HK1002700B - Galenic composition for topical use - Google Patents

Description

The invention relates to gallic compounds based on active substances which are introduced into the skin by means of novel micro-aggregates as carriers.

It is known that pharmacological active substances are liposomally encapsulated and applied topically as a dermatic. In DE-A-3542773 (J. Mueller) triamcinolonacetonide is proposed as a dermatological active substance.

For this reason, it has been proposed, inter alia, to use biologically inert carriers, e.g. fluorocarbons, for the transport of pharmacologically active substances. EP-A-91313 (York) proposes fluorocarbons with a vapour pressure of 1 to 16 mmHg, acting as carriers of water-sensitive or water-insoluble active substances, to be applied to the skin or eye. After evaporation of the fluorocarbon, the active substance remains on the skin in a dosed amount. EP-A-105584 (Yuha) describes a method to apply the action of a fluorocarbon emulsion with the help of chemotherapy and radiation therapy to hypoxic brain cells.

WO-A-89 00 848 describes a treatment and application procedure for medicinal products on the skin, in which fluorocarbons loaded with a therapeutic amount of oxygen, and, where appropriate, antibiotics or other medicinal products in the mixture, are applied to the skin. WO-A-89 08 459 describes a perfluorocarbon emulsion with phospholipid vesicles as a blood substitute, in which the phospholipid monomers are polymerized. WO-A-91 00110 reveals fluorocarbon emulsions with phospholipids in which the phospholipid has appropriate carbon bonds.

The present invention is intended to make pharmacologically active substances available in a biologically and chemically inert medium for therapeutic and diagnostic application on the skin or eye or for systemic application, while ensuring deeper penetration into the skin or transcutaneous transport.

According to the invention, a galenic composition for topical use consists of a lamellar phospholipid aggregate containing a fluorocarbon as a carrier of pharmacologically active substances, with a fluorocarbon or fluorocarbon-containing content in the range of 1 to 100% by weight/volume and a phospholipid phosphatidylcholine content of 30 to 99% by weight.

Surprisingly, the fluorocarbon, the active substance and the phospholipid interact to form an asymmetric lamellar aggregate with special properties compared to the dermal system. These new aggregates, unlike the known aqueous liposomes (vesicles), contain hydrophobic fluorocarbons in their core and thus form a monolayer with an inverse arrangement, whereby a build-up of bilayer layers may follow. According to the invention, the lamellar aggregates therefore have an asymmetric structure, unlike the known upper symmetric vesicles. Due to this modesty of their structural arrangement, the novel aggregates are called asymmetric lamellar tryptoplast. Their exceptional chemical stability is due to their high concentration in the cell membrane, which is also responsible for the synthesis of phospholipids (e.g. N-acetyl phosphatidyl phosphatidyl phospholipid) and their high concentration in the cell membrane, which is also due to the presence of a 99% N-acetyl phosphatidyl phosphatidyl phosphatidyl (PAPAP), and a 30% N-acetyl phospholipid phosphatidyl phosphatidyl phosphatidyl phosphatate (PA), respectively.

The nucleus of these aggregates is the fluorocarbon as a lipophilic substance. The lamellar structure and its asymmetrical arrangement have been demonstrated by 31P-NMR and in particular by special electron microscopic studies. The particle sizes and distributions have been determined by QLS studies. These range from 50 to 1000 nm in particle diameter. The particle sizes depend on the energy intensity of the homogenization process.

A wide variety of fluorocarbons may be used, e.g. aliphatic straight and branched chain fluoroalkanes, monocyclic or bicyclic and where appropriate fluoroalkyl substituted fluorocyclic alkanes, perfluorinated aliphatic or bicyclic amines, bis- (perfluoroalkyl) ethenes or mixtures thereof.

The concentration of fluorocarbons is in the range of 1 to 100% w/v, preferably in the range of 40 to 100%.

The phospholipids of the invention are natural phospholipids such as soy lecithin and eilecithin, synthetic phospholipids and/or partially hydrated phospholipids, where the phosphatidylcholine content of these phospholipids is in the range of 30 to 99% by weight, in particular 70 to 90%, i.e. in most cases, phosphatidylcholine enrichment occurs in the phospholipids.

In addition to phosphatidylcholine, lysolecithins may be present in the concentration range of 0.1 to 5% by weight. e claimed effect of phospholipids is verified by corresponding negative zeta potentials and by measuring charge densities (when titrated with a cationic polyelectrolyte).

