Page 1 of 7 LICENSING OPPORTUNITY PROPYLENE GLYCOL FREE MINOXIDIL TOPICAL FORMULATION FOR HAIR LOSS BASED ON PATENTED TECHNOLOGY NO PROPYLENE GLYCOL NO SCALP IRRITATION, NO GREASY HAIR BIOEQUIVALENT ABSORPTION TRHOUGH THE SKIN COMPARED TO REFERENCE PRODUCTS NO RESIDUAL CRYSTALLINE PRECIPITATE IN SCALP EASY AND COST-EFFECTIVE PRODUCTION AT A COMMERCIAL SCALE INTELLECTUAL PROPERTY RIGHTS UNTIL 2031 THE COMPANY Bionanoplus was founded in 2011 and combines the enthusiasm of a young company with more than 10 years of experience in the nanotechnology and drug delivery fields in academic institutions. Bionanoplus was born in the spirit of avoiding nanoparticles industrial scale-up issues that are decisive factors in many project failures. For this reason, we developed several technology platforms that allow the manufacturing of stable and homogeneous nanoparticles without the use of volatile organic solvents or special equipment, thus ensuring a cost-effectiveness and adequate scalability from lab to final production. In addition, all the materials used in the manufacturing of our nanoparticles compile with the regulatory requirements and are present as common excipients in many pharmaceuticals. The staff of Bionanoplus is formed by 8 people with extensive experience in scientific innovation and intellectual property management. Backing us up are more than 50 research articles in peer-reviewed journals and 6 patents. At the beginning of 2013, Bionanoplus was certified as compliant with the principles of Good Laboratory Practices (GLPs), a new step on the road to excellence on which we are embarked.
Page 2 of 7 MINOXIDIL & HAIR LOSS BACKGROUND Minoxidil is the only topical medication approved by the international regulatory agencies for the treatment of hair loss since the early 1990's. Minoxidil is available in both 2% and 5% concentrations and has clinically proven to slow the progression of hair loss and regrow hair after topical application. It is recommended that males use minoxidil 5% whilst females use minoxidil 2%. The most common side effect of minoxidil hair loss treatment is the scalp irritation and redness. All current minoxidil commercial formulations are made with alcohol-based agents as a media to maintain a stable composition, being propylene glycol the basic ingredient of these formulations. Propylene glycol is the main cause for scalp irritation and redness. In addition, minoxidil hair loss treatment side effects also include having greasy hair that may also be sticky and are hard to manage. Propylene glycol is also the reason for this wet appearance and oily and sticky to the touch. Minoxidil needs to be applied twice daily and must be used indefinitely for continued support of existing hair follicles and the maintenance of any experienced hair regrowth. Thus, for successful long-term use it is important to avoid uncomfortable side effects and allow a pleasant use on the cosmetic level. PRODUCT DESCRIPTION Bionanoplus propylene glycol free minoxidil formulation is a hydroalcoholic solution with low viscosity suitable for topical use in which all the excipients are approved by the international regulatory agencies for human topical use. The exact composition of the formulation is showed in the table below. % Minoxidil (w/v) % Gantrez ES (w/v) % Ethanol (v/v) % Carrier (v/v)* % Water (v/v) 2 or 5 0.75-1 50-60 10-25 Q.S.100 *Information available under a confidential disclosure agreement.
Page 3 of 7 The formulation can be easily and cost-effective produced at a commercial scale with standard processes of solution preparation. Bionanoplus has scale-up the process from 250 ml to 2 L without any significant technical issue. BIONANOPLUS MINOXIDIL FORMULATION IS PROPYLENE GLYCOL FREE AND STABLE AT ROOM TEMPERATURE Bionanoplus minoxidil formulation does not contain any propylene glycol and is stable for at least one year at room temperature in transparent glass vials. Initial Point 6 Months 12 Months Minoxidil Content (% by HPLC) Macroscopical characteristics* 5.1 ±0.1 4.9 ±0.2 4.9 ±0.1 Transp. No pp. CL Transp. No pp. SYC Transp. No pp. SYC * Transp= Transparent; No pp = No precipitation; CL= colorless; SYC= Slight yellow color. This propylene glycol free minoxidil formulation doesn t produce any scalp irritation and is significantly less oily and sticky than current commercial formulations. Therefore, Bionanoplus formulation presents both, a safety profile and cosmetic level which constitutes an unquestionable advantage for the patient using long-term treatment. NO RESIDUAL CRYSTALLINE PRECIPITATE POST SOLVENT EVAPORATION COMPARED TO COMMERCIAL PRODUCTS Minoxidil is somewhat soluble in both propylene glycol and alcohol, but nearly insoluble in water. Commercial formulations are supersaturated propylene glycol/minoxidil solutions that even tend to precipitate out some of the minoxidil at room temperature. Propylene glycol of commercial products evaporates after application and minoxidil precipitates on the scalp producing an unaesthetic dandruff effect and enhancing
