Dermatological composition

FIELD: medicine.

SUBSTANCE: composition comprises Clindamycin phosphate and water-soluble zinc salt taken in molar proportion of 1.2:1 to 1:2. Arising polymer gel is applicable in local treatment of acne vulgaris and acne rosacea under very low systemic Clindamycin level being retained. Aqueous nature of the drug prevents skin from drying. The drug exerts both immediate and prolonged action allowing its application once a day.

EFFECT: enhanced effectiveness of treatment.

39 cl, 5 dwg, 6 tbl

 

The present invention relates to dermatological compositions, including clindamycin and zinc, in particular, for the treatment of common and rosacea, to methods for treating dermatoses such compositions and to methods of producing such compositions.

Acne is a widespread skin disease, which reportedly affects up to 85% of teenagers. The pathomorphology of this disease are not fully known, but it appears that it is associated with the local metabolism of sex hormones during adolescence. It stimulates the increase in size of the sebaceous glands, which in turn leads to production of excess fat. This lipid enriched environment provides an excellent growth medium for Propionibacterium acnes (P. acnes).

Compacity trapped in the follicular canal and in the presence of P. Acnes block follicles be accompanied with the formation of tube (microgrid), which often increases progressively with the development of clinically detectable acne, non-inflammatory lesions, characteristic of vulgar eels (with white and black heads).

Anaerobic lipid enriched conditions created inside the follicle after the formation of microglia provide extremely favorable environment for the rapid multiplication of P. acnes. Then the metabolites of this bacterium can defund is encoded in the dermis, causing an inflammatory reaction mediated by T-cells-helper. The process can further be exacerbated by the tear duct and the involvement of certain types of Micrococcaceae.

Acne in and of themselves are not a serious disease. However, given their General social unacceptability, they can cause severe psychological and social problems, and therefore, accordingly, there is a great need in the search for effective treatment.

There are different ways of treatment regarding acne, but they generally preclude the fact that they are generally unreliable.

For the treatment of acne applies a limited number of antibiotics. In cases of moderate to high severity may be appropriate oral treatment, which is usually prescribed tetracycline, minocycline, doxycycline and erythromycin.

About acne from minor to moderate severity preferred treatment are topical preparations. Traditionally used benzoyl peroxide, but more widely began to apply the composition containing erythromycin or clindamycin. It has been shown that when applied individually, any of these compounds gave a reduction of inflammatory lesions from 50 to 60%.

Zineryt® contains 4% erythromycin and 1.2% zinc acetate. Research shows the t, this composition is 10% more efficient than a 2% erythromycin, and it has become a popular product. However, Zineryt® should be prepared by the pharmacist, and the retention period is only 5 weeks at room temperature. In addition, this fluid drug and uses alcohol media. So not only have problems applying lotion on the skin, but alcohol can also be a skin drying agent when used as the primary medium.

In the patent EP-A-506207 owned company Access Pharmaceuticais, describes how to obtain local pharmaceutical compositions containing the water-soluble zinc-containing compound and a pharmacologically active agents, including, among others, lincomycine as antibacterial agents. Separately also described compounds for the treatment of acne. The document does not disclose derivatives of pharmacologically active compounds and are not drawn to any particular aspect of interaction with zinc, which is present in them to create the effect of a reservoir in the skin. The result is to reduce the overall transdermal current active agent, but in amplification of the original absorption dermis, where in Association with zinc it is held in the form of a tank.

Clindamycine is a well-known antibiotic, is effective in Leche the Institute of acne. Unlike erythromycin is not suitable for systemic injections for this indication, but can be used as a substance other than erythromycin for the treatment of acne, helping thus to avoid proliferation (reproduction) resistant to erythromycin bacterial strains.

It was demonstrated that topical application of clindamycin (lotion for topical application Cleocin) is a safe and effective alternative to oral therapy with tetracycline when applied twice daily for 12 weeks in 43 patients with rosacea [Wilkin et al., Treatment of rosacea: topical clandamycin versus oral tetracycline Int. J.Dermatol. (1993); 32: 65-67]. Despite this study was the lack of development of local application of clindamycin for the treatment of rosacea.

In the patent US-A-4621075 issued nine qualities of God, revealed a combination of clindamycins and zinc acetate in a non-aqueous, pharmaceutically acceptable carrier for topical application. The composition can contain up to 5% of water without significant adverse impact on the formation of the desired gels, although examples of the water-containing compositions are not given. Aminobutiramida of sebacate is a required component of the carrier, and the other component is preferably ethyl alcohol. Disclosed compositions must be capable of gelation, and particularly it is shown that the molar ratio is osenia 1:1 does not form a gel. In this composition aminobutiramida of cebazat acts as an amplifier of the permeability of the skin.

The compositions of the patent US-A-4621075 very oily to the touch and do not form clear solutions, and large undissolved particles remain suspended in the final composition. They are not ideal for treatment of acne and due to the oily nature of the subject to treatment of diseases of the skin, and due to the presence of excessive amounts of ethanol in the composition. The fat composition is not only unlikely to contribute to patient medical prescriptions, but the fat composition is also not suitable for the treatment of acne. Large quantities of ethanol in unstable compositions quickly evaporate, leaving a thick oily or dry sediment, causing the output of condizionata from the solution and drying of the skin over time, thereby further enhancing oily effect and preventing trancdermalnaya absorption.

In document WO 97/15282 disclosed methods of treatment about dermatological diseases including three well-known type of means for the treatment of acne: antimicrobial agent, alpha - or beta-gidrokshikislotu and connection of zinc.

Surprisingly, the authors of the present invention have discovered that a stable, aqueous drug zinc salts and condizionata forms a polymer with a high molecular the th mass, which, as it turns out, is not absorbed through the skin, thereby further reducing fat excretion, and which should be applied only 1 time per day, compared with the scheme apply 2 times a day for other commercially available products clindamycin.

Thus, in a first aspect the present invention provides an aqueous preparation or composition for topical application comprising equimolar amount of condizionata and water-soluble zinc salts for use in the treatment of dermatoses.

For example, in patent US-A-4621075 noted that the presence of water prevents the formation of desirable gels simply with the introduction of the ingredients in the mortar without gelation.

The inventors have discovered that the formation of gels of condizionata with zinc salts in the presence of water provided that is used essentially neutral aqueous drug condizionata. Aqueous solutions of condizionata formed easily. If the alkaline solution is added to a mixture of condizionata and solvent in a quantity appropriate to bring the environment of the drug to neutral or even slightly alkaline, there is a tendency to rapid gel formation after addition of zinc salts. These gels have quality characteristics that exceed those for gels disclosed in the patent is US-A-4621075.

Thus, in a preferred embodiment, the implementation of the drugs of the present invention have an essentially neutral pH.

Conditions for the formation of the gel is preferably essentially neutral, preferably at pH from 5.5 to 8.0 and, in particular, from 7 to 7.5, in which the gel formation in General optimal. Once the gel has formed, the pH can be given the opportunity to vary in the range of essentially neutral pH values, in particular from pH 5.5 to 8.0, without destruction. For example, the original gel may be optional, optional essentially, divorced, other components, such as discussed below, which may lead to a change in pH. In addition, the gel formation can lead to a drop in pH, as described below. However, provided that such fall outside the above range, then the composition will generally stable.

The compositions of the patent US-A-4621075 not have pH because they are non-aqueous and is therefore not able to ensure the stability of the gel-forming medium of the present invention.

As noted above, the optimum pH for the formation of polymer zinc/condizionata is about pH 7. Clindamycine is zwitterion connection, and at pH 7 phosphate group largely deprotonated, while the tertiary amine essentially protonated. That is they way the phosphate group is able to form complexes with zinc ions zinc salts. The increase or decrease in pH outside the above ranges, in General, leads to the formation of other particles and, in addition, reduces the pharmacological efficacy of the composition.

Without limitation by theory, the inventors have discovered that essentially large, electrostatically linked polymer is formed in a substantially neutral aqueous preparations condizionata and zinc salts. These polymers preferably are formed when the molar amount of zinc salts is approximately equivalent to or greater than the number of condizionata. The polymer is formed, and when the amount of zinc salts and condizionata are not equimolar, but on the properties of the composition can influence the abundance of the ingredient that is present in larger quantities. This is less pronounced in case of excess zinc salts, but especially when the amount of zinc is much less than equimolar, any educated gel tends to be thin.

