WO2021233571A9

WO2021233571A9 - Treatment agent for antiviral therapy, applicator, and method for producing a treatment agent

Info

Publication number: WO2021233571A9
Application number: PCT/EP2021/000054
Authority: WO
Inventors: Nori RIEMER
Original assignee: Ninoderm Ug (Haftungsbeschränkt)
Priority date: 2020-04-30
Filing date: 2021-06-14
Publication date: 2022-01-27
Also published as: WO2021233571A8; EP4355297A1; WO2021233571A1

Abstract

The invention relates to a treatment agent for the antiviral therapy of external herpes simplex diseases, in particular herpes simplex labialis, and to a method for producing same which reduces the occurrence of side effects and/or interactions with a low degree of development complexity and which allows an application by the patient with an at least minimal level of pain. This is achieved in that the treatment agent consists of a topically applicable carrier material which, as a transdermally active antiviral drug, is provided solely with a local anesthetic.

Description

Treatment agent for antiviral therapy, applicator and method of making a treatment agent

The invention relates to a treatment agent for the antiviral therapy of external herpes simplex diseases, in particular herpes simplex labialis, and a method for its production.

Herpes simplex viruses are distributed worldwide and occur as type 1 and type 2, which have different forms of infection. The herpes simplex virus type 1 is significantly more common than the herpes simplex virus type 2. A large proportion of adults experience occasional to multiple recurrences (herpes simplex rezidivans) at least once in their lives, especially younger adults as a result of reactivation of an existing infection. Herpes simplex infections are very often localized on the skin and produce external clinical pictures. However, they can also have other localizations, such as herpes simplex retinitis or herpes simplex encephalitis.

A herpes simplex infection often shows up in the form of herpes labialis (cold sores, herpes simplex labialis). With herpes labialis, sores with blisters, so-called fever blisters, usually appear around the mouth, very often as recurrences.

As a local anesthetic, anesthetics become local Numbing (local anesthesia). A distinction is made between injectable local anesthetics and topical local anesthetics, which are applied directly to the skin or mucous membrane.

The anesthetic effect can be seen in the fact that the local anesthetics disrupt the transmission of stimuli.

The chemical structure of many local anesthetics is similar.

A basic distinction is made between aminoesters (ester-type local anesthetic) and aminoamides (amino-type local anesthetic).

Procaine is a known ester-type local anesthetic with molecular formula C ₁₃ H ₂₀ N ₂ O ₂ and structural formula

It is also sold under the brand name Novocain or Novocaine.

DE 10 2006 030 073 A1 describes a lipstick for treating herpes simplex labialis diseases and for protecting lips. A composition is not described. It is pointed out that this lipstick may contain aciclovir in particular.

DE 94 21 079 U1 describes a medicinal formulation with an antiviral effect, in particular against herpes viruses described, which also contains 9-{(2-hydroxyethoxy)methyl}-guanine, which is known under the international non-proprietary name aciclovir. It also describes that the formulation can also be in the form of a medicinal lipstick that can contain a substance with a local anesthetic effect, such as tetracaine, preferably in an amount of 0.1 to 5.0% by weight, based on the formulation. The antiviral effect unfolds here the aciclovir, whereby the anesthetic serves to relieve pain in the treated viral areas.

On the one hand, this combination of active ingredients may not be free of side effects or interactions. On the other hand, in some cases, aciclovir has not led to a clear healing effect.

A nano-vehicle for transcutaneous transport is disclosed in EP 2 061 432 B9. In this, acyclovir can also be used to treat herpes. Procaine can also be used here to support the anesthetic effect.

DE 10 2004 040 630 A1 describes a combination therapy with procaine, more precisely the production of a corresponding combination drug. Essentially, a function of procaine that enhances the effect of other pharmaceutical agents is used. Thus, procaine is always presented as a combination with other active ingredients. The form of administration ranges from a pharmaceutical composition that can be administered orally to a combination that can be administered topically in the form of an ointment, suspension, emulsion, plaster or in the form of a solution that can be applied externally. A combination of the dosage forms with specific applications is not disclosed.

