A NEW GENERATION OF CLEANING, PROTECTIVE, & PROTEASE INHIBITOR MEDICAL DEVICES (MDs) FOR THE TREATMENT OF TOPICAL SKIN & ENT PATHOLOGIES
Registered as Medical Device (2017 – LNE Gmed France)
Skin & mucosal pathologies, such as sore throat, rhinosinusitis, allergic rhinitis, piles/hemorrhoids, bacterial vaginosis, chronic diabetic wounds & ulcers, oral mucositis, labial herpes, & related diseases, are very common and represent nearly 80% sales of OTC drugs in the world. Each one of these pathologies generates sales above US$10 billion /year.
Common physiopathological features
These pathologies start as an initial injury (wounds, piles), infection (viral or bacterial), or reaction to allergen(s) (allergy) which usually goes undetected.
The initial damage triggers a multitude of physiological & immunological changes at the site of insult to heal the injury and to defend the body against the invader(s). But during this lead period, minor cellular destruction already starts creating an ideal environment for secondary bacterial infection. The immune system recognizes damaged cells, pathogens, or invaders, and secretes inflammatory proteins (cytokines) to trigger inflammation with the purpose of creating vasodilation and increase circulation to help the healing process. However, this also causes pain, redness, heat, swelling (oedema), & loss of function. Clinical symptoms are indeed mostly due to secondary bacterial infection & inflammation. Inflammation stops if the injury is healed but if the invader is not neutralized (ex. virus growth is not stopped, allergen exposure is not blocked, new cell growth has not filled the wound cavity, hemorrhoidal lesion has not regressed), inflammation becomes chronic, leading to marked increase in the concentration of inflammatory proteins, extended tissue destruction & production of proteolytic enzymes (proteins), which further increases bacterial growth, resulting in the lesion becoming chronic. The physiopathology of key diseases can be summarized as follows:
|Sore throat & infection,
Dry & Wet Coughs,
|Virus (influenza, Rhino & Herpes viruses)||Initial tissue damage, liberation of huge amount of virus particles on the surface of the lesion, extensive virus attack from outside & further tissue damage||Bacterial infection & deposits on the lesion surface (throat surface, herpes lesion or genital mucosa)||Real cause of symptoms: due to inflammation: pain & tissue damage||-Viral glycoproteins (GPs : ex. H1N1), leukoproteases
-Inflammatory cytokines TNF-α, IL-1β, IL-6 and IL-4
|-Further virus attachment, extensive bacterial growth, tissue damage.
-Inflammation, pain & chronic infection.
(Rhinovirus -particularly in children – & influenza in adults)
|Rhinitis, nasal drip, nasal congestion||Bacterial infection of URT & entry into sinuses||Sinusitis, sinus blockage, severe pain, chronic disease||-Viral glycoproteins
-Inflammatory cytokines TNF-α, IL-1β, IL-4, IL-5, IL-6
|Persistent infection, sinus pain, inflammation, chronic sinusitis|
|Bedsore, diabetic & venous leg ulcers & other injuries||Initial tissue damage||Development of small lesion, pain, inflammation||Bacterial growth, further tissue damage,||Dev. of chronic wound, pain, dryness||MMP 1, 3, 8, 9, 12 + others
|Destruction of ECM, no cell growth, no healing even after many months/yrs|
|Allergic rhinitis, atopic dermatitis||Immunological –
|Triggers allergic reaction, nasal / eye irritation, itching, pain, sneezing||Release of inflammatory proteins||Inflammation, nasal block, nasal drip||Histamine, IgE antibodies||Immune memory, inflammation, pain, severe allergy|
|Hemorrhoids||Vascular damage||Dev. of small haemorrhoid (initially)||Oedema, lesion protrusion,||Lesions can’t retract, grow in size, become chronic||Surface Inflammatory proteins||Chronic inflammation, pain|
What is common to all those diseases? 1.The causative organisms are present topically (on the surface); 2. They involve multiple proteins 3. They have no curative treatments.
Why is there no effective treatment? This is related to the fact that: (1) Multiple protein inhibiting treatments are not yet discovered! All available treatments are mono-target but these diseases are multifactorial; (2) Many treatments are chemicals: If applied topically, they exert cytotoxic effects; When administered systemically, they induce multiple side effects; (3) Causative agents are different: viruses, bacteria, allergens, and (4) are present on the surface where systemic treatments cannot act;(5) The disease physiopathology begins rapidly (within a few days & even a few minutes in case of topical allergic reaction) but treatments take time to act, and consequently (6) disease chronicity sets in rapidly too, with overproduction of various PROTEINS such as virus glycoproteins, inflammatory proteins, wound matrix-damaging proteins (ex. Matrix Metalloproteinases – MMPs), histamine, IgE antibodies… – BUT: there are no multiple-protein inhibitor drugs available!…
- The primary cause: If the primary cause is not blocked instantly, disease progression cannot be stopped. The infection continues spreading, destroying cells, offering shelter & food to bacteria, and subsequently impeding the healing process.
