RU2261088C2 - Phospholipid gel - Google Patents

Abstract

FIELD: cosmetics, pharmacy.

SUBSTANCE: invention relates to a phospholipid gel stabilized against dilution by addition of tetra-, penta- or hexa-atomic alcohol and/or sugar, and to a method for it preparing. Gel is useful for making cosmetic or pharmaceutical compositions. Invention provides preparing a phospholipid gel showing the higher stability in applying on skin as compared with known phospholipid gels, and also in the presence of a medicinal agent, buffer or salt added to this gel.

EFFECT: improved and valuable properties of gel.

25 cl, 4 tbl, 4 dwg, 5 ex

Description

Technical field

The present invention relates to a phospholipid gel and also relates to cosmetic and pharmaceutical formulations containing this gel.

State of the art

Phospholipid gels are known in the art. These gels are of interest as carriers of drug substances. The phospholipid is not only a carrier of the active substance, but also controls the bio-content of the drug substance. The reason for this is the special molecular structure of phospholipids capable of forming bilayer liposomes. The active substance is better absorbed, since phospholipids provide its easier absorption by target cells.

A method of manufacturing liposome solutions, which may contain a pharmacologically active substance, is disclosed, for example, in EP-B-0069307. In the manufacture of these solutions, liposome gels are first prepared, which can be used, for example, as an ointment base. In order to prevent gelation of the obtained liposome solutions according to EP-B-0069307, it is proposed to add an electrolyte, such as, for example, a physiological buffer system or sugar.

A liposome composition for medical or cosmetic purposes, containing 0.5-10% phospholipids, 20-50% C _2-4 alcohol, 0-30% glycol, at least 20% water and at least one active substance, is disclosed in WO 95/35095.

DE 19520659 discloses a pharmaceutical composition, which along with the active substance acyclovir has in its composition 5-35 wt.% Phospholipid, 15-50 wt.% Alcohol and 79-0 wt.% Water, while the alcohol is a two- and / or trihydric C _2-5 alcohol alone or in a mixture with ethanol, 1-propanol and / or 2-propanol.

US Pat. No. 5,820,848 discloses gels containing liposomes, and the gels may contain short chain alcohol such as methanol, ethanol, propanol, isopropanol or n-butanol, or polyols such as glycerol and ethylene glycol.

A disadvantage of the phospholipid gels known in the art is that when applied to the skin, they are easily liquefied. The thinning of the flagellum of the gel is more pronounced, the higher the sweat content on the skin. This disadvantage is inherent, in particular, to gels intended for application to mucous membranes. When using conventional phospholipid gels, patients often experience liquefaction and the unpleasant feeling of hydration associated with it.

In addition, a disadvantage of the known phospholipid gels is that they can already be liquefied during the injection of a drug, buffer or salt, in particular when readily soluble substances, such as, for example, diphenhydramine HCl, are introduced. In these cases, the composition can spread already under the influence of its own weight.

Such an effect is known, for example, from patent DE 4003783 A1. It discloses a phospholipid-containing gel, preserved with alcohols such as ethanol or 2-propanol. According to examples 7 and 9-12, the resulting gels are liquefied by adding a buffer or saline solution.

Thus, the objective of the proposed invention is to create a phospholipid gel, which, compared with the known phospholipid gels, has higher stability when applied to the skin, as well as in the presence of a drug, buffer or salt introduced into it.

SUMMARY OF THE INVENTION

According to the invention, it was found that this problem can be solved by incorporating a four-, five- or six-atomic alcohol and / or sugar into a phospholipid gel.

The present invention thus relates to a phospholipid gel containing:

- 5-60 wt.% At least one phospholipid;

- at least 1 wt.% of at least one di- or tri-atomic C _2-4 alcohol;

- 0.5-35 wt.% At least one four-, five- or six-atomic alcohol and / or at least one sugar;

- if necessary, one or more additives and water as the rest up to 100 wt.%, while the data in wt.% are given, respectively, with respect to the entire gel.

The phospholipid composition according to the invention contains phospholipids, preferably of natural origin. Plant phospholipids, for example soya lecithin, are particularly suitable. Phospholipids can be characterized by the content of phosphatidylcholine, which is the main ingredient of phospholipids.

In principle, hydrogenated and / or non-hydrogenated phospholipids can be used according to the invention. In unhydrogenated phospholipids, the content of phosphatidylcholine is at least about 70% by weight of the phospholipid, preferably the content of phosphatidylcholine is at least about 75% by weight. In hydrogenated phospholipids, the content of phosphatidylcholine is at least about 90 wt.%.

