Eye drops are aqueous or oily solutions or the finest suspensions. medicinal substances. 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.
During cooking 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 release from suspended particles that can cause mechanical injury to the membranes of the eye, eye drops filtered through the best grades of filter paper, with a small ball of long-fiber wool 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 pharmacopeia table (as well as in the section “Injection Solutions” in this textbook), the isotonic equivalent of sodium pilocarpine hydrochloride for chloride is 0.22, that is, 1 g of pilocarpine hydrochloride creates the same osmotic pressure as 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 drops
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 during storage and use. These include merthiolate (0.005%), ethanolmercurium 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 non-isotonic solutions are introduced into the eye, pain appears due to the difference in the osmotic pressure of the tear fluid and the solution. Isotonation of eye drops is achieved by their preparation on an isotonic sodium chloride solution (0.9 ± 0.2%) or on 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 make frequent installations, 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 zinc salts, some alkaloids, novocaine, mesatone in eye drops, an isotonic boric acid solution (1.9%) is used. 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 until 10 ml of solution is obtained.
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 GFH. From the pharmacopoeia table, it follows that the isotonic equivalent of pilocarpine hydrochloride for sodium chloride is 0.22, i.e., 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:
((0.9 - 1 · 0.22) / 100) · 10 \u003d 0.068 ≈ 0.07
A weighted amount of sodium chloride is dissolved in water for injection, in a half amount of this solution (5 ml) 0.1 g of pilocarpine hydrochloride is dissolved, 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. Apply eye films by laying behind 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.
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Based on the materials of I.S. Azhgikhin. Technology of drugs.
Eye LF are allocated in a special group in connection with the method of their use. Famous Soviet ophthalmologist Academician V.P. Filatov (1875 - 1956) wrote: "It can be said without exaggeration that among the human senses, the most valuable is the organ of vision." 90% of information about the world around a person receives through vision.
The mucous membrane of the eye is the most sensitive of all the mucous membranes of the body. It reacts sharply to external stimuli - mechanical impurities, a mismatch between the osmotic pressure and the pH value of the drug introduced into the eye by the osmotic pressure and pH value of the tear fluid. The tear fluid is a protective barrier for microorganisms due to the presence of lysozyme in it (the enzyme muromidase). With various eye diseases, the content of lysozyme in the lacrimal fluid is significantly reduced, which contributes to the multiplication of microorganisms that cause severe diseases. Therefore, along with the general requirements for many drugs, they are subject to increased requirements: sterility, stability, isotonicity, lack of mechanical impurities and irritating effects, dosing accuracy.
Currently, in the treatment and prevention of eye diseases, the following ophthalmic pharmaceutical preparations of industrial production are used: drops, ointments, films. The most common ophthalmic LF are drops.
The main requirements that eye drops must meet:
Sterility;
Lack of mechanical inclusions;
Comfort (isotonicity, optimal pH value);
Chemical stability;
Prolongation of action.
1. Ensuring sterility.
This is one of the main requirements. Contamination of eye drops with Pseudomonas aeruginosa and Staphylococcus aureus is especially dangerous. There were a number of cases of blindness that occurred as a result of the instillation of non-sterile eye drops. Microbial contamination also causes instability of eye drops during storage. A few days after manufacture, non-sterile eye drops show visible signs of microbial contamination - turbidity, mold, sediment.
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. In this regard, eye drops can be divided into three groups.
The 1st group includes eye drops that can be steam sterilized under pressure for 8 to 12 minutes without the addition of stabilizers. These are solutions of amidopyrine, atropine sulfate, boric acid, dikoin, 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.
The 2nd group includes eye drops with the addition of stabilizers, which can be sterilized with steam under pressure or with steam. Drops of this group are given below, when considering chemical eye drops.
The 3rd group includes eye drops containing thermolabile substances that cannot be sterilized by thermal methods (benzylpenicillin, streptomycin sulfate, collargol, protargol, resorcinol, etc.). To sterilize such laser droplets, filtering through microporous sterile filters can be used.
