Ophthalmic

Ophthalmics (from the Greek ophthalmos ὀφθαλμός "eye") are medicinal products for the treatment of local or, more rarely, systemic diseases that are intended for use on the eye. By definition, ophthalmic agents are “drugs and preparations for the local or systemic treatment of eye diseases, with local application being preferred to systemic”. The term ophthalmic drugs is often used colloquially.

The European Pharmacopoeia defines ophthalmic drugs as follows: "Preparations for use on the eye are sterile, liquid, semi-solid or solid preparations that are intended for administration to the eyeball and / or for use on the conjunctiva or for insertion into the conjunctival sac". The European Pharmacopoeia distinguishes between eye drops, eye baths, powders for eye drops and powders for eye baths, semi-solid preparations for use on the eye and eye inserts as dosage forms.

Ophthalmic drugs can be used for both diagnostic and therapeutic purposes. The intention is usually to have a local impact. Systemic side effects can be caused, among other things, by the application of parasympathomimetics, for example. These would lead to cardiovascular disorder.

Since the eye is a sensitive organ, all preparations for use on the eye have to meet special physical and microbiological (sterility) requirements, which must be checked by suitable tests. According to §54 of the Medicines Act ("AMG"), the pharmacopoeia, consisting of the European, German and homeopathic pharmacopoeia, is to be used with regard to the assessment of "quality, testing, storage, dispensing and designation of medicinal products and the substances used in their manufacture".

Groups of active substances in ophthalmology

• Mydriatics (pupil-expanding drugs)
• Miotics (pharmaceuticals that constrict pupils)
• Anti-infections such as antibiotics and antivirals
• Local anesthetics
• Enzymes
• Dyes for diagnostic purposes
• Anti-inflammatory drugs
• Complexing agents and antidotes
• Vegetative pharmaceuticals
• Vitamins
• Astringents and caustics
• Antiallergic drugs

history

Ophthalmics were produced as early as the 16th century BC and used for diseases of the eye. One of the oldest and most well-known documents about diseases and medical treatments of this time is the Ebers papyrus (1550 BC). In this reference is made to a black eyeshadow, which could be used for both care and decoration of the eyes. It consisted of a mixture of stibnite (antimony (III) sulfide) and fat. The preparation can also be found in the Old Testament, where it is referred to as "puk".

In the 5th century BC the Greeks used a form of medicine called "Kollyrion" (Collyrium, collyrium , from which in Middle Latin Collirium originated). It was elongated, cylindrical loaves of bread. The active ingredients, at that time usually minerals and drugs, were crushed, rubbed with water and mixed with resin or rubber to create a dough-like mass. After being elongated, it could be used immediately or kept dry for a later date. The finished mass could be applied directly to the eye, similar to an ointment. In addition to application to the eye, Kollyria were used to treat diseases in body cavities, urethra, ear canal, nasal cavity and the anus. After the remedy, all eye preparations such as powders, ointments and liquids were subordinated to this term. This term was used up to the 19th century and has only been replaced by specifying terms today (eye drops "Oculoguttae", eye baths "Oculobalnea", eye ointments "Unguenta ophthalmica").

Nowadays the formulations of ophthalmic drugs are adapted to the eye due to scientific progress with regard to the anatomical and physiological conditions of the eye with regard to tonicity, pH value and particle size.

Systematics of ophthalmics

Various dosage forms and systems can be used with ophthalmic agents. The systematic classification can change depending on the literature. Here is a list of the dosage forms that can be used for the eye.

• Eye baths ("Balnea ophthalmica"): Aqueous solutions in suitable containers to be able to bathe the eye
• Semi-solid preparations ("Unguenta opthalmica"): sterile ointments, creams and gels with suitable particle size and stability
• Eye sprays ("aerosols"): for spraying aerosols in suitable containers (pressure containers)
• Eye drops ("Oculoguttae"): aqueous / oily solutions, emulsions and suspensions that are dripped onto the cornea or into the conjunctival sac
• Eye washes ("Collyria"): aqueous solutions that are intended for rinsing or soaking eye compresses
• Inserts are solid or semi-solid, whereby the active ingredient can be embedded in a matrix or delimited by a membrane and introduced into the conjunctival sac
• Lamellae: flat, gelatin-based plates that are inserted into the conjunctival sac
• Contact lenses and care products: lubricants, cleaning agents, disinfectants for contact or adhesive lenses

