Preparation and examination of TPN systems for the individual clinical therapy
Ph.D. thesis
Judit Balogh Kovács Semmelweis University Doctoral School of Pharmaceutical and Pharmacological Sciences
Tutor: Dr. Romána Zelkó, Ph.D.
Budapest 2007.
SUMMARY Lipid emulsions have been used in routine clinical practice for more than 40 years. Intralipid, the first well tolerated lipid emulsion, is still the most commonly used lipid emulsion worldwide containing long-chain triglycerides (LCT) with a fatty acid chain length of 16-20 carbon atoms (long-chain fatty acids, LCFA). Structured triglycerides, in which both medium-chain fatty acids and long-chain fatty acids are esterified to the same glycerol molecule, have positive metabolic effects, which make them competitive or even more efficient as an energy source compared with conventional fat emulsions. The purpose of my thesis was to compare the kinetic stability of two admixtures containing different lipid components. A further aim was to collect more evidence for the stabilizing effect of structured triglycerides, with special concern to the ionic concentration of the mixtures. Kinetic stability of two total nutrient admixtures prepared with different lipid emulsions (Intralipid and Structolipid, respectively) was tracked under different storage conditions with an array of physicochemical methods. Several methods were applied for the assessment of physical stability of lipid emulsions, including particle size analysis via photon correlation spectroscopy, and microscopy. While these methods can follow physical changes, zetapotential and pH measurements are able to indicate chemical processes that take place along with storage. Dynamic surface tension measurements could provide additional information concerning the physicochemical processes that take place on the surface of the lipid droplets. Electrolytes play an especially important role from this point of view, as they are present in all admixtures and have a major effect on the zeta potential of the emulsions. Very likely, the formation of a “mixed” interfacial layer formed from the medium and the long chain fatty acids in case of structured triglycerides is responsible for the more efficient stabilization. Droplet size distribution and surface tension data showed that the emulsions containing structured lipids proved to be more stable, especially at lower storage temperatures. Higher electrolyte concentrations of the mixtures can adversely influence this stabilizing effect. The obtained results indicate that besides the advantageous metabolic effects of structured triglycerides, their application is recommended to improve the physical stability of TPN admixtures. •
J. Balogh, J. Bubenik, J. Dredán, F. Csempesz, D. Kiss, R. Zelkó: The effect of structured triglycerides on the kinetic stability of total nutrient admixtures. J. Pharm. Pharmaceut..Sci. 8(3):552-557, 2005.
•
J. Balogh, D. Kiss, J. Dredán, I. Puskás, F. Csempesz, R. Zelkó: Tracking of the Kinetic Stability of Two Types of Total Nutrient Admixtures Containing Different Lipid Emulsions. AAPS Pharm.Sci.Tech. 2006;7 (4) Article 98
ÖSSZEFOGLALÁS
A zsíremulziók közül az első, az emberi szervezet számára jól tolerálható iv. lipidemulzió az Intralipid volt, amely hosszú szénláncú triglicerideket (LCT) és 16-20 C atomos zsírsavat tartalmaz (LCFA). A struktúrált lipidek, amelyekben mind a közepes, mind a hosszú szénláncú zsírsavak ugyanazzal a glicerin molekulával létesítenek észterkötést, pozitív metabolikus hatással rendelkeznek, amely hatékonyabb energiaforrássá teszi őket, mint a konvencionális, csak hosszú szénláncú zsírsavat tartalmazó zsíremulziók. Nagyobb oxidációs sebességgel, gyorsabb clearance-szel, megnövelt N-megtartó képességgel rendelkeznek a kizárólag hosszú szénláncú zsírsavat tartalmazó emulziókhoz viszonyítva, valamint a retikuloendoteliális rendszerben kevésbé akkumulálódnak. Doktori értekezésem célja volt, hogy a struktúrált trigliceridek hatását vizsgáljam a teljes parenterális táplálásra szánt emulziók (TPN) kinetikai stabilitására, összehasonlítva a kizárólag hosszú szénláncú zsírsavat tartalmazókéval. Az Intralipid és Structolipid tartalmú különböző összetételű TPN oldatkeverékek kinetikai stabilitásának változását a tárolási körülmények (idő, hőmérséklet) függvényében különböző fizikai-kémiai módszerekkel (foton-korrelációs spektroszkópia, zéta-potenciál-mérés, dinamikus