WO2016071804A1

WO2016071804A1 - Pharmaceutical emulsion intended to establish therapeutic equilibrium of internal pressures of human and animal skin

Info

Publication number: WO2016071804A1
Application number: PCT/IB2015/058277
Authority: WO
Inventors: Jean Debetencourt
Original assignee: 45Sec Llc
Priority date: 2014-11-04
Filing date: 2015-10-27
Publication date: 2016-05-12

Abstract

A pharmaceutical composition optionally in sterile form, which rapidly penetrates the skin and tissues, which has the function of equilibrator of the internal pressures of inflammation, and which has the following functions: intentionally slowing down the chemical reactions of the skin and the migratory movement of fluids, serves to perform a more accurate metering of anti-inflammatory means; reduction of cutaneous tensions following cutting, including hemostases; pain reduction; syringe-free deep topical injection of medicaments by bringing the temperature of this composition to more than 45° so that, at the same time as the burning that it causes by its application, it opens circulatory channels while closing or slowing down the migratory flow of the internal liquids, by virtue of its immediately penetrating action.

Description

Patent Divisional Application No. BE2014 / 0812 filed 04.11.2014 for: Pharmaceutical emulsion for the therapeutic balance of internal pressures in human and animal skin.

î. Position of the problem

The skin is a multi-layered complex of various self-protection: epidermis / dermis and hypodermis traversed by the blood system, glands, for example sweat and their external orifices, sebaceous, nerve endings, strong pressure receptors (Vater-Pascini corpuscle) ), heat receptors (Ruffani organ), muscles (eg the horripilator corpuscle) and of course hairs.

When the skin is attacked (heat or cold too important, mechanical shocks, aggressive material, for example), it reacts most often violently without adapting its response to the height of aggression but it can also provide a local and targeted response, especially for minor hazards. The depth of the aggression is then taken into account to measure the reaction. The skin is connected to the brain by its nerve endings but also to several irrigation systems or circulation systems with information systems sent to vital organs, including solids, lymphatic system or interstitial fluid. There are many medicinal or cosmetic compositions for treating the skin with appropriate active ingredients such as cortisone, anti-inflammatories and disinfectants. But very often such medicinal assets potentially cause adverse effects in the medium and long term, such as corticosteroids.

The skin has its own means of reaction to external aggressions: for example, temperature regulation, relative sealing. It is therefore necessary to adapt this system of self-defense against external and internal aggression, by complementing self-protection mechanisms.

The skin protects and protects: it is a vast exchange with the outside of the body but is often relatively impermeable to the materials brought to cover it: several skin barriers act at different heights. The starting point of the invention is a highly penetrating chemical emulsion which interacts with the body reaction following skin inflammation. We are confronted with the speed and power of this reaction, sometimes exaggerated. The object of the invention is to quickly calm inflammation and pain without necessarily the use of medical means (lidocaine or analgesics for example) nor means of medical dermal penetration such as DMSO or hyaluronic acid or cortisone.

The interstitial gel in the skin is composed mainly of mucopolysaccharides probably related to collagen. Solid tissues are composed of collagen, elastin and other fibers such as fibroblasts. Internal pressures apply to surfaces, interstitial fluid, and volumes. The forces must be in balance and add up to form the Compression Force including blood vessels which themselves have their own oncotic pressure.

Inflammation breaks this balance.

The composition according to the present invention has the function of restoring this pressure balance by flooding or flooding the internal lesion site by means of lipids and water which not only interfere with the internal movements but above all act on the migrations of the fluids. Other factors also influence this balance: the electrical charges, the degree of hydration (equilibrium effect called "Donnan").

The variation of the ionic charges is transmitted to the brain which detects the inflammation and, within a certain period of time, trigger a defensive mechanism which is important if the inflammation is serious, and is superimposed on information transmitted chemically by the interstitial fluids. and lymphatic to the fundamental organs.

It is therefore necessary to act quickly to restore the balance of internal pressures and slow the flow of information on imbalances, which often cause an exaggerated body reaction, more serious than the inflammation itself. The image of the rapid appearance of a blistering or blistering blister filled with fluids illustrates such external pressures, (see A.Guyton et al., Fluid Pressure Interstitial et al., Physiological Review vol 51 No. 3 of July 1971).

