KR-102962971-B1 - Formulation for improving the efficacy of hydrophobic drugs

Abstract

A novel amphiphilic peptide, a peptide amphiphilic medium lipid micelle, a method for preparing a peptide amphiphilic medium lipid micelle comprising an amphiphilic peptide and a phospholipid and optionally a cargo molecule, and a method for using.

Inventors

• 호만 레이놀드
• 엘리엇 윌리엄 엘

Assignees

• 펩티노보 바이오파마, 인크.

Dates

Publication Date

20260512

Application Date

20160708

Priority Date

20150710

Claims (20)

1. delete
2. A peptide comprising an amino acid sequence selected from the group consisting of sequence identification number: 25; sequence identification number: 32; and sequence identification number: 35, wherein the peptide is acylated at the N-terminus, amidated at the C-terminus, or acylated at the N-terminus and amidated at the C-terminus.
3. As a peptide amphiphilic medium lipid micelle (PALM)-cargo composition, (a) (i) a peptide according to claim 2; (ii) lipid components comprising sphingomyelin and one or more additional phospholipids PALM including; and (b) at least one cargo molecule PALM-cargo composition comprising
4. A PALM-cargo composition according to claim 3, wherein at least one cargo molecule is a compound conjugate having the following formula (I): ARLX (Equation I) Here, A is a preparation selected from anticancer drugs and contrast agents having a hydroxyl or amine group; R is a hydroxyl or amine group of said preparation; L is a linker; and X is an anchor moiety selected from the group consisting of cholesterol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol.
5. A PALM-component according to claim 4, wherein R is a hydroxyl group and an anchor moiety is covalently bonded to the formulation by a carbonate ester bond.
6. A PALM-component according to claim 4, wherein R is an amine group and an anchor moiety is covalently bonded to the formulation by a carbamate ester bond.
7. A PALM-cargo composition according to claim 4, wherein the anchor moiety is cholesterol.
8. A PALM-compound composition according to claim 4, wherein the anchor moiety is δ-tocotrienol.
9. A PALM-component according to claim 4, wherein one or more additional phospholipids in the PALM are selected from the group consisting of phosphatidylcholine, polyethylene glycol-phosphatidylethanolamine (PEG-PE), phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, cardiolipin, or combinations thereof.
10. A PALM-cargo composition according to claim 9, wherein one or more additional phospholipids comprise phosphatidylcholine.
11. A PALM-component according to claim 10, wherein the phosphatidylcholine is 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC).
12. A PALM-component composition according to claim 4, wherein the formulation is an anticancer drug.
13. A PALM-cargo composition according to claim 12, further comprising a contrast agent.
14. A PALM-component composition according to claim 13, wherein the contrast agent is selected from the group consisting of 1,2-dipalmitoyl- sn -glycero-3-phosphoethanolamine-N-diethylenetriaminepentaacetic acid (gadolinium salt) (PE-DTPA(Gd)), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-diethylenetriaminepentaacetic acid (manganese salt) (PE-DTPA(Mn)), and 111 In-DTPA-A.
15. A PALM-component according to claim 12, wherein the anticancer drug is miriplatin or fenretinide.
16. A PALM-component according to claim 12, wherein the anticancer drug is hydroxycamptothecin; daunorubicin; paclitaxel; or docetaxel.
17. A PALM-component according to claim 12, wherein R is a hydroxyl group and the anchor moiety is covalently bonded to the formulation by a carbonate ester bond; or R is an amine group and the anchor moiety is covalently bonded to the formulation by a carbamate ester bond.
18. A PALM-component of claim 12, wherein the anchor moiety is cholesterol; or the anchor moiety is δ-tocotrienol.
19. A PALM composition according to claim 12, wherein one or more additional phospholipids in the PALM are selected from the group consisting of phosphatidylcholine, polyethylene glycol-phosphatidylethanolamine (PEG-PE), phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidylinositol, cardiolipin, or combinations thereof.
20. A PALM-cargo composition according to claim 19, wherein one or more additional phospholipids comprise phosphatidylcholine.

