MXPA00011077A - Biologically active composition - Google Patents

Abstract

The invention relates to a novel biologically active composition which comprises a biologically active agent to be released therefrom, said biologically active agent being dissolved and/or dispersed in a supersaturated state within a carrier, which carrier is a liquid and/or solid non-crystalline matrix, and where the precipitation of said biologically active agent is substantially, or completely, inhibited therein. Said supersaturated state is obtainable by subjecting one or more carrier starting substance(s) to such chemical operation(s) that a matrix is provided in which the degree of saturation of said biologically active agent is higher than the degree of saturation of said biologically active agent in said carrier starting substance(s), the biologically active agent being added either before said chemical operation(s) or after a predetermined point of time, after which the composition thus prepared is further subjected to said chemical operation(s).

Description

BIOLOGICALLY ACTIVE COMPOSITION Field of the Invention The present invention relates to a biologically active composition from which one or more biologically active components are to be released. More specifically, the invention relates to a biologically active composition wherein the biologically active agent is present in a supersaturated state within a carrier without being precipitated therefrom.

BACKGROUND OF THE INVENTION From the toxicological point of view termedia, it is frequently preferred, in the treatment of diseases or symptoms thereof, to deliver drugs directly to their site (s) of action. It is well known that the risks of obtaining harmful effects of systemic origin are markedly reduced frequently if a drug is delivered directly to its site (s) of action. In addition, the systemic supply frequently involves the metabolism of the drug before its appearance at the site of action, which leads to a subsequent reduction of its biological effect. Other aspect REF: 124948 important is that in, for example, the cases of impending overdose, allergic reactions or administration of contraindicated drugs, it is easy to eliminate topical compositions in contrast to drugs administered perorally or by injection. As used herein, topical administration comprises, inter alia, dermal, sublingual, gingival, buccal, transdermal, nasal, vaginal, and rectal administration, because of which the resulting biological effect may be local and / or systemic. In, for example, dermal, nasal, vaginal, buccal or subligual administration, only a very limited number of drugs are capable of penetrating within the human body by themselves in a useful proportion. Consequently, most of the research has been conducted in order to investigate the possibility of both the improvement of non-invasive, traditional delivery techniques and the development of new, non-invasive drug delivery systems or devices proposed for systemic use and / or internal. Three fundamentally different proposals towards this objective have been described. First, there is a well-known possibility of improving the penetration properties of the drug by chemical modification thereof. After the drug has entered the body, its pharmacologically active form is obtained by the chemical reaction (s) in vivo. However, this proposal commonly called prodrug is only occasionally a successful alternative. There are several reasons for this, such as i) the rate of penetration of the prodrug may still be too low, ii) the prodrug may be toxic or otherwise dangerous, or ii) the in vivo conversion to the active form of the drug is too slow and / or partially results in inactive or toxic compounds. A distantly related proposition is the preparation of an ion pair or an ion pair between a drug and an ion of opposite charge, appropriate. However, a pair of ions of this class in general does not exhibit any markedly improved penetration velocity through the barriers of humans. Second, the properties of the barrier can be changed in order to facilitate drug delivery. The methods for improving this are for example the ultra-sonification, the application of electric current or the use of the so-called penetration enhancers in the composition. All these methods act by disrupting the structure of the barrier, thereby facilitating the diffusion of the drug through the barrier within the body, and / or to improve the solubility of the drug in the barrier. However, methods involving eg heat, ultrasonification and electric current are not designed in general to be easily handled by the patient in a convenient manner, and therefore require hospitalization, which is a major disadvantage with the methods. In addition, all the methods which are based on the proposal to change the properties of the barrier are questionable from a toxicological point of view drunk to the observations that i) adverse effects on the cells of the barrier have been demonstrated, and ii) a reducing the protective properties of the barrier also results in an increased penetration rate for any substance, not just the drug, which is present at the site of administration. It should also be mentioned that most known chemical penetration enhancers require some time for the beginning of their action, that is, they exhibit a time delay of action, since these must be established in the barrier before it is observed the real increase in penetration speed.

