Solubility improvement


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In the continuing search for effective treatments for cancer, an emerging paradigm is the use of nanotechnology to uncap the full potential of existing chemotherapy agents . Integral physicochemical properties of nanovectors can be modulated to improve the antitumor efficacy of chemotherapeutic agents . For example, the shape and size of nanostructures can play a deterministic role in the biological outcome . Similarly, surface modifications to increase hydrophilicity can mask from the reticuloendothelial system, thereby increasing circulation time and altering the pharmacokinetics of the active agents . Such formulation accumulate preferentially in the tumors due to the unique leaky tumor vasculature coupled with impaired intratumoral lymphatic drainage, which contributes to an enhanced permeation and retention (EPR) effect . Indeed, these formulations were shown to deliver between 5–11× more to Kaposi sarcoma lesions than to normal skin . Similarly, the tumor paclitaxel concentration-time area under the curve was found to be 33% higher when administered as a nano-paclitaxel nanoparticle, and is currently approved for use in metastatic breast cancer .

We even took to next level to have nanomedicine engineered with two active molecules, hence making it much more effective than nano-paclitaxel alone. HYBRID-NANOENGINEERING™ IS A NEXT GENERATION OF NANOMEDICINE.

Cancer therapy using cytotoxic drugs has negative side effects on normal cells. To date, the pharmaceutical industry has not been able to produce a drug that can provide the dual functions of protecting normal cells while sensitizing tumor cells to cancer therapy using two or more drugs in one formulation and that too nanomedicine. With the discovery of HYBRID-NANOENGINEERING™, we have discovered a new and better treatment for cancer therapy problem.
Our team is strong and experienced, and all have more than 15 yr industry experience. Our Scientific Advisory Board is composed of experts with a variety of expertise related to drug discovery and drug development.