The present invention therefore aims to reduce inflammation within a very short time, of the order of less than 20 seconds (depending on the thickness of the skin), in order to restore the internal pressures of the irritated skin and without use necessarily a pharmaceutical active, or using it at low dose, in order to balance the internal pressures and limit the severity of the inflammation of which the burn is only an example. The invention indeed claims applications relating for example: hematomas, insect bites, plants, redness, dryness or wetness, desquamation. But it also applies in the surgical field. The pharmaceutical composition according to the invention therefore has the function of causing a specific mixture of solids, lipids and liquids to penetrate into the injured site in order to slow the deformations and to slow down the migration of the fluids and transmission mechanism.

information to the corporal organs. The parameters of the invention therefore relate to the internal and external pressures of the tissues, their interactions with each other, the information given by the tracers, such as the ions, to the central nervous system, or perhaps the keratinocytes (via the lymphatic system) to the organs. , by incorporating balancing substances whose speed of penetration and assimilation is the factor of success.

2.Approach of the invention

From palpable skin aggression and a certain level, the skin reacts: cold, excessive heat, shocks, rays, cut, electrosurgical high or low frequency but it also reacts more slowly during microbial attack, sunlight, gas, some chemicals etc.

The present invention is aimed first of all at the physical attacks which provoke a

Immediate inflammation requiring an urgent response of the skin, and an attenuation of the pain. It is also used in case of drought and recurrent irritation.

The invention approaches the inflammatory phenomenon from a new angle: it analyzes the internal pressures of the skin rather than looking for an active drug on

inflammation. And the answer is given by a "water-in-oil" type emulsion during manufacture, which is transformed in contact with the skin, which has a temperature of 32 to 37 ° C normally, skin which it penetrates quickly and is transformed into " oil in water "because it is spread and reacts to the cutaneous heat during penetration: the balance of the internal pressures to the skin is reached by saturation of the volume of the cutaneous tissues, by the out of phase emulsion which separates the various irritating actors of the skin and rebalances their interaction of respective pressures.

It is possible, rather than acting actively on the inflammations by targeted pharmaceutical products, to rebalance the internal pressures to reduce such inflammations and this by using an emulsion containing no pharmaceutical active ingredient dosed as such or by using them but at reduced dose.

Why do we get blisters or blisters and why do we need this external reservoir or reservoirs that are often pierced at the risk of infection?

Why does the skin swell? Why are some scars keloids and some not? Why is there pain inside the scar, yet beautiful from the outside? The approach of the invention is directed to the protective and compensatory systems of the skin.

This approach is not to ask what is suitable to repair it with this or that ointment or cream or drug or antiseptic but to ask if the cutaneous response to aggression is appropriate to the severity of it, depending on the thickness of the skin and the rapid reach of the dermis.

So we must analyze the cutaneous response and we realize that it is multiple: of course the pain, the thermal shocks the change of color, the external appearance but especially the hypersudation, the temperature, the edema, the seeps , the transmission of information to the brain and organs. The more the cream is applied, the more the tissues are saturated and the lower the inflammation.

Positive pressures (which "grow") and negative pressures ("attract") are distinguished in a complex system of local pressures / depressions through which circulatory flows such as blood vessels, lymphatic fluid, perspiration.

3. The invention

Modern medicine emphasizes the migratory phenomenon of fluids when skin contact with an aggressive agent. It is found that fluids come out of the skin by various existing channels (the hairs) or which are created for the occasion, sort of evacuation tunnels or filling (for example blood to prevent infections by the action of lymphocytes). These phenomena of sweating are observed for example in the sauna.

We also note that the blood or the blood plasma leaves its conduit, waterproof

normally, to irrigate or water the injured site and possibly cause a hyper-oxidation: the blood circulates under pressure (activated by the heart), so the vessels resist a certain pressure without encountering leaks but the opposite happens in case external vessel pressure change is the environment of the vessel contained in a variable compression sheath.

It is curiously observed that the application of the emulsion on the back of the hand or on the veins of the wrist causes within 10 seconds swelling of the veins. Of course, this vasodilatation system is superficial and not deep but the result is visible and palpable. An explanation of the phenomenon is the reduction of external pressures on the vein, the internal pressure of which inflates its sheath locally. External optical tracers ("vein finders") see their use improved by analytical laboratories. This vasodilatation affects the lymphatic system or other liquids that may be close to the surface of the skin.

These phenomena are either generated by osmosis or by pressure differentiation. For example, it is the oncotic pressure that causes the blood to come out of the veins and capillaries at the level of inflammation.