Description

Formulation for improving the efficacy of hydrophobic drugs Cross-reference regarding related applications This PCT application claims the benefit of U.S. provisional application serial number 62/190,909, filed July 10, 2015. The entire contents of the disclosure thereof are incorporated by reference. Sequence list The present application was created on January 29, 2018, at 2:29 pm, with a size of 29 KB, and includes by reference the full text of the sequence listing titled "236603-397087_Corrected_Sequence_Listing_ST25.txt" submitted electronically herein. field The present invention relates to the transport and delivery of therapeutic molecules to their sites of action through parenteral administration. More specifically, the present invention relates to a formulation technology that enables the incorporation of a drug into nanoparticles that can be easily administered parenterally for the safe and effective delivery of the drug incorporated into their therapeutic target. Many systemic therapeutic substances are not suitable for the relative simplicity of oral administration and must instead be administered parenterally. However, the same factors that complicate oral administration often interfere with the parenteral administration process. These factors result in inadequate plasma concentrations and/or exposure times, including poor water solubility due to hydrophobicity or other properties, drug instability in the gastrointestinal tract, insufficient absorption, or enhanced clearance after absorption. Options for handling hydrophobic drugs requiring parenteral administration generally involve the addition of various excipients to obtain stable suspensions, dispersions, or solutions suitable for injection. The types of excipients used include detergents, various types of polymers, oil emulsions, phospholipids, and albumins. In many cases, the excipients used to achieve the necessary drug solubilization are detergent-like substances. These include deoxycholates; Cremophor EL®, a polyethylloxated derivative of castor oil; and polysorbate 80. The latter two are typically used in combination with ethanol. While these formulations address solubilization issues, they possess toxic properties that introduce a high risk of hypersensitivity reactions. It is a standard requirement for patients injected with solutions containing Cremophor EL® or polysorbate 80 to be treated with anti-inflammatory drugs to alleviate formulation-dependent inflammation. The most serious consequences of hypersensitivity reactions are reduced tolerance to treatment and an increased risk of death. Examples of approved drug formulations containing Cremophore EL® or polysorbate 80 for solubilization include the hydrophobic anticancer drugs paclitaxel (Taxol®), docetaxel (Taxotere®), cabazitaxel (Jevtana®), and ixabepilone (Ixempra®). The immunosuppressants cyclosporine (Sandimmune®), tacrolimus (Prograf®), and temsirolimus (Torisel®) also rely on these formulations. In the case of paclitaxel, some progress is being made through the use of Cremophore EL® as a dispersant (i.e., Abraxane®) and the substitution of albumin with ethanol. The antifungal agent amphotericin B also requires measures to obtain a significantly hydrophobic and stable infusion suspension. Other administration challenges faced by many drugs include inactivation and rapid clearance by metabolic pathways. For example, the anticancer agent gemcitabine must be infused at high doses that overwhelm its breakdown by cytidine deaminase to achieve therapeutic levels. An additional problem limiting drug administration is the unintended exposure of non-target tissues to the effects of these drugs. This is particularly important for cytotoxic anticancer drugs. Although there are many descriptions for finding superior parenteral formulations including emulsions, micelles, liposomal formulations, polymers, and solid-lipid nanoparticles, many efforts are hampered by problems of low capture efficiency, drug instability, load leakage, and poor storage stability. Some success has been achieved with liposomal formulations. Examples include liposomal cytarabine (DepoCyt®) to reduce clearance, liposomal doxorubicin (Doxil®, Myocet®) to reduce cardiotoxicity, and liposomal amphotericin-B (e.g., AmBisome®) to improve solubilization. Figures 1A and 1B are Edmundson Wheel plots of the peptides of sequence identification numbers 3 and 25, respectively, showing their amphiphilic forms. Figures 1A and 1B further show the axial positions of the constituent amino acids (identified by standard single-letter abbreviations) around the long axis of the alpha-helix. The letter "B" represents 2-amino-isobutyric acid. The dashed line indicates the approximate boundary between the hydrophilic amino acids (shaded) forming the polar side of the peptide and the hydrophobic amino acids forming the non-polar side. Figures 1C and 1D are helical net plots of the peptides of sequence identification numbers 3 and 25,