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Erythromycin is one of the most common used macro lide antibiotics. Over the years after Abbott introduced Erythrocin (R) (erythromycin stearate) into the market, several generics and new brands have been introduced & # 8211; generics in the form of different drug formulations and new brands in the form of different erythromycin salts. All these derivatives have the same pharmacodynamic's and mechanism of action, but differ tremendously in their pharmacokinetics. This paper will give an introduction and a brief overview in the different stabilities and pharmacokinetics of the erythromycin salts and an introduction into new approaches in the field of macro lide antibiotics.
Table of Contents 1. Introduction 2 2. Erythromycin & # 8211; a brief chemical description 4 2. 1 Crystal structure and hygroscopic ity 7 2. 2 Mechanism of action 8 3. Derivatives of erythromycin base 9 3. 1 Erythromycin stearate 10 3. 2 Erythromycin ethyl succinate 10 3. 3 Erythromycin estate 11 3. 4 Comparison between erythromycin base and estate 13 4 Chemical derivatives of erythromycin 13 4. 1 Roxithromycin 13 4. 2 Clarithromycin 14 4. 3 Azithromycin 14 4. 4 Dirithromycin 15 4. 5 Flurithromycin 16 4. 6 Comparison of properties among the newer macrolide's 17 5 Discussion and conclusions 19 References 21 2. Erythromycin & # 8211; a brief chemical description Figure 2. 1 Advertisement for eyed (R) [ 3 ] Erythromycin belongs to the chemical group of macro lide antibiotics (macros [greek] = great, -olid as the suffix for lactone's).
It's microbiological activity mainly covers bacterial infections of the respiratory tract and other infections with gram positive bacteria. In the case of erythromycin base, the 14 -linked lactone ring (Erythronolid) is conjugated with one basic amino sugar (Desopamine) and one neutral sugar (Cladinose). Figure 2. 2 Erythromycin base showing the alyson (red), the basic amino sugar (green), and the neutral sugar (blue) [ 2 ] Erythromycin was first discovered in 1952 in Streptomyces erythreus. The spectrum of activity is equal to penicillin. The antibiotic activity is linked to the presence of the deoxy sugars. There are three known forms of erythromycin.
The structure of erythromycin-A is the most common used in formulations and differs from erythromycin-B in the hydroxyl-group in position 13 of the lactone ring. Erythromycin-C is missing the methoxy-group in the cladinose sugar. [ 8 ] Stability problems first were discovered when Erythrocin (R) was found to contain not the declared amount of erythromycin stearate. The first stability problem with erythromycin is because of its deliquescence. This could be prevented if erythromycin is stored under accurate conditions. Erythromycin has a poor water solubility and solutions decompose quicker if temperature is increased.
Figure 2. 1 shows the chemical degradation of erythromycin. The formation of the hemiketal is a dehydration and leads to the inactivation and loss of antibiotic activity. This step is highly pH sensitive. Figure 2. 3 Chemical degradation and inactivation of erythromycin [ 4 ] One other major problem is his pH-depended stability. The optimum stability of erythromycin ranges from pH 8 & # 8211; 9. 5. Especially ointments and injectable solutions have a high risk of instability and degradation.
Per os erythromycin base was enteric-coated due to its instability in acid mediums & # 8211; however, high amounts of erythromycin are still inactivated in the stomach. This has a great impact on the bioavailability of erythromycin and therefore on the efficacy of the therapy. Another issue is the pH-change in infected and inflammated tissue. The pH in such tissues decreases in regard ence to the increased activity of macrophages and other components and can be as low as pH 6. 5. At this pH, erythromycin is highly instable and the antibiotic activity is vanished.
Table 2. 1 lists the dependence and influence of pH and temperature on the stability of erythromycin solutions. Degradation of erythromycin under the influence of temperature and pH pH & # 8804; 6. 0 up to 100 % inactivation after 1 - 3 hours pH 7. 0 up to 14 % inactivation within 24 hours (at 25 ^ 0 C) pH 7. 4 stable for 24 hours (at 37 ^ 0 C) pH 8. 5 stable 4 ^ 0 C stable for 8 weeks (at pH 8. 5) 37 ^ 0 C stable for 4 days (at pH 8. 5) Table 2. 1 Influence of temperature and pH on the degradation of erythromycin [ 2 ] The microbial effect evaluation is one method to test the acid instability of erythromycin base. The substance is solved in simulated stomach fluid and after certain time points administered to a Bacillus subtilis culture medium. Table 2. 2 shows the rapid decrease of biological activity by degradation of erythromycin base in an acid environment. Time points Diameter of inhibition Concentration of active base 0 min. 3. 55 cm 94, 42 % 45 min. 2. 98 cm 78. 42 % 90 min. 2. 37 cm 62. 37 % Reference 3. 8 cm 100 % Table 2. 2 Decrease of erythromycin base activity in simulated stomach fluid [ 2 ] 2. 1 Crystal structure and hygroscopic ity The crystal structure of a drug has a great influence on many aspects of its stability, for example to form socrates, to integrate water in its crystal structure and therefore to be potentially degraded. Erythromycin A is marketed in three different forms & # 8211; erythromycin A dehydrate (the most common), erythromycin A anhydrite and amorphous erythromycin A.
