CA2381571A1 - Phospholipid gel - Google Patents
Phospholipid gel Download PDFInfo
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- CA2381571A1 CA2381571A1 CA002381571A CA2381571A CA2381571A1 CA 2381571 A1 CA2381571 A1 CA 2381571A1 CA 002381571 A CA002381571 A CA 002381571A CA 2381571 A CA2381571 A CA 2381571A CA 2381571 A1 CA2381571 A1 CA 2381571A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/04—Dispersions; Emulsions
- A61K8/042—Gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
- A61K8/34—Alcohols
- A61K8/345—Alcohols containing more than one hydroxy group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/55—Phosphorus compounds
- A61K8/553—Phospholipids, e.g. lecithin
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- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- 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
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- 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
- A61K9/1277—Processes for preparing; Proliposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/0052—Preparation of gels
- B01J13/0065—Preparation of gels containing an organic phase
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dispersion Chemistry (AREA)
- Birds (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biophysics (AREA)
- Organic Chemistry (AREA)
- Dermatology (AREA)
- Emergency Medicine (AREA)
- Biochemistry (AREA)
- Cosmetics (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Disclosed is a phospholipin gel which is stabilised against liquefying by adding a tetrahydric, pentahydric or hexahydric alcohol or sugar. The gel can be used for producing cosmetic and pharmaceutical formulations.
Description
, August 16 2000 K/T/sm Merckle GmbH
Ludwig-Merckle-Str. 3 D-89143 Blaubeuren Phospholipid gel The present invention relates to a phospholipid gel, and to cosmetic and pharmaceutical formulations which contain these gels.
Phospholipid gels are known in the prior art. These gels have found interest as pharmaceutical vehicles.
The phospholipid is not only a vehicle for the active substance here, but also controls the bioavailability of the pharmaceutical. The reason for this is the special molecular arrangement of the phospholipids, which can form stable liposomes consisting of bilayers.
The active compound is better absorbed, since the phospholipids make possible an easier absorption of the active compound into the target cells.
A process for the preparation of liposome solutions which can contain a pharmacological active compound is disclosed, for example, in EP-B-0 069 307. In the - 2 _ preparation of these solutions, liposome gels are firstly obtained which can be used, for example, as an ointment base. In order to suppress gelling of the liposome solutions obtained, EP-B-0 069 307 proposes adding an electrolyte such as, for example, a physiological buffer system or a sugar.
A liposomal composition for medicinal or cosmetic purposes which comprises 0.5-10% of phospholipids, 20-50% of a C2-4-alcohol, 0-30% of glycol, at least 20% of water and at least one active compound is disclosed in WO 95/35095.
DE 195 20 659 discloses a pharmaceutical preparation which, in addition to the active compound acyclovir, contains 5-35% by weight of a phospholipid, 15-50% by weight of an alcohol and 79-0% by weight of water, the alcohol being a di- and/or trihydric C2_5-alcohol on its own or as a mixture with ethanol, 1-propanol and/or 2 propanol.
US patent no. 5,820,848 discloses liposome-containing gels which can contain a short-chain alcohol such as methanol, ethanol, propanol, isopropanol or n-butanol or polyols such as glycerol and ethylene glycol.
The phospholipid gels known in the prior art have the disadvantage that they easily liquefy on application to the skin. Liquefaction of the gel strand is all the more strongly pronounced the higher the perspiration content on the skin. This is particularly disadvantageous in the case of gels which are intended for application to the mucous membranes. Patients frequently feel the liquefaction and consequently the watery feeling on application of the conventional phospholipid gels to be unpleasant.
Moreover, known phospholipid gels have the disadvantage that they can liquefy even on incorporation of a . . - 3 _ pharmaceutical, buffer or salt, in particular if readily soluble substances, such as, for example, diphenhydramine HC1, are incorporated. In these cases, the preparations may flow even under their own weight.
This effect is known, for example, from DE 40 03 783 A1. In this, a phospholipid-containing gel is disclosed which is preserved using alcohols such as ethanol or 2-propanol. According to examples 7 and 9-12, the gels obtained liquefy on addition of a buffer or salt solution.
An object of the present invention thus consists in making available a phospholipid gel which, compared with known phospholipid gels, has a higher stability on application to the skin and in the presence of an incorporated pharmaceutical, buffer or salt.
According to the invention, it has now been found that this problem can be solved by incorporating into the phospholipid gel a tetra-, penta- or hexahydric alcohol, and/or sugar.
The present invention thus relates to a phospholipid gel, comprising 5-60o by weight of at least one phospholipid;
at least 1°s by weight of at least one di- or tri-hydric CZ_4-alcohol;
0.5-35% by weight of at least one tetra-, penta-or hexahydric alcohol and/or at least one sugar;
optionally one or more additives and water to 100 by weight, the % by weight data in each case relating to the entire gel.
The phospholipid preparation according to the invention contains phospholipids which are preferably of natural origin. In particular, phospholipids from plants, such as, for example, soybean lecithin, are suitable. The phospholipids can be characterized by means of the phosphatidylcholine content, which is the main ingredient of phospholipids.
In principle, according to the invention either hydrogenated and/or nonhydrogenated phospholipids can be employed. In the case of the nonhydrogenated phospholipids, the phosphatidylcholine content is at least approximately 70% by weight based on the phospholipid, preferably the phosphatidylcholine content is at least approximately 75% by weight. In the case of the hydrogenated phospholipids, the phosphatidylcholine content is a least approximately 90% by weight.
The phospholipid used according to the invention can also be a mixture of various phospholipids and in particular a mixture of phosphatidylcholine and lysophosphatidylcholine. In such a mixture, the weight ratio of phosphatidylcholine to lysophosphatidylcholine should be between 97:3 and 40:60, higher phosphatidylcholine contents of at least 75% by weight (in the case of nonhydrogenated phospholipids) and preferably at least 90% by weight (in the case of hydrogenated phospholipids) based on the total phospholipid being preferred.
Known phospholipids which fulfill these properties are obtainable, for example, from Nattermann Phospholipid GmbH under the names Phospholipon° 80 and Phospholipon~
90 H. Phospholipon° 80 comprises approximately 76% of phosphatidylcholine and approximately 3% of lysophosphatidylcholine, Phospholipon° 90 H, a hydrogenated phosphatidylcholine, comprises at least 900 of phosphatidylcholine and at most 4% of lysophosphatidylcholine. Phospholipon° 80 is also obtainable as a 75% strength solution in ethanol (NAT
. _ 5 _ 8539) and as a 60% strength solution in propylene glycol (NAT 8450). Phospholipids from other manufacturers, however, can also be used for the gel according to the invention.
In one embodiment, hydrogenated phospholipids are employed. An advantage of this embodiment is that smaller amounts of phospholipids can be added. Thus, for example, approximately 20% of nonhydrogenated phospholipids can be replaced by approximately 10% of hydrogenated phospholipids so that a cost-saving results.
The content of phospholipids in the gel should be between 5 and 60% by weight. Below 5%, no gel formation is possible, and above 60%, acceptable gel can no longer be formulated. Preferably, the phospholipid content in the gel according to the invention is 5-35% by weight and particularly preferably 15-25% by weight.
As a further constituent, the gel according to the invention comprises at least 1% by weight, preferably 20 to 30% by weight, of at least one di- or trihydric CZ-9-alcohol. In higher concentrations, this alcohol acts as a preservative. Moreover, this alcohol acts as a solvent for the phospholipid and can also serve as a solubilizer for the active compound. Furthermore, this constituent can serve as a penetration enhancer.
Finally, the moistness of the skin can also be increased. A suitable dihydric alcohol is in particular a propanediol, propylene glycol (1,2-propanediol) having proven particularly advantageous. A trihydric alcohol which can be employed is, for example, glycerol. The gel can also contain mixtures of various types of these alcohols.
The content of the di- or trihydric CZ_4-alcohol in the gel according to the invention can vary over a wide range. A content o~ 1-90$ by weight is preferred, particularly preferably 15-30~ by weight, ~-~-- ,~°~ ~ If propylene glycol is employed on its own as the alcohol component, the propylene glycol content in the gel should preferably be between 25 and 30$ by weight. If glycerol is employed on its own as the alcohol component, the glycerol content in the gel should be between 20 and 30$ by weight. However, mixtures of, for example, 15-30~ by weight of propylene glycol and 0-10$ by weight, in particular 2.5-7.5~ by weight, of glycerol can also be present in the gel according to the invention.
As an essential constituent which decreases the proneness to liquefaction of the phospholipid gel, the gel according to the invention contains 0.5-35$ by weight of at least one tetra-, penta- or hexahydric alcohol or sugar. The term "sugar" is understood according to the invention as meaning mono-, di- and/
or oligosaccharides. The tetra-, penta- or hexahydric alcohols are preferably sugar alcohols. These include, for example, glucose, fructose, sucrose, trehalose, xylitol, maltitol, inositol, sorbitol and mannitol.
Mixtures of the additives mentioned, namely mixtures of various alcohols and/or various sugars, such as, for example, a mixture of sorbitol and glucose, can also be used.
In order to decrease the proneness of the phospholipid gel to liquefaction, the content of the polyhydric alcohol or sugar in the preparation can be varied over a wide range. The amount to be employed depends, for example, on the presence of other preservatives, the liquefying action of a pharmaceutical which may be present and the nature of a buffer which may be employed and on further additives present.
