Efficient Transdermal Delivery of Alendronate, a Nitrogen-Containing Bisphosphonate, Using Tip-Loaded Self-Dissolving Microneedle Arrays for the Treatment of Osteoporosis

Katsumi, Hidemasa; Tanaka, Yutaro; Hitomi, Kaori; Liu, Shu; Quan, Ying‐Shu; Kamiyama, Fumio; Sakane, Toshiyasu; Yamamoto, Akira

doi:10.3390/pharmaceutics9030029

Cited by 38 publications

(25 citation statements)

References 36 publications

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“…29 Therefore, it is expected that the development of a transdermally delivered formulation may reduce the necessary dose without compromising therapeutic efficacy. Many techniques to enhance drug delivery through transdermal routes have been studied, such as micro-needles 10,11 and iontophoresis. 14,15 Recently, it was reported that the ability of a drug to penetrate across the skin can be improved by taking advantage of the nanoparticle size.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, it is necessary to overcome the barrier properties of the skin if a drug is to be delivered via that route. The use of a micro-needle, 10,11 therapeutic 1 MHz frequency sonophoresis, 12,13 iontophoresis, 14,15 patches, 16,17 permeation enhancers, and liposomes 18 have been demonstrated to be helpful for overcoming the barrier properties of the skin. Formulations containing nanoparticles have been investigated as nanomedicines.…”

Section: Introductionmentioning

confidence: 99%

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Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment

Nagai¹,

Ogata²,

Otake³

et al. 2018

IJN

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PurposeIn the clinical setting, raloxifene, a second-generation selective estrogen receptor modulator, is administered orally; however, the bioavailability (BA) is only 2% because of its poor solubility in aqueous fluids and its extensive first-pass metabolism. Therefore, it is expected that the development of a transdermally delivered formulation may reduce the necessary dose without compromising its therapeutic efficacy. In this study, we designed transdermal formulations containing raloxifene nanoparticles and evaluated their usefulness for osteoporosis therapy.MethodsRaloxifene was crushed with methylcellulose by the bead mill method, and the milled raloxifene was gelled with or without menthol (a permeation enhancer) by Carbopol® 934 (without menthol, Ral-NPs; with menthol, mRal-NPs). The drug release and transdermal penetration were measured using a Franz diffusion cell, and the therapeutic evaluation of osteoporosis was determined in an ovariectomized rat model.ResultsThe mean particle size of raloxifene in the transdermal formulation (Ral-NPs) was 173.7 nm. Although the raloxifene released from Ral-NPs remained in the nanoparticle state, the skin penetration of raloxifene nanoparticles was prevented by the stratum corneum in rat. On the other hand, inclusion of menthol in the formulation attenuated the barrier function of the stratum corneum and permitted the penetration of raloxifene nanoparticles through the skin. Moreover, macropinocytosis relates to the skin penetration of the formulation including menthol (mRal-NPs), since penetration was inhibited by treatment with 2 µM rottlerin, a macropinocytosis inhibitor. In addition, the application of 0.3% mRal-NPs (once a day) attenuated the decreases in calcium level and stiffness of the bones of ovariectomized rat.ConclusionWe prepared raloxifene solid nanoparticles by a bead mill method and designed a novel transdermal formulation containing nanoparticles and permeation enhancers. These trans-dermal formulations overcome the barrier properties of the skin and show high drug penetration through the transdermal route (BA 8.5%). In addition, we found that raloxifene transdermal formulations are useful for the treatment of osteoporosis in ovariectomized rat.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment

Nagai¹,

Ogata²,

Otake³

et al. 2018

IJN

View full text Add to dashboard Cite

show abstract

“…There are recent reports of systems to deliver drugs into skin tissue, such as in situ gels. Iontophoresis [7], nanostructured lipid carriers [8,9], liposomes [10], dendrimers [11], phonophoresis [12], patches [13], micro-needles [14], and such systems can help overcome the low skin penetration [15]. However, the eyelid is easily stimulated by these systems, since the eyelid is the thinnest skin on the body and is highly sensitive to stimulus [16].…”

