidopyrine, atropine sulfate, homatropine hydrobromide, ephedrine hydrochloride, diphenhydramine, although after studying them using the accelerated aging method when stored in a thermostat at a temperature of 60 ° C for 22 days (corresponds to 1 year of storage in normal conditions) found traces of by-products. The solution of ethylmorphine hydrochloride turned out to be the least stable, in which a small amount of decomposition products appeared immediately after sterilization, and after 5-8 days. storage solutions turned yellow.

The main way to assess the effectiveness of all known sterilization methods to date remains the quantitative method, the essence of which is to determine the ratio of the number

viable microflora before and after sterilization. This assessment was the result of many years of research on the sterilization process, which showed that liberation from microflora does not mean total removal or destruction of microorganisms, but in fact only a partial decrease in their content. At the same time, its condition is recognized as a generally accepted designation of sterility of an object, in which “within 14 days (temperature 37 ° C) there is no growth of cultures accepted as sterilization bioassays”.

Thus, the concept of “sterility” is very relative and shows only a decrease in the number of microorganisms below a certain level. With an increase in the Efficiency of sterilization methods, the level of bacterial contamination gradually decreases to the values \u200b\u200bregulated by international specifications.

Table 2. Resistance of some microorganisms to the action of steamDegree Resistant ™ (min).Via microorganisms. 80 ° С 1№СWC134-CH I . Plasmodium   1-5 Tenderness
are activeFlagellum — __ _ _ Viruses — — — — Indisputable forms — — — ~ Yeast — — — . — Moldy — — — — Yeast spores and   5-10 1 Non-active
moldthe bacilli of bacilli pony   Zhnzya- 1-60, 1 Nezhyazne-Keshoy durability   active activeBacillus spores increased   - from 60 min 8Iawnings durability   up to 60 hoursAt_____________________ ^^_^^________ .................................. .............................. __ _^ ^_

Abroad, the values \u200b\u200bof the maximum permissible values \u200b\u200bof contamination are determined on the basis of the resistance of certain microorganisms to the effects of sterilizing agents. Thus, in Germany and a number of other countries, the classification of microorganisms according to their resistance to steam has been adopted, which allows us to establish the lower boundaries of microbial contaminants. As experiments showed, most eye drops were non-sterile, a significant difference in the number of microorganisms found in solutions prepared on the first and second days was not observed. Author

also indicates that some eye drops, such as a 0.005% solution of armin and a solution of phosphacol 1: 7500, prepared in domestic factories, 1-2 months after their manufacture contained microorganisms in amounts significantly exceeding the maximum permissible norms. In this regard, it is recommended that the technical conditions for the manufacture of eye drops in factories necessarily include a requirement to check them for microbiological purity with an indication of the maximum permissible bacterial content. The sterility of eye drops also largely depends on the accuracy of patients, especially in cases where bottles with screw-in pipettes are used. This is also reported by P. Ellis (1981), indicating that the sterility of eye drops, provided by heat treatment, persists only until they are used by patients. In this regard, the problem of selecting and introducing into the eye drops such substances that would have a disinfecting effect throughout the entire period of their use without violating the principle of physiological tolerance remains relevant.

The principle of isotonicity.

Isotonicity is an absolutely necessary condition for the preparation of such dosage forms as eye drops, since the drops prescribed by an ophthalmologist are usually not identical to the tear fluid in composition, pH and other properties. At the same time, it is known that both hypertonic and hypotonic solutions are poorly tolerated by patients. This is because when a solution with a large osmotic pressure (above 7.4 atm) is introduced, as a result of the difference in osmotic pressures, water is released from the cells in contact with the solution, which leads to their wrinkling. The introduction of a solution with a small osmotic pressure causes swelling of the cells, while the cell membrane ruptures. In both cases, these phenomena are accompanied by severe pain. Therefore, the task of the pharmacist is to prepare such drops, the osmotic pressure of which corresponded

would osmotic pressure of the tear fluid. One of the methods for calculating the isotonic concentration is based on the Van Goff law, with the help of which it is possible to determine the isotonic concentration of a diluted non-electrolyte solution. The relationship between the osmotic pressure, concentration and temperature in this case can be expressed by the Clapeyron equation, from which it follows that to prepare an isotonic solution of any non-electrolyte, it is necessary to take p, 29 g / mol of this substance per 1 liter of solution. When calculating the isotonic concentration of electrolytes, a correction factor called the isotonic coefficient is introduced into the Clapeyron equation. For solutions of completely dissociating electrolytes, it is approximately 0.143, for solutions of weakly dissociating electrolytes, 0.2. A more universal and accurate method for calculating isotonic concentrations of solutions is the method described in GF X (p. 997), based on the use of the so-called isotonic equivalents of drugs for sodium chloride. Isotonic concentrations can also be determined by other methods, for example, cryoscopic, based on a comparison of the constants of depression of the freezing temperature of blood plasma and solutions of the corresponding medicinal substances [Azhghikhin I. S, 1975]. You can list the following most common eye drops, which must be brought to an isotonic concentration provided that they are prepared only in water for injection.

Currently, methods of preparing eye drops in buffer solvents are increasingly being introduced into pharmaceutical practice. The use of buffer solvents, along with an increase in chemical stability, in some cases helps to increase the therapeutic activity of the drug components of eye drops, and also reduces the discomfort in the eyeball region. Mostly, borate (1.9% boric solution) is used as a solvent for drugs in eye drops. acids and 2.68% sodium tetraborate solution), borate-acetate (1.9% boric acid solution and 1.5% sodium acetate solution), borate-propionate (1.9% boric acid solution s and a 2% solution of sodium propionate) and phosphate (2.55% solution of sodium phosphate monosubstituted and 1.85% solution of sodium phosphate disubstituted) buffer solutions. The preparation of eye drops on buffer solvents is carried out by choosing such a buffer solution, the composition and pH of which in maximize the stability of the drug substance in the dosage form.

Abroad, other prescriptions of solvents for eye drops are also proposed, which have a buffer capacity to maintain a certain pH value and are isotonic with tear fluid. Properly selected solvents allow you to adjust the concentration of hydrogen ions not only to stabilize the solutions, but also to create a pH value at which the medicinal substances exhibit the maximum therapeutic effect. As an example, an isotonic boric acid solution of 1.9% with a pH of about 5.0 is recommended, which is recommended for the preparation of ophthalmic dosage forms with zinc salts, cocaine, novocaine, etc.

Separate reagents are used along with buffer solutions to stabilize eye solutions, including eye drops. In recent years, the requirement of isotonicity and stability for eye drops is considered

the vast majority of researchers. Issues related to the manufacture of stable solutions of eye drops in polymer packaging attract the attention of researchers [Gendrolis A. A., 1969, 1971, 1973, 1974, 1977; Artemyev A. M., Kuzmina L. I., 1977, and others]. According to experimental data obtained by Yu. I., Zelikson (1969), eye drops of a 1% solution of pilocarpine hydrochloride and a 1% solution of atropine sulfate prepared on a 1.9% solution of boric acid containing 0.2% levomycetin were stable during sterilization and storage. In these solutions, in comparison with solutions prepared with distilled water, a smaller shift in pH was observed. Considering the stabilizing, preserving and isotonizing properties of such a solution, the author recommended using this combination as a solvent for eye drops containing alkaloids salts, synthetic nitrogenous bases and other medicinal substances that are stable in an acidic environment. At the same time, it was established by Yu. I. Zelikson that solutions of pilocarpine hydrochloride and atropine sulfate prepared in borate and phosphate buffer solvents (pH 6.6–7.1) turn out to be unstable after sterilization by fluid steam at 100 ° C for 30 min: after a month, the decomposition of drugs occurs, leading to the preservation of only 5–31% of the initial activity. Therefore, the preparation of eye drops on buffer solvents having a pH of 6.6–7.1 should be only taking into account the physicochemical properties of the ingredients introduced into them, and this solvent can be mainly suitable only in the extemporaneous practice of pharmacies. Despite the fact that in some cases, buffer solutions play a positive role in the preparation of ophthalmic drugs, the need to use them for this purpose has long been called into question by many researchers. So, back in 1961, K. Munzel wrote that buffering agents should be introduced into solutions of eye drops only when the pH value should be maintained within the range of 6.0-8.0. If the pH of the eye drops does not go beyond this range, then, according to

according to the author, the use of a buffer solution in the composition of these dosage forms is impractical, since the lacrimal fluid itself in this case plays the role of a natural buffer. The same conclusion was reached by A. Poffs (1965), who suggested that buffer solutions should be administered only in such dosage forms in which the pH significantly deviates from physiologically acceptable norms. The relevance of the discussion of these issues is associated with insufficient knowledge of the dependence of the therapeutic activity of eye solutions on the concentration of hydrogen ions. A number of researchers have shown that the physiological activity of some solutions increases at pH close to 7.0 or more. Based on this, it was proposed to prepare eye drops on solvents that allow to increase the pH value. more than 7.0. However, R. Dynakovski and R. Figwiski (1972) questioned the advantage of such solutions over acidic ones. To date, an unequivocal answer to these questions has not been received, and therefore improving the technology for the manufacture of eye drops and the quality of this dosage form requires further research in this direction.

Tube manufacturing technologydroppers.

Over the 15 years of operation of the Kaunas Endocrine Drug Plant in the field of production of eye drops in polymer packaging, considerable experience has been gained in the large-scale production of these ophthalmic preparations. However, despite the continuous improvement of methods for their production, new questions arise that require urgent solutions.

The main problem remains the study of the possibility of extending the shelf life of drugs, since its solution has not only economic

value, but also to a large extent reflects the state of quality of drugs of this group [Tentsova A.I. et al., 1978; Babayan 3. A. et al., 1984]. Currently, the shelf life of eye drops produced in tube droppers with a wall thickness of 0.5 ± 0.1 mm does not exceed 2 years due to the evaporation of water from solutions. We have at our disposal experimental data indicating the possibility of extending the shelf life of eye drops provided that they are packed in dropper tubes with a wall thickness of 0.6-0.75 mm and an extension of the existing tolerance for the concentration range of active ingredients in these dosage forms. . 1

Studies have also been carried out on the storage of tube droppers with various preparations in a contour package of the “Servak” type made of polyvinyl chloride film (thickness 0.4 mm) and lacquered aluminum foil (thickness 0.05 mm) instead of micropackets made of cardboard [A. Gendrolis. , Zubkaite G.P., 1977]. The data obtained confirmed the possibility of extending the shelf life of eye drops. Another direction for further "improving the production of ophthalmic drugs in polymer packaging is our proposed method for producing conditionally sterile tubes of tubes

droppers. In the production of dropper tube cases using the current technology, the surface of the tubes was contaminated, which necessitated washing and sterilization. To eliminate this drawback, a device was proposed whose principle of operation is as follows (see. Fig. 1):

1) at the end of the conveyor belt and carrying blocks with tubes of
blowing machine 1, set the conveyor, which carries blocks on
punching stamp 8;

2) at the end of the conveyor install a special receiver for
accumulation of blocks 7;

3) under the punching stamp 8 set on the bed sterile Bix
with lid for cut-out tube droppers 9;

4) the surface of the conveyor belts is coated easily removable
with a film, and a cap for
eliminate contact with the environment;

5) for sterilization of transport tapes, rollers 3, 4, 5 are installed,
which periodically moisturize with a disinfectant;

6) the block with tubes from the receiver 7 is taken at the ends of the gate (without
touch the tubes) and lay in the die cutting stamp 8 for carving
tubes.

In this way, conditionally sterile cases of dropper tubes without surface contamination are obtained. As a result of the described technological process, conditions are created that allow you to abandon the subsequent washing of the tubes and increase the culture of production.

When trimming the hemisphere of the dropper tube housings, the sterile opening of the tube becomes dirty, as a result of which the cut-off tKopnyca must also be washed, dried, and gas sterilized.

A method for producing sterile cut-off cases of tube droppers is developed, which is implemented as follows:

1) the hemisphere trimming device is placed in an automatic assembly unit for filling and sealing dropper tubes on the assembly conveyor between the tube feeding and cannula screwing areas; 2) increase the height of the swivel sprockets to obtain
the ability to transfer whole tubes; 3) a device for cutting hemispheres of tubes is made of
bed, guides, upper and lower knives. The lower knife is attached to
riser, and the top - to the guides. To adjust the upper knife
knitting device. Guide movement
provided by the transmission of the central shaft of the automatic installation,
to which a disk with a figured notch attaches; 4) the cut hemispheres of the cases of tube droppers are squeezed out
machines through a funnel in a special box, after connecting the entire
ventilation system.

On the proposed device, it is possible to trim at once four cases of tube droppers, which are then transported by transport cells to the area for screwing the cannula and filling.

Our method allows us to abandon washing processes, gas sterilization of tube dropper bodies, which significantly reduces the time of the technological cycle, releases several people, leads to material savings (ethylene oxide, carbon dioxide, distilled water), electricity, and also eliminates the need to install complex instruments for determining residues of ethylene oxide in containers and finished products.

Technological process and schemeproduction of solutions for eyes in a tube-droppers and bottles.

Solutions in a dropper tube are prepared in rooms of class B cleanliness under aseptic conditions. The room and equipment are wet-cleaned, disinfected with a 3-5% phenol solution and sterilized with bactericidal lamps for 2 hours. Dissolution is carried out in reactors with stirrers, analyzed, the solution is freed from mechanical impurities, sterile filtered and collected in a sterilized apparatus for subsequent filling of the tube droppers.