The phospholipid used according to the invention may 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 in the range of 97: 3 to 40:60, with high proportions of phosphatidylcholine being at least 75 wt.% (In non-hydrogenated phospholipids) and preferably at least 90 wt.% (in hydrogenated phospholipids) in relation to the entire phospholipid.

Known phospholipids having the indicated qualities are, for example, manufactured by Nutmann Phospholipid GmbH under the name phospholipon® 80 and phospholipon® 90 N. Phospholipon® 80 contains about 76% phosphatidylcholine and about 3% lysophosphatidylcholine. Phospholipon® 90 N - hydrogenated phosphatidylcholine - contains at least 90% phosphatidylcholine and a maximum of 4% lysophosphatidylcholine. Phospholipon® 80 is also available as a 75% solution in ethanol (NAT 8539) and as a 60% solution in propylene glycol (NAT 8450). However, phospholipids from other manufacturers can be used for the gel according to the invention.

In one embodiment, hydrogenated phospholipids are used. The advantage of this option is that the amount of added phospholipids can be reduced. For example, about 20% of non-hydrogenated phospholipids can be replaced by about 10% hydrogenated phospholipids, which saves costs.

The content of phospholipids in the gel should be in the range from 5 to 60 wt.%. Below 5%, gelation is impossible, and above 60% it is no longer possible to obtain an acceptable gel. The content of phospholipid in the claimed gel is preferably 5-35 wt.% And particularly preferably 15-25 wt.%.

The gel in accordance with the invention contains as a next component at least 1 wt.%, Preferably from 20 to 30 wt.%, At least one diatomic or triatomic C _2-4 alcohol. At higher concentrations, this alcohol acts as a preservative. Furthermore, said alcohol acts as a phospholipid solvent and may also serve as a dissolution agent for the active substance. Further, this component can serve as a penetration enhancer. Finally, skin moisture can be increased. Propanediol is particularly suitable as a dihydric alcohol, with propylene glycol (1-2-propanediol) being particularly preferred. As the trihydric alcohol, for example, glycerol can be used. The gel may also contain mixtures of these different alcohols.

The content of the di- or triatomic C _2-4 alcohol in the proposed gel can be varied over a wide range. Preferred is a content of 1-40 wt.%, Particularly preferred 15-30 wt.%. If only propylene glycol is used as the alcohol component, the content of propylene glycol in the gel should preferably be from 25 to 30 wt.%. If only glycerol is used as the alcohol component, then the glycerol content in the gel should be in the range from 20 to 30 wt.%. However, mixtures of, for example, from 15-30 wt.% Propylene glycol and 0-10 wt.%, In particular 2.5-7.5 wt.%, Glycerol may also be contained in the claimed gel.

As an essential component that reduces the tendency of the phospholipid gel to liquefy, the claimed gel contains 0.5-35 wt.% At least one four-, five- or six-atomic alcohol or sugar. The term “sugar” according to the invention refers to mono-, di- and / or oligosaccharides. These four-, five- or six-atomic alcohols are preferably sugar alcohols (Zuckeralkohole - polyhydric, carbohydrate-like alcohols formed during the reduction of monosaccharides). Suitable for this purpose are, for example, glucose, fructose, sucrose, trialose, xylitol, maltitol, inositol, sorbitol and mannitol. Mixtures of these additives can also be used, namely mixtures of various alcohols and / or various sugars, such as, for example, a mixture of sorbitol and glucose.

To reduce the tendency of the phospholipid gel to thin, the content of polyhydric alcohol or sugar in the composition can vary over a wide range. The amount used depends, for example, on the presence of other preservatives, the diluting action of the drug substance present if necessary, and the type of buffer used if necessary, as well as other available additives. In addition, the content of polyhydric alcohol or sugar should be consistent with the intended use of the proposed gel. If the gel proposed according to the invention is intended, for example, for application to the mucous membranes of the nose, it must be borne in mind that in the nose, on the one hand, there is increased humidity, and on the other hand, there are salts that, like electrolytes, help to thin the gel. If the claimed gel is to be applied, for example, only to dry skin, then the thinning effect is reduced due to the lower moisture and salt content on the skin. The content of alcohol, sugar or sugar alcohol in the gel can be brought into line with the specified requirements. For gels that may come into contact with the gastrointestinal tract, such as lip gels and / or mucous membranes of the mouth, it must be taken into account that certain sugars have a sweet taste. On the other hand, refusal to use sugars may be preferred if the gel should be suitable for diabetics. In this case, sugar alcohols are preferred.

As it turned out, it is preferable that the content of polyhydric alcohol or sugar in the range from 2 to 20 wt.% And, in particular from 2.5 to 10 wt.%.