Section: Introductionmentioning

confidence: 99%

Development of Sustained-Release Ophthalmic Formulation Based on Tranilast Solid Nanoparticles

et al. 2020

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Eye drops containing Tranilast (TL), N-(3,4-dimethoxycinnamoyl) anthramilic acid, are used as an anti-allergic conjunctivitis drug in the ophthalmic field. Traditional eye drops are very patient compliant, although the bioavailability (BA) of most eye drops is low since eye drops cannot be instilled beyond the capacity of the conjunctival sac due to its limited volume. Thus, traditional eye drops have low BA and a short duration of the drug on the ocular surface, so solutions to these problems are highly anticipated. In this study, we designed a sustained-release drug-delivery system (DDS) for TL nanoparticles. TL nanoparticles were prepared by bead mill treatment, and the gel formulations containing TL nanoparticles (TL-NPs-Gel, particle size 50 nm–100 nm) were provided by carboxypolymethylene. The crystal structure of TL with and without bead mill treatment is the same, but the TL solubility in formulations containing nanoparticles was 5.3-fold higher compared with gel formulations containing TL microparticles (TL-MPs-Gel). The photo and thermal stabilities of TL-NPs-Gel are also higher than those of dissolved TL. Moreover, when TL-NPs-Gel is applied to the upper eyelid skin (outside), the TL is released as nanoparticles, and delivered to the lacrimal fluid through the meibomian glands. In addition, the TL release profile for TL-NPs-Gel was sustained over 180 min after the treatment. These findings can be used to develop a sustained-release DDS in the ophthalmic field.

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“…Furthermore, we reported the efficient transdermal delivery of ALN using a hydrophilic patch system [9]. We also used hyaluronic acid (HA) as a base material for the microneedle arrays for transdermal ALN delivery [10,11], because HA possesses versatile properties such as biocompatibility, non-immunogenicity, biodegradability, and viscoelasticity [12]. However, these technologies have not been applied clinically to date due to the complexities in manufacturing these technologies and devices.…”

Section: Introductionmentioning

confidence: 99%

Development of a Phosphoric Acid-Mediated Hyaluronic Acid Gel Sheet for Efficient Transdermal Delivery of Alendronate for Anti-Osteoporotic Therapy

et al. 2019

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For efficient transdermal delivery of alendronate (ALN) for anti-osteoporotic therapy, we developed a hyaluronic acid (HA) gel sheet that was prepared simply by enhancing HA noncovalent interactions using phosphoric acid and polyhydric alcohol (propanediol and glycerin). HA solution viscosity increased after addition of phosphoric acid, and the HA gel sheet formed after heated drying. The HA gel sheet could be converted to high viscosity state by addition of water. These results indicate that phosphoric acid enhances the noncovalent interactions of HA molecules. The HA gel sheet elicited no skin irritation over 7 days after a 24-h application. The permeation of ALN across rat and human skin was 109 and 7.17 µg/cm2, respectively, up to 24 h after application of the ALN-loaded HA gel sheet, which is sufficient for clinical treatment of osteoporosis. The bioavailability of ALN in rats was ~20% after application of the ALN-loaded HA gel sheet, and plasma calcium levels were effectively reduced 3 days after sheet application. Furthermore, in a rat osteoporosis model, the reduction in tibial bone density was suppressed by treatment with the ALN-loaded HA gel sheet. These results indicate that our phosphoric acid-mediated HA gel sheet is a promising transdermal formulation for efficient ALN delivery.

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Efficient Transdermal Delivery of Alendronate, a Nitrogen-Containing Bisphosphonate, Using Tip-Loaded Self-Dissolving Microneedle Arrays for the Treatment of Osteoporosis

Cited by 38 publications

References 36 publications

Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment

Design of a transdermal formulation containing raloxifene nanoparticles for osteoporosis treatment

Development of Sustained-Release Ophthalmic Formulation Based on Tranilast Solid Nanoparticles

Development of a Phosphoric Acid-Mediated Hyaluronic Acid Gel Sheet for Efficient Transdermal Delivery of Alendronate for Anti-Osteoporotic Therapy

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