In parallel with this, cases and caps of tube droppers are made. Fig. 2

a case with a capacity of 1.5 ± 0.15 ml and a wall thickness of 0.5 ± 0.1 mm is formed on the machine in several stages by blowing and stamping from granules of high pressure polyethylene brand 15803-020 or 16803-070. Caps with a pin for puncturing are poured under pressure from the molten granules of low pressure polyethylene grade 20906-040 or 20506-007. After manufacturing, they are washed with distilled water, dried, and gas sterilized at 40–50 with a mixture of ethylene oxide and 10% carbon dioxide for 2 hours. Ethylene oxide is removed from the products by keeping them for 12 hours in a sterile room. Further, under aseptic conditions in a unit with excess pressure of sterile air, the caps are screwed onto the body, filled with a solution of a medicinal substance using metering pumps and sealed by heat sealing. On a printing machine, an inscription with the name of the drug is applied to the body on both sides, indicating its concentration and volume. Filled tube droppers are visually checked for the absence of mechanical impurities on a black and white background when illuminated with a 60 W electric lamp, 5% of each batch is subjected to a complete analysis. The dropper tube is packed in single cases, in cardboard boxes or in polyvinyl chloride film.

In addition to this package, according to GOST 17768–80, glass bottles with a stopper-pipette from unstabilized low density polyethylene are recommended for eye drops. Before filling, the solution is sterilized by filtration, and pipette tubes by gas sterilization with ethylene oxide with 10% carbon dioxide.

Control of ophthalmic solutions onmechanical inclusions.

Eye drops should be completely clear and free fromno suspended particles that can cause mechanical injurymembranes of the eye. Eye drops should be filtered through the best varieties.filter paper, and under the filter should be laida small lump of long fiber wool. It is important that afterfiltration, the concentration of the solution and its total mass did not decreasemore than allowed by established standards. All saidabout filtering small amounts of solutions (see p. 396) fully and primarily refers to eye drops. According to the recipes that are often found in the recipe, it is advisable to resort to the help of intra-pharmacy blanks — concentrates prepared on time, which exempts from filtering small amounts of liquids.

The nomenclature of eye drops produced in tube droppers and vials.

Assortment of currently available eye dosage forms

factory time in the dropper tube is still small and certainly needs further expansion. However, this problem is not simple and easily solvable, since the development of technical standards for each new name of a medicinal substance is associated with the solution of a number of questions. First of all, from a huge number of prescriptions of ophthalmic medicines, one should select and analyze those that are constantly found in the ophthalmic practice of the whole country or, at least, in large settlements. Next, it is necessary to determine the most commonly used concentrations of the drug substance, and these values \u200b\u200bmust be sufficiently stable or maintained at a constant level by the addition of stabilizers. Finally, appropriate methods for analyzing both the drug substance itself and other components of the drug must be available or developed. Only after this can we begin to study the interaction of polymer packaging materials with a solution of a medicinal substance during production, sterilization and storage conditions. It should be borne in mind that at the final stage of these studies, which sometimes continue for a long time, negative results can be obtained. In this case, you have to start all over again and continue to search for other optimal options.

Methods for cleaning solutions of medicinal substances, along with ensuring sterility, an equally important problem in the industrial production of ophthalmic drugs in new forms of packaging is the absence of mechanical impurities in solutions. To solve it, it is planned to carry out appropriate measures in two directions: cleaning solutions of medicinal substances and maintaining industrial cleanliness in industrial premises.

Based on the results of studies on the influence of the process of freezing eye drop solutions on their physicochemical properties, notes were made in the Storage section to the appropriate

pharmacopoeia articles: “Freezing during transportation and storage is not a contraindication to its use.”

At the same time, additional experiments were put on storing eye drops in polymer packaging in a frozen state in order to study the possibility of extending their shelf life. For the experiments, preparations of sulfacyl sodium (20%) and zinc sulfate (0.25%) with boric acid (2%) produced by industry on a wide [industrial scale] were selected. Eye drops were stored at a temperature of - 10 ± 2 ° C, checking at certain intervals their qualitative and quantitative indicators for compliance with the requirements of pharmacopoeial articles.

Currently, work in this direction is ongoing. Increased shelf life of eye drops and improved technology for the production of plastic containers

Over the 15 years of operation of the Kaunas Endocrine Drug Plant in the field of production of eye drops in polymer packaging, considerable experience has been gained in the large-scale production of these ophthalmic preparations. However, despite the continuous improvement of methods v of their production, new questions arise that require urgent solutions.

The main problem remains the study of the possibility of extending the shelf life of drugs, since its solution is not only of economic importance, but also largely reflects the quality status of drugs of this group [Tentsova A. I. et al., 1978; Babayan E.A. et al., 1984] ,.

Eye ointments, implementation of the requirements of the GF USSRXipublications, nomenclature.

Ophthalmic ointments are a dosage form of soft consistency that can form a uniform continuous film when applied to the conjunctiva of the eye. Being an ancient dosage form, eye ointments have undergone a number of changes recently, relating both to the technology of their preparation, and mainly to the composition of their bases and packaging forms. In addition to the general requirements for the distribution of medicinal substances in the base as uniformly as possible, in order to ensure the accuracy of the dosage of the active ingredient when taken, stability and indifference of the base, eye ointments should also meet the following:

the following conditions: 1) medicinal substances insoluble in the ointment base must be crushed to a minimum degree of dispersion, which ensures the complete preservation of the mucous membrane and the absence of discomfort when applying the ointment; 2) the ointment base should not have foreign inclusions and impurities, it is necessary that it be sterile, neutral, easily and evenly distributed over the mucous membrane of the conjunctiva and eyes; 3) eye ointments should be prepared with strict observance of asepsis rules; 4) the pH of the ointment should correspond to that of the lacrimal fluid, since otherwise lacrimation occurs and the rapid leaching of the drug associated with it.

Ophthalmic ointments are used to lubricate the skin and edges of the eyelids or to be placed in the conjunctival sac.

Lubrication is carried out using a glass or plastic stick, and laying in the conjunctival sac is done using a spatula, having previously pulled the lower eyelid. It is unacceptable to apply ointments with the help of fingers, even washed, as this can cause infection in the eye. After laying the ointment, gently massage the eyelids in the closed state to achieve a better distribution of the medicine. The range of ointment bases used for the manufacture of eye ointments, unfortunately, is small and is expanding slowly. As a basis, GF X recommends a mixture of vaseline grade “for eye ointments” (90 parts) and rootless lanolin (10 parts). The advantage of this mixture over pure petroleum jelly is that the latter is poorly wetted by the tear fluid and, as a result, is unevenly distributed across the conjunctiva.

In recent years, more effective compositions have been proposed. So, for ointments with sodium sulfacyl, a mixture of petroleum jelly, water, liquid paraffin and anhydrous lanolin (7: 5: 3: 6) is recommended. Alcohols of wool wax are increasingly being used in eye ointment bases (Pharmacopoeia of the GDR VII).

In 1968, a base containing alcohols of wool wax, ceresin, paraffin oil and petroleum jelly in a ratio of 4: 24: 60: 10 was developed at KHNHFI. The bases of this type are known under the name "eucerin". In our country, they were investigated as possible carriers of antibiotics, and as a result of the work carried out, positive results were obtained that made it possible to release dibiomycin and ditetracycline eye ointments.

Some authors propose the use in eye ointments of hydrolysed hydrogenated lanolin, characterized by a low acid number, the absence of irritating, sensitizing and allergic effects [Barura G. S. et al., 1968; Alyushin M.T., Lee V.N., 1971]. | As another component of the base with hydroline, petrolatum is recommended (usually 1 part of petroleum jelly for 9 parts of hydroline). Ointments on this basis are characterized by high stability, which was the reason for using this base as a carrier of antibiotics. I. S. Azhgikhikhin V. G. Gandel (1972), V. M. Gretsky (1975) emphasize that in no other dosage form the role of the base in therapy is as determining as in ointments. The authors indicate that the ointment with the base has a significant effect on the condition, property, response during the pathological process of that area of \u200b\u200bthe skin or mucous membrane on which it was applied. At the same time, the base enters into a complex interaction with the medicinal substance introduced into it, improving or worsening its stability, contributing to or hindering its release and absorption, enhancing or weakening its pharmacological and therapeutic effect, and also significantly affecting the manifestation of various side effects   medicinal substance.

If the base is not specifically indicated, then in the manufacture of eye ointments, according to Article 709 of GP X, which sets out the general requirements for eye ointments, the already mentioned composition of 10 parts of anhydrous lanolin and 90 parts of petroleum jelly is used. All water soluble medicinal substances (salts

alkaloids, novocaine, silver preparations, etc.) are dissolved in a minimum amount of water for injection and only after that they are introduced into the composition of the bases. Insoluble or sparingly soluble substances - yellow mercury oxide, basic bismuth nitrate, amidochloride and mercury monochloride, xeroform, zinc oxide, copper citrate are introduced into the base in the form of finest powders after additional thorough grinding with a small amount of liquid paraffin, glycerol or water, depending on what composition the base will be used to make the ointment.

Checking the uniformity of the distribution of insoluble drugs in the basics is carried out according to GF X visually using slides. However, it is more perfect to use special scanning microscopes with a screen for this purpose, which have proven themselves in the industrial production of ointments.

For packaging eye ointments, mainly metal tubes with a varnished inner surface are used to prevent metal from contacting with the drug. Still, metal tubes should not be used when packing ointments containing ingredients that can interact with metals. Polymer materials for one-time packaging of ointments are becoming more widespread.

Solid dosage forms for the eyes.characteristic and nomenclature.

Solid dosage forms for the eyes include ophthalmic tablets, powders, and pencils.

Eye pills. This is a dosage form obtained by compression on tablet machines. Eye pills are twofold.

purpose: they can be used either directly by laying behind the lower eyelid, or used to pre-dissolve them in order to obtain eye drops or, less commonly, eye lotions. In both cases, the tablets should dissolve easily, without residue, in an appropriate solvent (usually in water for injection) and not contain irritating or traumatic eye components.

Pills of this type appeared at the end of the century before last, when the American firms Burrow Welkam and Park Davis started producing eye tablets based on milk sugar and soluble starch. In Russia, the first eye tablets were made in 1898 and contained a mixture of cocaine with atropine. They easily dissolved in water and, when placed in the lower conjunctival sac, caused a weak, rapidly passing irritation in the eye. Later, mainly pills from abroad began to be used in Russia. So, in 1912, A. S. Chemolosov tested the effect of foreign-made eye pills made on the basis of milk sugar. The tablets were prepared under sterile conditions; they contained medicinal substances widely used in ophthalmic practice in those years - cocaine, atropine, pilocarpine, dionine, zinc sulfate, etc. The time of their dissolution in the eye was only a few seconds.

M. M. Budzko (1910), who studied 45 tablets of ophthalmic tablets, came to the conclusion that the effect of drugs when laying the tablets in the conjunctival sac manifests itself in a more pronounced degree and for a longer time compared with the use of the same substances in the form of ophthalmic drops. The negative point is only the presence in tablets of excipients that irritate the conjunctiva.

Over time, ophthalmic tablets gradually became obsolete and returned to them only during the Second World War, and instead of pressed tablets, trituration tablets began to be prepared, i.e.

obtained by introducing moistened tablet mass into small forms, followed by drying. Such tablets are less durable and more porous than compressed, and as a result, they dissolve easier and faster in tear fluid. In 1944, N. N. Solomnik proposed a method for preparing ocular trituration tablets weighing 0.003 g, diameter 3 mm, and height 0.37 mm, containing pilocarpine in an amount of 0.00015 g. Lactose was used as a filler. The tablets packed in glass tubes were sterilized at a temperature of 115 ° C for 30 minutes; when introduced into the conjunctival sac, they dissolve very quickly.

Powders. Sterile dusting powders are prepared under aseptic conditions from medicines of the finest degree of dispersion, and non-thermolabile substances are subjected to additional heat sterilization (for example, many sulfanilamide preparations are sterilized with dry heat at 150 ° C for 15-30 minutes).

Pencils. Pencils used in ophthalmic practice for cauterizing mucous membranes (containing silver nitrate, alum, copper sulfate, etc.) are obtained either by melting the salt and then pouring it into special forms, where they solidify, or by rolling it out. In the latter case, medicinal substances are mixed with a pasty base. After rolling out the sticks during drying, lose moisture and harden.

The listed dosage forms are not limited to the possibility of using medicinal substances in ophthalmology. Among the promising in this regard should include pharmaceutical aerosols - a relatively new dosage form, created on the basis of the latest scientific achievements and the application of biopharmaceutical principles. Aerosol particles are well adsorbed on the mucous membrane, which ensures rapid absorption of the drug substance. The use of aerosols is painless, their use can significantly increase

therapeutic efficacy of drugs due to the high dispersion of particles.

Assortment and characteristicsfilm formers.

Eye films (Membranulae ophthalmicae). They are solid oval plates with smooth edges, measuring 9.0-6.0 mm in length, 3.0-4.5 mm in width, 0.35 mm thick and an average weight of 0.015 g. They are made from bio-soluble and compatible with tissues and polymer eye fluid. Medicinal substances are introduced into the composition of the films.