If the proposed gel is intended for use as a pharmaceutical composition, then it further includes one or more pharmaceutical active substances. The claimed gel is especially suitable for active substances that are readily soluble in water, since they, as a rule, even when ingested lead to the dilution of ordinary gels. The proposed gel is also preferred for poorly soluble or insoluble pharmaceutical active substances, since it exhibits its anti-fluidizing effect when applied, for example, to the skin or mucous membrane.

The pharmaceutical active substance may, for example, be selected from the group consisting of anti-inflammatory drugs, non-steroidal anti-rheumatic drugs, corticoids, peptides, hormones, enzymes, nucleic acids, virostatic drugs, vitamins, topical anesthetics, antifungal drugs, antibiotics, antipsoriazic drugs improving blood supply, α-sympathomimetic agents and rhinological agents. Preferably, virostatic agents, especially acyclovir, corticoids, hormones and, in particular, peptides, can be incorporated into the gel.

As pharmaceutical active substances, for example, acyclovir, heparin, diclofenac, hydrocortisone, xylometazoline, cyclosporine, diphenhydramine, calcitonin and indomethacin or a pharmaceutically acceptable salt thereof are mentioned. One of the advantages of the composition according to the invention is that not only active substances, but also pharmaceutically acceptable salts can be incorporated without problems.

The proposed composition of the phospholipid gel also allows topical application of such drugs that cannot be taken orally and would need to be administered parenterally. In this case, we are talking about such active substances as, for example, insulin, which can be taken, for example, through the nasal mucosa.

Using the phospholipid gels of the invention, it is also possible to administer vaccines, hormones or nucleic acids (preferably for vaccination). The claimed gels due to phospholipids provide good penetration through the skin. Therefore, the phospholipid gel according to the invention allows for a non-invasive form of administration of drugs that cannot be administered orally, such as, in particular, peptides or nucleic acids (for example, for vaccination). The gel structure, which can be obtained by the proposed phospholipid gels, makes it possible, for example, to apply the gel composition to the mucous membranes of the nose so that the active substance penetrates well through the mucous membrane.

Instead of or in addition to pharmaceutical active substances, the inventive gel may also contain cosmetically active components. Examples include vitamins, light filters, or α-hydroxy acids.

As another component of the proposed gel may contain up to 10 wt.% At least one alcohol selected from the group of ethanol, 1-propanol and 2-propanol. However, these monohydric alcohols are incorporated into the gel only in addition to the above dihydro and trihydric alcohols.

A significant advantage of the claimed gel is that due to the stabilization of the phospholipid gel with the present polyhydric alcohol and / or sugar, a buffer system can be introduced into the composition without causing the gel to dilute. In this case, the buffer should be selected so that it has a large buffer capacity within the optimal stability value of phosphatidylcholine. The optimum stability value of phosphatidylcholine is about 6.5 pH, so that the buffer should have a large buffer capacity in the range from 5.5 to 8.0 pH, preferably about 6.5 pH. Due to the buffering of the gel within the limits of the optimum stability value of phosphatidylcholine, the storage stability of the gel can be increased. This is due to a slowdown in the hydrolysis of phosphatidylcholine to lysophosphatidylcholine. For example, in a non-buffer gel, the decrease in phosphatidylcholine content was twenty-five weeks at 41 ° C 58%. And in the BISTRIS buffer gel, which was otherwise the same in formulation, the decrease after 36 weeks at 41 ° C was only 44%.

Suitable buffers were, in particular, BISTRIS (2- (bis (2-hydroxyethylimino) -2-hydroxymethyl) -1-3-propanediol) (buffer index 6.5), phosphate buffer (buffer range for secondary phosphate about 6, 2-8.2), hydrogen carbonate buffer (buffer range approximately 5.4-6.9), maleate buffer (buffer range approximately 6.0-6.8), TRIS: (trishydroxymethylaminomethane), MOPS: (3- [ N-morpholino] propanesulfonic acid) and HEPES: (N- [2-hydroxyethyl] piperazine-N '[2-ethanesulfonic acid]). Due to its buffering index of 6.5, BISTRIS was particularly preferred.

The amount of buffer added is not particularly critical, but should provide sufficient buffering. Particularly suitable is, for example, a concentration of BISTRIS buffer in a gel of about 0.075 M (1.57% by weight).

If desired, the desired pH in the gel can also be set by adding an acid or alkali, for example NaOH.

The gel according to the invention may also contain other additives, such as, for example, preservatives, colorants, odor improvers and flavor enhancers. Taste improvers can play a role especially when the substances themselves are not very palatable. Phospholipids derived from soybeans are also partly perceived as unpleasant in taste.

