Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/127—Liposomes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

• compositions based on cholinesterase inhibitors in liposomes on the preparation of such compositions and on their therapeutic applications.
• This effect occurs at very different concentrations of the agent in question, occurs at different receptor binding sites of the receptor, and can - in part depending on the concentration of the cholinesterase inhibitor itself and / or on the concurrent acetylcholine concentration - in one Blockage or an increase in the action of acetylcholine on the receptor result.
• galantamine since at concentrations that produce a therapeutically effective cholinesterase inhibition, it is an allosterically modulating ligand at a binding site distinct from the acetylcholine binding site (Samochocki et al., Acta Neurol Scand Suppl. 2000/176: 68-73; Dalas-Bailador et al., Mol Pharmacol. 2003; 64 (5): 1217-26). This will have the effect of inhibiting cholinesterase of galantamine potentiated increased concentration of acetylcholine additionally. Tacrine apparently also binds to this and another binding site of the receptor (Svensson and Nordberg, Neuroreport 1996; 7 (13): 2201-5).
• Nicotinic agonists have also been shown to be impaired in their therapeutic applicability by side effects such as high blood pressure and neurosuscular paralysis.
• Peripheral cholinesterase inhibitors are considered unsuitable for analgesic therapy in humans, mainly due to the problem of side effects (Ghelardini et al., Presynaptic Auto- and Heteroreceptors in the Cholinergic Regulation of Pain. In: Trends in Receptor Research, Elsevier Science Publishers BV , 1992).
• Transdermal formulations of cholinesterase inhibitors based on plasters which contain the active ingredient dissolved or distributed in a dermal penetration enhancer are known.
• passive transdermal systems include: EP-0376067, EP-0377147, EP-0667774, EP-0599952 and EP0517840 for Physostig in; WO-9934782 for rivastigmine; EP-0680325 for galantamine and WO-0132115 for huperzine.
• Moriearty et al. (Methods Find Exp Clin Pharmacol 1993; 15 (6): 407-12) describe such systems for metrifonate or its hydrolysis product, which is active as a cholinesterase inhibitor
• the active ingredient can also be temporarily deposited or bound in the subcutaneous fatty tissue in order to get from there In the skin itself there is intentionally only little retention of the active substance, and the systems mentioned are therefore unsuitable for the therapy of neuropathic pain or the impairment of the dermal sensory function by neurodegeneration controlled fre Is known active pharmaceutical ingredients (eg see overview in Ulrich, Biosci Rep. 2002; 22 (2): 129-50), in particular also for use in special transdermal “plaster” systems (for example disclosed in WO-8701938 and US-5718914) and in gels (US-5064655). Also the formulation of local anesthetics in topical applied liposomes are known to the person skilled in the art, eg describes US-4937078 Liposomes containing common sodium channel blockers such as tetracaine, lidocaine, etc.
• composition which produces an active substance depot in the skin from which substance is continuously released, which also achieves better bioavailability and a longer half-life compared to systemic use.
• these goals are achieved by providing a liposomal system for the topical administration of cholinesterase inhibitors.
• cholinesterase inhibitors in liposomes of a certain composition and size and subsequent formulation of these liposomes in suitable galenical systems for transdermal administration can achieve the aforementioned goals.
• the scalable process for active substance encapsulation disclosed in WO-0236257 has proven to be particularly advantageous for the production and loading of the liposomes with active substance on account of its high efficiency and at the same time extremely gentle process conditions.
• other methods known in the art for the production and loading of liposomes can also be used.
• the loading of liposomes with active substances can be divided into two main categories: loading the membrane and loading the intraliposomal aqueous phase.
• galantamine base is soluble in ethanol
• the proportion of membrane-bound and unbound galantamine was about the same. For this reason, an attempt was subsequently made to include the intraliposomal aqueous phase
• galantamine has chemical properties similar to doxorubicin and can be enclosed in liposomes by pH gradient-controlled loading.
• the most important characteristic is the liposome membrane / liposome medium distribution coefficient.
• the octanol / buffer distribution coefficient was found to be a good one
• the active ingredient must contain protonatable amino groups, so that the active ingredient is hydrophilic at low pH and lipophilic at neutral or alkaline pH.