Furthermore, the content of higher-hydric alcohol or ~ _ 7 _ sugar should be tailored to the intended use of the gel according to the invention. If the gel according to the invention is intended, for example, for application to the nasal mucous membranes, it should be taken into account that in the nose, on the one hand, increased moistness is present and on the other hand salts are present which, as electrolytes, favor liquefaction of the gel. If the gel according to the invention, however, is to be applied, for example, only to dry skin, the liquefying action is smaller on account of a lower moisture and salt content. on the skin. The alcohol, sugar or sugar alcohol content in the gel can be tailored according to these requirements. In the case of gels which can come into contact with the gastrointestinal tract, such as, for example, gels for lips and/or oral mucous membranes, it is to be taken into account that certain sugars produce a sweet taste.
On the other hand, however, it may be preferred not to use sugars if the gel is also to be suitable for diabetics. Sugar alcohols are then preferred.
A polyhydric alcohol or sugar content in the range from 2-20o by weight and in particular 2.5-loo by weight has proven advantageous.
If the gel according to the invention is to be employed as a pharmaceutical formulation, it additionally comprises one or more pharmaceutical active compounds.
The gel according to the invention is particularly advantageous for active compounds which are readily water-soluble substances, since these regularly already lead to liquefaction of conventional gels on incorporation. Advantageously, the gel according to the invention, however, is also suitable for poorly or nonsoluble pharmaceutical active compounds, since it then displays its liquefaction-inhibiting action on application, for example to the skin or mucous membrane.
. - $ -The pharmaceutical active compound can be selected, for example, from the group consisting of anti-inflammatories, nonsteroidal antirheumatics, corticoids, peptides, hormones, enzymes, nucleic acids, virustatics, vitamins, local anesthetics, antimycotics, antibiotics, antipsoriatics, circulation-promoting agents, a-sympathomimetics and nose drops. Preferably, virustatics, in particular acyclovir, corticoids, hormones and in particular peptides, can be incorporated into the gel according to the invention.
Pharmaceutical active compounds which may be mentioned are, for example, acyclovir, heparin, diclofenac, hydrocortisone, xylometazoline, cyclosporin, diphen-hydramine, calcitonin and indomethacin or their pharmaceutically acceptable salt. Lt is an advantage of the composition according to the invention that not only the active compounds, but also pharmaceutically acceptable salts can be incorporated without problems.
The phospholipid gel preparation according to the invention also makes possible a topical application of those medicaments which cannot be administered orally and otherwise have to be administered parenterally.
These active compounds are, for example, insulin, which can be absorbed, for example, via the nasal mucous membrane.
However, it is also possible, with the aid of the phospholipid gels according to the invention, to administer vaccines, hormones or nucleic acids (preferably for inoculation). On account of the phospholipids, the gels according to the invention make possible a good penetration of the skin. The phospholipid gel according to the invention therefore makes possible a noninvasive administration form of those pharmaceuticals which cannot be administered orally, such as, for example, peptides or nucleic acids (for example for inoculation). The gel structure which _ g _ can be achieved by means of the phospholipid gels according to the invention makes it possible, for example, to apply the gel preparation to the nasal mucous membranes in such a way that the active compound can readily penetrate the mucous membrane.
Instead of or in addition to pharmaceutical active compounds, the gel according to the invention, however, can also include constituents having a cosmetic action.
Examples of these are vitamins, sunscreen filters or a-hydroxy acids.
As a further constituent, the gel according to the invention can contain up to 10o by weight of at least one alcohol selected from ethanol, 1-propanol and 2-propanol. These monohydric alcohols, however, are incorporated into the gel only in addition to the abovementioned di- and trihydric alcohols.
A significant advantage of the gel according to the invention consists in the fact that, on account of the stabilization of the phospholipid gel by the polyhydric alcohol, and/or sugar, present, a buffer system can be incorporated into the preparation without liquefaction of the gel occurring. The buffer should be chosen here such that it has a high buffer capacity in the range of the stability optimum of the phosphatidylcholine. The stability optimum of phosphatidylcholine is at pH 6.5, so that the buffer should have a high buffer capacity in the range from pH 5.5-8.0 and preferably approximately pH 6.5. As a result of the buffering of the gel in the range of the stability optimum of the phosphatidylcholine, the storage stability of the gel can be increased. This is to be attributed to a slowing of the hydrolysis of the phosphatidylcholine to lysophosphatidylcholine. For example, in a nonbuffered gel the decrease in the phosphatidylcholine content after 25 weeks at 41°C was 58s. In a gel which was BISTRIS-buffered and otherwise of the same recipe, the decrease after 36 weeks at 41°C, however, was only 44~.
Buffers which have proven particularly suitable are BISTRIS (2-(bis(2-hydroxyethylimino)-2-hydroxymethyl)-1,3-propanediol) (pKa 6.5), phosphate buffer (buffer range sec-phosphate about 6.2-8.2), hydrogencarbonate buffer (buffer range about 5.4-6.9), maleate buffer (buffer range about 6.0-6.8), TRIS: (trishydroxymethyl-aminomethane), MOPS: (3-[N-morpholino]propanesulfonic acid) and HEPES (N-[2-hydroxyethyl]piperazine-N'[2-ethanesulfonic acid). On account of its pKa of 6.5, BISTRIS has proven particularly advantageous.
The amount of the buffer added is not particularly critical, but should be chosen to be so high that an adequate buffer action is achieved. For example, a BISTRIS concentration of approximately 0.075M (1.57 by weight) in the gel is particularly suitable.
If desired, a prespecified pH of the gel can, however, also be set by addition of an acid or alkali, such as, for example, NaOH.
The gel according to the invention can also contain further additives, such as, for example, preservatives, colorants, deodorants and taste enhancers. The taste enhancers can in particular play a role if the substances per se are otherwise not pleasant-tasting.
The phospholipids obtained from soybeans are in some cases also not felt to be pleasant as regards taste.
Unlike other gel preparations, the semisolid phospholipid gel preparation according to the invention preferably contains no further thickeners, emulsifiers, consistency-imparting agents or other gel-forming agents in the conventional sense. In particular, the gel preferably contains no further gel-forming agents, such as acrylates, cellulose derivatives, starch and starch derivatives, gelatin and alginates.
In addition to the constituents mentioned, the gel according to the invention contains water to 100 by weight. For pharmaceutical preparations, purified water according to pharmacopeia should be used.
The gel according to the invention is particularly suitable for the production of cosmetic or pharmaceutical formulations. The amount of the cosmetic substance or pharmaceutical to be incorporated into the phospholipid gel for this purpose can be varied over a wide range and depends on the substance.
The person skilled in the art can easily determine suitable concentrations, for example as a function of the efficacy of the active compound and of the intended purpose of use of the gel obtained. Acyclovir can be incorporated into the preparation, for example, in an amount of approximately 5~ by weight, diphenhydramine HCl in an amount of approximately 1% by weight, hydrocortisone in an amount of approximately 0.25-to by weight, heparin Na in an amount of 60 000 I.U. and calcitonin in an amount of 100 000 I.U. Further possible active compounds and amounts of active Compound can be taken from the examples.
A preferred base recipe according to the invention for pharmaceutical formulations comprises approximately 23.50 by weight of phospholipid, approximately 22.5 by weight of propylene glycol, approximately 5% by weight of ethanol, approximately 2.5~ by weight of sorbitol, a BISTRIS concentration of approximately 1.57% by weight, an active compound in suitable amount and water to 1000 by weight.
The cosmetic and pharmaceutical formulations according to the invention are suitable for application to the skin or mucous membrane, such as, for example, the skin '. ' - 12 -of the lip or the oral mucous membranes. Preferably, the phospholipid gel-containing formulations according to the invention, however, can also be applied to the nasal mucous membranes. Here, the effect according to the invention of the suppression of the liquefaction of the gel is particularly advantageous, since in the nose, on the one hand, increased moistness is present and on the other hand salts are also present which, as electrolytes, can lead to an increased liquefaction with conventional gels.
The phospholipid gels according to the invention can also be applied, however, even in the case of other mucous membranes. An appropriate cosmetic or pharmaceutical formulation can be, for example, a lip gel, nasal gel, ophthalmic gel, vaginal gel or anal gel, such as a hemorrhoid gel or a gel for the treatment of anal fissures.
The phospholipid gels according to the invention primarily serve for use in humans. However, it is also possible to employ these phospholipid gels in animals, such as, for example, for veterinary medical purposes, in particular for the treatment of dogs, cats or horses.
The gel according to the invention and the cosmetic or pharmaceutical formulation according to the invention can be prepared by mixing the constituents under vacuum or under an inert gas atmosphere. The mixing of the constituents and the gel formation can be carried out according to conventional processes known in the prior art. The absence of oxygen, which can be achieved by working under vacuum or an inert gas atmosphere, is advantageous here.
The gel according to the invention is preferably a gel having a semisolid consistency. The consistency of the gel can be determined using a' rotary viscometer. For -, ' - 13 -the present invention and in particular also in the following examples, a rotary viscometer (RheoStress RS 150) from HAAKE was used. The measurements were carried out at 20.0°C using measuring plates having a diameter of 35 mm. The measuring gap was 0.5 mm. The measurements were carried out as oscillation measurements with shear stress requirement at constant frequency (1.0 Hz). For this, the sample was introduced into the measuring gap and the measuring body was set into an oscillating motion (oscillation requirement) and the response function of the sample was measured. An accurate description of this method is found in the HAAKE publication "Characterization of Contact Adhesives (PSA systems)" by D. Eidman.