Unlike other gel formulations, the claimed semi-solid phospholipid gel composition preferably does not contain other thickeners, emulsifiers, consistency preservatives or other gelling agents in the usual sense. In particular, it is preferred that the gel does not contain such additional gelling agents as acrylates, cellulose derivatives, starch and starch derivatives, gelatin and alginates.

Along with these components, the proposed gel contains water as the rest up to 100 wt.%. For pharmaceutical compositions, it is necessary to use purified water according to the pharmacopeia.

The gel according to the invention is suitable, in particular, for the manufacture of cosmetic or pharmaceutical formulations. The amount of cosmetic or drug substance injected into the phospholipid gel for this purpose can vary widely and depends on the substance. The person skilled in the art can easily determine suitable concentrations depending, for example, on the effectiveness of the active substance and the purpose of the resulting gel. Acyclovir, for example, can be incorporated into the composition in an amount of about 5 wt.%, Diphenylhydramine HCl in an amount of about 1 wt.%, Hydrocortisone in an amount of about 0.25-1 wt.%, Heparin Na in an amount of 60,000 m. . and calcitonin - in the amount of 100,000 m.u. Other possible active substances and their amounts are given in the examples.

The preferred basic formulation for pharmaceutical compositions of the invention comprises about 23.5% by weight of phospholipid, about 22.5% by weight of propylene glycol, about 5% by weight of ethanol, about 2.5% by weight of sorbitol, a concentration of BISTRIS in an amount of 1.57 wt.%, a suitable amount of active substance and the rest is water up to 100%.

The cosmetic and pharmaceutical compositions of the invention are suitable for use on the skin or mucous membrane, for example on the skin of the lips or on the mucous membranes of the mouth. Preferably, the proposed compositions containing a phospholipid gel can also be applied to the nasal mucous membranes. Here, the gel thinning suppression effect of the gel according to the invention is especially favorable, since on the one hand there is moisture in the nose and, on the other hand, there are salts which, like electrolytes in the case of conventional gels, lead to their enhanced thinning.

The claimed phospholipid gels can be used for other mucous membranes. Appropriate cosmetic or pharmaceutical formulations may include, for example, a lip, nasal, ophthalmic, vaginal or anal gel, such as a hemorrhoidal gel or gel for treating anal fissures.

The proposed phospholipid gels are intended primarily for humans. However, for veterinary medical purposes, for example, it is possible to use these phospholipid gels and for animals, in particular for the treatment of dogs, cats or horses.

The claimed gel and the claimed cosmetic or pharmaceutical formulation can be made by mixing the components under vacuum or in an inert gas atmosphere. The mixing of the components and gelation can be carried out by conventional methods known in the art. In this case, the absence of oxygen is preferable, which is achieved when operating under vacuum or in an inert gas atmosphere.

The gel according to the invention is preferably a semi-solid consistency gel. The consistency of the gel can be determined by a rotational viscometer. For this invention, and in particular in the following examples, a rotational viscometer (RheoStress RS 150) from HAACK was used. The measurements were carried out at 20.0 ° C using measuring plates with a diameter of 35 mm. The measuring gap was 0.5 mm. The measurements were made as measurements of oscillations with a given shear stress at a constant frequency (1.0 Hz). To do this, the sample was placed in the measuring gap, the oscillating motion (setting the oscillations) was reported to the measuring element, and the response function of the sample was measured. An exact description of this method is contained in the HAAKE publication "Characterization of Contact Adhesives (PSA Systems)" by D. Aidman.

In this measurement method, the storage modulus G 'as part of the loading energy that can be elastically accumulated by the system, the loss modulus G "as part of the loading energy that is irreversibly transformed by the system into a viscous flow, and the loss angle δ as the phase delay between the oscillation and the response function can be determined depending on the shear stress τ.

The yield strength of a substance or composition is not well defined. One of the possibilities for determining the yield strength is presented in the above-described measurement of vibrations. At small amplitudes (shear stress m below the yield strength), the loss angle δ of the substance does not depend on τ (viscoelastic region). Under the influence of a higher shear stress, the loss angle 5 increases significantly, which allows us to speak more about rheological properties. The critical value of the shear stress during the transition from a linearly viscoelastic to a viscous region can be interpreted as the yield strength (see H.-M. Petri "Determining the yield stress of food products"). This value can be read from a graph in which the loss angle δ is plotted relative to the shear stress τ in the transition zone of the resulting curve from its almost horizontal part to the steeper part.

The increased yield strength, that is, a higher value of the critical shear stress, confirms the increased resistance of the measured sample to liquefaction. Qualitatively, such increased stability is also evident from the increase in the maximum storage modulus G 'when applying G' relative to τ.