Currently there are no topical antiviral, anti-injury, or anti-allergen drugs available. Antiviral medications like Tamiflu & Neuraminidase inhibitors act intracellularly, not topically, whereas the virus is present topically.
- The secondary cause: Microbial growth is the major cause of symptoms. If bacterial infection is not stopped, the disease continues progressing. If only antiseptics or antibiotics are used, damaged tissue will not heal due to the presence of chemicals, virus will continue growing, and they will not affect inflammatory or viral proteins, MMPs, histamine, or IgE.
Multiple antibacterial products are used, usually chemicals, along with anaesthetics to stop the pain. Currently, there are no topical anti-oedematous drugs to treat hemorrhoids, nor anything to block inflammation, or immune cell reaction on allergic surfaces.
- Only “undesired proteins” because some proteins are essential for healing & cell growth.
Multiple proteins are involved in each pathology but not all are identified yet, and no multi-protein inhibitor drug or mechanism has yet been discovered. A chemical or biological drug can hardly block one protein and associating many molecules into one drug may take >15 years of R&D and > US$ 1.5 billion investment.
An ideal treatment should therefore stop the primary cause of the disease + remove bacterial infection + block selectively the disease related & inflammatory “bad” proteins. In addition, the treatment should not be irritant, should act only topically without entering the body & without inducing any side effects, should keep the lesion/biological surface hydrated, should protect the lesion / organ if necessary, and should be absolutely cell-friendly.
Currently available multi-protein inhibitor drugs: Currently there is no multi-protein inhibiting drugs.
After Natural – Chemical & – Biological dugs, multiple protease inhibitors may represent the drugs of the future.
Current research targets:
The current dream of pharmaceutical industries is to find a single, patentable, multiple-protein inhibitor drug to propose an effective treatment for topical diseases. Unfortunately, this objective looks unachievable in the next 30-50 years because it’s not easy to find a single patentable molecule with multiple activities. No pharma company wants to spend billions of $ & wait 15-20 years for uncertain research outcome in an unknown field! Shareholders approve this strategy too.
VITROBIO France Research program
VITROBIO research was started in 1994 and was based on one simple observation: multiple proteins constitute our skin, and tannins (natural polymers) are used to block skin proteins to convert skin into leather. This skin protein–tannin binding is so strong that one can convert skin into leather but not leather back into skin. Tannin–protein binding is highly specific as only a particular association of multiple tannins or polymers is used for tanning (red wine, for ex., although rich in tannins, cannot tan the skin).
“There was some hope of blocking multiple proteins simultaneously” as virus glycoproteins (GPs), growth factors, Matrix Metalloproteinases (MMPs), histamine, IgE, & inflammatory cytokines – all are proteins.
Therefore, we thought that appropriately selected tannins or polymers could be used to block these specific proteins. Moreover, polymers are very big molecules, they are totally inert, non-toxic, they do not interact with or enter into the cells, but they have a strong affinity for certain macromolecules & proteins. Our aim was to conceive a film which can clean & protect the lesion on one hand, and on the other hand, could bind & neutralize target protein molecules.
Product R&D was conducted in 5 phases:
- Phase 1: Finding a non-irritant, non-chemical, cell-friendly, osmotically adjustable protective film for topical application.
- Phase 2: Rendering this film resistant, flexible & long-lasting to minimize applications to 3-4 /day.
- Phase 3: Identifying key proteins involved in each pathology.
- Phase 4: Introducing minimum number of inert polymers capable of binding with filmogen macromolecules on one hand, and blocking target protein molecules, on the other hand.
- Phase 5: Proving the claims, verifying clinical efficacy & safety, filing patents & registering the products as Medical Devices.
Methodology & results:
(1) Conceiving a topically applicable protective film: Multiple natural, food grade, non-irritant ingredients were tested in different concentrations to conceive a thin or thick liquid film, depending on the mode of application envisaged. We conceived & patented a glycerol-based solution termed VB-Gy (Int. PCT/FR99/01340), 18 times more osmotic than sea water (3.2% NaCl). Applying a hyper-osmotic film on a live biological membrane generates an outward osmotic liquid flow, a mechanical way of cleaning infected surfaces. The physical properties of the protective film and its osmotic activity were adjusted as per the therapeutic aim. For example, stronger osmotic activity is desired to detach bacteria from a highly infected surface such as the throat mucosa or to break open sinus-blocking biofilms, but a thicker and allergen-absorbing film is required to stop allergen contact with the nasal mucosa.
(2) Rendering the film flexible & resistant to mechanical pressures: To improve the duration of retention of such films on live biological membranes and to minimize the frequency of applications, we used polymer – macromolecule binding technology as some specific polymeric structures may bind with certain macromolecules (technique used to introduce flexibility in plastic films) and/or proteins. We selected > 182 synthetic or natural polymeric molecules (ex. plant tannins), using different extraction techniques, and evaluated their properties to bind with the molecules of the protective film. 32 inert, non-cytotoxic polymers rendered the film flexible & resistant to mechanical pressure while conserving its non-irritant, cell-friendly, and topically applicable properties. The film is formed instantly, can remain on the affected surface for 4-6h, conserve its osmotic properties, and protect the lesion/biological surface like a bandage during this period. The filmogen bandage was patented worldwide (PCT/EP2013/061835).
(3) Identification of proteins in each pathology: This work was conducted by establishing specific in vitro models for each pathology. For ex. to identify the role of 27 known wound matrix-destroying MMP proteins, an ECM specific to each cell type was prepared and cells were grown on the surface of ECM in the presence of different concentrations of each MMP vs control with no MMP. ECM-destroying MMPs (8/27) were then incubated with individual polymers to the select best polymeric association capable of neutralizing mainly these proteins.
(4) Introducing specific anti-protein properties in the film: According to each pathology, the proteins involved in viral infection (ex. viral glycoproteins), in blocking cell growth by destroying ECM (ex. MMPs in wound cavity), in secondary infection (ex. bacterial fibronectin), in acute & chronic inflammation (ex. TNF- alpha, Il-Interleukins), in uncontrolled cell growth typical of psoriasis & dermatitis (EGF, FGF), or in allergy (ex. histamine, IgE), were identified using in vitro technology. Proteins to be blocked were defined. Polymeric extracts of natural or synthetic sources were prepared in diverse ways and their specific binding properties for the group of proteins involved in a given pathology were evaluated. The protein – polymer binding depends on: (1) the affinity of the polymer for the protein; (2) the structures of proteins & tannins; (3) the length & molecular weight of polymers; (4) the isoelectric point of the protein to be neutralized; (5) the pH of the product; and (6) the tannin – protein molecular ratio.
Diverse natural polymers were prepared at the University of Lisbon (Portugal); cytokine & MMP inhibition studies were performed at InflamLab, University of Toulouse (France); in vitro experiments were conducted at VITROBIO; and clinical efficacy was evaluated at different Clinical R&D organizations in France, India & Spain.
Results show that: (1) Not all polymers bind with proteins, and (2) Polymer binding is highly specific. Therefore, polymer compositions were prepared according to their binding properties both with the filmogen ingredients and with the target proteins. These polymers were then incorporated in the filmogen solution.
Mode of action & advantages compared to existing drugs: (1) A new generation of 1st multitarget drugs for topical pathologies; (2) possibilities to incorporate simultaneous protective, cleaning, anti-microbial, anti-viral, anti-inflammatory & specific protease inhibitor properties into one product; (3) Filmogen bandage protects the injured surface from infection, allergens & external aggressions; (4) Osmotic activity attracts hypotonic liquid from the damaged surface, creating a strong hypotonic liquid outflow from inside the lesion/mucosa, detaching & draining all surface contaminants instantly (within 5-10 min); (5) Liquid flow equally keeps the lesion/mucosa hydrated over many hours; (6) Instant specific polymer – protein binding (5 min, see pharmacological results); (7) No side effects; (8) Clinical results proving instant and high effectiveness without any side effects (with possible exceptions in some rare patients allergic to one of the ingredients used in the composition); (9) Due to exclusively topical mode of action, these treatments were classified as Medical devices (Class I, IIa or IIb).
AFTER NATURAL, CHEMICAL, & BIOLOGICAL DRUGS, MULTIPLE PROTEIN INHIBITOR THERAPIES MAY REPRESENT THE DRUGS OF THE FUTURE. SYSTEMIC BIODEGRADABLE MULTI-PROTEIN INHIBITOR DRUGS ARE IN R&D PHASE.
Future competition: Being a completely new generation of drugs, having required 20 years of intensive research based on a totally new hypothesis of treatment for those pathologies (for which there was then no effective treatment), associating multiple modes of action into 1 single, safe, and patented medication, we think that this technology will replace traditional drugs within a few years.
Registered treatments: A few anti-viral, wound healing, psoriasis-eczema-dermatitis, anti-allergic, & URT treatment MDs are already acquired by major pharma companies such as URGO, BMS-UPSA (France), Bouchara Recordati (Italy), Wockhardt (SE Asia), Walmark (Poland), Siemens -Sidroga (Germany) and launched with success.
Current research: (1) Allergic rhinitis: topical protective, anti-histaminic, anti-IgE and anti-inflammatory MD is launched in 2018. (2) A long-acting articular lubricant gel, blocking cartilage-destructing proteins (MMPs), with anti-inflammatory activity, will be ready by the end of 2018. (3) A new generation of TRPA1 receptor channel-blocking, pain & migraine preventive nutritional supplement is available. The corresponding purified preparation is under development as a drug in collaboration with Neurodol (European Center for Pain Research) + the French Govt. Res. Organization INSERM + the University of Clermont (France). This project is expected to be completed in 2021. (4) Intra-articular gel with anti-inflammatory and anti-MMP properties for post-operative care after knee and joint surgeries.
Note: Combination chemotherapy for cancer treatment was also discovered by VITROBIO; the protocol was not patented but was published, and this research was awarded the French Academy of Science award.
For a specific pathology: Please see individual product section