Poly (amidoamine) dendrimer-mediated hybrid formulation for combination therapy of ramipril and hydrochlorothiazide.
We present a dendrimer-based hybrid formulation strategy to explore the potential of poly (amidoamine) PAMAM dendrimers to be used as drug carriers for combination therapy of an anti-hypertensive drug ramipril (RAPL) and a diuretic hydrochlorothiazide (HCTZ). The drug-dendrimer complexes were prepared by phase-equilibration method. The results showed that the solubility of RAPL and HCTZ was dependent on dendrimer concentration and pH of dendrimer solution. The solubility profile of both RAPL and HCTZ dendrimer complexes illustrated a non-linear relationship with dendrimer concentration. At 0.8% (w/v) dendrimer concentration, solubility of RAPL was increased 4.91 folds with amine-terminated while for HCTZ, solubility enhancement was highest (3.72 folds) with carboxy-terminated. The complexes were characterized by Fourier transform infrared spectroscopy, nuclear magnetic resonance analysis and high performance liquid chromatography. In-vitro drug dissolution performance of pure drugs, individual drug loaded dendrimer formulations and hybrid formulations was studied in USP dissolution medium (pH7.0) and in simulated gastric fluid (pH1.2). Dendrimer mediated formulations showed faster and complete dissolution compared to pure RAPL or HCTZ. Surprisingly, similar pattern of dissolution profile was established with hybrid formulations as compared to individual drug loaded dendrimers. The dendrimer-based hybrid formulations were found to be stable at dark and refrigerated conditions up to 5weeks. Conclusively, the proposed formulation strategy establishes a novel multitasking platform using dendrimer for simultaneous loading and delivery of multiple drugs for pharmaceutical applications.
Institute of Pharmacy, Bundelkhand University, Jhansi, Uttar Pradesh 284 128, India; Medicinal Chemistry & Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
Mayank Kumar
MK
Singh
Medicinal Chemistry & Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
Deep
D
Pooja
Medicinal Chemistry & Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; IICT-RMIT Joint Research Centre, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
Hitesh
H
Kulhari
Institute of Pharmacy, Bundelkhand University, Jhansi, Uttar Pradesh 284 128, India.
Sanjay Kumar
SK
Jain
Medicinal Chemistry & Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India.
Ramakrishna
R
Sistla
Concordia University Wisconsin-School of Pharmacy, Mequon, WI 53097, USA. Electronic address: abhay.chauhan@cuw.edu.
Abhay Singh
AS
Chauhan
D000959:Antihypertensive Agents / Q000737:chemistry; D050091:Dendrimers / Q000737:chemistry*; D004232:Diuretics / Q000737:chemistry; D004338:Drug Combinations; D004339:Drug Compounding; D065546:Drug Liberation; D004355:Drug Stability; D006852:Hydrochlorothiazide / Q000737:chemistry*; D017257:Ramipril / Q000737:chemistry*; D012995:Solubility
D000959:Antihypertensive Agents; D050091:Dendrimers; D004232:Diuretics; D004338:Drug Combinations; C104700:PAMAM Starburst; D006852:Hydrochlorothiazide; D017257:Ramipril
Acetonitrile (PubChem CID: 6342); Combination therapy; DAB G4.0 PAMAM-OH (NS-D274) and DAB G3.5 PAMAM-COONa (NS-D233); Dendrimers; Dendrimers: Diaminobutane (DAB) G4.0 PAMAM-NH(2) (NS-D204); Dissolution; HPLC Water (PubChem CID: 962); Hydrochloric Acid (PubChem CID: 313); Hydrochlorothiazide; Hydrochlorothiazide (PubChem CID: 3639); Orthophosphoric Acid (PubChem CID: 1004); Ramipril; Ramipril (PubChem CID: 5362129); Sodium Hydroxide (PubChem CID: 14798); Sodium Perchlorate (PubChem CID: 522606); Solubility