In this measuring process, the storage modulus G' can be determined as a component of the strain energy which can be stored elastically by the system, the loss modulus G" as a component of the strain energy which is irreversibly converted into viscous flow by the system, and the loss angle 8 as the phase delay between the oscillation requirement and response function as a function of the shear stress i.
The flow limit of a substance or of a composition is not precisely defined. One possibility for the determination of the flow limit consists, however, in the oscillation measurement described above. With small amplitudes (shear stress i below the flow limit), the loss angle 8 of the substance does not depend on i (viscoelastic range). Under the influence of higher shear stress, 8 increases greatly, which allows a rather viscous behavior to be concluded. The critical shear stress value on the transition from the linear viscoelastic to the viscous range can be interpreted as the flow limit (cf. H.-M. Petri in the HAAKE
publication "Determination of the Flow Limit in Foodstuffs"). This value can be read off from a graph in which the loss angle b is plotted against the shear -_ ' - 14 -stress i, at the transition of the resulting curve from its virtually horizontal part to the steeper part.
An increased flow limit, that is an increased value for the critical shear stress, confirms an increased stability of the measurement sample with respect to liquefaction. Qualitatively, such an increased stability can also be recognized from an increase in the maximum storage modulus G' in a plot of G' against i.
As guidance for the assessment of the liquefaction, a division can be used according to which a cosmetic milk has a flow limit at a critical shear stress of < 10 Pa, a lotion a flow limit at a critical shear stress of 10-Pa and a cream a flow limit at a critical shear stress of usually > 100 Pa. The flow limit of the gels according to the invention is preferably at a critical shear stress of above 20 Pa and particularly preferably 20 between 20 and 200 Pa. Gels having a flow limit at a critical shear stress of below about 20 Pa begin according to experience to flow under their own weight.
Semisolid gels are mainly understood in particular as meaning those gels which do not flow under their own weight.
However, it must be stressed that the above-described critical shear stress at the flow limit of the gels according to invention is of minor importance as an absolute value for the present invention, since this essentially depends on the determination method.
Moreover, according to the invention it is rather significant that the sugar- or alcohol-containing gel has a higher stability to liquefaction compared with conventional, that is sugar- or alcohol-free, gels.
This effect is marked by a relative increase in the critical shear stress at the flow limit or a relative increase in the maximum storage modulus G' in comparison with conventional gels.
The phospholipid gels according to the invention are distinguished in particular by the stability of their consistency to the incorporation of additives, such as pharmaceuticals or buffers, and in their application to the skin or mucous membrane. The consistency of the gels is stabilized in such a way that even on incorporation of additives the semisolid state is retained. Moreover, the properties of spreadability on application to the skin or mucous membrane are also retained.
Fig. 1 A shows the dependence of the loss angle 8 as a function of the shear stress i for a gel not according to the invention with addition of NaCl. Sometimes no NaCl (~), sometimes 0.2~ NaCl (~), sometimes 0.4$ NaCl (~) and sometimes 0.8~ NaC1 (~) were employed. From figure 1 A, it is evident that the shear stress changes with increasing salt concentration.
Fig. 1 B shows the dependence of the storage modulus G' as a function of the shear stress i for a gel not according to the invention with addition of NaCl. Here, no NaCl (0),0.2$ NaCl (O),0.4~ NaCl (D) and 0.8~ NaCl (O) were employed in the experiment. From figure 1 B, it is evident that the maximum storage modulus G' decreases with increasing salt concentration.
Fig. 2 A shows the dependence of the loss angle 8 as a function of the shear stress i for a gel according to invention, to which various amounts of NaCl have been added. The symbols correspond to those of figure 1 A.
Fig. 2 B shows that in the gel according to the invention the values hardly change even on addition of NaCl. The meaning of the symbols of figure 2 B
corresponds to that of figure 1 B. The fact that the values hardly change due to addition of NaCl shows the superiority of the gel according to invention.
Fig. 3 shows the dependence of the loss angle 8 (closed symbols) and the storage modulus G' (open symbols) as a function of the shear stress i for a gel not according to the invention with and without BISTRIS buffer.
Fig. 4 shows the dependence of the loss angle b (closed symbols) and the storage modulus G' (open symbols) as a function of the shear stress i for a gel according to the invention with and without BISTRIS
buffer.
The invention is illustrated in more detail by the following examples without being restricted to these.
Example 1 In this example, various pharmaceutical-containing gels according to the invention are prepared. Examples 1.1 to 1.4 show that various pharmaceuticals having different solubility properties and in different concentrations can be incorporated into the preparation according to the invention.
Gels having the following compositions were prepared (details in % by weight, if not stated otherwise):
Example 1.1 Acyclovir 5.0~
Nonhydrogenated lecithin 23.50 Propylene glycol 20.0 Ethanol 10.0 Sorbitol 2.50 Phosphate buffer 0.05M
Water to 100.0 Example 1.2 _ 17 _ Diphenhydramine HC1 1.0~
Nonhydrogenated lecithi 20.0 Propylene glycol 22.5s Ethanol 5.0°s Mannitol 5.0%
Water to 100.0 Example 1.3 Hydrocortisone 0.25 Nonhydrogenated lecithin 25.0 Propylene glycol 27.5 Trehalose 10.0%
BISTRIS 0.075M
Water to 100.0 Example 1.4 Calcitonin 100,000 I. U.
Nonhydrogenated lecithin 18.0g Propylene glycol 25.0g Glycerol 5.0g Sucrose 6.0g Water to 100.0g Acyclovir is a substance which is poorly soluble in water. Diphenhydramine HCl is a hydrophilic substance which is very readily soluble in water as a salt.
Hydrocortisone is a lipophilic substance which is more soluble in lipophilic solvents than in water.
Calcitonin is a hydrophilic protein which is soluble in water.
This example shows that, with addition of pharmaceuticals having very different dissolving properties, phospholipid gels according to the invention can be obtained.
Example 2 Table 1 below contains a listing of the compositions of further gels according to the invention. In addition to a favorite base recipe, these gels contain various pharmaceuticals in various concentrations. The quantitative data of the individual constituents are stated in % by weight based on the overall composition.
Table 1 Pharmaceutical PL PG EtOH BISTRIS Sorbi-tol Heparin Na 60 000 23.5 22.5 5 1.57 2.5 I.U
Diclofenac Na 1~ 23.5 22.5 5 1.57 2.5 Hydrocortisone l0 23.5 22.5 5 1.57 2.5 Xylometazoline HCl 23.5 22.5 5 1.57 2.5 0.1%
Indomethacin 1s 23.5 22.5 5 1.57 2.5 PL - phospholipid (Phospholipon 80); PG - propylene glycol; EtOH = ethanol Example 3 When incorporating pharmaceuticals or additives into phospholipid gels, electrolytes are frequently introduced into the preparations. Moreover, when applying the gels to the skin, in particular the mucous membrane, electrolytes such as, for example, salts from the perspiration are dissolved in the gels. These electrolytes can lead to a liquefaction of the gels.
This example shows the action of an addition of salt on a phospholipid gel with and without sorbitol. The base recipe of the phospholipid gel had the following composition: 23.5% by weight of phospholipid PL80, 22.50 by weight of propylene glycol, 5% by weight of ethanol, 1.570 by weight of BISTRIS, remainder water.
0; 0.2; 0.4 and 0.8o by weight of NaCl were added to this base recipe and using the oscillation measurement generally described above, the loss angle 8 and the storage modulus G' was determined for each recipe (not according to the invention) as a function of the shear stress i. The result of these measurements is shown in figure 1 A and 1 B. It is seen that the critical shear stress, that is the shear stress value at which the curves shown climb steeply from their virtually horizontal course, falls with increasing salt concentrations. Moreover, the maximum storage modulus G' falls with increasing salt content. This shows that the flow limit of the gels falis with increasing salt content and the gels thus liquefy more easily with increasing salt concentration.
Figures 2 A and 2 B show the result of the same measurement, 2.5o by weight of sorbitol and 0.2; 0.4 and 0.8% by weight of NaCl in each case being added to the base recipe. It is seen that as a result of the addition of sorbitol the influence of the electrolyte on the flow limit and the maximum storage modulus G' of the gel is virtually suppressed.
This experiment shows that the consistency of phospholipid gels according to the invention is retained despite addition of electrolytes such as NaCl.
Analogous measurements were carried out with addition of various pharmaceuticals, such as acyclovir, heparin Na and diclofenac Na, and various sugar alcohols and sugars, such as glucose, sucrose, trehalose, xylitol and fructose, comparable results being obtained.
Example 4 In this example, a buffer was added to a base recipe of 23.5% by weight of phospholipid, 22.5 by weight of propylene glycol, 5.0o by weight of ethanol and water to 100.0% by weight without and in the presence of 2.5°s of sorbitol and the effect of this addition on the proneness of the composition to liquefaction was investigated.
BISTRIS was added to the recipe as a buffer. The buffer concentration was 1.57 by weight.