Ophthalmic medicinal films (GLP) have several advantages over eye ointments, emulsions, etc. With their help, it is possible to prolong the action and increase the concentration of drugs in the tissues of the eye, reduce the number of injections from 5-8 to 1-2 times per day, GLP put in a conjunctival sac, for 10-15 s they are moistened with lacrimal fluid and become elastic. After 20-30 minutes, the film turns into a viscous bunch of polymer, which completely dissolves after 75-90 minutes, creating a thin, uniform film.

Polyacrylamide or its copolymers with monomers of acrylic and vinyl series, polyvinyl alcohol, NaKMU, are used as a film former. All-Russian Research Institute of Medical Technology has proposed a base for HFR (VFS-42-439-75), consisting of 60 parts of acrylamide copolymer, 20 parts of vinyl pyrrolidone, 20 parts of ethyl acrylate and 50 parts of plasticizer - polyethylene glycol succinate.

The production of eye films.

Obtaining SODI is as follows. A 16-18% polymer solution is obtained in the reactor. The components are mixed with 96% ethanol to loosen them, then water is added, the mixture is heated to 50 ° C and mixed until completely dissolved, cooled to 30 ° C and filtered through a layer of calico. Separately, a drug solution is prepared and introduced into the polymer solution.

The resulting composition is homogenized by stirring for 1 hour and centrifuged for 2 hours to remove air bubbles. The resulting solution using a special installation is applied in two layers (through a slit) on the surface of a metal strip treated with ethanol and moving at a speed of 0.13-0.14 m / min, dried in a chamber with five drying zones from 40 to 48 ° C, cooled to 38 ° C and removed the film from a metal tape in the form of a roll with a diameter of 30 mm It is left for 6-8 hours to remove strain stresses, cut into strips and using the stamp get the HFD of the required size. Pack HLP of 30 pieces in special dispenser cases, ensuring tightness and aseptic conditions during storage and use. They also use contour-cell packaging in aluminum foil and PVC film of 10 GLP each, which are placed in cardboard boxes of 20-100 pieces. Sterilization is carried out by γ-irradiation at a dose of 20 kGy or by treatment with a mixture of ethylene oxide and carbon dioxide. Sterility persists throughout the year. Evaluation of the quality of HFD is carried out according to physico-chemical properties: surface roughness, the presence of cracks, tears, elasticity, strength, gloss. The medical industry produces eye films with pilocarpine hydrochloride, neomycin, dicain, sodium pyridazine and florenal.

A promising dosage form is intraocular drug films (ILP), made on the basis of collagen with gentamicin or kanamycin sulfate and trimecaine. They are hemmed into the anterior chamber of the eye during planned surgical interventions, gradually releasing medicinal substances and eliminating the occurrence of secondary infection. HLP is completely dissolved on the 10th day.

In addition to GLP, lamels are used - small gelatinous oval disks with a diameter of 3 mm. The composition of the gelatinous mass is injected with various medicinal substances. For therapeutic purposes, special contact lenses are used - gelatin or from polyglyceryl methacrylate in the form of cups filled with medicinal substances, which are slowly released during use, providing prolonged action. Disposable ophthalmic dosage forms are minima - containers made of polymer with a capacity of 4 to 12 drops of solution or 0, 5 g of ointment. A feature of the minima is that they are easily opened and make it easy to dose the drug by squeezing the contents onto the mucous membrane. Conclusions and offers.

Widely used in eye practice, drops and ointments as dosage forms do not completely satisfy ophthalmologists. The reasons are: 1) a relatively short period of therapeutic action; 2) irritation associated with the basics used and the frequent administration of the drug; 3) inaccuracy of dosage when using the drug; 4) the possibility of developing allergic reactions to the drug with its repeated use.

The prolongation of the action of drugs in ophthalmology can be achieved by increasing the viscosity of eye drops. There are two ways to increase the viscosity of eye drops: by adding high molecular weight substances (IUDs) or by replacing distilled water with various oils. However, the latter method is often unpleasant for the patient, since an oil film, as already noted, impairs vision.

The addition of an IUD has proven more acceptable. The industry produces some prescriptions for eye drops with the addition of a solution of MC. However, ophthalmologists do not recommend the frequent use of MCs, since

this may delay the restoration of corneal epithelium. PVA has found application in the treatment of ulcers, burns and other diseases of the cornea. Its positive properties include compatibility. with the majoritymedicinal substances and preservatives used in eye practice.Due to rapid thickening, PVA solutions are used inconcentration not higher than 2%.

List of references.1.Gendrolis Yu.A. Ophthalmic dosage forms. - M., 1988. - 256 p.

2. The State Pharmacopoeia of the USSR. E-11th ed. - M., 1987, - Vol. 1336 s, M., 1990.- Vol. 2 -397s.

Z. Muravyov I.A. Technology of medicines: Textbook in 2 volumes.- M., 1980.-Volume 1- 390 s, Volume 2 -704s.

4. The pharmacist's guide / Ed. Tentsovoi A.I.-M, 1981.-383p.

5. Technology of dosage forms: Textbook in 2 volumes, volume 1 / Ed. T.S. Kondratieva.-M., 1991.-496s, Volume 2 / Ed. L.A. Ivanova.-M., 1991.-554C.

Content:
  Introduction .............................................................. 3
  Objectives ……………………………………………………………………………………………………………………… 4
  Eye drops ……………………………………………………………… page 5
  Internal pharmaceutical preparations drops formulation .............................................. page 11

Ophthalmic suspensions and emulsions ………………………………………………… .page 12

  Ophthalmic ointments …………………………………………………………………… ..page 13
  Vacation and preparation of ophthalmic dosage forms
  Conclusion …………………………………………………………………………… .. page 20
  List of used literature ……………………………………… ... page 21

Introduction

Ophthalmic dosage forms occupy a special place among other drugs due to the specifics of their use and arising from this preparation. The area of \u200b\u200beye resorption is the cornea, a typical lipoid barrier with a thickness of about 1 mm. It is well permeable to fat-soluble drugs. There is a water chamber behind the lipid barrier. The expected effect when using ophthalmic drugs is the availability of eye tissue for the drug, and therefore it is necessary to overcome the lipid and water barriers. The preparation of ophthalmic medicines is an important section of pharmacy work that requires strict adherence to special rules.

In ophthalmic practice, a variety of drugs are used both to create a local effect for diagnostic or therapeutic purposes, and to realize a pharmacological effect in adjacent tissues.

Of the dosage forms in ophthalmology, drops, ointments, lotions, eye sprays, and eye films are used. Of greatest interest are eye drops and ointments, both in terms of production volumes at pharmaceutical enterprises and in sales through pharmacy chains.

No less important is the task of creating a simple, convenient, aesthetic, informative and economically viable packaging for ophthalmic medicines, which allows them to be kept in a sterile and chemically unchanged state for a long time, and to ensure the speed of administration at the time of use. Lately, practical packaging of buffus has been included in everyday life.

Purpose: The study of eye drops and ointments as the most convenient and effective dosage form. A variety of dosage forms are prepared in industrial production, but eye ointments and drops are of the greatest importance, because using them creates the optimal therapeutic effect and ease of use of these dosage forms. The increase in the number of eye diseases is determined by many factors, including adverse environmental conditions, technogenic influences, the load on the organ of vision, which increases with the development of civilization. All drugs for ophthalmic practice are a special group of drugs. This is determined by a number of reasons of a social, medical and pharmaceutical nature: the exclusive role of the organ of vision in ensuring the level and quality of human life; the special complexity and specificity of the anatomical, biophysical and physico-optical mechanisms of vision; the possibility and necessity of a medicinal effect on the anterior part of the eye; strict requirements for the quality and safety of ophthalmic dosage forms; significant technological difficulties in the development of compositions and technologies. However, far from always with the help of eye drops a full therapeutic effect is achieved, a greater effect will be achieved if you use a combination of drops and ointments.

Eye Dosage Forms

Eye drops - liquid dosage forms, which are aqueous or oily solutions, the thinnest suspensions or emulsions of medicinal substances, dosed by drops. Aqueous solutions. Since these solutions are intended for such a delicate and sensitive organ as the eye, and, moreover, still sick, they must be prepared under the following conditions.

Sterility. Eye drops must be sterile because the conjunctiva of the eye must be protected from infection. Normally, infection is prevented by lysozyme contained in the lacrimal fluid, which lyses microorganisms that enter the conjunctiva. In case of eye diseases, the tear fluid usually contains little lysozyme and the conjunctiva of the eye is unprotected from exposure to microorganisms. Infection of the eye with non-sterile drops can cause severe (consequences, sometimes leading to loss of vision). The need to make eye drops, ointments and lotions under aseptic conditions is caused by the fact that these forms are applied to the conjunctiva of the eye, which can become infected. Normally, the tear fluid contains a special antibiotic substance - lysozyme, which has the ability to destroy microorganisms that enter the conjunctiva. In a number of diseases, the lacrimal fluid contains little lysozyme and the eye is exposed to microorganisms.
   At the time of preparation of eye drops, their sterility is easily achieved by sterilization and the use of asepsis. However, already at the first application (opening the bottle), the drops are seeded with microflora. In this regard, along with thermal sterilization, preservatives must be added to the eye drops to maintain sterility both for storage and for repeated use.
  Methods for sterilizing eye drops:
   The choice of the method of thermal sterilization of eye drops is determined by the degree of stability of drug substances in solutions when heated. Steam sterilization is carried out under pressure at 120 ° C for 8 minutes or at 110 ° C for 30 minutes. This is the most reliable and effective sterilization method for solutions of thermostable substances. Less stable substances are sterilized by fluid steam at 100 ° C for 30 minutes. The sterility of the eye drops is achieved by the same methods as the sterility of the solutions for injection - preparation under aseptic conditions and using one or another sterilization method. The method of sterilizing eye drops depends on the resistance of the drug in solutions to temperature exposure.
   Bacterial filtration under aseptic conditions through microporous (pore diameter 1-2 microns) sterile filters is mainly used in the factory.
   Regardless of the method of sterilization, eye drops should be prepared under aseptic conditions. Of particular importance is the aseptic manufacture of eye drops - solutions of thermolabile substances that are not sterilized.
Soviet scientists studied numerous substances as preservatives for eye drops. The following antiseptics are most effective against pathogenic staphylococcus, hay and Escherichia coli, blue-green pus bacteria, yeast, mold and mushroom fungi: merthiolate at a concentration of up to 0.005%, chloro-butanol hydrate-0.5%, benzalkonium chloride-0, 01%, cetylpyridinium chloride - 0.01%, phenylmercury nitrate (borate, acetate) - up to 0.004%, a mixture of methyl (2 parts) and propyl (1 part) esters of parahydroxybenzoic acid (nipagin and nipazole) - up to 0.15 % ", chloramphenicol - 0.2% in combination with boric acid-2%, as well as other preservatives and their combinations. Numbers in brackets ah indicate the percentage of the substance of the total volume of the solution
   There is a risk of microbial contamination of eye drops during use. To reduce the growth and reproduction of microorganisms that have fallen into the solution, carefully selected preservatives are added to its composition.
   In industrial production, eye drops in a dropper tube are prepared in rooms of the II class of cleanliness under aseptic conditions. The room and equipment are wet-cleaned, disinfected with 3-5% phenol solution and sterilized with bactericidal lamps for 2 hours.
   The dissolution is carried out in stirred tank reactors, then analyzed and subjected to filtering in turn (first for purification from mechanical impurities, and then for sterilization). The resulting solution is placed in a sterilized apparatus for filling tube droppers. The dropper tube (they consist of a body and a cap with a piercing pin), after manufacturing, is washed with distilled water, dried, gas sterilized at 40-50 ° C with a mixture of ethylene oxide and 10% carbon dioxide for 2 hours. Then, the dropper tube kept in a sterile room for 12 hours in order to completely remove ethylene oxide from them.
Screwing the caps onto the body, filling it with a solution of a medicinal substance, sealing by heat sealing occurs in the unit with excessive pressure of sterile air under aseptic conditions. Next, an inscription with the name of the drug, its concentration and volume is applied to the body. Then a visual inspection is carried out on a black and white background when illuminated with a 60 W electric lamp for the absence of mechanical inclusions. In addition to a tube dropper, according to GOST 17768-80, glass bottles with a stopper pipette made of unstabilized low density polyethylene are used for packaging eye drops. The drug solution is sterilized by filtration, and pipette plugs by gas sterilization with ethylene oxide with 10% carbon dioxide.
   Isotonicity. Eye drops need isotonation with respect to the lacrimal fluid (unless the medicinal substances are prescribed in high concentrations and in addition to solutions of collargol and protargol). When non-isotonic solutions are introduced into the eye, pain appears. Unfortunately, the principle of mandatory isotonation of eye drops is not maintained by all pharmacies. Their work can be greatly facilitated if eye drops with a concentration of medicinal substances up to 3% are allowed to be prepared on an isotonic sodium chloride solution or other isotonic solvent without any calculations. Some pharmacopoeias (USA) allow this. Special prescriptions should be considered eye drops, the components of which together increase the osmotic pressure of the drops above 1.1% equivalent concentration of sodium chloride.
   If eye drops are prescribed by a doctor in hypotonic concentration, then in this case the pharmacist himself achieves isotonicity in the manufacture of the solution. In this case, isotonic equivalents of medicinal substances for sodium chloride are used in accordance with the provisions of the State Pharmacopoeia.
   Normally, the tear fluid has an osmotic pressure, the same as blood plasma and as isotonic (0.9%) sodium chloride solution. It is desirable that the eye drops have such an osmotic pressure. Deviations are allowed and it is shown that eye drops cause discomfort at concentrations from 0.7 to 1.1%.
Stability. In eye drops, the stability of dissolved medicinal substances must be ensured. Thermal sterilization (if it was not performed under optimal conditions) and long-term storage of eye solutions in a glass container lead to the destruction of many medicinal substances (alkaloids, anesthetics, etc.) due to hydrolysis, oxidation, etc.
   To stabilizing factors, of course, should be attributed; preservatives, substances that regulate pH and antioxidants. Medicinal substances used in the form of eye drops can be divided into three groups depending on the pH of the solutions corresponding to the greatest stability.
  The first group includes salts of alkaloids and synthetic nitrogenous bases, as well as other substances resistant to hydrolysis and oxidation in an acidic environment. It is recommended to stabilize these substances with boric acid at a concentration of 1.9-2%. Boric acid is an ineffective stabilizer for eye drops - solutions of atropine sulfate, polycarpin hydrochloride, scopolamine hydrobromide, dicain and novocaine.
   The second group consists of drugs that are stable in a neutral or slightly acidic environment: salts of benzylpenicillin, streptomycin, chloramphenicol, etc. To stabilize such drugs, various buffer mixtures, sodium citrate, etc. can be used.
   The third group includes drugs that are stable in an alkaline environment: sulfacyl sodium, norsulfazole sodium, etc. They can be stabilized with caustic sodium, sodium bicarbonate, sodium tetraborate, and buffer mixtures with alkaline pH values.
   To stabilize eye drops-solutions of low-oxidizing substances, antioxidants are used that are used to inhibit the oxidation of injection solutions - sodium sulfite and metabisulfite. For example, a 30% solution of sulfacyl sodium is effectively stabilized with sodium metabisulfite in an amount of 0.5%, and a 1% solution of ethyl morphine hydrochloride with the same antioxidant in an amount of 0.1%.
  Prolongation. Eye drops should have the longest lasting effect. Extension of action can be achieved by increasing the viscosity of aqueous solutions. The optimum for eye drops is considered a viscosity of 5-15 cP. Viscosity should not exceed 40-50 cP, as in this case, dosing will be difficult.
Polyvinyl alcohol, megyl cellulose and sodium carboxymethyl cellulose proved to be suitable for this purpose. These substances do not cloud vision and, due to their good adhesive properties, provide the necessary contact with the eye without irritating it. The diluted solutions of PVA and Na-KMC, (1.5) and MC (0.5%) are easily sterilized, and remain transparent when stored in the refrigerator.
   The disadvantage of eye drops is a short period of therapeutic action. This necessitates their frequent installation, and also poses a danger to the eye.
   Transparency. Eye drops should be completely transparent and not containing any suspended particles that can cause mechanical injury to the membranes of the eye. Eye drops should be filtered through the best grades of filter paper, with a small lump of long-fiber wool placed under the filter. It is important that after filtration, the concentration of the solution and its total mass do not decrease more than is allowed by established standards. All that has been said about filtering small amounts of solutions fully and primarily relates to eye drops. According to the recipes that are often found in the recipe, it is advisable to resort to the help of intra-pharmacy blanks, concentrates, prepared on time, which exempts from filtering small amounts of liquids.
  Internal pharmacy blanks recipe. Drops are prepared aseptically, isotonized with sodium chloride, hermetically sealed for running-in and sterilized with steam at 100 ° C for 30 minutes.
   Distilled water must be freshly boiled. Riboflavin plays an important role in maintaining the normal visual function of the eye.
   Rp: Novocaini 0.1
  Zinci sulfatis 0.025
  Ac. borici g.s ut ayu sol. Isotonica 10.0
  D.S 2 drops 3 times a day
  In the formulation, it is necessary to calculate the amount of boric acid to obtain an isotonic solution. The above recipe may vary. So, instead of novocaine, dicain can be prescribed, instead of a solution of boric acid, a “case” of drops can be written out a solution of mercury cyanate 1: 5000 or 1% solution of resorcinol. Alum may be added instead of boric acid. A 1: 1000 solution of adrenaline hydrochloride may be included in the recipe. To accelerate the dispensing, pharmacies often procure for future use a “case” of drops of a 0.25% zinc sulfate solution in a 2% boric acid solution.
  Rp .: Sol. Sulfacyli-natrii 20% 10.0
  DS. Eye drops
Drops of sulfacyl sodium (albucid) are prepared in water for injection in a pre-washed and sterilized container necessary for this, including a dispensing bottle. 2 g of sulfacyl sodium are dissolved in 5 ml of water for injection and the resulting solution is filtered through a small paper filter pre-washed with water for injection into a dry sterile bottle. Then the rest of the water is added to the solution, passing it through the same filter to obtain 10 ml of solution.