A guideline for evaluating the dilution can be a classification according to which cosmetic milk has a yield strength at a critical shear stress of less than 10 Pa, lotion a yield strength at a critical shear stress of 10 to 20 Pa, and a cream a yield strength at a critical shear stress of usually more than 100 Pa. The claimed gel has a yield strength at a critical shear stress of predominantly above 20 Pa, preferably in the range from 20 to 200 Pa. As experience shows, gels with a yield strength at a critical shear stress of approximately below 20 Pa begin to flow under the action of their own weight. Semi-solid gels in this case are understood, in particular, those gels that do not flow under the influence of their own weight.

It should, however, be emphasized that the critical shear stress described above at the yield strength of the claimed gels for the present invention as an absolute value is of secondary importance, since it substantially depends on the determination method. In addition, in accordance with the invention, it is much more significant that the gel containing sugar or alcohol, compared with conventional, that is, not containing sugar or alcohol, gels has a higher resistance to liquefaction. This effect is detected due to a relative increase in the critical shear stress at the yield point or a relative increase in the maximum storage modulus G 'compared to conventional gels.

The phospholipid gels according to the invention are distinguished, in particular, by the stability of their consistency to the ingestion of additives, such as drugs or buffers, as well as by their stability when applied to the skin or mucous membrane. The consistency of the gels is so stabilized that when ingesting additives, a semi-solid state is maintained. In addition, the abrasion properties are retained when applied to the skin or mucous membrane.

, затем применяли 0,2% NaCl

, применяли 0,4% NaCl

и применяли 0,8% NaCl

. На фиг. 1А видно, что напряжение сдвига т изменяется с увеличением концентрации соли.FIG. 1A shows the dependence of the loss angle δ on shear stress τ for a known gel upon addition of NaCl. In one case, NaCl was not used.

then 0.2% NaCl was used

used 0.4% NaCl

and used 0.8% NaCl

. In FIG. 1A shows that the shear stress m varies with increasing salt concentration.

, затем применяли 0,2% NaCl (О), применяли 0,4% NaCl

и применяли 0,8% NaCl

. На фиг. 1В видно, что максимальный модуль аккумуляции G' уменьшается с увеличением концентрации соли.FIG. 1B shows the dependence of the storage modulus G 'on the shear stress τ for a known gel with the addition of NaCl. Here, during the experiment, in one case, NaCl was not used.

then 0.2% NaCl (O) was used, 0.4% NaCl was used

and used 0.8% NaCl

. In FIG. 1B shows that the maximum storage modulus G 'decreases with increasing salt concentration.

FIG. 2A shows the dependence of the loss angle δ on shear stress τ for a known gel into which various amounts of NaCl were added. Symbols correspond to the symbols in figure 1A.

FIG. 2B shows that in the gel according to the invention, the parameters almost do not change when NaCl is added. The meanings of the symbols in Figure 2B correspond to the meanings in Figure 1B. The fact that with the addition of NaCl the parameters are almost not changed, indicates the advantages of the claimed gel.

FIG. 3 shows the dependence of the loss angle δ (closed symbols) and the storage modulus G '(open symbols) on shear stress τ for a known gel with or without BISTRIS buffer.

FIG. 4 shows the dependence of the loss angle δ (closed symbols) and the storage modulus G '(open symbols) on the shear stress τ for the claimed gel with or without BISTRIS buffer.

The invention is explained in more detail by the following examples, not limited to.

Example 1

In this example, various gels according to the invention are made containing medicinal substances. Examples 1.1-1.4 show that various medicinal substances with different solubility properties and with different concentrations can be introduced into the proposed composition.

The gels of the following compositions were made (data in wt.% And in other units):

Example 1.1.

Acyclovir 5.0% Non-hydrogenated lecithin 23.5% Propylene glycol 20.0% Ethanol 10.0% Sorbitol 2.5% Phosphate buffer 0.05M Water rest up to 100.0%

Example 1.2

Diphenylhydramine HCl 1,0% Non hydrogenated lecithin 20.0% Propylene glycol 22.5% Ethanol 5.0% Mannitol 5.0% Water rest up to 100.0%

Example 1.3

Hydrocortisone 0.25% Non-hydrogenated lecithin 25.0% Propylene glycol 27.5% Trehalosis 10.0% BISTRIS 0.075M Water rest up to 100.0%

Example 1.4

Calcitonin 100,000 cu Non-hydrogenated lecithin 18.0 g Propylene glycol 25.0 g Glycerol 5.0 g Sucrose 6.0 g Water rest up to 100.0 g

Acyclovir is a substance that is difficult to dissolve in water.