Eye drops made aseptically, or sterile drops, may become contaminated with microorganisms during use. In this regard, there is a need to add preservatives to the eye drops, which prevent the growth and reproduction of microorganisms that fall into the eye drops, and help to maintain their sterility during the entire time of use. The following preservatives are used: chlorobutanol hydrate (0.5%), benzyl alcohol (0.9%), paraoxybenzoic acid esters (nipagin and nipazole, 0 ”%), quaternary ammonium salts (benzalkonium chloride, 0) 1%), sorbic acid (0.05 - 0.2%).
A group of Leningrad ophthalmologists proposed as a preservative for eye drops the addition of a mixture consisting of 0.2% chloramphenicol and 2% boric acid.
2. Ensuring the absence of mechanical impurities.
By analogy with injection solutions, eye drops are filtered through glass, paper or membrane filters with simultaneous sterilization.
Since large losses occur during filtration, and this affects the accuracy of the concentration of drugs in eye drops, especially at very low concentrations of drugs, resort to the use of concentrated solutions.
3. Providing comfort.
In most cases, the discomfort when using eye drops is due to the mismatch of the osmotic pressure and the pH of the eye drops with those in the tear fluid.
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%.
Sometimes doctors prescribe hypertonic eye drops, as they have a faster, especially antimicrobial effect. But hypertonic eye drops are poorly tolerated by children.
The comfort of eye drops is greatly influenced by the pH value. Most eye drops have a pH between 4.5 and 9.
The optimal value is 7.4. At pH\u003e 9 and< 4,5 глазные капли вызывают при закапывании сильное слезотечение, чувство жжения, рези.
4. Ensuring chemical stability.
The main methods for stabilizing eye drops are the regulation of pH values \u200b\u200band the introduction of antioxidants into solutions containing readily oxidizing substances. Buffer solvents are used to regulate the pH value. Most often, a boric acid of 1.9 - 2% is used as a buffer solvent. As antioxidants: sodium
sulfite, sodium metabisulfite and trilon B.
5. Provision of prolonged action.
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. For example, the maximum hypotensive effect of an aqueous solution of pilocarpine hydrochloride in patients with glaucoma is observed only within 2 hours, so you have to perform eye drops instillation up to 6 times per roll. Frequent instillations of the aqueous solution wash away the tear fluid containing lysozyme, and thereby create the conditions for infection.
Reducing the frequency of eye drop excision and at the same time increasing the time of contact with eye tissues can be achieved by prolonging the inclusion of viscous solvents in the composition of eye drops, which slow the rapid leaching of drugs from the conjunctival sac. Oils (refined sunflower, peach or apricot) were previously used as such substances. However, synthetic hydrophilic IUDs, such as MC (0.5% - 2%), Na - CMC salt (0.5 - 2%) polyvinol (1.5%), and microbial PS aubazidan (proved to be more effective prolongers for eye drops) 0.1 - 0.3%), polyglucin, etc. These substances do not irritate the mucous membrane of the eye, and are also compatible with many drugs and preservatives.
Strengthening and prolonging the action is explained by the increase in the duration of the substance in the conjunctival sac, slow but complete absorption through the cornea. For example, the number of instillations of 2% pilocarpine hydrochloride solutions prepared with 2% Na CMC in patients was reduced to 3 times a day instead of 6 instillations of an aqueous solution without the addition of prolongators.
Eye Drop Technology.
Eye drops are aqueous or oily solutions, the finest suspensions and emulsions for instillation into the conjunctival sac. The solvents are water for injection, sterile fatty oils - peach, almond and liquid paraffin.
The features of their industrial production are the use, in addition to antioxidants, of gas protection for readily oxidizing substances (morphine hydrochloride, sodium sulfacyl, ascorbic acid), improvement of packaging (tube - drops - droppers).
Solutions in tube droppers are prepared in rooms of the 2nd class of cleanliness under aseptic conditions. The dissolution is carried out in reactors with stirrers, the solution is freed from mechanical impurities, subjected to sterile filtration and collected in a sterilized apparatus for subsequent filling of the tube - droppers.