The result for the oscillation measurement as described above for the sorbitol-free gels (not according to the invention) with and without BISTRIS is shown in figure 3. It is seen that the level of the storage modulus G' is lowered in the presence of BISTRIS, just as the critical shear stress, which is a measure of the flow limit.
The result of the oscillation measurement using the sorbitol-containing gels according to the invention with and without BISTRIS is shown in figure 4. It is seen that no lowering of the level of the storage modulus G' or of the critical shear stress takes place.
The measured courses of the curves are virtually identical.
This example shows that the addition of sorbitol to a phospholipid gel virtually abolishes the proneness of the gel to liquefaction on addition of a buffer. By means of this, it is possible by incorporation of a buffer into a phospholipid gel to increase significantly the stability of this gel and thus the storability of this gel.
Example 5 In this example, the subjective feeling on the topical application of phospholipid gels according to the invention and not according to the invention is investigated. The compositions of the gels investigated are shown in table 2, the compositions A, B, D and F being compositions according to the invention and the sorbitol-free composition C serving as a comparison composition not according to the invention. As an additional comparison composition, a conventional acyclovir cream (composition E) was included in the test.
Table 2 A B C D F
NAT 8450 20.0 20.0 20.0 5.0 -PL 90 H 7.5 - - 7.5 6.0 Propylene glycol 20.0 30.0 20.0 30.0 20.0 Glycerol - 7.5 12.5 - -Sorbitol 5.0 10.0 - 10.0 10.0 Acyclovir 5.0 5.0 5.0 5.0 5.0 PL 90 H = Phospholipon~ 90 H (hydrogenated) NAT 8540 - 60% solution of Phospholipon 80 in propylene glycol The quantitative data in table 2 are in % by weight based on the total composition, these in each case being made up to 100% by weight with water.
The study was carried out as follows. Before the start of the experiment, both lower arms and, before each application, the index finger of each patient, were wiped with Kleenex~. After each application cycle (all six bases are applied), the application sites were wiped with Kleenex~. A total of three cycles were carried out. Per cycle, the subject once wore a strip of 1 cm length on the inside of the lower arm and spread this with the index finger. Per lower arm, three formulations were applied.
The diameter of the base spread along the arm should be at most 5 cm. The individual application sites should not intersect.
After each application cycle, the subjects were ordered to assess the spreadability on application (consistency, cosmetic feel, etc), the appearance of the formulation (hypo-/lipophilicity) and the remaining feeling after the application (stickiness, skin tautness, etc) and to assign the formulations to a rank according to their popularity. Rank 1 had the best assessment, rank 6 the worst.
The test was carried out with 13 subjects (spreacl ability and hydro-/lipophilicity) or 11 subjects (remaining feeling).
The evaluation was carried out according to the rank total test (L. Sacks, Statistical Methods, Planning and Evaluation, p. 85 ff). For this, the ranks which had been assigned to a composition by each subject for each investigated criterion (target criterion) were summed (rank total) and compared with one another. A lower rank total shows a greater popularity of a composition in comparison and conversely.
The results of this investigation are shown in table 3.
For each composition A-F, for each target criterion (I
- spreadability, II - hydro-/lipophilicity, III -remaining feeling), the rank to which each subject (1-13) has assigned this is indicated. The subject 1 has, for example, favored composition C (rank 1) in the assessment of the spreadability (target criterion I) and assessed the composition E to be the worst (rank 6). Moreover, the standard deviation (sdv), the rank total (T - total of all ranks) and the number of respective subjects (j) are indicated in the table for each composition and each target criterion.
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y0 E -n O ,.~ Ei .n O U cb f~ c~ E1 It is seen that the subjective feeling was preferred both for the spreadability on application and for the appearance of the formulation for the gels according to the invention (A, B, D and F) both compared with the sorbitol-free gel not according to the invention (C), and compared with the conventional cream (E). Although for the remaining feeling a composition according to the invention (F) was also favored, overall, however, no uniform picture resulted.
Ludwig-Merckle-Str. 3 D-89143 Blaubeuren Phospholipid gel The present invention relates to a phospholipid gel, and to cosmetic and pharmaceutical formulations which contain these gels.
Phospholipid gels are known in the prior art. These gels have found interest as pharmaceutical vehicles.
The phospholipid is not only a vehicle for the active substance here, but also controls the bioavailability of the pharmaceutical. The reason for this is the special molecular arrangement of the phospholipids, which can form stable liposomes consisting of bilayers.
The active compound is better absorbed, since the phospholipids make possible an easier absorption of the active compound into the target cells.
A process for the preparation of liposome solutions which can contain a pharmacological active compound is disclosed, for example, in EP-B-0 069 307. In the - 2 _ preparation of these solutions, liposome gels are firstly obtained which can be used, for example, as an ointment base. In order to suppress gelling of the liposome solutions obtained, EP-B-0 069 307 proposes adding an electrolyte such as, for example, a physiological buffer system or a sugar.
A liposomal composition for medicinal or cosmetic purposes which comprises 0.5-10% of phospholipids, 20-50% of a C2-4-alcohol, 0-30% of glycol, at least 20% of water and at least one active compound is disclosed in WO 95/35095.
DE 195 20 659 discloses a pharmaceutical preparation which, in addition to the active compound acyclovir, contains 5-35% by weight of a phospholipid, 15-50% by weight of an alcohol and 79-0% by weight of water, the alcohol being a di- and/or trihydric C2_5-alcohol on its own or as a mixture with ethanol, 1-propanol and/or 2 propanol.
US patent no. 5,820,848 discloses liposome-containing gels which can contain a short-chain alcohol such as methanol, ethanol, propanol, isopropanol or n-butanol or polyols such as glycerol and ethylene glycol.
The phospholipid gels known in the prior art have the disadvantage that they easily liquefy on application to the skin. Liquefaction of the gel strand is all the more strongly pronounced the higher the perspiration content on the skin. This is particularly disadvantageous in the case of gels which are intended for application to the mucous membranes. Patients frequently feel the liquefaction and consequently the watery feeling on application of the conventional phospholipid gels to be unpleasant.
Moreover, known phospholipid gels have the disadvantage that they can liquefy even on incorporation of a . . - 3 _ pharmaceutical, buffer or salt, in particular if readily soluble substances, such as, for example, diphenhydramine HC1, are incorporated. In these cases, the preparations may flow even under their own weight.
This effect is known, for example, from DE 40 03 783 A1. In this, a phospholipid-containing gel is disclosed which is preserved using alcohols such as ethanol or 2-propanol. According to examples 7 and 9-12, the gels obtained liquefy on addition of a buffer or salt solution.
An object of the present invention thus consists in making available a phospholipid gel which, compared with known phospholipid gels, has a higher stability on application to the skin and in the presence of an incorporated pharmaceutical, buffer or salt.
According to the invention, it has now been found that this problem can be solved by incorporating into the phospholipid gel a tetra-, penta- or hexahydric alcohol, and/or sugar.
The present invention thus relates to a phospholipid gel, comprising 5-60o by weight of at least one phospholipid;
at least 1°s by weight of at least one di- or tri-hydric CZ_4-alcohol;
0.5-35% by weight of at least one tetra-, penta-or hexahydric alcohol and/or at least one sugar;
optionally one or more additives and water to 100 by weight, the % by weight data in each case relating to the entire gel.
The phospholipid preparation according to the invention contains phospholipids which are preferably of natural origin. In particular, phospholipids from plants, such as, for example, soybean lecithin, are suitable. The phospholipids can be characterized by means of the phosphatidylcholine content, which is the main ingredient of phospholipids.
In principle, according to the invention either hydrogenated and/or nonhydrogenated phospholipids can be employed. In the case of the nonhydrogenated phospholipids, the phosphatidylcholine content is at least approximately 70% by weight based on the phospholipid, preferably the phosphatidylcholine content is at least approximately 75% by weight. In the case of the hydrogenated phospholipids, the phosphatidylcholine content is a least approximately 90% by weight.
The phospholipid used according to the invention can also be a mixture of various phospholipids and in particular a mixture of phosphatidylcholine and lysophosphatidylcholine. In such a mixture, the weight ratio of phosphatidylcholine to lysophosphatidylcholine should be between 97:3 and 40:60, higher phosphatidylcholine contents of at least 75% by weight (in the case of nonhydrogenated phospholipids) and preferably at least 90% by weight (in the case of hydrogenated phospholipids) based on the total phospholipid being preferred.
Known phospholipids which fulfill these properties are obtainable, for example, from Nattermann Phospholipid GmbH under the names Phospholipon° 80 and Phospholipon~
90 H. Phospholipon° 80 comprises approximately 76% of phosphatidylcholine and approximately 3% of lysophosphatidylcholine, Phospholipon° 90 H, a hydrogenated phosphatidylcholine, comprises at least 900 of phosphatidylcholine and at most 4% of lysophosphatidylcholine. Phospholipon° 80 is also obtainable as a 75% strength solution in ethanol (NAT
. _ 5 _ 8539) and as a 60% strength solution in propylene glycol (NAT 8450). Phospholipids from other manufacturers, however, can also be used for the gel according to the invention.
In one embodiment, hydrogenated phospholipids are employed. An advantage of this embodiment is that smaller amounts of phospholipids can be added. Thus, for example, approximately 20% of nonhydrogenated phospholipids can be replaced by approximately 10% of hydrogenated phospholipids so that a cost-saving results.