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Solubility improvement

  1. 1. MewTaxel Next Generation nanomedicine Hybrid-Nanoengineering™ MewTaxel LLc. 4000 McHugh Rd. Zachary,LA70791 Think big and different, start small, and fail fast and often to succeed for sure-----MewTaxel is the outcome of that!
  2. 2. Ongoing path to success • 1st year Preclinical IND 26 weeks 2nd Year Safety study in dogs 3rd Year license out to vet market 4th & 5th Year Phase-l and Phase-ll EXIT Efficacy in canine $25M 8-15% Rl $3M
  3. 3. Problem • Currently, about 30% of drugs that appear on the World Health Organization (WHO) Essential Drug List were reported to be poorly water-soluble, based on the Biopharmaceutics Classification System (BCS) . • Over 40% of newly developed pharmaceutically active substances have solubility issues. • The poor dissolution and/or permeability of these drugs often result in low and highly variable bioavailability. • The major obstacle of successfully commercializing these compounds is the difficulty of enhancing their dissolution rate and extent of dissolution
  4. 4. More Specific Problems • In a word: bioavailability. As much as $40 billion is invested annually in drug discovery. Unfortunately, many of the drug leads that result exhibit poor water solubility and an inability to deliver therapeutic agents in vivo. In fact, it's estimated that 40-50 percent of these new chemical entities are poorly water soluble. (which leads to a number of otherwise promising technologies to be abandoned) • Despite the solubility issue, worldwide sales of poorly soluble drugs are about $108 billion and it is going to increase further. It is reasonably expected that improving water solubility would only increase this number. • The result is inefficiency in the R&D process. Due to the challenges of evaluating efficacy in biologic models for a poorly bio-available compound, these compounds are often shelved with no further development activity—even if they show promising therapeutic activity in cell culture. • Meda’s hybrid formulation technology addresses this problem by improving water solubility, bioavailability, effectiveness and efficiency. • Poor water solubility for many drugs and drug candidates remains a major obstacle to their development and clinical application. Conventional formulations to improve solubility suffer from low bioavailability and poor pharmacokinetics, with some carriers rendering systemic toxicities (e.g. Cremophor1 EL).
  5. 5. Available Solutions & Limitations Here are some basic pluses and minuses of the different options. • pH adjustment is the best option if you can get decent solubility and good stability within a reasonable pH range. Although you have probably heard pH 4 – pH 10 batted around, there is really no fixed range of acceptable pH. It depends on rate, duration, and route (small vein versus large vein) of administration and on the buffer capacity of the formulation. • Cyclodextrins are the next best option in terms of safety and ease of preparation, but until someone forks out the cash for a good enough lawyer to challenge the very questionable Jannsen/J&J patent on hydroxypropyl-beta-cyclodextrin, there will be licensing arrangements and royalties involved. Nephrotoxicity is the primary physiological issue associated with cyclodextrins, but as long as you don’t give too much too fast, you should be okay. • Co-solvent formulations typically require very high concentrations of co-solvents, and these formulations are not dilutable without precipitation. Because of their high osmolality, these formulations must be administered through a large vein, where there is good blood flow. • Micellar formulations are easy to prepare but have a major liability, which is that they tend to cause the occasional patient to go into anaphylaxis. In many cases a drug can be dissolved in a mixture of a solvent and a surfactant such as Cremophor or Polysorbate to provide a dilute-for-use formulation. Generally patients will need to be pre-dosed with steroids and antihistamines so that the drug product doesn’t accidentally kill them. • Emulsions and liposomes have generally low toxicity profiles but are a pain to make. Liposomes tend to have a lot of physical stability issues and are typically lyophilized. However, this is good and bad since, unlike emulsions, they can be lyophilized quite easily. The one caveat to the good safety profile of these formulations is that they can cause hyperlipidemia and liver enzyme elevation if too much is administered too fast. • Analytical Methods The main analytical consideration specific to poorly soluble drugs is being sure that the sample preparation solvent will fully dissolve the drug without, of course, messing up the chromatography. Another consideration is that in doing particulates testing (USP<788>) you will be looking not only for foreign particles but for precipitated drug as well. The microscopic method of USP<788> is helpful in determining the difference between the two. • Preclinical Testing You need to be wary of the effects the formulation can have on different species of animals in selecting toxicology species. For example, dogs are particularly susceptible to surfactant-induced anaphylaxis and cannot be used for evaluation of micellar formulations.
  6. 6. What We Offer • New concept and new approach • There have never been used two active molecule in nanomedicine • There have never been developed a hybrid nanomedicine • There have never been used an active molecule to developed a water soluble drug formulation • Two water insoluble drugs have never been used to developed a water soluble formulation, at least without changing the chemistry • Chemistry of individual drugs remains unchanged • IT IS NOT JUST SOLUBILITY BUT A BETTER TREATMENT