The polymer formed by zinc and clindamycinduration, has no tendency to penetrate into the skin, and it is likely that the polymer is included in orogovevshi layer. This may be due to the nature of the polymer, but the authors also noted that when using in vitro cellulose membranes increased is the same as a serviceable zinc additionally reduce the ability of percutaneous penetration condizionata.

It turns out that when applied to the skin clindamycine or complex condizionata and zinc rapidly adsorbed in orogovevshi layer, and is not absorbed into the dermis, as previously observed in this area in relation to compositions comprising zinc.

More specifically, when such compositions of the prior art, as Dalacin® T, applied to the skin in a controlled environment, although a number of condizionata penetrates through the dermis and into the plasma, most of condizionata remains on the skin surface and can be removed by wiping with a swab. In contrast, the levels of condizionata removed from the skin after 48 h after application of the composition of the invention, falling to 50%. However, while applying Dalacin® clindamycine easily detected in the dermis, and in the plasma, the composition of the present invention show little or no detectable amount of condizionata present in the dermis, and significantly reduced levels of condizionata in plasma.

Accordingly, compositions of the present invention have advantages over the prior art in several respects. Water nature of the composition prevents drying of the skin, a common problem observed in the application of compositions containing an excess of ethanol. Although zinc, likely is, effect of reservoir that is known from the prior art, it also serves to bind condizionata in the form of a polymer, so that the application of the compositions of the invention leads to a systemic concentrations of condizionata, which can be neglected. Further, in contrast to clindamycin, continued to impact on the skin's surface, it is rapidly absorbed or adsorbed in the surface layers of the skin, by protecting this product from washing off. This is particularly useful, because it simulates the effect of providing much higher levels of clindamycin without a simultaneous risk of lifting his system levels. In addition, compositions of the invention it is pleasant to apply, and they are acceptable compiled for submission of squeezing the tube or bottle, for example, compared with the compositions of the patent US-A-4621075, which tend to be brittle.

Compositions of the present invention include a polymer combination of zinc and condizionata, which is in dynamic equilibrium with its constituent parts. Thus, at any given time zinc and clindamycine can be separately identified within the drug. The number of complex or polymer will vary in accordance with the conditions and composition, and on the skin. Application of the composition on the skin serves to SRAS is to apply clindamycine, but especially the polymer acts as a slow release composition, produce clindamycine in the skin. Thus, there is an immediate and long-term action, which allows to apply the compositions of the present invention only 1 time a day, but at the same time to have the same therapeutic effect as the accepted drugs clindamycin.

The coordination complex of condizionata and zinc does not depend on the nature of the anion associated with zinc, in the original zinc salts. Itself zinc salts used in the present invention, is not critical for the invention. However, it should be understood that the selected anion must be pharmaceutically acceptable compositions for local application. Salt should be selected from salts of suitable organic or inorganic acids, and it preferably should be easily soluble in water or in the mixture of solvents used for dissolving condizionata.

Suitable zinc salts can be selected from salts that can be obtained from organic and inorganic acids. When zinc salts derived from organic acids, in General, it is preferable that the acid had a small, easy dissociirovati anion such as acetate, propionate or pyruvate, saturated, preferably lower alcamovia acids is their hydrated forms, especially zinc acetate and, in particular, the dihydrate zinc acetate. It should be understood that the anion has little or no value for the polymer, so that a primary consideration is that zinc salts was able to provide a zinc cation and the anion did not prevent formation of the polymer. It should also be understood that the anion must be pharmaceutically acceptable. Similar considerations would apply to any selected inorganic anion. In General, the preferred small anions, but can be chosen larger anions for their therapeutic activity, for example, as in the case of organic anions. In General, however, preferred a simple anions, such as chloride, and simple organic anions preferable inorganic, because they are more soluble in mixtures of water/cosolvent.

Although the primary means of stabilizing compositions of the present invention consists in the regulation of pH, other means include the use of agents against crystallization, such as propylene glycol, and thickeners, as discussed later, as well as solvents and other substances that do not adversely impact on the final composition, or which provide the advantages of the composition, such as ethanol. It should be understood that all such additional substances, for which they are a part of the final composition, should preferably be pharmaceutically acceptable.

Ethanol or other replacement hydrocarbons suitable to assist in the dissolution of condizionata during the initial formation of the complex, and it can also be used to obtain the final composition. As noted above, clindamycine poorly soluble in water, and even in the presence of a suitable base, such as sodium hydroxide or potassium compound is not readily soluble. Accordingly, it is preferable to use a co-solvent, such as ethanol, to achieve dissolution.

It should be understood that the person skilled in the art will easily determine the required amount of co-solvent. In General, you can use any number of co-solvent, which enhances the dissolution, and it is preferable to use not more than 7.0 wt.%/wt. co-solvent. Suitable alcohols are liquid at room temperature and preferably are lower alcohols, such as ethanol or isopropanol. The preferred co-solvent is ethanol, as it is pharmaceutically acceptable and is easily mixed with water. However, it can be any pharmaceutically acceptable, non-aqueous co-solvent, provided that it mixes easily with water.

Since, in General, preferably in order to minimize the amount of co-solvent to minimize any expected or other disadvantages of such a co-solvent, it is preferable to use not more than 50% ethanol, and preferably not more than 25%. The formation of the initial complex may involve approximately 60% ethanol, although inherently preferable equal amounts of water and alcohol.

It should also be understood that the amount of co-solvent can be increased to the maximum to achieve dissolution with subsequent removal of all or part of the co-solvent prior to receipt of the final composition. The final composition can represent the complex formed is neutralized of condizionata and zinc salts in water and co-solvent or with a remote co-solvent. More preferably, the final composition comprises additional ingredients such as diluents and/or stabilizers, as discussed below.

Although the polymer formed in the form of a coordination complex of zinc and condizionata, forms a gel in aqueous conditions, it is preferable to use low concentrations of condizionata in compositions for topical application.

Preferred concentrations are in the range from 0.1 to 10%, and more preferred concentration is from 0.5 to 5%, especially approximately from 1 to 2 wt.%. At these concentrations the gel, formed by the interaction of clindamycins and zinc, is not especially strong, so thus estwenno, it may be desirable the inclusion of a thickener. Suitable thickening agents include silicon dioxide, silicates, carbomer and connection of cellulose, such as hydroxymethylcellulose, hydroxypropylcellulose and hydroxyethylcellulose, and presently preferred hydroxyethylcellulose. Can also be used any other suitable thickeners provided that they essentially do not prevent the formation of a coordination complex of zinc/condizionata and are pharmaceutically acceptable.

When using these thickeners is only necessary that they be applied in sufficient quantities to prevent the fluidity of the gel. If desired, you can use quantities greater than listed, to achieve desired consistency.

Particularly preferable to use cellulose compounds as thickeners or texture modifiers, because they also tend to the ability to retain water in the composition. In addition, the impact on the final composition as a whole consists in the modification of the flow characteristics in order to give the song character yield pseudoplastic-type, which gives the composition a satisfactory texture and promotes, for example, applying the composition.

Suitable amounts of thickeners or relative who's compounds can be in the range of from about 0.2 to about 8 wt.%/wt., although more effectively such gel-forming compounds can be applied at lower levels, such as from about 0.5 to about 3%, preferably from about 0.7 to about 2%, and can be used levels from about 0.8 to about 1.5%, especially in the case of, for example, cellulose derivatives.

As noted above, the preferred pH for the formation of polymer is about 7. The present invention generally preferable to first obtain a solution or suspension of condizionata, and then bring the pH of this drug to about 7. More specifically, in accordance with the conditions in the examples, the authors found that pH 7.5 provides good results. At this pH clindamycine completely soluble, especially in the presence of, for example, ethanol.

After adjusting the pH to essentially neutral salt of zinc, such as zinc acetate. This is preferably done after the fact, as a solution with increased pH was stirred to dissolve all condizionata, but this is not necessary. Mixing this resulting mixture leads in General immediately or within a few minutes to salustiano solution. There are no particular restrictions on the type of mixing. Mixing is carried out in a convenient way, and mixing with high shear, especially when receiving the AI large quantities, ensures that the resulting gel is homogeneous.

Then such compositions can be used directly or preferably diluted to the preferred concentrations, as noted above, together with the inclusion of any preferred fillers, surfactants, dyes, stabilizers, gelling agents, and any other materials which it is desirable to include in the final composition.