The content of phospholipids in the gel should be between 5 and 60% by weight. Below 5%, no gel formation is possible, and above 60%, acceptable gel can no longer be formulated. Preferably, the phospholipid content in the gel according to the invention is 5-35% by weight and particularly preferably 15-25% by weight.
As a further constituent, the gel according to the invention comprises at least 1% by weight, preferably 20 to 30% by weight, of at least one di- or trihydric CZ-9-alcohol. In higher concentrations, this alcohol acts as a preservative. Moreover, this alcohol acts as a solvent for the phospholipid and can also serve as a solubilizer for the active compound. Furthermore, this constituent can serve as a penetration enhancer.
Finally, the moistness of the skin can also be increased. A suitable dihydric alcohol is in particular a propanediol, propylene glycol (1,2-propanediol) having proven particularly advantageous. A trihydric alcohol which can be employed is, for example, glycerol. The gel can also contain mixtures of various types of these alcohols.
The content of the di- or trihydric CZ_4-alcohol in the gel according to the invention can vary over a wide range. A content o~ 1-90$ by weight is preferred, particularly preferably 15-30~ by weight, ~-~-- ,~°~ ~ If propylene glycol is employed on its own as the alcohol component, the propylene glycol content in the gel should preferably be between 25 and 30$ by weight. If glycerol is employed on its own as the alcohol component, the glycerol content in the gel should be between 20 and 30$ by weight. However, mixtures of, for example, 15-30~ by weight of propylene glycol and 0-10$ by weight, in particular 2.5-7.5~ by weight, of glycerol can also be present in the gel according to the invention.
As an essential constituent which decreases the proneness to liquefaction of the phospholipid gel, the gel according to the invention contains 0.5-35$ by weight of at least one tetra-, penta- or hexahydric alcohol or sugar. The term "sugar" is understood according to the invention as meaning mono-, di- and/
or oligosaccharides. The tetra-, penta- or hexahydric alcohols are preferably sugar alcohols. These include, for example, glucose, fructose, sucrose, trehalose, xylitol, maltitol, inositol, sorbitol and mannitol.
Mixtures of the additives mentioned, namely mixtures of various alcohols and/or various sugars, such as, for example, a mixture of sorbitol and glucose, can also be used.
In order to decrease the proneness of the phospholipid gel to liquefaction, the content of the polyhydric alcohol or sugar in the preparation can be varied over a wide range. The amount to be employed depends, for example, on the presence of other preservatives, the liquefying action of a pharmaceutical which may be present and the nature of a buffer which may be employed and on further additives present.
Furthermore, the content of higher-hydric alcohol or ~ _ 7 _ sugar should be tailored to the intended use of the gel according to the invention. If the gel according to the invention is intended, for example, for application to the nasal mucous membranes, it should be taken into account that in the nose, on the one hand, increased moistness is present and on the other hand salts are present which, as electrolytes, favor liquefaction of the gel. If the gel according to the invention, however, is to be applied, for example, only to dry skin, the liquefying action is smaller on account of a lower moisture and salt content. on the skin. The alcohol, sugar or sugar alcohol content in the gel can be tailored according to these requirements. In the case of gels which can come into contact with the gastrointestinal tract, such as, for example, gels for lips and/or oral mucous membranes, it is to be taken into account that certain sugars produce a sweet taste.
On the other hand, however, it may be preferred not to use sugars if the gel is also to be suitable for diabetics. Sugar alcohols are then preferred.
A polyhydric alcohol or sugar content in the range from 2-20o by weight and in particular 2.5-loo by weight has proven advantageous.
If the gel according to the invention is to be employed as a pharmaceutical formulation, it additionally comprises one or more pharmaceutical active compounds.
The gel according to the invention is particularly advantageous for active compounds which are readily water-soluble substances, since these regularly already lead to liquefaction of conventional gels on incorporation. Advantageously, the gel according to the invention, however, is also suitable for poorly or nonsoluble pharmaceutical active compounds, since it then displays its liquefaction-inhibiting action on application, for example to the skin or mucous membrane.
. - $ -The pharmaceutical active compound can be selected, for example, from the group consisting of anti-inflammatories, nonsteroidal antirheumatics, corticoids, peptides, hormones, enzymes, nucleic acids, virustatics, vitamins, local anesthetics, antimycotics, antibiotics, antipsoriatics, circulation-promoting agents, a-sympathomimetics and nose drops. Preferably, virustatics, in particular acyclovir, corticoids, hormones and in particular peptides, can be incorporated into the gel according to the invention.
Pharmaceutical active compounds which may be mentioned are, for example, acyclovir, heparin, diclofenac, hydrocortisone, xylometazoline, cyclosporin, diphen-hydramine, calcitonin and indomethacin or their pharmaceutically acceptable salt. Lt is an advantage of the composition according to the invention that not only the active compounds, but also pharmaceutically acceptable salts can be incorporated without problems.
The phospholipid gel preparation according to the invention also makes possible a topical application of those medicaments which cannot be administered orally and otherwise have to be administered parenterally.
These active compounds are, for example, insulin, which can be absorbed, for example, via the nasal mucous membrane.
However, it is also possible, with the aid of the phospholipid gels according to the invention, to administer vaccines, hormones or nucleic acids (preferably for inoculation). On account of the phospholipids, the gels according to the invention make possible a good penetration of the skin. The phospholipid gel according to the invention therefore makes possible a noninvasive administration form of those pharmaceuticals which cannot be administered orally, such as, for example, peptides or nucleic acids (for example for inoculation). The gel structure which _ g _ can be achieved by means of the phospholipid gels according to the invention makes it possible, for example, to apply the gel preparation to the nasal mucous membranes in such a way that the active compound can readily penetrate the mucous membrane.
Instead of or in addition to pharmaceutical active compounds, the gel according to the invention, however, can also include constituents having a cosmetic action.
Examples of these are vitamins, sunscreen filters or a-hydroxy acids.
As a further constituent, the gel according to the invention can contain up to 10o by weight of at least one alcohol selected from ethanol, 1-propanol and 2-propanol. These monohydric alcohols, however, are incorporated into the gel only in addition to the abovementioned di- and trihydric alcohols.
A significant advantage of the gel according to the invention consists in the fact that, on account of the stabilization of the phospholipid gel by the polyhydric alcohol, and/or sugar, present, a buffer system can be incorporated into the preparation without liquefaction of the gel occurring. The buffer should be chosen here such that it has a high buffer capacity in the range of the stability optimum of the phosphatidylcholine. The stability optimum of phosphatidylcholine is at pH 6.5, so that the buffer should have a high buffer capacity in the range from pH 5.5-8.0 and preferably approximately pH 6.5. As a result of the buffering of the gel in the range of the stability optimum of the phosphatidylcholine, the storage stability of the gel can be increased. This is to be attributed to a slowing of the hydrolysis of the phosphatidylcholine to lysophosphatidylcholine. For example, in a nonbuffered gel the decrease in the phosphatidylcholine content after 25 weeks at 41°C was 58s. In a gel which was BISTRIS-buffered and otherwise of the same recipe, the decrease after 36 weeks at 41°C, however, was only 44~.
Buffers which have proven particularly suitable are BISTRIS (2-(bis(2-hydroxyethylimino)-2-hydroxymethyl)-1,3-propanediol) (pKa 6.5), phosphate buffer (buffer range sec-phosphate about 6.2-8.2), hydrogencarbonate buffer (buffer range about 5.4-6.9), maleate buffer (buffer range about 6.0-6.8), TRIS: (trishydroxymethyl-aminomethane), MOPS: (3-[N-morpholino]propanesulfonic acid) and HEPES (N-[2-hydroxyethyl]piperazine-N'[2-ethanesulfonic acid). On account of its pKa of 6.5, BISTRIS has proven particularly advantageous.
The amount of the buffer added is not particularly critical, but should be chosen to be so high that an adequate buffer action is achieved. For example, a BISTRIS concentration of approximately 0.075M (1.57 by weight) in the gel is particularly suitable.
If desired, a prespecified pH of the gel can, however, also be set by addition of an acid or alkali, such as, for example, NaOH.
The gel according to the invention can also contain further additives, such as, for example, preservatives, colorants, deodorants and taste enhancers. The taste enhancers can in particular play a role if the substances per se are otherwise not pleasant-tasting.
The phospholipids obtained from soybeans are in some cases also not felt to be pleasant as regards taste.
Unlike other gel preparations, the semisolid phospholipid gel preparation according to the invention preferably contains no further thickeners, emulsifiers, consistency-imparting agents or other gel-forming agents in the conventional sense. In particular, the gel preferably contains no further gel-forming agents, such as acrylates, cellulose derivatives, starch and starch derivatives, gelatin and alginates.
In addition to the constituents mentioned, the gel according to the invention contains water to 100 by weight. For pharmaceutical preparations, purified water according to pharmacopeia should be used.
The gel according to the invention is particularly suitable for the production of cosmetic or pharmaceutical formulations. The amount of the cosmetic substance or pharmaceutical to be incorporated into the phospholipid gel for this purpose can be varied over a wide range and depends on the substance.