Properties of physiological tear fluid

properties	values
Refractive index	1.336-1.357
relativ density	1.004-1.005
Freezing Point Depression	−0.55 to −0.64 ° C
Electric conductivity	0.5 * 10 −5 ohm
Surface tension	40-50 dynes / cm
Osmolality	310-334 mmol / kg
PH value	7.1-7.6
temperature	30-35 ° C
viscosity	1.3-5.9 mPa * s

conditions

General requirements

sterility

All ophthalmic products must be sterile and comply with the “sterility test” (Ph. Eur. 2.6.1) according to the European Pharmacopoeia.

Preservatives

According to the Pharmacopoeia, all aqueous eye drops and eye baths are preserved in multi-dose containers. Single-dose and multi-dose containers that prevent contamination after opening can be excluded; Preparations that are used for surgical interventions and first aid measures must not be preserved. The pharmacopoeia requires preservatives to be compatible with the other ingredients and to be sufficiently effective over the duration of use.

Common preservatives are:

• Alcohols
  • Benzalkonium chloride
    • Concentration: 0.001-0.02%
    • Tolerance: up to 0.01%, even with prolonged use
    • Bactericidal or bacteriostatic according to concentration
  • Chlorobutanol
    • Concentration: 0.2-0.5%
    • Tolerance: less than 0.5%, otherwise a damaging effect on the cornea
    • additional local anesthetic effect
  • 2- phenylethyl alcohol
    • Concentration: 0.5-0.6%
    • Tolerance: from 0.6% possible irritations can be observed
• Carboxylic acids
  • p-hydroxybenzoic acid
• Quaternary ammonium compounds
  • Benzalkonium chloride
• Organo-mercury compounds
  • Phenymercury acetate / nitrate / borate
    • Concentration: 0.002%
  • Thimerosal
    • Concentration: 0.01-0.02%
• Chlorhexidine
  • Concentration: 0.1-0.2%
• Polymyxin B sulfate
• Phenoxyethanol
  • Concentration: 1–2%

Basically, low concentrations of around 0.001–2% are used. In addition, the pharmacopoeia writes the “test for sufficient preservation” (Ph. Eur. 5.1.3).

Particle size

The particle size plays a role in eye drop suspensions and in semi-solid preparations. The examination can be carried out under a microscope, for example. An area of ​​the spread preparation is counted which corresponds to 10 μg of solid active ingredient. When counting, there may be a maximum of 20 particles larger than 25 μm, a maximum of 2 particles larger than 50 μm and no particle larger than 90 μm.

Aqueous eye drops

→ Main article : eye drops

concentration

The pharmacological effect and the penetration of an active substance into the aqueous humor depend on its concentration. This can be influenced by the tear fluid and the applied drop size. The tear fluid is less than 0.01 mL in a healthy and non-irritated eye. The applied drop size is 0.05 to 0.075 mL. This lowers the concentration of the active substance in the drop only slightly. One problem is the removal of larger volumes of liquid. This is why some specialist literature claims that the usual drop size of 0.05 to 0.075 is too large.

Tonicity

Eye drops do not have to be isotonic, but they have to be manufactured in such a way that they do not cause irritation or physiological damage to the eye. In 1958 Trolle-Lassen found out that a 0.7 to 1.4% sodium chloride solution is perceived as painless. That is a range from 240 to 480 mosmol / L. It was also found that hypotonic preparations are less damaging and do not change the permeability of the active ingredient in the uninjured eye. With an inflamed eye, the area that is felt to be painless becomes narrower. Possible aids to adjust the tonicity are sodium chloride, potassium nitrate, boric acid, glucose, mannitol and others. In order to calculate the amount that has to be added to a preparation in order to isotonize it, nomograms, the sodium chloride equivalence method, isotonization according to DAC or Roult's law can be determined.