  7. 7. Success: Technology Parallel in Humans • Hybrid-Nanoengineering™ • Like Abraxane approved for human • Doxil • In process to raise $25-26M for human trials
  8. 8. Hybrid-Nanoengineering™ Technology Advantages • New discovery and patented • Synergistic effects • Potentiating effects • Passive targeted nanomedicine • Less toxic • Low manufacturing cost • Multiple mode of action A major driving force in the hybrid drug development community is to overcome one of the worst things that can happen to a drug: the development of resistance in its target population. In most such hybrids, the two drug like portions, also called pharmacophores, have independent modes of action that make the emergence of drug resistance less likely.
  9. 9. Technology
  10. 10. Mode of action Mewtaxel A better approach
  11. 11. Mode of action
  12. 12. Next Steps • cGMP manufacturing and pre clinical • Determine maximum tolerated dose, safety and therapeutic efficacy • Evaluate efficacy in canine indications • Perform a Phase I clinical trial in companion dogs presenting with …….. • Human clinical • Approvals
  13. 13. Road Map To Clinical, Funding And Exit MewTaxel (Hybrid-Paclitaxel) 2013 2014 2015 2016 2017 Clinical Financial Seed Round $1M $5M $5-7M $10-12M Final Pre-Clinical A Round File IND Phase-I B Round Phase-II C Round Exit or Move to NDA. At this point we have multiple options for FundingProject has a potential of $500M if Exit after NDA
  14. 14. • PROOF OF CONCEPT ------ESTABLISHED • R & D----------------------------ESTABLISHED • PILOT SCALE MANUFACTURING ---ESTABLISHED • IN-VITRO STUDY---PRELIMINARY TESTING ESTABLISHED • Pre clinical-------------- • Phase-l • Phase-ll MewTaxel
  15. 15. Why Paclitaxel? • There are 1989 ongoing clinical trials associated with Paclitaxel in various combinations and formulation compositions. Among them 83 are with nanoparticles. This reflect a further growth of the product.
  16. 16. Team • Dr.Mewa Singh- 15 years of drug discovery • Dr.Timothy A,M.D-20 years drug development • Dr.Khushi Matta- 40 years of cancer research
  17. 17. Contact Information Mewa Singh PhD 609-902-7128
  18. 18. Technology • The technology comes under nanotechnology : Nanotechnology is science, engineering, and technology conducted at the nanoscale, which is about 1 to 100 nanometers. 1- 1000000000 Nano Nanotechnology
  19. 19. Why nanotechnology ? • To increase the surface area to come in contact with target, more means efficacy, penetration and concentration
  20. 20. Why Nanotechnology Drug crystals Toxic Hybrid-Nanoengineering™ Double edge
  21. 21. Passive Targeting Enhanced Permeability and Retention (EPR) Effect Passive Targeting Less hindrance more concentrationHybrid-Nanoengineering™ Double edge
  22. 22. Overview of available Nanotechnology 1. Nephrotoxicity is the primary physiological issue associated with cyclodextrins. 2. Does not work with every drug like that.
  23. 23. Overview of available Nanotechnology • Micellar formulations 1. Generally patients will need to be pre-dosed with steroids and antihistamines 2. Toxic Detergent. oil etc.
  24. 24. Overview of available Nanotechnology • Emulsions and liposomes 1. cause hyperlipidemia and liver enzyme elevation 2. Expensive manufacturing 3. Tailored for individual molecule
  25. 25. Why after Abraxane is success? • The data from the study, presented at ASCO by lead investigator Hope Rugo at the University of California, San Francisco, stated that median progression- free survival was 10.6 months for those receiving paclitaxel, 9.2 months for nab- paclitaxel, and 7.6 months for ixabepilone.
  26. 26. Vision…Strategy……Approach • Hypothesis and Vision: I was looking to take nanotechnology to next level by; a) Hybrid in nature to achieve better potency b) Different material to create nanomedicine c) Less expensive to manufacture d) To beat the state being in use but a rose is a rose and is still a rose almost 400 years after Shakespeare’s death. Basically, there are still only a small handful of ways of solubilizing a drug and still not killing the patient. These include pH adjustment, co-solvents, molecular complexation agents (cyclodextrins), micellar dispersions, emulsions, liposomes, but really not anything else. If anyone knows a truly different method not listed above, please let me know. We have beaten this statement by our invention.
  27. 27. Discovery • Discovered a universal molecule to be used for nanomedicine development. • The molecule is a drug in nature. • The molecule has a capability to treat cancer • The molecule has never been used to create nano particles. • Beat me-to concept • Many more properties…….
  28. 28. Paclitaxel in its native Crystals
  29. 29. Paclitaxel Molecule
  30. 30. Hybridization under control conditions A powerful formulation to treat cancer
  31. 31. Paclitaxel To MewTaxel Under microscope
  32. 32. Zeta Potential Of Hybrid Paclitaxel in serum No aggregation
  33. 33. Specific Application for Paclitaxel • Why it is better than other available Nano formulations specially Abraxane; • It is less expensive to manufacture • It is attacking the disease by multiple mode of action • It gave more life to branded
  34. 34. Hybrid-Nanoengineering™(MewTaxel) x Proprietary Docetaxe l IL-6 TNF P13 EGRF Efflux Pump The COX-2 produced by a malignant tumor and COX-2 produced by the surrounding host tissue both contribute to new vessel formation, which explains how selective COX-2 inhibition reduces tumor growth where the tumor COX-2 gene has been silenced by methylation