Pulmonary Arterial Hypertension (PAH) remains a formidable challenge in cardiovascular therapeutics. Despite numerous pharmacological advances, the disease demands innovative strategies that address both patient compliance and long-term efficacy. This article explores a novel formulation concept—encapsulated mini tablets (MTs)—combining immediate-release Sildenafil Citrate (SDC) and sustained-release Bosentan (BSN) to optimize PAH therapy.
Redefining the Therapeutic Landscape of PAH
PAH is characterized by progressive narrowing of the pulmonary arteries, leading to increased vascular resistance and subsequent right ventricular failure. Common symptoms such as fatigue, dyspnea, and syncope often mask its early stages, leading to diagnostic delays and suboptimal outcomes. Conventional treatment modalities target three principal biological pathways:
- Nitric oxide–cGMP pathway, modulated by phosphodiesterase-5 inhibitors like Sildenafil Citrate.
- Endothelin pathway, inhibited by endothelin receptor antagonists such as Bosentan.
- Prostacyclin pathway, enhanced by prostacyclin analogues and receptor agonists.
While monotherapy has its place, a more rational and effective approach is combination therapy, simultaneously targeting multiple pathophysiological pathways. However, patient adherence to complex regimens remains a significant obstacle—this is where the concept of encapsulated MTs holds great promise.
The Innovation: A Capsule of Controlled Complexity
At the heart of this study lies a dual-drug formulation—encapsulating multiple unit MTs, with:
- Fast-release SDC: ensuring a rapid vasodilatory response by inhibiting PDE5, leading to increased cGMP levels.
- Sustained-release BSN: maintaining therapeutic plasma levels by antagonizing both ETA and ETB endothelin receptors.
The MTs were developed using a direct compression technique and filled into size 1 hard gelatin capsules. Each capsule contained nine MTs—four delivering 5 mg SDC each (20 mg total) and five delivering 12.5 mg BSN each (62.5 mg total).
This strategy integrates pharmacokinetic and pharmacodynamic advantages, offering rapid symptom relief while maintaining long-term control of vascular remodeling—thus improving therapeutic outcomes and simplifying administration.
Formulation Architecture and Compatibility Assurance
Formulating such a dual-drug system required meticulous attention to material compatibility and release behavior. The excipients were carefully selected and categorized as follows:
- Superdisintegrants: sodium starch glycolate, magnesium aluminum silicate, and cross-linked PVP were explored in varying concentrations (1–5%) for SDC MTs to ensure immediate release.
- Polymers: HPMC K15M, ethyl cellulose, and sodium CMC were tested for BSN MTs to achieve desired sustained release properties.
Compatibility Assessment
Two analytical techniques—Fourier Transform Infrared Spectroscopy (FTIR) and Differential Scanning Calorimetry (DSC)—were employed to verify the absence of drug-excipient interactions.
- FTIR confirmed characteristic functional group vibrations for both SDC and BSN, with no shifting or disappearance of peaks when combined with excipients.
- DSC thermograms revealed preserved endothermic peaks, indicating no physicochemical incompatibility between drugs and formulation agents.
These results validated the integrity of the formulation throughout the manufacturing and storage processes.
Mini Tablet Fabrication and Coating Process
All ingredients were sieved through a 40-mesh screen and directly compressed into 3 mm mini tablets. BSN MTs underwent dip coating with a film-forming solution containing polyvinylpyrrolidone (PVP) and Sunset Yellow FCF dissolved in a 60:40 mix of isopropyl alcohol and dichloromethane.
Dip coating offered:
- Uniform and reproducible coating layers.
- Enhanced control over drug release kinetics.
- Improved protection and aesthetics.
MTs were then encapsulated into size 1 hard gelatin capsules, combining both drug types into a single dosage unit.
Post-Compression Evaluation and Drug Release Profiles
The MTs were evaluated for:
- Hardness (2.4–5.6 kg/cm²),
- Friability (<0.5% across all formulations),
- Content uniformity (within 95–99.5%),
- Weight variation (all within pharmacopoeial limits).
