Internet for Pharmaceutical and Biotech Communities
| Newsletter | Advertising |
 
 
 

  

Pharm/Biotech
Resources

Outsourcing Guide

Cont. Education

Software/Reports

Training Courses

Web Seminars

Jobs

Buyer's Guide

Home Page

Pharm Patents /
Licensing

Pharm News

Federal Register

Pharm Stocks

FDA Links

FDA Warning Letters

FDA Doc/cGMP

Pharm/Biotech Events

Consultants

Advertiser Info

Newsletter Subscription

Web Links

Suggestions

Site Map
 

 
   

 

  Pharmaceutical Patents  

 

Title:  Glutathione based delivery system
United States Patent: 
7,446,096
Issued: 
November 4, 2008

Inventors: 
Wang; Ae-June (Hsinchu, TW), Jian; Chi-Heng (Yilan County, TW), Li; Shyh-Dar (Miaoli County, TW), Lin; Yi-Fong (Taipei County, TW), Liu; Shih-Jr (Hsinchu, TW)
Assignee: 
Industrial Technology Research Institute (Hsinchu, TW)
Appl. No.: 
11/303,934
Filed:
 December 19, 2005


 

Executive MBA in Pharmaceutical Management, U. Colorado


Abstract

A delivery system. The delivery system includes a carrier or an active compound and a glutathione or a glutathione derivative grafted thereon. The invention also provides a compound including a moiety comprising a vitamin E derivative or a phospholipid derivative, a polyethylene glycol (PEG) or a polyethylene glycol derivative bonded thereto, and a glutathione (GSH) or a glutathione derivative bonded to the polyethylene glycol or the polyethylene glycol derivative.

Description of the Invention

BACKGROUND

The invention relates to a biological delivery system, and more specifically to a glutathione based delivery system.

The blood brain barrier (BBB) is composed of brain endothelial cells capable of blocking foreign substances, such as toxin, due to the tight junction therebetween. Hydrophobic or low-molecular-weight molecules, however, can pass through the BBB via passive diffusion.

Nevertheless, active compounds, such as hydrophilic protein drugs for treating cerebral or nervous diseases and analgesic peptide drugs acting on the central nervous system, cannot enter brain tissue thereby due to their large molecular weight or hydrophilicity, resulting in decomposition by enzymes.

Current researches forward various methods of allowing active compounds to pass through the BBB, including structural modification to increase hydrophobicity of drugs, absorption-mediated transport (AMT) allowing positive-charged carriers to pass via charge absorption, carrier-mediated transcytosis (CMT) allowing hydrophilic metal ions such as Na.sup.+ and K.sup.+, di-peptides, tri-peptides or glucose to pass via transporters, and receptor-mediated transcytosis (RMT) allowing macro molecules such as insulin, transferrin, or low-density lipoprotein (LDL) to pass via transcytosis.

Glutathione (GSH) is an endogenous antioxidant. If its concentration in serum is insufficient, some nervous diseases, such as chronic fatigue syndrome (CFS), may occur.

In 1988, Kiwada Hiroshi provided a liposome capable of accumulation in liver comprising a N-acylglutathione such as N-palmitoylglutathione and a phospholipid such as phosphotidylcholine to target and treat liver diseases recited in JP63002922.

In 1994, Berislav V. Zlokovic asserted that glutathione (GSH) reaches and passes through the BBB of a guinea pig via a special route, such as GSH-transporter, without decomposition.

In 1995, Berislav V. Zlokovic asserted that glutathione (GSH) exists in brain astrocyte and endothelial cells with millimolar concentration.

In 1995, Ram Kannan asserted that GSH uptake depends on Na.sup.+ concentration. If Na.sup.+ concentration is low, GSH uptake from brain endothelial cells may be inhibited. He also pointed Na-dependent GSH transporter located on the luminal side of the BBB manages GSH uptake and Na-independent GSH transporter located on the luminal side of the BBB manages efflux of GSH. Additionally, Kannan built a rat hepatic canalicular GSH transporter (RcGSHT) system using the brains of mice and guinea pigs to analyze cDNA fragments 5, 7, and 11. The results indicate that fragment 7 represents Na-dependent GSH transporter and fragments 5 and 11 represent Na-dependent GSH transporter.

In 1999, Ram Kannan built a mouse brain endothelial cell line (MBEC-4) model simulating BBB situations. The model proved that Na-dependent GSH transporter is located on the luminal side of the MBEC-4 cell.

In 2000, Ram Kannan asserted that GSH passes through the BBB via Na-dependent GSH transporter in human cerebrovascular endothelial cells (HCEC) and Na-dependent GSH transporter exists in the luminal plasma membrane of HCEC.

In 2003, Zhao Zhiyang provided an anti-cancer pro-drug bonded with glutathione s-transferase (GST)/glutathione (GSH) by sulfonamide covalent bonds to target and treat specific cancer cells after broken of the sulfonamide bonds recited in US2003109555. This modification can protect amino groups of drugs, increase solubility thereof, and alter absorption and distribution thereof in body.

SUMMARY

The invention provides a delivery system comprising a carrier or an active compound and a glutathione or a glutathione derivative grafted thereon.

The invention also provides a compound comprising a moiety comprising a vitamin E derivative or a phospholipid derivative, a polyethylene glycol (PEG) or a polyethylene glycol derivative bonded thereto, and a glutathione (GSH) or a glutathione derivative bonded to the polyethylene glycol or the polyethylene glycol derivative.

DETAILED DESCRIPTION

The invention provides a delivery system comprising a carrier or an active compound and a glutathione or a glutathione derivative grafted thereon. The carrier may comprise nanoparticle, polymeric nanoparticle, solid liquid nanoparticle, polymeric micelle, liposome, microemulsion, or liquid-based nanoparticle. The liposome comprises at least one of lecithin such as soy lecithin and hydrogenated lecithin such as hydrogenated soy lecithin.

