DE4305460A1 - Pharmaceutical or cosmetic preparation comprising enzymes, process for their preparation and their use - Google Patents

Description

The invention relates to pharmaceutical or cosmetic preparations comprising enzymes gene, in particular pharmaceutical or cosmetic preparations with enzymes, which in are able to enzymatically break down the sebum in the skin in existing skin to prevent pH values. The invention also relates to a method of manufacture such pharmaceutical or cosmetic preparations. In another aspect The invention relates to the use of such pharmaceutical preparations, for example in the treatment of and prevention of acne vulgaris. Furthermore The invention relates to the use of such cosmetic preparations in the if necessary preventive care of the skin.

The causes of acne vulgaris are still not fully resolved of the sebum-rich areas of the skin (primarily the face, neck, chest and back) that occurs primarily at puberty and usually only in the middle of the third Decade of life.

A large number of influencing factors, which can be seen from FIG. 1, have been proven in medical research for acne vulgaris. For example, hyperkeratosis, ie thickening of the horny layer of the skin, for example due to increased formation of horny cells, can occur due to exogenous influencing factors (soot, dust, hormones or pharmaceuticals). On the other hand - also caused by exogenous factors - the skin can be stimulated to produce more sebum. This is often caused by an excess of androgenic hormones, for example during puberty. Hyperkeratosis and increased sebum production inside the skin - sometimes also synergistically - lead to the formation of so-called sebum plugs (comedones, also called "blackheads"). Microorganisms present in the skin or on the skin and enzyme systems produced by them (esterases, lipases) break down the triglycerides of the sebum graft into glycerol and free fatty acids. These lead to a strong shift in the natural skin pH into the strongly acidic range, sometimes up to pH 1. Such microorganisms are, for example, Corynebacterium acnes and Staphylococcus albus and lipophilic yeasts of the genus Pityrosporum. The formation of free fatty acids leads to so-called "sterile inflammation".

A comparable "reaction sequence" also often occurs when the sebaceous glands are blocked outputs from external factors such as dust and soot, but also cosmetic preparations from.

As can be seen from Fig. 2, the conventional acne therapy was essentially conducted in three ways ( 1 ), ( 2 ) and ( 3 ). Most acne therapeutics intervene in the area of inhibiting increased sebum production and / or eliminating hyperkeratosis. To inhibit the increased sebum production, preparations containing sulfur, resorcinol, hormones, alcohols or vitamin A acid were regularly administered. Preparations containing sulfur, resorcinol, salicylic acid, vitamin A acid and thioxolone were administered against hyperkeratosis.

All preparations are sometimes associated with considerable side effects. So she leads Treatment with sulfur often causes comedones to develop to an even greater extent Form (blackheads). In addition, sulfur - administered in higher doses - can Absorption can also cause toxic damage.

Practice preparations containing vitamin A acid - depending on the dose, skin region and individual factors - also toxic side effects. You can also click on skin redness, flaking and burning sensation. Vitamin A acid is also with one A large number of other agents or medications are not compatible. It also becomes sensitive skin's ability to withstand sunlight.

Treatment with hormones - in this case predominantly estrogenic hormones - The therapy of acne vulgaris leads to side effects, which are primarily in the undesirable effects of the estrogen hormones on the total hormone balance. Hormone treatment also led to further side effects.

The external treatment of the skin with antibiotics as well as local disinfectants results primarily to eliminate or inhibit the activity of the microorganisms the skin or in the skin, which break down the triglycerides to free fatty acids and Induce glycerin. Disadvantage of the - necessary for the acne vulgaris treatment -  Frequent skin treatment with disinfectants is that natural Colonization of the skin with microorganisms unselectively destroyed and thus an important one Protective function of the microorganisms for protection against skin diseases is revealed.

It was therefore an object of the invention to provide a pharmaceutical preparation to be used to treat acne vulgaris or even prevent acne vulgaris is suitable without the above-mentioned side effects. Especially should be prevented that the pharmacological mechanism of action in the Influencing only one of the many decisive factors for triggering Acne vulgaris Factors.

Another object of the invention was to provide a pharmaceutical preparation to provide, which can be adapted to the severity of the clinical picture "Acne vulgaris" and attacks several factors that trigger the disease at the same time.

Another object of the invention was to provide a pharmaceutical preparation which combats the causes of acne vulgaris on the broadest possible level, without addressing the skin areas or in the whole organism to cause side effects.

Another object of the invention was to provide a cosmetic preparation places that are skin-friendly and caring for the skin and do not cause skin reactions leads to the development of acne in a reaction mechanism.

