HRP930663A2 - Penetration enhancing substance - Google Patents

Description

Lanolin derivatives as substances that help penetration and their applications in medicinal substances or other formulations containing biologically active substances.

The invention relates to lanolin derivatives themselves or in a mixture with esters of isopropyl alcohol with long-chain fatty acids and/or polyethylene glycol ethers of long-chain fatty alcohols as substances in medicinal substances that aid penetration or other formulations containing biologically active substances.

Transdermal application provides a number of advantages for a large number of pharmaceutical active substances or other active substances:

skin is unlimitedly accessible

no environmental changes occur as with oral administration

use is simple and comfortable

one time is enough instead of multiple daily administration

positive physiological effects can be noted

continuous long-term treatment is possible

treatment can be stopped at any time

a constant plasma level is guaranteed for a long time

a too high level in the plasma at the beginning, as with intravenous administration, is avoided, which results in a smaller proportion of side effects

there is less risk of overdosing or underdosing

the release of active substances is guaranteed, especially with a low therapeutic index.

In many cases, the drugs, which are ideal candidates based on their high "first-pass" effect, their low dosage and their high degree of action, have such a low skin penetration that it is not possible to achieve therapeutic values in plasma with conventional systems. For all these medicinal substances, it is necessary to give the system so-called penetration enhancers. In this sense, a large number of substances have been described, which are listed in the following patent documents.

US 4 299 826, US 4 343 798, US 4 046 886, US 4 130 643, US 4 405 616, US 4 335 115, US 4 130 667, US 3 903 256, US 4 379 454, US 3 527 864, US 3,952,099, US 3,896,238, US 3,772,931.

Substances that support penetration must, in addition to their specific task, have the following properties:

They must also be tolerable to the skin even if left on the skin for a long time under occlusive conditions, must not have an allergenic potential and must be compatible with the active substance.

These enhancers known from the literature can be classified under different chemical classes:

1. Primary and secondary alcohols

1.1. Short-chain primary alcohols C2 to C8

1.2. Long-chain primary alcohols C4 to C16

1.3. Secondary alcohols C3 to C5

2. Anionic surfactants

3. Saturated and unsaturated fatty acids

4. Azones and derivatives (1-alkylazacycloheptan-2-one, 1-alkylazacycloalkanone)

5. Amides such as N,N-diethyl-3-methylbenzamide (DEET), N,N-diethyl-m-toluamides

6. Alkyl-N,N-dialkylaminoacetate

7. Macrocyclic ketones and lactones

8. Pyrrolidones

9. Esters such as ethyl acetate, isopropylministat, glycerin monolaurate, diethyl sebacate. Propylene glycol esters of saturated fatty acids

10. Terpenes such as limonene, menthol, cineole

11. Phospholipids

12. Organic acid such as citric acid, salicylic acid, etc.

13. Cationic surfactants or amen

The large number of different substances of the most diverse chemical structure with said penetration-facilitating action allows a single mechanism of action to appear improbable. Thus, different mechanisms are also considered, i.e. combinations of mechanisms.

1. Solvent action in relation to the active substance and skin lipids.

2. Actions on the lipid structure of the membrane.

3. Effects on keratin and skin protein structure.

Due to the large number of interactions within the skin and the different chemical nature of the active substances, it is difficult to predict the properties that support the penetration of all these so-called enhancers of the respective active substance. According to experience, it is known that extremely rarely a substance that supports the penetration or certain mixture for several drugs or groups of drugs fulfills the required properties. The task of the invention is to prepare substances that support penetration, which are tolerable to the skin and compatible with the active substance, as well as not having the potential to cause allergies, in addition, they are easily accessible and economical and at the same time have an effect that supports the penetration of more than one active substance. Now, in a surprising way, it has been discovered that certain lanolin derivatives have the ability to increase the penetration of certain drugs or of active substances through the skin. These substances are usually put into cosmetics to make creams and lotions.

According to the invention, this task is solved by lanolin derivatives alone or in a mixture with esters of isopropyl alcohol with a long-chain fatty acid and/or polyethylene glycol ethers of long-chain fatty alcohols, which act as substances that help the penetration of medicinal substances or formulations containing other biologically active substances.

The lanolin derivatives assumed are selected from the group consisting of acetylated lanolin, acetylated lonolin alcohol, alkoxylated lanolin, lonolinic acid, polyethoxylated lanolinic acid, polyethoxylated lanolin alcohol, lanolinic acid esters with short chain aliphatic alcohols such as isopropyl lanolate, polyethylglycol ether lanolin alcohol and lanolin alcohol ester with long-chain fatty acids. If polyethoxylated lanolin derivatives are used, the number of ethylene oxide molecules can be 2 to 50.