Rp .: Ribeflavini 0.001
   Ac. ascorbinici 0.1
  Aq. pro inject. 10.0
   MDS Eye drops
  Ascorbic acid is dissolved in water for injection. Riboflavin is administered as a 1: 5000 solution (intra-pharmacy blank).

Eye suspensions and emulsions

   Eye suspensions are the finest suspensions of powders of medicinal substances in an aqueous or oily dispersion medium. They are obtained by the dispersion method when the suspension, when the suspension is formed due to a gradual decrease in the degree of dispersion of the initial insoluble matter, i.e. grinding it, or by condensation, when the formation of the suspension occurs as a result of an increase in the degree of dispersion of the starting material, which was previously in the ionic, molecular or colloidal degree of dispersion.
   In the case of overcoming the sedimentation instability of the suspension and preserving fine particles in them, the resulting preparations do not cause unpleasant sensations in patients and have the same effect as eye drops.
   Suspensions for eyes used in medical practice are prepared in the factory, before use, it is enough to dilute them with water.
   Emulsions for use in ophthalmic practice are prepared using sterile non-aqueous solvents in which solutions of drug substances are emulsified. The aqueous phase of the emulsion has a pH of 4.5-7.0, the most favorable value is considered to be pH 6.0.
   By the mechanism of action, emulsifiers are divided into surfactants that stabilize emulsions mainly due to a sharp decrease in surface tension at the phase boundary; gelling agents that stabilize emulsions by forming strong adsorption films at the interface; mixed action emulsifiers, most often used in eye practice.
   Currently, in the form of suspensions for ophthalmology, steroid hormone preparations are used. In order to prevent the formation of aggregates or flakes that are poorly wetted by a dispersion medium, it is recommended to introduce PEG-400 and 0.1-0.15% sodium chloride solution into their composition.
Emulsions for use in ophthalmic practice are prepared using sterile non-aqueous solvents in which solutions of drug substances are emulsified. So, for example, for the treatment of glaucoma, pilocarpine ophthalmic emulsions are proposed containing 0.25-8.0% aqueous solutions of pilocarpine hydrochloride, a 10-80% solution of an indifferent oil and emulsifier.
  Eye ointments
   Ointments are intended for application to the conjunctiva of the eye by laying under the eyelid with the help of special spatulas. Eye ointments should be made on the basis of the highest quality and contain a solid phase in a state of finest dispersion. As a basis in eye ointments, vaseline of the “eye ointment” variety and alloy of this petroleum jelly with lanolin in various proportions, often containing a small amount of water, are used. If the basis is not indicated, then, according to article No. 709 of the State Pharmacopoeia, which sets out the general requirements for eye ointments, an alloy of 10 parts of anhydrous lanolin and 90 parts of petroleum jelly is used. In some cases, hydrophilic bases are also used as bases in eye ointments.
   Sometimes, freshly prepared glycerin ointment is used as such a base. It is quite stable in relation to the action of microflora, sharply hydrophilic and neutral. The disadvantage of glycerin ointment is a fairly strong water-taking effect and the associated irritating effect, somewhat mitigated by the enveloping effect of starch contained in the ointment.
   Ophthalmic ointments are prepared under aseptic conditions in small glass mortars or, even better, on frosted glass plates using flat glass pestles. In the latter case, homogeneity is easily checked by examining a thin layer of ointment in transmitted light.
  Since the conjunctiva of the eye is a very delicate and vulnerable mucous membrane, additional requirements are imposed on eye ointments:

   eye ointments should not contain solid particles with sharp edges that can injure the conjunctiva, as well as irritating substances and concentrated acids;
   eye ointments should be easily and spontaneously distributed over the mucous membrane.

   The main requirements are:

   sterility (manufacturing is carried out only under aseptic conditions);
   the minimum degree of dispersion (for comfort and safety of use) of drugs in eye suspensions;
   ease and uniformity of distribution on the mucous membrane of the conjunctiva and eyes, provided by the structure of the eye ointment;
the absence of irritating components in the composition of the ointment (especially acids);
   the necessary pH value of the eye ointment is in the range of 4.5-9.0, otherwise tearing and leaching of the ointment from the eye is possible.

  Requirements for the bases for eye ointments:

   sterility;
   lack of irritating properties;
   chemical indifference;
   good distribution ability;
   hydrophilicity, providing emulsification with tear fluid;
   the melting temperature of the base 32-33 ° C.

   Often the basis for eye ointments is vaseline, which does not contain reducing substances, as well as an alloy of such vaseline with lanolin, sometimes with a small amount of water. The addition of water and lanolin to petroleum jelly as a result leads to the formation of an “water-oil” emulsion and provides the necessary absorption of drugs. Pure petroleum jelly has a local effect, as it is hydrophobic and poorly distributed in the conjunctiva.
   If the doctor has not indicated the basis in the prescription, then according to the State Pharmacopoeia, a sterile mixture of 10 parts of anhydrous lanolin and 90 parts of “For eye ointments” grade vaseline should be used. The mixture must be fused, filtered through paper in a funnel for hot filtration and placed in a dry sterilized jar in hot condition, tied with parchment paper and sterilized in an air sterilizer at 180 ° C for 30 minutes or at 200 ° C for 15 minutes. Store in a dark place at a temperature of no higher than 25 ° C for 2 days or at 3-5 ° C no more than 30 days.
   All soluble medicinal substances are introduced into the composition of eye ointments after mandatory dissolution in sterile water. Insoluble or sparingly soluble substances - yellow mercury, basic bismuth nitrate, mercury amidochloride, mercury monochloride, xeroform, zinc oxide, copper citrate, etc., are introduced in the form of fine powders after additional thorough grinding with a small amount of auxiliary liquid (liquid paraffin, glycerol or water) depending on the composition of the base. All auxiliary materials, ointment base, medicinal substances (thermostable), cans are sterilized according to the instructions of the State Pharmacopoeia.
   In the manufacture of ointments, the administered medicinal substances must have an optimal degree of dispersion. The required degree of dispersion is achieved by dissolving in sterile water or thoroughly grinding in a small amount of water or a related base, and then mixing with an ointment base.
Improving the technology of eye ointments contributes to the directed flow of new ointment bases, in particular the use of carbopol gel. On the basis of carbopol gel, ointments with anti-inflammatory drugs and vitamins are prepared.
   The formulation of eye ointments is diverse. These are mainly bivalent and more complex disperse systems.
   Yellow mercury ointment (eye ointment) - Unguentura Hydrargyri oxydi flavi. The ointment is official in accordance with the GFH prescription (Article No. 343), contains 2% yellow oxide mercury:
  Rp .: Hydrargyri oxydi flavi 2.0 01.
   Vaselini 2.0 Vaselini 80.0 v
   Lanolini anhydrici 16.0

  The basis of the ointment is an alloy of petroleum jelly (5 parts) and lanolin ”(1 part). Yellow mercury oxide: thoroughly triturated with liquid paraffin, after which sterile, almost cooled base is mixed in parts. Ointment is always prepared ex tempore. They are stored in a place protected from sunlight, since yellow mercury oxide decomposes under the influence of light with the release of metallic mercury, and also "can interact with lanolin fatty acids to form poisonous mercury soaps. Do not use a metal spatula in the manufacture of this ointment.
  Rp .: Cupri citratis 0.3
   Ung. Glycerini 10.0
   M. f. ung.
   DS. Pawn forever 2-3 times a day
  First, prepare a glycerin ointment according to the prescription GF1X (the ointment consists of 93 g of glycerin and 7 g of wheat starch). To do this, wheat starch is thoroughly mixed with an equal amount of water in a porcelain cup, after which glycerin is added. When stirring, the mixture is carefully heated on a grid over low heat until a uniform translucent mass is obtained. Freshly prepared ointment is sterile in itself. Copper nitrate is thoroughly triturated in a few drops of water, and then the base is mixed in parts.
  In the formulation of eye ointments, ointments with antibiotics are often found, which are prepared under aseptic conditions.
  Rp .: Benzylpenicillini - Natrii 100,000 ED
   Lanolini
   Vaselini pro oculis aa 5.0
   M. f. ung.
   DS. Pawn forever 2-3 times a day
  First prepare the base, which is sterilized by dry heat. At the same time, the mortar, pestle and temper jar are sterilized. In a sterile mortar, benzylpenicillin-sodium salt is thoroughly mixed with a small amount of the base, after which the remainder is mixed in parts.
  Vacation and preparation of ophthalmic dosage forms
Ophthalmic medicines are dispensed from pharmacies in sterile, hermetically sealed containers. Eye drops are released in penicillin vials, hermetically sealed with rubber stoppers and aluminum caps using an Islamgulov machine.
  Ophthalmic ointments are released in porcelain or glass jars (if necessary, orange glass), as well as in metal or plastic tubes. Tubes are filled using special sterilized devices operating on the principle of a syringe. Metal tubes should not be used for packaging ointments containing ingredients that can interact with metals. The tubes can be equipped with screw-on tips, allowing you to enter ointment for the eyelid.
   Labels of pink color are glued on packages with eye drops and eye ointments.
  Eye lotions and rinses are released in sterile bottles equipped with tight-fitting stoppers.
  All ophthalmic medicines should be stored in a well-closed container in a cool, dark place with the label "Store in a cool and dark place."

conclusions
  Eye diseases are one of the most dangerous, because most of the information about the world around us we receive with their use. And eye diseases can lead to complete or partial loss of vision, which will have both social and economic significance.
   The development of pharmaceuticals leads to the improvement of the manufacture of medicines, to the expansion of their assortment, to the improvement of the quality of manufactured preparations, this is also confirmed by the dynamics of development of ophthalmic medicines. Significant scientific and technological efforts have been made to improve these dosage forms. Work is underway to enhance their medicinal effect, new active substances are being developed for this, the effect of their various combinations is investigated, and the term of action (prolongation) of the medicinal substance is increased. Combined drugs are also being developed to improve the treatment of eye diseases, mainly glaucoma and to improve the treatment of patients. These drugs contain substances that have a different mechanism of antihypertensive action and with the simultaneous use of which an additive effect is manifested, which in turn affects the decrease in the level of ophthalmic diseases among the population.