In parallel with this, cases and caps are made of tube - droppers. A case with a capacity of 1.5 ml is obtained on the machine in several stages by blowing and stamping from high-pressure polyethylene granules. Caps with a pin for puncturing are poured under pressure from the molten pellets of low pressure PE. After manufacturing, they are washed with purified water, dried and subjected to gas sterilization at 40-50 ° C with a mixture of ethylene oxide and 10% CO2 for 2 hours. Ethylene oxide is removed from the products by keeping them for 12 hours in a sterile room.
Then, under aseptic conditions, in a unit with excess pressure of sterile air, the caps are screwed onto the body, filled with a solution of the drug using metering pumps and sealed by heat sealing.
A tube filled with droppers is visually checked for the absence of mechanical inclusions on a black and white background with a 60 W electric lamp.
Eye ointments.
Eye ointments are applied by laying over the eyelid. The composition of ointments is diverse - with a / b, sulfonamides, with mercury oxide, etc. The purpose of use can be different (disinfection, anesthesia, dilated or narrowed pupil, decreased intraocular pressure).
In addition to general requirements for eye ointments (uniformity of drug distribution, indifference and resistance of the base), a number of additional requirements are made, which is explained by the method of their application:
The ointment base should not contain any impurities, should be neutral, sterile, evenly distributed over the mucous membrane of the eye;
Eye ointments must be prepared in compliance with aseptic conditions;
Drugs in eye ointments should be in the most dispersed state in order to avoid damage to the mucous membrane.
As the basis of an ophthalmic ointment, a mixture consisting of 10 parts of b / w lanolin and 90 parts of petroleum jelly (grade for eye ointments) was used earlier. Its preparation consists in the fact that ordinary petroleum jelly is dissolved in an enameled reactor and 1 - 2% activated carbon is added there. After further heating to 150 ° C for 1 to 2 hours, the mixture is filtered. Recently, IUD gels have been increasingly used as the basis for eye ointments: gums, sodium alginate, sodium CMC and others. Like all hydrophilic bases, they are well distributed over the mucous membrane of the eye and easily give off drugs. Their disadvantage: they are susceptible to spoilage under the influence of microorganisms and need preservatives (nipagin + nipazole, 0.12% + 0.02%; sorbic acid 0.1 - 0.2%).
The technology of eye ointments takes into account all the requirements for this LF.
Packing: the most convenient - tubes with a screw cap. The tubes can be equipped with screw-on tips, allowing you to enter ointment for the eyelid.
Eye films. (HFP).
They are solid oval plates with smooth edges (6 - 9 mm long, 3 - 4.5 mm wide, 0.35 mm thick, weight 0.015 g).
HLPs have a number of advantages over other ophthalmic drugs: with their help it is possible to prolong the action and increase the concentration of drug in the tissues of the eye, reduce the number of injections from 5 - 8 to 1 - 2 times a day. HLP is placed in the conjunctival sac, in 10 - 15 seconds they are moistened with lacrimal fluid and become elastic. After 20-30 minutes, the film turns into a viscous clot of polymer, which after about 90 minutes completely dissolves, creating a thin, uniform film.
As the film former, polyacrylamide or its copolymers with acrylic and vinyl monomers, polyvinyl alcohol, NaKMTS. The basis for HFD is proposed: 60 parts of acrylamide copolymer, 20 parts of vinyl pyrrolidone, 20 parts of ethyl acrylate and 50 parts of plasticizer - polyethylene glycol succinate.
SOD technology: in the reactor, a 16–18% polymer solution is obtained, mixed with 96% ethanol to loosen the components, water is added, the mixture is heated to 50 ° C and stirred until complete dissolution, cooled to 30 ° C and filtered. Separately, a drug solution is prepared and introduced into the polymer solution. The resulting composition was stirred for 1 hour and centrifuged for 2 hours to remove air bubbles. The resulting solution is applied to the surface of a metal tape and dried in a chamber at a temperature of 40 - 48 ° C, then it is cooled to 38 ° C and a film is removed from the tape in the form of a roll. Leave for 6 - 8 hours to relieve strain stresses. Received with the help of the HLP stamp in a blister pack of 10 pieces and pack in cardboard boxes. Sterilization with a mixture of ethylene oxide and CO2.