felületi feszültség meghatározása, pH-és vezetőképesség-mérés) vizsgáltam. Az elvégzett vizsgálatok szerint a kizárólag hosszú szénláncú triglicerideket tartalmazó (Intralipid) emulziók cseppmérete 4 nap után jelentős növekedést mutatott a struktúrált lipidkomponenst (Structolipid) tartalmazóval szemben. Megállapítható, hogy a magasabb elektrolit-koncentráció csökkenti a struktúrált lipidkomponens előnyös hatását a zéta-potenciálra. Amennyiben TPN emulziók ionkoncentrációja azonos, és a zéta-potenciál, valamint a pH értékek a tárolás során nem mutattak érzékelhető változást az idő függvényében, a kisebb fizikai–kémiai stabilitás az LCT tartalmú emulziók esetében nem tulajdonítható elektrokémiai vagy kémiai bomlásnak. A struktúrált trigliceridet tartalmazó hosszú- és közepes szénláncú zsírsavak keveréke felületi réteget képez a zsírcsepp felszínén, amely feltételezéseim szerint a nagyobb stabilitásért felelős, ugyanakkor a struktúrált lipidek előnyös stabilizáló hatását a magasabb ionkoncentráció csökkentheti. A részecskeméret-analízis és a felületi feszültség mérés adatai alapján megállapítható, hogy a struktúrált trigliceridet tartalmazó zsíremulziók stabilabbak, különösen az alacsonyabb tárolási hőmérsékleten. A magasabb elektrolit koncentráció kedvezőtlen hatást fejt ki a stabilizáló hatással szemben. A kapott eredmények alapján megállapítható, hogy a struktúrált trigliceridek kedvező metabolikus hatásuk mellett a TPN emulziók fizikai stabilitását is növelik, így alkalmazásuk ajánlott a teljes parenterális táplálásra szánt emulziók előállításánál. •
J. Balogh, J. Bubenik, J. Dredán, F. Csempesz, D. Kiss, R. Zelkó: The effect of structured triglycerides on the kinetic stability of total nutrient admixtures. J. Pharm. Pharmaceut..Sci. 8(3):552-557, 2005.
•
J. Balogh, D. Kiss, J. Dredán, I. Puskás, F. Csempesz, R. Zelkó: Tracking of the Kinetic Stability of Two Types of Total Nutrient Admixtures Containing Different Lipid Emulsions. AAPS Pharm.Sci.Tech. 2006;7 (4) Article 98
1. INTRODUCTION Parenteral nutrition formulations are designed to provide nutrients in doses sufficient to meet the patient’s daily requirements. Because parenteral nutrition is an extremely complex admixture containing amino acids, dextrose, lipids, water, electrolytes, trace elements, and vitamins–40 or more components–errors in their formulation and compounding have led to serious and lethal complications. As a result, parenteral nutrition formulation design must consider the stability, compatibility, which in some cases limits one’s ability to individualize nutrient doses. Safety issues related to parenteral nutrition formulations have led to the development of guidelines for safe practices. The two major types of parenteral nutrient solutions are the traditional dextrose-amino acid solution and the TNA1. The TNA System involves the addition of dextrose, amino acids, and lipid emulsion (with electrolytes, vitamins, trace minerals, and other additives) into a single container. TNA formulations are used frequently because of the convenience of only one infusion for parenteral nutrition purposes and the improved tolerance and oxidation of intravenous fatty acids. The stability of these formulations is a concern, however, because of the destabilization of the emulsion in the presence of an acidic pH and because of exposure to extremes of temperature. For parenteral nutrition, these concerns limit the doses of some nutrients such as divalent cations, zinc, and iron as well as amino acids. Nutrients are mixed just prior to infusions, by breaking the plastic connectors between the compartments, then vitamins and trace elements are added extemporaneously to the bag. Shelf –life of these bags is at least 12 months, but allow only for standardized formulas. Due to their easy application „all-in-one” TPN2 systems should save preparation and handling time on the ward, thus resulting in decreased manpower cost. The use of three-compartment TPN bags is less expensive in terms of application costs than separete bottles or hospital-compounded bag systems. TPN application costs are partly transfered from the pharmacy to the ward in the three-compartment bag system compared to hospital-compounded bags. Detailed manpower times measured in the present studies are published, allowing hospitals to calculate their own application costs using local salaries, product prices and production costs.