These parameters reflect excellent mechanical strength and content consistency—crucial for scale-up and commercial viability.
In Vitro Dissolution Results
Release profiles for optimized formulations were strikingly efficient:
- SD6 (SDC MTs with 3% magnesium aluminum silicate) showed >90% release within 15 minutes.
- BS3 (BSN MTs with 5% HPMC K15M) demonstrated a prolonged release of 82.31% over 24 hours.
The use of magnesium aluminum silicate, with its swelling and strain recovery properties, explained the rapid disintegration in SDC MTs. HPMC K15M formed a controlled gel layer around BSN MTs, achieving predictable and prolonged drug diffusion.
Pharmacokinetic Insights: From Bench to Body
To validate in vivo relevance, pharmacokinetic studies were performed using Wistar rats. Each group (n=6) received either the SDC or BSN MTs orally, followed by blood sample collection at defined intervals.
Results for optimized formulations were as follows:
| Parameter | Sildenafil Citrate | Bosentan |
|---|---|---|
| Cmax (ng/ml) | 15,602 ± 212 | 14,323 ± 321 |
| Tmax (h) | 1.01 ± 0.02 | 4.03 ± 0.03 |
| AUC (ng·h/mL) | 94,257 ± 124 | 142,438 ± 324 |
| MRT (h) | 2.12 ± 0.23 | 5.32 ± 0.34 |
| Clearance (mL/h) | 38,365 ± 31 | 24,493 ± 26 |
| Vd (mL) | 17,261 ± 23 | 83,928 ± 12 |
These findings confirm that the formulation achieved its intended pharmacokinetic goals: rapid systemic availability of SDC and sustained release of BSN with minimal fluctuations in plasma concentration.
Stability and Shelf Life Projection
Stability studies were conducted under ICH-recommended conditions over six months. Evaluated parameters included drug content, hardness, and uniformity.
Results showed no statistically significant changes, confirming the physical and chemical stability of the MTs.
Using regression modeling (Minitab v22.1), shelf life was estimated as:
- SDC MTs (SD6): ~10.7 months
- BSN MTs (BS3): ~6.3 months
Both fall within acceptable stability limits for clinical use, although enhancements to extend BSN MT shelf life may be warranted in future iterations.
Clinical Translation: From Lab Concept to Bedside Promise
The encapsulated MT strategy simplifies combination therapy by merging two mechanistically distinct agents into a single, easy-to-swallow dosage form. The potential advantages extend far beyond mere convenience:
- Enhanced patient compliance: One capsule replaces multiple tablets.
- Reduced side effects: Sustained release of BSN avoids peak plasma fluctuations.
- Flexible dosing: MTs can be adjusted per patient-specific needs.
- Manufacturing scalability: Direct compression and dip-coating methods are industry-standard.
This formulation approach can serve as a versatile platform for other drug combinations targeting chronic conditions requiring multimodal therapy.
FAQ: Common Questions about the Dual-Release Encapsulated MTs
1. Why are mini tablets preferred over conventional tablets in this formulation?
Mini tablets offer a precise and reproducible method for combining drugs with different release kinetics. Their small size allows for better control of disintegration and dissolution behavior, facilitates patient swallowing, and enables flexible dosing by adjusting the number of MTs per capsule.
2. What ensures that Sildenafil is released immediately while Bosentan is sustained?
The use of magnesium aluminum silicate in SDC MTs ensures rapid disintegration due to its swelling properties. Conversely, HPMC K15M in BSN MTs forms a gel matrix that gradually releases the drug over 24 hours. Film coating of BSN MTs further slows down the release.
3. Can this dual-release approach be applied to other therapeutic areas?
Yes, the encapsulated MT model is adaptable for any condition requiring combination therapy with drugs of differing release profiles—such as hypertension, diabetes, or even oncology—pending suitable pharmacokinetic alignment and drug compatibility.
Reference
https://www.sciencedirect.com/science/article/pii/S2211715624003485