A promising form is intraocular drugs obtained on the basis of collagen with gentamicin sulfate and trimecain. They are hemmed into the anterior chamber of the eye during surgical operations, gradually releasing the drug. HLP is completely dissolved on the 10th day.
Contact lenses - gelatin in the form of cups filled with drugs that provide a prolonged effect.
The technological process for the production of eye drops in industrial conditions
Eye drops in the factory are prepared in compliance with all requirements of the factory technology of injection solutions. In the factory, eye drops are prepared in the form of aqueous solutions in water for injection, as well as in the form of oil solutions in sterile fatty oils (peach, almond), liquid paraffin (oil pyrophos solution 0.01% and 0.02%), and in the form of suspensions and emulsions.
Features of industrial production of eye drops
The following features are distinguished:
the use of antioxidants and gas protection for readily oxidizing substances (sodium sulfacyl, ascorbic acid);
the introduction of preservatives: the preservative benzalkonium chloride is part of the eye drops Allergodil / azelastine / 0.05% solution - made in Germany;
Introduction of prolongators (MC - for the preparation of eye drops of pilocarpine hydrochloride, sodium CMC, polyvinyl alcohol - forpreparation of Ophthalmic Ophthalmic Gel - manufactured in Finland);
Improving packaging: dropper tube, dropper bottles.
Eye ointments
Ophthalmic ointments are a dosage form of soft consistency that can form a uniform continuous film when applied to the conjunctiva of the eye. Eye ointments are prescribed for laying the floor of the lower eyelid in the conjunctival sac or for lubricating the skin and edges of the eyelids
Requirements for eye ointments . For eye ointments, in addition to the general requirements for dermatological ointments, a number of additional requirements are made:
The ointment base should not have foreign inclusions and impurities, it should be sterile, neutral and evenly distributed over the mucous membrane of the eye;
Medicinal substances administered by the type of suspension should be crushed to a minimum degree of dispersion in order to avoid damage to the mucous membrane of the eye and the absence of discomfort;
The pH value of the ointment should correspond to the pH of the tear fluid in order to avoid lacrimation and leaching of the drug.
Eye ointments, like others dosage forms for eyes, prepared under aseptic conditions.
Ointment Foundation
As a basis for ophthalmic ointments, GF XI recommends the use of an alloy of vaseline grade “for eye ointments” (90 parts) and anhydrous lanolin (10 parts) if the ointment is unofficial (the base is lipophilic-hydrophilic, absorption). The mixture is melted, filtered while hot to remove mechanical impurities in sterile jars and sterilized by air at 180 ° or 200 ° (time varies depending on the mass of the base). The basis due to the content of lanolin in it contributes to the fixation of the ointment on the mucous membrane of the eye and a more complete return of medicinal substances. For the preparation of eye ointments, petroleum jelly of the “for eye ointments” variety is used. In its absence, ordinary petrolatum is subjected to special purification by the Weissman method of reducing substances with activated carbon in an amount of 1-2% at a temperature of 150 ° for 1-2 hours with stirring in an air sterilizer. Hot petrolatum is filtered and checked for the absence of reducing substances. Many eye ointments with antibiotics are prepared on the basis of an alloy of anhydrous lanolin with petrolatum in a ratio of 4: 6. Also, gels of macromolecular compounds - hydrophilic bases (methyl cellulose, sodium CMC, sodium alginate, etc.) are proposed as bases for eye ointments. The basics are well distributed over the mucous membrane of the eye, they easily give up medicinal substances, but they undergo microbial contamination. Therefore, preservatives are introduced into their composition: sorbic acid, benzalkonium chloride, etc. The use of polyethylene oxide bases is not recommended because of the sharp difference in osmotic pressure. Emulsion bases such as m / v are not very suitable due to strong blurred vision and the need for stabilization,
Eye ointment technology in conditions pharmacies
Substances in the composition of eye ointments are administered according to the general rules for their introduction into dermatological ointments. Water-soluble medicinal substances (salts of alkaloids, novocaine, etc.) are dissolved in a minimum amount of water, mixed with the base, adding it in parts (ointment-emulsion).