An antiviral effect is also attributed to procaine itself, but again in combination with other antivirals. Furthermore, this publication indicates a treatment of herpes simplex viruses, but here again in a combination with other active ingredients. For herpes simplex treatment it is disclosed that the combination of procaine with virustatics can be injected directly into the zona zoster areas or into areas infected with herpes simplex viruses.

Such a combination therapy always requires precise adjustment of the combination for a specific treatment, which entails a high development effort. In addition, the risk of side effects and/or interactions occurring increases. In addition, the combination therapy against herpes simplex specified in the prior art is not very patient-friendly, because the injection of the combination drug provided into the infected areas is associated with considerable pain. In addition, an injection can trigger allergic reactions.

It is therefore the object of the invention to specify a treatment agent for antiviral therapy and a method for its production which, with little development effort, reduces the occurrence of side effects and/or interactions and allows at least painless application by the patient himself.

This task is solved by the fact that Treatment agent for antiviral therapy in particular in Herpesviridae, in particular of external herpes simplex diseases of the oral/nasal mucosa/lips and other localizations, in particular of herpes simplex labialis, consists of a topically applicable carrier material to which a local anesthetic is exclusively added as a transdermally acting antiviral .

According to the invention, it was found that the antiviral effect of local anesthetics, in particular local anesthetics of the ester type, in particular procaine, is entirely sufficient for the treatment of herpes labialis. The anesthetic effect of the local anesthetic supports the therapy particularly advantageously. If this is applied diluted in a carrier material to the area affected externally with herpes simplex, in particular with herpes simplex labialis, the anesthetic effect first occurs, in that pressure and itching of the herpes area is suppressed immediately. The patient feels an immediate positive effect. This is particularly advantageous because a psychological effect cannot be ruled out in this disease. The immediate relief of pain, itching and pressure has a positive psychological influence on the therapy.

Because the carrier material remains on the herpes area for a while, the local anesthetic in it penetrates transdermally and unfolds its antiviral effect. The spread of the virus is prevented. For this reason, it is advisable to use the treatment agent according to the invention immediately after a possible disease has been identified. the antiviral effect but also shows a significant support in wound healing. Finally, it can be stated that the recurrence of an external herpes simplex, in particular a herpes simplex labialis disease, is significantly slowed down or even avoided.

To set a dilution, it has proven to be expedient for a local anesthetic to be added to the carrier material in a ratio of 0.5 to 3% by weight. On the one hand, such a concentration is sufficient for the therapy. On the other hand, this concentration also allows it to be offered as a cosmetic treatment agent if an appropriate dosage form and a local anesthetic that does not fall under the Narcotics Act is selected.

The local anesthetic can be an amino-type local anesthetic as well as a local anesthetic.

In particular, the ester-type local anesthetic may be procaine or one of its ester-type relatives.

In order to increase the time that the treatment agent remains on the area affected by herpes simplex, it is possible for a non-liquid material to be chosen as the carrier material. Here, for example, a gel can be used as a carrier material.

In particular for use in a herpes simplex labialis disease, however, it is also possible for the carrier material to consist of oil and wax in the manner of a lipstick carrier material. Such a The carrier material remains on the lips for a long time and ensures a long-term effect of the local anesthetic on the herpes labialis area with the effects described above. In this case, it makes sense for the carrier material to be in the form of a lipstick.

In order to be able to optically correct the appearance of the herpes labialis area, it is possible for the carrier material to contain opaque and/or colored additives. The opaque additives optically cover the area and the colored additives lead to an evenly colored appearance of the lips, including the herpes labialis areas.

However, it is also possible for the carrier material to be viscous with a viscosity on the order of 100 to 106 mPa·s. Such a carrier material can have a honey-like consistency, for example. If this is applied to the diseased areas, it remains there unless it is removed by licking or washing off, and can develop the effect described above.

On the other hand, it is also possible for the treatment material to consist of an aqueous 0.5 to 3% solution of the local anesthetic. This can be applied with a cotton swab, for example. Due to the roughness of the surface of the areas affected by herpes simplex, the aqueous solution penetrates relatively quickly and unfolds its effect.

The invention also relates to an applicator for applying a treatment agent according to the invention. This applicator has a first chamber with a closable opening through which the treatment agent can be applied.