Another object of the invention was to provide a method for producing a pharmaceutical to provide or cosmetic preparation, in which the components involved either prepared on an industrial scale for the application or for the Preparation can be provided by the user.  

Surprisingly, it has been found that a pharmaceutical or cosmetic preparation according to the invention both for the almost side-effect-free treatment of acne vulgaris as well as preventing acne vulgaris without the occurrence of unwanted Side effects is suitable.

The invention relates to a pharmaceutical or cosmetic preparation, the one or several enzyme (s) from the group acting in the pH range between 4.0 and 8.5 Proteinases, lysozymes, elastases, α-lipases and α-amylase and optionally pharmaceutically acceptable carriers and excipients.

In a further aspect, the invention relates to a method for producing a such pharmaceutical or cosmetic preparation, where appropriate in enzyme (s) provided in a plurality of containers and, if appropriate, pharmazeu table or cosmetically acceptable additives, carriers and / or auxiliaries and optionally a pharmaceutical or suitable for the desired application form cosmetically acceptable solvents with each other intimately providing the application finished preparation mixed.

In a further aspect, the invention also relates to the use of such pharmaceutical preparation for the treatment of and / or for the prevention of acne vulgaris.

In a further aspect, the invention also relates to the use of a cosmetic Preparation for the care and cleaning of the skin and / or decorative application on the Skin.

The pharmaceutical or cosmetic preparation according to the invention comprises one or several enzyme (s) from the group acting in the pH range between 4.0 and 8.5 Proteinases, lysozymes, elastases, α-lipases and α-amylase and optionally pharmaceutically or cosmetically acceptable carriers and adjuvants. The specified pH Range of values for the spectrum of activity of the / according to the invention in the pharmaceutical or cosmetic preparation (s) used enzyme (s) includes the natural and the  Presence of acne vulgaris may change the pH range of the involved skin areas. In a preferred embodiment of the invention pharmaceutical or cosmetic preparation is the enzyme or are the enzymes that belong to the enzyme subclass "proteinases", selected from trypsin, chymotrypsin, Bromelain, Papain and Ficin. The proteinases bromelain and are particularly preferred Papain.

The enzyme or the enzymes from the class of proteinases can be used alone used to be pharmaceutical or cosmetic active against acne vulgaris To provide preparations according to the invention. However, it is also possible to have several Proteinases of the group mentioned together or together with other enzymes to use.

In a further, likewise preferred embodiment, the pharmaceutical or Cosmetic preparation according to the invention as Lysozyme, ie the cell walls of Microorganism-dissolving enzymes, muramidase, which in the narrower sense are called "Lysozyme" is known (EC 3.2. 1. 17). This can also be done alone or together with others Enzymes can be used. Use together with proteinases is preferred, such as with trypsin, chymotrypsin, bromelain, papain and ficin. Especially Preferred is a pharmaceutical or cosmetic preparation that contains an enzyme com combination of bromelain, papain and lysozyme.

In a further, likewise preferred embodiment, the pharmaceutical or cosmetic preparation as an enzymatically active ingredient pancreatin. Pancreatin usually contains a mixture of all pancreatic digestive enzymes, primarily proteinases such as trypsin and chymotrypsin, elastases, lipases, α-amylase and optionally also ribonuclease. Pancreatin can be used in pharmaceutical or Cosmetic preparation according to the invention either alone or together with others Enzymes can be used. Pharmaceutical or cosmetic are particularly preferred Preparations which, in addition to pancreatin, also contain one or more of the enzymes bromelain, Papain and lysozyme include.  

In a further preferred embodiment, the pharmaceutical comprises or Cosmetic preparation according to the invention in addition to the enzymes mentioned Complexing agent. Chelating agents are advantageous because they contain metal ions, in particular Calcium ions, in the form of so-called chelates, which are complex for the bacterial metabolism are no longer available. Basically everyone is pharmaceutically acceptable complexing agent suitable for the purposes of the invention. Pharmaceutical or cosmetic preparations in which as Complexing agent ethylenediaminetetraacetic acid (EDTA) and its complexing agents Salts, citric acid and their complexing salts, ascorbic acid and their complexing salts, nitrilotriacetic acid (NTA) and their complexing active salts and possibly combinations of several such compounds are included. The salts are primarily soluble in the natural application environment Salts, especially alkali metal salts, very particularly preferably sodium salts.

In a further preferred embodiment, the pharmaceutical or cosmetic preparations according to the invention additionally one or more include pharmaceutically or cosmetically acceptable additives. These serve special purposes, purposes of providing certain formulations or also aesthetic purposes.