• liposomes with different lipid compositions were prepared in a suitable loading buffer, preferably in a citric acid / sodium carbonate buffer. After the liposomes were made at low pH, the surrounding medium was alkalized and a pH gradient was created. After adding galantamine to the alkalized medium, the active ingredient migrated into the liposomes thanks to this pH gradient, where it was protonated and remained stable in the liposomes.
• the extent of the loading or the loading capacity is primarily determined by the ratio of the pH values inside and outside the liposomes.
• active substance / lipid ratios in the range of 200-400 nmol active substance per ⁇ mol lipid were able to achieve values similar to those known from the literature on actively loaded liposomes.
• An increase in the active substance concentration in the loading medium did not lead to an increase in the loading capacity.
• the active loading described above is a three-stage process consisting of vesicle formation, addition of active ingredients and alkalization. It was therefore a further object of the invention to establish a one-step manufacturing process which could be implemented using the cross-flow module disclosed in WO-0236257. For this purpose, galantamine was dissolved in citric acid solution using
• the examples below show, among other things, that the quality of the liposomes loaded with active ingredients can be improved by variation, in particular by reducing the cholesterol content in the vesicle membrane, especially with regard to their ability to penetrate the skin.
• stability tests for the products from the three-stage and the one-stage process prove that both products even after more than six months Storage, the product stability and quality has remained unchanged.
• the loading capacity can be further increased by increasing the average liposome size from approximately 150-200 nm (as is mostly used in the experiments described herein) to 300 to 500 nm.
• the efficiency of the process i.e. the amount of liposomally enclosed active ingredient per ml of suspension, by increasing the
• Fig.l shows a schematic representation of a device for producing the liposomes.
• Fig.2 shows HPLC results from galantamine inclusion experiments in liposomes. Dark bars represent galantamine in the retentate (i.e. liposomal galantamine), light bars on the other hand in the filtrate (not included galantamine) and the empty bar the total amount of galantamine; Ordinate: galantamine in ⁇ g / ml.
• Fig.3 shows HPLC results of galantamine inclusion experiments in liposomes. Dark bars represent galantamine in the retentate (i.e.
• liposomal galantamine liposomal galantamine
• light bars on the other hand, in the filtrate (not included galantamine) and the empty bars represent the total amount of galantamine; first three bars: positively charged liposomes with stearylamine; last three bars: negatively charged liposomes with E-PG; 3A: galantamine HBr; 3B: Galantamine base.
• Fig.4 shows HPLC results of galantamine inclusion experiments in liposomes. Dark bars represent galantamine in the retentate (ie liposomal galantamine), light bars on the other hand in the filtrate (not included galantamine) and the empty bar the total amount of galantamine.
• Fig.5 shows the results of a stability test with actively loaded galantamine liposomes at different pH values aqueous phase; Ordinate: active substance concentration in nmol active substance per ⁇ mol lipid; Abscissa: period in weeks since the preparation of the preparations.
• Fig.6 shows HPLC data of loading preformed liposomes with galantamine as a function of temperature and loading time. Data in percent of the presented galantamine concentration.
• Fig.7 shows HPLC data of actively loaded liposomes in the presence of an excess of galantamine from two production attempts. Dark bars represent the amount of non-trapped, light bars that of liposomally trapped galantamine. The light line between the triangle symbols (associated values: right ordinate) indicates the stable lipid / drug ratio.
• Fig.8 shows stability data of a liposome preparation, in which the liposomes were actively loaded with galantamine in a one-step process.
• Ordinate active substance concentration in nmol active substance per ⁇ mol lipid; Abscissa: period in weeks since the preparation of the preparations.
• Fig. 9 shows stability data of actively loaded galantamine liposomes: A) produced in a three-step process; B) produced in a one-step process.
• Fig.10 shows galantamine inclusion rates and stability of actively loaded DMPC liposomes.
• Fig.11 shows the galantamine intake in DPPC liposomes depending on the cholesterol content.
• Fig.12 shows a stability test of galantamine liposomes, produced according to the ammonium sulfate gradient method.
• Fl, F2, F3 denote filtrate samples, R stands for retentate.
• Fig.13 shows the stability of galantamine liposomes with lipids of different chain lengths (A: C16 and B: C14) in hydrogel formulations.
• Fig. 14 shows the result of in vitro skin penetration studies with liposomal galantamine preparations with different lipid compositions. Ordinate: ng galantamine absolutely in the respective sample; Abscissa: variations in lipid composition.
