HK1079455B - Medical active agent patch optically less visible on skin - Google Patents

Description

The present invention relates to medical patches, in particular transdermal therapeutic systems, with a single or multilayered matrix containing the active substance and a back layer attached to this matrix, which, when worn on the skin, are characterised by an improved visual appearance. The invention also covers processes which enable the manufacture of such patches.

Many of the active substances or excipients which are suitable for the manufacture of patches or TTS have a tendency to discolor, for example to turn yellow, during storage.

These changes are mostly due to oxidative degradation processes, which occur in particular when the patch is stored or worn on the skin in contact with airborne oxygen and moisture and may be facilitated by light exposure, in particular pharmaceutical active substances, antioxidants, various enhancers (i.e. substances that support or accelerate transdermal absorption of the active substance) and oxidation sensitive components in the patch of the active adhesive, such as adhesive resins.

The degree of degradation of ingredients does not necessarily have an adverse effect on the pharmaceutical quality of the products, for example if the degradation products produced represent only a fraction of the weight of the starting compound and if these degradation products are toxicologically harmless. Thus, cosmetic product defects often result from the colourings without any deterioration in the pharmaceutical quality. These adverse changes in the apparent pharmaceutical appearance of the active patches are often associated by users or patients, particularly in the case of medicinal products, with damage or deterioration, which leads to a loss of safety. These changes are often yellow, brown or red, as is typical in chemical decomposition, and even minor changes in colour can be interpreted by users or patients as indications of a deterioration in the quality of the medicinal product.

The problem of discoloration arises in particular when the product, fresh after manufacture, appears to the human eye to be colourless or white and the discoloration does not appear until after a certain period of storage or when a patch is applied to the skin.

In the field of medical patches, transparent and colourless patches are the ideal cosmetic option because they are perceived as inconspicuous on the skin of the user by the user or by others.

Transparent and translucent patches are known from WO 01/78678, WO 02/34200 and US 6.361.790.

If a transparent design of an active substance patch is not appropriate, for example because of existing colours of the ingredients or cosmetic discoloration during storage, the patch may be provided with an opaque backing which prevents the colour or discoloration from being perceived visually during application.

The disadvantage of the latter is that patches or TTS with an opaque backing at the site of application, i.e. on the patient's skin, are much more noticeable than transparent or colourless patches. A technique which is known and often used at the present time is to paint the opaque backing with skin colours. However, this poses a further problem, as it is extremely difficult to find a skin tone which is equally suitable and cosmetically acceptable for a larger number of users with different skin colours. It is impossible to find a skin tone which is identical among different skin types in the population. This is a problem which could be solved by means of a unique and complex solution, and which is therefore not possible to achieve.

The present invention was therefore intended to provide active patches which, despite existing or occurring staining, would ensure an optically inconspicuous appearance of the patch, particularly if the patch is at the site of application, in order to find a uniform solution suitable for the most diverse skin tones of the world's population. The purpose of the invention was also to demonstrate the methods of obtaining such patches.

These tasks are solved by medical patches as claimed 1 and by manufacturing processes as claimed 11 and by the embodiments described in the dependent claims.

Accordingly, the abovementioned disadvantages do not occur or only occur in attenuated form in the medical patches described in the general term of claim 1 if the patch is transparent or at least translucent and if, when applied to the skin of a first person, the patch has a luminosity value L1 at a patch-covered skin area of not less than 50% and not more than 200% of the luminosity value L2, where L2 is the luminosity value at the area of skin surrounding the applied patch of the same person and the same is true for the skin of a second or more persons, provided that L2 is within the range of 5° and 100° for all of those persons, and in particular 90° and 20° for each of those persons, and the luminosity difference between the two types of skin samples can be determined by means of measurements of the luminosity of the skin samples.

Err1:Expecting ',' delimiter: line 1 column 82 (char 81)

Surprisingly, it has been found that patches with the above-mentioned features of the invention have an unobtrusive appearance at the site of application, i.e. on the skin, and that such patches appear visually unobtrusive on a wide variety of skin colour types of the world population. For example, an active patch of the invention has an equally unobtrusive appearance when applied to the skin of a user with a caucasian, lighter skin colour or to the skin of a user with a darker, more blackish skin colour.

