Liposomal, hormone-containing formulation

Abstract

Liposomal, hormone-containing formulation comprising the components 345 parts by weight of 85% aqueous glycerol; 40 parts by weight of water; 15 parts by weight of lecithin; 50 parts by weight of medium-chain triglycerides; 40 parts by weight of isopropanol; 5 g hormone or hormone compound; 5 parts by weight of xanthan gum; the hormone propionate content and the xanthan gum content are each kept between 1% by weight and 4% by weight of the total mass, and the masses of the other ingredients can each be kept up to 30% higher or lower.

Description

[0001] The present invention can be assigned to the scientific field of liposome production. Liposomes are vesicles whose shell is formed from at least two layers of amphiphilic molecules. Liposomes potentially offer the possibility of encapsulating an active ingredient and applying it transdermally.

[0002] Typical methods for producing liposomes include the dripping of a hydrophilic phase into a lipid phase, the homogenizing extrusion of liposome mixtures through fine pores, the high-pressure homogenization of emulsions, or the ultrasonic conditioning of aqueous solutions.

[0003] The present invention is located in the field of these methods and is directed to liposomal formulations in the field of pharmaceuticals, in particular steroid hormones and non-steroidal anti-rheumatic drugs.

[0004] Steroid hormones include: pregnenolone, testosterone, estradiol, estriol, progesterone, aldosterone, dehydroepiandrosterone.

[0005] Non-steroidal anti-inflammatory drugs include diclofenac and ibuprofen.

[0006] If testosterone or estradiol are administered orally, they are detrimentally eliminated in the liver through the first-pass effect. Approaches such as those disclosed in EP 000000220030 B1 involve combining active ingredients or hormones with components that the body recognizes as essential components and incorporates them via carrier systems. A disadvantage is that the carrier systems work in a molecule-specific manner; attached additives or accompanying molecules that significantly alter the three-dimensional shape make effective incorporation impossible, and the previously described degradation occurs again before the hormone can reach a target tissue or target compartment of the body or system. STATE OF THE ART

[0007] In men, testosterone deficiency (hypogonadism) has numerous negative effects, such as changes in secondary sexual characteristics, decreased libido, erectile dysfunction, depression and reduced bone mass.

[0008] Injection of the active ingredients or transdermal application bypasses the digestive tract, but must subsequently re-penetrate membranes and separating vessel walls to be active at the respective target site. For example, a pharmacy product with the trade name "Testogel" contains 5 g of application mass and is formulated as a liposomal testosterone gel. The disadvantages of such gels are large amounts of very expensive testosterone (at least 10% by weight of the respective hormone compound is common and frequently encountered), ethanol, and co-emulsifiers. This also has an environmental impact, as hormones are among the most effective substances and their use should be technologically limited to an absolute minimum.The disadvantages of the transdermal steroid products in the form of capsules or gels currently available on the market are the relatively high amounts of active ingredient, the high alcohol content, and the use of co-emulsifiers, which simultaneously reduce the activity and prevent targeted permeation to a target site.

[0009] The object of the present invention is therefore to overcome the disadvantages of the prior art and to provide a formulation which, despite transdermal application, provides better permeation of hormones and hormone compounds at reduced manufacturing costs.

[0010] The problem is solved according to the features of the independent claim. Advantageous features, measures, and embodiments emerge from the dependent claims and the following description. SUMMARY OF THE INVENTION

[0011] According to the invention, a liposomal, hormone-containing formulation comprises 345 parts by weight of 85% aqueous glycerol 40 parts by weight of water 15 parts by weight of lecithin 50 parts by weight of medium-chain triglycerides, 40 parts by weight of isopropanol, 5 g hormone or hormone compound, 5 parts by weight of xanthan, whereby the content of hormone propionate and also the content of xanthan is each between 1% by weight and 4% by weight of the total mass and the masses of the other components can each be up to 30% higher or lower. DESCRIPTION OF THE INVENTION AND ADVANTAGEOUS FEATURES

[0012] According to the invention, a liposomal, hormone-containing formulation comprises 345 parts by weight of 85% aqueous glycerol 40 parts by weight of water 15 parts by weight of lecithin 50 parts by weight medium-chain triglyceride 40 parts by weight of isopropanol, 5 g hormone or hormone compound, 5 parts by weight of xanthan, whereby the content of hormone propionate and also the content of xanthan is each between 1% by weight and 4% by weight of the total mass and the masses of the other components can each be up to 30% higher or lower.