As esters of lanolinic acid with short-chain aliphatic alcohols, straight or branched alcohols with C1 to C4, which are primarily primary or secondary, come into consideration. Examples of this are methanol, ethanol, n-propanol, n-butanol, isopropanol. For esters of lanolin alcohol with long-chain fatty acids, saturated or unsaturated fatty acids such as lauric acid, palmitic acid, stearic acid as well as myristic acid, palmitic acid, oleic acid and lanolin acid come into consideration.

If esters of isopropanol with long-chain fatty acids and/or polyethylene glycol ethers of long-chain fatty alcohols are added in connection with the derivatives, then they come into consideration as fatty acid components of the respective esters of the previously mentioned fatty acid. As long-chain typical fatty alcohols, alcohols corresponding to the above-mentioned fatty acids such as oleyl alcohol, lazryl alcohol, cetyl alcohol and stearyl alcohol, or their polyethylene glycol ethers, which are obtained from the corresponding alcohols by reaction with different molar amounts of ethylene oxide, are considered. Known products are condensation products of oleyl alcohol with 2 to 50 moles of ethylene oxide, lauryl alcohol with 2 to 40, cetyl alcohol with 2 to 45 and stearyl alcohol with 2 to 100 moles of ethylene oxide.

The substance that supports the penetration that is assumed consists of up to 1 to 100 wt.-%, especially up to 1 to 60 wt.-% of lanolin derivatives, up to 0 to 60 wt.-%, especially 10 to 30 wt.-% of isopropyl ester of alcohol and up to 0 to 99, especially 30 to 90 wt.-% polyethylene glycol ether of fatty alcohol (sum of components is equal to 100). If there is an application of a substance that aids penetration in the therapeutic transdermal system (TTS), then this consists of a last layer impermeable to the active substance, at least one container containing an active substance that is connected to it, which contains a part that aids penetration, a device for attaching to the skin and in a given case a protective layer that can be detached again. In the simplest case, this represents a so-called single-layer formulation, in which the substance that supports penetration (together with the active substance) is distributed in a primarily self-adhesive matrix, which is provided with a removable protective layer on the side facing the skin and with a cover film on the side away from the skin. . In addition to such a single-layer formulation, in which the penetration-enhancing agent is introduced into the primarily self-adhesive matrix from a solution or suspension, the drug can also be rubbed with penetration-enhancing substances, after which the mixture is applied to the carrier, primarily a piece of non-woven fabric or fabric or foamy substance. The carrier is then attached to the skin using self-adhesive foil.

In addition, it is also possible to apply multi-layered TTS. In such a case, for example, the drug can be placed on the carrier either alone or with a part of the substance that helps the penetration, which is placed on or in the first adhesive layer of the cover film, viewed from the side of the skin. Thus, substances that support penetration can be found in different layers at different concentrations or quantity. It has been shown that the substances according to the invention, which are applied as agents that support penetration, can both together with the drug in the usual matrix formulations with self-adhesive properties known to the expert and together with the drug or medicinal substance in a gel solidified in a therapeutic system, cream or placed in ointment and bring these into contact directly with intact skin. Despite repeated application, skin irritation could not be determined.

Particularly favorable is the action that supports penetration with the active substances Verapamil and Gallopamil. Verapamil has previously been described as promoting the penetration of isopropyl myristate from PCT/WO87/00042. The lanolin derivatives used according to the invention, on the other hand, have a significantly stronger effect that supports the penetration of Vepramil, as shown by the following examples.

The invention is explained in more detail with the following examples:

A. One-layer formulation

With recipes labeled "single-layer formulation" it is easy to p? self-adhesive matrix formulation with subsequent construction of TTS (see picture).

A self-adhesive matrix (2) is placed on the detachable protective layer (I), which is covered with a cover film (3).

One-letter wording example 1:

A pharmaceutical product according to the present invention with a single-layer construction of an adhesive matrix containing penetration-enhancing components and a drug, consisting of:

0.170 kg of polyisobutylene (average molecular weight from 900,000 to 1,400,000)

0.202 kg of solid aliphatic hydrocarbon resin (trade name Hercures C, m.mass approx. 1100)

0.152 kg of polyterpene resin

0.072 kg ethylene oxide polymer hO (Ch2-Ch2-O))nH n = 200 (PEG 200)

0.072 kg of colloidal silicon dioxide

0.072 kg of isopropyl myristate

0.181 kg Gallopamil

1,200 kg of special gasoline 80-110 as a solvent is applied to the protective layer vaporized on one side with aluminum and made separable on both sides, so that after evaporation of the solvent, a corresponding layer of 82 g/m2 is obtained.