• Fig.15 shows the result of in vitro skin penetration studies with liposomal galantamine preparations after repeated application.
• Fig. 16 shows the result of in vitro skin penetration studies with liposomal galantamine preparations depending on the amount of sample and the duration of penetration.
• Fig.17 shows the result of in vitro skin penetration studies with liposomal galantamine preparations depending on the hydrogel concentration.
• Fig. 18 shows the result of in vitro skin penetration studies with galantamine preparations in the form of microemulsions.
• Fig. 19 shows the result of in vitro skin penetration studies with hydrogel preparations based on freely available galantamine in comparison to galantamine enclosed in liposomes.
• Fig.20 shows the result of in vitro skin penetration studies with liposomal galantamine preparations in the form of a suspension or as a gel.
• Fig. 21 shows the result of in vitro skin penetration studies with liposomal galantamine preparations on various skin samples.
• Liposomes can be adapted to the physicochemical properties of these molecules.
• Synthetic dipalmitoylphosphatidylcholine (DPPC, Genzyme, Switzerland) and cholesterol (Solvay, The Netherlands) were used to produce the vesicles.
• the liposomes were preferred by means of the shear force-free ones
• the detection of entrapped galantamine was carried out after ultrafiltration and / or diafiltration in a stirred cell (Amicon, USA) or after gel filtration over Sephadex G25 columns (Pharmacia, Germany) by means of rp-HPLC (reversed phase high performance liquid chromatography).
• rp-HPLC reversed phase high performance liquid chromatography
• the in-house rp-HPLC technology allows the quantitative determination of the membrane component cholesterol and the active ingredient galantamine within a single run. Liposome size and distribution were determined using photon correlation spectroscopy (PCS).
• the liposomes are preferably produced using cross-flow technology.
• the device for liposome production consists of a cross-flow injection module 1, containers for the polar phase (injection buffer 2 and dilution buffer 3), a container for the ethanol / lipid solution 4 and a nitrogen compressor 5.
• the injection opening in Cross-flow module has a diameter of approx. 250 ⁇ m.
• the lipid mixture is preferably dissolved in 96% ethanol at a temperature in the range of - depending on the lipid selection or lipid composition - 25 to 60 ° C, for example in the case of DPPC liposomes at a temperature of 50 to 55 ° C, with stirring.
• the buffer solutions are also preferably heated to the same temperature, for example 55 ° C.
• a pump 6 e.g. a peristaltic pump
• the ethanol / lipid solution is simultaneously injected into the polar phase under any preselectable pressure.
• DPPC cholesterol and stearylamine (molar ratio 7: 2: 1) are dissolved together with galantamine in 96% ethanol and in PBS- Buffer injected. After the liposomes have formed spontaneously, they are filtered and both the retentate and the filtrate are analyzed by rp-HPLC. As can be seen from Fig. 2, galantamine cannot be integrated into the liposomes in a stable manner. Filtrate (not included galantamine) and retentate (liposomally included galantamine) show identical drug concentrations. In Fig. 2, the 1st bar means: the total amount of galantamine provided; the 2nd and 3rd bars: the active ingredient distribution in filtrate and retentate after the first (2nd bar) and after a further diafiltration (3rd bar).
• Variant II The lipids were again dissolved in ethanol.
• stearylamine was replaced by hen's egg phosphatidylglycerol (E-PG).
• E-PG hen's egg phosphatidylglycerol
• the ethanol / lipid solution is injected either into a solution of PBS / galantamine base or into a PBS / galantamine HBr solution.
• the proportion of galantamine in the filtrate is considerably lower than in the retentate, which confirms that a large part of the galantamine obviously migrates into the liposomes along this pH gradient, is protonated and remains in the acidic environment within the liposomes.
• the 1st bar means: the total amount of galantamine provided; the 2nd and 3rd bars: the active ingredient distribution in filtrate and retentate after the first (2nd bar) or after a further diafiltration (3rd bar).
• Fig. 5 shows the product stability over a period of 9 weeks.
• Fig. 6 shows that the entire amount of galantamine migrates into the liposomes within about 15 minutes and that an incubation temperature in the region of room temperature (18 - 22 ° C) is favorable for both the absorption of active substances and the retention of active substances within the liposomes.
• the differences determined for a range of 22 - 40 ° C are small and in any case do not play a significant role.
• the negative influence of higher incubation temperatures appears to have an impact primarily on the stability of the loaded liposomes, whereby at a temperature of 60 ° C the loss of active ingredient is already in a range of approx. 20 - 25% after 3 h incubation (Fig. 6).
• Galantamine prepared per ml of solution. As can be seen from Fig.7, however, an excess of galantamine (dark bars; left ordinate) cannot improve the ratio of active substance / lipid, which remains constant in this experiment at around 200 - 300 nmol galantamine per ⁇ mol lipid (light line between the triangle symbols ; right Ordinate).
• the effective loading amount with active external loading via a pH gradient thus appears to be primarily dependent on the gradient and less on the active substance concentration presented.
• Buffer solution pH 9.0 - 9.5
• the amount of galantamine taken up in such a liposomal manner - depending on the pH value or pH gradient - was in a range of at least 100 nmol galantamine per ⁇ mol lipid, preferably in a range of at least 150-400, for example at a pH value of 3 , 5 often in the range of 250 to 350 ( Figures 8-11).
• the stability of this product was fully preserved over an observation period of 6 weeks (see Fig.8).
• Example 2 Preparation and comparison of galantamine preparations in the form of liposomes or microemulsions with a variable lipid composition
• DPPC dipalmitoylphosphatidylcholine
• DMPC dimyristoylphosphatidylcholine
• cholesterol Solvay, Netherlands
• Galantamine Sanochemia AG, Austria
• Citric acid / sodium carbonate was used as the buffer solution.
• the ammonium sulfate gradient method was used as the second option for active loading.
• Cross-current technology was used again.
• preparations in the form of microemulsions were also produced by vigorous mixing with gradual heating with several heating cycles (heating up to 80 ° C).
• IPM Isopropyl myristate
• Tween and Span 20 were used as emulsifiers and co-emulsifiers.
• Fig.9A shows stability data of the first liposome sample successfully loaded with galantamine using the active method (three-stage method).
• the liposomes were prepared in the presence of 0.3 mol of citric acid (pH 3.5-4.5). After vesicle formation, galantamine was added and at the same time the pH of the solution outside the liposomes was raised to 7.5. The resulting pH gradient between the inside and outside of the liposomes led to the uptake of galantamine in the liposomes, depending on the H + ion concentration within the liposomes.
• Fig. 9B shows stability data of liposome samples with a similar composition, but the vesicle formation and galantamine loading were carried out using the cross-flow technique in a one-step process.
• the data clearly show that the pH gradient and thus the content of liposomally entrapped galantamine has remained constant over a period of more than half a year.
• various liposome suspensions with different lipid compositions were prepared and tested. In the first place
• Phospholipids optionally in combination with cholesterol, are used. However, it is within the scope of the invention to replace or supplement phospholipids with other lipids, for example with glycolipids, cerebrosides, sulfatides or galactosides.
• Typical representatives of the lipids that can be used are e.g. Phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, cardiolipin, sphingomyeline, plasmalogens, glyceroglycolipids, ceramide, glycosphingolipids, neutral glycosphingolipids.
• DPPC a phospholipid with an acyl chain length of 16 carbon atoms
• DMPC chain length of 14 carbon atoms
• Fig.10 shows inclusion rates of such liposome suspensions, which were prepared using pH gradients of 3.5 - 7.5 and 4.0 - 7.5. After satisfactory inclusion rates (comparable to those when using DPPC) were achieved, samples were taken and checked for their stability (Fig.10).
• a second way to lower the membrane rigidity and to increase the fluidity is to reduce the cholesterol content in the membrane.
• DPPC cholesterol ratio of 55: 45 mol% (as described in the literature for liposome loading)
• the amount of cholesterol was successively reduced to 38 or 30%, based on the total lipid content.
• Figure 11 shows a slight decrease in the galantamine load compared to previous data with higher cholesterol levels. These liposomes showed however, improved skin penetration properties, as will be described below.
• Fig.11 also shows that the loaded liposomes remained stable in the long-term experiment and no galantamine was lost.
• cholesterol-free liposomes could also be produced stably and successfully loaded with active substance, so that, according to the invention, the cholesterol content is in a range from 0 to 50 mol%, based on the total lipid content.
• a third way to make liposomal membranes more flexible is to replace the fully saturated DPPC or DMPC lipids with chicken egg phosphatidylcholine (E-PC), a natural lipid mixture with unsaturated phospholipids.