The person skilled in the art can easily determine suitable concentrations, for example as a function of the efficacy of the active compound and of the intended purpose of use of the gel obtained. Acyclovir can be incorporated into the preparation, for example, in an amount of approximately 5~ by weight, diphenhydramine HCl in an amount of approximately 1% by weight, hydrocortisone in an amount of approximately 0.25-to by weight, heparin Na in an amount of 60 000 I.U. and calcitonin in an amount of 100 000 I.U. Further possible active compounds and amounts of active Compound can be taken from the examples.
A preferred base recipe according to the invention for pharmaceutical formulations comprises approximately 23.50 by weight of phospholipid, approximately 22.5 by weight of propylene glycol, approximately 5% by weight of ethanol, approximately 2.5~ by weight of sorbitol, a BISTRIS concentration of approximately 1.57% by weight, an active compound in suitable amount and water to 1000 by weight.
The cosmetic and pharmaceutical formulations according to the invention are suitable for application to the skin or mucous membrane, such as, for example, the skin '. ' - 12 -of the lip or the oral mucous membranes. Preferably, the phospholipid gel-containing formulations according to the invention, however, can also be applied to the nasal mucous membranes. Here, the effect according to the invention of the suppression of the liquefaction of the gel is particularly advantageous, since in the nose, on the one hand, increased moistness is present and on the other hand salts are also present which, as electrolytes, can lead to an increased liquefaction with conventional gels.
The phospholipid gels according to the invention can also be applied, however, even in the case of other mucous membranes. An appropriate cosmetic or pharmaceutical formulation can be, for example, a lip gel, nasal gel, ophthalmic gel, vaginal gel or anal gel, such as a hemorrhoid gel or a gel for the treatment of anal fissures.
The phospholipid gels according to the invention primarily serve for use in humans. However, it is also possible to employ these phospholipid gels in animals, such as, for example, for veterinary medical purposes, in particular for the treatment of dogs, cats or horses.
The gel according to the invention and the cosmetic or pharmaceutical formulation according to the invention can be prepared by mixing the constituents under vacuum or under an inert gas atmosphere. The mixing of the constituents and the gel formation can be carried out according to conventional processes known in the prior art. The absence of oxygen, which can be achieved by working under vacuum or an inert gas atmosphere, is advantageous here.
The gel according to the invention is preferably a gel having a semisolid consistency. The consistency of the gel can be determined using a' rotary viscometer. For -, ' - 13 -the present invention and in particular also in the following examples, a rotary viscometer (RheoStress RS 150) from HAAKE was used. The measurements were carried out at 20.0°C using measuring plates having a diameter of 35 mm. The measuring gap was 0.5 mm. The measurements were carried out as oscillation measurements with shear stress requirement at constant frequency (1.0 Hz). For this, the sample was introduced into the measuring gap and the measuring body was set into an oscillating motion (oscillation requirement) and the response function of the sample was measured. An accurate description of this method is found in the HAAKE publication "Characterization of Contact Adhesives (PSA systems)" by D. Eidman.
In this measuring process, the storage modulus G' can be determined as a component of the strain energy which can be stored elastically by the system, the loss modulus G" as a component of the strain energy which is irreversibly converted into viscous flow by the system, and the loss angle 8 as the phase delay between the oscillation requirement and response function as a function of the shear stress i.
The flow limit of a substance or of a composition is not precisely defined. One possibility for the determination of the flow limit consists, however, in the oscillation measurement described above. With small amplitudes (shear stress i below the flow limit), the loss angle 8 of the substance does not depend on i (viscoelastic range). Under the influence of higher shear stress, 8 increases greatly, which allows a rather viscous behavior to be concluded. The critical shear stress value on the transition from the linear viscoelastic to the viscous range can be interpreted as the flow limit (cf. H.-M. Petri in the HAAKE
publication "Determination of the Flow Limit in Foodstuffs"). This value can be read off from a graph in which the loss angle b is plotted against the shear -_ ' - 14 -stress i, at the transition of the resulting curve from its virtually horizontal part to the steeper part.
An increased flow limit, that is an increased value for the critical shear stress, confirms an increased stability of the measurement sample with respect to liquefaction. Qualitatively, such an increased stability can also be recognized from an increase in the maximum storage modulus G' in a plot of G' against i.
As guidance for the assessment of the liquefaction, a division can be used according to which a cosmetic milk has a flow limit at a critical shear stress of < 10 Pa, a lotion a flow limit at a critical shear stress of 10-Pa and a cream a flow limit at a critical shear stress of usually > 100 Pa. The flow limit of the gels according to the invention is preferably at a critical shear stress of above 20 Pa and particularly preferably 20 between 20 and 200 Pa. Gels having a flow limit at a critical shear stress of below about 20 Pa begin according to experience to flow under their own weight.
Semisolid gels are mainly understood in particular as meaning those gels which do not flow under their own weight.
However, it must be stressed that the above-described critical shear stress at the flow limit of the gels according to invention is of minor importance as an absolute value for the present invention, since this essentially depends on the determination method.
Moreover, according to the invention it is rather significant that the sugar- or alcohol-containing gel has a higher stability to liquefaction compared with conventional, that is sugar- or alcohol-free, gels.
This effect is marked by a relative increase in the critical shear stress at the flow limit or a relative increase in the maximum storage modulus G' in comparison with conventional gels.
The phospholipid gels according to the invention are distinguished in particular by the stability of their consistency to the incorporation of additives, such as pharmaceuticals or buffers, and in their application to the skin or mucous membrane. The consistency of the gels is stabilized in such a way that even on incorporation of additives the semisolid state is retained. Moreover, the properties of spreadability on application to the skin or mucous membrane are also retained.
Fig. 1 A shows the dependence of the loss angle 8 as a function of the shear stress i for a gel not according to the invention with addition of NaCl. Sometimes no NaCl (~), sometimes 0.2~ NaCl (~), sometimes 0.4$ NaCl (~) and sometimes 0.8~ NaC1 (~) were employed. From figure 1 A, it is evident that the shear stress changes with increasing salt concentration.
Fig. 1 B shows the dependence of the storage modulus G' as a function of the shear stress i for a gel not according to the invention with addition of NaCl. Here, no NaCl (0),0.2$ NaCl (O),0.4~ NaCl (D) and 0.8~ NaCl (O) were employed in the experiment. From figure 1 B, it is evident that the maximum storage modulus G' decreases with increasing salt concentration.
Fig. 2 A shows the dependence of the loss angle 8 as a function of the shear stress i for a gel according to invention, to which various amounts of NaCl have been added. The symbols correspond to those of figure 1 A.
Fig. 2 B shows that in the gel according to the invention the values hardly change even on addition of NaCl. The meaning of the symbols of figure 2 B
corresponds to that of figure 1 B. The fact that the values hardly change due to addition of NaCl shows the superiority of the gel according to invention.
Fig. 3 shows the dependence of the loss angle 8 (closed symbols) and the storage modulus G' (open symbols) as a function of the shear stress i for a gel not according to the invention with and without BISTRIS buffer.
Fig. 4 shows the dependence of the loss angle b (closed symbols) and the storage modulus G' (open symbols) as a function of the shear stress i for a gel according to the invention with and without BISTRIS
buffer.
The invention is illustrated in more detail by the following examples without being restricted to these.
Example 1 In this example, various pharmaceutical-containing gels according to the invention are prepared. Examples 1.1 to 1.4 show that various pharmaceuticals having different solubility properties and in different concentrations can be incorporated into the preparation according to the invention.
Gels having the following compositions were prepared (details in % by weight, if not stated otherwise):
Example 1.1 Acyclovir 5.0~
Nonhydrogenated lecithin 23.50 Propylene glycol 20.0 Ethanol 10.0 Sorbitol 2.50 Phosphate buffer 0.05M
Water to 100.0 Example 1.2 _ 17 _ Diphenhydramine HC1 1.0~
Nonhydrogenated lecithi 20.0 Propylene glycol 22.5s Ethanol 5.0°s Mannitol 5.0%
Water to 100.0 Example 1.3 Hydrocortisone 0.25 Nonhydrogenated lecithin 25.0 Propylene glycol 27.5 Trehalose 10.0%
BISTRIS 0.075M
Water to 100.0 Example 1.4 Calcitonin 100,000 I. U.
Nonhydrogenated lecithin 18.0g Propylene glycol 25.0g Glycerol 5.0g Sucrose 6.0g Water to 100.0g Acyclovir is a substance which is poorly soluble in water. Diphenhydramine HCl is a hydrophilic substance which is very readily soluble in water as a salt.
Hydrocortisone is a lipophilic substance which is more soluble in lipophilic solvents than in water.
Calcitonin is a hydrophilic protein which is soluble in water.
This example shows that, with addition of pharmaceuticals having very different dissolving properties, phospholipid gels according to the invention can be obtained.
Example 2 Table 1 below contains a listing of the compositions of further gels according to the invention. In addition to a favorite base recipe, these gels contain various pharmaceuticals in various concentrations. The quantitative data of the individual constituents are stated in % by weight based on the overall composition.
Table 1 Pharmaceutical PL PG EtOH BISTRIS Sorbi-tol Heparin Na 60 000 23.5 22.5 5 1.57 2.5 I.U
Diclofenac Na 1~ 23.5 22.5 5 1.57 2.5 Hydrocortisone l0 23.5 22.5 5 1.57 2.5 Xylometazoline HCl 23.5 22.5 5 1.57 2.5 0.1%
Indomethacin 1s 23.5 22.5 5 1.57 2.5 PL - phospholipid (Phospholipon 80); PG - propylene glycol; EtOH = ethanol Example 3 When incorporating pharmaceuticals or additives into phospholipid gels, electrolytes are frequently introduced into the preparations. Moreover, when applying the gels to the skin, in particular the mucous membrane, electrolytes such as, for example, salts from the perspiration are dissolved in the gels. These electrolytes can lead to a liquefaction of the gels.