Third, the driving force of the drug to enter the body can be changed. That is, the difference in the electrochemical potential of the drug between the drug receptacle and the body can be increased. Drug delivery systems based on this proposal result in high drug flow through the barrier and usually also exhibit a reduced time delay of action. In the methods based on the iontophoresis, this proposal is used when applying a gradient of electric potential through the barrier. Obviously, these methods are mainly suitable for drugs that have a net charge and therefore are much less efficient for uncharged species and for amphoteric ozone ion, since the flow of the last two species is mainly improved due to, for example, the osmotic and electroosmotic drive forces. Iontophoresis methods also have the disadvantage that they can alter the structure of the barrier. In another proposal, the flow of a drug within the body can be increased by increasing the chemical potential of the drug in the carrier therefor. This is usually done by chemical optimization of the drug composition by adjusting the degree of saturation of the drug in the carrier. The methods based on this proposal offer several advantages compared with the previously mentioned methods, since the flow of the drug increases in comparison with the subsaturated and saturated systems. In addition, the properties of the barrier itself are less affected comparatively and the time of initiation delay for the pharmacological effect is reduced. Two aspects are particularly important in this proposal: i) the creation of a chemical potential, high, initial of the drug in the composition ii) the maintenance of a chemical potential, high of the drug in the vicinity of the barrier after the application of the composition. Therefore, it is usually desirable to prepare pharmaceutical compositions which are saturated with respect to the drug. During the application, another important aspect of the composition is that the solubility and diffusion properties of the drug in the vehicle used must prevent the depletion or depletion of the drug in the vicinity of the barrier. Examples of the compositions used for this purpose are microemulsions and emulsions. Another proposal towards the maintenance of the saturated composition is the use of an excessive amount of drug (not solubilized) in the carrier, due to which the drug dissolves subsequently when it replaces the drug which has penetrated through the barrier. Still another proposal is the use of a supersaturated composition of the drug. In the present, the driving force of the drug to penetrate the barrier is greater than in the saturated composition, since the drug in a supersaturated composition has a higher chemical potential as compared to the corresponding saturated composition. For example, such compositions have been prepared according to the following means or principles: i) the dissolution of the drug at temperatures and / or pressures in which the solubility of the drug is greater compared to those temperatures and / or pressures that are relevant for medical treatment (WL Chou and S. Tiegelmann, < J. Pharm. Sci., Vol. 60, No. 9, pages 1281-1302, 1971; WO 97/10812), ii) the use of solid dispersions or mixtures Eutectic or low-level crystallinity or high-energy polymorph solid drug particles (WL Chou and S. Riegelmann, supra), and ii) mixing a saturated drug solution with a non-solvent for the same, to perform due to that a physical only operation, in or before the application, with or without the presence of an antinuclear agent (U.S. Patent No. 4 940 701; U.S. Patent No. 4 767 751), iv) the evaporation of the solvent to the surrounding air (Coldman et al., J. Pharm. Sci., 58, No. 9 (1969), pages 1098-1102), v) the penetration of the solvent into the human body, vi) the uptake of water in the composition of the human body, vi i) the changes in pH in the composition caused by the uptake of H + by the human body, or vi ii) the dispersion of an aqueous solution or an emulsion of a drug in a dispersion of a polymeric latex (Lichtenberger et al., "Polymer films from aqueous polymer dispersions as carriers for transdermal delivery of lipophilic drugs", 15th Int Symp CRS: Basel 1988; Abstr 89). A common denominator, important of iv) -vii) is that the super-unsaturation is not initially present in the composition, and therefore is not actually realized until the composition is applied to a human body. In addition, a major problem with all compositions i) -viii) is that the drug generally precipitates in a relatively short time, in which case the degree of saturation becomes markedly reduced. In DD 217 989, a subsaturated solution of a drug is mixed with a solution or suspension of an acrylate, then with the mixture thus prepared being dried, because of that a supersaturated composition is obtained by using an exclusively physical operation. W.L. Chou and S. Riegelmann (J. Pharm. Sci., Vol. 58, No. 12, pages 1505-1510, 1969) have reported that in matrices of polyethylene glycols of higher molecular weight, the precipitation of a supersaturated drug dissolved therein is usually slow. In the document, supersaturation was obtained through either direct fusion or solvent concentration, that is, through the use of typical physical operations. As in the prior art, reference is also made to WO 97/00670, which describes a composition based on ingredients similar to those used in the present invention. However, the reference does not disclose or suggest any supersaturated state or even less those characteristics and measures of the present invention that have been found crucial to transmit a supersaturated, stable state to such a composition. Another prior art of interest is WO 97/10812, which discloses a method for preparing supersaturated systems, wherein a mixture of the drug and the polymer having a reduced melting temperature, calculated is heated to a temperature above the calculated temperature , due to that the drug dissolves in the polymeric material and the supersaturation thereof is obtained through the cooling of the heated solution. However, the present invention does not relate to the preparation of supersaturated systems by exploiting or exploiting the reduced melting temperature, calculated from a mixture through a completely physical operation. GB 2 306 885 can also be mentioned, which uses the natural ability of the skin to dampen applied liquids. Here, a supersaturated system binds itself if a sub-saturated drug composition having a pH of 7-12 or 3-4 is applied to the skin, where the damping effect of the skin causes a pH change to 4.5 -6.5, so that a supersaturated composition is obtained by means of a change in the degree of protonation of the drug. The preparation of the supersaturated systems according to the present invention does not depend on such proton exchange.