PH value

The pH value is one of the parameters that influences the tolerability, pharmacological effect, stability and solubility of a drug form. A pH range from 7 to 9 is perceived as irritation-free and the range from 5 to 10 as painless. These areas do not show a drastic increase in tear flow. The preparation can be buffered within the pain-free area. Sodium acetate / boric acid, phosphate and acetate buffers are used here. The pH can also be adjusted using sodium hydroxide solution or hydrochloric acid.

viscosity

The viscosity is important for the even distribution of the preparation on the eye. Lid spasms and the flow of tears transport all components in the direction of the tear ducts, so that the residence time of the active ingredient is reduced. Viscosity-increasing substances such as methyl cellulose or polyvinyl alcohol extend the length of stay and enable better eye therapy. Furthermore, viscosity-increasing substances improve the film formation and adhesion of the preparation and reduce the sensation of irritation. A viscosity in the range from 10 to 25 mPa * s is considered advantageous. If the viscosity is increased, particular care must be taken to ensure that the refractive index of the tear fluid is kept from 1.366 to 1.377 and that the effectiveness of low-concentration preservatives is guaranteed.

Dosage forms and their application

Aqueous eye drops

Aqueous eye drops are the most frequently used dosage form among the ophthalmic drugs. They have a short duration of action and usually do not show any visual impairment.

Oily eye drops

Oily eye drops are used less frequently than watery ones. However, these allow a longer contact time and a delayed release of the active ingredient and can help to maintain a certain concentration level in the eye. In addition, the oily eye drops stick less to the edge of the eyelids than ointments. The water-free preparation also enables active ingredients that are sensitive to oxidation, such as alkaloids, to be preserved and thus made longer lasting. Suitable oils include castor oil, neutral oil and olive oil, as these are less prone to going rancid. A peroxide sample to determine the peroxide number as a measure of the intactness should be carried out as a quality test

Eye ointments / gels

Advantages:

• softening effect
• Shelf life, especially with regard to antibiotics
• delayed drug release
• less loss of active ingredient through removal via the tear ducts
• Protective film formation

Disadvantage:

• smeary film that clouds the view
• higher risk of sensitization due to the long contact time

Inactive ointments are used as lubricants and against drying out on the eyes.

Optimizing the effectiveness of eye drops

Pharmaceutical Technologies

The aim of an optimization is to lengthen the contact time and to lose less active substance due to the removal via the tear ducts. Less loss can be achieved with a drop size smaller than 0.05 mL or 0.075 mL. So-called micro-drop devices can be used for this, which enable drops with a volume of 0.01 mL to be applied. In addition to the commonly used viscosity-increasing substances, longer contact times can be achieved through pseudoplastic sols and sol-gel conversions. A typical representative for the production of pseudoplastic brines is hyaluronic acid. The viscosity of this substance changes due to the shear stress caused by blinking. It has a higher viscosity at rest than after blinking. Sol-gel conversions can be carried out, for example, with cellulose acetate phthalate latex, which becomes liquid at pH 4.5 and semi-solid at pH 7.4, gellan gum, which becomes semi-solid at a sodium ion concentration of 2.6 g / L, or with Poloxamer 127, which becomes semi-solid at pH 7.4 temperature higher than 25 ° C becomes more viscous.

application

The application of ophthalmic drugs can also be optimized. Good advice from the doctor and pharmacist is therefore important. Before use, the preparation should be brought to body temperature (eye temperature around 32–34 ° C). This can prevent increased tear flow. Attention should be paid to vertical dripping in order to be able to apply constant drop sizes and thus constant concentrations. In addition, older patients run the risk of not being able to use much force to achieve correct application. The three-finger grip should be recommended for successful dosing and therapy. After application, the eyelids should be kept closed for 1 to 5 minutes. In addition, the tear tubes, which are located at the root of the nose, should be closed for the same amount of time. This practice is called nasolacrimal occlusion.

Advantages and disadvantages

Advantages include a high drug concentration in the eye and good selectivity in contrast to systemic administration.

Disadvantages are the low absorption capacity, possible development of irritation after application, a possible systemic absorption of the active ingredient through the connection to the nasal mucosa and the long penetration time through the cornea during therapies in the eye chambers.