Resorcinol and zinc sulfate, unlike dermatological ointments, are dissolved in water. Insoluble or insoluble drug substances: xeroform, zinc oxide, mercury oxide yellow are introduced into the base in the form of fine powders when dispersed with a liquid, related base (liquid paraffin, glycerin or purified water). Substances soluble in the base are dissolved in it.
Ophthalmic ointment is an ointment of yellow mercury oxide 2% (HF X), which is prepared on the basis of vaseline oil-2 parts (for dispersing the drug), anhydrous lanolin-16 parts and Vaseline varieties for eye ointments -80 parts. Preparation: yellow mercury oxide is carefully dispersed with an equal amount of sterile liquid paraffin, after which the finished sterile base is added in parts. In all cases when a yellow mercury ointment is prescribed (regardless of concentration), it is always prepared on a pharmacopeia basis for an eye ointment. Standard prescriptions according to order No. 214 are: pilocarpic ointment 1 and 2% and thiamine ointment 0.5 and 1%, which is prepared on an ophthalmic basis - petrolatum with anhydrous lanolin (90:10). Quality control of eye ointments is carried out similarly to dermatological ointments, including checking the uniformity with the microscopic method for heterogeneous ointments. Eye ointments prepared in pharmacies are dispensed in sterilized jars with screw-on plastic lids with sterile parchment pads.
Features of the production of eye ointments in the factory
These include:
grinding medicinal substances insoluble in an ointment base using appropriate equipment and sieving them through sieves with a hole diameter of 0.1 mm,
expanding the range of bases due to the widespread use of emulsion bases of the IM type, since their use can significantly reduce the dose of a drug substance by increasing the efficiency of their release from the bases,
metal tubes with a varnished inner surface are used to package eye ointments in order to prevent metal from contacting with the medicinal substance; polymeric materials for packaging a single dose of ointment are becoming more common.
As a result of scientific research to find more advanced ophthalmic dosage forms, domestic researchers have proposed a new dosage form - ophthalmic dosage films.
Ophthalmic drug films (HFP), characteristic
HLPs are oval-shaped mechanically strong solid plates with smooth edges and flat surfaces 6–9 mm long, 3–4.5 mm wide, 0.35 mm thick, and an average weight of 0.015 g.
Benefits of Ophthalmic Medicinal Filmsare:
Exact dosage of drugs;
Prolongation of the action of drugs and increase themtherapeutic concentration in the tissues of the eye;
reducing the number of injections of the drug to 1-2 times a day;
reduction of the course of treatment by 2-3 times;
Convenience in transportation, economical use of medicinal substances.
Polyacrylamide or its copolymers with acrylic and vinyl monomers, polyvinyl alcohol, sodium CMC are used as film-forming agents.
The stages of the technological process of production of HFThese include: preparing a polymer solution, preparing a drug solution, mixing solutions, deaerating, casting a film web, preparing films — stamping, packaging, sterilization, quality control. HFP quality assessment is carried out according to physicochemical properties: gloss, surface roughness, presence of cracks, tears, elasticity, strength. Ophthalmic films are produced with pilocarpine hydrochloride, dicain, atropine sulfate, fibrinolysin (400 units), SILP Pilaren (pilocarpine hydrochloride with adrenaline hydrotartrate), etc.
The main directions of improving technology and quality ophthalmic dosage forms
development of devices and apparatus for filtering, dosing, packaging and sterilizing eye drops;
expansion of the range of excipients: preservatives, stabilizers, prolongators;
unification of the formulation, expansion of the intra-pharmacy procurement of eye drops, solutions;
expansion of the range of ophthalmic dosage forms of factory production in single-use packaging.
Ophthalmic single-use dosage forms are:
Lamels- gelatinous oval disks with a diameter of 3 mm, containing various medicinal substances in the composition of the gelatinous mass.