Thus, the present invention also provides a method of manufacture of the drug, as described above, includes a first dissolution or suspension of condizionata in aqueous media, and then bringing the pH of the resulting solution or suspension is essentially to neutral values, preferably from pH 7.0 to pH 7.5, inclusive.

There is definitely the preferred alkali, but the authors find a suitable potassium hydroxide, especially sodium hydroxide. The quantity it is necessary to bring the pH of the aqueous product containing clindamycine, to a value of from 7 to 7.5, more generally, to the value of pH from 5.5 to 8.0. Aqueous preparations containing clindamycine may be in the form of a solution, a suspension, a simple mixture, or any combination of these forms. After adding alkali, in particular, to a final pH of about 6.5, astushi what I dissolved clindamycine quickly goes into solution at ambient temperature in the presence of co-solvent, preferably at least 25 wt.%, especially when the co-solvent is an ethanol.

Adding zinc salts in clindamycine the formation of complexes of zinc with deprotonirovannymi phosphate groups leads to the formation of a neutral polymer, but releases the proton and the anion, it is not only easily soluble in any mixture of water and co-solvent zinc salts, so that will be the trend in the acid solution. When the anion is, for example, acetate, but also forms a less alkaline or acid solutions in Association with protons than inorganic anions, such as chloride.

Thus, the amount of alkali is preferably chosen not only for deprotonization phosphate groups clindamycin, which, as it turns out, occurs at pH 7 or above, but which, in particular, depending on conditions, may occur at lower pH values, but also to obtain a final composition having a pH above 5.5, preferably 6.0 or above, after adding and include zinc salts.

Used herein, the term "aqueous medium" refers to any suitable liquid carrier that includes a significant amount of water, preferably at least 30%.

In General, it is preferable that the given source drug condizionata and Sol is zinc in aqueous media was used to obtain the final composition. Generally, it is preferable that the original drug was formed less than 50 wt.% the final composition, and the remaining ingredients were added after the addition of zinc salts. This allows the formation of polymer in optimal conditions prior to the preparation of the final composition.

Of course, zinc salts can be added prior to the addition of alkali or at the same time, but this may prevent impacts on clindamycins and generally is not preferred.

The final composition should generally be chosen in such a bleed, not to promote the decomposition of the polymer. Any dilution of the media containing the original complex, likely to lead to a definite quantity of decomposed polymer, especially if the breeding produced a large portion of water. Accordingly, it is preferable to use a suitable carrier for topical application, comprising a significant amount of non-aqueous carrier or diluent. In this regard, a significant amount is generally at least 40% and can reach about 80 wt.%.

In General preferably freely to maintain the same ratio between aqueous and non-aqueous media during the whole process of obtaining the original complex, and final composition. There is no specific ratio, which should be observed is the substance, but it is preferable to consider the solubility of condizionata and zinc salts. Clindamycine is not particularly easy soluble substance in pure ethanol, while zinc salts, such as acetate, slightly soluble in water and to a lesser extent in ethanol, so that the ratio of approximately 2:1 non-aqueous and aqueous media in General can be used in the final composition, although also suitable range from about 1:1 to 2.5:1. In particular, if the original receipt of the gel, you can use a higher amount of non-aqueous co-solvent. For professionals in this field will be immediately obvious to other ranges. The above combination provides the opportunity for sufficient dissolution of condizionata, at the same time retaining a sufficient amount of water to facilitate the dissolution of zinc ions and interaction with zwitterionic clindamycinduration.

It should also be understood that the cosolvent for the final composition does not necessarily have to participate in the maintenance of condizionata in solution, provided that they are actively not displace. Instead, they can participate in other aspects of the composition, such as described in more detail below. However, in General it is desirable to include a certain amount of co-solvent to enhance, stimulate or support the project of condizionata in solution, and it may be acceptable to form part of the non-aqueous component of the final composition.

Thus, it is preferable to use the levels of correlation between the non-aqueous and aqueous media from 4:1 to 2:3, more preferably from 3:1 to 1:1, in particular from 2.5:1 to 1.5:1, and especially about 2:1, and in the media source, and in the final composition, and the ratio is the same or different, preferably the same for both solvents).

Compositions of the present invention can be presented in any suitable form and may be in the form of creams, ointments, lotions, gels or in any other suitable form, but they preferably are sufficiently viscous so as not to drain from the area of skin to which they are applied, and such that a suitable amount of the composition can be applied to the selected area. Aqueous and non-aqueous components can accordingly be selected to achieve the desired composition type. The preferred form of the composition is a gel.

The advantage of the present invention also consists in the fact that in General there is no need to use amplifier permeability of the skin, such as aminobutiramida of sebacate. In particular, the presence of such amplifier leads to a greater increase in the content of condizionata in the dermis and inevitably to higher levels Clint mizina in the plasma. On the contrary, this is generally avoided when using the compositions of the present invention, particularly in the absence of amplifiers permeability of the skin.

The inventors have found that in the present invention, it is preferable to use physically stabilizing the connection. Aqueous compositions of zinc and condizionata after storage can form crystals, and this is undesirable. Thus, it was found that it is possible to avoid such formation of crystals by the inclusion of agents, such as propylene glycol. Although it was found that propylene glycol can be used in the present invention may be used any other suitable hydrophilic solvent, which is also pharmaceutically acceptable, such as glycerin, or different grades of polyethylene glycols, or macrogol. Such stabilizing compounds can be used in any suitable amount, ranging from about 1 to about 80 wt.%.

If desired, such hydrophilic solvents or co-solvents can be used as essentially all additional non-aqueous phase of the final composition. More preferably, additional non-aqueous material to be added to achieve the final composition contains a quantity of any of the original co-solvent used when getting out the underwater drug complex condizionata/zinc. This number can be up to 100%, but is preferably from 10 to 50% of additional non-aqueous component, and more preferably from 15 to 30%, for example, about 20%. Large quantities can have a tendency to evaporate and concentrate the solution, and this may not be desirable.

Any non-aqueous substance that is added to achieve the final composition is preferably non-volatile, or not so volatile as to be essentially completely evaporate within a short period after application to the skin. In this respect, the ethanol can be considered as a volatile compound, while, for example, propylene glycol can be considered as a fixed connection.

It was also discovered that the compositions of the present invention are thixotropic, and in General when storing their viscosity increases. Storage no special problems, and the preferred compositions of the present invention can be stored for at least two years without any unwanted effects.

In addition, there are methods of treatment of dermatoses, including the application of a pharmacologically effective amount of a composition as described above. A suitable amount of the composition for application to the skin may include from about 0.01 to about 0.3 ml/cm2for example, more preferably from about 0.05 to about 0.1 ml/cm2but not the particularly preferred scheme, and simply apply the composition to the affected area or the area which it is desirable to treat.

Dermatitis suitable for treatment using the present invention, in particular, include acne vulgaris, but also include any other disease that can be treated with clindamycin or clindamycin phosphate, in particular rosacea.

Hereinafter the present invention will be illustrated using the following non-limiting examples. The materials used in the examples were obtained from the following sources: Clindamycine (USP BN B21946), Genzyme; granules of sodium hydroxide (BN B552682), dihydrate zinc acetate (BN D0325), hydroxyethylcellulose (BN 9906B038) and propylene glycol (BN 08101-1), August Wolff; ethanol (99-100%/about.) and ethanol (96 vol.%/vol.), BDH; propylene glycol 400, Sigma Pharmaceuticals; zinc acetate (anhydrous), Aldrich Chemical Co.; aminobutiramida of cebazat, A&E Connock Ltd.; and membrane Spectra/Por® Biotech CE (MWCO 5000), NBS Biologicals, Cambs, UK. Deionized water was obtained using a water purifier Option 3 (Elga).

Examples will be illustrated using the accompanying drawings, in which:

Figure 1 shows the yield curves representing the behavior of compositions having a molar ratio between clindamycinduration (KF) and zinc acetate (ZnA) is 1:1.5.

Figure 2 shows yield curves representing the behaviour is of the compositions of examples II and IV of the patent US-A-4621075, compared with the compositions of the present invention.

Figure 3 shows yield curves, representing the behavior of the compositions of the patent US-A-4621075, but containing water in amounts from 0 to 40%.

Figure 4 shows the effect of the release of KF P&G II, P&G IV, complex according to the invention and compositions of the invention (molar ratio of CP:ZnA 1:1) over time.

Figure 5 demonstrates the effect of adding water in an amount of 5, 15 and 40% in the composition of the P&G on the rate of release of condizionata.

Example 1

Gel clindamycin 1%/wt.