List of references:
  1. Industrial technology of drugs: Uch., In 2 volumes. Chueshov V.I., Chernov M.Yu., Khokhlova L.M. X.: MTK- Book; NFAA Publishing House, 2002.
2. The technology of dosage forms. Volume 1, 2. Ed. L.A. Ivanova M., 1991

4.XI State Pharmacopoeia of the USSR. Vol. 1, 2. M.: Medicine, 1987 (Issue 1), 1989 (Issue 2)

5.Muraviev I.A. Technology of drugs. In 2 volumes. M., 1980

Eye drops are aqueous or oily solutions or the finest suspensions of drugs. Like other medicines for the eyes, they must be sterile, stable, not contain mechanical impurities visible to the naked eye.

The main requirements for eye drops are set out in general article No. 319 of the GFH.

In the process of preparing eye drops, their sterility is ensured by thermal sterilization (if the stability of the drug substance allows this) and adherence to asepsis. But already at the first application (associated with opening the bottle), the drops are seeded with microflora. Along with thermal sterilization, antimicrobial substances are introduced into most eye drops prepared under pharmacy conditions to maintain sterility as during storage. so when applied. These include merthiolate (0.005% ), ethanol mercury chloride (0.01%), cytylpyrimidine chloride (0.01%), chlorethone (0.6%), nipagin (0.1%), chloramphenicol (0.15%), benzyl alcohol (0.9%) . The most active antimicrobial effect is provided in the presence of boric acid.

Eye drops need isotonation with respect to tear fluid. When injected into the eye. non-isotonic solutions appear pain caused by the difference in the osmotic pressure of the tear fluid and the solution. Isotonation of eye drops is achieved by preparing them in an isotonic sodium chloride solution (0.9 ± 0.2%) or in another isotonic solvent. When the content of drugs in eye drops in concentrations of more than 4% isotonation is no longer necessary, since the osmotic pressure of such solutions approaches the osmotic pressure of the tear fluid.

Since water for injection is most often used as a solvent for eye drops, the period of their therapeutic effect is short, as a result of which the patient has to perform frequent instillations, which in turn can have an adverse effect on the eye: often there is an allergy to the drug substance, the likelihood of infection increases. In this regard, it is desirable to increase the duration of action of drugs used in the form of eye drops. This was possible with the introduction of substances that increase the viscosity of the solution. As the latter, polyvinyl alcohol, methyl cellulose (in the form of a 1% solution) or sodium carboxymethyl cellulose can be used.

In the eye drops, the stability of the drug substance must also be ensured. Thermal sterilization and long-term storage of eye solutions in a glass container lead to the destruction of many medicinal substances (alkaloids, painkillers, etc.) due to oxidation, alkaline hydrolysis, etc. In the manufacture of eye drops in pharmacies, it is often necessary to stabilize them, i.e. . in the addition of auxiliary substances that increase the resistance of drugs to adverse effects.

To stabilize in the eye drops zinc salts, some alkaloids, novocaine, mesatone are used. isotonic boric acid solution (1.9%). For salts of adrenaline and physostigmine, 100 mg of sodium sulfite is added for every 100 ml of solution. The stabilization of solutions of salts of atropine, ephedrine, pilocarpine and scopolamine is carried out using sodium chloride, mono- and disubstituted sodium phosphate.

To get rid of suspended particles that can cause mechanical injury to the membranes of the eyes, eye drops are filtered through the best grades of filter paper, and a small lump of long-fiber cotton wool is placed under the filter. It is important to ensure that after filtering the concentration of the solution and its total volume do not decrease more than is allowed by established standards.

In the manufacture of eye drops in prescriptions, which are often found in pharmacy prescriptions, it is advisable to resort to the help of intra-pharmacy blanks - concentrates, calculated for a specified time frame. This speeds up the preparation of eye drops and eliminates the need for filtering small amounts of liquid. The concentrated solutions used for eye drops, as well as the drops themselves, in accordance with the instructions of the GFC, should be prepared under aseptic conditions.

No. 135. Rp .: Sol. Sulfacyli-natrii 20% 10.0 DS. Eye drops

Drops of sulfacyl sodium (albucid) are prepared in water for injection in a pre-washed and sterilized container necessary for this, including a dispensing bottle. 2 g of sulfacyl sodium are dissolved in 5 ml of water for injection and the resulting solution is filtered through a small paper filter pre-washed with water for injection into a dry sterile bottle. Then the rest of the water is added to the solution, passing it through the same filter to obtain 10 ml of solution.

No. 136. Rp .: Ribeflavini 0.001

Ac. ascorbinici 0.1

Aq. pro inject. 10.0

MDS Eye drops

Ascorbic acid is dissolved in water for injection. Riboflavin is administered as a 1: 5000 solution (intra-pharmacy blank).

No. 137. Rp .: Sol. Pilocarpini hydrochloridi 1% 10.0

DS. 1-2 drops in each eye 3-4 times a day

Since the solution of pilocarpine hydrochloride indicated in the recipe is highly hypotonic and causes discomfort when instilled into the eye, it must be isotonized with sodium chloride. The corresponding calculation of isotonic equivalents is given in GF on p. 997. From the pharmacopoeia table (as well as in the present textbook in the section “Injection solutions”) it follows that the isotonic equivalent of pilocarpine hydrochloride for sodium chloride is 0.22, that is, 1 g of pilocarpine hydrochloride creates the same osmotic pressure as 0 22 g of sodium chloride. Therefore, to bring the solution to an isotonic concentration of sodium chloride, you should take:

A weighted amount of sodium chloride is dissolved in water for injection, 0.1 g of pilocarpine hydrochloride is dissolved in half of this solution (5 ml), filtered into a dispensing flask through a washed filter, and then the remaining solution is added to the solution through the filter. The flask is drawn up for vacation, remembering that pilocarpine hydrochloride is a substance of List A. The label “Handle with care” is glued.

No. 138. Rp .: Novocaini 0,1

Zinci sulfatis 0.025

Ac. borici q. s. ut f. sol. isotonica 10.0

DS. 2 drops 3 times a day

The recipe provides for the calculation of the required amount of boric acid to obtain an isotonic solution, which is carried out similarly to the above example. To speed up the holiday, you can also use the blank “0.25% solution of zinc sulfate in a 2% solution of boric acid”, which should be taken 10 ml, dissolving 0.1 g of novocaine in it.

Antibiotic preparations, especially streptomycin sulfate and chloramphenicol, are widely prescribed in eye drops. To increase stability, eye drops with antibiotics are prepared in sterile buffer solutions. So, for example, eye drops with chloramphenicol are prepared on a borate buffer solution having the following composition:

Sodium Chloride

Sodium tetraborate aa 0.2

Boric Acid 1.1

Distilled water 100.0

The specified solution is pre-sterilized at 100 ° C for 30 minutes

Eye drops with other antibiotics are prepared using an isotonic sodium chloride solution. If benzylpenicillin-sodium (potassium) salt is used in eye drops with a concentration of 20,000-100,000 IU / ml, scopolamine, atropine, dionine, and morphine solutions are also used as a solvent.

Recently, Yu. F. Maychuk et al. a new ophthalmic dosage form has been proposed — ophthalmic dosage films, which are polymer plates soluble in tear fluid and containing the corresponding medicinal substances. Ophthalmic films are used by laying over the eyelid, where they are moistened with tear fluid, gain elasticity and gradually dissolve within 10-40 minutes, releasing the water-soluble medicinal substances contained in them.

Eye Dosage Forms - a special group of dosage forms that differ in the way they are used - instillation on the mucous membrane of the eye.

A feature of the mucous membrane of the eye is the greatest sensitivity in comparison with all the mucous membranes of the body. It reacts sharply to external stimuli: mechanical inclusions, a mismatch between the osmotic pressure and pH values \u200b\u200bof drugs introduced into the eye to osmotic pressure and the pH value of the lacrimal fluid.

Lacrimal fluid is a protective barrier for microorganisms. In a healthy eye, it is bactericidal, due to the presence of lysozyme. But with pathological conditions of the eye, the content of lysozyme in the tear fluid is significantly reduced.

Another protective barrier for microorganisms is the corneal epithelium. If this barrier is damaged, then some microorganisms multiply rapidly, causing severe diseases, including loss of vision.

Thus, for the manufacture of ophthalmic dosage forms, it is necessary to take into account the anatomical, physiological and biochemical characteristics of the organ of vision, as well as factors affecting the therapeutic activity of this group of dosage forms.

Classification of ophthalmic dosage forms

Ophthalmic dosage forms are divided into 4 types:

Drops;

Solutions;

Ointments;

Films.

Eye drops are a liquid dosage form intended for instillation in the eye. They are aqueous or oily solutions of medicinal substances, most often antiseptics, anesthetics and substances that reduce intraocular pressure.

Main disadvantage eye drops is the low bioavailability of drugs as a result of a complex mechanism of absorption, an ineffective route of administration (drops) and rinsing of the drug with tear fluid during blinking. It is established that only one tenth of the dose of the drug penetrates the eye. Therefore, the employee of the pharmacy institution is obliged to inform the patient how to properly apply eye drops.

application

How to dig into the eye. Consumer Information

1. Wash your hands.

2. If the droplet bottle is clear, check the solution before use (if the color has changed, if there is a precipitate).

3. Tilt your head back, look at the ceiling.

4. Pull the lower eyelid down with your finger.

5. In the cavity formed behind the lower eyelid, drop one drop of the solution from a pipette or vial. You can use a mirror or call someone for help.

IMPORTANT: the pipette or tip of the vial should be as close as possible to the eye, but not touch it.

6. If possible, keep the eyelid open without blinking for 30 s.

7. To increase the efficiency of the installation, press the outer corner of the eye with your finger to prevent blinking for 1 minute.

8. Close the vial tightly.

Fig. 30.1.Proper instillation of the solution into the eye

30.1. GF REQUIREMENTS FOR EYE DROPS

Eye drops should:

- be prepared under aseptic conditions and be sterile;

- withstand mechanical inclusion tests;

- be comfortable when taking (isotonic, isohydric with tear fluid);

- be stable in conditions of frequently opened packaging. To stabilize physico-chemical, microbiological

and rheological properties in the composition of the drops introduced excipients: preservatives, antioxidants, thickeners, stabilizers, prolongators.

Rule 1

Order of the Ministry of Health? 214 found: the concentration and volume (or mass) of isotonic and stabilizing substances added to eye drops should be indicated not only in the passports, but also on the recipes.

30.2. EYE DROP PRODUCTION TECHNOLOGY

The manufacture and quality control of sterile solutions in pharmacies is carried out in accordance with the requirements of the current Global Fund, guidelines for the manufacture of sterile solutions in pharmacies, regulatory documents, orders and instructions.

The technology for making eye drops is no different from making drops for domestic usebut has the features below.

30.2.1. Sterility assurance

According to the Global Fund, sterility is a necessary requirement for all ophthalmic dosage forms. Sterility - the absence of viable microbial contamination. Seed-free drugs can cause eye infections, which can lead to loss of vision.

Rule 2

Ophthalmic dosage forms are prepared under aseptic conditions similarly to injection solutions.

Rule 3

Sterile solvents are used to prepare ophthalmic drops: purified water, isotonic buffer solutions, oils, etc. Sterile solutions are packaged in sterile vials.

Rule 4

Eye drops should be sterile.

The method of sterilizing eye drops depends on the resistance of drugs in solutions to temperature exposure and is determined by order of MOH? 214 dated July 16, 1997 (similar to injection).

