Bothell, WA, United States

Pharmain Corporation

www.pharmain.com
Bothell, WA, United States

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The present invention relates to a soluble hydrophobic-core carrier composition comprising (i) a linear polymeric backbone; (ii) a plurality of hydrophilic polymeric protective chains covalently linked and pendant to the polymeric backbone and (iii) at least one hydrophobic moiety covalently linked and pendant to the polymeric backbone. In certain embodiments, the weight ratio of hydrophilic protective chains to hydrophobic moieties in the carrier is at least 15:1. In other embodiments, at least 90% of the residues of the polymeric backbone are coupled to a hydrophilic polymeric protective chain or a hydrophobic moiety. In other embodiments, the composition further comprises (iv) a hydrophobic load molecule dissociably linked to the hydrophobic moiety of the carrier.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 600.00K | Year: 2012

DESCRIPTION (provided by applicant): Lyso, a metalloendopeptidase that is bacteriolytic for S. aureus, is a potential systemic therapy for treating methicillin-resistant S. aureus (MRSA) mediated infections including endocarditis, osteomyelitis, catheter related infections, and MRSA-mediated community acquired furunculosis and pneumonia. However, the short half-life of this enzyme in vivo has precluded its development thus far as a systemic therapy, despite positive clinical trial data. Our company, PharmaIN, has developed a nanocarrier, Protected Graft Copolymers (PGC), that can reversibly bind peptides and/or proteins (US patent #7,138,105) with measurable dissociation constant (Kd). Importantly, because of its size, PGC nanocarrier concentrates at sites of increased vascular permeability and thus can potentially concentrate lyso at the site of infection. Our goal is to develop a formulation of lyso to provide life-saving treatment against MRSA and to suppress the emergence of resistance. Our preliminary data demonstrates that PGC can reversibly associate with lyso, increase blood half-life 14-fold, and increase its in vivo efficacy against MRSA by 100-fold. We propose to prepare endotoxin- free lyso and create a master cell-line bank (E. coli expressing lyso) that will be used for: 1) this project to supply our lyso needs, and 2) as reference cells for the planned post-SBIR IND filing and clinical trial. We will also optimize the structure of PGC by synthesizing variations (at least 10) of the effectivePGC shown in the preliminary data with the intention to further extend the half-life to at least 30 fold. This is important before we put a lot of resource towards IND. To this end, we will continue the development of PGC-lyso formulation by doing bindingstudies of at least 10 new carrier variations. We will do PKs and biodistribution studies on at least 6 selected lyso formulations. We will determine and compare with commercially available antibiotics the effectiveness of our lyso formulation in vivo against MRSA. PharmaIN Corp. Confidential PUBLIC HEALTH RELEVANCE: We will develop a formulation of lysostaphin (lyso) to provide a life-saving treatment against MRSA and to suppress the emergence of resistance. To this end, we will optimize the structure of PGC to extend lyso blood residence time by 30 fold and effectiveness in vivo against MRSA by more than 100-fold. We also propose to prepare endotoxin-free lyso and create a master cell-line bank (E. coli expressing lyso) that will be used for:1) this project to supply our lyso needs, and 2) as reference cells for the planned post-SBIR IND filing and clinical trial. PharmaIN Corp. Confidential


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 372.13K | Year: 2012

DESCRIPTION (provided by applicant): Psoriasis is a chronic inflammatory skin disease that to this date is only insufficiently controlled by currently available treatments which can also come with severe, and sometimes life threatening side effects. In this application, we propose to create a new class of biologics drug for the treatment of this debilitating disease. We are proposing to formulate the immunomodulatory neuropeptide vasoactive intestinal peptide (VIP) into a long-acting formulation that will be tested as a drug candidate for the treatment of psoriasis. From preliminary experiments we know that our formulation can be injected subcutaneously (s.c.) which is of advantage for patients with severe disease, and we envision that it can be applied topically for less severe cases. During the Phase I of this project, we propose to synthesize a new batch of drug carrier that we used for the formulation of VIP in preliminary experiments. This formulation has increased in vivo half-life and provides better safety properties compared to unformulated VIP. In the proposed project, we will collect data about bioavailability of VIP after s.c. and topical administration, and, as VIP can decrease the arterial blood pressure, measure the blood pressure in the tail of VIP treated mice after topical administration. Blood pressure data already exists for s.c. administration of our VIP formulation. VIP has been shown to be efficacious in many animal models of chronic inflammatory conditions in which efficacy overlapswith efficacy for psoriasis; however, it has not been tested directly in models of psoriasis. We therefore also propose in this application to test efficacy of our long-acting VIP formulation after s.c. administration and topical application in a mouse model of psoriasis. If Phase I is successful, we are planning to conduct a formal toxicity study during Phase II, further develop the topical formulation and file a investigational new drug application with the FDA at the end of Phase II. PUBLIC HEALTH RELEVANCE: Psoriasis is a debilitating chronic inflammatory skin condition with an immense burden on the economy and, despite treatments advances, is still a largely unmet medical need. This proposal would create a new class of biologics drug that can be administered both by subcutaneous injection and for less severe cases by topical application that has the potential of changing the lives of the patients.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 225.00K | Year: 2014