The way to obtain

1. COMPOSITION

The composition is as shown below:

IngredientThe composition of standard dosage forms (wt.%/wt.)
Complex
Clindamycine1,1881,2
Purified waterto 12.0
Ethanol 96%10,0
Sodium hydroxide 30 wt.%/wt.how much is required to bring the pH to 7.5
The dihydrate zinc acetate0,516
Track
Hydroxyethylcellulose1,0
Propylene glycol40,0
10,0
Purified wateras required (q.s.) up to 100%
1Equivalent to 1.0% of the clindamycin

2For convenience it is referred to clindamycin 1%

3With the amendment boot party on the activity of condizionata

2. MANUFACTURING

Complex

a) Mix the ethanol and purified water using a homogenizer.

b) With continuous homogenization add clindamycine (adjusted mass analysis and water content) to form a suspension.

c) With continued mixing slowly add the sodium hydroxide 30 wt.%/wt. to pH 7.5 (allowing clindamycine to dissolve). To register pH and calculate the total quantity of water added.

d) Dissolving the dihydrate zinc acetate in purified water and mix until a clear solution is formed.

(e) continuing the homogenization add a solution of zinc acetate to a pH 7.5 solution condizionata. Continue mixing until a homogeneous, transparent, white gel.

This process can be performed in the production of a number of smaller batch.

Cellulose-based gel

f) Mix propylene glycol and ethanol 96% to obtain a homogeneous mass.

g) When the homogenization add hydroxyethylcellulose is as long until it forms a transparent, homogeneous gel.

The manufacture of the final form gel

h) Add complex condizionata and zinc based gel and mix until until a homogeneous, white opaque gel.

i) Add water up to 100% and mix until smooth.

j) Fill in the tubes.

Example 2

In the patent US-A-4621075 disclosed combination of condizionata and zinc acetate in nonaqueous media for local use in a molar ratio of more than 1:1,2. The patent States that the ratio below this lead to a poor gelation or it is missing. This example sets the differences between the compositions of the present invention and the patent US-A-4621075 (referred to here as "patent P&G" or simply "P&G"). Used herein, the abbreviation KF represents clindamycine, a ZnA is the dihydrate zinc acetate.

In contrast to patent it was found that the gel formation occurred at a molar ratio of CP:ZnA 1:1. All tracks P&G have very oily to the touch.

The rheology of the compositions of the present invention and compositions P&G is investigated in this example. Simple fluid, the flow rate of which is directly connected with the applied pressure, can be considered as a Newtonian fluid. However, most pharmaceutical liquid does not follow this law, because the fluid viscosity varies with shear rate, and they are thus considered non-Newtonian fluid. One deviation is the plastic fluidity, which occurs when the yield curve does not pass through the origin, but intersects with the axis of the shear forces at the point referred to as the "yield point". This is because the plastic material does not flow until, until it exceeded this value of shear forces. At lower values the efforts substance behaves as a solid (elastic) material.

Pseudoplastic-type fluctuation of the source occurs because there is no yield point, the material will flow as soon as the applied shear force. However, the slope of the curve gradually increases with increasing shear rate. The viscosity of a pseudoplastic-type materials are removed from the reciprocal of the linear part of the curve fluidity or any tangent held to it (as with other substances). Accordingly, for pseudoplastic-type materials, the viscosity decreases with increasing shear rate.

This example is divided into three parts. In the first complex P&G was obtained as described in example V of the patent US-A-4621075 at molar ratios of condizionata and zinc acetate 1:0,5, 1:1, 1:1,5 and 1:2, and their rheology against the Vali with the rheology of the preferred compositions of the present invention, obtained in similar proportions CP:ZnA. As in other parts of this example, the preferred composition of the present invention was obtained in the form of a complex, and in the final composition.

In the second part of this example, the composition of the P&G was obtained as described in examples II and IV of the patent US-A-4621075, and rheology compared with the rheology of the preferred compositions of the present invention.

In the third part of the composition of the P&G was obtained as described in example V of the patent US-A-4621075 at molar ratios between clindamycinduration and zinc acetate is 1:1.5, and the impact of 5, 15 and 40% (wt./wt.) water on the rheology of the composition was compared with the rheology of the preferred compositions of the present invention.

Part 1

Composition P&G

28,0 g aminobutiramida sebacate weighed in a beaker. Then weighed and 70.5 g of ethanol and add to the beaker. Data two components are then mixed together under moderate stirring using a magnetic stirrer. The beaker is kept closed during mixing to minimize evaporation of the ethanol. 1.0 g of condizionata added to the beaker and stirring is continued for approximately two minutes. Then add 0.5 g of zinc acetate (anhydrous) and stirring is continued until, until the mixture thickens. The stirrer is removed and the mixture aside. After a few hours is formed n Otradny gel.

The molar ratio between clindamycinduration and zinc acetate (anhydrous) change, changing both molarity of zinc acetate (brought anhydrous ethanol), and both molarity of condizionata is maintained constant. Investigated the relationship between clindamycinduration and zinc acetate (molar) were as follows: 1:0,5, 1:1,0; 1:1,5 and 2.0.

Compositions of the invention

The complex was obtained as follows. 40 g of ethanol and 40 g of purified water are mixed using a homogenizer. With constant homogenization add clindamycine (adjusted mass analysis and water content) to form a suspension. Continuing the mixing, add 30 wt.%/wt. of sodium hydroxide to pH 7.5 (register rn and the total amount of water). 2,064 g dihydrate zinc acetate dissolved in 8 g of purified water and mix until until it forms a clear solution. With the continued homogenization add a solution of zinc acetate in a solution of condizionata with pH 7.5. Mixing continues until, until it forms a transparent gel.

The composition was prepared as follows. 160 g of propylene glycol mixed with 40 g of ethanol (96.about.) to obtain a homogeneous mass. Continuing homogenization, add 4 g of hydroxyethyl cellulose as long until it forms a transparent gel. Then, the so formed gel add recipients who have complex condizionata:zinc acetate and mix until until you have a white opaque gel. Add water until, until you reach the final weight of 400 g, and mix. The molar ratio between clindamycinduration and dihydrate zinc acetate change change polyarnosti the dihydrate zinc acetate (adjustable water) while maintaining polyarnosti clindamycin at a constant level.

After obtaining compositions retain at room temperature for 30 min before research rheology and diffusion, which perform at the same time. This sequence of operations ensures that all songs will be tested after the same storage period.

Ingredientwt.%/wt.
Complex
Clindamicina1,188
Purified waterto 12.0
Ethanol 96%10,0
* Sodium hydroxide 30 wt.%/wt.how much is required to bring the pH to 7.5
The dihydrate zinc acetate0,516
Base gel
Hydroxyethylcellulose1,0
Propylene glycol40,0
Ethanol 96%10
Purified waterhow much you want to 100%
* Receive 30% (wt./about.) aqueous sodium hydroxide: 3 g of sodium hydroxide dissolved in 10 ml of water.

Part 2

Compositions of the invention

Get them, as described above in part 1.

Composition P&G

Example II the patent US-A-4621075: 25,0 g of polyethylene glycol weighed in a beaker. Then give 73,4 g of ethanol and add to the beaker. Data two components are then mixed together under moderate stirring using a magnetic stirrer. The beaker is kept closed during mixing to minimize evaporation of the ethanol. 1.0 g of condizionata added to the beaker and stirring is continued for approximately two minutes. Then add 0,54 g of zinc acetate (anhydrous) and stirring is continued until, until the mixture thickens. The stirrer is removed and the mixture aside. After a few hours is formed a transparent gel.

Ingredientwt.%/wt.
Clindamycine1,0
Zinc acetate0,54
The polyethylene glycol 40025,0
Ethanol (anhydrous)73,46
KF:Zn (molar ratio 1:1.5)

Example IV the patent US-A-4621075: 99,23 g of ethanol weighed and added to the beaker. 0.50 g of condizionata added to the beaker and stirring is continued for approximately two minutes. The beaker is kept closed during mixing to minimize evaporation of the ethanol. Then added 0.27 g of zinc acetate (anhydrous) and stirring is continued until, until the mixture thickens. The stirrer is removed and the mixture is put aside. After a few hours is formed a transparent gel.

Ingredientwt.%/wt.
Clindamycine0,50
Zinc acetate0,27
Ethanol (anhydrous)99,23
KF:Zn (molar ratio 1:1.5)

Part 3

Compositions of the invention

Get them, as described above in part 1.