Such an applicator can have a closure which can close the opening and has a rod arranged thereon, the rod being immersed in the first chamber and its free end being designed to be able to receive the carrier provided with the active substance.

The rod can be provided with a brush or a sponge at its free end. The brush or sponge is used in particular to apply gel.

In one embodiment it is provided that the opening is closed with a spray mechanism. A treatment agent with a low viscosity or a liquid treatment agent can be easily and evenly sprayed with it, particularly on large diseased areas.

Another embodiment provides that the opening is closed with a roll-on mechanism. This is the design with a movable, roughened ball, which absorbs the treatment agent when it enters the chamber and transports it to the outside, where it can be stripped off again. The function is known from the so-called "deodorant stick".

It is also possible to design the applicator as a two-chamber applicator by providing a second chamber with one of the configurations of the first chamber, which is arranged coaxially or axially parallel to the first chamber is .

Such a two-chamber applicator makes it possible to combine a protective (more liquid gel-serum-like) and an acute (more viscous gel) dosage form in one product. This has, for example, a small roll-on attachment on one side of the chamber and a stick similar to lip gloss with a brush, brush or sponge attachment on the other side of the chamber. This means that two phases of the disease can be covered with one product at the same time, if required.

The object of the invention is also achieved by a method for producing a treatment agent for the antiviral therapy of external herpes simplex diseases, in particular herpes simplex labialis. In this case, only a local anesthetic is used as a transdermally acting antiviral, which is added to a carrier material that can be applied topically. A treating agent having the effects and advantages outlined above is produced by this method.

It is possible here for the local anesthetic to be added to the carrier material in a ratio of 0.5 to 3% by weight.

As the local anesthetic, either an amino type local anesthetic or an ester type local anesthetic can be used.

In particular, it is advantageous when procaine or a relative corresponding to the ester type is used as the ester type local anesthetic. It is also possible for a non-liquid material to be selected as the carrier material.

A gel can be used as the carrier material.

In particular for the use of a treatment agent produced according to the invention for herpes simplex labialis, it is also possible for a lipstick carrier material, consisting predominantly of oil and wax, to be used as the carrier material.

A further possibility of designing the method according to the invention is that the carrier material is made viscous with a viscosity in the order of magnitude of 100 to 106 mPa·s.

It is also possible for the treatment agent to consist of an aqueous 0.5 to 3% solution of the local anesthetic.

The use of an aqueous solution, a water-containing or water-based carrier can prove to be particularly useful if the existing polarities of the molecules of a fat-loving, lipophilic carrier do not match the water-loving, hydrophilic properties of the herpes vesicles and thus the transport of the Hinder active ingredient procaine to the site of action.

The carrier material can also have a reciprocal viscosity. This means that, contrary to normal behavior, the viscosity of some materials increases as the temperature rises. Such materials are thin in the refrigerator and become more viscous at higher temperatures. The advantage of a gel with reciprocal viscosity is the relative increase in viscosity with heat. This means that the gel stays where it belongs, eg on the lips. Other gels usually become liquid under the influence of heat and "run away". The increase in viscosity under heat could be described as a "liquid patch", which becomes firmer after application to the skin, yet remains elastic and keeps the active ingredient in place.

It is also possible for an adhesive material, in particular in the form of mastic or a polymer solution, to be used as the carrier material. As a result, the active substance is kept on the treatment area as a kind of patch.

The invention will be explained in more detail below using exemplary embodiments.

Shown in the accompanying drawings

1 shows a two-chamber applicator with a roll-on side and a brush side,

2 shows a two-chamber applicator with a roll-on side and a spray side,

3 shows a two-chamber applicator with two roll-on sides and

4 shows a two-chamber applicator with two brush sides.

The applicators shown in FIGS. 1 to 4 have a first chamber 1 with a closable opening 2 through which the treatment agent can be applied. The applicator shown in FIG. 1 has a closure 3 which can close the opening 2 and has a rod 4 arranged thereon. The rod 4 is immersed in the first chamber 1 . At its free end 5 it is designed to be receivable with a carrier agent provided with the active substance.

The rod is provided at its free end 5 with a brush or a sponge.

