DE4305460C2 - Pharmaceutical or cosmetic preparation containing enzymes, process for their preparation and their use - Google Patents

Description

The invention relates to pharmaceutical or cosmetic preparations containing enzymes. 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 such as 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 incompatible. It also sensitivity of the skin against sunlight.

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

In the publication C.A. 116: 158.965s (corresponding to HU-A 57.608) become healed Metical means, among other things, for the prevention and treatment of acne vulgaris on the Skin described as the active ingredient SH proteins of plant origin and especially bromelain and papain in addition to lysozyme. From a salary to the Enzymes elastase, α-lipases or α-amylase in the preparation is out of the question.

The publication WO 84/02846 relates to an anti-inflammatory on the skin upper surface to be applied ointment, which acts as an enzyme component, a plurality of curative contains proteolytic enzymes. The cell walls of microorganisms dissolving Enzymes such as lysozyme as well as complexing agents are disclosed in the Preparations not included.

The document FR-PS 2,556,218 relates to anhydrous, for example based on glycerol formulated preparations which contain α-chymotrypsin as the enzymatic component can. The use of lysozyme and a complexing agent is included in this Documentation not evident.

The document US-PS 3,860,702 relates to an anti-inflammatory preparation proteolytic enzymes, which however contain neither lysozyme nor a complexing agent. In addition, the active ingredients in the preparation according to the document mentioned using cocoa butter or partially hydrolyzed cocoa butter as a carrier administered transdermally, which is incompatible with the object of the present invention is.

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 or to provide cosmetic preparation in which the components involved can be provided for preparation 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 pharmaceutical or cosmetic preparations according to claim 1. Advantageous embodiments of the preparation result from subclaims 2-5.

In a further aspect, the invention relates to a method for producing a such pharmaceutical or cosmetic preparation according to claim 6.

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 for decorative application on the Skin.

The pharmaceutical or cosmetic preparation according to the invention contains enzymes from the group acting in the pH range between 4.0 or 8.5 Proteinases, lysozyme, pancreatin (elastases, α-lipases and α-amylase) and, if appropriate pharmaceutically or cosmetically acceptable carriers and adjuvants. The specified pH Value range for the spectrum of activity of the invention in pharmaceutical or cosmetic preparation used includes the natural and the  Presence of acne vulgaris may change the pH range of the involve areas of skin. In 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 pharmaceutical or Cosmetic preparation according to the invention contains lysozyme, a cell wall of Microorganism-dissolving enzyme, also called muramidase (EC 3.2.1.17). A pharmaceutical or cosmetic preparation is preferred which contains an enzyme comm combination of bromelain, papain and lysozyme.

According to the invention, the pharmaceutical or cosmetic preparation as an enzymatically active component also 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 is used in pharmaceutical or cosmetic preparation according to the invention together with the others above Enzymes used. Pharmaceutical or cosmetic are particularly preferred Preparations which, in addition to pancreatin, contain the enzymes bromelain, Papain and lysozyme include.  

According to the invention, the pharmaceutical or cosmetic preparation 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.

The pharmaceutical or Cosmetic preparations according to the invention additionally contain one or more 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.  

The pharmaceutical or cosmetic preparation also contains carriers and Auxiliaries. 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 preparations contain auxiliaries suitable for cosmetic purposes, 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 preferred embodiment a lot of the enzymes in the range from 0.1 to 33.3% by weight, an amount of one or more complexing agents in the range of more than 0 to 4% by weight and the remainder 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 used 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 represent externally applicable preparation Form. 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 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 responsible for the growth of Bacteria needed calcium ions, sodium ions and aluminum ions in the form of Bind complexes.  

The pharmaceutical or cosmetic preparations according to the Invention can be in solid form (for example as a powder), but also in be formulated essential aqueous base. For forms of preparation such as Creams, emulsions, ointments, gels, solutions, lotions, sprays or aerosols are 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.

In general, the pharmaceutical or cosmetic preparations can be prepared that the enzymes, complexing agents and 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 known manner, the manufacturing process 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 the invention that the components are in a variety of for withdrawal for administration filled in suitable containers and the separately provided components - as users - immediately before administration, for example immediately before tropical 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 combination of enzymes together with suitable ones 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 represents a different combination of Enzymes contain as the pharmaceutical preparation intended for 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) carry. 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 - optionally 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 coordinate 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 will.

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 epidermis,
• - Escherichia coli,
• - Bacillus subtilis, and
• - Klebsiella.

Two holes were punched in each of the culture media. There was a hole in one of the holes pharmaceutical preparation filled with 1 mg lysozyme and 1 drop aqua destillata. In the second hole was a pharmaceutical preparation of 1 mg lysozyme, 1 mg EDTA and 1 drop of aqua destillata.

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 farm in 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 amount of the enzymes tested was 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 dest.
  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 (10)

1. Pharmaceutical or cosmetic preparation consisting of

• - lysozyme;
• one or more proteinases from the group of trypsin, chymotrypsin, bromelain, papain and ficin;
• - pancreatin;
• - One or more complexing agents from the group ethylenediaminetetraacetic acid (EDTA) and their complexing salts; Citric acid and its complexing salts; Ascorbic acid and its complexing salts; Nitrilotriacetic acid and its complexing salts; such as
• - Pharmaceutically or cosmetically acceptable additives, carriers and / or auxiliaries.

2. Preparation according to claim 1, wherein the proportion of the enzymes together 0.1 to 33 wt .-% and the proportion of the complexing agent (s) is more than 0 to a maximum of 4% by weight. 3. Preparation according to one of claims 1 or 2, wherein the proteinases bromelain and Papain are. 4. Preparation according to one of claims 1 to 3, wherein the pharmaceutical or cosmetically acceptable additives are selected from the group pH buffers, Emulsifiers, stabilizers and preservatives.   5. Preparation according to one of claims 1 to 4 in the form of a cream, an emulsion, an ointment, a gel, a solution, a lotion, a powder, a spray or one Aerosols. 6. Process for the manufacture of a pharmaceutical or cosmetic preparation according to one or more of claims 1 to 5, wherein optionally in a plurality enzymes provided by containers, one or more complexing agents and pharmaceutically or cosmetically acceptable additives, carriers and / or Excipients and, if necessary, a suitable one for the desired application form pharmaceutically or cosmetically acceptable solvent in for removal Administration fills suitable containers and the separately provided components immediately before administration mixed. 7. Use of a preparation according to one or more of claims 1 to 5 in the Treatment or prevention of acne vulgaris. 8. Use of a preparation according to one or more of claims 1 to 5 for Skin care. 9. Use of a preparation according to one or more of claims 1 to 5 for Cleaning the skin. 10. Use of a preparation according to one or more of claims 1 to 5 for decorative application to the skin.