Hydrofenhydramine HCl is a hydrophilic substance that, as a salt, dissolves very well in water. Hydrocortisone is a lipophilic substance that dissolves in lipophilic solvents better than in water. Calcitonin is a hydrophilic, water soluble protein.

This example shows that the phospholipid gels according to the invention can be preserved by the addition of drugs with very different solubility properties.

Example 2

The following table 1 lists the compositions of other gels according to the invention. These gels along with the preferred basic formulation contain various medicinal substances in different concentrations. Data on the number of individual components are indicated in wt.% In relation to the total composition.

Where PL - Phospholipid (phospholipid 80); PG - Propylene glycol; EtOH - Ethanol.

Example 3

When injecting drugs or additives into phospholipid gels, electrolytes are often added to the composition. In addition, when applying gels to the skin, in particular to the mucous membrane, electrolytes such as sweat salts dissolve in the gels. These electrolytes can lead to gel dilution.

This example shows the effect of a salt supplement on a phospholipid gel with or without sorbitol. The basic formulation of the phospholipid gel had the following composition: 23.5 wt.% Phospholipid PL80, 22.5 wt.% Propylene glycol, 5 wt.% Ethanol, 1.57 wt.% BISTRIS, the rest was water.

0 was added to this basic formulation; 0.2; 0.4 and 0.8 wt.% NaCl and using the generally described oscillation measurements described above for each (not claimed) formulation, the loss angle δ and the storage modulus G 'depending on the shear stress τ. The result of these measurements is reflected in figures 1A and 1B. It is seen that the critical shear stress, that is, the value of the shear stress at which the curves depicted from their almost horizontal position abruptly go up, decreases with increasing salt concentration. In addition, with increasing salt concentration, the maximum storage modulus G 'decreases. This shows that the yield strength of the gels decreases with increasing salt content and, thus, the gels more easily liquefy with increasing salt concentration.

Figures 2A and 2B show the result of the same measurement when, respectively, 2.5 wt.% Sorbitol and 0.2 were added to the base formulation; 0.4 and 0.8 wt.% NaCl. It can be seen that the addition of sorbitol almost eliminates the effect of electrolytes on the yield strength and maximum storage modulus G 'of the gel.

This experience shows that the consistency of the gels according to the invention is maintained despite the addition of electrolytes such as NaCl.

Similar measurements were carried out with the addition of various medicinal substances, such as acyclovir, heparin Na and diclofenac Na, and various sugar alcohols and sugars, such as glucose, sucrose, trialose, xylitol and fructose, with comparable results.

Example 4

In this example, in a basic formulation comprising 23.5 wt.% Phospholipid, 22.5 wt.% Propylene glycol, 5.0 wt.% Ethanol and - as a rest - water up to 100.0 wt.%, In the absence or presence sorbitol was added to the buffer and the effects of such an additive on the tendency of the composition to liquefy were investigated.

BISTRIS was added to the formulation as a buffer. The concentration of the buffer was 1.57 wt.%.

The result of the above-described method of measuring vibrations for sorbitol-free (undeclared) gels with or without BISTRIS is shown in Figure 3.

It can be seen that the level of the storage modulus G 'in the presence of BISTRIS decreases as well as the critical shear stress, which is a measure of the yield strength.

The result of the measurement of vibrations for the proposed according to the invention sorbitol-containing gels with or without BISTRIS is shown in Figure 4. It can be seen that there is no decrease in the level of the storage modulus G 'or critical shear stress. The measured forms of the curves are almost identical.

This example shows that incorporation of sorbitol into a phospholipid gel virtually eliminates the tendency of the gel to liquefy with the addition of buffer. This allows, by injecting the buffer into the phospholipid gel, to significantly increase the stability of this gel and, therefore, its storage stability.

Example 5

This example examines the subjective sensation of topical application of phospholipid gels according to the invention and phospholipid gels not related to the invention. The compositions of the investigated gels are shown in table 2, where compositions A, B, D and F are the claimed compounds, and sorbitol-free composition C serves as a comparative composition that is not related to the invention. As an additional comparative composition, the test included the usual acyclovir cream (composition E).

table 2 A IN FROM D F NAT 8450
PL90H
Propylene glycol
Glycerol
Sorbitol
Acyclovir 20,0
7.5
20,0
-
5,0
5,0 20,0
-
30,0
7.5
10.0
5,0 20,0
-
20,0
12.5
-
5,0 5,0
7.5
30,0
-
10.0
5,0 -
6.0
20,0
-
10.0
5,0

Where PL 90 N - phospholipon® 90 N (hydrogenated);

NAT 8450 - 60% solution of phospholipone 80 in propylene glycol.

