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Conjugates of membrane translocating agents and pharmaceutically active agents

a technology of membrane translocation agent and conjugate, applied in the field of peptides, can solve the problems of adverse effects, patient discomfort, and studies that do not address the use of membrane translocation peptides, and achieve the effects of preventing pathological disorders, diagnosing pathological disorders, and preventing pathological disorders

Inactive Publication Date: 2005-05-12
SARLAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides membrane translocating peptides (MTLPs) and nucleotide sequences coding for them, as well as MTLP-active agent complexes and MTLP-active particle complexes. These MTLPs enhance the movement of active agents or particles across lipid membranes and into cells. The invention also includes methods of making and using these compositions. The technical effects of the invention include improved delivery of active agents or particles into cells and across cell layers in animals, including humans."

Problems solved by technology

However, these studies do not address the use of membrane translocating peptides to enhance active agent uptake into a cell into and out of an intracellular compartment, or across a cell layer when the active agent is complexed to a membrane translocating peptide or when the active agent is incorporated into a particle and the particle is modified with (hereinafter, “complexed to”) a membrane translocating peptide.
Intravenous administration can result in adverse effects from rapid accumulation of high concentrations of drug, in patient discomfort and in infection at the injection site.
Intramuscular administration can cause pain at the injection site.
Subcutaneous administration is not suitable for large volumes or for irritating substances.
Although oral administration is the preferred route, many active agents are not absorbed efficiently across the GIT epithelium.

Method used

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  • Conjugates of membrane translocating agents and pharmaceutically active agents
  • Conjugates of membrane translocating agents and pharmaceutically active agents
  • Conjugates of membrane translocating agents and pharmaceutically active agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

Peptide Synthesis

[0152] The membrane translocating peptides ZElan094, 204N and 204 and the targeting peptides HAX42, PAX2, P31 and Sni34 (U.S. patent application Ser. Nos. 09 / 079,819, 09 / 079,723 and 09 / 079,678) were synthesized chemically using a fmoc synthesis protocol (Anaspec, Inc., San Jose, Calif.). A dansyl group was added at the N-terminus of each sequence in order to enable the detection of the peptide with anti-dansyl antibody (Table 1).

[0153] The physical characteristics of Zelan094 (SEQ ID NO:2) are shown in Table 3.

TABLE 3Physical characteristics of ZElan 094 (SEQ ID NO: 2)Mass (M+H+):1838.03Solubility1 mg / ml waterAppearancewhite powderHPLC purity>95%Kyle-Doolittle Hydropathy Plot

example 2

Preparation of MTLP-Active Particle Complexes and of Targeting Peptide-Active Particle Complexes

[0154] Active particles were prepared from a polymer using a coacervation method. Preferably, particle size is between about 5 nm and 750 μm, more preferably between about 10 nm and 500 μm and most preferably between about 50 nm and 800 nm. MTLPs or targeting peptides were complexed to the particles using various methods known to those skilled in the art.

[0155] The following is a general method for preparation of coacervated particles.

[0156] Phase A A polymer agent, a surface-active agent, a surface-stabilizing agent, a surface-modifying agent or a surfactant is dissolved in water (A). Preferably the agent is a polyvinyl alcohol (herein after “PVA”) or a derivative thereof having a % hydrolysis of about 50-100 and a molecular weight range of about 500-500,000 kDa. More preferably the agent is a PVA having a % hydrolysis of 80-100 and a molecular weight range of about 10,000-150,000 kD...

example 3

Bovine Insulin Loaded-MTLP Coated Nanoparticles—MTLP Added in the Final Wash

[0163] Fast acting bovine insulin (28.1 IU / mg) was incorporated into polylactide-co-glycolide (PLGA, Boehringer Ingelheim, Indianapolis, Ind.) at a theoretical loading of 300 IU of insulin / 210 mg of nanoparticles and the nanoparticles were coated with the dansylated ZElan094 (SEQ ID NO: 2).

COMPONENTAMOUNTPLGA RG504H (Lot # 250583)2gAcetone45mlsEthanol5mlsPVA (5% w / v) (13-23 kDa, 98% hydrolysis)400mlsBovine Insulin (Lot # 86HO674)100mgZElan094 (SEQ. ID NO: 2)10 mg / 50 ml dH20

Preparation: [0164] 1. Water was heated to near boiling, PVA was added to 5% w / v and the solution was stirred until cool (phase A). [0165] 2. Acetone and ethanol were mixed to form the organic phase (phase B). [0166] 3. PLGA was added to the acetone and ethanol (step 2) and dissolved by stirring (phase B). [0167] 4. An IKA™ reactor vessel was set at 25° C. Phase A (step 1) was added into the reactor vessel and stirred at 400 rpm. [016...

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Abstract

Membrane translocation peptides, compositions comprising them, chimeric molecules comprising them, and methods of using them to achieve transmembrane transport of various agents.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation-in-part of application Ser. No. 09 / 671,089 filed Sep. 27, 2000, incorporated by reference herein in its entirety, and also claims the benefit of U.S. provisional application Ser. No. ______ filed Apr. 30, 2001 with the title “Lipid-Comprising Drug Delivery Complexes and Method for Their Production”, incorporated herein in its entirety.FIELD OF THE INVENTION [0002] The present invention relates to peptides, which enhance uptake of a pharmaceutically active agent into a cell, into or out of an intracellular compartment, and across a cell layer. More particularly, the present invention relates to membrane translocating peptides, thereof and to the nucleotide sequences coding therefor, which enhance uptake of a pharmaceutically active agent into a cell, into or out of an intracellular compartment, and across a cell layer either directly or from a pharmaceutically active agent loaded particle. BACKGROUND OF...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/127A61K9/51A61K38/28A61K47/48A61K48/00C07K7/08C07K14/50C07K14/665C12N15/88
CPCA61K9/1271C12N15/88A61K9/5153A61K38/17A61K38/28A61K47/48238A61K47/48246A61K47/48338A61K47/48907A61K48/00B82Y5/00C07K7/08C07K14/50C07K14/665C07K2319/00A61K9/5138A61K47/65A61K47/62A61K47/64A61K47/6935
Inventor O'MAHONY, DANIELLAMBKIN, IMELDAPINILLA, CLEMENCIAHOUGHTEN, RICHARD
Owner SARLAN
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