Pharmaceutically or cosmetically acceptable additives can be used, for example, as buffers Setting or buffering a specific pH of the pharmaceutical or cosmetic preparation. As such, for example, so-called "Tris buffers" (Tris (hydroxymethyl-) aminomethane) to name. However, there are others as well pharmaceutically or cosmetically acceptable buffer substances can be used.

For certain applications, emulsifiers, stabilizers and Preservatives must be present. Such substances are as such from the prior art Technology known. Of course, only such additives can be used that with the other components of the pharmaceutical or cosmetic according to the invention Preparation and are compatible with the skin.  

In addition, in a further preferred embodiment, the pharmaceutical or cosmetic preparation, and carriers adapted to the form of administration Include excipients. These can be, for example, fragrance and aroma substances that the ready-to-use pharmaceutical or cosmetic preparations one for the Give users a pleasant fragrance. Of course, you can also click on the one you want Use or administration form of coordinated gelling agents, ointments, basics, Powder carrier, spray or aerosol carrier or liquid solvent or carrier for Solutions and lotions are present. It is also possible that cosmetic preparation genes suitable for cosmetic purposes include, for example moisturizers, the skin care or cleansing substances or for decorative cosmetic purposes certain or suitable excipients; e.g. B. color pigments. For all substances mentioned it applies that they are not only compatible with the other components - also in the long term must, but also must be tailored to the desired application form, in particular must be skin-friendly. In addition, a pharmaceutical or cosmetic preparation according to the present invention in a further preferred Embodiment also generally other substances customary for such preparations included as with the compounding, ready-to-use preparation and Application familiar expert knows from the prior art. For this too Additives apply that they work with the other components, especially with the pH Range between 4.0 and 8.5 acting enzymes, must be compatible and above Furthermore, no incompatibility with the area of application of pharmaceutical or cosmetic preparation may have, so in particular no incompatibility with of human skin.

Pharmaceutical or cosmetic preparations according to the invention contain in a another preferred embodiment, an amount of one or more enzymes in the range from 0.1 to 33.3 wt .-%, an amount of one or more complexing agents - if present - in the range of 0 to 4% by weight and the rest pharmaceutical or cosmetic acceptable additives, carriers and / or auxiliaries, in particular such additives, Carriers and / or auxiliaries as detailed above. Cosmetic Preparations regularly contain smaller amounts of the enzymes and Complexing agents as pharmaceutical preparations.  

Pharmaceutical or cosmetic preparations according to the invention are with the above specified components preferably in the form of a cream, an emulsion, an ointment, a gel, solution, lotion, powder, spray or aerosol provided. All of the mentioned forms of preparation are externally applicable preparations tion forms. This has the advantage that they are applied specifically to the site can, which is affected by Acne vulgaris. Especially for cosmetic preparations according to The invention relates to creams, emulsions, ointments, gels, solutions, lotions and powders preferred forms of preparation.

Without being bound to a specific theory, it is assumed that the active substances according to the invention present in the pharmaceutical preparations specifically target the factors triggering acne vulgaris according to path ( 2 ) and ( 3 ) in FIG. 2. This is how papain and bromelain loosen and dissolve the thick, superfluous cornea (keratolysis). They also weaken the action of the sebum-releasing enzyme groups of the esterases and lipases and act lytically on the proteins of fungi and bacteria until their cell wall is digested or destroyed (bactericidal or bacteriostatic effect). The digested protein fragments also have - as was surprisingly found - emulsifying and thus support the cleaning and healing effects of the preparations according to the invention.

Lysozyme is a muramidase physiologically occurring in humans, the bacterio has a static and bactericidal effect. Lysozyme is found in the lacrimal, nasal and Intestinal mucosa as well as in bacteriophages and polymorphonuclear leucocytes. Pharmacolo Lysozyme is also used in throat tablets or eye drops or ointments. It destroys the cell wall material (murein) on the skin and in the execution ducts of the sebum and sweat glands colonized bacteria.

The complexing agents such as EDTA also act as pH buffers. In addition activate and strengthen the action of the enzymes and prevent the growth of Fungi and bacteria or increase their lysis because they are necessary for the growth of the Bacteria needed calcium ions, sodium ions and aluminum ions in the form of Bind complexes.  

It is understood that the pharmaceutical or cosmetic preparations according to the Invention if they are not in solid form (for example as a powder), in the essential aqueous base are formulated. Consequently, in the case of preparation forms such as Creams, emulsions, ointments, gels, solutions, lotions, sprays or aerosols aqueous Preparations preferred. Of course, it is also possible to use others with the enzymes compatible solvents, provided they are skin-friendly. As examples are Mixture of water with physiologically acceptable alcohols or alcohols alone to call.

According to the invention, the pharmaceutical or cosmetic preparations are thereby prepared that the enzyme or enzymes and optionally pharmaceutical or cosmetically acceptable additives, carriers and / or auxiliaries and optionally a for the desired application form suitable pharmaceutically acceptable solvent intimately mixes with each other. A preparation ready for use is regularly used provided.

In a preferred embodiment, the method according to the invention can be used therein exist that you want the desired for the respective pharmaceutical preparation Components mixed together on an industrial scale and the ready-to-use Mixture in for administration or withdrawal for administration by the user filled in suitable dispensing containers. For example, bottles, tubes, Aerosols, sprays, etc. Straighten the dispensing containers used in individual cases of course according to the form of administration.

Alternatively, it corresponds to a further preferred embodiment of the invention, that the components are in a variety of for withdrawal for administration filled in suitable containers and the separately provided components - as a user immediately before administration, for example immediately before topical Application, mixed to provide the ready-to-use preparation.  

The last-mentioned, preferred embodiment can consist, for example, in that suitable containers, for example in bags, in separate compartments in one Chamber the enzyme or the combination of enzymes together with suitable Additives are provided, for example with one or more complexing agents, one or more aromas or fragrances and / or one or more emulsifiers, while ultrapure water is provided in the other compartment. The user mixes the contents of both compartments ("double chamber bag") with each other and applies the pharmaceutical or cosmetic preparation thus prepared to the affected skin.

In the same way, it is possible that different pharmaceutical preparations Composition provides to meet different pharmacological needs at the beginning of treatment and after the first success of treatment. So For example, it may be advantageous to initially combine several enzymes pharmaceutical preparation containing one another, optionally with others, above mentioned additives, carriers and / or auxiliaries to provide while one for ready to continue treatment of pharmaceutical preparations according to the invention provides that only an enzyme or possibly a different combination of Enzymes contain as the pharmaceutical preparation intended for the initial treatment. In this way, specific treatment requirements can advantageously be dependent on this be taken into account by the individual clinical picture.

Cosmetic preparations can also be used in a preferred embodiment are provided in different compositions, for example different skin conditions (e.g. dry or oily skin), different Skin types (e.g. robust or sensitive skin) or different applications purposes (e.g. moisturizer, nutrient cream, night cream, day cream) wear. Of course, the components of such preparations - also long-term - with the enzymes and possibly complexing agents, as well as the others Components, but also be compatible with human skin.  

The preparations according to the invention are - if necessary also in different Composition - either for the treatment of acute acne vulgaris and blemishes units as well as hyperkeratoses or can also be used to counteract To prevent acne vulgaris and blemishes as well as hyperkeratosis or the skin to condition accordingly.

In the same way, the preparations according to the invention are also for other purposes usable, for example for a bacteriostatic or bactericidal treatment of Skin surface, if it should be indicated for certain reasons.

Cosmetic preparations according to the invention can be used for skin care, for Skin cleaning or to keep the skin moist. Another The range of use of the cosmetic preparations according to the invention is in the range the so-called decorative cosmetics: preparations according to the invention can also be used for decorative application to the skin, for example as a powder or blush become.

The invention is explained in more detail below with reference to the examples.

example 1

The bactericidal or bacteriostatic effect of pharmaceutical preparations according to the invention was investigated as follows: commercially available culture media (agar, Blood agar) were provided in standard dishes. The entire nutrient surface was coated with bacteria from the following strains:

• - Staphylococcus areus,
• - Staphylococcus epidermidis,
• - Escherichia coli,
• - Bacillus subtilis, and
• - Klebsiella.

Two holes were punched into each of the culture media. A pharmaceutical preparation consisting of 1 mg lysozyme and 1 drop aqua destillata was filled into one of the holes. In the second hole, a pharmaceutical preparation consisting of 1 mg lysozyme, 1 mg EDTA and 1 drop of aqua destillata was filled.
The culture media were incubated at 37 ° C for 24 hours.

It was shown in all cases that around the punched hole into which the lysozyme, EDTA and water existing preparation had been filled, a significantly larger bakt rienfrei courtyard than around the hole in which only a preparation of lysozyme and Water had been filled.

Comparative Example 1

An example 1 corresponding experimental setup, but with only one hole in the distilled water was provided. Around the punched hole there was no bacteria-free yard in the agar.

Example 2

The experimental setup essentially corresponded to the experimental setup according to Example 1. Es however, only agar media were used. The strain of bacteria used was Staphylococcus epidermidis.

The amounts of the enzymes tested were 1 mg in all cases.

The following pharmaceutical preparations according to the Invention filled:

• (a) Lysozyme + aqua dest. and lysozyme + EDTA + aqua dest.
• The courtyards formed were in an area ratio of 1: 2.
• (b) Papain + EDTA + Aqua dest. and papain + lysozyme + EDTA + aqua dest.
• The bacteria-free courtyards formed were in an area ratio of 1: 3.
• (c) Bromelain + EDTA + aqua dest. and bromelain + lysozyme + EDTA + aqua least
• The bacteria-free courtyards formed were in an area ratio of 1: 3.
• (d) papain + bromelain + EDTA + aqua dest. and papain + bromelain + lysozyme + EDTA + aqua dest.
• The bacteria-free courtyards formed had an area ratio of 2: 3.

Comparative Example 2

A bowl with 2 holes was made according to the experimental setup of Examples 1 and 2 used. Only aqua dest. filled. Was in the other hole filled with an aqueous EDTA solution. After the first mentioned hole had Incubation no bacteria-free yard formed. Around the second hole had one extremely narrow, bacteria-free courtyard, hardly distinguishable from the first hole.

Claims (19)

1. Pharmaceutical or cosmetic preparation which has one or more pH Range between 4.0 and 8.5 active enzyme (s) from the group proteinases, lysozymes, Elastases, α-lipases and α-amylase and optionally pharmaceutical or cosmetic acceptable carriers and adjuvants. 2. Preparation according to claim 1, wherein the enzyme (s) from the group of Proteinases are selected from trypsin, chymotrypsin, bromelain, papain and ficin. 3. Preparation according to claim 2, wherein the enzyme (s) from the group of Proteinases are selected from bromelain and papain. 4. Preparation according to one of claims 1 to 3, wherein lysozymes the cell walls of Enzymes that dissolve microorganisms, preferably muramidase (“lysozyme”). 5. Preparation according to one of claims 1 to 4, the pancreatin as enzymatic active ingredient includes. 6. Preparation according to one or more of claims 1 to 5, which additionally one Complexing agent includes.   7. Preparation according to claim 6, wherein the complexing agent is chosen from ethylenedi aminetetraacetic acid (EDTA) and its complexing salts, citric acid and their complexing salts, ascorbic acid and their complexing effective salts, nitrilotriacetic acid (NTA) and their complex-forming salts and combinations of several such compounds. 8. Preparation according to one or more of claims 1 to 7, which additionally one or several pharmaceutically or cosmetically acceptable additives from the group pH Buffers, emulsifiers, stabilizers, preservatives and on the administration or Form of application matched carriers and auxiliary substances. 9. Preparation according to one or more of claims 1 to 8, the

• 0.1 to 33.3% by weight of one or more enzymes;
• 0 to 4% by weight of one or more complexing agents;
• - And the remainder includes pharmaceutically or cosmetically acceptable additives, carriers and / or auxiliaries.

10. Preparation according to one or more of claims 1 to 9, which an Enzymkom combination of bromelain, papain and lysozyme. 11. Preparation according to one or more of claims 1 to 10 in the form of a cream, an emulsion, an ointment, a gel, a solution, a lotion, a powder, one Sprays or an aerosol. 12. The method for producing a pharmaceutical or cosmetic preparation according to one or more of claims 1 to 11, wherein optionally in a plurality enzyme (s) provided by containers and optionally pharmaceutical or cosmetically acceptable additives, carriers and / or auxiliaries and optionally a for the desired application form is pharmaceutically or cosmetically acceptable  Solvents with each other intimately providing the ready-to-use preparation mixed. 13. The method of claim 12, wherein the components are on an industrial scale mixed and in suitable for administration or withdrawal for administration Filled in tax containers. 14. The method according to claim 12, wherein the components in for removal Administration fills suitable containers and the separately provided components immediately before administration, providing the ready-to-use preparation mixed. 15. Use of a preparation according to one or more of claims 1 to 11 for Treatment of acne vulgaris. 16. Use of a preparation according to one or more of claims 1 to 11 for Prevention of acne vulgaris. 17. Use of a preparation according to one or more of claims 1 to 11 for Skin care. 18. Use of a preparation according to one or more of claims 1 to 11 for Cleaning the skin. 19. Use of a preparation according to one or more of claims 1 to 11 for decorative application to the skin.