Minima- containers made of polymer with a capacity of 4-12 drops of solution or 0.5 g of ointment. The shape of the container makes it easy to open and dose the drug by squeezing the contents onto the mucous membrane. After opening the minima are thrown out. They are made on a special molding machine from granular high-pressure polyethylene, which is sterilized with ethylene oxide. Fill with a dosing machine sterile solution or ointment. After filling, they are sealed under aseptic conditions and sterilized again.
The release of eye drops in lyophilized form (eye drops of complex composition with riboflavin based on polyglucin), liposomal eye drops of Cyclolip, etc., was mastered.
TARGET: Be able to prepare eye drops, lotions, arrange for vacation and evaluate their quality.
MATERIAL EQUIPMENT
1.Tables. 2. Penicillin vials with a capacity of 10 to 20 ml. 3.Cylinders: 5 ml, 10 ml, glass funnels, sticks, coasters. 4. Mortars with pestles of various sizes, evaporative porcelain cups, ointment glass jars with a capacity of 20, 50 g with lids. 5. Baths are electric. 6. SCM weights of various standard sizes with weights, technical pharmacy scales up to 1 kg. 7. Ashless filters, glass filters No. 2 and No. 3. 8. A heater for heating and melting ointment bases. 6. Sterile substances of medicinal, auxiliary substances and bases for ointments. 9. Metal or plastic spatulas, celluloid plates (scrapers). 10. Pharmaceutical substances, concentrated solutions. 11. Cotton wool, filter paper. 8. Scissors and paper capsules. 9. Alcohol-ether mixture (1: 1). 10. Labels: “External”, “Eye drops”, “Store in a dark place”, “Store in a cool place at a temperature of 8 0 С-15 0 С”, auxiliary material for registration for dispensing of dosage forms. 11. A device for crimping caps on POK-3 bottles. 12. A device for monitoring injection solutions for mechanical inclusions UK-2. 13. Steam and air sterilizers, sterilization and sterilization apparatus. 14. Starch paste. 15. Samples of prepared and decorated for the release of eye drops and lotions.
TEST QUESTIONS
1. Dosage forms used in ocular practice. The conditions necessary in the manufacture of dosage forms for the eyes. Requirements for eye drops.
2. Features of the technology of eye drops. Container and packaging for packaging.
3. Filter materials used to filter the solutions of eye drops.
4. Substances used for isotonizing eye drops. Buffer solutions used for eye drops.
5. The conditions for the preparation and storage of concentrated solutions used for the preparation of eye drops. Equipment used in the manufacture of eye drops.
6. Vacation of eye drops and their shelf life. Assessment of the quality of eye drops and lotions. Eye films.
EDUCATIONAL MATERIAL
Ophthalmic dosage forms - a group of dosage forms used by 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, mismatch of osmotic pressure and pH values \u200b\u200bintroduced into the eye medicines osmotic pressure and pH of the tear fluid.
Lacrimal fluid is a protective barrier for microorganisms. In a healthy eye, it is bactericidal, which is explained by the presence of lysozyme (muromidase), which is able to lyse microorganisms that enter the conjunctiva. 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 serious illnesses, 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.
A pharmacy worker is required to draw the patient's attention to the correct use of eye drops (Fig. 81).
Fig. 81. Proper instillation of the solution 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.
It is important that the pipette or tip of the bottle 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.
Ophthalmic dosage forms are divided into 4 types:
ü solutions;
ü films.
In eye practice, instillation of solutions is widely used, ointments, films, tablets, lamellas are placed in the conjunctival sac; extinguishing and dusting the surface of the cornea or conjunctiva, the introduction of drugs intrathoracic, retrobulbar, into the tenon space and using electrophoresis.
Eye drops - 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.
The 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. It was found that only 1 \\ 10 doses 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.
Eye drops should:
ü be prepared under aseptic conditions and be sterile;
ü pass tests for mechanical inclusions;
ü should not have toxic and irritating effects;
ü be comfortable in use (isotonic, isohydric with tear fluid);
ü to be stable in the conditions of often opened packaging.