The quantitative data in table 2 are given in wt.% In relation to the total composition, which was supplemented with water to 100 wt.%.

The study was conducted as follows. Before the start of the experiment, each test subject with Kleenex® wiped both forearms, and before each application, the index finger. After each application cycle (all six substrates were applied), the application site was wiped with Klenex®. In general, three cycles were conducted. In each cycle, the subject in one step applied a 1 cm long flagellum to the inner side of the forearm and rubbed it with the index finger. Three compositions were applied to each forearm.

The diameter of the base rubbed along the arm should be a maximum of 5 cm. Individual application spots should not overlap.

After each application cycle, the subjects were asked to evaluate the rubbing upon application (consistency, cosmetic perception, etc.), the appearance of the composition (hypophilia / lipophilia) and the feeling remaining after application (stickiness, skin tension, etc.), and rank songs to a certain category in terms of their popularity. Rank 1 had the best rating, rank 6 the worst.

The test was conducted with thirteen subjects for rubbing and hydro- / lipophilia and eleven subjects for sensation remaining after application.

The results were summed up by the sum of the digits (see L. Zax, Statistical Methods, Planning and Data Processing, p. 85ff). For this, the categories, which according to each investigated criterion (target criterion) were assigned by each subject to a certain composition, were summarized (the sum of the categories) and compared among themselves. The lower amount of discharges when comparing testified to the greater popularity of the composition and vice versa.

The results of this study are shown in Table 3. For each A-F composition, for each target criterion (I - rubbing, II - hydro- / lipophilia, III - remaining sensation), the category established for this criterion by each subject is indicated (1-13). Subject 1, for example, when evaluating the rubbability (target criterion I) preferred composition C (rank 1) and rated composition E as the worst (rank 6). In addition, the table for each composition and each target criterion indicates deviations from the standard (sdv), the sum of the digits (T is the sum of all digits) and the number of corresponding subjects (j).

For better clarity, the results shown in table 3 are again shown in the following table 4, where they are classified according to target criteria (T - the sum of the categories, j - the number of subjects).

It can be seen that according to the subjective perception of the rubbability of the composition upon application, as well as its appearance, preference was given to the declared gels (A, B, D and F), as compared with a gel (C) free from sorbitol and not related to the invention , and in comparison with conventional cream (E). Regarding the remaining sensation, although the gel (F) of the present invention was preferred, the overall picture was not uniform.

Industrial applicability.

The invention can be easily implemented on existing modern technological equipment using known components required for the production of such phospholipid gels.

Table 3 Test subject A IN FROM D E F I II III I II III I II III I II III I II III I II III 1 3 4 4 2 3 2 1 1 1 4 2 3 6 6 6 5 5 5 2 3 6 4 4 6 3 2 2 5 5 1 1 3 4 6 4 3 5 1 1 4 3 2 2 5 6 3 2 5 1 6 4 3 4 4 2 2 2 5 5 5 4 3 3 6 6 6 1 1 1 5 4 6 6 3 4 3 2 2 4 6 5 5 5 3 2 1 1 1 6 1,5 2,5 2 1,5 2,5 3 4 5 1 6 4 6 5 6 5 3 1 4 7 1 1 5 2 2 6 6 6 4 3 5 1 5 3 3 4 4 2 8 2 2 2 5 3 6 4 6 4 3 5 5 6 4 1 1 1 3 nine 3 1 5 4 2 3 5 5 2 1 3 4 6 4 6 2 6 1 10 2 2 4 3 5 4 3 5 6 6 1 1 eleven 4 3 6 2 2 5 3 6 3 1 1 2 5 4 1 6 5 4 12 6 2 4 1 6 1 2 5 5 3 4 6 4 3 3 5 1 2 thirteen 4 6 5 5 5 4 3 4 3 2 3 6 6 2 2 1 1 1 sdv 1.33 1.96 1.35 1.33 1.34 1.79 1.76 1.55 1.4 1,61 1.39 1.72 0.66 1.42 2.01 1.96 1.96 1.79 T 40.5 46.5 47 38.5 43.5 36 47 56 35 40 44 46 71 55 37 36 29th thirty j thirteen thirteen eleven eleven thirteen eleven thirteen thirteen eleven thirteen thirteen eleven thirteen thirteen eleven thirteen thirteen eleven

Table 4 I. Rubbing II. Hydro / Lipophilia III. Remaining feeling A B C D E F A B C D E F A B C D E F T 40.5 38.5 47 40 71 36 45.5 43.5 56 44 55 29th 47 36 35 46 37 thirty j thirteen thirteen thirteen thirteen thirteen thirteen thirteen thirteen thirteen thirteen thirteen thirteen eleven eleven eleven eleven eleven eleven