General Description of the Invention A new proposal has now been developed to obtain a biologically active composition with an excellent rate of supply of its active component (s), wherein the composition comprises a biologically active agent which is present in a supersaturated state, substantially stable. In a brief summary, it has been found that by holding a carrier substance from start to chemical operation (s) such that a carrier matrix of substantially non-crystalline or amorphous nature is created, in which the degree of saturation of a biologically active agent is greater than the degree of saturation of the agent in the starting carrier substance, a surprisingly stable supersaturated composition can be obtained. In the composition in this prepared manner, the precipitation of the agent is substantially, or completely, inhibited by the carrier matrix per se. The term "biologically active agent", as used herein, also comprises such precursors thereto which are readily transformable, eg enzymatically and / or hydrolytically, to a biologically active agent per se. In this manner, the present invention relates to a new biologically active composition which comprises a biologically active agent to be released therefrom, the biologically active agent that is dissolved and / or dispersed in a supersaturated state within a carrier, the carrier which is a substantially non-crystalline, liquid and / or solid matrix, and wherein the precipitation of the biologically active agent is substantially, or completely, inhibited therein. The term "liquid" as used in connection with the present invention should be interpreted in a broad sense, i.e. as any material that is a mobile or viscous liquid, rubber, glass or plastic; including in this way solutions, creams, pastes, ointments and gels within the scope of the claims. The present invention also relates to a method for the preparation of a biologically active composition comprising a biologically active agent dissolved and / or dispersed in a supersaturated state in a carrier therefor as well as to the composition for use as a medicament. . The term "pharmaceutically active agent", as used herein, also comprises such precursors, eg, prodrugs, which are readily transformable, eg, enzymatically and / or hydrolytically, to a pharmaceutically active agent per se. One of the objects of the present invention is to provide in this way a supersaturated composition which exhibits no significant precipitation or loss of effect during long-term storage at room temperature, or even above or below room temperature, during, for example months or even years. Another objective of the present invention is to provide a supersaturated composition which exhibits no significant precipitation or loss of effect during its application to a human or animal patient. Still another object of the present invention is to provide a carrier matrix which is suitable in the preparation of a composition having a particularly high degree of supersaturation of a drug (vide infra).

Still another objective is to provide a supersaturated, adequate composition which is easily handled and does not require professional assistance in its use. As a result of the high delivery rate of its active component (s), another objective of the present invention is to provide a composition which allows topical, efficient treatment, preferably dermal or transdermal administration to small areas, which is a general advantage in topical drug administration.