The manufacture of patches with the general term of claim 1 and the materials suitable for manufacture are generally known to the professional. For example, the matrix layer may be made of polyacrylates, polymeth) acrylates, adhesives, cellulosic derivatives, polyisobutylene, styrene-isoprene-styrene-blockcopolymers, styrene-butadiene-styrene-blockcopolymers, polydimethylsiloxane, ethylene-lacethyl vinyl acetate and vinyl acetate, with the addition of several known additives to the matrix layer. At least one of the matrix layers contains an active substance, in particular a drug or a preparation.

The patches of the invention, which consist of a matrix and a backing layer, are essentially transparent or at least translucent (i.e. transparent), at least not opaque.

The backing is made of polyester, such as polyethylene terephthalate (PET) and polybutylene terephthalate, but also of almost any other skin-friendly plastic, such as polyvinyl chloride, ethylene vinyl acetate, vinyl acetate, polyethylene, polypropylene, cellulose derivatives and many others.

The patches of the invention contain in at least one layer one or more substances from the group of dyes and pigments. This, combined with the transparent or translucent properties of the patch, ensures that a colouring of the matrix ingredients which has been present from the beginning or a colouring which has begun and progresses after the end of manufacture is optically masked. At the same time, the colouring is sufficiently adapted or adjusted to the skin tone of the site of application so that the patch is imperceptibly different on the different skin colour types. Preferably, the matrix used for the optical masking is the matrix selected from the group of pigments and contains at least one or more colouring coatings of the patch.

In another particularly favourable embodiment, the optical masking is achieved by having the transparent or translucent backing layer contain at least one substance selected from the group of dyes and pigments. This can be achieved in particular by coating the backing layer of the patch on the outside, i.e. on the side opposite the skin, with a coating or varnish containing at least one dye or at least one pigment. This variant has the additional advantage that the colouring cannot come into contact with the skin or the matrix containing the active substance.

It may also be advantageous if both the matrix layer and the back layer have a content of dyes and/or pigments.

Surprisingly, it has been shown that the determining factor for the achievement of an adaptive effect is not the alignment of the dyes or pigments to the skin tone, but that this effect is determined mainly by the concentrations of the dyes or/and pigments used. The optical brightness of an active substance patch is determined mainly by the concentrations of the dyes and pigments contained in it, with additional consideration of the layer thickness of the patch.

At low concentrations of coloured or discoloured ingredients in the matrix, colours or colouring pigments which are clearly different from the colour of the skin underneath at the application site may still be visually unnoticeable. The same applies if the patch has a low layer thickness. The low concentration and/or low layer thickness gives room for concentration or corresponding variation in layer thickness, which provides the conditions for the optical masking of discolorations of ingredients from active substance patches by the addition of dyes and/or pigments.

A further improvement in the visual appearance of active patches applied to the skin can be achieved by, in a particularly favourable embodiment, providing at least the skin-facing surface of the back layer with reduced reflective properties, either by physical means or by applying an anti-reflective coating. Such a coating preferably contains an optical matrix or a combination of at least two matrix agents. This anti-reflective coating may also contain a dye/pigment mask to add to the patch ingredients as described above.

The matting can also eliminate or attenuate the cause of the optical abnormality of a patch based on light reflections, which often occur in patches with a transparent back layer with a smooth surface structure. The reflective properties of these back-layer materials are very different from those of human skin, which is why such patches are visually striking on the skin.

The patches of the present invention are particularly advantageous if at least one layer of the matrix contains one or more coloured ingredients. These may be, in particular, a substance or substances which are colourless in their original state and which tend to discolor or become coloured during storage or application. Particular preference is given to patches of active ingredients which contain one or more pharmaceutical ingredients as coloured or tending to discolor, with nicotine being particularly preferred.

The above-mentioned patches are preferably transdermal therapeutic systems, characterised by the fact that they allow the continuous delivery of medicinal products through the skin over a period of time, and the structure and manufacture of such systems are generally known to the professional.