According to the sterilization regimen established by the order of the Ministry of Health? 214, eye drops can be divided into 3 groups:

1. Drops without the addition of stabilizers, sterilized by steam at a pressure of 1.1 atm and 120 ° C for 8-12 minutes or fluid steam for 30 minutes.

In this way, solutions are sterilized: atropine sulfate, boric acid, dicain, potassium iodide, calcium chloride, sodium chloride, nicotinic acid, pilocarpine hydrochloride, proserin, riboflavin, sulfopyridazine sodium, furacilin, zinc sulfate, ephedrine hydrochloride, as well as eye drops containing riboflavin in combination with ascorbic acid and glucose, etc.

2. Drops with the addition of stabilizers, which can be sterilized with steam under pressure or with fluid steam (see the appendix to the order of the Ministry of Health of the Russian Federation? 214).

3. Drops containing thermolabile substances that cannot be sterilized by thermal methods. Sterilizing filtration is carried out through 0.22 μm membranes. By this technology, solutions are prepared: benzylpenicillin, streptomycin sulfate, collargol, protargol, resorcinol, adrenaline hydrochloride, citral, etc.

Checking the sterility of eye drops manufactured in pharmacies is assigned to the district centers for sanitary and epidemiological surveillance (TsGSEN).

Rule 5

Eye drops should remain sterile under conditions of frequently opened packaging.

Eye drops, regardless of sterilization conditions, can be contaminated with microorganisms during use (repeated use from one bottle). To prevent microbial contamination of eye drops during application, it is proposed to introduce the following preservatives: chlorobutanol hydrate (0.5%), benzyl alcohol (0.9%), and paraoxybenzoic acid esters

you (nipagin and nipazole, 0.2%), quaternary ammonium salts (benzalkonium chloride, 0.01%), sorbic acid (0.05-0.2%), etc. (Table 30.1).

Table 30.1.The maximum concentration of preservatives in ophthalmic solutions

Rule 6

Preservatives do not produce a sterilizing effect. The introduction of preservatives does not guarantee sterility, but maintains a steady level of microbial contamination in frequently opened packaging.

Regardless of the presence of preservatives, patients should be advised to seal the vial after use and boil pipettes.

30.2.2. Ensuring the absence of mechanical impurities

In the manufacture of intra-pharmacy blanks, equipment for filtering injection solutions is used.

In the case of manufacturing small volumes (10-30 ml), a pre-moistened and washed paper filter is used. Filtering is carried out in a bottle pre-rinsed with filtered water.

In the manufacturing process, the solutions are subjected to primary and secondary control for the absence of mechanical impurities, according to the instructions of the order of the Ministry of Health of the Russian Federation? 214.

Initial control is carried out after filtering and packaging the solution. In this case, each bottle with a solution is viewed. If mechanical impurities are found, the solution is re-filtered, re-examined, corked, labeled and sterilized.

Secondary control is also subject to 100% of the bottles with solutions that have passed the stage of sterilization before their design and packaging.

Quality control of the intra-pharmaceutical procurement is carried out by viewing 30 bottles for the absence of mechanical impurities. The control time, respectively, is: from 2 to 5 bottles with a capacity of 5-50 ml - 8-10 s.

30.2.3. Ensuring the accuracy of dosage of drugs

The accuracy of the concentration of drugs in eye drops is affected by the accuracy of weighing the substance, especially when its amount is less than 0.05 g. The way out of this situation is the use of concentrated solutions. The requirements for the manufacture, packaging, closure and storage of concentrated solutions are similar to the requirements for eye drops. For the manufacture of eye drops use: 0.02% riboflavin solution, 4% boric acid solution, 2% zinc sulfate solution, 2, 10% ascorbic acid solution or combined solutions consisting of 2 drugs. The list of concentrates and their storage periods are indicated in the order of the Ministry of Health? 214.

30.2.4. Comfort

The comfort of using eye drops is one of the biopharmaceutical factors that determines the absence of discomfort during the instillation of a drug. It is achieved by isotonizing eye drops or adjusting the pH to a pH of the tear fluid.

Isotonization is carried out by introducing into the solution a calculated amount of sodium chloride (see infusion solutions).

It was shown that eye drops do not cause discomfort if their osmotic pressure corresponds to the osmotic pressure of sodium chloride in a concentration of 0.7 to 1.1% solution. The use of solutions with an osmotic pressure value of

beyond these limits, it leads to burning and irritation of the mucous membrane of the eye (table. 30.2).

Table 30.2.Compositions of iso-, hyper- and hypotonic eye drops

30.2.5. PH regulation

The comfort of eye drops is greatly influenced by the pH value. The average pH of the tear fluid is 7.4. Relatively comfortable to use drops having a pH of 4.5

up to 9.0 (tab. 30.3).

To adjust the pH of the eye drops, sodium bicarbonate and boric acid are used. It is preferable to use buffer solutions as boron solvents: boric acetate and phosphate (Table 30.4). The use of hydrochloric acid or alkali is impractical, although often used.

Table 30.3.Recommended pH values \u200b\u200bfor eye drops

Note:According to the order of the Ministry of Health of the Russian Federation? 214

Table 30.4.The composition of the phosphate buffer solution

Note.According to USP XXI, p. 1338.

30.2.6. Chemical stability

Carried out by:

PH regulation;

The introduction of antioxidants.

The pH level affects the solubility of drugs (see solutions). To prevent hydrolysis and the transition of salts to the base, it is necessary to adjust the pH of ophthalmic solutions. Some drugs may undergo oxidative degradation. To prevent this, antioxidants and anticatalysts are introduced into the composition of ophthalmic solutions (Table 30.5, 30.6). It should be borne in mind that the introduction of sulfur derivatives of low valency can lead to allergic reactionsespecially in children.

Table 30.5.Allowed Antioxidant Concentrations

Note.According to USP XXI, p. 1338.

30.2.7. Provision for prolongation of action

The disadvantage of eye drops is a short period of therapeutic action. This necessitates their frequent installation, which is inconvenient for patients and medical personnel, and also poses a danger to the eye. For example, the maximum hypotensive effect of an aqueous solution of pilocarpine hydrochloride in patients with glaucoma is observed only for 2 hours, so the installation of eye drops has to be carried out up to 6 times a day. In this case, there are sharp fluctuations in intraocular pressure. Frequent installations of the aqueous solution wash away the tear fluid containing lysozyme, and thereby create the conditions for the occurrence of an infectious process.

Prolongation allows to reduce the frequency of installations of eye drops and at the same time increase the time of contact with eye tissues. Prolongation is achieved by increasing the elm-

bone solution. Viscosity determines the rate of runoff of a drug solution along the mucous membrane of the eye. The higher the viscosity of the solution, the longer the solution is retained, the higher the bioavailability.

The first method of prolongation is the inclusion of viscous solvents in the composition of eye drops, which slow the rapid leaching of drugs from the conjunctival sac. As such components of eye drops, oils are used (refined sunflower, peach or apricot, fish oil).

The second way to prolong the action of eye drops is to increase the viscosity of solutions by introducing synthetic thickeners (see table. 30.6). Natural thickeners reduce the microbiological stability of the drug, therefore, are not used.

Example 1

Stabilization of sodium sulfacyl solutions by adjusting the pH and the introduction of antioxidants

30% prescription sulfacyl sodium solution for factory manufacture

10; 20; 30% solution of sulfacyl sodium, including 10 and 20% for newborns, according to the pharmacy prescription

Sulfacyl sodium - 300 g Sodium metabisulfite - 5 g Sodium hydroxide solution - 1 g to pH 7,7-8,0 Water for injection - up to 1 liter Packing: bottles for running-in Sterilization conditions: temperature 100? C - 30 minutes Shelf life - 26 months

Sulfacyl sodium - 100 g, 200 g, 300 g Sodium thiosulfate - 1.5 g, 1.5 g, 1.5 g 1M hydrochloric acid solution: 3.5 ml; 3.5 ml; 3.5 ml of purified water - up to 1 l. The pH of the solution is 7.5-8.5. Packaging: bottles for running in. Sterilization conditions: temperature 120? C - 8 min Shelf life - 1 month Feature: reduced irritating effect of alkali and sodium metabisulfite on the mucous membrane of the eye

Note.According to the order of the Ministry of Health? 308.

Table 30.6.Prolonging the action of eye drops

Note.According to the FDA Advisory Review Panel on OTC Ophthalmic Drug Products, Final report, Dec. 1979.

30.3. TARE AND PACKAGING FOR PACKING OF OPHTHALMIC SOLUTIONS

For ophthalmic solutions, dropper bottles (Fig. 30.2) and glass tube bottles are used, which are closed with rubber stoppers and sealed with aluminum caps. Bottles are made of a glass tube (droot) brand NS; bottles are intended for packaging and storage of medicines. Vials correspond to TU 9461-010-00480514-99 (Fig. 30.2).

Rubber stoppers AB are designed for corking bottles from a drone with drugs. Rubber stoppers comply with TU 38.006108-95.

Caps aluminum K-l (TU 9467-004-39798422-99). They are made of aluminum foil with a thickness of 0.2 mm (Fig. 30.3).

Fig. 30.2.Polyethylene and glass dropper bottles

Fig. 30.3.Bottles from a glass tube (droot) brand NS; plugs made of rubber grade AB; caps aluminum K-l

In the production process, it is imperative to carry out degreasing after stamping and chemical treatment to clean engine oil.

30.4. EYE-DROP EQUIPMENT

Tool for crimping aluminum caps POK-1

(Fig. 30.4). Designed for corking bottles with blood substitutes and infusion solutions, as well as vials from drone with a diameter of 20 mm of any capacity.

Principle of operation: the device operates using a manual drive. The crimping of the cap is carried out by moving the crimping nozzle in a vertical plane down; the nozzle captures the neck of the bottle (bottle) and crimps by compressing the toroidal spring.

Key features and benefits:

Compact, portable desktop type;

Low weight (no more than 5 kg);

Possibility of quick change of crimping heads and supports;

Easy to reconfigure to different types of bottles and bottles.

Semi-automatic seaming machine PZR-M. Designed for corking any type of vial and bottle with a smooth and screw neck with a capacity of 10 to 500 ml aluminum caps K-1, K-2, K-3, K-4, K-5 for pharmacy and pharmaceutical production. Meets GMP pharmaceutical equipment requirements. Productivity - up to 1300 fl./h

(Fig. 30.5).

Installation for pumping and portioned filling of drugs. The Kontur-P4 installation is intended for filtering, pumping and portion filling liquid medicine   doses in multiples of 5 ml. It is used for any liquids allowing long-term contact with silicone rubber. With its help, drugs, biological and other liquids are poured into containers with a capacity of 10 to 400 ml. Its fluid path is easily washed and sterilized.

Principle of operation: the liquid substance to be dispensed is filtered at the inlet of the peristaltic metering pump, which, through a peristaltic silicone hose and a portable filling head, delivers 5 ml of liquid to the filling bottle.

30.5. TECHNOLOGICAL SCHEME FOR PRODUCING EYE DROPS AND SOLUTIONS

Wash new dishes from the outside and inside with tap water, soak for 20-25 minutes in washing solutions, heated to 50-60 ° C. A suspension of mustard 1:20, 0.25% solution of Desmol, 0.5% solutions of Progress, Lotus, Astra, 1% solution of SPMS (a mixture of sulfanol with sodium tripolyphosphate 1:10) are also used. In case of severe contamination, the dishes are soaked for 2-3 hours in a 5% suspension of mustard or a solution of detergents in accordance with special instructions.

Washed dishes are sterilized with hot air at 260 ° C for 60 minutes. Dishes that were in use are disinfected with a 1% solution

Fig. 30.4.POK-1 devices

activated chloramine - 30 min; 3% freshly prepared hydrogen peroxide solution with the addition of 0.5% detergents - 80 minutes or 0.5% Desmol solution - 80 minutes.

Purified water is used freshly prepared and sterilized in the appropriate mode.

For corking bottles use tubes of special types of rubber: IR-21 (silicone), IR-119, IR-119A (butyl rubber). New rubber plugs are treated to remove sulfur, zinc and other substances from their surface in accordance with the instructions. Used stoppers are washed with purified water and boiled in it 2 times for 20 minutes, sterilized at 121 + 2? C for 45 minutes.

Vials with solutions, corked with rubber stoppers, control for the absence of mechanical impurities. When detecting mechanical impurities during the initial control of the solution, it is filtered.

After manufacturing, the solutions are subjected to chemical analysis, which consists in determining the authenticity (qualitative analysis) and the quantitative content of the medicinal substances that make up the dosage form (quantitative analysis). If the result is positive, they are rolled in with metal caps.

Rolled solution bottles are marked with an aluminum cap, indicating the name, batch number.

Labeled vials are placed in an autoclave and sterilized in accordance with the instructions of the Global Fund, given the volume of solution in the vessel. After sterilization, the solutions are analyzed for the content of mechanical inclusions by order? 308. Rejected vials cannot be recycled.

The rejected vials are sent for a complete analysis in accordance with the requirements of the Global Fund or Federal Assembly.

A sample is taken for sterility analysis. In case of a positive result, they are marked and packaged in corrugated boxes. A typical scheme for obtaining ophthalmic solutions is presented in scheme 30.1.

