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Injectable Sustained-Release Depots of PLGA Microspheres for Insoluble Drugs Prepared by hot-Melt Extrusion

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Abstract

Purpose

Progesterone (PRG) was selected as a model drug to develop a long-acting injection system for poorly water-soluble drugs.

Methods

Microspheres with high density-low porosity were prepared by hot-melt extrusion (HME) combined with wet-milling as the representative formulation, and a microcrystal suspension was also studied as a comparison. The morphology, particle size and distribution, polymorphism, drug distribution, density and porosity were characterized by scanning electron microscopy, laser diffraction particle size analyzer, power X-ray diffraction and DSC respectively. The in vivo performance of the different formulations within 7 days after intramuscular injection was evaluated in male SD rats.

Results

The drug-loading rate of the microspheres could be as high as 40%. The average initial burst release of the microspheres (PLGA lactide:glycolide = 75:25) was only 6.7% much lower than that of the microsuspension (25.7%) and a sustained release was exhibited for at least 7 days. The release mechanism was speculated to be as follows. The microspheres are a drug depot with drug microcrystals in the PLGA matrix which is a layer by layer honeycomb structure.

Conclusions

Microspheres prepared by HME combined with wet-milling could achieve a long-term sustained release effect as a novel long-acting formulation strategy.

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Abbreviations

API:

Active pharmaceutical ingredient

ART:

Assisted reproductive technology

AUC0–∞ :

Area under the plsma concentration-time curve

Cmax :

Maximum plasma drug concnetration

CSD:

Cambridge structural database

DSC:

Differential scanning calorimetry

FDA:

Food and Drug Administration

HME:

Hot-melt extrusion

HPMC:

Hydroxypropyl methylcellulose

HSP:

Hansen solubility parameters

i.m.:

Intramuscular

LC–MS/MS:

Liquid chromatography–mass spectrometry/mass spectrometry

PBS:

Phosphate buffered saline

PLGA:

Poly d,l-lactic-co-glycolic acid

PMC:

Progesterone microcrystal suspension

PMS:

Progesterone microspheres

PRG:

Progesterone

PXRD:

Powder x-ray diffraction

SD:

Sprague-dawley

s.c.:

Subcutaneous

SDS:

Sodium dodecyl sulfate

SEM:

Scanning electron microscopy

SP:

Span value

T1/2 :

Plasma half-life

Tmax :

Peak time

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Acknowledgments and Disclosures

We thank David Jack for linguistic assistance during the preparation of this manuscript. This work is supported by the National Natural Science Foundation of China No.81673378.

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Authors and Affiliations

  1. School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, 110016, China

    Yuting Guo, Yunning Yang, Luying He, Rong Sun, Chenguang Pu, Bin Xie, Haibing He, Yu Zhang, Yanjiao Wang & Xing Tang

  2. School of Functional food and Wine, Shenyang Pharmaceutical University, Shenyang, China

    Tian Yin

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  1. Yuting Guo
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  2. Yunning Yang
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  3. Luying He
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  7. Haibing He
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  8. Yu Zhang
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  9. Tian Yin
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  10. Yanjiao Wang
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  11. Xing Tang
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Correspondence to Tian Yin or Yanjiao Wang.

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Guo, Y., Yang, Y., He, L. et al. Injectable Sustained-Release Depots of PLGA Microspheres for Insoluble Drugs Prepared by hot-Melt Extrusion. Pharm Res 34, 2211–2222 (2017). https://doi.org/10.1007/s11095-017-2228-x

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  • DOI: https://doi.org/10.1007/s11095-017-2228-x

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