The invention also covers processes for the manufacture of the active substance patches described above, which consist of the following steps: (a) Manufacture of a system comprising a single or multilayer active matrix and an associated back-layer, where the matrix is produced using matrix polymers, active substances and auxiliaries, and to which the matrix or/and back-layer is added one or more substances selected from the group of dyes and pigments; (b) Manufacture of at least one further system according to step (a), where this system differs by 50% in the concentration of the dyes and/or pigments and/or by the type of dyes and/or pigments used; (c) Manufacture of plane sections or strips of the stages (a) and (b) where one or more of the selected dyes and pigments are mixed; (d) Manufacture of a system which produces values of 90° or less than 200° L1 or less than 200° L2 (l1 or less) in the range of L1 and L2 in the individual colour systems; (e) Manufacture of a system where the colour difference between the colour and/or pigments is not less than 90° L1 or less; (f) Manufacture of a system where the colour and/or pigments used are not less than 200° L1 or less; (g) Manufacture of a system where the colour and/or pigments are not more than 200° L1 and L2 in the range of L1 and L2 in the individual colour systems; (e)

The present invention makes it possible to manufacture active patches which, despite containing coloured or discoloured ingredients, are not easily visible to an observer when worn on the skin and are not visually noticeable, whether the patch is applied to the skin of a fair-skinned or dark-skinned person.

The invention is explained in more detail by the following examples.

Examples 1. production of backcoats with different pigment concentrations

Coating masses were produced from ethyl cellulose and different proportions of a pigment mixture (see Table 1) and coated with a rakel onto a PET film of 15 μm thickness (area weight 7-10 g/m2). Other Tabelle 1:

Nr.	Ethylcellulose [Gew.-%]	Pigmentgemisch [Gew.-%]
1	99,75	0,25
2	99,5	0,5
3	99,0	1,0
4	98,0	2,0
5	96,0	4,0

Pigment mixed:

The Commission has decided to initiate the procedure provided for in Article 93 (2) of the Treaty.

The following controls were used: (6) PET film, aluminised and resistant to nicotine (not transparent) (7) PET film, 15 μm, transparent (8) Scotchpak 1006

Manufacture of skin patches

The skin patches were produced using the back-layers mentioned below: Durotak® 2052 (Fa. National Starch & Chemical B.V.) with a surface area of 80 g/m2 was coated and covered with one of the back-layers mentioned below.

The manufacture of colour plates corresponding to human skin colours

Err1:Expecting ',' delimiter: line 1 column 66 (char 65)

Err1:Expecting ',' delimiter: line 1 column 79 (char 78) Tabelle 2:

Farbtafel Nr.	Farbton	Rot	Grün	Blau	Sättigung	Intensität
A	16	255	215	191	255	223
B	21	50	25	0	255	25
C	21	80	40	0	255	40
D	21	255	236	217	255	236
E	21	197	137	77	130	137
F	21	72	36	0	255	36
G	21	117	78	39	128	78
H	25	255	226	183	255	219

Err1:Expecting ',' delimiter: line 1 column 85 (char 84) Tabelle 3:

Farbtafel Nr.		a-Wert	b-Wert
A	82,464	10,986	13,634
B	21,791	-3,203	8,877
C	25,776	5,905	14,758
D	88,086	4,945	9,572
E	50,596	10,893	36,304
F	25,811	3,747	12,968
G	32,562	5,519	21,015
H	83,228	6,712	24,95
Mittelwert*	51,289	5,688	17,758

Tabelle 3:

* Hierbei handelt es sich jeweils um den Mittelwert, der aus den Werten der 8 Farbtafeln gebildet wurde.

As can be seen, the colour value of the brightness L varies most strongly, whereas the a-value varies only slightly.

Err1:Expecting ',' delimiter: line 1 column 191 (char 190)

The difference in luminance between the two measurements is calculated by the following equation:

The skin patch strips described in section 2 were glued to the colour plates described in section 3. The measurement method described in section 3 was then used to determine the L1 colour brightness values of the glued patches. From the L1 measurements obtained, the difference amount to the L2 colour brightness value of the respective substrate (i.e. the colour plate) was calculated in each case. The percentage differences between the L1 colour brightness values of the A to H colour plates on the side of a glued patch (No 1 to 5 and controls No 6 to 8) and the L2 colour brightness values of the respective colour plates are shown in sections A to 4.

This shows that the transparent PET film (7) shows the smallest variations in brightness on all colour plates (positive control), while the controls (6) and (8) show the greatest variations.

The following is a summary of the results:

Since it is known that human colour perception may differ from the colourimetrically determined data, a visual evaluation of the test patches affixed to the colour plates A to H, including comparison samples 6 to 8, was carried out by subjects.