[0013] 'Hormones' in the sense of the present invention include hormones such as testosterone, progesterone and non-steroidal anti-inflammatory drugs.

[0014] The formulation is preferably obtained by a) preparing a hydrophilic, glycerol-water-based mixture; b) adding vegetable oils, alcohol (isopropanol or ethanol) and steroid hormone, e.g., testosterone; c) stirring thoroughly until a mechanically pre-homogenized mixture is formed; d) immediately transferring the pre-homogenized mixture to a homogenizer and homogenizing the mixture under cavitation until the temperature has risen by 10°C to 30°C without reaching boiling point; e) immediately transferring it to a pre-heated stirrer and adding the xanthan to create a gel. In this way, opaque, translucent gels are obtained without the need for a co-emulsifier, which achieve demonstrable effects combined with significantly faster permeation to the target tissue using just a fraction of the usual amount of active ingredient - in practical measurements, as little as 1 / 10.

[0015] Preferably, a homogeneous mixture without gelling agent is first prepared. After intensive stirring of the mixture, this pre-homogenized mixture is sonicated at 150 Ws / ml using ultrasound. The warm liposomal formulation thus produced is then placed in a preheated mixer and gelled with 5 g of xanthan gum. The present invention is technologically based on previous international applications, with the crucial difference that after sonication using ultrasound, the liposomal formulation is not quenched (i.e., rapidly cooled and metastably fixed), but is immediately gelled in the heat with a suitable gelling agent. This slows down the particle movement of the liposomal formulation and simultaneously increases microbiological stability. The inventors further assume that liposomal formulations can also exhibit aging processes similar to Ostwald ripening.Direct gelation initially reduces the diffusion rate in the product and slows down Ostwald ripening. The resulting gel is thus a fresh product or formulation that—made fresh on demand—can provide superior efficacy for days to weeks at significantly lower costs.

[0016] Additional refrigeration and optimized packaging can extend this time to several months: If the produced gel is placed in an airless dispenser with a dispensing volume of 0.5 g (e.g. a Dospenser from Pohli (Wuppertal)), a quantity of 0.5 g can provide 4 mg of testosterone, which was able to produce a better increase in testosterone blood levels than an established formulation with several times the hormone content using identical transdermal application. In addition, thanks to encapsulated portioning and storage in the refrigerator, the product was easily stable for several weeks and showed no deterioration in its kinetics of action. In this advantageous packaging, liposomal, steroid-containing gels - here with testosterone as the hormone - were repeatedly able to produce superior increases in blood testosterone levels with an applied quantity equivalent to 4 mg of testosterone.A shelf life of 6 months could be achieved with proper storage without the need for problematic phenoxyethanols / sorbates as preservatives or stabilizers. DETAILED EXPLANATION OF THE INVENTION USING EXEMPLARY EMBODIMENTS Example 1: Testosterone Gel

[0017] In a blender, 345 g of 85% glycerol and 40 g of water are mixed with 15 g of sunflower lecithin by vigorous stirring. Then, while stirring, add 50 g of medium-chain triglycerides, 40 g of isopropanol, and 5 g of testosterone propionate.

[0018] After intensive stirring, this pre-homogenized mixture is ultrasonically treated at 150 Ws / ml. The resulting warm liposomal formulation is then poured into a preheated mixer and gelled with 5 g of xanthan gum.

[0019] The resulting gel is dispensed into a 0.5g airless dispenser from Pohli (Wuppertal). This 0.5g volume corresponds to 4mg of testosterone, which has a positive effect on testosterone blood levels when applied transdermally. Example 02: Progesterone Gel

[0020] In a blender, 335 g of 85% glycerol and 40 g of water are mixed with 15 g of sunflower lecithin by vigorous stirring. Then, while stirring, add 40 g of medium-chain triglycerides, 40 g of isopropanol, and 15 g of progesterone.