1 2
TNA= Total Nutrient Admixture TPN= Total Parenteral Nutrition
2. OBJECTIVES For patients unable to tolerate any form of enteral feeding, the administration of fluid and nutrients via a parenteral route is necessary. For long-term care a balanced diet containing all the essential nutrients, including vitamins and trace elements, must be provided. Combining all the constituents of a daily TPN feed into one container can result in the production of very complex pharmaceutical systems including 15-20 individual crystalline amino acids, hydrated dextrose, multiple electrolytes, vitamins and minerals, as well as lipid emulsion. The obtained systems are oil-in-water emulsions stabilized by an emulsifier that imparts a net negative charge to the surface of the globules which stabilizes the dispersion. These highly complex formulations are subject to an array of potential interactions, both favorable and unfavorable, thus resulting stability changes of the system. When the emulsion becomes unstable, these homogeneously distributed droplets begin to aggregate and ultimately coalesce into large fat globules. Phase separation typically occurs when the volume-weighted percent fat greater than 5 μm exceeds 0,4 % of the total lipid present in a formulation. Moreover, when the size of the droplets reaches a dimension of 5 μm or larger, the infused globules may lodge into the pulmonary capillaries and produce a fat embolism syndrome. For such systems, product evaluation and quality control are therefore highly dependent on methods for accurate determination of both average particle size and the distribution of sizes present in any given sample. To evaluate an emulsion from the standpoint of its physiological suitability, it may be more important to demonstrate the presence or absence of droplets above a certain critical size, rather than to accurately quantify their amount. Concerning the above reasons the purpose of my thesis was: •
to track the physicochemical stability of TPN mixtures, successfully applied in treatment of newborns and young children,
•
to analyse the possible interactrions between the components,
•
to compare the kinetic and chemical stability of TPN admixtures containing two kinds of triglycerides(structured and exclusively long-chain triglycerides),
•
to monitor the stability of TPNs as a function of storage conditions (temperature, storage time).
3. METHODS Photon correlation spectroscopy The particle size distribution of TPN emulsions of different compositions was examined before storage and after 4, 7 and 10 days. Dynamic light scattering measurements were carried out for checking the kinetic stability of the TPN emulsions. The apparatus (Brookhaven Instruments Corporation) used consisted of a BI-200SM goniometer and a BI9000BO Correlator. An Argon-Ion Laser (Omnichrome 543 AP) set to the wavelength of 488 nm was applied as a light source. The homodyne autocorrelation function in channel 238 was determined at real time mode using logarithmic timescale with a range of 1-200000 μs. Detector angle was set to 90.0 deg., and the gap was 100 μm. Before the measurements the emulsions were diluted to reach the appropriate count rate value. The time of measurement was 180s. 6 parallel examinations were carried out on each sample (four different samples – according to the temperature of storage and the type of lipid emulsion used for the preparation). Data were evaluated assuming an exponential distribution of the emulsion particles. The results were plotted as intensity vs. particle size of the emulsion droplets.
Particle size measurement Mean size, size distribution and polydispersity of the emulsion droplets were measured at 25ºC by an advanced technique of photon correlation spectroscopy (PCS) using a Malvern Zetasizer 4 apparatus (Malvern Instruments, UK) with autosizing mode and auto sample time. Analysis of the fluctuations in the intensity of light scattered from particles undergoing random Brownian motion enables the determination of an autocorrelation function G(τ) that, in effect, is measure of the probability of a particle moving a given distance in a τ time (τ is the correlation delay time). Gi (τ ) ∝ ∑ ki exp [− τ/t c,i (ai )]
(1)
The relaxation time (tc) of fluctuations is related to the diffusion coefficient (D) of particles: t c = 1 / DK 2
(2)
from which the particle size can be calculated via the Stokes – Einstein equation, (K) is the wave vector.
By determining the autocorrelation function for the dispersions stored at 2-8 °C and 37 ± 0.5°C for various times, the diffusion coefficient and the hydrodynamic radii (ai) of emulsion droplets have been evaluated. Zeta-potential measurements Laser Doppler-electrophoresis (LDE) was used for investigating the surface-electric properties of the emulsion droplets. Measurements were carried out before storage and after 4, 7 and 10 days. For electrically charged particles moving in response to an applied electric field, a correlation function of laser Doppler-shift was measured with a Malvern Zetasizer 4 apparatus at 25 ± 1°C (Malvern Instruments, UK), and the resulting frequency spectrum was translated to electrophoretic mobility. Using an AZ 104 type cell, 5 mobility measurements were ordinarily done on each sample (four different samples – according to the temperature of storage and the type of lipid emulsion used for the preparation) in cross beam mode. The zeta potential (η) of the particles was calculated from the mobility measurements, using the Smoluchowsky formula. Optical microscopy The emulsions were observed under a Carl Zeiss Axiostar plus optical microscope (Carl Zeiss, Germany) which was equipped with a video camera. The size and arrangements of the droplets were studied at 400x magnification. pH measurements pH values of the TPN mixtures were measured right after preparation and after 1, 4, 7 and 10 days of storage with a Radelkis OP-300 electroanalytical analyser. Dynamic Surface Tension Measurements The examinations were carried out on the day of preparation and after 1, 4, 7 and 10 days. The surface tension of emulsions was determined by dynamic method, applying Du-Noüy ring and Wilhelmy plate operations of a computer-controlled KSV Sigma 70 tensiometer (KSV Sigma 70, RBM-R. Braumann GmbH, Germany) at 25°C ± 0.5 °C. The method determines the maximum mass of liquid pulled from the surface by lifting the specified solid (e.g. ring or plate). The force (f) measured on the electric balance is necessary for lifting out and pushing down the solid measuring device from the surface of the liquid. The contact angle can be calculated from the extrapolated buoyancy slope: cos θ = f/pγLV
where θ is the contact angle, f is the force measured on the balance, p is the measured plate perimeter and γLV is the surface tension (interfacial free energy between the liquid and
vapour) of the examined liquid. 3 parallel measurements were carried out on all four kinds of samples. Statistical evaluation Zeta-potential values of the two kinds of mixtures at different temperatures and storage intervals were compared using the two-sample t-test assuming equal variances. In this case, the comparison was made between Intralipid-containing infusions and Structolipid-containing ones. Surface tension values measured after different storage intervals were compared via the paired two-sample t-test for both kinds of mixtures. The comparison was made between data obtained right after preparation and after 1, 4, 7 and 10 days, respectively. The statistics were calculated using Microsoft Excel 2002.
4. NEW SCIENTIFIC RESULTS AND CONCLUSION •
Kinetic stability of two total nutrient admixtures prepared with different lipid emulsions (Intralipid and Structolipid, respectively) was tracked for 10 days with an array of several physicochemical methods, including particle size analysis via photon correlation spectroscopy, light obscuration, laser diffraction or microscopy . While these methods can follow the physical changes, zeta-potential and pH measurements are able to indicate chemical processes that take place along with storage. Dynamic surface tension measurements could provide additional information concerning the physicochemical processes that take place on the surface of the lipid droplets, therefore the method enabled the tracking of the destabilizing interaction during the storage of TPN mixtures.
•
Electrolytes play an especially important role from stability aspects, as they are present in all admixtures and have a major effect on the zeta potential of the emulsions. In the case of nonspecific adsorption, they physically adhere to the surface of the lipid droplets, and above the Critical Flocculation Concentration (CFC) cause the disappearance of repulsive forces. Specific adsorption occurs; when besides the physical ones, chemical interactions also arise (e.g. Ca2+ and phospholipids). In this case, further adsorption is possible above the CFC, and repulsive forces arise again. In the case of the examined emulsions, however, notable differences in the zeta potential of the droplets of the two compositions of different lipid components could not be detected even after longer storage times and at either temperature. This might be attributed to the higher Na+, Mg2+ and Ca2+ content. The higher electrolyte concentrations could have deteriorated the advantageous effects of the structured lipids on the zeta potential values.
•
The formation of a “mixed” interfacial layer formed from the medium and the long chain fatty acids in case of structured triglycerides is responsible for the more efficient stabilization.
•
The favorable stabilizing effect of structured lipids can be deteriorated by the ionic concentration of the media of the emulsions.
•
Droplet size distribution and surface tension data showed that the emulsions containing structured lipids proved to be more stable, especially at lower storage temperatures.
•
The practical usability of our results is that in addition to the advantageous metabolic effects of structured triglycerides, their application is recommended also to improve the physical stability of TPN admixtures, which could decrease the risk of fat embolism in the clinical practice.
5. PUBLICATIONS 1. Kovácsné Balogh Judit, Zelkó Romána, Vincze Zoltán: A parenterális táplálás gyógyszerészi vonatkozásai I. Gyógyszerészet 48. 666-671, 2004. 2. Kovácsné Balogh Judit, Zelkó Romána, Vincze Zoltán: A parenterális táplálás gyógyszerészi vonatkozásai II. Egyedi parenterális oldatkeverékek. Gyógyszerészet 49. 92-97, 2005. 3. J. Balogh, J. Bubenik, J. Dredán, F. Csempesz, D. Kiss, R. Zelkó: The effect of structured triglycerides on the kinetic stability of total nutrient admixtures. J. Pharm. Pharmaceut..Sci.(www.cspsCanada.org) 8(3):552-557, 2005. 4. J. Balogh, D. Kiss, J. Dredán, I. Puskás, F. Csempesz, R. Zelkó: Tracking of the Kinetic Stability of Two Types of Total Nutrient Admixtures Containing Different Lipid
Emulsions.
AAPS
Pharm.Sci.Tech.
2006;7
(4)
Article
98
(http://www.aapspharmscitech.org).
Other publications: 1. Kovácsné Balogh Judit, Dr. Szász Györgyné: Atropin tabletta és szemcsepp kvantitatív ellenőrzése indikátorszinezék módszerrel. Semmelweis OTE Egyetemi Gyógyszertár Gyógyszerügyi Szervezési Intézet Acta Pharmaceutica Hungarica 53. 150-153. 1983. 2. Kovácsné Dr. Balogh Judit, Dr. Zalai Károly: Gyógyszerésznők Magyarországon. Gyógyszerészet 42. 468-474. 1998. 3. Balpataki Rita, Kovácsné Dr. Balogh Judit, Dr. Zelkó Romána, Dr. Vincze Zoltán: Antibiotikum-felhasználás költségeinek elemzése. Acta Pharmaceutica Hungarica 71. 108-113. 2000. 4. Kovácsné Balogh Judit, Zelkó Romána, Vincze Zoltán: Minőségbiztosításminőségügyi definíciók és tevékenységek Gyógyszerészet 45.418-420, 2001. 5. Reszkető Zsuzsa, Dr. Szlávik J., Kovácsné Dr. Balogh Judit, Dr. Zelkó Romána, Dr. Vincze Zoltán: HIV/AIDS betegek gyógyszeres kezelésének lehetőségei és a terápiás módszerek értékelése. Acta Pharmaceutica Hungarica 71. 428-432. 2001.
6. Jelinekné Nikolics Mária, Stampf György, Kovácsné Balogh Judit, Zelkó Romána, Turmezeiné Horváth Judit: Glukóz infúziók technológiai, stabilitási és additív-képzési problémái. Gyógyszerészet 47.725-728, 2003. 7. Major Csilla, Vincze Zoltán, Meskó Attiláné, Balogh Judit, Zelkó Romána, Németh Erzsébet: Gyógyszerelés a rendelőn kívül, Orvosi Hetilap 148.7.291-X 2007 8. Major Csilla, Vincze Zoltán, Meskó Attiláné, Balogh Judit, Németh Erzsébet: Az öngyógyszerezés helyzete Magyarországon - szakmai szemmel. Gyógyszerészet 51. 2007. március
Lectures: 1. Kovácsné Dr. Balogh Judit, Dr. Buday Tamásné, Dr. Meskó Attiláné, Dr. Soós Gyöngyvér:
Klinikai
laboratóriumi
vizsgálatokhoz
használt
kémszerek
és
festékoldatok előállításának klinikai és gazdaságossági jelentősége. Congressus Pharmaceuticus Hungaricus XI. Gyógyszerészet 1999. október 6-10. 36.oldal 2. Kovácsné Dr. Balogh Judit, Dr. Buday Tamásné, Dr. Rókusfalvy Andrea, Dr. Rixer András, Gável Mónika: „Párhuzamos” klinikák gyógyszerfelhasználásának elemzése a Semmelweis Egyetemen I. Magyar Kórházi Gyógyszerészek XII. Kongresszusa Budapest, 2000. 3. Jelinekné Nikolics Mária, Stampf György, Kovácsné Balogh Judit, Zelkó Romána: Glukóz infúziók, terápiás igények, technológiai problémák. XIV. Országos Gyógyszertechnológiai Konferencia Hévíz, 2002. nov. 8-10. 4. Balpataki Rita, Kovácsné Dr. Balogh Judit, Dr. Buday Tamásné: „Párhuzamos” klinikák antibiotikum felhasználásának elemzése a Semmelweis Egyetemen II. Kórházi gyógyszerészek XIII. Kongresszusa Szeged 2002. 5. Kovácsné Balogh Judit, Jelinekné Nikolics Mária, Komlódi Tibor, Turmezeiné Horváth Judit, Vincze Zoltán: A parenterális táplálás gyógyszerészi szempontból. Congressus Pharmaceuticus Hungaricus XII. Budapest, 2003. május 8-10. 6. Turmezeiné Horváth J. Kincs J. Bókay J. Kovácsné Balogh J. Zelkó R., Vincze Z.: Keverékinfúzió sikeres alkalmazása súlyosan atrophiás csecsemőnél. Congressus Pharmaceuticus Hungaricus XII. Budapest, 2003. május 8-10.
7. Balpataki Rita, Buday Tamásné, Kovácsné Balogh Judit, Vincze Zoltán: Szisztémás antibiotikum felhasználás elemzése a Semmelweis Egyetemen. Congressus Pharmaceuticus Hungaricus XII., Budapest 2003. május 8-10. 8. Kovácsné Balogh Judit, Jelinekné Nikolics Mária, Túrmezeiné Horváth Judit, Vincze Zoltán: A parenterális táplálás gyógyszerészi vonatkozásai.I. Magyar Mesterséges Táplálási Társaság 2003. évi Kongresszusa, Budapest 2003. november 21-22. 9. Kovácsné Balogh J., Farkas E., Vincze Z., Zelkó R.:A parenterális táplálás gyógyszerészi vonatkozásai II. A TPN emulziók stabilitási vizsgálata. Magyar Mesterséges Táplálási Társaság 2003. évi Kongresszusa Budapest, 2003. november 21-22. 10. Kovácsné Balogh Judit: Teljes parenterális táplálás a Semmelweis Egyetem Gyermekgyógyászati Klinikáin. Magyar Kórházi Gyógyszerészek XIV. Kongresszusa Debrecen, 2004. május 13-15. 11. Kovácsné Balogh Judit, Jelinekné Nikolics Mária, Farkas Edit, Kiss Dorottya, Vincze Zoltán, Zelkó Romána: Egyedi összetételű „all in one” oldatok stabilitásával, inkompatibilitásával
kapcsolatos
összefüggések
vizsgálata.
Magyar
Kórházi
Gyógyszerészek XIV. Kongresszusa Debrecen, 2004. május 13-15. 12. Kovácsné Balogh Judit, Jelinekné Nikolics Mária, Farkas Edit, Vincze Zoltán, Zelkó Romána:
Egyedi
összetételű
all
in
one
oldatkeverékek
összehasonlítása
energiatartalom és stabilitás szempontjából. Gyógyszer az ezredfordulón V. Sopron, 2004. március 25-27. 13. Kovácsné Balogh Judit, Dredán Judit, Csempesz Ferenc, Kiss Dorottya, Jelinekné Nikolics Mária, Zelkó Romána: Strukturált trigliceridek hatása teljes parenterális táplálásra szánt oldatkeverékek fizikai stabilitására. Magyar Mesterséges Táplálási Társaság 2005. évi Kongresszusa Budapest, 2005. november 18-19. 14. Judit Balogh, Mária Nikolics, Judit Dredán, Ferenc Csempesz, Romána Zelkó: Comparison of the physical stability of two different brands of lipid emulsion for total nutrient admixtures. BBBB Conference on Pharmaceutical Sciences September 26-28, 2005. Siófok, Hungary
15. Judit Balogh, Mária Nikolics, Judit Dredán, Ferenc Csempesz, Romána Zelkó: Comparison of the physical stability of two different brands of lipid emulsion for total nutrient admixtures. Pharmacy: Smart Molecules for Therapy. Semi-centennial conference of Semmelweis University, Faculty of Pharmacy. Hungarian Academy of Sciences October 12-14, 2005. Budapest, Hungary 16. Kovácsné Balogh Judit: Egyedi öszetételű teljes parenterális tápláló oldatok előállítása
és
minőségellenőrzésük
szempontjai.
Congressus
Pharmaceuticus
Hungaricus XIII. Budapest, 2006. május 25-27. 17. Rácz Bernadett, Kovácsné Balogh Judit, Zelkó Romána: Teljes parenterális táplálás gyógyszerészi szempontból. Magyar Mesterséges Táplálási Társaság 2006.évi Kongresszusa Galyatető 2006. október 27-28. 18. Szép Ágnes, Kovácsné Balogh Judit, Zelkó Romána: Lipid-tartalmú teljes parenterális táplálásra szánt emulziós oldatkeverékek fizikai-kémiai stabilitásának vizsgálata. Magyar Mesterséges Táplálási Társaság 2006. évi Kongresszusa Galyatető, 2006. október 27-28.