Detailed Description of the Invention More specifically, the invention relates to a biologically active composition comprising a biologically active agent dissolved and / or dispersed in a carrier therefor, wherein the carrier is a substantially non-crystalline, liquid and / or matrix. solid in which the biologically active agent is present in a supersaturated state and in which the precipitation of the biologically active agent is substantially, or completely, inhibited by the matrix, the supersaturated state that can be obtained, is obtained, by subjecting one or more starting substance (s) to chemical preparation (s) such that a substantially non-crystalline, liquid and / or solid matrix is provided in which the degree of saturation of the biologically active agent is increased by comparison with the degree of saturation of the agent in the starting substance (s), the biologically active agent that is added before that the operation (s) have been completed. As used herein, the term "chemical operation" refers to a measure that results in the formation or division of covalent bonds. The formation or the division can comprise or indirectly produce a change in the pH of the composition, thus involving a transfer of protons that in some cases can be considered as the formation or division of a covalent bond. However, such a pH change is, in this context, the result of a chemical operation which does not only comprise a proton transfer but also comprises the formation or division of other types of covalent bonds. In one embodiment of the invention, the supersaturated state can be obtained by holding one or more carrier substance (s) from start to chemical operation (s) such that a matrix is provided in which the The degree of saturation of the biologically active agent is greater than the degree of saturation of the biologically active agent in the carrier substance (s) of initiation, the biologically active agent that is added at a predetermined point of time after which the chemical operation (s) have been initiated, after which the composition in this prepared manner is subjected additionally to the chemical operation (s). Other preferred embodiments of the claimed composition will be defined in the claims or will be referred to below in connection with the method. Thus, the present invention also relates to a method for the preparation of a biologically active composition comprising a biologically active agent dissolved and / or dispersed in a carrier therefor, wherein a starting carrier substance, or a mixture of two or more different starting substances, is (are) subjected to chemical operation (s) such that a carrier, non-crystalline, liquid and / or solid matrix is formed, in which the The degree of saturation of a biologically active agent is greater than the degree of saturation of the agent in the carrier substance (s) of initiation, the biologically active agent that is added before it has been (have) been completed ( s) the chemical operation (s) and in such an amount that a supersaturated state is obtained. In general, this means that the chemical operation (s) is (are) initiated either: i) in the presence of the biologically active agent; or ii) in the absence of the biologically active agent, after which the agent is added at a predetermined time point and the composition thus prepared is further subjected to the chemical operation (s); in addition to the biologically active agent in both i) and ii) that an amount is used such that a supersaturated state is obtained. In one embodiment of the invention, the degree of saturation of a biologically active agent is greater as a result of chemical operation (s) such that a carrier matrix, non-crystalline, liquid and / or solid, is formed in wherein the solubility of a biologically active agent is less than the solubility of the agent in the initiating carrier substance (s). In another embodiment of the invention, the degree of saturation of a biologically active agent is greater as a result of chemical operation (s) such that a carrier matrix, non-crystalline, liquid and / or solid, is formed in which the degree of dissociation, aggregation and / or the degree of protonation of a biologically active agent is different from the degree of dissociation, aggregation and / or the degree of protonation of the agent in the carrier substance (s) Of start. As a non-limiting example, this embodiment allows the formation in itself of a suitably charged, for example protonated or deprotonated, or uncharged form of the biologically active agent, which form has a higher penetration rate of the skin compared to the form of the agent present before the chemical operation (s) is initiated. In yet another embodiment of the invention, the degree of saturation of a biologically active agent is increased by such chemical operation (s) that both the above-discussed modes are practiced either simultaneously or consecutively. In one embodiment of the invention, the biologically active agent is being added, either above or at about room temperature, in the solid and / or liquid state, ie, molten and subsequently dissolved in the substance (s). ) starting either above or approximately at room temperature. In another embodiment of the invention, the biologically active agent is being added, either above or at about room temperature, as a solution or dispersion and is subsequently dissolved in the starting substance (s) either above or below. or approximately at room temperature. In accordance with the present invention, above the ambient temperature is a temperature above about 25 ° C, such as about 25-200 ° C, preferably about 30-150 ° C. Examples of other suitable temperatures are about 35-100 ° C and 40-80 ° C. The particular addition method used for the agent can be any common inclusion technique available to a person skilled in the art, and the solution or dispersion of the biologically active agent can be prepared in terially by evaporation of the solvent, lyophilization or by the use of any of the methods i) -vii) (vide supra). Preferably, in the composition according to the invention as well as in the method for the preparation thereof, the starting substance (s) acts as a solvent or dispersion medium.

