Skip to main content
SpringerLink
Log in

Flexible New Dosage Forms Containing Carvedilol for the Treatment of Patients with Cardiovascular Disorders: Development, Stability, Palatability, and Microbiological Studies

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

The development of formulations adapted to the patient’s age is a challenge in the pharmaceutical industry. Pediatric and geriatric patients may have difficulties in swallowing oral medications when an adequate formulation is not available. Carvedilol is a poorly water-soluble drug used to treat cardiovascular problems; it is commercialized in several countries only as solid oral formulations, which are often manipulated at the point of administration to treat pediatric or geriatric patients. The purpose of this work was to obtain a new dosage form of Carvedilol using safe excipients, suitable for administration to pediatric and geriatric patients. To improve the solubility of Carvedilol, the effect of several factors was analyzed and optimized. Subsequently, to improve the physical stability of the formulations, two preparation methods were analyzed by adding HPMC. In “method 1,” HPMC was dissolved in buffer and incorporated into a mixture of Carvedilol-PEG 400, while in “method 2,” Carvedilol was solubilized in buffer containing PEG 400, and then, HPMC was added. Finally, microbiological tests were performed to the stable formulations. The factors “pH value” and “concentration of PEG” affected the solubility of Carvedilol. A formulation containing Carvedilol (3 mg/mL), pH=3, PEG 400 (15% v/v), and HPMC (0.25% w/v) prepared by method 2 was stable for 180 days at 4 °C while those containing Carvedilol (5 mg/mL), pH=3, PEG 400 (27% v/v), and HPMC (0.5% w/v), prepared by method 2, were stable for 180 days at 4 and 25°C. These oral liquid formulations were physicochemical and microbiologically stable for 6 months.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Ivanovska V, Rademaker CMA, van Dijk L, Mantel-Teeuwisse AK. Pediatric drug formulations: a review of challenges and progress. Pediatrics. 2014;134:361–72. https://doi.org/10.1542/peds.2013-32251.

    Article  PubMed  Google Scholar 

  2. Mieiro L, Beuscart J-B, Knol W, Van Riet-Nales D, Orlu M. Achieving appropriate medication for older adults: a multidimensional perspective. Maturitas. 2019;124:43–7. https://doi.org/10.1016/j.maturitas.2019.03.0071.

    Article  PubMed  Google Scholar 

  3. Walshe M. Oropharyngeal dysphagia in neurodegenerative disease. J Gastroenterol Hepatol Res. 2014;3:1265–71. https://doi.org/10.6051/j.issn.2224-3992.2014.03.408-21.

    Article  Google Scholar 

  4. Hanning SM, Lopez FL, Wong ICK, Ernest TB, Tuleu COGM. Patient centric formulations for paediatrics and geriatrics: similarities and differences. Int J Pharm. 2016;9.1:512–355.

    Google Scholar 

  5. Lopez FL, Ernest TB, Tuleu C, Gul MO. Formulation approaches to pediatric oral drug delivery: benefits and limitations of current platforms. Exp Opin Drug Deliv. 2015;12:1727–40. https://doi.org/10.1517/17425247.2015.10602181.

    Article  CAS  Google Scholar 

  6. Galanopoulou O, Rozou S, Antoniadou-Vyza E. HPLC analysis, isolation and identification of a new degradation product in carvedilol tablets. J Pharma Biomed Anal. 2008;48:70–7. https://doi.org/10.1016/j.jpba.2008.05.0041.

    Article  CAS  Google Scholar 

  7. Loftsson T, Vogensen SB, Desbos C, Jansook P. Carvedilol: solubilization and cyclodextrin complexation: a technical note. AAPS PharmSciTech. 2008;9:425–30. https://doi.org/10.1208/s12249-008-9055-71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Masarone D, Valente F, Rubino M, et al. Pediatric heart failure: a practical guide to diagnosis and management. Pediatr Neonatol. 2017;58:303–12. https://doi.org/10.1016/j.pedneo.2017.01.0011.

    Article  PubMed  Google Scholar 

  9. FDA Listing of Authorized Generics 2022. Available at https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/fda-listing-authorized-generics1.

  10. Carvedilol. Available at https://medlineplus.gov/spanish/druginfo/meds/a697042-es.html1.

  11. Menon TV, Sajeeth CL. Formulation and evaluation of sustained release sodium alginate microbeads of Carvedilol. J Pharm Technol. 2013;6:392–397.1.