The eye drops are not required to be pyrogen-free. It is proved that with this method of use, pyrogenic substances do not enter the bloodstream. In this regard, eye drops are prepared on purified waterrather than water for injection.
To stabilize the physicochemical, microbiological and rheological properties, drops are introduced into the composition excipients:
ü preservatives,
ü antioxidants,
ü thickeners,
ü stabilizers,
ü prolongators.
The concentration and volume (or mass) of isotonic and stabilizing substances added to the eye drops should be indicated not only in the passports, but also on the recipes.
The manufacture and quality control of sterile solutions in pharmacies is carried out in accordance with the requirements of the State Pharmacopoeia. The technology for making eye drops is no different from making drops for domestic usebut has some features. Particular attention in the manufacture of ophthalmic dosage forms should be given to observing the principles of sterility and isotonicity, which primarily ensure the safety of the effects of drugs by gradually dissolving the film in the tear fluid, reduce the number of injections of drugs (up to 1-2 times per day), increase their therapeutic concentration in the tissues of the eye, reduce the course of treatment by 2-3 times, and also conduct treatment in such conditions when other methods of using drugs are difficult or and impossible.
According to the GF RB, sterility - a necessary requirement for all ophthalmic dosage forms. Sterility - the absence of microbial contamination of the dosage form. Seed-free drugs can cause eye infections, which can lead to loss of vision.
Ophthalmic dosage forms are prepared under aseptic conditions similarly to injection solutions. Compliance with strict aseptic rules is the same for dosage forms that are not exposed, and subjected to further sterilization. Of course, the role of asepsis increases for those forms that are not subsequently subjected to heat treatment (ophthalmic dosage forms containing thermolabile substances; emulsions; suspensions). In this case, compliance with aseptic rules is the only way to ensure the proper quality of ophthalmic funds.
However, aseptic manufacturing conditions do not guarantee complete protection of the dosage form, including eye drops, from microbial contamination. In this regard, the eye forms are subject to sterilization.
Sterile solvents are used to prepare ophthalmic drops: purified water, isotonic buffer solutions, oils, etc. Sterile solutions are packaged in sterile vials.
Eye drops should be sterile.
The method of sterilizing eye drops depends on the resistance of drugs in solutions to temperature exposure. According to the sterilization mode, eye drops can be divided into 3 groups:
1. Drops without the addition of stabilizers, sterilized for 8-12 minutes with steam under a pressure of 1.1 atm and 120 0 C or 30 minutes with flowing steam.
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 by steam under pressure or fluid steam.
Checking the sterility of eye drops manufactured in pharmacies is assigned to the bacteriological laboratories of the territorial centers of hygiene, epidemiology and public health (CHE and OZ).
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 :
ü chlorobutanol hydrate (0.5%),
ü benzyl alcohol (0.9%),
ü esters of paraoxybenzoic acid (nipagin and nipazole, 0.2%),
ü Quaternary ammonium salts (benzalkonium chloride, 0.01%),
ü sorbic acid (0.05-0.2%) and others (table. 46).
Table 46. The maximum concentration of preservatives in ophthalmic solutions
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.
For ophthalmic solutions use dropper bottles (Fig. 82) and bottles from a glass tube, which are closed with stoppers made of rubber and rolled up 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. 82. Dropper bottles made of polyethylene and glass.
Rubber stoppers AB are designed for corking bottles from a drone with drugs. Rubber stoppers comply with TU 38.006108-95.
Caps aluminum K-1 (TU 9467-004-39798422-99). They are made of aluminum foil with a thickness of 0.2 mm (Fig. 83).
In the production process, it is imperative to carry out degreasing after stamping and chemical treatment to clean engine oil.
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. Stoppers that were in use are washed with purified water and boiled in it 2 times for 20 minutes, sterilized at 121 + 2 ° С for 45 minutes.
Fig. 83. Bottles from a glass tube (droot) brand NS; plugs made of rubber grade AB; caps aluminum K-1.