Composition P&G

Example V the patent US-A-4621075: 28,0 g aminobutiramida sebacate weighed in a beaker. Then give 70,46 g or other amount in accordance with the water content (see table below) ethanol and add to the beaker. Data two components are then mixed together under moderate stirring using a magnetic stirrer. The beaker is kept closed during mixing to minimize evaporation of the ethanol. 1.0 g of the Kli is dizingoff added to the beaker and stirring is continued for approximately two minutes. Then add 0,54 g of zinc acetate (anhydrous) and stirring is continued until, until the mixture thickens. Then the mixture was added water (if possible) and stirring is continued until, until it forms a homogeneous mixture. The stirrer is removed and the mixture is put aside. After a few hours is formed a transparent gel. The molar ratio between clindamycinduration and zinc acetate (anhydrous) remains constant, while the addition of water is replaced by ethanol content.

IngredientKF:Zn (1:1,5)% (wt./wt.)KF:Zn (1:1,5)% (wt./wt.)KF:Zn (1:1,5)% (wt./wt.)KF:Zn (1:1,5)% (wt./wt.)
Clindamycine1,001,001,001,00
Zinc acetate0,540,540,540,54
Water05,015,040,0
Ethanol (anhydrous)70,4665,4655,4630,46
Aminobutiramida of cebazat28,028,028,028,0
KF:Zn (molar ratio 1:1.5)

Rheology

Rheological measurements the wire is whether using rheometer (Carri-Med CSL100 when parameters shown in the table below.

a) 2 ml of the composition, subject to investigation, was pushed out of the syringe (5 ml) with an approximate rate of 1 ml/S.

b) Then the sample was carefully placed in the center of the platform using a spatula.

c) the Device used in the mode of shear forces to build yield curves.

d) the Number of repeated measurements for each composition depended on the time required to build each yield curve.

1.Prior to application of shear forces0PA
2.Time before shift00:00:00hour:min:sec
3.Time trim00:01:00hour:min:sec
4.The type of experimentThe distribution of shear forces
5.Temperature15,0°
6.Initial voltage0PA
7.*Ultimate shear force10,00PA
8.Mode voltageLinear
9.*Ascent/td> 00:05:00hour:min:sec
10.The type of measuring deviceParallel plate
11.Diameter of plate4,0cm
12.The gap measuring250mcm
device
13.Inertia measurement1,440mcns2
device
*Ultimate shear force and lift time was changed depending on the nature of the composition, but during the whole experiment for all compositions supported speed of the application voltage 2 PA/min

Results

None of the gel obtained in accordance with example V the patent US-A-4621075, was not transparent, and all gels contained undissolved KF.

Research rheology

When a molar ratio of CP:ZnA 1:0.5 to yield curves and complex of the invention, and the composition of the P&G pointed to the plastic fluidity, whereas the curve of the fluidity of the composition of the invention was typical of pseudoplastic-type of fluidity. It was found that the data nablyudeniyami for all other molar ratios of CP:ZnA, and they are shown in figure 1 for the molar ratio of CP:ZnA 1:1,5. As the molar ratio of CP:ZnA was increased from 1:0.5 to 1:1.5, the observed increase in the yield strength of the complex of the invention and compositions P&G. However, a statistically significant difference of yield between molar ratios of 1:1.5 and 1:2 was observed (p>0,05) for both systems.

Figure 1 shows the yield curves representing the behavior of a composition having a molar ratio of CP:ZnA 1:1,5. As in other drawings, "Complex" and "Composition" respectively denote the complex and the composition of the invention.

The results presented in table 1 clearly show that the composition with the highest ηarrwas obtained at all molar ratios of CP:ZnA in the composition of the invention. There was also an increase ηarr(apparent viscosity obtained by the reciprocal of the slope of the curve), as both molarity ZrA increased from 0.5 to 2.0 for all investigated compositions (with the exception of the composition P&G at a molar ratio of CP:ZnA 1:2). The obvious trend was not observed when the composition of the P&G was compared with the complex of the invention. It was found that a molar ratio of CP:ZnA 1:0,5 ηarrcomplex of the invention significantly (p<0,05) than the composition P&G. However, although it was found that ηarr composition P&G more than a complex of the invention in all other molar ratios of CP:ZnA, a significant difference (p>0,05) were observed.

Table 1

The average apparent viscosity (ηapp)defined by a reverse gradient, obtained by the linear region of the curve yield
Trackηarr(PA. sec) Average ± standard deviation (n=2 to 6)The value of P as compared with the composition of the invention
CP:ZnA (1:0,5)
Composition P&G0,0017±0,0001P<0,05
Complex inventions0,0021±0,00003P<0,05
Track0,0338±0,0031
CP:ZnA (1:1)
Composition P&G0,0029±0,0005P<0,05
Complex inventions0,0024±0,0001P<0,05
Track0,0581±0,00154
CP:ZnA (1:1,5)
Composition P&G0,0056±0,0036P<0,05
Complex inventions0,0025±is 0.0002P<0,05
Track0,0699±0,0052
CP:ZnA (1:2)
Composition P&G0,0042±0,0017P<0,05
Complex inventions0,0035±is 0.0002P<0,05
Track0,1147±0,0214

Part 2

In this part of the compared curves yield complex and compositions of the invention (CP:ZnA 1:1) and P&G from examples II and IV. As mentioned earlier, the complex and the composition of the invention showed properties of plastic and pseudoplastic-type of fluidity. Curve fluidity to the composition P&G from example II was impossible to build because of its too large yield strength (>350 PA). Curve fluidity of the composition P&G from example IV demonstrates significantly (p<0,05) expressed more properties of the plastic yield strength compared to the complex composition of the invention.

The results are shown in table 2, which illustrates the yield curves representing the behavior of the investigated compositions.

Table 2 compares the values ηarrthe investigated compositions. It was found that ηarrcomposition P&G from example IV is significant not great for the is (p> 0,05) from the complex of the invention. However, it was found that the value of ηarrthe composition of the invention significantly (p<0,05) more than and complex of the invention, and the composition of the P&G from example IV.

Table 2

The average apparent viscosity (ηarr)defined by a reverse gradient, obtained by the linear region of the curve yield
Trackηarr(PA·sec)Average ± standard deviation (n=3 to 5)The value of R, compared with the composition
Composition P&G from example IV0,0018±0,0014P<0,05
Complex, CP:ZnA (1:1)0,0024±0,0001P<0,05
Composition, CP:ZnA (1:1)0,0581±0,0015

Part 3

In this part of the compared curves fluidity of the composition P&G (CP:ZnA 1:1,5) with 40% (wt./wt.) water complex of the invention and compositions of the invention. As mentioned earlier, the complex and the composition of the invention and the final composition showed properties respectively of plastic and pseudoplastic-type of fluidity. And again, it was found that the yield curves of the compositions P&G pointed to the plastic fluidity. However, after adding water to the composition and P& G was not observed apparent trend in yield curves. The results are shown in table 3, which illustrates the yield curves representing the behavior of the investigated compositions. It was found that the properties of the plastic fluidity of the compositions P&G with 5 and 15% (wt./wt.) water is the same, although the composition P&G with 0 and 40% (wt./wt.) water also showed the same properties of plastic yield, but had significantly greater yield strength. Curves yield of the investigated compositions P&G were characterized by more plastic compared to the complex of the invention.

Table 3 shows the values ηarrthe investigated compositions. And again the results did not show any obvious trend in the composition of the P&G the percentage of water was increased to 40% (wt./wt.). Meaningful difference ηarrwas not observed between songs P&G with 5% and 15% (wt./wt.) water, and found that it was the same for 0 and 40% (wt./wt.). It is important that, as it was found that all investigated compositions P&G in this study were significantly greater (p<0.05) as ηarrcompared with the complex of the invention (CP:ZnA 1:1), although it was found that ηarrthe composition of the invention was significantly greater (p<0.05)than all other studied systems.

Table 3

The average apparent viscosity (ηarr)defined by a reverse gradient, obtained by the linear region of the curve yield
Trackηarr(PA·sec) Average ± standard deviation (n=3 to 5)The value of P as compared with the composition
P&G (CP:ZnA, 1:1.5 to 0% water0,0056±0,0036P<0,05
P&G (CP:ZnA, 1:1.5 to 5% water0,0037±0,0003P<0,05
P&G (CP:ZnA, 1:1.5 to 15% water0,0038±0,0007P<0,05
P&G (CP:ZnA, 1:1.5 to 40% of water0,0048±0,00007P<0,05
The complex of the invention, CP:ZnA (1:1)0,0024±0,0001P<0,05
The composition of the invention, CP:ZnA (1:1)0,0581±0,0015

It was found that the plastic fluidity, exemplified by the complex of the invention and the compositions P&G in parts 1, 2 and 3, depended on the formation of a complex between EF and ZnA. This was clearly demonstrated in part 1, when ηarrcompositions in General increased as the molar ratio of CP:ZnA increased from 1:0.5 to 1:2.