The chemical operation (s) generally involves one or more chemical reactions, preferably etherification, esterification, hydrolysis, substitution, addition, elimination, oligomerization and / or polymerization reactions, wherein the Polymerization reactions are most preferred. The starting carrier substance (s), the one (s) which is (are) subsequently (s) subject to the above operation (s), are selected from monomers, acids , such as mono-, di- or tri-acids or higher acids, alcohols, including mono-, di- or triols, ketones, aldehydes, amines, amides, anhydrides, lactides, glycolides, saccharides and derivatives thereof, acrylic-type compouor acrylamide, such as methyl methacrylate, PEO-diacrylate monomers (PEO = polyethylene oxide), cyanoacrylate, acrylate saccharides, including acrylate starch, acrylate lactate, acrylate glycolate, isocyanates, ethylene oxide, propylene oxide , pyrrolidone, PEO-diacrylate, ethylene vinyl acetate, organic siloxane monomers and oligomers, polymers or prepolymers thereof. As indicated first, one, two or more of the above substances may be selected to allow for the formation of copolymers and / or higher polymers.

It can be understood by a person skilled in the art that the chemical operation (s) is performed to a degree of completion such that a carrier matrix, non-crystalline, desired matrix is obtained. it is optimal for a biologically active agent, particular in a particular context. In this way, all (s) the starting substance (s) present when the chemical operation (s) is initiated, do not necessarily have to react completely in order to carry out invention, as long as the desired degree of supersaturation is achieved. In a preferred embodiment of the present invention, the starting carrier substances are an acid and an alcohol, the non-crystalline matrix, formed comprising, or which is, an ester and / or polyester thereof.

In a more preferred embodiment, the starting carrier substances are citric acid and propylene glycol. In an alternative embodiment, the starting substance is only a bi- or multi-functional substance, which when subjected to the chemical operation (s) provides the non-crystalline carrier matrix desired by the ( s) chemical reaction (s) with it. In a non-limiting description, this starting substance may be citric acid, which when subjected to the esterification conditions provides an ester matrix and / or non-crystalline citric acid polyester * according to the invention. In accordance with the present invention, the appropriate chemical operation (s) involve (s) securing the initiating carrier substance (s) to such polymerization conditions that are normally used, according to the official reference literature, for the selected start substance (s) or combinations thereof. Furthermore, such polymerization conditions must be selected in order to optimize the manufacturing process, with respect to, for example, the stability of the agent, the time of manufacture and the degree of supersaturation, for the particular biologically active agent used. Typically, the conditions comprise for example holding the starting carrier substance (s) at a temperature of about -50 ° C to about 300 ° C, preferably about 0-150 ° C. Other examples of useful temperature ranges are 20-100 ° C and 50-80 ° C. The temperature ranges are particularly preferred when the starting substance (s) are a mixture of citric acid and propylene glycol. Naturally, the chemical reaction (s) is (are) selected and carried out so that in each case the maximum or optimum delivery rate of the biologically active agent is obtained. Preferably, the chemical reaction (s) is (are) carried out for a period of time from 1 minute to 6 months, more preferably from 0.5 hours to 4 months.