DESCRIPTION (provided by applicant): Female sexual arousal disorder (FSAD), one of the conditions commonly described as Female sexual dysfunction (FSD) is common among older women and can be a significant reason for decreased quality of life in the aging population. FSAD is defined as the persistent or recurring inability to attain or maintain sufficient sexual excitement, causing personal distress. Disorders of arousal often include insufficient vaginal lubrication, decreased clitoral and labial sensation,decreased clitoral and labial engorgement and/or lack of vaginal smooth muscle relaxation. Often, physiological causes like previous pelvic trauma, pelvic surgery, decreased vaginal or clitoral blood flow (e.g. due to cardiovascular problems) or the sideeffects of certain medications, for example selective serotonin reuptake inhibitors, play an important role in the etiology of the condition. Vasoactive intestinal peptide s an important neurotransmitter in the female genitalia with smooth muscle rela


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 599.95K | Year: 2011

DESCRIPTION (provided by applicant): Despite the success of TNF-inhibitors and other new biological drugs for the treatment of autoimmune and other chronic inflammatory diseases, there are still many patients that respond poorly. Suppressing NF-kB induction as treatment of chronic inflammatory diseases with a primary Th1-type cytokine profile (like e.g. Rheumatoid Arthritis, Multiple sclerosis, Type 1 diabetes and others) is the goal of majority of treatments including TNF-inhibitors. Intracellularly-actingNF-kB activation-inhibitors, such as IkB-kinase inhibitor and NF-kB nuclear translocation inhibitor, are very effective in cultured cells. However, in vivo use of these agents against chronic inflammatory diseases is severely limited by their very short half-life in blood. Formulating these inhibitors into a nanocarrier can protect these inhibitors from enzyme degradation in the blood and rapid excretion by the kidney. In this application these two inhibitors will be formulated into nanocarriers. The nanocarriers are a Protected Graft Copolymer (PGC), in which a polymer backbone is grafted with: 1) polyethylene glycol (PEG) side chains, and 2) reversible binders of the peptide inhibitors. The inhibitors will bind to PGC and the PEG-side chains will protectthese inhibitors from enzyme degradation in the blood and rapid excretion by the kidney. Because of size (15-30nm), the complex will accumulate at site of inflammation and will release the inhibitors by an affinity based driven release, which is an equilibrium or dissociation constant (Kd) driven release. Because the inhibitors contain cell penetrating sequences, they will readily enter cells at site of inflammation, inhibit NF-kB activation, and thus suppress inflammatory diseases. Collagen induced arthritis, a mouse model of rheumatoid arthritis, will be treated in this particular application to show proof of concept. The acute and chronic toxicity of the formulations will also be evaluated in this proposed project. Our goal for this project is to developa product for the treatment for chronic inflammatory diseases that will lead to FDA approved treatment for humans. PUBLIC HEALTH RELEVANCE: Intracellularly-acting NF-kB activation inhibitors, such as IkB-kinase inhibitor and NF-kB nuclear translocation inhibitor, are very effective in cultured cells. However, in vivo use of these agents against chronic inflammatory diseases, although effective, is severely limited by their very short half-life in blood. In this project, these inhibitors will be formulated into nanocarriers that: 1) accumulates at sites of inflammation; 2) can protect these inhibitors from enzyme degradation in the blood; and 3) prevent rapid excretion by the kidney. The project will allow use of these agents in many human inflammatorydiseases.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 782.93K | Year: 2010

DESCRIPTION (provided by applicant): This application pertains to the development of Medication for Hepatic Fibrosis. Established cirrhosis has a 10-year mortality of 34-66%, largely dependent on the cause of the cirrhosis; alcoholic cirrhosis has a worse prognosis than primary biliary cirrhosis and cirrhosis due to hepatitis. This application will be of interest to National institute of Alcohol Abuse and Alcoholism. Cirrhosis is long-term liver damage from the buildup of scar tissue (fibrosis) caused by infections, alcohol, excess fat, bile obstruction, and iron or cupper overload. Approximately 400,000 Americans suffer from liver cirrhosis. Cirrhosis affects millions of patients worldwide and remains an unresolved challenge for clinicians. Given the morbidity/mortality associated with this disease, there is an urgent need for translation of emerging anti-fibrotic molecules into effective therapies. Expediting clinical trials for compounds that have successfully undergone preclinical studies has the potential to make much needed medications available and reduce the need for liver transplantations. The scarring process in liver cirrhosis is mediated by Transforming Growth Factor 2 (TGF2) which is the most powerful fibrotic agent. Many known blockers of TGF2 are mostly peptides and proteins which cannot be easily developed onto drugs due to rapid degradation and kidney elimination once it reaches the blood stream. In this application, we propose to formulate three known TGF2 blocker peptides using advanced affinity-based nanocarrier technology. This will prevent rapid degradation and elimination and will maintain relatively constant concentration of active anti-fibrotic peptides in the blood, thus facilitating the transition of these peptide drugs from pre-clinical to clinical setting. We will synthesize nanocarriers appropriate for each of the anti-fibrotic peptides and we will determine affinity (1/Kd, where Kd is the dissociation constant) of the peptide for these nanocarriers. We will then formulate these peptides with appropriate nanocarriers and evaluate the in vivo pharmacokinetics in rats. Finally we will test the efficacy of formulated peptides in animal models of liver fibrosis. PUBLIC HEALTH RELEVANCE: Cirrhosis affects millions of patients worldwide and remains an unresolved challenge for clinicians. Cirrhosis is mediated by Transforming Growth Factor 2 (TGF2) and many known blockers of TGF2 action are peptides and proteins which cannot be easily developed onto drugs due to their rapid degradation and kidney elimination once they reach the blood stream. In this application, we propose to formulate known peptide blockers of TGF2 using advanced affinity-based nanocarrier technology that will prevent their rapid degradation and elimination and will maintain relatively constant concentration of anti-fibrotic peptides in the blood. This will facilitate the transition of these possible peptide drugs from pre-clinical to clinical settings.


The present invention relates, in part, to a biocompatible hydrophobic-core carrier comprising a carrier, and a plurality of hydrophobic groups covalently linked to the polymeric carrier. The hydrophobic groups are capable of dissociably linking load molecules such as therapeutic agents. The hydrophobic-core carrier may also comprise protective side chains, orienting molecules, and targeting molecules.


Provided herein is a process of preparing a semi-random graft co-polymer, the product of which is difficult to fully characterize chemically. The product of the present disclosure has unique and useful properties of 1) binding to a peptide and 2) upon co-administration of the product and the peptide into animals the product prolongs the blood circulation time and elevates the level of the peptide, compared to the peptide alone without the product of the disclosure.


Patent
Pharmain Corporation | Date: 2015-06-15

The invention describes compositions of peptide analogs that are active in blood or cleavable in blood to release an active peptide. The peptide analogs have a general formula: A-(Cm)_(x)-Peptide (SEQ ID NO: 76), wherein A is hydrophobic moiety or a metal binding moiety, e.g., a chemical group or moiety containing 1) an alkyl group having 6 to 36 carbon units, 2) a nitrilotriacetic acid group, 3) an imidiodacetic acid group, or 4) a moiety of formula (Z_(y)His_(w))_(p )(SEQ ID NO: 50), wherein Z is any amino acid residue other than histidine, His is histidine, y is an integer from 0-6; w is an integer from 1-6; and p is an integer from 1-6; wherein if A has alkyl group with 6 to 36 carbon units x is greater than 0; and Cm is a cleavable moiety consisting of glycine or alanine or lysine or arginine or N-Arginine or N-lysine, wherein x is an integer between 0-6 and N may be any amino acid or none. The peptide analogs are complexed with polymeric carrier to provide enhanced half-life.


Patent
Pharmain Corporation | Date: 2011-04-27

The invention describes compositions of peptide analogs that are active in blood or cleavable in blood to release an active peptide. The peptide analogs have a general formula: A-(Cm)_(x)-Peptide (SEQ ID NO: 76), wherein A is hydrophobic moiety or a metal binding moiety, e.g., a chemical group or moiety containing 1) an alkyl group having 6 to 36 carbon units, 2) a nitrilotriacetic acid group, 3) an imidodiacetic acid group, or 4) a moiety of formula (Z_(y)His_(w))_(p )(SEQ ID NO: 50), wherein Z is any amino acid residue other than histidine, His is histidine, y is an integer from 0-6; w is an integer from 1-6; and p is an integer from 1-6; wherein if A has alkyl group with 6 to 36 carbon units x is greater than 0; and Cm is a cleavable moiety consisting of glycine or alanine or lysine or arginine or N-Arginine or N-lysine, wherein x is an integer between 0-6 and N may be any amino acid or none. The peptide analogs are complexed with polymeric carrier to provide enhanced half-life.

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