Pseudoplastic-type fluidity demonstrated for all compositions of the invention when all olyarnik ratios CP:ZnA, may be due to present them hydroxyethyl cellulose. Curve fluidity to the composition P&G from example II is not built, and high yield strength testified fragile gel structure.

All investigated compositions P&G showed more plastic fluidity than the complexes of the invention, although direct comparisons cannot be drawn between the compositions of the invention and the compositions P&G, since both sets of compositions showed different properties yield strength. This was true even for compositions P&G, prepared with water (as opposed to the provisions of the patent US-A-4621075), and the presence of water has made surprisingly little difference in the properties of the compositions P&g

The results show that zinc has a significant effect on the rheological properties of the complexes of the invention and compositions P&G, and found that the properties of the plastic yield strength increases as the ratio of CP:ZnA increases from 1:0.5 to 1:1,5, although significant difference was not observed between the ratio of CP:ZnA 1:1.5 and 1:2 for any composition. However, it was found that all tracks P&G (except CP:ZnA 1:0,5) were significantly higher ηarrwhen compared with the corresponding complexes of the invention that indicates the presence of distinct mechanisms in the composition is X.

The influence of CP:ZnA was not as important for the compositions of the invention, and pseudoplastic-type fluidity exhibited by compositions of the invention, testified that the composition P&G was significantly different from the compositions of the invention. This was confirmed with the data from part 2. The fact that the addition of various quantities of water in the composition of the P&G has not made a difference in the rheological properties of these compositions, in addition suggests that the composition P&G and compositions of the invention differ significantly.

Thus, on the basis of the obtained rheological data we can conclude that the composition of the invention, and the composition of the P&G behave very differently from the point of view of the mechanisms involved in the formation of complexes with KF Zn and the ultimate effect on the rheology.

Example 3

Research release

In this example, the value of the speed of release of clindamycin from compositions P&G was compared with the values of the speed of release of the compositions of the present invention through a synthetic membrane.

Follow the recommendations on the basis of leadership SUPAC-SS for non-sterile semi-solid dosage forms [ZCG 31T; FDA (CDER), 1997, Guidance for industry SUPAC-SS Non-sterile Semisolid Dosage Forms, Scale-up and post-approval changes: Chemistry, manufacturing and controls; in vitro release testing and in vivo bioequivalence documentation]. The guide is addressed to nest relnum semi-solid preparations, such as creams, gels, lotions and ointments intended for local routes of administration.

This example was made in three parts and using the compositions obtained as described above in paragraphs 1, 2 and 3 of example 2.

the pH of all subject to the investigation of the compositions was measured at the beginning and at the end of the experiment. The test compositions were carried out in accordance with the recommendations of the Administration of food and drugs SUPAC In vitro release testing and in vivo bioequivalence (see above).

For each lot used 6 devices with diffusion cell Franz (hole diameter 18 mm), equipped with a synthetic membrane (ester of cellulose, MWCO 3500) with deionized water as the host liquid. Accurately weighed amount (300 mg) of the composition, corresponding to the condition unspecified doses evenly applied on the membrane and sealed Parafilm® to prevent evaporation of the solvent and lineup changes. The Franz cell was placed in a water bath at 32°C. a Sample (500 µl) receptor phase was removed through 1, 2, 3, 4, 5, 6 and 8 o'clock Any aliquot number deleted from the reception chamber was replaced aliquot quantity of fresh receptor fluid (deionized water). Samples removed from the receptor phase were analyzed on the content of the drug is highly effective liquid HRO what ecografia (HPLC).

Methodology HPLC

Mobile phase: 80:20, pH of 2.5 phosphate buffer:acetonitrile

Column: Supelcosil LC-8, 25 cm × 4.6 mm, 5 µm

Detector: 210 nm

Flow rate: 1.0 ml/min

Volume of injection: 100 ál

Temperature 35°

Preparation of buffer: potassium phosphate buffer (13,6 mg/ml), pH of 2.5 is obtained by dissolution of 68 g of dihydroorotate potassium in 4 l of water. the pH of the solution was adjusted to 2.5 with phosphoric acid, and add water up to 5 HP If required, the buffer should be filtered.

Mobile phase: 80 obtala pH of 2.5 phosphate buffer mixed with 20 objatami acetonitrile with purification suitable for HPLC. Mobile phase was filtered before use.

Construct a graph showing the change over time of the percentage release. He gives a straight line, the slope of which represents the rate of release. 6 samples give 6 values of the slope for each song, giving the value of the speed of release in vitro.

Were determined in the pH of the facility and all of the compositions are shown below.

6,16
TrackpH before studypH after research
The complex (CP:ZnA)
1:0,56,876,86
1:1the 6.066,04
1:1,56,14
1:2to 6.196,17
Composition (CP:ZnA)
1:0,57,34to 7.32
1:16,256,23
1:1,55,985,97
1:25,975,97

In addition, before testing measured the pH of the compositions P&G, which were as follows:

TrackpH before study
Part 1 (CP:ZnA)
1:0,5(6,3)
1:1(5,1)
1:1,5(6,1)
1:2(5,5)
Part 2 (CP:ZnA).
1:1,56,2
Part 3 (wt.%/wt. water)
0(6,1)
5the 5.7
155,5
40a 4.9

The numbers in parentheses indicate the absence of pH values, and the numbers represent the apparent pH value displayed pH-meter in the absence of water in the product.

Part 1

The release profiles of each of the C tested compositions at all molar ratios of CP:ZnA shown in table 4. It is seen that different molar ratio of CP:ZnA significant (<0,05) affect the rate of release of CF from all tracks through the membrane of cellulose acetate, and compositions of the invention ("Composition" in table below) show little change. It can be noted that the lowest level of release is the composition of the invention at a molar ratio of CP:ZnA 1:1 in accordance with a preferred aspect of the present invention.

Table 4

The magnitude of the speed of release of CF from P&G, the complex of the invention and compositions, sravnivayete at the same molar ratios
TrackThe rate of release (%/h) Average ± standard error (n=5, 6)The value of P as compared with the composition
CP:ZnA (1:0,5)
Composition P&G0,657±0,088P<0,05
Complex inventions0,356±0,040P<0,05
Track0,207±0,025
CP:ZnA (1:1)
Composition P&G0,276±0,045P<0,05
The complex image is the shadow 0,221±0,023P<0,05
Track0,140±0,009
CP:ZnA (1:1,5)
Composition P&Gof 0.182±0,041P<0,05
Complex inventionsof € 0.195±0,016P<0,05
Track0,223±0,020
CP:ZnA (1:2)
Composition P&G0,098±0,026P<0,05
Complex inventionsto 0.108±0,008P<0,05
Track0,245±0,031

Part 2

The results of this part are shown in table 5 and figure 4. Figure 4 shows the effect of the release of KF P&G II, P&G IV complex of the invention and compositions of the invention (molar ratio of CP:ZnA 1:1) over time, average ± standard error (n=5, 6).

The results show that the rate of release of the composition P&G IV was more than twice the composition P&G II. It was found that both compositions P&G was produced significantly greater release of KF than or complex, or composition of the invention. These data suggest that Svobodnye KF through the membrane of the complex cellulose ether is increased, when the polyethylene glycol 400 in P&G II was replaced by ethanol (P&G IV) even at half the concentration of KF.

Table 5

The magnitude of the speed of release of CF from P&G, the complex of the invention and compositions
TrackThe rate of release (%/h) Average ± standard error (n=5, 6)The value of P as compared with the composition
P&G II0,276±0,035P<0,05
P&G IV0,612±0,050P<0,05
The complex of the invention (CP:ZnA 1:1)0,221±0,023P<0,05
The composition of the invention (CP:ZnA 1:1)0,140±0,009

Part 3

The results are shown in table 6 and figure 5. Figure 5 shows the effect of adding water in a proportion of 5, 15 and 40% to the composition P&G at a molar ratio of CP:ZnA 1:1.5 in comparison with the complex and the composition of the invention (CP:ZnA 1:1). It was found that the rate of release of CF from the composition P&G (when all the water content) was significantly higher (p>0.05)than from the compositions of the invention (CP:ZnA 1:1), which provide a longer duration of delivery, in accordance with a preferred aspect of the present invention.