For this purpose, a certain number (e.g. 10) of each test patch (1 to 8) was glued to colour plates A to H, which were presented to a group of subjects under standardised conditions (lighting, distance, observation time) and the number of patches not perceived by the subjects is used as a measure of the optical inconspicuousness or effectiveness of the optical masking of a patch, after statistical analysis of the data. In Figure 1 the individual test patches 1 to 8 are shown in the form of a bar diagram in the order of their visual opacity (vertical axis).

Claims (11)

1. Medical active substance patch comprising a matrix of monolayer or multilayer configuration as well as a backing layer connected with said matrix, wherein at least one layer of the matrix contains active substance, and wherein said active substance patch is characterized in that

   - at least one layer of the matrix contains one or more ingredient(s) which is/are coloured, or which is/are colourless in its/their initial state and which has/have a tendency to discolour or which discolour(s) during storage or during the application period,

   - it is transparent or at least translucent,

   - it comprises one or more substance(s) selected from the group of the dyes and pigments in at least one of the layers mentioned,

   - in the state of having been applied to a first person's skin the said patch, at a place of the skin covered with the patch, has a lightness colour value L₁ which is not less than 50% and not more than 200% of a lightness colour value L₂, with L₂ being the lightness value of the region of the skin of the same person which surrounds the applied patch, and

   - that the same applies in respect of the skin of a second or any other person, provided that L₂ is in the range from 5° to 100°, especially in the range from 20° to 90°.
2. Active substance patch according to claim 1, characterized in that the lightness colour value L₂ of the said first person is the lightness colour value of a person of light, Caucasian skin colour, and that the lightness colour value L₂ of the said second person is the lightness colour value of a person of dark, Negroid skin colour, or vice versa.
3. Active substance patch according to claim 1 or 2, characterized in that it contains the said substance(s) selected from the group of the dyes and pigments in the matrix layer or in at least one of the matrix layers.
4. Active substance patch according to any one of the preceding claims, characterized in that on the side averted from the skin the backing layer of the patch is covered with a coating, in particular a lacquer, containing a dye or dyes or/and a pigment or pigments.
5. Active substance patch according to any one of the preceding claims, characterized in that at least that surface of the backing layer which is averted from the skin has reduced reflection properties.
6. Active substance patch according to claim 5, characterized in that the reduction in reflection properties is accomplished by means of physical methods.
7. Active substance patch according to any one of the preceding claims, characterized in that on the side of the backing layer which is averted from the skin there is applied an antireflection layer which preferably contains an optical dulling agent or a combination of at least two optical dulling agents.
8. Active substance patch according to claim 7, characterized in that said antireflection layer additionally contains at least one substance selected from the group of the dyes and pigments.
9. Active substance patch according to any one of the preceding claims, characterized in that the said ingredient which is colourless in its initial state and which has a tendency to discolour or which discolour(s) during storage or during the application period is a pharmaceutical active substance, particularly nicotine.
10. Active substance patch according to any one of the preceding claims, characterized in that it is a transdermal therapeutic system.
11. Process for the production of an active substance patch according to any one of the preceding claims, characterized in that said process comprises the following steps:

    a) producing a system comprising a mono- or multilayer active substance-containing matrix and a backing layer connected therewith, wherein the matrix is produced using a matrix polymer or matrix polymers, an active substance or active substances and auxiliary agents, and wherein one or more substance(s) selected from the group of the dyes and pigments is/are incorporated into the matrix or/and the backing layer;

    b) producing at least one further system according to step (a), this system being different in terms of the concentration of the dyes or/and pigments, and/or in terms of the type of the dyes or/and pigments used;

    c) producing surface sections or punched pieces from the systems obtained in steps (a) and (b);

    d) producing or providing colour charts having lightness colour values L₂ in the range from 5° to 100°, particularly in the range from 20° to 90°,

    e) applying or affixing the sections or systems obtained in step (c) to the colour charts mentioned in (d);

    f) measuring the colour values of the lightness L₁ of the systems located on the colour charts and determining the difference between L₂ and L₁ in each particular case;

    g) selecting those systems with a colour value of the lightness L₁ which is not less than 50% and not more than 200% of the lightness colour value L₂.