Page 4 of 7 irritation. In contrast, Bionanoplus formulation doesn t precipitate in a crystalline form after application and evaporation of the solvent. Figure 1: Comparison of crystalline precipitation of minoxidil in pork skin post solvent evaporation between Bionanoplus formulation and commercial products. A) Observation of minoxidil 5% formulations by optical microscopy. B) Observation of minoxidil 2% formulations by scanning electron microscopy. SYSTEMIC EXPOSURE OF MINOXIDIL AFTER TOPICAL ADMINISTRATION IS NOT HIGHER THAN COMMERCIAL PRODUCTS THEREFORE NO SYSTEMIC EFFECTS ARE EXPECTED In the 1970s Minoxidil was a drug used to treat hypertension, classified as a potassium channel opener with effects on expansion of peripheral vascular. For this reason, another minoxidil topical administration treatment side effect is changes in the blood pressure and, consequently, minoxidil absorption into the blood after topical administration must be as low as possible. Despite its higher skin residence time, Bionanoplus minoxidil absorption into the blood after its topical administration is
Page 5 of 7 bioequivalent to commercial products and, in consequence, shows a consistent safety profile. Figure 2: Comparison of minoxidil absorption into the blood over 24 hours. Penetration of minoxidil through the epidermis was evaluated in Franz diffusion cells using fresh pork ear skin. The absorption grade was evaluated measuring minoxidil levels in the receptor compartment (similar to blood) over a 24 hours period. LACOVIN (Galderma) is a standard formulation of minoxidil with propylene glycol. ALOPEXY (Pierre Fabre) is a formulation with gamma-cyclodextrin which enhances the solubility of minoxidil in water and decreases the requirement for propylene glycol. REGULATORY AFFAIRS The legal basis for submission of a marketing-authorization of the Bionanoplus minoxidil formulation is the approved reference listed drugs which contains minoxidil for topic use. Bionanoplus minoxidil formulation is a hydroalcoholic solution for topical application with non-active ingredients that differ from the reference listed drug product, thus the regulation specifies that this difference must be characterized and it has to be provided
Page 6 of 7 information demonstrating that do not affect the safety or efficacy of the proposed drug product. According to the different international regulatory agencies, there are two options to provide this information: 1. Results from an in vivo bioequivalence study. 2. A waiver of the in vivo bioequivalence study supported with expert justifications and/or data from in vitro assays. Bionanoplus believes that it is not necessary to obtain clinical data and that the second option would be easier and faster because: 1. The formulation has the same active ingredient in the same concentration and dosage form as the reference listed drug product. 2. There is a considerable knowledge about the efficacy and safety of the active substance collected during more than thirty years of topic use for the treatment of hair loss. 3. All the non-active ingredients are approved by the international regulatory agencies for human topical use and are currently present as common excipients in many pharmaceuticals. 4. Minoxidil is a locally acting product that exerts its effect at the site of application. As in this case, a change in non-active ingredients may influence the safety of the product modifying the penetration of the active, thus this effect needs to be carefully investigated. For locally acting well-known active substances as minoxidil, the international regulatory agencies do not consider necessary full toxicological and clinical data if it is not expected that the amount of active ingredient reaching the systemic circulation is higher than for the original product. An in vitro assay in Franz diffusion cells has shown that Bionanoplus minoxidil absorption into the blood after its topical administration is bioequivalent to the reference listed drug product and, therefore, it is not necessary to obtain clinical data. In any case, before submission of a marketing-authorization, it is recommended to request scientific advice from the corresponding regulatory agency.
Page 7 of 7 INTELLECTUAL PROPERTY STATUS AND PARTNERSHIP CONDICTIONS Bionanoplus holds the intellectual property rights of this propylene glycol free Minoxidil topical formulation worldwide in the patent PCT/EP2012/056900 (priority date 15/04/2011). The second written opinion of the International Preliminary Examining Authority (April 2013) has established novelty, inventive step and industrial applicability in all the key claims. Bionanoplus seeks to license the further development and commercialization of its minoxidil formulation for hair lost treatment. The ideal partner would be: A company with a strong therapeutic focus in the dermatology market. Willing to commit investment to develop the product worldwide. Marketing experience with capacity to put on the market place the product directly or through alliances. Bionanoplus is open to different format of partnering modalities including: Worldwide exclusive licensing. Country based exclusive licensing. Opt-in rights + research fee. CONTACT DETAILS Hesham Salman CEO hsalman@bionanoplus.com Ricardo Palacios Business Development Manager rpalacios@bionanoplus.com