FIG. 2 shows that the opening 2 is closed with a spray mechanism 7 .

In the applicator according to FIG. 3 the opening is closed with a roll-on mechanism 8 .

The applicator is shown as a two-chamber applicator in FIGS. 1 to 4 . A second chamber 9 is provided with one of the configurations of the first chamber 1 as described above. The first chamber 1 and the second chamber 9 are arranged coaxially with one another. The same reference symbols indicate the same design features.

A two-chamber applicator can be designed for gel as an acute variant (tube alternative) and on the other side with a base cream as a care variant (similar to lip gloss).

A two-chamber applicator with one lip gloss stick per chamber without a roll-on would certainly work easier.

As a possible protective variant, a procaine-containing lip balm could come into play for all Labello lovers, for example for those who don't Have symptoms, but know from experience that too much sun exposure when going to the beach/swimming pool will cause problems afterwards.

The brush or sponge 6 is used to apply gel. Gel also suitable as a roll-on liquid for the roll-on mechanisms. It is advantageous to design a gel with reciprocal viscosity, which is liquid in the refrigerator, for example, and the warmer it gets, the more liquid it becomes.

The recipe of such a gel could look like this:

Procaine HCL Gel 2%:

Procaine Hydrochloride 1.000g Poloxamer 407 10.000g Potassium Sorbate 0.070g

Citric acid (anhydrous) 0.035g water, purified ad 50.000g

5g poloxamer 407 are primarily used for the roll-on solution so that it has a slightly higher viscosity than the aqueous injection variant of procaine HCl. That would probably lend itself better to "rolling up".

Any cracks that the skin shows in the course of an advanced herpes infection as part of the healing process could be treated supportively by using a procaine-containing base cream. This could, for example, also be used simply for care by users of other herpes remedies. This would result in a small modular principle that everyone affected could "use" according to the stage.

The recipe for such a base cream could look like this: Procaine HCL 2% in DAC base cream: Procaine hydrochloride 2.000g DAC base cream ad 100.000 g

DAC base cream: glycerol monostearate 60, cetyl alcohol, medium-chain triglycerides, white petroleum jelly, macrogol-20-glycerol monostearate, propylene glycol, demineralized water

In a test, several patients with acute herpes simplex labialis symptoms were treated, in whom therapy with known drugs for herpes treatment was unsuccessful. According to the invention, the local anesthetic was applied transdermally as a 2% solution.

For this purpose, small sterile gauze compresses were soaked with the contents of a commercially available ampoule (2 ml) and placed on the affected areas in the lip area for around 15 minutes. Initially, there was a significant reduction in pain in the patients. As part of the therapy, the patients were instructed to continue this procedure independently several times a day at home. When they came back to the doctor after about seven days, those affected reported that the measure had responded well. In addition to a significant reduction in pain, the patients experienced rapid drying of the existing vesicles or blisters in the lip area and a significant reduction in the sometimes very unpleasant accompanying itching. This was perceived as very pleasant.

Over time, the diseased areas of skin encrusted and regenerated almost completely within 14 days to four weeks. Thereafter, the therapy was repeatedly applied to both male and female patients. In a modified application, 2% procaine solution from commercially available ampoules (2 ml) was dabbed onto the diseased areas using cotton swabs several times a day over a period of one week and allowed to take effect. The experiences described by the patients were confirmed here:

- Pain relief

- rapid reduction in the feeling of tension

- Drying of vesicles/blisters

- Intermittent dark red to blackish crusting of the diseased areas

- finally complete healing within 14 days to 6 weeks (depending on severity / stage)

- Basically: the earlier the start of therapy is chosen, the shorter the healing time

In addition, there was a delay an absence of the typical recurrences known in herpes simplex labialis for up to 30 months.

The effect of procaine according to the invention is currently seen in the following partial functions:

- Blockade of voltage-dependent sodium channels blocks/hinders not only the transmission of stimuli (pain) but also the transport of viruses along the nerve fibers, - increase in membrane permeability increases metabolism in the tissue and facilitates the defense process of the body's own defense cells,

- Reversal of DNA methylation as a repair process in the genome affects viruses themselves structurally or prevents them from penetrating or replicating (the cycle) via existing or created weak points in the host cells.