This example shows the action of an addition of salt on a phospholipid gel with and without sorbitol. The base recipe of the phospholipid gel had the following composition: 23.5% by weight of phospholipid PL80, 22.50 by weight of propylene glycol, 5% by weight of ethanol, 1.570 by weight of BISTRIS, remainder water.
0; 0.2; 0.4 and 0.8o by weight of NaCl were added to this base recipe and using the oscillation measurement generally described above, the loss angle 8 and the storage modulus G' was determined for each recipe (not according to the invention) as a function of the shear stress i. The result of these measurements is shown in figure 1 A and 1 B. It is seen that the critical shear stress, that is the shear stress value at which the curves shown climb steeply from their virtually horizontal course, falls with increasing salt concentrations. Moreover, the maximum storage modulus G' falls with increasing salt content. This shows that the flow limit of the gels falis with increasing salt content and the gels thus liquefy more easily with increasing salt concentration.
Figures 2 A and 2 B show the result of the same measurement, 2.5o by weight of sorbitol and 0.2; 0.4 and 0.8% by weight of NaCl in each case being added to the base recipe. It is seen that as a result of the addition of sorbitol the influence of the electrolyte on the flow limit and the maximum storage modulus G' of the gel is virtually suppressed.
This experiment shows that the consistency of phospholipid gels according to the invention is retained despite addition of electrolytes such as NaCl.
Analogous measurements were carried out with addition of various pharmaceuticals, such as acyclovir, heparin Na and diclofenac Na, and various sugar alcohols and sugars, such as glucose, sucrose, trehalose, xylitol and fructose, comparable results being obtained.
Example 4 In this example, a buffer was added to a base recipe of 23.5% by weight of phospholipid, 22.5 by weight of propylene glycol, 5.0o by weight of ethanol and water to 100.0% by weight without and in the presence of 2.5°s of sorbitol and the effect of this addition on the proneness of the composition to liquefaction was investigated.
BISTRIS was added to the recipe as a buffer. The buffer concentration was 1.57 by weight.
The result for the oscillation measurement as described above for the sorbitol-free gels (not according to the invention) with and without BISTRIS is shown in figure 3. It is seen that the level of the storage modulus G' is lowered in the presence of BISTRIS, just as the critical shear stress, which is a measure of the flow limit.
The result of the oscillation measurement using the sorbitol-containing gels according to the invention with and without BISTRIS is shown in figure 4. It is seen that no lowering of the level of the storage modulus G' or of the critical shear stress takes place.
The measured courses of the curves are virtually identical.
This example shows that the addition of sorbitol to a phospholipid gel virtually abolishes the proneness of the gel to liquefaction on addition of a buffer. By means of this, it is possible by incorporation of a buffer into a phospholipid gel to increase significantly the stability of this gel and thus the storability of this gel.
Example 5 In this example, the subjective feeling on the topical application of phospholipid gels according to the invention and not according to the invention is investigated. The compositions of the gels investigated are shown in table 2, the compositions A, B, D and F being compositions according to the invention and the sorbitol-free composition C serving as a comparison composition not according to the invention. As an additional comparison composition, a conventional acyclovir cream (composition E) was included in the test.
Table 2 A B C D F
NAT 8450 20.0 20.0 20.0 5.0 -PL 90 H 7.5 - - 7.5 6.0 Propylene glycol 20.0 30.0 20.0 30.0 20.0 Glycerol - 7.5 12.5 - -Sorbitol 5.0 10.0 - 10.0 10.0 Acyclovir 5.0 5.0 5.0 5.0 5.0 PL 90 H = Phospholipon~ 90 H (hydrogenated) NAT 8540 - 60% solution of Phospholipon 80 in propylene glycol The quantitative data in table 2 are in % by weight based on the total composition, these in each case being made up to 100% by weight with water.
The study was carried out as follows. Before the start of the experiment, both lower arms and, before each application, the index finger of each patient, were wiped with Kleenex~. After each application cycle (all six bases are applied), the application sites were wiped with Kleenex~. A total of three cycles were carried out. Per cycle, the subject once wore a strip of 1 cm length on the inside of the lower arm and spread this with the index finger. Per lower arm, three formulations were applied.
The diameter of the base spread along the arm should be at most 5 cm. The individual application sites should not intersect.
After each application cycle, the subjects were ordered to assess the spreadability on application (consistency, cosmetic feel, etc), the appearance of the formulation (hypo-/lipophilicity) and the remaining feeling after the application (stickiness, skin tautness, etc) and to assign the formulations to a rank according to their popularity. Rank 1 had the best assessment, rank 6 the worst.
The test was carried out with 13 subjects (spreacl ability and hydro-/lipophilicity) or 11 subjects (remaining feeling).
The evaluation was carried out according to the rank total test (L. Sacks, Statistical Methods, Planning and Evaluation, p. 85 ff). For this, the ranks which had been assigned to a composition by each subject for each investigated criterion (target criterion) were summed (rank total) and compared with one another. A lower rank total shows a greater popularity of a composition in comparison and conversely.
The results of this investigation are shown in table 3.
For each composition A-F, for each target criterion (I
- spreadability, II - hydro-/lipophilicity, III -remaining feeling), the rank to which each subject (1-13) has assigned this is indicated. The subject 1 has, for example, favored composition C (rank 1) in the assessment of the spreadability (target criterion I) and assessed the composition E to be the worst (rank 6). Moreover, the standard deviation (sdv), the rank total (T - total of all ranks) and the number of respective subjects (j) are indicated in the table for each composition and each target criterion.
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y0 E -n O ,.~ Ei .n O U cb f~ c~ E1 It is seen that the subjective feeling was preferred both for the spreadability on application and for the appearance of the formulation for the gels according to the invention (A, B, D and F) both compared with the sorbitol-free gel not according to the invention (C), and compared with the conventional cream (E). Although for the remaining feeling a composition according to the invention (F) was also favored, overall, however, no uniform picture resulted.
Claims (23)
1. A phospholipid gel, comprising 5-60% by weight of at least one phospholipid;
at least 1% by weight of at least one di- or tri-hydric C2-4-alcohol;
0.5-35% by weight of at least one tetra-, penta-or hexahydric alcohol and/or at least one sugar;
optionally one or more additives and water to 100%
by weight, the % by weight data in each case relating to the total gel.
at least 1% by weight of at least one di- or tri-hydric C2-4-alcohol;
0.5-35% by weight of at least one tetra-, penta-or hexahydric alcohol and/or at least one sugar;
optionally one or more additives and water to 100%
by weight, the % by weight data in each case relating to the total gel.
2. A phospholipid gel as claimed in claim 1, characterized in that the sugar is a mono-, di- and/or an oligosaccharide.
3. The phospholipid gel as claimed in claim 1 or 2, in which the phospholipid has a phosphatidylcholine content of at least 70% by weight based on the phospholipid.
4. A phospholipid gel as claimed in claim 3, in which the phospholipid is a nonhydrogenated phospholipid having a phosphatidylcholine content of at least 70% by weight based on the phospholipid.
5. A phospholipid gel as claimed in claim 4, in which the phospholipid comprises a mixture of phosphatidylcholine and lysophosphatidylcholine and this mixture contains at least 75% by weight of phosphatidylcholine.
6. A phospholipid gel as claimed in claim 1 or 2, in which the phospholipid comprises a hydrogenated phospholipid which contains at least 90% by weight of phosphatidylcholine.
7. A phospholipid gel as claimed in one of the preceding claims, comprising 5-35% by weight, preferably 15-25% by weight, of at least one phospholipid.
8. A phospholipid gel as claimed in one of the preceding claims, in which the di- or trihydric C2-4-alcohol is propanediol, in particular propylene glycol, glycerol or a mixture of these alcohols.
9. A phospholipid gel as claimed in one of the preceding claims, comprising 1-40% by weight, preferably 15-40% by weight, of at least one di- or trihydric C2-4-alcohol.
10. A phospholipid gel as claimed in claim 9, comprising 15-30% by weight of propylene glycol and 0-10% by weight, in particular 2.5-7.5% by weight, of glycerol.
11. A phospholipid gel as claimed in one of the preceding claims, in which the tetra-, penta- or hexa-hydric alcohol or sugar is selected from glucose, fructose, sucrose, trehalose, xylitol, maltitol;
inositol, inositol, sorbitol and mannitol.
inositol, inositol, sorbitol and mannitol.
12. A phospholipid gel as claimed in one of the preceding claims, comprising 2-20% by weight, in particular 2.5-10% by weight, of at least one tetra-, penta- or hexahydric alcohol or sugar.
13. A phospholipid gel as claimed in one of the preceding claims, comprising a pharmaceutical active compound selected from the group consisting of anti-inflammatories, nonsteroidal antirheumatics, corticoids, peptides, hormones, enzymes, nucleic acids, virustatics, vitamins, local anesthetics, antimycotics, antibiotics, circulation-promoting agents, .alpha.-sympatho-mimetics, antipsoriatics and nose drops.