The liposome may further comprise cholesterol, water-soluble vitamin E, or octadecyl amine to increase serum resistance or charge amounts. The molar composition ratio of the liposome may be 0.5-100% of lecithin or hydrogenated lecithin, 0.005-75% of cholesterol or water-soluble vitamin E, 0.001-25% of octadecyl amine.

Additionally, the carrier may encapsulate the active compound in an encapsulation efficiency of about 0.5-100%. The active compound may comprise small molecule compounds such as gabapentin, peptides such as enkephalin, proteins, DNA plasmids, oligonucleotides, or gene fragments and have a molar ratio of about 0.0005-95% in the carrier.

The targeted carrier or the active compound may target on glutathione transporters of organs such as heart, lung, liver, kidney, or blood brain barrier.

Specifically, the active compound can pass through the blood-brain-barrier (BBB), such as brain endothelial cells, with the targeted carrier and has a cell penetration rate of about 0.01-100%.

The invention also provides a compound comprising a moiety comprising a vitamin E derivative or a phospholipid derivative, a polyethylene glycol (PEG) or a polyethylene glycol derivative bonded thereto, and a glutathione (GSH) or a glutathione derivative bonded to the polyethylene glycol or the polyethylene glycol derivative.

The vitamin E derivative comprises tocopherol derivatives or tocotrienol derivatives and may be .alpha.-tocopherol, .beta.-tocopherol, .gamma.-tocopherol, .delta.-tocopherol, .alpha.-tocotrienol, .beta.-tocotrienol, .gamma.-tocotrienol, .delta.-tocotrienol, .alpha.-tocopherol succinate, .beta.-tocopherol succinate, .gamma.-tocopherol succinate, .delta.-tocopherol succinate, .alpha.-tocotrienol succinate, .beta.-tocotrienol succinate, .gamma.-tocotrienol succinate, .delta.-tocotrienol succinate, .alpha.-tocopherol acetate, .beta.-tocopherol acetate, .gamma.-tocopherol acetate, .delta.-tocopherol acetate, .alpha.-tocotrienol acetate, .beta.-tocotrienol acetate, .gamma.-tocotrienol acetate, .delta.-tocotrienol acetate, .alpha.-tocopherol nicotinate, .beta.-tocopherol nicotinate, .gamma.-tocopherol nicotinate, .delta.-tocopherol nicotinate, .alpha.-tocotrienol nicotinate, .beta.-tocotrienol nicotinate, .gamma.-tocotrienol nicotinate, .delta.-tocotrienol nicotinate, .alpha.-tocopherol phosphate, .beta.-tocopherol phosphate, .delta.-tocopherol phosphate, .delta.-tocopherol phosphate, .alpha.-tocotrienol phosphate, .beta.-tocotrienol phosphate, .gamma.-tocotrienol phosphate, or .delta.-tocotrienol phosphate.

The phorpholipid derivative may have the following formulae comprising R.sub.1-A.sub.1- (I) -- see Original Patent.

The polyethylene glycol (PEG) or the polyethylene glycol derivative has a polymerization number (n) of about 6-210. The molecular weight of the polyethylene glycol (PEG) or the polyethylene glycol derivative may be altered with various vitamin E derivatives or phospholipid derivatives. For example, when PEG or its derivative is bonded to vitamin E derivatives, it may have a molecular weight of about 300-10000, when PEG or its derivative is bonded to the phospholipid derivatives represented by formula (I), it may have a molecular weight of about 750-5000, and when PEG or its derivative is bonded to the phospholipid derivatives represented by formula (II), it may have a molecular weight of about 350-5000.

The polyethylene glycol derivative may comprise carboxylic acid, maleimide, PDP, amide, or biotin.

Referring to FIG. 1 (see Original Patent), the delivery system of the invention is illustrated. The delivery system 10 comprises a liposome 20 and a ligand 30 grafted thereon. The ligand 30 comprises a moiety 40 comprising a vitamin E derivative or a phospholipid derivative, a polyethylene glycol (PEG) or a polyethylene glycol derivative 50 bonded thereto, and a glutathione (GSH) or a glutathione derivative 60 bonded to the polyethylene glycol and the polyethylene glycol derivative.

Active compounds, such as proteins, peptides, or small molecules, transported by the targeted carrier with a novel glutathione (GSH) ligand provided by the invention can effectively pass through blood-brain-barrier by carrier-mediated transcytosis (CMT) or receptor-mediated transcytosis (RMT) to treat cerebral or nervous diseases.
 

Claim 1 of 12 Claims

1. A delivery system, comprising: a carrier which comprises glutathione, wherein said glutathione is covalently bound to polyethylene glycol, wherein the polyethylene glycol is covalently bound to vitamin E or a phospholipid, and wherein the vitamin E or phospholipid is intercalated into the carrier such that the glutathione is on an outside surface of the carrier.
 

 

 

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.

 

 

     
[ Outsourcing Guide ] [ Cont. Education ] [ Software/Reports ] [ Training Courses ]
[ Web Seminars ] [ Jobs ] [ Consultants ] [ Buyer's Guide ] [ Advertiser Info ]

[ Home ] [ Pharm Patents / Licensing ] [ Pharm News ] [ Federal Register ]
[ Pharm Stocks ] [ FDA Links ] [ FDA Warning Letters ] [ FDA Doc/cGMP ]
[ Pharm/Biotech Events ] [ Newsletter Subscription ] [ Web Links ] [ Suggestions ]
[ Site Map ]