This gave rise to the idea according to the invention of producing an easy-to-handle, over-the-counter product

Application form e.g. in the form of a gel as a single dose in a multiple pack (e.g. 10 x 1ml cosmetic vials each) for application to the skin.

It may also be possible to use it in tumor therapy.

LIST OF REFERENCE NUMERALS 1 first chamber

2 opening

3 clasp

4 staff

5 free end 6 brush or sponge

7 spray mechanism

8 roll-on mechanism

9 second chamber

Claims

Treatment agent for antiviral therapy of external herpes simplex diseases, in particular herpes simplex labialis, consisting of a topically applicable carrier material to which exclusively a local anesthetic is added as a transdermally acting antiviral. Treatment agent according to Claim 1, characterized in that a local anesthetic is added to the carrier material in a ratio of 0.5 to 3% by weight. Treatment agent according to claim 1 or 2, characterized in that the local anesthetic is a local anesthetic of the amino type. Treatment agent according to claim 1 or 2, characterized in that the local anesthetic is a local anesthetic of the ester type. Treatment agent according to claim 4, characterized in that the local anesthetic is procaine. Treatment agent according to one of the preceding claims, characterized in that a non-liquid material is selected as the carrier material. Treatment agent according to claim 6, characterized in that a gel is used as the carrier material. Treatment agent according to claim 6, characterized in that the carrier material consists of oil and wax in the manner of a lipstick carrier material. Treatment agent according to claim 8, characterized in that it is designed as a lipstick. Treatment agent according to Claim 9, in that the carrier material contains non-transparent and/or colored additives. Treatment agent according to one of Claims 1 to 5, characterized in that the carrier material is thick with a viscosity of the order of 10° to 10 ⁶ mPa-s. Treatment agent according to one of Claims 1 to 5, which consists of an aqueous 0.5 to 3% solution of the local anaesthetic. Applicator for applying a treatment agent one of the preceding claims, characterized in that this applicator has a first chamber with a closable opening through which the treatment agent can be applied. Applicator according to claim 13, characterized in that a closure which can be closed the opening is also provided with a rod arranged thereon, the rod being immersed in the first chamber and its free end being designed to be able to be received with a carrier means provided with the active substance. Applicator according to Claim 13, characterized in that the rod is provided with a brush or a sponge at its free end. Applicator according to claim 13, characterized in that the opening is closed with a spray mechanism. Applicator according to Claim 13, characterized in that the opening is closed with a roll-on mechanism. Applicator according to one of Claims 16 to 20, characterized in that a second chamber is provided with one of the configurations of the first chamber, which is arranged coaxially or axially parallel to the first chamber. Process for preparing a treatment agent for antiviral therapy of external herpes simplex diseases, in particular herpes simplex labialis, with only a local anesthetic being used as a transdermal antiviral agent, which is added to a topically applicable carrier material.

20. The method according to claim 20, d a d u r c h g e k e n n z e i c h n e t that the local anesthetic is added to the carrier material in a ratio of 0.5 to 3% by weight.

21. The method according to claim 20 or 21, d a d u r c h g e k e n n z e i c h n e t that a local anesthetic of the amino type is used as the local anesthetic.

22. The method according to claim 20 or 21, d a d u r c h g e k e n n z e i c h n e t that a local anesthetic of the ester type, in particular procaine, is used as the local anesthetic.

23. The method according to claim 20 or 21, d a d u r c h g e k e n n z e i c h n e t that a non-liquid material, in particular a gel, is selected as the carrier material.

24. The method according to claim 24, characterized in that the carrier material is formed viscous with a viscosity in the order of 10 ° to 10 ⁶ mPa * s.

25. The method according to claim 24 or 25, characterized in that the carrier material has a reciprocal viscosity.

26. The method according to claim 20 or 21, d a d u r c h g e k e n n z e i c h n e t that a lipstick carrier material, mainly consisting of oil and wax, is used as the carrier material. 27. The method according to claim 20 or 21, d a d u r c h g e k e n n z e i c h n e t that an adhesive material, in particular in the form of mastic or a polymer solution, is used as the carrier material.