14. A phospholipid gel as claimed in one of the preceding claims, comprising a pharmaceutical active compound selected from acyclovir, heparin, diclophenac, hydrocortisone, xylometazoline, diphenhydramine, calcitonin, cyclosporin, indomethacin and insulin.
15. A phospholipid gel as claimed in one of the preceding claims, comprising up to 10% by weight of at least one alcohol selected from ethanol, 1-propanol and 2-propanol.
16. A phospholipid gel as claimed in one of the preceding claims, comprising at least one buffer having a high buffer capacity in the range from pH 5.5-8.0, preferably approximately pH 6.5.
17. A phospholipid gel as claimed in claim 16; in which the buffer is selected from BISTRIS, phosphate buffer, hydrogencarbonate buffer, maleate buffer, HEPES, TRIS and MOPS.
18. A phospholipid gel as claimed in one of the preceding claims, which is free of other thickeners, emulsifiers, consistency-imparting agents and/or gel-forming agents.
19. A cosmetic or pharmaceutical formulation, comprising a phospholipid gel as claimed in one of claims 1-18.
20. A cosmetic or pharmaceutical formulation as claimed in claim 19 for topical application.
21. A cosmetic or pharmaceutical formulation as claimed in claim 19, it being a lip gel, nasal gel, ophthalmic gel, vaginal gel or anal gel.
22. The use of a phospholipid gel as claimed in one of claims 1-18 for the production of a cosmetic or pharmaceutical formulation.
23. A process for the production of a phospholipid gel as claimed in one of claims 1-18 or of a cosmetic or pharmaceutical formulation as claimed in one of claims 19 to 21, in which the gel is prepared by mixing the constituents under vacuum or under an inert gas atmosphere.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19940227A DE19940227A1 (en) | 1999-08-25 | 1999-08-25 | Phospholipid gel |
| DE19940227.2 | 1999-08-25 | ||
| PCT/EP2000/007993 WO2001013887A2 (en) | 1999-08-25 | 2000-08-16 | Phospholipin gel |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2381571A1 true CA2381571A1 (en) | 2001-03-01 |
Family
ID=7919498
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002381571A Abandoned CA2381571A1 (en) | 1999-08-25 | 2000-08-16 | Phospholipid gel |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP1206245A2 (en) |
| JP (1) | JP2003507408A (en) |
| AU (1) | AU776766B2 (en) |
| CA (1) | CA2381571A1 (en) |
| CZ (1) | CZ2002561A3 (en) |
| DE (1) | DE19940227A1 (en) |
| HU (1) | HUP0203097A3 (en) |
| NO (1) | NO20020768L (en) |
| PL (1) | PL353215A1 (en) |
| RU (1) | RU2261088C2 (en) |
| SK (1) | SK2442002A3 (en) |
| WO (1) | WO2001013887A2 (en) |
| ZA (1) | ZA200201506B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITMI20081862A1 (en) * | 2008-10-21 | 2010-04-22 | Funziona Srl | COMPOSITION FOR TOPIC USE FOR THE TREATMENT OF LOCALIZED ADIPOSITIES AND RELATED IMAGINATIONS |
| US8361496B2 (en) | 2004-06-24 | 2013-01-29 | Idexx Laboratories Inc. | Phospholipid gel compositions for drug delivery and methods of treating conditions using same |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002062316A1 (en) * | 2001-02-08 | 2002-08-15 | Vectron Therapeutics Ag | Invasomes for the treatment of disease states, production and use thereof |
| CN1335182A (en) * | 2001-08-08 | 2002-02-13 | 华中科技大学 | Insulin spray for oral cavity and its prepn process |
| DE10255285A1 (en) * | 2002-11-26 | 2004-06-03 | Mcs Micro Carrier Systems Gmbh | Self-forming phospholipid gels |
| DE10255195A1 (en) * | 2002-11-27 | 2004-06-09 | Lipoid Gmbh | Micellar water-soluble concentrates |
| AU2003301174A1 (en) * | 2002-12-20 | 2004-07-22 | Idexx Laboratories, Inc. | Liposomal analgesic formulation and use |
| FI20065222L (en) * | 2006-04-05 | 2007-10-06 | Finnfeeds Finland Oy | Use of inositol |
| CN103349285A (en) * | 2008-11-14 | 2013-10-16 | 阿彻丹尼尔斯米德兰德公司 | Rganogel compositions and processes for producing |
| EP2210589B1 (en) * | 2009-01-22 | 2015-05-06 | Ludwig-Maximilians-Universität München | Vesicular phospholipid gels comprising proteinaceous substances |
| BE1018506A3 (en) * | 2009-02-26 | 2011-02-01 | Bogaert Gina Van | COMPOSITION OF A HYDROCORTISONE, ITS DERIVATIVES, METABOLITES, PRODRUGS OR MIXTURES, LIPOSOMAL GEL AND ITS USE. |
| MX339957B (en) | 2010-05-14 | 2016-06-20 | Archer Daniels Midland Co | Food compositions comprising organogels. |
| JP2017214299A (en) * | 2016-05-30 | 2017-12-07 | ライオン株式会社 | Semisolid formulation and method for producing the same |
| US11426349B2 (en) | 2017-03-23 | 2022-08-30 | Lipid Systems Sp. Z.O.O. | High-efficiency encapsulation of hydrophilic compounds in unilamellar liposomes |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3585967D1 (en) * | 1984-03-08 | 1992-06-11 | Phares Pharma Holland | LIPOSOME FORMING COMPOSITION. |
| JP2501336B2 (en) * | 1987-07-02 | 1996-05-29 | 第一製薬株式会社 | Stable liposomal formulation |
| WO1990012565A1 (en) * | 1989-04-25 | 1990-11-01 | Nattermann, A. & Cie. Gmbh | Water-containing formulations with phospholipids |
| US5820848A (en) * | 1990-01-12 | 1998-10-13 | The Liposome Company, Inc. | Methods of preparing interdigitation-fusion liposomes and gels which encapsulate a bioactive agent |
| DE4003783C2 (en) * | 1990-02-08 | 1999-03-25 | Nattermann A & Cie | Phospholipid-containing gel, process for its preparation and use |
| DE4021082C2 (en) * | 1990-07-03 | 1995-08-17 | Hans Dr Lautenschlaeger | High lipid-containing skin treatment agent using a bilayer-containing system, organic acid salts, alcohol and stabilizer |
| DE19520659A1 (en) * | 1995-06-09 | 1996-12-12 | Mika Pharma Ges Fuer Die Entwi | Compsn. to treat virus infections of skin etc |
| DE19719604A1 (en) * | 1997-05-09 | 1998-07-16 | Henkel Kgaa | Hair dye, for human hair, that are easier to formulate and apply |
-
1999
- 1999-08-25 DE DE19940227A patent/DE19940227A1/en not_active Withdrawn
-
2000
- 2000-08-16 CA CA002381571A patent/CA2381571A1/en not_active Abandoned
- 2000-08-16 EP EP00960468A patent/EP1206245A2/en not_active Withdrawn
- 2000-08-16 SK SK244-2002A patent/SK2442002A3/en unknown
- 2000-08-16 RU RU2002104972/15A patent/RU2261088C2/en not_active IP Right Cessation
- 2000-08-16 PL PL00353215A patent/PL353215A1/en not_active Application Discontinuation
- 2000-08-16 JP JP2001518026A patent/JP2003507408A/en active Pending
- 2000-08-16 AU AU72767/00A patent/AU776766B2/en not_active Ceased
- 2000-08-16 CZ CZ2002561A patent/CZ2002561A3/en unknown
- 2000-08-16 HU HU0203097A patent/HUP0203097A3/en unknown
- 2000-08-16 WO PCT/EP2000/007993 patent/WO2001013887A2/en not_active Application Discontinuation
-
2002
- 2002-02-15 NO NO20020768A patent/NO20020768L/en not_active Application Discontinuation
- 2002-02-22 ZA ZA200201506A patent/ZA200201506B/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8361496B2 (en) | 2004-06-24 | 2013-01-29 | Idexx Laboratories Inc. | Phospholipid gel compositions for drug delivery and methods of treating conditions using same |
| ITMI20081862A1 (en) * | 2008-10-21 | 2010-04-22 | Funziona Srl | COMPOSITION FOR TOPIC USE FOR THE TREATMENT OF LOCALIZED ADIPOSITIES AND RELATED IMAGINATIONS |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2003507408A (en) | 2003-02-25 |
| NO20020768D0 (en) | 2002-02-15 |
| AU776766B2 (en) | 2004-09-23 |
| WO2001013887A3 (en) | 2001-09-20 |
| HUP0203097A2 (en) | 2003-01-28 |
| SK2442002A3 (en) | 2002-08-06 |
| HUP0203097A3 (en) | 2006-11-28 |
| DE19940227A1 (en) | 2001-03-08 |
| CZ2002561A3 (en) | 2002-07-17 |
| RU2261088C2 (en) | 2005-09-27 |
| NO20020768L (en) | 2002-02-15 |
| ZA200201506B (en) | 2003-05-28 |
| WO2001013887A2 (en) | 2001-03-01 |
| PL353215A1 (en) | 2003-11-03 |
| EP1206245A2 (en) | 2002-05-22 |
| AU7276700A (en) | 2001-03-19 |
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| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |