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Marta Vicario De La Torre, Nuria SANZ MENÉNDEZ, José Ángel SÁNCHEZ GARCÍA, José Carlos IGLESIAS SÁNCHEZ, Luis SANTE SERNA
Laboratorios Farmalider S.A.
Abstract
The present article relates to the advantages of new developed liquid pharmaceutical composition for oral administration in the form of suspension of ibuprofen and phenylephrine HCL, in a pharmaceutically acceptable salt thereof, as active substances, and relatively low allergic excipients. The combination drugs can ease the patient’s condition and help shorten the duration of the illness provided that they are administered in due time. The discussed drug formulation is stable, has good organoleptic properties and shows excellent pharmacokinetic profile, providing quick absorption of the drugs. The present development also relates to the use of the composition for treating the symptoms of flu and common cold, particularly in adults and in children over 7 years old.
Introduction
Acute respiratory infections are of the greatest significance among all infectious diseases in the worldwide.
Well known, that currently, for most acute respiratory viral infections, there are no specific drugs with direct action, the effectiveness of which has been proven in numerous clinical trials. Therefore, combination drugs with anti-inflammatory, antipyretic, and decongestant effects are of particular interest as symptomatic and pathogenetic therapy.
Development
The discussed development relates to a liquid pharmaceutical composition in the form of suspension comprising the combination of ibuprofen and phenylephrine HCL, which is stable and particularly suitable for the treatment of symptoms of flu and common cold in adults and children.
The combined use of analgesics and decongestants for the relief of symptoms such as headache, fever, sinusitis and related to common cold minor body aches and pains, is a well-known therapeutic strategy.
The ibuprofen and phenylephrine combination were initially developed in USA motivated to decrease the availability of pseudoephedrine-containing products and thus decrease the opportunity for illicit conversion of pseudoephedrine to methamphetamine, substituting pseudoephedrine with phenylephrine.
The rational for this kind of combination is to treat multiple symptoms through the different mechanisms of the active substances and to improve the treatment compliance. In this combination, ibuprofen targets the pain associated with a common cold and phenylephrine HCL targets nasal congestion. These active substances have proven efficacy and safety in such indications. Hence, both actives work in synergy to alleviate the symptoms of a common cold and flu. The safety and efficacy of the combination is also backed with the availability of this combination in multiple countries, including as OTC products.
So far, the combination ibuprofen/phenylephrine HCL is available in the market only as solid oral dosage forms, and it is noticeable that all the available medicines are only intended for adults and children 12 years of age and over.
But it is recognized that the use of solid oral dosage forms may not be suitable for some patient populations who may have difficulties for swallowing whole tablets or capsules, including the pediatric, geriatric or disabled patients.
For those patient populations, the use of liquid formulations is generally regarded as advantageous. In addition, a liquid formulation may be more suitable for adjusting the dose of the active substances according to the age of the patients and for having a greater control over the amount of medicine administered. In this regards, Spanish developer pharmaceutical company register and initiate the marketing of combination ibuprofen/phenylephrine hydrochloride (400/10mg and 200/5 mg) in liquid suspension form.
Moreover, the composition also remained physically stable in those storage conditions, and neither aggregation nor precipitation phenomena were detected. This is important to ensure that a correct dose of the active substances is administered along the whole shelf-life of the medicinal product.
Safety and Efficacy
Initially, to analyze the safety of given combination and systematize the results of preclinical and clinical trials a search was carried out in different scientific publications like PubMed, Clinical Key ELSEVIER and Google Scholar databases. The search depth was more than 10 years. The results of numerous comparative and placebo-controlled trials showed that the use of fixed-dose combinations of analgesics and decongestant justified, safe, and effective in relieving symptoms of flu and common cold.
The comprehensive post-marketing surveillance data and pre-clinical toxicology review identified no new safety concerns for the combination formulation beyond those associated with individual components. No serious adverse drug reactions were identified that would preclude approval.
Subsequent to the FDA approval, the identical Ibuprofen combination has been approved in multiple European countries and other territories. Spanish developer aimed to conduct the in vivo bio-equivalence of suspension against already marketed tablets and did the data evaluation.
Clinical pharmacology evaluation included pharmacokinetic/pharmacodynamic (PK/PD) modeling that assessed the potential clinical significance of observed alterations in ibuprofen time-to-maximum-concentration (Tmax) when administered with phenylephrine HCL. The FDA concluded that observed Tmax delays of 0.5-0.6 hours did not result in clinically meaningful differences in analgesic efficacy, as predicted by mathematical PK/PD modeling.
Found that the biological availability of ibuprofen was higher in those subjects taking the composition of the present invention than in those taking the reference medicine, with approximately 10% greater absorption of ibuprofen in the former. This was considered surprising, since the present composition comprises maltitol, an active excipient which is known for enhancing gastric motility and reducing the permanence time of the drugs in the intestinal lumen and, therefore, a lower, rather than higher, bioavailability would be expected.