Vials with solutions, corked with rubber stoppers, control for the absence of mechanical impurities. If mechanical inclusions are detected 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 impurities. Rejected vials are not recyclable.
The rejected vials are sent for a full analysis in accordance with the requirements of the State Pharmacopoeia of Belarus or FS.
A sample is taken for sterility analysis. In case of a positive result, they are marked and packaged in corrugated boxes.
Thus, technology for ophthalmic solutions (Fig. 84) 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 to use concentrated solutions.
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Fig. 84. A typical scheme for obtaining ophthalmic solutions.
No mechanical impurities in drops is achieved by filtration. Use paper filters, glass No. 3 and No. 4. Currently, membrane filtration is widely used (membrane filters with a maximum pore diameter of 0.3 μm), which allow not only to release solutions from mechanical impurities, but also to carry out filter sterilization (especially for thermolabile substances). Filtering is carried out in a bottle pre-rinsed with filtered water.
Eye drops are made in small volumes of 5-10 ml. To ensure the preservation of the active substances and the volume of the dosage form, the so-called “double cylinder” method is used. There are three cases:
1. The substance is readily soluble in water, less than 3% is prescribed. The solvent is measured, divided into two parts. In one, the substance is dissolved, the resulting solution is filtered through a pre-washed with purified water filter into a flask for tempering. Then the remaining amount of solvent is passed through the same filter.
2. The substance is readily soluble in water, but more than 3% is prescribed. The difference is that the solution is filtered not in a bottle for tempering, but in a graduated cylinder. First, a solution is passed through the filter, then a pure solvent, the last portions are added dropwise.
3. The substance is soluble in the entire prescribed volume of water. In this case, the solution is filtered through a dry filter into a graduated cylinder, and then a certain amount of pure solvent is passed through the filter, which displaces the solution from the filter.
In the manufacturing process, the solutions are subjected to primary and secondary control for the absence of mechanical impurities.
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.
Comfort the use of eye drops is one of the biopharmaceutical factors that determines the absence of discomfort during the instillation of the 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.
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 that goes beyond the specified limits leads to burning and irritation of the mucous membrane of the eye (Table 47).
Sometimes doctors specifically prescribe hypertonic eye drops. The action of drugs in this case, especially antimicrobial, occurs much faster.
Table 47. Compositions of iso-, hyper- and hypotonic eye drops
| Copy | Equivalent concentration of sodium chloride,% | The amount of sodium chloride required for isotonization, g | |
| Isotonic solutions | |||
| 1.Riboflavinum 0.002 Solutio Kalii lodidi 3% 10 ml 2. Solutio Zinci sulfatis 0.25% 10 ml Acidum boricum 0.2 | 1.5 (0.35 × 0.3 × 10) 1.6 (0.53 × 0.2 × 10) | - | |
| Hypertonic solutions | |||
| 3.Solutio Sulfacyli-natrii 30% 10 ml Ribonavinum 0.002 4. Kalium iodidum 0.3 Solutio acidi borici 2% 10 ml | 6.9 (0.23 × 3 × 10) 2.1 (0.35 × 0.3 × 10 + 0.53 × 0.2 × 10) | - | |
| Hypotonic solutions | |||
| 5. Solutio Pilocarpini hydrochloridi 1% 10ml Riboflavinum 0.002 6. Acidum ascorbinicum 0.02 Solutio Glucosi 2% 10 ml | 0.22 (0.22 × 0.1 × 10) 0.36 (0.26 × 0.2 × 10) | 0,068 (0,09-0,022) 0,054 (0,09-0,036) | |
Very often, eye drops turn out to be hypotonic, their osmotic pressure must be “brought” to the osmotic pressure of the lacrimal fluid.
That is, so that eye drops do not cause discomfort, they must be isotonic and isohydric to the lacrimal fluid.
The requirement of isotonicity is pharmacopoeial. Upon receipt of a prescription for eye drops in a pharmacy, they are necessarily checked for isotonicity. Sodium chloride is most often used as an isotonic agent. If sodium chloride cannot be used, then sodium sulfate or sodium nitrate is used.