The dependence of penetration rate and depth of penetration on the particle size of the aggregates was experimentally determined by separate animal studies with labelled encapsulated fluorocarbons. Afterwards, smaller particles migrate faster and deeper into the skin tissue than larger particles. The selection of fluorocarbons or their mixtures according to their lipid solubility (as indicated by their critical solubility temperature CST in n-hexane) as another important criterion allows the regulation of the time spent in the tissue. While, for example, perfluorocarbons (PF-TBA, CST 59° C) with a high CST and poorly soluble lipid mixture can be used to produce a greater solubility over time, the opposite is done in a correspondingly targeted way.

The content of fluorocarbons as active substance carriers in lamellar aggregates may vary from 1 to 100% w/v depending on the purpose of use. Aliphatic straight-chain and branched-chain alkanes with 6 to 12 carbon atoms, such as perfluorohexane, perfluorooctane, perfluornonan; monocyclic or bicyclic cycloalkanes, where appropriate substituted with F-alkyl, such as perfluoromethylcyclohexane, perfluordecalin; aliphatic tertiary amines, N-containing polycyclenes such as perfluoro-tripropylamine, perfluoro-tribulamine, F-cyclohexylmethylmorpholine; Perfluorethers, such as aliphatic ether, F-alkyl furanes, bicyclic and substituted bicyclic ether with 2 or 3 oxygen atoms in the molecule, such as perfluoridehexylethers, perfluorbutyltetrahydrofurans, perfluoropolyethers; Perfluoroalkyl halogenides, such as perfluorooctyl bromide, perfluorohexyl bromide, perfluorooctyl chloride; Bis-F (alkyl) ethers, such as bis-F (butyl) ethers, bis-F (hexyl) ethers.

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Individual fluorine atoms may also be replaced by other halogen atoms such as bromine or chlorine.

The phospholipids are naturally occurring phospholipids such as soy or oleocitins, as well as synthetically produced lecithins (phospholipids), which are known to be skin friendly and skin-care friendly. Because of their beneficial effect on the stability of asymmetric lamellar aggregates, phospholipid blends with a content of 30 to 99% phosphatidylcholine are used alongside other naturally occurring co-products.

The new lamellar phospholipid aggregates have the advantageous property of crossing the stratum corneum after topical application and of making the active substance available in the epidermal, dermal and adjacent tissues or of making it available to the vessel for systemic absorption. These penetration properties are used in accordance with the invention to transport pharmaceuticals into the skin tissue in interaction with the fluorocarbon and the phospholipid and to achieve a favourable therapeutic or diagnostic effect there or elsewhere, contrary to the specifications of the invention described in the present invention, which do not permit the transport of fluorocarbons into the deeper regions of the skin.

The galenic composition of the invention contains, as pharmacological active substances, in particular those of the following group: dermatological active substances, such as virostatics or virucidal medicinal products, antifungals, heparins (such as heparin, calcium, heparin sodium, low molecular weight heparin), antibiotics, corticosteroids, anti-infectious agents, acne agents, local anaesthetics, antiphlogistic agents, antihistamines or antipsoriatic agents; systemic agents, such as non-steroidal analgesics/ anti-rheumatic agents (e. g. diclofenac sodium, diclofenac diethylamine salt, etofenamate, flufenamic acid, 2-hydroxyethylsalicylate, ibuprofen, indomethacin, piroxicam), opioid receptor agonists and antagonists (e. g. buprenorphine, fentanyl, pentazocin, pethidine, tildidine, tramadol, naloxone), histamine antagonists (e. g. bamilamine lactate, chlorophenoxyl HCl, clemastin hydrochloride, dimenophenate, phenirophene hydrochloride), their regulators and inhibitors (e. g. border hormones and their inhibitors, sedatives and/ or hormones), their insulins, their peptides and their inhibitors (e. g. border hormones, sedatives, diaphragmins, and/ or their antagonists); Active substances in the group of cytotoxic agents, oncostatics, immunomodulators, vaccines.

A preferred dermatological active substance is, for example, rosmarinic acid or another plant virucide or virostatic agent. A preferred systemic active substance is, for example, a low- or high-molecular heparin, an oligopeptide or a polypeptide. Other preferred active substances are vitamins (E, A, B, C), muramyl peptides, doxorubicin, gentamycin, grammycidin, dexamethasone, hydrocortisone, progesterone, prednisolone or their derivatives and/ or acid or base additive salts.

With relevant active substances and combinations of active substances, antineoplastic therapy, antimicrobial and antiviral therapy and other therapies are possible for appropriate indications.

In general, the therapeutic amounts of active substances are very low, so that, for example, in the case of soluble active substances, solutions of 0.5 to 12 g/100 ml fluorocarbon are sufficient for medical use. If these solutions are not available, emulsification by means of the not yet fully elucidated interaction of fluorocarbon and phospholipid using known methods is also possible to obtain the corresponding galenic composition.

The invention also relates to a method for the preparation of a phospholipid-containing galenic composition consisting of emulsifying phospholipids with a phosphatidylcholine content of 30 to 99% by weight with a fluorocarbon or fluorocarbon mixture, incorporating a pharmacologically active substance or combination of active substances into the emulsion and with a fluorocarbon content in the range of 1 to 100% by weight/volume, and incorporating the resulting asymmetric lamellar aggregates as active substance carriers with a particle size of 50 to 1000 nm into an excipient suitable for topical application.

The most commonly used is a water-soluble lipophilic active substance or combination of active substances which dissolve or are dispersed/suspended in the fluorocarbon. Fluorocarbons are basically highly hydrophobic organic liquids. However, the wide range of chemical molecular structures allows for grading of the lipophilic properties, i.e. the different solubility properties of the active substances can then be adapted to a selected fluorocarbon in individual cases.

The present manufacturing process must take account of the often complex and delicate molecular structure of the active substances with different binding stability. Particular attention must be paid to this in the loading of the fluorocarbons or fluorocarbon chemicals, in the interaction with the phospholipids and in the homogenisation process, since the homogenisation process involves an external energy input to produce the lamellar phospholipid aggregates. This energy input must be measured in such a way as to preserve the molecular structure of the pharmaceutical. Homogenisation may be carried out by mechanical mixers, ultrasonic mixers, pressure homogenisers, etc., and may be adapted by the pharmaceutical specialist concerned. Fluorocarbons may also serve as an oxygen injection, to prevent the use of auto-antioxidants.

The invention is explained in more detail below by means of examples. Fig.1 Graph of critical solubility temperatures (CSTs) of perfluorocarbon chemicals in n-hexane with perfluoridecaline as the starting pointFig.2 Graph of critical solubility temperatures of perfluorocarbon chemicals in n-hexane with F-octyl bromide as the starting point.

Table 1 shows some selected fluorocarbons and their O2 solubility, vapour pressure and critical solubility temperature, which allow the selection of the desired skin penetration characteristics for fluorocarbon mixtures using the composition of the invention. Other Tabelle 1

Fluorcarbon	O₂-Löslichkeit [ml] O₂/100 ml FC]		CST [°C]
Perfluoroctylbromid	50	14	-24,5
Perfluordecalin	40	12,5	22
Bis-F(Butyl)ethen	50	12,6	22,5
F-cyclohexylmethylmorpholin	42	4	38,5
F-Tripropylamin	45	18,5	43
F-Dihexylether	45	2	59
F-Tributylamin	40	1	59
Perfluordecalin-F-Tributyl-amin 1/1	40	7	42
Perfluorbutyltetrahydrofuran	52	51	29
F-methylcyclohexan	57	180	8,2
F-Hexan	58	414	20

Example 1

A 10% aqueous phospholipid solution of soy lecithin and 40% phosphatidylcholine was mixed with a fluorocarbon mixture of perfluoredecalin (90%) and F-dibutylmethylamine (10%) and a pharmacological agent in an ultrasonic disintegrator under cooling, and the resulting asymmetric lamellar phospholipid aggregates had a mean particle size of approximately 240 nm and contained the pharmacological agent in interaction with the fluorocarbamide.

Example 2 Gel

The product obtained in example 1 was mixed with the individual components using the methods common to galenic processes, resulting in the following proportions of the finished galenic preparation. Other

asymmetrische lamellare Phospholipidaggregate	30 %
Diazepam	2 %
Polyacrylsäure	1 %
TEA	1 %
Konservierungsmittel	0,8 %
Aqua dest.	ad 100 %

Example 3 Alcoholic lotion

The following components were used as in example 2 Other

asymmetrische lamellare Phospholipidaggregate	20 %
Ethanol	16 %
Heparin-Na	150.000 iE
Aqua dest.	ad 100 %

Example 4 Cream

The following components were used as in example 2 Other

asymmetrische lamellare Phospholipidaggregate	20 %
Clotrimazol	1 %
Vaselinum album	79 %

Example 5 Lotion

The following components were used as in example 2 Other

asymmetrische lamellare Phospholipidaggregate	20 %
Estradiol	0,5 %
Polyacrylsäure	0,2 %
TEA	0,2 %
HCOH (37 %)	0,2 %
Aqua dest.	ad 100 %

Claims (16)

1. Pharmaceutical composition for topical administration with phospholipids and fluorocarbons, characterised by asymmetric lamellar aggregates, consisting of phospholipids having a phosphatidylcholine content of 30 to 99 % by weight, pharmacological active compounds and fluorocarbons or fluorocarbon mixtures, the amount of fluorocarbon being in the range from 1 to 100 % weight/volume, in a pharmaceutical excipient suitable for topical administration.
2. Composition according to Claim 1, characterised in that the lamellar aggregates have an asymmetric, preferably 3-layer, structure originating from their fluorocarbon core.
3. Composition according to Claim 1, characterised in that the fluorocarbons are selected from the group which consists of aliphatic straight-chain and branched fluoroalkanes, mono- or bicyclic optionally fluoroalkyl-substituted fluorocycloalkanes, perfluorinated aliphatic or bicyclic amines, bis(perfluoroalkyl)ethenes and mixtures thereof.
4. Composition according to Claim 3, characterised in that the fluorocarbons are selected from the group which consists of perfluorodecalin, F-butyltetrahydrofuran, perfluorotributylamine, perfluorooctyl bromide, bis-fluoro(butyl)ethene or C₆-C₉-perfluoroalkanes.
5. Composition according to Claims 1, characterised in that the amount of fluorocarbons is in the range from 20 to 100 % weight/volume, preferably in the range from 40 to 100 %, in particular in the range from 70 to 100 %.
6. Composition according to Claim 1, characterised in that the phospholipids are selected from the group consisting of natural phospholipids such as soya lecithin and egg lecithin as well as synthetic phospholipids, and/or partially hydrogenated phospholipids, in a concentration between 0.5 and 20 %.
7. Composition according to Claim 1, characterised in that phosphatidylcholine is present in an amount from 70 to 90 %.
8. Composition according to Claim 1, characterised in that in the lipid fraction used, in addition to phosphatidylcholine, lysolecithins are present in the concentration range from 1 to 5 % by weight.
9. Composition according to Claim 1, characterised in that as active compounds it contains one or more of the following groups, dermatological active compounds, systemic active compounds, cytostatics, cancerostatics, immunomodulators and vaccines.
10. Composition according to Claim 9, characterised in that the active compound is a pharmaceutical from the group consisting of virustatics or virucidal pharmaceuticals, antimycotics, heparins, antibiotics, corticoids, antiinfectious agents, acne active compounds, local anaesthetics, antiinflammatories, antihistamines or antipsoriatic agents.
11. Composition according to Claim 9, characterised in that the systemic active compound is a pharmaceutical from the group consisting of the non-steroidal analgesics/antirheumatics, opiate receptor agonists, opiate receptor antagonists, heparins, histamine antagonists, insulins, regulatory peptides, sedatives or hypnotics.
12. Composition according to Claim 9, characterised in that the dermatological active compound is rosmarinic acid or another virucidal or virustatic active compound found in plants.
13. Composition according to Claim 11, characterised in that the systemic active compound is a low molecular weight or high molecular weight heparin, or an oligopeptide or polypeptide.
14. Process for the preparation of a phospholipidcontaining pharmaceutical composition, characterised in that phospholipids having a phosphatidylcholine content of 30 to 99 % by weight are emulsified with a fluorocarbon or fluorocarbon mixture, a pharmacological active compound or an active compound combination being incorporated into the emulsion, and the amount of fluorocarbon being in the range from 1 to 100 per cent weight/volume, and the asymmetric lamellar aggregates obtained in this way being incorporated into an excipient suitable for topical administration as active compound carriers having a particle size from 50 to 1000 nm.
15. Process according to Claim 14, characterised in that the amount of fluorocarbons is in the range from 20 to 100 % by weight/volume, preferably in the range from 40 to 100 %, and the amount of phosphatidylcholine in the phospholipid is in the range from 70 to 90 %.
16. Use of a pharmaceutical composition for producing a system by topical application containing phospholipids having a phosphatidylcholine content of 30 to 99 % by weight, pharmacological active compounds and fluorocarbons in the form of asymmetric lamellar aggregates, the fluorocarbon content being in the range from 0.2 to 100 % weight/volume and the system being present in a carrier which is typical for topical administration, such as ointments, creams, lotions, pastes, gels and powders, if appropriate on a dressing or a plaster or as a spray.