Thus, the technology for producing ophthalmic solutions practically does not differ from the technology for producing injection solutions, except that due to the small volumes of eye drops, it often becomes necessary to weigh a sample of substances from lists A and B weighing less than 0.05 g, which is prohibited by the requirements of the Pharmacopoeia. To overcome this obstacle, it is recommended

Scheme 30.1.Technology for producing eye drops and ophthalmic solutions

use concentrated solutions, the composition and technology of which are presented in the order of the Ministry of Health of the Russian Federation? 214.

30.6 EXAMPLES OF MANUFACTURING EYE DROPS

Example 1

Preparation of eye drops by dissolution of the medicinal substance Rp .: Solutionis Atropini sulfatis 1% - 10 ml

D.S. 2 drops 2 times a day in the left eye. In the order of the Ministry of Health? 214 are indicated:

- composition of the solution: 0.1 g of atropine sulfate, 0.08 g of sodium chloride, purified water to a volume of 10 ml;

- sterilization conditions: temperature 100 "C - 30 min;

- storage: according to list A;

- expiration date: at a temperature of 3-5 "C - 30 days.

Under aseptic conditions, 0.1 g of atropine sulfate and 0.08 g of sodium chloride are dissolved in a sterile stand in approximately 5 ml of purified water from a cylinder containing 10 ml of purified water. The solution is filtered through pre-washed filter paper and medical cotton wool (or a sterile glass filter with pore sizes of 10-16 μm) into a sterile neutral glass bottle, the remaining amount of water is filtered through the same filter.

The solution is monitored for the qualitative and quantitative content of atropine sulfate and sodium chloride and for the absence of mechanical impurities.

The bottle is corked, wrapped in an aluminum cap, marked and sterilized in a steam sterilizer with flowing steam. After sterilization, eye drops are checked for the absence of mechanical impurities, they are decorated with a pink label and the additional label “Handle with care”. The bottle is sealed and a copy of the recipe is made out.

Example 2

Preparation of eye drops from concentrated solutions of Rp .: Riboflavini 0.001 Acidi ascorbinici 0.02 Kalii iodidi 0.3

Solutionis acidi borici 2% - 10 ml

M.D.S. 2 drops 3 times a day in both eyes.

There is no ND for this recipe. The calculation indicates that due to the prescribed amounts of potassium iodide and acid, the boric solution is hypertonic. All ingredients are in the form of sterile concentrated solutions.

3.3 ml of purified water, 5 ml of a 0.02% riboflavin solution in combination with a 4% solution of boric acid, 0.2 ml of a 10% solution of ascorbic acid, 1.5 ml of a 20% potassium iodide solution are measured in a sterile vial.

The solution is monitored for the absence of mechanical impurities. The bottle is corked and filled with a label.

Example 3

Internal pharmacy preparation of eye drops Rp .: Riboflavini 0.002 Solutionis Citrali 0.01% - 10 ml

In accordance with the words specified in the order of the Ministry of Health, a solution for 10 bottles is prepared as follows: 0.02 g of riboflavin and 0.9 g of sodium chloride are dissolved in 99 ml of purified hot water. The solution is filtered and sterilized. After cooling the solution, 1 ml of a 1% alcohol citral solution is added to it under aseptic conditions.

Rule 7

Citral does not withstand sterilization and is absorbed by the rubber stopper material. Therefore, its alcohol solution is injected under a stopper of a sterile ophthalmic solution under aseptic conditions.

Shelf life - 2 days at a temperature of no higher than 25 ° C or 5 days - at a temperature of 3-5 ° C. The reason for the short shelf life of the drops is a decrease in the concentration of citral due to its sorption with a rubber stopper.

Capping the bottles with plastic caps allows you to increase the shelf life of the drops up to 1 month when stored in a cool dark place.

30.7. EYE SOLUTIONS

Ophthalmic solutions are used in the form of lotions, irrigation solutions (for irrigation in ophthalmic surgery), solutions for cleaning, disinfecting and storing soft contact lenses.

Ways to ensure the quality of eye solutions are basically the same as eye drops: they must be sterile, stable, not contain mechanical impurities. Lotions and irrigation solutions should be isotonic, and this is more important than in the manufacture of drops. Most often, eye lotions are prescribed solutions: furatsilina, sodium bicarbonate, boric acid, ethacridine lactate.

Example 4

Rp .: Solutionis Furacilini 1: 5000 100 ml D.S. Eye lotion.

Order of the Ministry of Health? 214 0.02% furatsilina solution isotonized with sodium chloride (0.85%). The solution is sterilized at a temperature of 100 ° C for 30 minutes or at 120 + 2 "C for 8 minutes.

The shelf life of the solution is 30 days at a temperature not exceeding 25 ° C in a dark place.

Under aseptic conditions, 0.02 g of furatsilina and 0.85 g of sodium chloride are dissolved in a sterile stand in 100 ml of purified hot water. The solution is filtered into a sterile bottle of neutral glass, check for the absence of mechanical impurities. The solution bottle is corked with a rubber stopper, wrapped in an aluminum cap, marked and sterilized. After sterilization, the solution is re-checked for the absence of mechanical impurities and filled out with a label.

30.8. EYE OILS

In addition to solutions and thin suspensions, ointments are used in the form of ophthalmic dosage forms, which are used by laying over the eyelid. The composition of ointments is diverse. Often there are eye ointments with antibiotics, sulfonamides, etc.

The purpose of the application may be different (disinfection, anesthesia, expansion or contraction of the pupil, lowering of intraocular pressure, etc.).

Rule 8

Eye ointments have the property of delaying the drug in the conjunctiva of the eye longer than suspensions and solutions. Most ointments after administration temporarily impair vision, as they are viscous and are not washed off by tear fluid. Therefore, eye ointments are recommended for use at night.

For eye ointments, in addition to general requirements (uniform distribution of drugs, indifference and persistence of the base), a number of additional requirements are made, which is explained by the method of their application:

1. The ointment base should not contain any impurities, should be neutral, sterile, evenly distributed over the mucous membrane of the eye.

2. Eye ointments must be prepared in compliance with aseptic conditions.

3. The particle size of the drug should be kept to a minimum to prevent eye irritation.

30.8.1. Ointment Foundation

Vaseline is widely used as an ointment for ophthalmic ointments due to the absence of irritating properties, persistence, and chemical indifference. But vaseline due to hydrophobicity does not mix well with the tear fluid washing the cornea, and as a basis for eye ointments is uncomfortable.

GF provides as a basis a mixture consisting of 10 parts of anhydrous lanolin and 90 parts of petroleum jelly (a grade for eye ointments). In the absence of petroleum jelly of this sort, ordinary petroleum jelly is purified as follows: petroleum jelly is melted in an enameled vessel and 1-2% of activated carbon is added. The temperature of the mixture was raised to 150 ° C and heating continued for 1–2 hours. The hot vaseline was filtered through a paper filter and poured into sterile jars. After chemical analysis for the absence of organic impurities and neutralization, petroleum jelly is used as a base.

30.8.2. The technology of manufacturing eye ointments

Eye ointments are prepared, like dermatological ointments, but subject to aseptic conditions. All auxiliary materials, ointment base, drugs that can withstand the action of high temperature, cans are sterilized according to the methods specified in the Global Fund. An important factor in the manufacture of eye ointments is the achievement of the optimal degree of dispersion of the administered medicinal substances. The required dispersion of substances is achieved by pre-dissolving or thoroughly rubbing them with a small amount of liquid, related basis. Substances that are soluble in water, such as salts of alkaloids, novocaine, protargol, etc., are dissolved in a minimum amount of sterile water, and then mixed with an ointment base.

Rule 2

Insoluble or sparingly soluble substances (xeroform, zinc oxide) are introduced into the composition of eye ointments in the form of fine powders after they are carefully dispersed with a small amount of sterile liquid paraffin, glycerin or water.

Rule 10

Particular attention is paid to the manufacture of ointments containing substances that can cause burns (zinc sulfate, protargol), etc. They are introduced into the eye ointments, only previously dissolved in water, excluding the ingress of crystals on the mucous membrane of the eye.

Example 5

Rp .: Unguenti Zinci sulfatis 0.5% - 10.0 D.S. Eye ointment. For the eyelid of the right eye 2 times a day. Under aseptic conditions, 0.05 g of zinc sulfate is dissolved in a sterile mortar in a few drops of sterile purified water (unlike dermatological ointments with the same medicinal substance), 10 g of a sterile base for eye ointments are added, mixed thoroughly. The ointment is transferred to a sterilized glass jar, which is corked with a screw-on plastic lid with a sterilized gasket, decorated with a pink eye ointment label.

In the manufacture of eye ointments, as well as eye drops, it is advisable to add preservatives, as indicated in the Global Fund of the latest edition and in pharmacopeias of foreign countries. For this purpose, benzalkonium chloride 1: 1000, a mixture of nipagin and nipazole in the ratio of nipagin 0.12% and nipazole 0.02%, sorbic acid (0.1-0.2%) and other preservatives approved for medical use are proposed.

Packaging

Eye ointments are released in sterile glass or porcelain jars with tight-fitting lids. So that the ointment is not contaminated during use, it is advisable to release it with a sterile spatula, with which the patient must lay the ointment behind the eyelid. The use of eye tubes is recommended.

having a narrow tip that allows you to enter ointment for the eyelid, and low capacity (up to 3.5 g of ointment).

Quality control

Quality control is carried out in accordance with the requirements of the pharmacopeia and the orders of the Ministry of Health? 305 and 214.

application

How to apply eye ointment. Patient Information (fig. 30.7)

1. Wash your hands.

2. Hold the tube with ointment in your hand for several minutes to melt the base.

3. Standing in front of the mirror, look up, and pull the lower eyelid slightly down.

4. Carefully lay a small amount of ointment over the edge of the eyelid (approximately 0.5-1.0 cm).

IMPORTANT: Be very careful when applying the ointment. Do not allow the tip of the tube to touch the eyelid, eyeball, finger, or any surface.

5. Close the eye and, slowly rotating the eyeball, distribute the ointment. You can blink several times so that the ointment is evenly distributed.

7. Close the tube cover. After you apply the ointment, your eyesight will temporarily worsen. Do not worry - it will pass.

Fig. 30.7. Proper application of eye ointment

test questions

1. What are the possible causes of secondary eye infection after instillation of eye drops? What should be the technology of eye drops to exclude such cases?

2. Compare the quality indicators of eye drops and injectable solutions. What conclusions can be drawn from this comparison?

3. How can sterility of eye drops be ensured during their use?

4. The composition of eye drops - anaprilin solution includes excipients: thiourea, cetylpyridinium chloride and citrate-phosphate buffer solvent. What is the functional purpose of these substances?

5. What are the possible causes of unpleasant sensations arising after the instillation of eye drops, and what are the ways to eliminate these phenomena?

6. Compare the quality indicators of ophthalmic solutions (prolonged action and stability). Give examples of ensuring these indicators.

7. What is the similarity of the technology for the manufacture of dermatological and eye ointments? How to explain the difference in their technology?

8. What are the main directions for improving the quality and manufacturing technology of ophthalmic dosage forms?

Tests

1.   Order of the Ministry of Health? 214 established - the concentration and volume (or mass) of isotonic and stabilizing substances added to eye drops should be indicated:

1. Not only in passports, but also on recipes.

2. On the passports.

3. On the recipes.

4. On the requirements and be accompanied by appropriate inscriptions in the registration books.

2. Ophthalmic dosage forms are prepared under aseptic conditions similarly to injection solutions, if they:

1. Sterile.

2. Non-sterile.

3. Regardless of the mode and conditions of sterilization.

3. Choose the wrong answer: for the preparation of eye drops use:

1. Sterile solvents - purified water, isotonic buffer solutions, oils.

2. Sterile vials and plugs.

3. Sterile auxiliary materials (filters, funnels, pipettes).

4. Sterile drugs.

4. Choose the wrong answer: in the case of manufacturing small volumes (up to 30 ml):

1. Use a pre-moistened and washed paper filter.

2. Rinsed sterile water with a purified bottle for dispensing.

3. Dissolution is carried out in half the volume of solvent.

4. The volume of the solution should be equal to the nominal.

5.   The manufacture of concentrated solutions for ophthalmic dosage forms and mixtures for children under the age of 1 month differs from the manufacture of concentrates for a buret installation by the stage:

1. Creating aseptic manufacturing conditions.

2. Sterilization of auxiliary materials and utensils.

3. Sterilization of the solution after manufacture in accordance with ND.

4. Filtering.

5. Standardization.

6.   To make 30 ml of an isotonic solution of magnesium sulfate (the isotonic equivalent of sodium chloride is 0.14), the medicinal substance should be taken:

1.4 g

2.6 g

3. 1.92 g.

4. 0.04 g.

5.27 g.

7.   For the manufacture of 10 ml of a 1% solution of pilocarpine hydrochloride, sodium chloride should be taken (the isotonic equivalent of sodium chloride is 0.22):

1.0.022 g.

2.0.090 g

3.2.220 g.

4.0.068 g

5.680 g.

6. 0.000 g.

7. 0.900 g.