[0021] After intensive stirring, this pre-homogenized mixture is ultrasonically treated at 150 Ws / ml. The resulting warm liposomal formulation is then poured into a preheated mixer and gelled with 5 g of xanthan gum.

[0022] The resulting gel is dispensed into an airless dispenser with a dispensing volume of 0.5 g from Pohli (Wuppertal). This 0.5 g contains 15 mg of progesterone, which has a positive effect on blood progesterone levels when applied transdermally. If necessary, multiple doses can be applied depending on the patient's cycle, as directed by a physician. Example 03: Diclofenac Gel

[0023] In a blender, 350 g of 85% glycerol and 45 g of water are mixed with 15 g of sunflower lecithin by vigorous stirring. Then, while stirring, add 40 g of medium-chain triglycerides, 40 g of isopropanol, and 10 g of diclofenac.

[0024] After intensive stirring, this pre-homogenized mixture is ultrasonically treated at 150 Ws / ml. The resulting warm liposomal formulation is then poured into a preheated mixer and gelled with 5 g of xanthan gum.

[0025] The resulting gel is dispensed into a 1-g airless dispenser from Pohli (Wuppertal). This 1-g quantity contains 20 mg of diclofenac, which provides a good analgesic effect via transdermal application. Example 04:

[0026] In an advantageous embodiment, several of the above-described formulations are filled into a multidispenser as a gel. The multidispenser thus contains at least two gels and, for each gel, the enclosed, airtight dispensing function of an airless dispenser, which operates without the penetration of outside air. This allows active ingredients to be combined topically or applied individually; in particular, the combination of pain-relieving and regeneration / revitalizing active ingredients is possible directly and particularly effectively.

[0027] Particularly preferably, the multi-dispenser includes a separate dosing device for each gel; this allows even the amounts of active ingredients to be coordinated and applied within the framework of a controlled, balanced rehabilitation. QUOTES CONTAINED IN THE DESCRIPTION

[0000] This list of documents submitted by the applicant was generated automatically and is included solely for the convenience of the reader. This list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions. Cited patent literature

[0000] EP 000000220030 B1

[0006]

Claims

[1] Liposomal hormone-containing formulation comprising the components 345 parts by weight of 85% aqueous glycerol; 40 parts by weight of water; 15 parts by weight of lecithin; 50 parts by weight of medium-chain triglycerides; 40 parts by weight of isopropanol; 5 g of hormone or hormone compound; 5 parts by weight of xanthan gum; wherein the content of hormone propionate and also the content of xanthan gum is each kept between 1 percent by weight and 4 percent by weight of the total mass, and the masses of the other components may each be kept up to 30% higher or lower. [2] Liposomal formulation according to the preceding claim, wherein the formulation was obtained by a) preparing a hydrophilic, glycerol-water-based first mixture; b) adding an oleophilic, alcoholic mixture containing a hormone or hormone compound; c) stirring thoroughly until a mechanically pre-homogenized mixture is obtained; d) immediately transferring the pre-homogenized mixture to a homogenizer and homogenizing the mixture under cavitation until the temperature has increased by 10°C to 30°C without reaching the boiling point; e) immediately transferring the mixture to a preheated stirrer and adding xanthan gum to produce a gel. [3] Liposomal formulation according to the preceding claim, characterized by , that in step d an ultrasonic homogenizer is used as a homogenizer. [4] Liposomal formulation according to one of the two preceding claims, characterized by, that in step e the liposomal formulation is gelled immediately after ultrasonic homogenization in the preheated stirrer with at least one additional gelling agent. [5] Liposomal formulation according to any of the preceding claims, characterized by that the formulation is filled into an airtight container with a closed dosing function that is airtight to the outside without the ingress of outside air. [6] Testosterone gel according to any of the preceding claims. [7] Progesterone gel according to any one of claims 1 to 5. [8] Diclofenac gel according to any one of claims 1 to 5. [9] Multi-dispenser containing at least two gels according to one of the preceding claims, each containing a gel having a closed, airtight dispensing function that operates without the ingress of outside air. [10] Multi-dispenser according to the preceding claim, further comprising a separate dispensing device for each gel.