Figure 2. 1 shows the crystalline structure of erythromycin A dehydrate observed through a diffraction microscope. Figure 2. 4 Crystalline structure of erythromycin A dehydrate [ 1 ] One important issue of these different forms is their ability to absorb water in regard ence of the relative surrounding humidity. A study showed the relationship between weight gain and relative humidity (Figure 2. 2). Figure 2. 6 Moisture sorption isotherms for erythromycin A dehydrate, erythromycin A anhydrite, and amorphous erythromycin A at 25 ^ 0 C [ 5 ] Although the hygroscopic ity of erythromycin A differs tremendously between the crystal structures, the crystalline lattice of the compounds is retained. Interestingly, the anhydrous and the amorphous form are nearly the same between 0 and 20 % relative humidity, while the dehydrate form gains back most of its water lost due to the weight equilibration before. Because erythromycin A dehydrate contains less water than the stoichiometric dehydrate form at low humidity (0 & # 8211; 20 %), it is referred to as the 'dehydrated-dehydrate'; .
Between 20 and 90 % relative humidity both the dehydrate and the amorphous form are stable at 25 ^ 0 C. Amorphous forms are generally considered to be hygroscopic. In this case, the dehydrated-dehydrate is apparently more hygroscopic at low humanities than even the amorphous form. However, within the range of 20 & # 8211; 90 % relative humidity erythromycin A dehydrate and amorphous erythromycin A are stable and do not undergo huge degradation rates. 2. 2 Mechanism of action Erythromycin and it's derivatives belong to the family of antibiotics that block the bacterial protein biosynthesis by interacting with ribosomes. These ribosomes play an important role in the translation of RNA to form proteins. Part of the rRNA forms the ribosomes to process the translation of amino acids to polypeptides.
Two other RNA molecules are involved, mRNA and tRNA. mRNA provides the information necessary to translate from DNA into polypeptides. tRNA is the linker between the side of action at the ribosomes and the peptides to be bound to it. The macrolide's can interact with two different subunits (50 S and 30 S) of the ribosome. Erythromycin and its derivatives all interact with the 50 S subunit. Erythromycin binding blocks polypeptide translation.
Instead prematurely peptidyl-tRNA intermediates are released from the 50 S unit and the elongation of the polypeptide is blocked. Figure 2. 7 Mode of action for macro lide antibiotics (left: binding of macrolide's at the 50 S polypeptide exit tunnel; right: interaction with 23 S RNA bases) [ 6 ] 3. Derivatives of erythromycin base As mentioned before, as a result of the acid instability of erythromycin base, a enteric-coated tablet formulation has been used to protect the base against stomach fluid. Other investigations included the formulation of enteric-coated micro capsules (Monomycin (R) ) to increase the uptake rate (multi unit pellet system).
Chemical derivatives of erythromycin base have very many characteristics in common, including pharmacodynamic's, mechanism of action, spectrum of activity and fluctuant pharmacokinetics. However, the aim was an increase in acid stability and therefore an increase in bioavailability. All derivatives show a variation at the basic amino sugar. Esters can be formed at the 2 '-hydroxyl group as well as salts at the dimethyl amino group.
Figure 3. 1 Erythromycin base with sides of possible ester (red) or salt (green) derivation [ 2 ] These derivatives themselves are instable & # 8211; especially at the side of conjugation. However, the rate of degradation in acid medium is not as high compared to erythromycin base. The most common used erythromycin derivatives for the oral treatment are discussed in the following paragraphs. 3. 1 Erythromycin stearate Figure 3. 2 Erythromycin stearate [ 2 ] Erythromycin stearate is described as the salt of erythromycin base with stearic acid. Besides that, the ester is also used.
Both seem to have the same stability and bioavailability. The stearate salt has a very poor water solubility, higher acid stability then erythromycin base with a wider pH optimum between pH 7 - 10. 5 and dissociates to erythromycin base in the small intestines. The deliquescence is equal to erythromycin base so that the storage conditions include water protection. The resorption rate depends on two major factors: administration with enough water and shortly before a meal. 3. 2 Erythromycin ethyl succinate Figure 3. 3 Erythromycin ethyl succinate [ 2 ] The 2 ' hydroxyl ester of erythromycin base with ethyl succinic acid is available in tablet and suspension formulations for oral administration as well as for intramuscular injection. Because of the derivation with a water soluble acid, the water solubility is increased compared to erythromycin base and erythromycin stearate. However, the solubility is limited and can be described as poor.
The pH stability ranges from pH 6 - 8. 5. That makes erythromycin ethyl succinate a potential candidate for combination treatments. However, until now there are no combination products with erythromycin on the market, probably due to other interactions or incompatibilities. Both erythromycin ethyl succinate and erythromycin base are absorbed and can be found in the plasma, although only the free base is pharmacological active. The deliquescence is equal to the other substances mentioned before. Like erythromycin stearate, the resorption rate increases two-fold if the drug is administered with food. 3. 3 Erythromycin estate Figure 3. 4 Erythromycin estate (sodium dodecyl sulfuric acid not displayed) [ 2 ] The ester formation of the base with prop ionic acid and the sali fication with sodium dodecyl sulfuric acid leads to the most stable erythromycin derivative for oral administration.
Although the water solubility is as poor as of the ethyl succinate, the resorption rate is up to 90 % - that is about 50 & # 8211; 60 % more than for all other erythromycin derivatives. Due to it's high acid stability with a pH range between pH 3 & # 8211; 7. 5, erythromycin estate resorption is not dependent on food administration. The different formulations include capsules, tablets and suspensions. There are several other advanta...
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Research essay sample on Stability And Bioavailability Of Different Erythromycin Derivatives