8.   Eye drops containing 0.2 pilocarpine hydrochloride in 10 ml of purified water (the isotonic equivalent of sodium chloride is 0.22), lacrimal fluid:

1. Isotonic.

2. Hypotonic.

3. Hypertonic.

9.   Eye drops - 10% sodium tetraborate solution 10 ml (the isotonic equivalent of sodium chloride is 0.34), tear fluid:

1. Isotonic.

2. Hypotonic.

3. Hypertonic.

10. You have to make eye drops composition:

Riboflavini 0 02% - 10 ml Acidi Borici 0.2.

Which manufacturing option do you choose as optimal:

1. Dissolution of solids.

2. The use of one-component concentrated solutions.

3. The use of combined concentrated solutions.

11. Add stabilizer in the manufacture of eye drops:

1. Riboflavin.

2. Pilocarpine hydrochloride.

3. Sodium sulfacyl.

4. Collargol.

12. Thermally sterilized eye drops containing:

1. Benzylpenicillin.

2. Resorcinol.

3. Collargol.

4. Chloramphenicol.

Eye drops are aqueous, oily solutions; the thinnest suspensions and emulsions intended for eye instillation and dosed by drops.

This is an official dosage form. The Global Fund has a common group article. In addition to eye drops, eye ointments, eye films, lotions and solutions for electrophoresis of the eye are used to treat the eyes.

Eye Drop Requirements:

1. Sterility.

The tear fluid of a healthy eye is sterile. It contains a natural antibiotic substance - lysozyme. In inflammatory eye diseases, the amount of lysozyme decreases and the administration of non-sterile fluid can lead to eye infection, up to and including loss of vision.

Therefore, eye drops prepared in a pharmacy should be sterile without the advice of a doctor. In accordance with order No. 308, eye drops are made under aseptic conditions.

The nomenclature and sterilization regimen for eye drops are given in Order No. 214 (Appendix No. 10).

For sterilization, 2 modes are used: saturated steam under pressure at 120 0 -8 minutes or fluid steam at 100 0 -30 minutes. The choice of sterilization method depends on the properties of the drug when heated and is indicated in order No. 214.

Sterility of eye drops 2 times a quarter is checked for LHC analysis.

When using eye drops, sterility is impaired. To prevent microbial seeding in factory and pharmacy conditions, the volume of eye drops does not exceed 5-15 ml. In the factory, preservatives are added in accordance with TU: nipagin, nipazole, chlorobutanol hydrate and others.

In pharmacy conditions, preservatives are added as directed by the doctor.

Preservative properties are possessed by: 2% solution of boric acid, 0.2% solution of chloramphenicol in connection with their pharmacological action.

2. Cleanliness.

The presence of mechanical impurities, which can additionally irritate the mucous membrane of the eye, injure it, is not allowed. Eye drops are filtered through wetted SSBF with a long-fiber cotton swab. Check for cleanliness 2 times: before and after sterilization.

3. Isotonicity.

All eye drops should be isotonic to avoid discomfort during instillation (itching, burning, pain, lacrimation, redness of the mucosa).

Eye drops are isotonic, regardless of the doctor's instructions.

Isotonizing agents: sodium chloride, sodium nitrate, sodium sulfate.

Sodium sulfate or sodium nitrate is used in cases where sodium

chloride enters into a chemical reaction with the drug:

Silver nitrate solutions are isotonized with sodium nitrate.

Zinc sulfate solutions are isotonized with sodium sulfate.

· Calculations per 10 ml

· Calculations for 5ml

0,045 - (sample of the drug * isotonic equivalent)

· On isotonic sodium chloride solution

drops with chloramphenicol, citral, riboflavin, furacilin are prepared.

In this case, the sample weight is insignificant and does not create osmotic pressure.

· Do not isotone:

1. If the concentration of the drug is 3% or more

2. Solutions of collargol, protargol. Sodium chloride is an electrolyte and destroys colloidal solutions.

4. Accuracy of concentration.

Preparation is carried out by mass - volumetric method bringing to volume.

PHC - 1 time before sterilization:

Mandatory: eye drops and ointments with preparations subject to PKU

(narcotic, potent, Schedule A)

Eye drops for newborns

Concentrated solutions of eye drops

The rest: selectively, first of all. Particular attention to LF for children, but at least 3 dosage forms per shift.

5. Stability (resistance).

Stabilizers are added in accordance with Order No. 214 or as directed by a physician. The amount of stabilizer is indicated in the control panel and on back side   recipe.

6. Prolongation of action.

For physiological reasons, eye drops cannot be on the mucosa for a long time. This leads to the use of eye drops several times a day. Increasing the viscosity of the solution prolongs the effect. To increase the viscosity, carboxymethyl cellulose and polyvinyl alcohol may be administered as directed by a physician. Prolongation is predominantly carried out in the factory in accordance with TU.

Rules for the preparation of eye drops:

1. The doctor prescribes eye drops in accordance with order No. 110.

2. It is necessary to check the compatibility of ingredients in complex prescriptions

3. Pay attention to concentration.

4. As solvents are used:

· Water for injections. Eye drops are made in a box, where there is usually freshly distilled water for injection.

· Purified water devoid of carbon dioxide, ammonium salts, reducing substances.

· Oils are sterile.

· The sodium chloride solution is isotonic.

5. Eye drops are prepared under aseptic conditions, so the label is prescribed in advance in accordance with the “Uniform rules for design ...”. The composition is placed on the label, since the requirements and recipes are not entered in the box.

6. Choose a cooking method and carry out calculations on the back of the control panel.

7. The amount of the isotonizing agent is indicated in the AUC and on the back of the recipe.

8. The cooking time in the PPC do not indicate there is no requirement of pyrogen-free.

9. Cork under a run-in, at the same time carry out marking for sterilization similarly to solutions for injections.

10. Eye drops are selectively given for analysis.

11. After sterilization, marriage is mandatory for cleanliness, color, integrity of the vial, tightness of the cork.

Methods (methods) of preparing eye drops.

· The method of "two cylinders"

· Two-cylinder method using concentrated solutions

· Double amount method.

The choice of preparation method depends on the volume of the prepared solution and the ability to accurately weigh a sample of the drug.

The “two cylinder” method.

It is used when the volume of the solution does not exceed 10 ml and a sample of the drug can be weighed on a manual scale in accordance with the rules of weighing.

In this case, accuracy of concentration and volume is achieved.

In a half amount of the prescribed volume of water in a penicillin vial, dissolve medicinal substances, an isotonizing agent and filter the solution through a moistened SBP with PTDV into a measuring cylinder. Through the same filter, bring water to a predetermined volume; poured into a penicillin bottle for vacation.

The task.

Prepare a solution of pilocarpine hydrochloride 1% - 10 ml eye drops according to the prescription for a chronic patient.

Response algorithm.

Rp: Sol. Pilocarpini hydrochloridi 1% - 10 ml 0.1 pilocarpine

D.S. Eye drops. 0.068 (0.07) NaCl

up to 10 ml of water for in.

Characteristic:

Features

1. Pilocarpine hydrochloride is a Schedule A drug, but is not subject to PKU. Prescription form Form 107-U is additionally issued with the inscription “To a chronic patient. Release 2 vials every 10 days for 1 year. ” The additional inscription is sealed with the seal and signature of the doctor and the seal "For recipes" The recipe is valid for 1 year.

2. We check the concentration by order No. 214 (1%, 2%, 4%, 6%) and underline in red pencil (order No. 330).

6. Eye drops should be isotonic.

0.09 - (sample of the drug * isotonic equivalent)

= 0,09 –(0,1*0,22)=0,068=0,07

The amount of isotonizing agent is indicated in the PPC and on the reverse side.

The calculated amount of pilocarpine can be weighed on a hand-held scale, the solution volume is 10 ml, so we use the “two cylinders” method for preparation.

8. The drug is a list A, therefore:

· We receive from the pharmacist-technologist with filling in the back of the recipe

· In the passport - “A”

· PHC - mandatory 1 time before sterilization

· Additional label “Handle with care”

· It is not sealed up, as a corking under run-in.

10. Eye drops should be sterile. 120 0 - 8 min. Additional label "Sterile" is not needed.

11. Shelf life of 30 days.

12. The patient is kept in a safe until leave.

13. It is used in the treatment of glaucoma.

Cooking.

We pour about 5 ml of water into the penicillin vial, we get from the pharmacist - technologist dissolve 0.1 pilocarpine hydrochloride. Weigh and dissolve 0.07 sodium chloride. We prepare the filter. We filter the solution into the cylinder and, through the same filter, bring the volume to 10 ml, pour 1 ml for analysis. Fill in the PPC.

The solution is poured into a penicillin bottle for dispensing, checked for cleanliness, corked for a run-in, pre-marked:

Sol. Pilocarp. 1%

09.09.09 Signature.

We sterilize in an autoclave at 120 0 - 8 min. We carry out a marriage. We make out for vacation.

The task.

To prepare a solution of sodium sulfacil 10% 10 ml eye drops according to the prescription

Response algorithm.

Rp: Sol. Sulfacyli- Natrii 10% - 10 ml 1, 0 sodium sulfacyl

D.S. Eye drops. 0.015 (0.02) Sodium thiosulfate

0.1 M HCl -0.35 ml

up to 10 ml of water for in.

Characteristic:   This dosage form is a complex liquid, aqueous true solution for eye instillation.

Features

2. We check the concentration by order No. 214 (10%, 20%, 30%).

3. We write out a label with the composition of the “Unified rules for registration ...”.

5. Eye drops should be isotonic. In this case, the concentration is large and the drops are hypertonic. When dispensing drops, the patient must be warned of discomfort.

6. Eye drops should be stable. Sulfacyl sodium is an easily oxidized substance. Stabilization in accordance with order No. 214.

The composition of the stabilizer per 10 ml, regardless of concentration

0.015 Sodium thiosulfate

0.1 M HCl -0.35 ml

HCl + Na 2 S 2 O 3 NaCl + H 2 O + SO 2 + S

SO 2 - acts as an antioxidant.

The amount of stabilizer is indicated in the PPC and on the back of the recipe.

7. The concentration of the solution must be accurate.

The calculated amount of the drug can be weighed on a hand-held scale, the solution volume is 10 ml, so we use the “two cylinders” method for preparation.

8. 0.1 M HCl is added with an analytical pipette, as an exception in drops.

9. The dissolution order: sodium thiosulfate, sodium sulfacyl, 0.1 M HCl.

10. Eye drops should be clean. Filter through wetted SSF with PTDV. We check for cleanliness 2 times.

11. PHC - selectively primarily 1 time before sterilization.

12. Eye drops should be sterile. Sterilize at 120 0 - 8 min. Additional label "Sterile" is not needed.

13. Shelf life of 30 days.

14. It is used in the treatment of conjunctivitis, the prevention of gonoblenorrhea of \u200b\u200bthe newborn.

The task.

Prepare eye drops with prescription glycerin.

Response algorithm.

Rp: Sol. Glycerini 40% - 10 ml 4.44 glycerin 90%

D.S. Eye drops. up to 10 ml of water for in.

Characteristic:   This dosage form is a complex liquid, aqueous true solution for eye instillation.

Features

1. Check the prescription. Prescription form Form 107-U.

2. Check the concentration in accordance with the therapeutic effect.

3. We write out the label with the composition of the “Unified rules for registration ...”

4. We cook under aseptic conditions by order No. 308 and 309.

5. We carry out calculations on the reverse side of the control panel.

6. Glycerin count in terms of anhydrous

7. Eye drops should be isotonic. In this case, the concentration is large and the drops are hypertonic. When dispensing drops, the patient must be warned of discomfort.

In this case, we prepare by mass - volumetric method, since glycerin is a viscous liquid.

9. Eye drops should be clean. Filter through wetted SSF with PTDV. We check for cleanliness 2 times.

12. Shelf life 30 days.

13. It is used as a dehydrating agent.

The task.

To prepare prescription eye drops with quinine hydrochloride.

Response algorithm.

Rp: Sol. Chinini hydrochloridi 1% - 10 ml 0, 1 quinine hydrochloride

D.S. Eye drops. 0.08 NaCl

Up to 10 ml of water for in.

Characteristic:   This dosage form is a complex liquid, aqueous true solution for eye instillation.

Features

1. Check the prescription. Prescription form Form 107-U. List B. Drug

2. We check the concentration by order No. 214 (1%).

3. We write out a label with the composition of the “Unified rules for registration ...”.

4. We cook under aseptic conditions by order No. 308 and 309.

5. Quinine hydrochloride MP 1:30, dissolve in hot water.

6. Eye drops should be isotonic.

0.09 - (sample of the drug * isotonic equivalent)

= 0,09 –(0,1*0,14)=0,076=0,08

The amount of the isotonizing agent is indicated in the AUC and on the back of the recipe.

7. Eye drops should be stable. Quinine hydrochloride is an alkaloid salt; in the presence of the ion of the same name, the base may precipitate. Therefore, quinine hydrochloride is dissolved in 7-8 ml of hot water. Sodium chloride is added after complete cooling.

8. The concentration of the solution must be accurate.

The calculated amount of the drug can be weighed on a manual scale, the solution volume is 10 ml, so we use the “two cylinders” method for preparation.

9. Eye drops should be clean. Filter through wetted SSF with PTDV. We check for cleanliness 2 times.

10. PHC - selectively primarily 1 time before sterilization.

11. Eye drops should be sterile. Sterilize at 120 0 - 8 min. Additional label "Sterile" is not needed.

12. Shelf life of 120 days.

13. It is used in the treatment of diseases caused by simple microorganisms.