    Google Scholar 

  12. Krstić M, Radojević M, Stojanović D, Radojević V, Uskoković P, Ibrić S. Formulation and characterization of nanofibers and films with carvedilol prepared by electrospinning and solution casting method. Eur J Pharm Sci. 2017;101:160–6. https://doi.org/10.1016/j.ejps.2017.02.0061.

    Article  PubMed  Google Scholar 

  13. Han H, Li Y, Peng Z, et al. A Soluplus/Poloxamer 407-based self-nanoemulsifying drug delivery system for the weakly basic drug carvedilol to improve its bioavailability. Nanomed Nanotechnol Biol Med. 2020;27:102199. https://doi.org/10.1016/j.nano.2020.1021991.

    Article  CAS  Google Scholar 

  14. Mishra A, Imam SS, Aqil M, et al. Carvedilol nano lipid carriers: formulation, characterization and in-vivo evaluation. Drug Deliv. 2016;23:1486–94. https://doi.org/10.3109/10717544.2016.11653141.

    Article  CAS  PubMed  Google Scholar 

  15. Wegmann M, Parola L, Bertera FM, et al. Novel carvedilol paediatric nanomicelle formulation: in-vitro characterization and in-vivo evaluation. J Pharm Pharmacol. 2017;69:544–53. https://doi.org/10.1111/jphp.126051.

    Article  CAS  PubMed  Google Scholar 

  16. Medarević D, Djuriš J, Ibrić S, Mitrić M, Kachrimanis K. Optimization of formulation and process parameters for the production of carvedilol nanosuspension by wet media milling. Int J Pharm. 2018;540:150–61. https://doi.org/10.1016/j.ijpharm.2018.02.0111.

    Article  PubMed  Google Scholar 

  17. Buontempo F, Bernabeu E, Glisoni RJ, Quiroga E, DA BCC. Carvedilol stability in paediatric oral liquid formulations. Farmacia Hospitalaria. 2010;34:293–7.1.

    Article  CAS  PubMed  Google Scholar 

  18. (ICH) INTERNATIONAL CONFERENCE ON HARMONISATION. Validation of analytical procedures Q2(R2), in: 2022.1. https://www.ema.europa.eu/en/ich-q2r2-validation-analytical-procedures-scientific-guideline

  19. Patel RP, Wanandy T, Zani R, Jose MD, Shastri M, Zaidi STR. Stability of trimethoprim in newly formulated liquid dosage form. J Pharm Pract Res. 2016;46:10–4. https://doi.org/10.1002/jppr.11271.

    Article  Google Scholar 

  20. Ellis DP, Rozek T, Milne RW. Stability of a compounded oral liquid formulation of clopidogrel for infants. J Pharm Pract Res. 2020;50:321–8. https://doi.org/10.1002/jppr.16121.

    Article  Google Scholar 

  21. European Pharmacopoeia. European Directorate for the Quality of Medicines EDQM, seventh ed. Strasbourg; 2010. pp. 163–167, 519–520.

  22. Morri M, Casabonne C, Leonardi D., Vignaduzzo S. Orphan formulations for pediatric use: development and stability control of two sildenafil citrate solutions for the treatment of pulmonary hypertension. AAPS Pharmscitech. 2020:21. https://doi.org/10.1208/s12249-020-01768-z1.

  23. Hamed R, Awadallah A, Sunoqrot S, et al. pH-dependent solubility and dissolution behavior of carvedilol—case example of a weakly basic BCS class II drug. AAPS PharmSciTech. 2016;17:418–26. https://doi.org/10.1208/s12249-015-0365-21.

    Article  CAS  PubMed  Google Scholar 

  24. Santos Souza HF, Real D, Leonardi D, et al. Development and in vitro/in vivo evaluation of a novel benznidazole liquid dosage form using a quality-by-design approach. TM & IH. 2017;22:1514–22. https://doi.org/10.1111/tmi.129801.

    Article  CAS  Google Scholar 

  25. Provenza N, Calpena AC, Mallandrich M, Halbaut L, Clares B. Design and physicochemical stability studies of paediatric oral formulations of sildenafil. Int J Pharm. 2014;460:234–9. https://doi.org/10.1016/j.ijpharm.2013.11.0061.

    Article  CAS  PubMed  Google Scholar 

  26. Morri M, Castellano P, Leonardi D, Vignaduzzo S. First development, optimization, and stability control of a pediatric oral atenolol formulation. AAPS PharmSciTech. 2018;19:1781–8. https://doi.org/10.1208/s12249-018-0992-51.

    Article  CAS  PubMed  Google Scholar 

  27. Plummer DT. Introducción a la bioquímica práctica (No. 574.192 P5Y 1981). 1981. https://books.google.com.co/books?id=LFzyWzsCVlsC&printsec=frontcover#v=onepage&q&f=false

  28. van der Vossen AC, van der Velde I, Smeets OSNM, et al. Formulating a poorly water soluble drug into an oral solution suitable for paediatric patients; lorazepam as a model drug. Eur J Pharm Sci. 2017;100:205–10. https://doi.org/10.1016/j.ejps.2017.01.0251.

    Article  PubMed  Google Scholar 

  29. Strickley RG. Solubilizing excipients used in commercially available oral and injectable formulations. Pharm Res. 2004;21:201–230.1.

    Article  CAS  PubMed  Google Scholar 

  30. (ICH) INTERNATIONAL CONFERENCE ON HARMONISATION, Q1A (R2) Stability testing of new drug substances and drug products In:2003. Available at https://www.ema.europa.eu/en/ich-q1a-r2-stability-testing-new-drug-substances-drug-products-scientific-guideline%0A1.

  31. Raghavan S, Trividic A, Davis A, Hadgraft J. Crystallization of hydrocortisone acetate: influence of polymers. Int J Pharm. 2001;212:213–21. https://doi.org/10.1016/S0378-5173(00)00610-41.

    Article  CAS  PubMed  Google Scholar 

  32. (ICH) INTERNATIONAL CONFERENCE ON HARMONISATION. Evaluation for Stability Data Q1E, 2003. https://database.ich.org/sites/default/files/Q1EGuideline.pdf.

  33. European Medicines Agency. Reflection paper: formulation of choice for the paediatric population (EMEA/CHMP/PEG/194810/2005). Eur Med Agency. EMEA/CHMP/:1–45.1. 2006. https://www.ema.europa.eu/en/documents/scientific-guideline/reflection-paper-formulations-choice-paediatricpopulation_en.pdf

  34. Ortega O, Martín A, Clavé P. Diagnosis and management of oropharyngeal dysphagia among older persons, state of the art. J Am Med Dir Assoc. 2017;18:576–82. https://doi.org/10.1016/j.jamda.2017.02.0151.

    Article  PubMed  Google Scholar 

  35. Siddiqi N, Shatat IF. Antihypertensive agents: a long way to safe drug prescribing in children. Pediatric Nephrol. 2020;35:2049–65. https://doi.org/10.1007/s00467-019-04314-71.

    Article  Google Scholar 

  36. Leonetti Luparini R, Celli V, Piccirillo G, Guidi V, Cacciafesta M, Marigliano V. Carvedilol in elderly patients with chronic heart failure, a 12 weeks randomized, placebo controlled open trial. Arch Gerontol Geriatr. 2000;29:275–82. https://doi.org/10.1016/S0167-4943(99)00040-01.

    Article  Google Scholar 

Download references

Funding

The authors gratefully acknowledge the Universidad Nacional de Rosario Argentina and CONICET (PUE 2016), Ministerio de Producción, Ciencia y Tecnología de Santa Fe (ASACTEI) Argentina for financial support.

Author information

Authors and Affiliations

  1. Área Análisis de Medicamentos, Departamento Química Orgánica, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK, Rosario, Argentina

    María Alejandra Operto, Rubén Maggio & Silvana Vignaduzzo

  2. IQUIR-CONICET, Suipacha 570, S2002LRK, Rosario, Argentina

    Rubén Maggio, Darío Leonardi & Silvana Vignaduzzo

  3. Área Técnica Farmacéutica, Departamento Farmacia, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK, Rosario, Argentina

    Darío Leonardi

Authors
  1. María Alejandra Operto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rubén Maggio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Darío Leonardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Silvana Vignaduzzo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M. A. Operto: conception and design of study, analysis and interpretation of data, and acquisition of data, R.M. Maggio.: analysis and interpretation of data, S. E. Vignaduzzo interpretation of data, and drafting the manuscript, D. Leonardi: writing and revising the manuscript.

Corresponding authors

Correspondence to Darío Leonardi or Silvana Vignaduzzo.

Ethics declarations

Competing interest

The authors report no declarations of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Operto, M.A., Maggio, R., Leonardi, D. et al. Flexible New Dosage Forms Containing Carvedilol for the Treatment of Patients with Cardiovascular Disorders: Development, Stability, Palatability, and Microbiological Studies. AAPS PharmSciTech 24, 159 (2023). https://doi.org/10.1208/s12249-023-02612-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-023-02612-w

Keywords

Search

Navigation