Formulation for topical non-invasive application in vivo

Abstract

A formulation comprising molecular arrangements capable of penetrating pores in a barrier, owing to penetrant adaptability, despite the fact that the average diameter of said pores is smaller than the average penetrant diameter, provided that the prenetrants can transport agents or else enable agent permeation through the pores after penetrants have entered pores, characterized in that the formulation comprises at least one consistency builder in an amount that increases the formulation to maximally 5 Nm / s so that spreading over, and retention at, the application area is enabled and / or at least one antioxidant in an amount that reduces the increase of oxidation index to less than 100% per 6 months and / or at least one microbiocide in an amount that reduces the bacterial count of 1 million germs added per g of total mass of the formulation to less than 100 in the case of aerobic bacteria, to less than 10 in the case of entero-bacteria, and to less than 1 in the case of Pseudomonas aeruginosa or Staphilococcus aureus, after a period of 4 days.

Description

FIELD OF THE INVENTION [0001] The invention relates to formulations comprising molecular arrangements which, owing to penetrant adaptability, are capable of penetrating pores in a barrier, despite the fact that the average diameter of said pores is smaller than the average penetrant diameter. The penetrants can transport agents or else enable agent permeation through the pores after said penetrants have entered said pores. The invention especially relates to new additives to said formulations, such as consistency builders, anti-oxidants or microbicides. It further relates to the preparation and use of such formulations wherein the agent is selected from corticosteroids. Finally, it relates to a method for the preparation of all such formulations. BACKGROUND INFORMATION [0002] The efficacy of any drug action is a multiparameter function in which the instrinsic potency, the accumulation as well as the elimination kinetics of the drug all play a role. While the former is entirely deter...

AI Technical Summary

Benefits of technology

[0032] Generally, material abrasion from the surface shortens the therapeutic effect in a conventional cream or lotion. It is another advantage of the present invention that such problems are not obversed with the formulations based on highly adaptable agent carriers which thus exert a much longer biological action than standard corresponding medications. This is due to the fact that such highly adaptable agent carriers generate a drug depot in the viable skin portions, rather than on the skin surface.

[0033] It is a characteristic feature of the present invention, that a formulation comprising molecular arrangements capable of penetrating pores in a barrier, owing to penetrant adaptability, despite the fact that the average diameter of said pores is smaller than the average penetrant diameter, provided that the penetrants can transport agents or else enable agent permeation through the pores after penetrants have entered pores comprises at least one consistency builder in an amount that increases the formulation viscosity above that of the non-thickened corresponding formulation to maximally 5 Nm / s so that spreading over, and retention at, the application area is enabled and / or at least one antioxidant in an amount that reduces the increase of oxidation index to less than 100% per 6 months and / or at least one microbicide in an amount that reduces the bacterial count of 1 million germs added per g of total mass of the formulation to less than 100 in the case of aerobic bacteria, to less than 10 in the case of entero-bacteria, and to less than 1 in the case of Pseudomonas aeruginosa or Staphilococcus aureus, after a period of 4 days. It thus is possible to prolong storage and use of the formulation and to advantageously increase practicability of the formulation.

[0034] It then is preferred if said at least one consistency buildner is added in an amount that increases the formulation viscosity to up to 1 Nm / s and more preferably to up to 0.2 Nm / s.

[0035] It also is preferred if said at least one antioxidant is added in an amount that reduces the increase of oxidation index to less than 100% per 12 months and more preferably to less than 50% per 12 months.

[0036] For a formulation comprising soy bean phosphatidylcholine as the main degrading species, the increase of the oxidation index is reduced to less than 0.45 units, preferably to less than 0.22 units and even more preferably to less than 0.1 units, per 12 month.

[0037] In preferred embodiments of the invention said at least one microbicide is added in an amount that reduces the bacterial count of 1 million germs added per g of total mass of the formulation to less than 100 in the case of aerobic bacteria, to less than 10 in the case of entero-bacteria, and to less than 1 in the case of Pseudomonas aeruginosa or Staphilococcus aureus, after a period of 3 days, and more preferably after a period of 1 day.

Problems solved by technology

For example, if an epicutaneously administered drug is incapable of getting into and / or across the skin barrier such a drug has no practical value even if it has a high intrinsic potency.

The same is true for the drugs that get into the skin easily but are there eliminated too rapidly to fully develop the desired biological action.

Storage related problems most often arise through lack of chemical resistance of the formulation against oxidative degradation of its components.

Any oxidative process involving formulation components may not only degrade carrier and agent molecules and therefore continuously destroy both carrier and agent properties, but may also even lead to the formation of free radicals which then will cause further chemical attack on carrier and agent molecules, and therefore lead to an accelerated degradation of the components in the formulation.

Another storage-related problem lies in the prevention of the formulation against affection with microbes, such as bacteria and fungi, as this may also lead to degradation of carrier components and associated agent.

Microbiological affection will not only reduce or eliminate both penetration ability of the carrier and activity of the agent, but can moreover lead to severe side-effects during the application of the drug.

Supraceding this limit reduces the efficacy of the concentration-driven drug permeation into the skin below the therapeutically accepatable level; superceding such drug amounts may result in intolerable local, or even systemic, side effects or else is simply not achievable by means of the classical galenic formulations.

However, using a highly concentrated drug solution on the skin incurs the danger of agent precipitation on the skin and the greater likeliness of undesired side-effects.

High skin irritation potential of many depot formulations, for example, is a serious obstacle for the successful therapeutic application of such medications.

One of the chief reasons for this is that the currently used skin ointments or creams typically contain at least 0.1% and sometimes up to 5% of active ingredient as well as, a relative great amount of skin permeation enhancers in order to fluidize, which means to “soften” the skin which are however also very harmful to the skin.

This is especially true when such drugs are used repeatedly and / or highly concentrated which often results in severe side effects, such as skin atrophy, which then enforces discontinuation of the therapy.

Classical galenic formulations thus are generally lacking in potency and duration of biological functions if undesired severe side-effects evoked by a repeated treatment necessary to obtain sufficient agent concentration are to be avoided.

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