Formulation and Evaluation of Microbubbles by Using Ultrasonication for Treatment of Hypertension

Abstract

Microbubbles (MBs) are microscopic gas-filled bubbles with diameters ranging from 1 to 10µm, commonly used in medical applications such as drug delivery and ultrasound-based imaging. Their unique properties, including a large surface area and responsiveness to ultrasound, make them promising candidates for targeted therapeutic treatments, particularly in diseases such as cancer, hypertension, and heart conditions. This study investigates the preparation, characterization, and potential applications of microbubbles for the targeted delivery of Nicardipine, an antihypertensive drug used in the treatment of hypertension. The microbubbles are composed of a stabilizing albumin shell, encapsulating Nicardipine within the core. A series of techniques, including emulsification, sonication, and heat treatment, are employed to form and stabilize the microbubbles, which are then characterized using optical microscopy and optical spectroscopy for size distribution and concentration. The stability and behavior of the microbubbles under ultrasound exposure are also assessed to evaluate their effectiveness in drug delivery and imaging. The study aims to provide insights into the optimization of microbubble formulations for enhancing therapeutic efficacy while minimizing side effects in hypertension treatment. Additionally, the potential for using microbubbles in combination with ultrasound as a non-invasive method for monitoring blood pressure and improving drug absorption in targeted tissues is explored. These findings could contribute to the development of advanced drug delivery systems, offering a new approach to managing hypertension and related cardiovascular diseases.[5]

Introduction

1. Microbubbles (MBs)

• Definition: Microbubbles are gas-filled spheres (1–10 μm) with an inner gas core, outer liquid phase, and a stabilizing shell.

• Applications: Widely used in medical imaging and drug delivery, particularly in cancer, diabetes, and heart disease treatment.

• Advantages: Large surface area, ultrasound responsiveness, biocompatibility, and targeted delivery capabilities.

2. Hypertension

• Definition: A chronic condition with systolic BP ≥ 130 mm Hg or diastolic BP ≥ 80 mm Hg.

• Health Impact: Major risk factor for stroke, heart disease, kidney disease, and increased mortality.

• Stages:

  • Normal: <120/<80 mm Hg

  • Elevated: 120–129/<80 mm Hg

  • Stage 1: 130–139/80–89 mm Hg

  • Stage 2: ≥140/≥90 mm Hg

  • Hypertensive Crisis: >180/120 mm Hg

Symptoms (at severe stages):

Headaches, chest pain, vision changes, dizziness, fatigue, palpitations, etc.

3. Causes of Hypertension

• Primary (Essential) – ~90–95% cases; influenced by:

  • Genetics

  • Aging

  • Poor diet, inactivity, stress, obesity

• Secondary – ~5–10% cases; due to:

  • Kidney disease, endocrine disorders (e.g., Cushing’s), thyroid issues

  • Medications (NSAIDs, contraceptives), sleep apnea, vascular defects

4. Literature Highlights

• Microbubbles combined with ultrasound can help measure blood pressure, enhance drug delivery, and facilitate gene transfer.

• Studies support the stability and effectiveness of microbubbles in both diagnostics and therapeutics.

5. Materials Used

Drug: Nicardipine

• Class: Calcium channel blocker

• Function: Relaxes blood vessels, lowers BP, improves oxygen flow to the heart

• Formulations: Capsules, extended-release tablets

• Side Effects: Heart failure, kidney/liver issues, low BP, allergic reactions

Shell Materials for Microbubbles:

• Protein (e.g., Human Serum Albumin)

• Phospholipids, Surfactants (e.g., PEG), Polymers (PEM)

Gases Used:

• Air (short-lived)

• Perfluorocarbons (e.g., perfluoro butane, hexane) – more stable

• Sulfur Hexafluoride (SF6) – stable, used in imaging

• Oxygen, Nitrogen – used based on application

Buffer: Phosphate Buffered Saline (PBS) – maintains pH

6. Equipment Used

• Cyclomixer: Creates uniform mixing

• Sonicator: Uses ultrasound to form microbubbles via cavitation

• Centrifuge: Separates components based on density

7. Method of Preparation

• Ultrasonication Method:

  1. Prepare albumin and Nicardipine solutions

  2. Mix and emulsify the two

  3. Sonicate to form microbubbles

  4. Heat treat at 90°C to stabilize shell

  5. Wash to remove unbound drug

8. Evaluation of Microbubbles

• Size Analysis: Optical microscopy confirms spherical shape, ~5–10 μm

• Concentration & Stability: Assessed via spectroscopy and ultrasound imaging

• Performance: Verified using ultrasonography and microbubble detection tests

9. Results & Observations

• Shape: Spherical

• Size: 5–10 μm

• Stability: Improved through sonication and heat treatment

• Potential: Effective for targeted Nicardipine delivery in hypertension management

Conclusion

In conclusion, microbubbles (MBs) represent a promising and innovative tool in the field of medical treatment, particularly for drug delivery and imaging. Their unique structure, consisting of a gas-filled core surrounded by a biocompatible stabilizing shell, enables efficient therapeutic targeting and enhances the effectiveness of ultrasound in both diagnostic and therapeutic applications. This study demonstrated that the combination of Nicardipine, a calcium channel blocker, with albumin-coated microbubbles offers a novel approach to treating hypertension. The preparation of these microbubbles through emulsification, sonication, and heat treatment successfully encapsulated Nicardipine within the microbubbles, preserving both the drug\'s activity and the stability of the microbubble formulation. Characterization of the microbubbles revealed a consistent size distribution, suitable for circulation within the bloodstream, and their stability was maintained under ultrasound exposure, suggesting their potential for safe, non-invasive, and targeted drug delivery. Additionally, the ability of microbubbles to improve drug absorption and provide real-time imaging could revolutionize the treatment of hypertension and other cardiovascular diseases, offering greater precision in monitoring and controlling blood pressure. This study underscores the importance of optimizing microbubble formulations for enhanced therapeutic outcomes and provides a foundation for future research exploring the broader applications of microbubbles in medical fields. By addressing critical issues such as drug stability, microbubble size, and ultrasound responsiveness, further development of microbubble-based drug delivery systems holds the potential to significantly improve the management of hypertension, reduce side effects, and enhance patient outcomes in cardiovascular therapy.

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Copyright

Copyright © 2025 Apurva Shelar, Satish Mendake, Om Malpote, Pratiksha Mandlik, Kiran Marathe, Pranav Mendgule, Prathamesh Mengade . This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.