Claims (25)

1. Phospholipid gel containing 5-60 wt.% At least one phospholipid, at least 1 wt.% At least one diatomic or triatomic C _2-4 alcohol, 0.5-35 wt.% At least one four-, five- or six-atomic alcohol and / or at least one sugar, if necessary, one or more additives and water as the rest up to 100 wt.%, while data in wt.% are given, respectively, with respect to the entire gel. 2. The phospholipid gel according to claim 1, characterized in that the sugar is a mono-, di- and / or oligosaccharide. 3. The phospholipid gel according to claim 1 or 2, in which the phospholipid contains phosphatidylcholine in an amount of not less than 70 wt.% With respect to the phospholipid. 4. The phospholipid gel according to claim 3, wherein the phospholipid is a non-hydrogenated phospholipid with a content of phosphatidylcholine in an amount of at least 70 wt.% With respect to the phospholipid. 5. The phospholipid gel according to claim 4, in which the phospholipid contains a mixture of phosphatidylcholine and lysophosphatidylcholine and this mixture comprises at least 75 wt.% Phosphatidylcholine. 6. The phospholipid gel according to claim 1 or 2, in which the phospholipid contains a hydrogenated phospholipid, comprising at least 90 wt.% Phosphatidylcholine. 7. The phospholipid gel according to claims 1-6, containing 5-35 wt.%, Preferably 15-25 wt.%, Of at least one phospholipid. 8. The phospholipid gel according to claims 1 to 7, in which the di- or triatomic C _2-4 alcohol is propanediol, in particular propylene glycol, glycerol or a mixture of these alcohols. 9. The phospholipid gel according to claims 1 to 8, containing 1-40 wt.%, Mainly 15-40 wt.%, At least one diatomic or triatomic C _2-4 alcohol. 10. The phospholipid gel according to claim 9, containing 15-30 wt.% Propylene glycol and 0-10 wt.%, In particular 2.5-7.5 wt.%, Glycerol. 11. The phospholipid gel according to claims 1-10, wherein the four-, five- or six-atomic alcohol or sugar is selected from the group consisting of glucose, fructose, sucrose, trialose, xylitol, maltitol, inositol, sorbitol and mannitol. 12. The phospholipid gel according to claims 1-11, containing 2-20 wt.%, In particular 2.5-10 wt.%, At least one four-, five- or six-atomic alcohol or sugar. 13. The phospholipid gel according to claims 1-12, containing a pharmaceutical active substance selected from the group comprising anti-inflammatory drugs, non-steroidal anti-rheumatic drugs, corticoids, peptides, hormones, enzymes, nucleic acids, virostatic drugs, vitamins, local anesthetics, antifungal agents, antibiotics, blood circulation improvers, α-sympathomimetic agents, antipsoriazic agents and rhinological agents. 14. The phospholipid gel according to claims 1 to 13, containing a pharmaceutical active substance selected from the group consisting of acyclovir, heparin, diclofenac, hydrocortisone, xylometazoline, diphenhydramine, calcitonin, cyclosporine, indomethacin and insulin. 15. The phospholipid gel according to claims 1-14, containing up to 10 wt.% Of at least one alcohol selected from the group consisting of ethanol, 1-propanol and 2-propanol. 16. Phospholipid gel according to claims 1-15, containing at least one buffer with a large buffer capacity in the range from 5.5 to 8.0 pH, preferably about 6.5 pH. 17. The phospholipid gel of claim 16, wherein the buffer is selected from the group consisting of BISTRIS, phosphate buffer, hydrogen carbonate buffer, maleate buffer, HEPES, TRIS and MOPS. 18. The phospholipid gel according to claims 1-17, free from other thickeners, emulsifiers, masticators and / or gelling agents. 19. A cosmetic composition containing a phospholipid gel according to one of claims 1 to 18. 20. The cosmetic composition according to claim 19 for local application. 21. The cosmetic composition according to claim 19, which is a labial, nasal, ophthalmic gel, vaginal or anal gel. 22. A pharmaceutical composition containing a phospholipid gel according to one of claims 1 to 18. 23. The pharmaceutical composition according to item 22 for local application. 24. The pharmaceutical composition according to item 22, which is a labial, nasal, ophthalmic gel, vaginal or anal gel. 25. A method of manufacturing a phospholipid gel according to one of claims 1-18, or cosmetic according to one of claims 19-21, or a pharmaceutical composition according to one of claims 22-24, according to which the gel is made by mixing the components in a vacuum or in the atmosphere inert gas.

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