In the case of a hematoma, we can consider the phenomenon as violent pressure of crushing due to the blow, followed by depression as violent causing an aspiration of the blood contained in the vessels. This is the phenomenon of the "blue" skin, which until now was soothing the pain by cold or menthol cream. This analysis shows the phenomenon of internal "pressures" of the tissues and specifically of the skin.

It is also necessary to take into account the factor "time" of reaction of the body: the reaction by the migration of the fluids takes place after a few seconds or minutes but can continue for several hours or even days. The emulsion according to the invention consists in quantitatively controlling the phenomenon

inflammatory to regulate it either to immediately reduce exaggerations or to complete deficits, internally of the skin and tissues.

It mainly involves injecting neutral fluids to balance the pressures of the internal fluids. The excessive evacuation of the fluids towards the outside of the skin poses the possible problem of the dressings and the management of the exudates, perspiration influencing the body's thermics. The reduction of fluids, especially TEWL, causes the skin to become depressed, which attracts other moving elements and causes swelling which must be removed later.

The emulsion therefore claims subcutaneous injection, by immediate hyperhydration, and not by syringes, using selected aqueous and lipidic fluids, to control the internal and external migration of body fluids following inflammation of the injured skin site (s). This injection must take place before the migratory reaction of the fluids, or during, because afterwards, apparently it will be too late, except to have a migratory brake reaction. Research will determine this, taking into account the time factor case by case. This is why the composition of the emulsion is essential to achieve penetration in less than 20 seconds and even 12 seconds.

Of course, it is possible to alternate the application of the emulsion with periods of rest which aim to evacuate the cutaneous waste via the internal pressure: it is therefore a regulation of the pressures by temporary application of the emulsion.

We are located in a dynamic phenomenon of interaction on the pressures. The invention refers to the following publication, describing an inflammatory phenomenon in the case of burns (which are only an example of inflammation):

The course Higher education Doctors 49: Understanding and evaluating burns EMERGENCIES 2003 Coordinator P.Goldstein (Lille -France): understanding burns.

LBargues and H. Carsin) 02_EnsSupMed_SFMU_LC 24/02/03 13:56 Page 49sq.

Under the heading of the changes of the capillary exchanges:

"The fluid leak of a porous capillary backed by a blotter explains the intensity of the fluid leak. Lymphatic drainage, however greatly increased, does not compensate for this leakage and results in edema. This edema is followed by a modification of the gel that is the interstitium: from a certain hydration its compliance increases, the edema promotes edema. Leaking liquids have a composition close to that of plasma, resulting in hemoconcentration which induces rheological disorders.

The eschar of the burn is very rich in salt, the denatured collagen would have the property of fixing the sodium thus maintaining a hyper osmolarity.

The modeling of capillary exchanges taking into account the hyperpermeability could never explain the intensity of the liquid leak observed in the burns. It lacked a force, calculated at 300 mm Hg by Arturson. The work of Lund explained it. "Lund T. Edema generation following thermal injury: an update. J Burn Care Rehabil 1999; 20: 445-452.

The present composition shows that burn is an inflammatory phenomenon which is part of the research on the influences of internal pressures. A literature search showed research on internal skin pressures but remained fixed on the principle action / reaction by seeking a solid base: the non-mobile fluid, to obtain a pressure increase effect, like a lever on the fluid mobile free and generating a pressure increase of 16 to 60mm Hg).

(Intertitial Fluid Pressure: Physiological Review Vol 51 No. 3, July 1971 Arthur G Guyon, H Granger and A Taylor

The present invention takes into account not the local phenomena described above but their reciprocal reactions in a volume facing internal pressure variations in the presence, depressions and overpressures to restore equilibrium, and imbalances, even empirically and therefore it does not focus on the intrinsic phenomena analyzed individually in the case of burns but on the contrary: it analyzes for all inflammatory pathologies the consequences, globally, by immediate intake of water mixed with lipids embedding the inflammatory system: for example in the case of severe burns, the emulsion may act on the activation of Factor XII, the starting point of a cascade involving coagulation, fibrinolysis, activation of phospholipase

membrane, histamine (acting on arteriolar vasodilatation), serotonin and PAF-acether which is a phospholipid influencing capillary permeability and which is myocardial-depressant. The bursting of the interstitial gel coating the collagen fibers generates by heat a significant interstitial negative pressure draining the zones. peri-burns. The assumption of activity of the mixture restoring the equilibrium of pressures and thus of slowing of the bodily reactions, is validated by results of acceleration of healing, by the clear regression or disappearance of the phlyctenes and edemas and that by the action of the emulsion according to the invention. But far beyond the burn phenomenon, the invention claims to be applied to any inflammatory skin phenomenon requiring a balance of internal pressures: hematomas, possibly with addition of arnica dosed at least 0.05%; skin dryness, blue spots on the legs due to poor blood circulation; exposure of the skin to radiation during oncological treatment; the bites of insects, irritating plants, spiders, jellyfish, ants with for example at least 1% of alpha bisaboliol oil eventually supplemented with 0.3% of Lavandula essential oil, temporary and recurrent skin irritations.

Research on psoriasis could be conducted not on a therapeutic basis, but rather to provide water to the site generating desquamation.

Of course, the highly penetrating nature of the emulsion according to the invention makes it possible to consider it as a base for injection without syringe of medicinal active ingredients such as lidocaine and anesthetic derivatives, diclofenac and other nonsteroidal agents (NSAIDs); Aciclovir-like assets for herpes; virucides, including melaleuca alterniflora in case of mosquito bites whose saliva is infected with a pathogenic virus, subject to the speed of systemic contaminating action of such a virus, knowing that the emulsion acts within 10 seconds but it takes time to apply it, benzethonium chloride and other antimicrobials such as cells with antimicrobial activity.

The invention therefore makes it possible, for example, to assimilate the treatment of hematomas (the "bruises", the pinching of a finger, the hammer blow, the fist of the boxer) with the treatment of burns while accelerating its effectiveness by the speed action of the cream according to the new formula object of the present application, one of the main characteristics is the speed of penetration, which will be explained by its formula.

The emulsion will preferably be packaged in low capacity doses (eg 5ml) to be transportable anywhere and therefore still available as a credit card.

It will be noted in the formula disclosed in this patent application that the amount of water it contains is similar to the amount of water contained in the body cells, so more than 65%.

Unlike the teaching of US Patent 2011/0212033 Tamarkin, the invention highlights the water to pass the skin barriers. (0004). Moreover a fast penetrating cream does not fear the "wash off", the cleaning. (005). It should be noted that the invention may serve as a basis for active agents such as analgesics, antipruritics, anti-perspirants, antifungals, anti-herpes, sunscreens, antioxidants, vitamins and amino acids.

The invention is similar to PCT patent application WO2011 / 070168, which describes the phenomenon of "pre-burn" in that it applies immediately during the

cutaneous transformation but it deviates from it in that it is based on the speed of penetration, not only to avoid the shrinking movements of the chairs but more generally to balance the internal pressures and influence the transmission of information to the organs of the body, depending on the severity of the inflammation. Rather than interfering with skin changes, the emulsion immediately floods the site and its speed is due to the dosage of sweet almond oil combined with the other ingredients. Its spectrum is therefore much wider and covers all external or internal inflammations of tissues.

The rapidity of action is important, for example, for the cream in the sterile version according to the invention of the present patent application, during use during surgical operations requiring, for example, haemostasis which the surgeon performs by cauterizing the vessels at high temperature. and that it will immediately dab after cautery to reduce the inflammation produced by both the vessels and surrounding tissues. Moreover the phenomenon of TEWL is common to the skin but also to the different tissues of it: envelope of organs, intestines, stomach, heart, kidneys. The inflammation covers the consequences of burns but also other pathologies specific to these organs.

It should be noted that the topically applied topical emulsion will be used topically inside the body to reduce internal inflammation during healing.

4. Industrial character of the invention

The invention is based in particular on the pharmaceutical preparation for treating cutaneous thermal burns (US Patent No. 13/514625 and EPO Patent No. 2509584).

It optionally uses the mixture claimed therein, optionally adding DMSO (dimethylsulfoxide) and other active ingredients such as hyaluronic acid, salicylic acid, depending on the pathologies not concerned by thermal burns.

But it essentially claims the rapid penetration of the skin, of the order of 12 seconds and its ability to balance the pressures disturbed by a phenomenon

inflammatory that goes well beyond skin burns.

A simple test was done: put a dab of cream on the back of the hand, massage: automatically the veins appear on the surface of the skin, inflated, and this within 10 seconds. Of course, this unexpected effect can be seen in a method for detecting the location of the veins in case of transfusion or sampling for medical analyzes.

But it is suggestive of two phenomena: the cream has become immediately penetrating and it lowers the external pressure of the blood system which becomes flush with the skin and dilated because its compression sheath has been lightened. This effect did not exist when the dosage of sweet almond oil was 1%,

possibly supplemented with muscat rose oil dosed at 1%. There is therefore the amount of sweet almond oil in the prescribed mixture exceeds 2% but is less than 3.5%.

For the chemical composition of the sweet almond oil, reference is made to the publication J.Agric.food chem 2007,55,8498-8507: "Almond (Prunus dulcis). Skins as a Potential Source of Bioactive Polyphenols signed by Maria Monagas and others. This study extols the effects of polyphenols and mainly sterols / flavonols that influence pharmacokinetic and play an anti-oxidant role.

Quercetin or quercetol is a flavinoid of the flavonol type found in plants as a secondary metabolite.

Quercetol is the most active flavonoid and many medicinal plants owe their effectiveness to their high quercetol content. In vitro and in vivo studies have shown that it is an excellent antioxidant. The certificate of analysis of this well-known oil shows that it is mostly composed of oleic acid (66%) and linoleic acid (over 20%) and sterols of more than 73%. % of Beta-sitosterol It will also be noted that according to the article published in Pathl Biol 2002; 50: 93-101 "reaction

Inflammation and infection in severe burns "under the signature of H. Carsin et al .:" There is currently no effective drug therapy for the inflammatory response "

The literature does not mention the penetrating properties of sweet almond oil. The penetrating effect of the chosen assay is therefore curious and surprising in the pharmaceutical composition.

It appears that several parameters must be considered to treat inflammation: a. Immediate penetration of the skin. If this urgency is not reached, the inflammatory reaction takes precedence and prevents the penetration of the emulsion. This would be due to a "chimney" effect that opens channels into the skin and ejects fluids to the outside, preventing external fluids from penetrating the skin. This is also what we notice when we sweat. A balance between fluid evacuation and emulsion penetration is also possible, potentially reducing inflammation. b. Supply of ingredients that slow down the external migratory movement, according to the formula of the invention. vs. Progressive recovery of internal pressure balancing to control the movements of fluids.

Indeed, by restoring the internal pressures of the skin, it is possible to add medicinal active agents specific to the healing or amelioration of the pathologies concerned.

For example, an acne-prone skin disinfectant, or one or more hormones.

Another example: edema due to a stroke can be controlled and the loss of blood which gives the hematoma blue / black color can be controlled by controlling the oncotic pressure of the blood vessels.

From the "operating mode" point of view, it will be noted that, in the state of science, it is difficult to assess the rapid evolution of the internal pressures of the skin: this is why it must be done in a way that intuitive application saturation of the emulsion or gel to block all or part of the fluid migration reaction, and gradually, depending on the severity of the inflammation, decrease the doses and allow to a lesser extent the migration of fluids. For example: application of low doses of the product according to the invention, three times the first 10 minutes and then once every 60 minutes the next three hours: the practitioner must adapt according to the evolution of the phenomena that he must watch in severe cases.

It is understood that an influx of internal fluid to the skin balances the pressures by filling the sectoral voids created by inflammation which induces a slowing down of chemical chain reactions, including PAF-acether. But the invention goes beyond the specific cases of burns, to treat any type of cutaneous inflammation is any internal disorder due to pressure differences resulting in migratory flows of fluids.

Another application claimed according to the invention: since the body reacts to

inflammation and that are created evacuation corridors following the migration of fluids, and that, according to the teaching of patent EPO 2509584, it is known that the water acts internally to the skin and that also the This patent application claims the balance of pressures internal to the skin by adding liquid / external fluid before the excessive reaction of the body by the action of the migration of fluids, the invention claims to heat the emulsion according to the following protocol:

1. Heat the emulsion to reach a low temperature of skin burn, between 46 and 65 ° C, preferably 50 ° C, or to initiate the inflammatory process.

2. Apply to healthy skin and therefore cause a mild burn and therefore a

inflammation that opens more or less deep channels. It is considered that there is a burn as soon as the contact with the skin has a temperature of more than 45 ° C.

3. Take advantage of these channels to inject an active ingredient without syringe, for example lidocaine or diclofenac or a disinfectant while stabilizing the burn by balancing the internal pressures. The inflammation of the voluntary burn is controlled, while the assets are added relatively deep. Contrary to so-called "Rubbing" processes, the ignition agent is at the same time the repairing agent, by balancing the generated differential pressures.

It will also be noted, for example, that hemostasis is often accomplished by means of electrodes connected to a cauterizer which carry them to more than 100 ° C and thus burn blood vessels to close them and prevent the blood from forming. flood the operative field. The surgeon can apply the sterile emulsion according to the invention to a pad to reduce the inflammation caused by cauterization. Such a topical method could reduce the internal pain of wounds by decreasing internal inflammation but such a reduction is difficult to objectify because very personal and difficult to compare: it would measure two sites of the same patient, one treated the other not.

The emulsion in sterile form participates in this surgical procedure which applies to other tissues than the skin: the walls of organs or the venous system. In such cases the TEWL is different from that caused by a skin burn.

It will also be noted that the phenomenon of hematoma differs from that of the burn, focused on the sudden rise in temperature of the injured site, while

the hematoma is mainly based on an aspiration of the blood that leaks through the vessels and therefore on a pressure difference and not temperature.

Donor tissue implantation assays will be performed by applying the emulsion to the recipient site (presumed to be depressed as open) to calm

inflammation of this site following introduction and fixation of the external implant and its components, including vessels and nerves. An activity of fibroblasts and me-fibroplasts is supposed to reduce the contractions and migrations of keratinocytes. The polysaccharides contained in the formula according to the invention should help healing.

Other examples and experiments will be developed in the dependent and / or development patents.

5. Formulas

The invention claims a water-in-oil emulsion with fragile stability out of its packaging and transforming itself by massage (in contact with moist tissues and their body heat) into: "oil in water" while it is stable in its sealed package .

A simple test consists of putting a few ml of the emulsion in a glass of water heated to more than 30 ° and the dispersion is seen to proceed with slight agitation. The formula claims: the purified water with minimal electrical conduction to isolate the nerve endings and reduce the information transmitted electrically to the brain, ions including sodium and potassium as to the pain felt.

Experience shows that the percentage of sweet almond oil in the emulsion must be accurate and is essential; it also requires an increase of sorbitan stearate. The other components are known in the formula of EP2010 / 069412 and granted derivatives.

COMPOSITION based on ingredient weight: per 100 grams

osm water> 70%

sorbitol> 3%

cetearl oct> 5%

glycerin> 2%

synthetic beeswax> 2%

dimethicones> 2%

polysorbate 60 1.5%

prunus dulcis> 2.5%

sorbitan stearate spam 1.7%

cetyl alcohol> 1%

trano copolymer> 0.5%

Panthenol <0.5%

sodium carbomer 0.3%

imidazolidinyl urea 0.31%

phenoxyethanol 0.75% Note on preservatives: the preservatives imidazolidinyl urea (which emits weakly of formaldehyde) and phenoxyethanol can be replaced by food preservatives (possible correction of the PH by lactic or citric acid):

0.5% sorbic acid CAS 110-44-1 Einecs 203-768-7 0.2% potassium sorbate CAS 24634-61-5 / 590-00-1 Einecs 246-376-1

0.2% Sodium benzoate CAS 532-32-1 Einecs 208-534-8

It should be noted that the basic formula does not contain any substances

medications at the percentage used. Of course, this formula can be supplemented by medicinal substances such as diclofenac (NSAIDs) and derivatives; lidocaine and derivatives; cortisone: DMSO; hyaluronic acid, acyclovir, a disinfectant such as melaleuca alterniflora, active substances according to specific pathologies such as: acne, muscular and sciatic pains; topical pain; hematomas; pinches of fingers; accidents.

The cream is also in sterile form for, for example, application in post-radiation oncology, (for example for masectomy), surgery (especially for haemostasis), open wounds. The sterile emulsion is passed under gamma rays at 25KGy or 50kgGy, in the primary packaging on secondary packaging: the primary packaging is unpacked in a sterile zone.

The invention extends to any similar formula or substitute ingredient. On the other hand, it does not claim film-forming protection incorporating the same ingredients but at different percentages, allowing little skin penetration. It claims the speed of skin penetration, less than 45 seconds, and even 12 seconds, depending on the location of the body where it is applied, and it claims the clear decrease in pain as it appears in clinical tests.

Curiously this speed of penetration has been increased by sweet almond oil dosed at more than 2% and at maximum 3.5% because beyond there is reversion of skin penetration results. The sweet almond oil therefore acts in the case of the emulsion in contrast to the role we know: external skin protection. This oil is poorly soluble in ethanol at 96% v / v but is miscible in petroleum ether. It contains between 73 and 87% of Beta-sitosterol.