Table 6

The effect of water on the velocities of KF P&G (molar ratio of CP:ZnA 1:1,5) in comparison with the complex and the composition of the invention (CP:ZnA 1:1)
TrackThe rate of release (%/h) Average ± standard error (n=5, 6)
CP:ZnA (1:1,5)
composition P&G (0% H2O)0/182±0,041
composition P&G (5% H2O)0,301±0,073
composition P&G (15% N2O)0,435±being 0.036
composition P&G (40% N2O)0,672±0,093
CP:ZnA (1:1)
complex inventions0,221±0,023
the composition of the invention0,140±0,009

Example 2 shows that when the molar concentration of CP:ZnA 1:1,5 nonaqueous composition P&G was significantly different (p>0,05) from aqueous systems of the invention. Therefore, it was impossible to expect that the addition of water in the composition P&G will change the rate of release of CF from the composition P&G. However, it was found that the rate of release of CF was significantly increased, as the percentage of water was increased from 0 to 40%, indicating that water greatly affects skorostyu.ishodny KF composition of P& G. in Addition, the composition of the invention contains about 40% water, but has the rate of release of constituting about 20% of the speed of the composition P&G (with the same amount of water), indicating that these two compositions behave in a different way.

Therefore, from the observed data diffusion can be concluded that the composition of the invention, and the composition of the P&G behave very differently from the point of view of the mechanisms involved in the formation of complexes with KF Zn and the resulting impact on thermodynamic activity of KF (release preparation).

1. Preparation for local application water-based, including clindamycine and water-soluble zinc salts in a molar ratio of from 1.2:1 to 1:2, having a pH from 5.5 to 8.0, for use in the treatment of dermatoses.

2. The preparation according to claim 1, having an essentially neutral pH.

3. The preparation according to claim 1 or 2, having a pH above 5.5.

4. The preparation according to claim 3 having a pH of 6.0 or above.

5. The drug according to any one of claims 1 to 4, in which the concentration of clindamycin is from 0.1 to 10 wt.%.

6. The preparation according to claim 5, in which the concentration of clindamycin is from 0.5 to 5% wt./wt.

7. The preparation according to claim 6, in which the concentration of clindamycin is from 1 to 2% wt./wt.

8. The drug according to any one of claims 1 to 7, in which the zinc salt is a zinc acetate.

9. The drug according to any one of claims 1 to 8,in which the zinc salt is an acetate dihydrate zinc.

10. The drug according to any one of claims 1 to 9, comprising a non-aqueous carrier or diluent in an amount of from 40 to 80 wt.%.

11. The preparation of claim 10, in which the ratio between the non-aqueous and aqueous components is from 4:1 to 2:3.

12. The preparation according to item 11, in which the ratio is from 2.5:1 to 1.5:1.

13. The drug according to any one of claims 1 to 12, comprising a pharmacologically acceptable hydrophilic co-solvent.

14. The drug is indicated in paragraph 13, in which the co-solvent includes one or more components selected from propylene glycol, glycerol, polyethylene glycol, macrogol and ethanol.

15. The drug for 14 comprising ethanol in an amount of from 10 to 50 wt.% drug.

16. The drug is indicated in paragraph 15, comprising from 20 to 30% ethanol.

17. The drug according to any one of claims 1 to 16, comprising a thickener.

18. The drug on 17, in which the thickener is selected from carbomer and cellulose derivatives.

19. The drug p, in which the thickener is selected from hydroxymethylcellulose, hydroxypropylcellulose and hydroxyethyl cellulose.

20. The drug p, in which the thickener is a hydroxyethyl cellulose.

21. The drug according to any one of p-20, in which the thickener is present in an amount of from 0.5 to 3 wt.% drug.

22. The drug according to any one of claims 1 to 21 slow release.

23. The preparation according to claim 1, in which the molar ratio of the amount of clindamycin phosphate with is whether zinc is from 1:1 to 1:1,5.

24. The drug in item 23, in which the molar ratio of the amount of clindamycin phosphate to zinc salts is about 1:1.

25. The method of producing drug, as defined in any one of claims 1 to 24, comprising mixing a specified condizionata with water, bringing the pH of the mixture to values from 6.5 to 8.0, and then adding the specified zinc salts.

26. The method according to p. 25, further comprising mixing the specified condizionata with a co-solvent.

27. The method according A.25, including bringing the pH to values from 7.0 to 7.5.

28. The method according to p or 27, in which the co-solvent is an ethanol up to 70 wt.% solvent mixture.

29. The method according to any of PP-28, which use essentially equal amounts of water and alcohol.

30. The method according to any of PP-29, comprising essentially complete dissolution of condizionata in the solvent mixture before the addition of zinc salts.

31. The method according to any of PP-30, in which the pH was adjusted using concentrated sodium hydroxide solution.

32. The method according to any of p-31, in which water is at least 30 wt.% solvent mixture.

33. The method according to any of p-32, in which the pharmacologically acceptable, hydrophilic co-solvent is included in an amount of from 1 to 80 wt.%.

34. The method according to any of PP-33, in which the co-solvent comprises a volatile not odny component and non-volatile non-aqueous component and in which the volatile nonaqueous component is from 10 to 50 wt.% just co-solvent.

35. The method according to clause 34, in which the volatile nonaqueous component represents ethanol, and non-volatile non-aqueous component is a propylene glycol.

36. A method for the treatment of dermatological diseases, including the application of a pharmacologically effective amount of the preparation according to any one of claims 1 to 24 to the skin in need thereof of a patient.

37. The drug according to any one of claims 1 to 24 for use in the treatment of diseases to be treated with clindamycin or clindamycinduration.

38. The drug according to any one of claims 1 to 24 for use in the treatment of acne vulgar.

39. The drug according to any one of claims 1 to 24 for use in the treatment of rosacea.



 

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FIELD: organic chemistry, vitamins, medicine, pharmacy.

SUBSTANCE: invention relates to a new compound of the formula (I): wherein X means hydrogen atom or hydroxy group; R1 and R2 that can be similar or different mean hydrogen atom, (C1-C4)-alkyl; R3 means hydrogen atom, methyl group, fluorine or chlorine atom. Also, invention relates to its esters able to hydrolysis in vivo in combination with pharmaceutically acceptable acids. Also, invention relates to a pharmaceutical composition eliciting the inhibitory activity with respect to proliferation and promoting differentiation of cells and comprising the effective dose of compound of the formula (I) in common with pharmaceutically acceptable carriers and/or excipients. Also, invention relates to applying compound of the formula (I) for preparing a medicine used in treatment and prophylaxis of disease characterizing by abnormal differentiation of cells and/or proliferation of cells.

EFFECT: valuable medicinal properties of compounds.

13 cl, 3 sch, 3 tbl, 6 ex

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EFFECT: higher efficiency of anti-acne therapy.

13 ex, 4 tbl

FIELD: pharmaceutics.

SUBSTANCE: the suggested composition has got viscosity being below of about 15000 cP and pH being approximately 3.0-9.0 for treating human skin diseases. He suggested composition consists of (a) therapeutically efficient quantity of, at least, one compound being useful in treating the above-mentioned disease; (b) pharmaceutically acceptable, partially bound polymer of polyacrylic acid being compatible with the compound; (c) not obligatory, a solvent being mixed with water, (d) not obligatory, a conserving agent, (e) not obligatory, a component of butyric phase and acceptable surface-active substance, and (f) water. The suggested composition is useful to treat inflammatory skin disease, acne or acne erythematosa. The composition of low viscosity has got its advantage in the fact that it is applied more accurately when in contact with a container that doses the composition in the form of drops.

EFFECT: higher efficiency of application.

23 cl, 15 ex, 19 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention proposes new compounds of the general formula (I):

wherein R1 means one or more similar or different substitutes taken among the group consisting of hydroxy-group, halogen atom including F, Cl, Br and J, (C1-C5)-alkyl, (C1-C5)-alkoxy-group under condition that when R1 means one substitute then it is in ortho-position and when R1 means above one substitute then at least one substitute at R1 is in ortho-position; R2 means halogen atom including F, Cl, Br and J, (C1-C5)-alkyl, (C1-C5)-alkoxy-group; R3 means halogen atom including F, Cl, Br and J; R6 means hydrogen atom or methyl; and its salts with pharmaceutically acceptable acids, hydrates or solvates. Compounds elicit activity against acne and acne-related diseases.

