Table 7.
Examples of formulations of poorly soluble small molecule drugs in polymeric micelles of amphiphilic block copolymers evaluated for treatment of various diseases and other medical use.
| Therapeutic agent | Drug class / mechanism | Block copolymers | Main study results |
|---|---|---|---|
| Dexamethasone | Corticosteroids /Anti-inflammatory | PEG-b-PCL | The polymeric micelles exhibited longer systemic circulation compared to conventional drug format and accumulated preferentially in inflamed joints. Reduced joint swelling, bone erosion, and inflammatory cytokine expression were observed in joint tissue and serum for the micelle formulation treatments in a rat model [327]. |
| Betamethasone phosphate | Corticosteroids /Anti-inflammatory | PLA and PEG-b-PLGA | In in vivo studies, a 35% decrease in paw inflammation was observed in the first day of treatment and the efficacy of the formulation maintained for 9 days with a single injection. In AbIA mice, a single injection of the micelle formulation resulted in complete remission of the inflammatory response after 1 week [328]. |
| Andrographolide | Labdane diterpenoids / Anti-inflammatory and anti-platelet aggregation | PEG-b-poly(propylene sulphide) | Due to the reactive oxygen species (ROS)-responsive nature of the polymer, the micelle not only serves as a stimuli-responsive drug carrier to quickly release andrographolide, but also consumes ROS at the pathologic sites, resulting in synchronical alleviation of inflammation and oxidative stress [329]. |
| Rivastigmine | Acetylcholinesterase inhibitor | PEG-b-PCL | The PK study in rats indicated that the brain uptake of rivastigmine-loaded micelle was significantly higher than that of the free drug. Pharmacodynamic studies using the Morris water maze test confirmed that faster regain of memory loss with micellar formulation when compared to the free drug solution [330]. |
| Amphotericin B | Aminoglycosides / Antifungal | Pluronic F127 | Amphotericin B-containing Poloxamer P407-based polymeric micelles were the most efficient among the polymeric micelle, amphotericin B and Ambisome® in a mouse model of Leishmania amazonensis. Low parasitism, Th1 immunity and no significant toxicity were seen in the treated animals [331]. |
| Protoporphyrin IX | Porphyrin / Photosensitizer | PEG-b -PCL and PCL-b- PBAE | Bacterial killing of multidrug resistant Staphylococcus aureus biofilms by protoporphyrin IX-loaded micelles was superior compared to the control formulation. Staphylococcus aureus infection was eradicated by daily intravenous injection of the micelle formulation combined with its light-activation at the infected site in the mouse models of the bacteria infection [332]. |
| Naphthoquinone derivative | Naphthoquinones / Antileishmanial | Poloxamer 407 | The polymeric micelle formulation was more effective to treat Leishmania amazonensis infected mice in comparison to amphotericin B and its liposomal formulation, Ambisome®. No severe toxicity was identified in the treated animal model [333]. |
| 8-Hydroxyquinoline | Quinolones / Antifungal | Poloxamer 407 | The 8-hydroxyquinoline loaded poloxamer 407 micelle showed significant reduction in the average lesion diameter of the infected tissue and in the parasite burden in the skin and all infected organs (spleen, liver and draining lymph nodes) compared to controls in the mouse model of Leishmania amazonensis infection [334]. |
| Itraconazole | Azoles /Antifungal | Linear-dendritic PEG-b-PCL | Itraconazole loaded micelle had similar efficacy against Candida albicans to that of the free drug in in vitro. In vivo PK study in healthy mice demonstrated that the micelle formulation could improve tissue distribution of itraconazole [335]. |
| PDLLA and PEG-b-PDLLA | Single or repeated doses of itraconazole in rats and dogs equivalent to the drug clinical doses, were well tolerated. The plasma levels of the micellar itraconazole and its major metabolite were comparable to those of the control formulations (Sporanox® Injection and Oral Solution) [336]. | ||
| Efavirenz | Benzoxazines / Antiretrovirals | Pluronic F127 and Tetronic® T904 | The polymeric micelle formulation exhibited a dramatic drug solubility increase (over 8400-fold) and superior stability in comparison with the control formulations [337]. |
| Ocular disease | |||
| α-Lipoic acid | Heterocyclic thia fatty acids / Antioxidant | Polyvinyl caprolactam-b-poly(vinyl acetate)-b-PEG | The polymeric micelle formulation improved solubility and accumulation of enhanced α-lipoic acid into the bovine cornea compared to regular eye drops format of this agent. Drug containing polymeric micelles tolerated dilution in lachrymal fluid and freeze-drying [338]. |
| Diclofenac | Phenylacetic acid derivatives /Anti-inflammatory | PEG-b-PCL | The polymeric micelles increased diclofenac permeability up to 17-fold compared to that of conventional diclofenac eye drops in the rabbit cornea. In vivo PK study revealed that the diclofenac in the polymeric micelles has 2-fold greater drug exposure than the eye drops [339]. |
| Pain management | |||
| Propofol | Cumenes / Anesthetics | PVP-b-PDLLA | Propofol loaded polymeric micelles induced anesthesia effect in healthy rats. PK profile of the drug in the micelles was not significantly different from that of an emulsion formulation (Diprivan®) [340]. |
| Rapamycin | Macrolides / mTOR inhibitor | PEG-b-PCL | In a rat model of pulmonary arterial hypertension of mTOR inhibitor Rapamycin in polymeric micelles administered intravenously displayed lower toxicity, increased accumulation in lungs, and similar efficacy as the free drug in DMSO administered intraperitoneally [341]. |
| Tacrolimus | Macrolides / Immunosuppressant | mPEG-b-dihexyl substituted polylactide | Tacrolimus in polymeric micelle formulation showed improved drug solubility (by 400-fold), and drug disposition in porcine and human skin compared to tacrolimus ointment formulation (Protopic®) [342]. |
| Retinoic acid | Vitamers of vitamin A / Anti-acne | mPEG-b-dihexyl substituted polylactide | Retinoic acid in polymeric micelles showed improved drug disposition in porcine and human skin compared to commercially available gel formulation (Retin-A micro) [343]. |
| Spinal cord injury | |||
| Methylprednisolone | Steroids / Anti-inflammatory | PEG-b-PPO-b-PEG | Polymeric micelles increased the methylprednisolone level in plasma and spinal cord compared to the free drug solution in rabbit model. Increased expression of anti-apoptotic proteins was seen in animal group treated with micellar [344]. |
| Dexamethasone acetate | Corticosteroids /Anti-inflammatory | mPEG-b-PCL | Polymeric micelles improved dexamethasone solubility and the drug neuroprotective effect in the hemisection spinal cord injury model of rats [345]. |
| Zonisamide | Benzisoxazoles /Anticonvulsant | mPEG-b-PLLA-poly(trimethylene carbonate) | In the hemisection spinal cord injury rat model IV injection of zonisamide in polymeric micelles improved the motor function and neuron density compared to the effect of the drug in dimethyl sulfoxide [346]. |
| Wound healing | |||
| Curcumin | Curcuminoids / Anti-inflammatory and antioxidant activities | PEG-b-PCL | Curcumin loaded polymeric micelle exhibited good tissue adhesion and could release curcumin for an extended period in vitro. In animal excision model and histopathologic examination in rats, the formulation exhibited enhancement of cutaneous wound repair [347]. |