Ongoing official clinical trials will complete the file. Tests on non penetration of the skin but of the muscle, adipose tissue and coatings of the internal organs should also be conducted by surgical teams, of course using the sterile cream version, simply coated on a sterile gauze and buffered on the zone. injured, possibly supplemented by a disinfectant such as betadine.

One of the essential elements of the formula is osmosis water. It must be as pure as possible. It should be noted that its dosage is more than 70% in the basic formula. This differentiates it from the formula contained in the US "foam" patent

2008 / 0206155A1 TAMARKIN, which combines the water with selected Petrolatum, but all the medicinal elements of the market can also be incorporated in principle in the formula according to the invention: of course their percentage will vary the percentage of the osmosis water. The stability of the emulsion according to the invention is more than 36 months; the challenge tests confirm the protection against pathogenic microbes for both types of preservatives.

Curiously we can add between 1 and 5% of soda ingredients after the emulsion has been made while maintaining a correct viscosity. Since ingredients such as lidocaine or diclofenac exceed 10% it is advisable to add ingredients stabilizing the formula to evenly distribute the assets in the volume of the cream.

The base cream according to the invention may be mixed with micronized clay, in particular green clay, which is incorporated therein by adding less than 20% of water, and forms a progressive cutaneous penetration plaster, mixing the two properties

penetrating emulsion and especially green clay. Examples of incorporated active elements; Sodium diclofenac; lidocaine / prilocaine; Acyclovir. The advantage of this solution is to firmly and durably incorporate such assets evenly distributed in the mass of the clay incorporated in the emulsion. Of course the penetrating effect will be slower than that of the emulsion without clay, which can be applied

immediately before the clay plaster also incorporating the emulsion. But this effect will be progressive over time (about 45 minutes)

The process for manufacturing the plaster is as follows: manufacturing the emulsion according to the invention and incorporating with stirring lidocaine and diclofenac; to this mixture add 10% green clay. This gives a compact package that easily fits into airless tubes. Tests have been made on the following pathologies: acne vulgaris (in this case the treatment includes a hormonal contribution and progressive exposure to UV, the disinfectant active is the melaleuca alterniflora dosed at 1 to 3% of the final mixture), the pains Muscle-like low back pain: results are reported in 20% of cases in 2015. A positive result is reported for sciatica by dorsal application. Of course this treatment is not effective at the bone level but tests on arthritis and osteoarthritis in the shoulder are in progress. The advantage of the plaster is that it acts as a long-lasting patch of activity, in a thin layer giving little clay dust, to be brushed after 45 minutes.

For minor inflammations, there is no need for a pharmaceutical active ingredient. For example, a mechanic hammered his thumb, causing a throbbing pain during sleep, and an irritation forcing him to scratch his thumb constantly. After two topical applications of the cream, the internal pressures were restored and there was no had more pain even during the night.

Another example: a person closes a swing door on his finger which is pinched. Immediate pain strong. Application of the emulsion without drug active. Quick stop of pain. Little trace of blue bruise. It is noted that it is urgent to immediately apply the pharmaceutical composition to the injured site and that its rapid skin penetration is essential.

Claims

6. Claims

1. A pharmaceutical composition in the form of a water-in-oil emulsion comprising a mixture of purified osmosis water dosed at more than 60% and synthetic beeswax dosed at least 2%, and cetearyl ethyl hexanoate or cetearyl octanoate at least 5% added with at least 2% of fluid silicones, preferably 350cc, and at least 0.3% of Dexpanthenol, surfactants and glycerin at least 2%, characterized in that also includes vegetable oils containing omegas and sterols such as flavonols, including quercetol, preferably sweet almond oil in excess of 2%, and at least 2.5% dimethicones with at least 1.5% added of sorbitan stearate, for use in balancing the internal pressures of the skin and mammalian tissues, in case of inflammation.

2. Pharmaceutical composition in the form of a water-in-oil emulsion according to the

claim 1 characterized in that it is applied to an injured skin with an even incipient inflammation, to penetrate completely in less than 30 seconds after application.

3. Pharmaceutical composition in the form of a water-in-oil emulsion according to the

Claims 1 and 2 characterized in that its almost immediate penetration without medicated means dosed as such, balances internal cutaneous pressures in a time less than the migration of fluids generated topically and externally in case of inflammation.