After covering the adhesive layer with an impermeable cover layer, which consists of polyester, the resulting laminate is divided into individual pieces according to the therapeutic requirements.

Result example 1:

Content: 14.80 mg/10 cm2 Gallopamil

Penetration

(mouse skin): 9.61 mg Gallopamil/10 cm2/24 h

Single-layer formulation example 2:

Production according to example 1:

Composition:

0.213 kg of polyisobutylene

0.253 kg of hydrocarbon resin

0.190 kg of polyterpene resin

0.045 kg of PEG 200

0.091 kg Aerosil 200

0.050 kg of isopropyl lanolate?

0.045 kg of isopropyl myristate

0.113 kg of Verapamil

1,400 kg of special gasoline 80-110

A clinging layer afterwards

solvent evaporation: 74 g/m2

Result example 2:

Content: 8.4 mg Verapamil/10 cm2

Penetration

(mouse skin): 5.71 mg Verapamil/10 cm2/24 h

Single-layer formulation example 3:

Production according to example 1.

Composition:

0.213 kg of polyisoburylene

0.253 kg of hydrocarbon resin

0.190 kg of polyterpene resin

0.045 kg of PEG 200

0.091 kg Aerosil 200

0.050 kg of isopropyl lanolate

0.045 kg POA (10) oleyl alcohol ether

0.113 kg of Verapamil

1,300 kg of special gasoline 80-100

A clinging layer afterwards

solvent evaporation 85 g/m2

Result example 3

Content: 9.62 mg Verepamil/10 cm2

Penetration

(mouse skin) 6.14 mg Verepamil/10 cm2/24 h

Single-layer formulations example 4:

Production according to example 1.

Composition: 0.223 kg of polyisobutylene

0.265 kg of hydrocarbon resin

0.199 kg of polyterpene resin

0.047 kg of PEG 200

0.095 kg Aerosil 200

0.050 kg of isopropyl lanolate

0.119 kg Gallopamil

1,210 kg of special gasoline 80-110

A clinging layer afterwards

solvent evaporation: 75 g/m2

Result example 4:

Content 8.89 mg Gallopamil/10 cm2

Penetration

(mouse skin): 5.71 Gallopamil/10 cm2/24 h

For the production of further self-adhesive matrix formulations, the substances listed in the Table are mixed in the form of their solution or suspension (solvent or dispersing agent; gasoline), applied to a protective layer equipped with a removable agent using a layer application device, freed from the solvent by heating and laminated with a cover film. The dry mass of the self-adhesive matrix (FG) is listed in the table in g/m2.

(T stands for mass fractions).

The protective layer and the cover layer are the same as in Examples 1 to 4.

[image]

A. One-layer formulation

[image]

B. Formulation with smear tank

In the case of recipes under B., it is about rubbing the medicine with substances that help the penetration given in the table. To make TTS, this mixture is applied to the carrier in the concentration specified in the table.

This carrier can consist of:

fabrics,

nonwovens

foam material (open cell)

Such a circular panel of foam material, fabric or non-woven fabric not melted by smearing is attached to the skin by means of self-adhesive foil.

Example 13:

On the patch, which consists of a self-adhesive cover layer and a central non-woven fabric, apply to the non-woven fabric 130 mg of a mixture (by smearing) consisting of:

2.0 g of Verapamil

1.0 g of isopropul lanolate

1.0 g POA (10) oleyl alcohol ether

1.0 g of isopropyl myristate.

Drug penetration through mouse skin after administration:

15.26 mg Verapamil/2.54 cm2/24 h

Example 14:

On the patch, which consists of a self-adhesive cover layer and a central non-woven fabric, 53 mg of the smearing mixture is applied to the non-woven fabric, which consists of:

2.0 g of Verapamil

1.0 g of isopropyl lanolate.

Drug penetration through mouse skin after administration:

6.76 mg Verapamil: 2.54 cm2/24 h.

B. Formulation with container (spreading)

[image]

C. Multilayer formulation

In the following descriptions, multilayer formulations have the following construction (see Figure 2):

An adhesive layer (2) is placed on the protective film (1), which is equipped with a removable agent, or in about? which is placed tank (3). The container (3) consists of an adhesive round plate, which is impregnated with the drug and polyethylene glycol ether of oleo alcohol. The tank (3) is covered with a cover film (5) on which glue (4) is applied.