• E-PC chicken egg phosphatidylcholine
• the ammonium sulfate gradient method is also frequently used. With this method, liposomes are formed in the presence of an ammonium sulfate buffer (125 mmol). After vesicle formation, the ammonium sulfate solution outside the liposomes is replaced by a 5% glucose solution by means of diafiltration, as a result of which small amphiphilic molecules can be loaded into the liposomes and protonated there, while in turn NH3 escapes from the liposomes. This process is known to be the milder process compared to the citric acid / sodium carbonate process.
• citric acid could also be replaced by another suitable, pharmaceutically acceptable acid, for example a mineral acid such as phosphoric acid, or preferably by an organic acid, in particular from the group of edible organic acids, such as malic acid, fumaric acid, tartaric acid
• sodium carbonate could also be replaced by another base, in particular by another alkali or alkaline earth carbonate or bicarbonate.
• “functionally equivalent” is to be understood as the ability to be able to form a pH gradient across the lipid bilayer membrane of the liposomes and not to destroy the membrane integrity, so that the enclosed, in particular protonated, active ingredient is stable - in the sense of the stability criteria disclosed herein - remains in the liposomes.
• a liposomal galantamine composition As a topical therapeutic agent, the liposomes are preferably mixed into a hydrogel which is easier to apply to the skin than a pure suspension.
• it is within the scope of the present invention to also produce and topically apply other galenical formulations for the galantamine liposomes in particular formulations in the form of solutions, lotions, emulsions, tinctures, sprays, ointments, creams or optionally also in the form of impregnated textile fabrics or dressing materials.
• Other possibilities are familiar to the person skilled in the art, as are the pharmaceutically permissible accompanying substances and additives required for producing the various pharmaceutical formulations.
• Carbopol 981NF a hydrogel that can be used in very low concentrations, has proven itself in previous experiments. It is approved for pharmaceutical use, relatively cheap to buy and in large quantities available.
• the vesicle suspensions were concentrated by ultrafiltration and subsequently stirred with a prefabricated, sterile gel base mixed. With this method, the liposomal galantamine concentrations can be varied either via the ultrafiltration or via the initial concentration of the gel base, which is diluted to a carbopol concentration of 0.5% with the vesicle suspension.
• microemulsions In addition to liposomes, microemulsions have also attracted increasing attention for topical applications of certain active ingredients in recent years. Microemulsions are dispersions of two immiscible components that are stabilized by a third, amphoteric component. However, due to the presence of surface-active substances such as emulsifiers and co-emulsifiers, microemulsions can damage the skin in a similar way to transdermal patches.
• Microemulsions prepared with galantamine as the active ingredient and then subjected to penetration tests with the Franz diffusion cell (results see Examples 3 to 10).
• Table 1 Microemulsions lecithin ME W / O ME O / W ME 10 ml IPM 7.2 ml IPM 5.5 g H20 1.9 g SPC 0.2 g Chol 2.5 g IPM 135 ⁇ l H20 0.5 g H20 2 g Tween / Span20 10 mg Gal 2g Tween / Span20 11 mg Gal-HBr 10 mg Gal 5 mg Gal
• the diffusion cell was from PermGear, USA.
• the equipment included three diffusion cells, each with a double jacket filled with water, mounted on a stirrer console and connected to a water bath for temperature control.
• the cells themselves have a volume of 8 ml each, a skin holder with a surface area of 0.78 cm2 and a feed chamber with 2 ml Volume capacity.
• Pig skin was used for the tests in the Franz diffusion cell. To ensure an intact skin surface, each piece of skin was tested before and after the experiment. After the skin had been attached to the skin holder of the diffusion cell, 2 ml of buffer were applied to the skin and the temperature was raised to 32 ° C. +1. After 30 minutes, electrical conductivity, a measure of skin resistance and skin quality, was measured. The measured value depends on the origin of the skin, its thickness, the buffer system used and the equipment used for the measurement. On the basis of several basic experiments, a limit value for the electrical conductivity of the intact skin of ⁇ 1 mS / cm2 was determined before the application of a sample. Skin samples that did not meet this requirement were not approved for the penetration experiments.
• the excess galantamine sample was removed by washing the surface with buffer.
• the electrical conductivity was then measured again and the skin sample removed from the holder.