EFFECT: valuable medicinal properties of compounds.

7 cl, 4 tbl, 43 ex

The invention relates to medicine, cosmetology and can be used to treat acne

The invention relates to sunscreen compositions containing a derivative dibenzoylmethane (UV-a filter), such as 4-(1,1-dimethylethyl)-4'-methoxybenzoate and stabilizer derived dibenzoylmethane having the formula (I) or (II), or a mixture of

< / BR>
< / BR>
in which R1the same or different means, each alkyl group having 1-22 carbon atoms or a diol having the structure BUT R2HE or polyglycol, having a structure BUT R3-(-O-R2)mHE, and in which R2and R3identical or different, denote each alkylenes group with unbranched or branched chain, having 1 to 6 carbon atoms, m and n each is 1-100, or a mixture

The invention relates to new compounds of the formula (I)

< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)

The invention relates to the field of medicine and relates to a composition for local application on the skin to treat skin diseases such as acne, seborrhea, dandruff, etc

FIELD: medicine.

SUBSTANCE: method involves utilizing bioflavonoid production waste products from larch wood for obtaining preparations possessing antiradiation activity containing 1-3% by volume of 5-dihydroquercitine and 99-97% by volume of Arabinogalactane.

EFFECT: high antiradiation activity; no additional drugs required; increased bioavailability.

5 cl, 2 dwg, 2 tbl

FIELD: medicine, dermatology.

SUBSTANCE: invention proposes oxygen-, sulfur or selenium-containing analogs of fatty acids in treatment of proliferative cutaneous disorders or for inhibition of proliferation and/or induction of keratinocytes differentiation, and a method for treatment of cutaneous disorders. Indicated analogs of fatty acids (in particular, tetradecylthioacetic acid and tetradecylselenoacetic acid) inhibit proliferation of NKH cells effectively and cause the strong expression of gene-markers of keratinocytes differentiation. Method provides improvement in desquamation and erythema, decreasing skin injury and stopping itching.

EFFECT: enhanced effectiveness and valuable medicinal properties of substances.

16 cl, 3 dwg, 4 ex

FIELD: medicine, dermatology.

SUBSTANCE: invention proposes oxygen-, sulfur or selenium-containing analogs of fatty acids in treatment of proliferative cutaneous disorders or for inhibition of proliferation and/or induction of keratinocytes differentiation, and a method for treatment of cutaneous disorders. Indicated analogs of fatty acids (in particular, tetradecylthioacetic acid and tetradecylselenoacetic acid) inhibit proliferation of NKH cells effectively and cause the strong expression of gene-markers of keratinocytes differentiation. Method provides improvement in desquamation and erythema, decreasing skin injury and stopping itching.

EFFECT: enhanced effectiveness and valuable medicinal properties of substances.

16 cl, 3 dwg, 4 ex

FIELD: medicine, dermatology.

SUBSTANCE: invention proposes oxygen-, sulfur or selenium-containing analogs of fatty acids in treatment of proliferative cutaneous disorders or for inhibition of proliferation and/or induction of keratinocytes differentiation, and a method for treatment of cutaneous disorders. Indicated analogs of fatty acids (in particular, tetradecylthioacetic acid and tetradecylselenoacetic acid) inhibit proliferation of NKH cells effectively and cause the strong expression of gene-markers of keratinocytes differentiation. Method provides improvement in desquamation and erythema, decreasing skin injury and stopping itching.

EFFECT: enhanced effectiveness and valuable medicinal properties of substances.

16 cl, 3 dwg, 4 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition containing minoxidil as an active component and designated for increase of hair growth. The composition comprises also dibutylhydroxytoluene and butylhydroxyanisole taken in the amount 0.005-0.5 mass part per one part of minoxidil in the concentration of minoxidil from 3% to 6% and at pH value 5.5-7.0 or 5.7-6.3 (variants), and to a method for prevention of staining the minoxidil-containing composition. Compositions prevent staining minoxidil as time passes and provide uniform dissolving and stability of active component.

EFFECT: improved and valuable properties of composition.

5 cl, 2 tbl, 11 ex

FIELD: medicine, in particular cosmetology, acne treatment.

SUBSTANCE: method includes multiple administration of isotretinoin in single dose of 0.1-0.3 mg/kg per day followed by dose increasing wherein total dose is 10-40 mg/kg with simultaneous chemical piling and cosmetic clearing.

EFFECT: effective treatment using decreased preparation doses and reduced side effects.

3 ex, 1 tbl, 2 cl

FIELD: cosmetology, esthetic surgery, applied biopharmacology.

SUBSTANCE: invention relates to medicative and cosmetic agents, and uses of biologically active substances based on natural biological complexes. Claimed method includes application of Mirralgin balm having analgesic, anti-inflammation and resolving action, Reventon balm, having vessel restorative action, for edema reducing and microcirculation improving. In process of blepharoplastic eye boundary bandage microemulsion having recovery and animative action on eaves skin is applied, and in process of facelifting cream mask having bactericide, vessel restorative and recovering action, and enhancing of local immunity is applied. Mirralgin balm and Reventon balm treatment is carried out sequentially or alternatively. In another embodiment after skin cleaning and treatment of damaged zone with anti-septic agent Bacteriophage gel, which disinfects skin surface, prevents biofilm forming, accelerates cicatrizing process is applied, then posttraumatic zone is treated with cleaning milk, toned up with tonic lotion and cream mask having bactericide, vessel restorative and recovering action, and enhancing of local immunity is applied.

EFFECT: method for skin structure recovering without skin trauma.

4 cl, 7 ex, 1 tbl

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active heterocyclic retinoid compounds. Invention describes retinoid compounds corresponding to the formula (I): or their pharmaceutically acceptable salts, solvates or hydrates wherein n means a whole number from 0 to 2; A represents optionally substituted phenyl; B represents oxygen (O), sulfur (S) atom or -NR6 wherein R6 represents hydrogen atom or alkyl; Y represents -OR7 wherein R7 represents hydrogen atom, alkyl, optionally substituted phenyl, aralkyl wherein aryl fragment means optionally substituted phenyl, cycloalkyl or cycloalkylalkyl; Z represents -C(R101)2-, -R102C=CR102-, -C≡C-, -C(R103)2S-, -C(O)O- or -C(O)NR10- wherein each among R10, R101, R102 and R103 represents independently hydrogen atom or alkyl; R1 and R2 represent independently hydrogen atom or alkyl; R3 represents hydrogen atom or alkyl; R4 and R5 represent independently hydrogen atom, (C1-C8)-alkyl or arylalkyl wherein aryl fragment means optionally substituted phenyl. Also, invention describes methods for preparing retinoid compounds, a pharmaceutical composition based on thereof and a method for treatment and/or prophylaxis of respiratory ways obstructive disease, cancer or dermatological disturbance or disorder. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: improved treatment method, valuable medicinal properties of compounds and composition.

28 cl, 10 tbl, 16 ex

FIELD: medicine.

SUBSTANCE: invention proposes the biologically active complex comprising phospholipids and the following biologically active substances - fatty acids, serines, peptides, amino acids, vitamins trace elements and extraction from cattle testicles prepared by successive fractionation with carbon dioxide and ethyl alcohol. The complex provides expanding spectrum of medicinal agents used in dermatological and urological practice and improving quality of the preparation. Invention can be used in treatment of psoriasis, prostatitis caused by prostatitis of sexual disorders.

EFFECT: valuable medicinal properties of complex.

2 tbl

FIELD: medicine, dermatology, pharmaceutical industry, phytotherapy.

SUBSTANCE: invention relates to using extracts from Serenoa repens and Vitis vinifera for preparing oral compositions used in treatment and prophylaxis of alopecia, dandruff and seborrhea. Oral compositions prepared of extracts of Serenoa repens and Vitis vinifera promote to the effective treatment and prophylaxis of alopecia, dandruff and seborrhea. Invention is used in treatment and prophylaxis of alopecia, dandruff and seborrhea.

EFFECT: valuable medicinal properties of compositions.

4 tbl, 2 ex

Antispasmodic drug // 2232018
The invention relates to the medical industry, namely antispasmodic drug, containing drotaverine hydrochloride used for relief of muscle spasm
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