To create such a system, proceed as follows:

The protective film (1) equipped with a release agent coated with adhesive (2) is supplied with a circular plate (3) made of non-woven fabric. This circular plate of non-woven fabric is supplied with the formulation of the active substance. Then the cover film (5) coated with glue is applied by lamination.

Example 18:

Making of:

A protective foil, aluminized on one side and equipped with a release agent on both sides, is coated with a mixture consisting of:

71.1 g of polyacrylate glue solution

32.2 g of basic polyacrylate

6.7 g isopropyl lanolate,?

that after evaporation of the solvent, the surface mass of the layer with the separating agent is 50 g/m2 (glue 2-matrix).

On this layer with a release agent, a circular panel of non-woven fabric is placed, which is supplied with a mixture consisting of equal parts of Verapamil and POA (10) oleyl alcohol ether.

Verapamil concentration in the non-woven fabric after application:

65.3 mg/13.85 cm2.

The filled non-woven fabric and the coated protective film are covered (laminated) with a self-adhering cover film, which consists of a polyacrylate matrix with a surface mass of 100 g/m2 and a polyester film, so that the filled non-woven fabric is surrounded on both sides by self-adhering matrices. The resulting laminate is cut in such a way that next to the non-woven fabric there remains a 1 cm wider edge with a release agent without an active substance.

Mouse skin penetration: 3.78 mg Verapramil/2.54 cm2/24h.

Claims (8)

1. The use of lanolin derivatives together with polyethylene glycol ethers of fatty alcohols of long chains as substances, characterized by the fact that they facilitate the penetration of the ingredients of medicines or other biologically active substances contained in the formulation. 2. Formulation for increasing the transdermal penetration of ingredients of drugs or other biologically active substances, characterized by the fact that it facilitates penetration with the content of lanolin derivatives together with polyethylene glycol ether of fatty alcohols of long chains as a substance that enhances penetration. 3. Formulation according to claim 2, characterized in that the lanolin derivatives are selected from the group consisting of acetylated lanolin, acetylated lanolin alcohol, alkylated lanolin, lanolin acid, polyethoxylated lanolin acid, polyethoxylated lanolin alcohol, lanolin acid esters with allopathic short-chain alcohols such as isopropyl lanolate and ester of lanolin alcohol with long chain fatty acids. 4. Formulation according to claim 2, characterized in that polyethylglycol ethers of long-chain fatty alcohols are selected from the group consisting of conversion products of oleyl alcohol with 2 to 50 moles of ethylene oxide, lauryl alcohol with 2 to 40 moles of ethylene oxide, cetyl alcohol with 2 to 45 moles of ethylene oxide and of stearyl alcohol with 2 to 100 moles of ethylene oxide. 5. Formulation according to one of the claims 1 to 4, characterized in that the penetrating or penetration-facilitating substance consists of at least 1 wt.%, primarily 1 to 60 wt.% of a lanolin derivative and up to 99 wt.% primarily 30 -90 wt.% from one polyethylene glycol ether of long-chain fatty alcohols, whereby the sum of the components always amounts to 100. 6. Formulation for administration of Verapamil or Gallopamil through the skin (dermally), indicated in order to increase transdermal penetration, as ingredients that promote penetration, contain portions of lanolin derivatives in a mixture with polyethylene glycol ethers of long-chain fatty alcohols. 7. Application of lanolin derivatives, characterized by the fact that they are primarily selected from the group consisting of acetylated lanolin, acetylated lanolin alcohol, lanolinic acid, polyethoxylated lanolinic acid, polyethoxylated lanolinic alcohol, lanolinic acid esters with short-chain aliphatic alcohols such as isopropyl lanolate and lanolinic alcohol ester with long-chain fatty acids in a mixture with esters of isopropyl alcohol with long-chain fatty acids, primarily selected from the group consisting of isopropyl isosteareate, isopropyl laurate, isopropyl linoleate, isopropyl myristate, isopropyl palminate, isopropyl stearate and/or with polyethylene glycol ethers of long-chain fatty alcohols, primarily selected from the group , which consists of conversion products of oleyl alcohol with 2 to 50 moles of ethylene oxide, lauryl alcohol with 2 to 40 moles of ethylene oxide, cetyl alcohol with 2 to 45 moles of ethylene oxide and stearyl alcohol with 2 to 100 moles of ethylene oxide as substances that improve penet raid for Verapamil or Gallopamil containing formulations. 8. Transdermal therapeutic system for the administration of Gallopamil or Varapamil, characterized in that it contains the formulation according to one of claims 2 to 6.