Elixir Dosage Form in Pharmaceutical Practice [PDF]

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DOI 10.1007/s11094-017-1527-1 Pharmaceutical Chemistry Journal, Vol. 50, No. 11, February, 2017 (Russian Original Vol. 50, No. 11, November, 2016)



ELIXIR DOSAGE FORM IN PHARMACEUTICAL PRACTICE E. I. Sakanyan,1,* M. N. Lyakina,1 A. S. Alekseeva,1 L. I. Shishova,1 and T. B. Shemeryankina1 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 50, No. 11, pp. 47 – 50, November, 2016.



Original article submitted October 10, 2016. The elixir dosage form according to Russian and foreign pharmacopoeias was analyzed. A list of currently registered Russian and foreign drugs in this dosage form was given. The quality parameters by which drugs in the elixir dosage form must be standardized were listed based on an analysis and generalization of information provided in regulatory documentation of Russian and foreign drug manufacturers. Keywords: elixir, balm, pharmacopoeial monographs, regulatory documentation.



According to the State Drug Registry (SDR) of the Russian Federation (RF), 44 medicines in Elixir dosage form (DF) currently appear on the pharmaceutical market. Of these, 22 are Russian; 22, foreign. Table 1 presents a list of these formulations. Despite the fact that elixirs are one of the oldest DF that continues to be crucial even today, a general pharmacopoeial monograph (GPM) on it is still missing in the State Pharmacopoeia (SP) of the RF [1]. The term “elixir” originated in Arabic as “al-ixir”. Elixirs during the times of alchemy were understood to be powders that could transform ordinary metals into gold or prolong life and cure the ill (so-called elixir vitae or elixir of life). Later, elixirs meant various liquid tinctures with curative powers. They were often prepared with added honey that functioned as not only a solvent but also a therapeutic [2]. The Brockhaus and Efron Encyclopedic Dictionary presents the following definition of this DF: “Elixir (Elixirium) is designated in many pharmacopoeias as various liquid medicines, mostly tinctures and mixtures, prepared in weak alcohol, wine, or aromatic aqueous alcohol and, with several exceptions, intended for oral use. Many elixirs (e.g., Elix. ad longam vitam, Elix. amarum, Elix. Aurantii compos., Elix. pectorale Hufelandii, etc.) were used, sometimes with great acclaim; now they have justifiably been obliterated” [3]. The history of elixir DF development began with the attempts of alchemists to find an elixir that would turn an old man into a young one. However, this was never found. Owing to the 1 *



searches, pharmacists created formulations that had positive effects on the human body. Therefore, elixirs were rather common DF in the XVIII-XIX centuries. Elixirs as medicines were described in the Russian Pharmacopoeia and the Pharmacopoeia of the USSR (1866, 1871, 1880, 1891, 1902, 1910, 1934, 1946). Thus, the 1866 – 1891 editions contained only one “Elixir aurantiorum compositum”. The V-VI editions included two monographs on elixirs, “Bitter elixir” and “Elixir aurantiorum compositum”. The SP VIIth Ed. (1934) also had two monographs, “Elixir aurantiorum compositum” and “Licorice (pectoral) elixir”, the latter of which was retained in the SP VIIIth Ed. (1946). The USA Pharmacopeia (39th Ed.) gives only the definition of the DF in the monograph “Pharmaceutical dosage forms” (1151), in which it states that “elixirs, as a rule, are clear, aromatic, sweetened hydroalcoholic liquids intended for oral use” [4]. The Japanese Pharmacopeia (XVIth Ed.) gives the following definition of elixirs as DF in the monograph “General Rules for Preparations; Monographs for Preparations; Preparations for Oral Administration”: “clear, sweetened, and aromatic liquid preparations containing ethanol and intended for oral use” and a brief description of the method for producing them consisting of “dissolution of solid active ingredients or their extracts in ethanol and purified water with added flavors and sucrose, other sugars or sweeteners, clarified (purified) by filtration or another method” [5]. General and specific monographs on elixirs do not appear in the European Pharmacopoeia [6].



Scientific Center for Expert Evaluation of Medical Products, Ministry of Health of the Russian Federation, Moscow, 127051 Russia;. e-mail: [email protected].



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Elixir Dosage Form in Pharmaceutical Practice



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TABLE 1. Russian and Foreign Drugs in Elixir Dosage Form No.



Trade name



Dosage form



Manufacturer



1



Altakskii



elixir



Russian



2



Balsam Moskovia



elixir



Russian



3



Balsam Pervoprestolnyi



elixir



Russian



4



Bronkhofit



elixir



Russian



5



Vivaton



elixir



Russian



6



Elixir pectoralis



elixir



Russian



7



Demidoff Elixir



elixir



Russian



8



Ishimskii



elixir for oral use



Russian



9



Kedrovit



elixir



Russian



10



Kliofit



elixir



Russian



11



Codelac Broncho with thyme



elixir



Russian



12



Codelac fito



elixir



Russian



13



Lyukram



elixir



Russian



14



Moskovia-1



elixir



Russian



15



Panta-Forte



elixir for oral use



Russian



16



Sodekor



elixir



Russian



17



Travokhol



elixir



Russian



18



Fitogalenika®



elixir for oral use



Russian



19



Fitoimmunal



elixir



Russian



20



Evalar



elixir



Russian



21



Echinocor



elixir for oral use



Russian



22



Balsam Golden Dragon



elixir



foreign (Vietnam)



23



Balsam Maurera Original



elixir



foreign (Austria)



24



Biovital Classic



elixir



foreign (Germany)



25



Bittner Herbal Elixir



elixir



foreign (Austria)



26



Bromhexine elixir



elixir



foreign (India)



27



Bronchicum



elixir



foreign (Germany)



28



Bronchicum TP



elixir



foreign (Germany)



29



Gerimax Ginseng



elixir



foreign (Austria)



30



Doctor Petrov



elixir



foreign (Republic of Belarus)



31



Doctor Theiss Gerovital



elixir



foreign (Germany)



32



Doppelherz Ginseng Aktiv



elixir



foreign (Germany)



33



Doppelherz Cardiotonic



elixir



foreign (Germany)



34



Doppelherz Nerve Tonic



elixir



foreign (Germany)



35



Doppelherz Energy Tonic



elixir



foreign (Germany)



36



Klosterfrau Melisana



elixir



foreign (Germany)



37



Gaiduk Legend



elixir



foreign (Moldova)



38



Original Large Bittner Balsam



elixir



foreign (Austria)



39



Solvin



elixir



foreign (India)



40



Tonic Agent with hawthorn



elixir



foreign (Germany)



41



Sham Bo Dai Kui



elixir



foreign (Vietnam)



766



The British Pharmacopoeia (2013) states that “elixirs are clear aromatic solutions for oral use that contain one or more active ingredients dissolved in a solvent, usually containing a high proportion of sucrose, or in a suitable polyatomic alcohol or alcohols and can also contain ethanol (96%) or a dilution” (Monograph “Oral liquids of the British Pharmacopoeia”) [7]. The pharmacopoeias of the Republic of Belarus, Republic of Kazakhstan, and Ukraine contain no information on elixirs [8 – 11]. However, the demand for preparations in elixir DF indicates that the corresponding GPM must be included in the SP RF. It is noteworthy that elixirs can be produced in two ways. One of them consists of extraction of one or several types of medicinal plant raw material (collection), the quality of which satisfies requirements of pharmacopoeial monographs or regulatory documentation, by a suitable extractant. The principal extraction methods remain the traditional maceration and percolation. Ethanol (96%) and EtOH at lower concentrations were used as extractants. Solvents that can be added to the elixir of active compounds are glycerin and certain other polyatomic alcohols. The other method consists of mixing previously obtained tinctures and extracts. Both ways provide for addition of both active compounds and excipients, as necessary. The obligatory components of elixirs are taste adjusters, flavors, and preservatives. Excipients allowed for oral use in medical practice could be added as the taste adjusters and flavors in elixirs. Preservatives in elixirs include methyl-para-hydroxybenzoate, propyl-para-hydroxybenzoate, and other excipients also allowed for oral use in medical practice. In several instances, a slight precipitate can form during storage. A specific feature of this DF is that the formulation can include plant raw materials used in the food industry as spices, e.g., ginger root, cardamom seeds, nutmeg, etc. Food ingredients such as black currants, cranberries, various juices (as a rule, apple), honey, and coffee are also added to elixirs. It is noteworthy that the term “balsam” is not used entirely correctly in naming medicines in elixir DF. Examples of such are the following elixir trade names: Balsam Moskovia, Balsam Pervoprestolnyi, Balsam Maurera Original, Original Large Balsam Bittner, etc. In contrast with elixirs, balsams are liquid or soft DF for topical use that are, as a rule, homogeneous mixtures of pharmaceutical substances of plant origin (resins, essential oils, natural balsams, etc.) with or without added active substances and excipients. They were included earlier in Russian pharmacopoeias and were highly popular (copaiba balsam, Peruvian balsam, etc.). Balsams are categorized as soft DF, namely liniments and ointments, the quality requirements for which are given in the GPM “Ointments”. Considering the specific features of this DF (composition and production technology), the current understanding of



E. I. Sakanyan et al.



“elixir” is as follows. Elixirs are a liquid dosage form consisting of an aqueous alcohol extract of medicinal plant raw material and/or a mixture of tinctures and/or extracts with or without added active substances and taste and aroma adjusters, preservatives, and other excipients that is intended for oral use. Based on an analysis and generalization of information given in regulatory documentation of Russian and foreign manufacturers, a list of quality parameters according to which medicines in elixir DF should be standardized was determined. Description. Medicines in elixir DF are liquids colored from reddish-brown to dark-brown, clear, and in several instances, with a characteristic scent. Opalescence and, as a rule, formation of a slight precipitate over time are allowed during storage. Identity. Identity is established by identifying biologically active compounds (BAC) that transfer from the medicinal plant raw material and are responsible for the pharmacological activity of the preparation and also active compounds included in the elixirs. A number of methods including qualitative group reactions (e.g., for tanning agents, with acidic FeCl3 or basic lead acetate solution; for phenolic compounds, with ferric ammonium sulfate; for reducing sugars, with copper-tartrate reagent; for flavonoids, with Mg powder in acidic solution; for terpenoids, with p-dimethylbenzaldehyde or vanillin in H2SO4; for compounds containing N/amine groups, with ninhydrin solution; a sample for foam formation confirming the presence of saponins; and UV spectral characteristics) are used to identify BAC of plant origin. Modern physicochemical analytical methods, most often TLC and HPLC/GC using standards and the appropriate detecting reagents, are used if the medicinal preparation contains aqueous alcohol extract that was obtained from more than 3 – 5 types of medicinal plant raw material. Alcohol. The alcohol content is determined according to SP XIIIth Ed., GPM “Determination of ethanol in drugs”. The standards for content are different and, as a rule, fall in the range 35 – 60%; more rarely, 14 – 20%. Density. In several instances (mainly with low alcohol content), the quality is additionally regulated according to this parameter according to the GPM “Density”. Dry residue. This parameter for elixir DF does not objectively evaluate the content of extracted compounds because excipients in the formulation can make a significant contribution. Heavy metals. The heavy-metal content is determined according to the GPM “Heavy metals”. The quality of the preparation is controlled by this parameter only for those medicines that contain aqueous alcohol extracts. If dry/thick/liquid tinctures or extracts are used to produce the elixir, tests for heavy metals are not required because they are already evaluated according to this parameter. Microbiological purity. Requirements of the GPM “Microbiological purity” should be used as a guide to evaluate the microbiological purity of elixirs.



Elixir Dosage Form in Pharmaceutical Practice



Quantitation. The quality of elixirs is evaluated according to this parameter by using physicochemical analytical methods such as UV and visible spectrophotometry and GC and HPLC to determine individual BAC or groups of BAC, e.g., glycyrrhizic acid, total flavonoids calculated as rutin or luteolin, and total hydroxycinnamic acids calculated a caffeic acid. In several instances, HPLC was used to determine the total flavonoid content. Analytical titrations were used to determine the contents of reducing sugars, organic acids, and oxidizable substances calculated as tannin. In conclusion, it should be noted that elixirs are currently a requested DF, the development of regulatory documentation for which is crucial and necessary. REFERENCES 1. State Drug Registry of the Russian Federation; URL: http: // grls.rosminzdrav.ru / 2. Elixirs [in Russian], V. G. Makarov (ed.), St. Petersburg (1999).



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3. F. A. Brockhaus and I. A. Efron, Encyclopedic Dictionary [in Russian], St. Petersburg (1890)-(1907). 4. United States Pharmacopeia, 39th Ed., United States Pharmacopeial Convention, URL: http: // www.uspnf.com / uspnf / login 5. The Japanese Pharmacopeia, 16th Ed., Pharmaceuticals and Medical Devices Agency, Tokyo (2011). 6. European Pharmacopoeia, EDQM, 9th Ed., http: // online.edqm.eu / entry.htm 7. British Pharmacopoeia, British Pharmacopoeia Commission (2015), Vol. 3; http: // www.pharmacopoeia.co.uk / 8. State Pharmacopoeia of the Republic of Belarus, Vol. 1, UP Center for Evaluation and Testing in Healthcare, Minsk (2015). 9. State Pharmacopoeia of the Republic of Kazakhstan, Vol. 1, ID Zhibek Zholy, Astana (2015). 10. State Pharmacopoeia of the Republic of Kazakhstan, Vol. 3, ID Zhibek Zholy, Astana (2014). 11. State Pharmacopoeia of Ukraine, GP Ukraine Scientific Pharmacopoeial Center for Drug Quality, 1st Ed., Suppl. 2, transl. from Ukrainian, SP Ukraine Scientific Pharmacopoeial Center for Drug Quality, Kharkov (2015).