• Membrane compositions of the liposomes were obtained by using different lipids and different cholesterol contents (see Examples 1 and 2).
• the following penetration studies were carried out with different sample volumes, single and multiple sample tasks, samples being taken at intervals to determine galantamine.
• the results shown in Figures 14 to 21 are each based on a triple penetration experiment.
• the diagrams show the results in ng galantamine absolutely for each sample analyzed.
• Example 3 the results of various DPPC (C16) liposomes with different cholesterol contents are compared to those of DMPC (C14) liposomes and E-PC liposomes.
• a sample volume of 50 ⁇ l was applied once and allowed to penetrate over a period of 4 hours. All preparations tested had comparable amounts of entrapped galantamine and were suspended in 0.5% Carbopol 981NF.
• the most effective formulation in this experiment was the sample with the C16 / 70/30 (acyl chain length / mol% phospholipid / mol% cholesterol) lipid composition. In this gel, the cholesterol concentration in the liposomes was 30 mol%.
• the other two preparations had significantly higher cholesterol levels (38 and 45 mol%) and were therefore much more rigid.
• Example 4 the penetration properties of gel samples after repeated application to the skin were examined. Two different gels with different lipid compositions and the same cholesterol content were compared. The samples were applied three times with 50 ⁇ l each and every 4 hours. Excess material was removed before the next sample was applied.
• Example 5 gels with Cl6 liposomes with high and low cholesterol contents were compared after a single application. Sample volumes of 150 ul and 50 ul were allowed to penetrate for 4 and 10 hours, respectively. The highest levels of galantamine in the skin were found again when using liposomes with a low cholesterol content. Low doses seem to be more advantageous here too. After 4 and 10 hours, high amounts of galantamine were found in the epidermis when 50 ⁇ l was used. These results confirm the values that were achieved in Examples 3 and 4, ie the administration of liposomes with low cholesterol contents and at the same time a low application amount overall, could represent a favorable strategy for the topical application of the preparations according to the invention in prophylactic or therapeutic use ( Fig.16).
• Example 6 the influence of the gel concentration in connection with three different concentrations of free galantamine suspended in the gel was investigated. 50 ⁇ l of each formulation was applied once and the penetration experiment was carried out over 4 or 10 hours (Fig.17). The first three bars in Fig.17 represent the results with 1% Carbopol 981NF after 4 h, the next three bars those with 0.5% Carbopol 981NF after 10 h. The results after 4 hours show that free galantamine diffuses into the skin tissue relatively quickly. However, as can be seen from the 10 h values, the free active ingredient was also found in high concentrations in the receptor fluid, so that only a slight depot effect can be expected (Fig. 17).
• Example 7 various application strategies were tested. It is known from the literature that microemulsions can be useful tools as carrier systems for the administration of small amphiphilic molecules. In order to check this concept, various microemulsions (lecithin; water in oil; oil in water) with 1 mg galantamine per ml each were produced (see Examples 1 and 2).
• the amount of galantamine in the skin is lower than when using the hydrogel with liposomes.
• the active ingredient was equally distributed in the dermis (dermis) and receptor fluid, which suggests that rapid penetration with at best marginal storage in the skin tissue took place (Fig.18).
• Example 8 the results with free galantamine in hydrogel and microemulsions were compared to those of the preferred liposome composition (C16 low cholesterol phospholipids). In all experiments, comparable concentrations of galantamine were examined under similar conditions.
• Example 9 liposomal formulations in suspension and in hydrogel were compared with one another.
• the administration of an excess of 1 ml of liposomal suspension over a period of at least 24 hours resulted in only a slight decrease Penetration effectiveness (Fig.20). So it seems to be confirmed that a suitable gel matrix not only stabilizes the liposomes and makes application more pleasant and convenient, but also brings the liposomes closer to the skin and thus increases the penetration effect.
• Fig. 20 they mean: (chain length / phospholipid / cholesterol / sample amount / penetration time / type)
• liposomal galantamine formulations in hydrophilic gel represent an advantageous dosage form if the place of treatment is in the dermal tissue (dermis), even if the active ingredient is only applied to the skin twice a day.
• a mild depot effect in the epidermis and a slow, uniform release of the active ingredient into the underlying dermal tissue can be achieved by the inventive, mild, non-invasive and non-irritating use of the liposomally enclosed active ingredient.

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