Moreover, such comparative test also showed that the time to reach the maximum concentration observed in plasma (Tmax) of both ibuprofen and phenylephrine was quicker in those subjects taking the composition according to the present invention than in those taking the reference medicine. Thus, Tmax for ibuprofen was about 1h shorter (namely, the value of Tmax was 1.0 h compared to 2.0 h for ibuprofen in the reference compound) and Tmax for phenylephrine HCL was 0.34 h shorter (namely, the value of Tmax was 0.33 h compared to 0.67 h for phenylephrine in the reference compound).
This surprising quicker absorption would provide also a quicker therapeutic effect, thus making the current composition a fast-acting medicine that provides a favorable environment for early and potent therapeutic effect.
Importance of the development and use of composition
Laboratory have developed an aqueous liquid pharmaceutical composition in the form of suspension which comprises the combination of ibuprofen and phenylephrine HCL as active ingredients, which has optimal physicochemical characteristics, in particular, it is outstandingly stable, despite the fact that phenylephrine is known to be highly susceptible to degradation. Thus, the content of both active substances, ibuprofen and phenylephrine HCL, remained between 95- 105% and the degradation products derived from the active substances were below 0.1% in all storage conditions, namely, 25°C-60%RH for 36 months, 30°C-65% RH for 36 months, 30°C-75%RH for 36 months and 40°C-75% RH for 6 months.
Furthermore, the formulation has also excellent pharmacokinetic properties, providing very quick absorption of both drugs and optimal biological availability and has good organoleptic properties; so, the bitter taste of ibuprofen and phenylephrine as well as the burning sensation commonly associated to ibuprofen are generally masked.
In addition, another advantage of the present composition, compared to the commercial solid oral formulations, is the dosage flexibility. Thus, for example, the administered dose of ibuprofen could range from about 40 mg, for example, to about 400 or 600 mg, associated with from about 1 mg to about 10 or 15 mg, for example, of phenylephrine HCL (expressed as equivalent phenylephrine hydrochloride), among other options.
This dosage flexibility allows to customize the doses according to the severity of symptoms and to the age of the patients, particularly for pediatric patients. In this way, for example, children with ages ranging from 7 can take 200 mg of ibuprofen and 5 mg of phenylephrine HCL and adults and elderly can take 400 ibuprofen and 10 mg of phenylephrine HCL, wherein the amount of phenylephrine HCL is expressed as the equivalent weight of phenylephrine hydrochloride.
Conclusions: The main aspect of the developed formulation is the new liquid pharmaceutical combination for oral administration in the form of suspension as defined above, for use in medicine, in particular, for use in the treatment of symptoms of flu and common cold. The proposed liquid suspension is suitable for the use both in adults, including elder adults, and in children, particularly in children over 7 years.
References:
BRUSHAN: „Resolution of enantiomers of ibuprofen by liquid chromatography: a review”, BIOMED. CHROMATOGR., vol. 12, no. 6, 1998, pages 309, no. 61-76-7
J.P REMINGTONA. R. GENARO: „Remington The Science and Practice of Pharmacy”, 2000, LIPPINCOTT, WILLIAMS & WILKINS
M.E. AULTONK.M.G. TAYLOR: „Aulton’s Pharmaceutics, the design and manufacture of medicines”, 2013, ELSEVIER
R.C. ROWEP.J. SHESKEYP.J. WELLER: „Handbook of Pharmaceutical Excipients”, 2009, PHARMACEUTICAL PRESS
Public Assessment Report (400 mg ibuprofen /10 mg phenylephrine HCl) oral suspension.
Nutra Essential OTC, S.L. AEMPS. Retrieved from: https://cima.aemps.es/cima/pdfs/ipe/90050/IPE_90050.pdf
Public Assessment Report (200 mg ibuprofen /5 mg phenylephrine HCl) oral suspension. Nutra Essential OTC, S.L. AEMPS. Retrieved from: https://cima.aemps.es/cima/pdfs/ipe/90049/IPE_90049.pdf
Summary Review of Advil Congestion Relief (200 mg ibuprofen /10 mg phenylephrine HCl) Tablets. Wyeth Consumer Healthcare. U.S. Food and Drug Administration.
Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022565s000SumR.pdf
Clinical Pharmacology Biopharmaceutics Review of Advil Congestion Relief (200 mg ibuprofen /10 mg phenylephrine HCl) Tablets. Wyeth Consumer Healthcare. U.S. Food and Drug Administration. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022565s000ClinPharmR.pdf
Medical Review of Advil Congestion Relief (200 mg ibuprofen /10 mg phenylephrine HCl) Tablets. Wyeth Consumer Healthcare. U.S. Food and Drug Administration. Retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022565s000MedR.pdf
MHRA, 2008. MHRA. (2008). UK Public Assessment Report of Lemsip Max/Nurofen All Day Cold and Flu Tablets/Flu Relief Tablets/Flu Relief (PL 00063/0541). Available on URL: Find product information about medicines
De Sutter AI, Eriksson L, van Driel ML. Oral antihistamine-decongestant-analgesic combinations for the common cold. Cochrane Database Syst Rev. 2022 Jan 21;1(1): CD004976.a
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