Literature and Sources

• Opthalmics: pharmacology, biopharmacy and galenics of ophthalmic drugs, Dolder and Skinner, 4th edition, Wissenschaftliche Verlagsgesellschaft mbH Stuttgart
• Pharmaceutical technology for studies and work, Rudolf Voigt, 11th edition, Deutscher Apotheker Verlag
• European Pharmacopoeia 8th Edition, Official German Edition 1st, slipcase, 3 bound books, Deutscher Apotheker Verlag

Individual evidence

1. ^ Konradin Medien GmbH, Leinfelden-Echterdingen: What does Ophthalmic mean | Foreign words for ophthalmic | http://www.wissen.de/fremdwort/ophthalmikum. Retrieved July 19, 2017 . 
2. ↑ Paech, Volker .: therapy lexicon Dermatology and Allergy Therapy compact from A to Z . 2nd, completely revised edition Springer, Berlin 2005, ISBN 978-3-540-27648-7 .
3. ↑ General section, monograph groups . 8th edition, basic work 2014 edition. German Apotheker-Verl. [u. a.], Stuttgart [u. a.] 2014, ISBN 3-7692-6253-0 .
4. ^ Voigt, Rudolf: Voigt Pharmaceutical technology for study and work . 12th, completely revised edition. Deutscher Apotheker Verlag, Stuttgart 2015, ISBN 3-7692-6194-1 .
5. ↑ BfArM - Pharmacopoeia. (No longer available online.) Archived from the original on July 20, 2017 ; Retrieved July 19, 2017 . Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice.  
6. ↑ ^{a b c} Dolder, Rolf .: Ophthalmics: Pharmacology, biopharmacy and galenics of ophthalmic drugs: a monograph of the Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik eV (APV) Mainz . 4th, reviewed and supplemented edition. Wissenschaftliche Verlagsgesellschaft, Stuttgart 1990, ISBN 3-8047-1060-3 , p. 351-352 .
7. ↑ Juan Murube: Collyrium: Where Does This Word Come From? In: The Ocular Surface . tape 5 , no. 4 , October 1, 2007, p. 264-268 , doi : 10.1016 / S1542-0124 (12) 70091-5 ( sciencedirect.com [accessed July 19, 2017]).
8. ↑ Dolder, Skinner: Ophthalmics: Pharmacology, biopharmacy and galenics of ophthalmic drugs: a monograph of the Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik eV (APV) . 4th edition. S. 353 .
9. ↑ Dolder, Skinner: Ophthalmics: Pharmacology, biopharmacy and galenics of ophthalmic drugs: a monograph of the Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik eV (APV) . 4th edition. S. 13 .
10. ↑ Dolder, Skinner: Ophthalmics: Pharmacology, biopharmacy and galenics of ophthalmic drugs: a monograph of the Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik eV (APV) . 4th edition. S. 415-441 .
11. ↑ Dolder, Skinner: Ophthalmics: Pharmacology, biopharmacy and galenics of ophthalmic drugs: a monograph of the Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik eV (APV) . 4th edition. S. 363-364 .
12. ↑ Dolder, Skinner: Ophthalmics: Pharmacology, biopharmacy and galenics of ophthalmic drugs: a monograph of the Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik eV (APV) . 4th edition. S. 357-361 .
13. ↑ Dolder, Skinner: Ophthalmics, Pharmacology, Biopharmacy and Galenics of Ophthalmic Medicines . 4th edition. Scientific Contracting Company Stuttgart, S. 358 .
14. ↑ Dolder, Skinner: Ophthalmics: Pharmacology, biopharmacy and galenics of ophthalmic drugs: a monograph of the Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik eV (APV) . 4th edition. S. 11 .
15. ↑ Drug Dosing Systems in Ophthalmology. (PDF) Retrieved July 20, 2017 . 
16. ↑ Robinson, JR, Mlynek, GM: Bioadhesive and phase-change polymers for ocular drug delivery . 16th edition. S. 45-50 .
17. ^ Gurny, R: Design and evaluation of controlled release systems for the eye . 6th edition. S. 367-373 .
18. ↑ Keipert, S .: Gel-forming eye drops, a new therapy concept in the treatment of glaucoma . 7/8 edition. S. 44-49 .
19. ↑ Avoxa & # 150; Mediengruppe Deutscher Apotheker GmbH: Pharmaceutical newspaper online: Galenic tricks for use on the eye. Retrieved July 20, 2017 . 

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