4. Pharmaceutical composition in the form of a water-in-oil emulsion according to the

claims 1 to 3 characterized in that it is brought to a temperature of 46 ° C to 70 ° C to generate by the light burn it generates, channels of evacuation of migratory fluids and to use these channels to inject mechanically, quickly and deeply this emulsion

5. Pharmaceutical composition in the form of a water-in-oil emulsion according to the

Claims 1 to 4 characterized in that it may incorporate medicinal or cosmetic active ingredients from the following families: diclofenac, lidocaine and its derivatives including opiates, hormones, skin-compatible disinfectants such as chlorhexidine, HE melaleuca alterniflora; DMSO, hyaluronic acid, botulinum toxins, Acyclovir, arnica, mint essential oil, alginates, stem cells and any topical active drug.

6. The pharmaceutical composition in the form of a water-in-water emulsion according to claims 1 to 5, characterized in that its water and lipid content compensates for the TEWL, ie the trans-epidermal water losss or the transepidermal water loss contained in the interstitial gel. coating the collagen of the skin, by its immediate action due to the combination of water mixture, cetearyl octanotae, fluid silicones conjugated with sweet almond oil dosed at more than 2% and dexpanthenol.

7. Pharmaceutical composition in the form of a water-in-oil emulsion according to the

Claims 1 to 6, characterized in that the counterpressure it generates prevents or inhibits, within 60 seconds, the excess production of oxygen free radicals responsible for hyperperoxidation due to the influx of blood liquid by leakage of the blood vessels due to the oncotic pressure of these in a low pressure zone.

8. Pharmaceutical composition in the form of a water-in-oil emulsion according to the

Claims 1 to 7, characterized in that it alleviates the compression of the tissues and muscles due to sudden shocks or compression of the skeleton on the muscles, particularly the gluteal muscles, for example in the case of a sitting position or excessive immobility.

9. Pharmaceutical composition in the form of a water-in-oil emulsion according to the

Claims 1 to 8 characterized in that its sterile version balances the local internal pressures following cicatrization, skin cuts, and haemostasis, especially after surgery or exploration and therefore not only at the level of the skin but of the tissues and muscles.

Pharmaceutical composition in the form of a water-in-oil emulsion according to

claims 1 to 9 characterized in that it is applied to the skin covering the veins and arteries and capillary blood system to dilate and locate immediately before injection by intravenous syringe or blood sample.

11. Pharmaceutical composition in the form of a sterile emulsion: water in oil according to claims 1 to 10, characterized in that it is de-aerated inside the skin and the tissues and that it is applied during the surgical procedures on the skin. the muscles, the circulatory system and organs damaged by cautery or cut with a scalpel

12. Pharmaceutical composition in the form of a water-in-oil emulsion according to claims 1 to 11 characterized in that it mixes with green clay, after incorporation of active ingredients such as lidocaine, diclofenac or HE melaleuca alterniflora, and is applied as a plaster on the injured part to gradually penetrate its active ingredients in the skin or tissues.

13. Pharmaceutical composition in the form of a water-in-oil emulsion according to claims 1 to 12, characterized in that depending on the active ingredients added to it, it penetrates the skin partially or completely in less than 20 seconds.

14. Skin injection method by topical spreading of the pharmaceutical composition on the skin according to claims 1 to 13, characterized in that it restores all or part of the internal balance of the pressures of the damaged skin by braking, by the counterpressure that it generates, an excessive reaction of external or internal migration of the fluids following inflammation.

15. Process for the application of the pharmaceutical composition according to claims 1 to 14, characterized in that its applied volume represents a transcutaneous assay calculated as a function of the internal parameters of the damaged skin, in particular by the increase in interleukin-6 (IL6 ), after it was applied arbitrarily in an emergency at least 3 times the first 10 minutes and at least once an hour for 6 hours after the onset of inflammation.

16.The method according to claims 1 to 15 characterized in that it identifies in less than 60 seconds, the precise positioning of the surface blood circuit by combining the process of swelling vessels in deep system by ultrasonic ultrasound positioning identification or tracer light for the purpose of blood sampling or transfusion.

17 .Procédé according to claims 1 to 16 characterized in that the emulsion is applied to the graft recipient site to generate a depression before receiving the implant graft to promote the assimilation of the graft.

18. Pharmaceutical composition in the form of a water-in-oil emulsion according to the

Claims 1 to 17 characterized in that it slows by its liquids and lipids, the transmission to body organs such as the liver, lungs and heart, as to the information of the seriously injured site, by flooding this site internally and thus by interfering with the transmission of information by tracers or electrical pulses, with the aim of curbing an excessive reaction of the body with respect to the severity of the lesions.