As an example, the time period can also be 1 hour to 3 months or 1 to 2 months. The predetermined time point (vide supra), measured after the chemical operation (s) has been initiated, is generally from 1 minute to 6 months, preferably from 0.5 hours to 4 months, after which the composition thus obtained was subjected additionally to the chemical operation (s) over a period of time from about 1 minute to 6 months, preferably 0.5. hours to 4 months. As an example, the predetermined time point can also be 1 hour to 3 months or 1 to 2 months. The chemical reaction (s) used in the present invention preferably comprises a polymerization reaction and more preferably such a reaction in which ether and / or ester linkages are formed. Other preferred polymerization reactions are the gradual polymerization reaction and the chain polymerization reactions comprising either radial initiation, ionic initiation or the initiation of coordination complexes. According to the present invention, some of the above monofunctional substance (s), for example, monoacids and -alcohols, can also be used to form a non-crystalline matrix consisting of for example, monoesters and monoethers. The monofunctional monomers can also be introduced into the chemical reaction as a means to modify the reaction or to control the end point thereof. As already indicated, in order to efficiently inhibit the precipitation of the supersaturated biologically active agent, the matrix formed is of a substantially non-crystalline, or amorphous, nature. The polymers, copolymers, oligomers and ethers or esters of the starting substance (s) previously summarized (s) (vide supra) are particularly useful for this purpose. A number of different parameters have been of interest in the development of the present invention. As an example of this parameter, a reaction which results in the formation of a non-crystalline matrix, which consists of molecules with a molecular weight greater than the starting substance (s), may result in an increase of the thermodynamic potential of the form of the biologically active agent (s) which diffuses through a biological barrier, such as the skin. During the progress of a reaction of this kind, in many cases a decreased solubility of the biologically active agent in the matrix will be observed, although it should be emphasized here that the decreased solubility may not always be necessary in order to produce a thermodynamic potential, increased in the form of the biologically active agent which actually diffuses through the skin. In addition, the degree of dissociation, aggregation and / or protonation of the biologically active agent, for example, as a result of pH changes, is often relevant in the production of the desired, increased, thermodynamic potential of the form (s). ) of the agent that diffuses through the skin. Non-limiting examples of biologically active agents, preferably pharmaceutically active agents, which are suitable for use in the present invention are, for example, guanosides, corticosteroids, psychopharmaceutical hormones, oxicams, peptides, proteins as well as agents selected from the group of antibiotics, antivirals, antimicrobials, anticancer agents, antifungals, estrogens, anti-inflammatory agents, neuroleptic agents, melanocyte stimulants and gland stimulants, preferentially stimulators of sebaceous and pilo-sebaceous glands, and agents with an effect on the secretion of mast cells or mastzelle. In an alternative embodiment of the present invention, the biologically active agent can also react reversibly with the starting substance (s) in a manner such that they form, for example, esters, ethers, co-polymers and / or other conjugates. In this manner, this embodiment allows the preparation of a non-crystalline matrix containing both the biologically active agent in a supersaturated, substantially stable and conjugated (s) thereof, while the conjugate (s) may be present in a state either subsaturated, saturated or supersaturated. Alternatively, the conjugate (s) may be present in a supersaturated state, so long as the biologically active agent is present in either a saturated, supersaturated or supersaturated state. Therefore, in the case where the biologically active agent is a drug, this particular mode allows the formation in itself of a corresponding drug precursor, which may function either as a prodrug or as a reservoir of the supersaturated drug, or a combination of both. As an example of this embodiment, a biologically active agent containing a carboxylic acid or an alcohol functionality can form an ester with the carrier substance (s) of initiation when a mixture of the same (s) ) is subject to the conditions of esterification. In another embodiment of the present invention, the starting substance (s) may be an ester and / or polyester matrix, or an ether and / or polyether matrix, to which a biologically active agent is added. active, after which the dispersion or the solution formed is subjected to a hydrolysis reaction which provides a carrier, non-crystalline, liquid and / or solid matrix in which the degree of saturation of the biologically active agent is greater than the degree of saturation of the biologically active agent in the starting substance (s), in this way a dispersion or a supersaturated, stable solution is obtained. As a non-limiting example of this embodiment, the starting substance (s) may consist of several esters and / or polyesters, of which one or more are hydrolysable much more easily compared to all other substances present, including the biologically active agent. In yet another embodiment of the invention, a minor amount of the starting substance (s) is subject to the chemical conditions, preferably a polymerization, in the presence of a solvent, whereby a matrix is formed. one or two phases, supersaturated, such as a non-crystalline, liquid / solid matrix. However, in the most preferred embodiment, the biologically active composition consists solely of a liquid or solid phase. As indicated first, in another embodiment of the present invention the initiating carrier substance (s) can be subjected to the chemical reaction (s), preferably a polymerization, early and without the presence of the biologically active agent. By using this proposal, a non-crystalline, liquid and / or solid, prefabricated matrix is provided, to which a biologically active agent can subsequently be added at a predetermined time point by the use of any suitable inclusion method, such as for example, mixing, heating, lyophilization and / or evaporation of the solvent, after which the composition thus prepared is further subjected to the chemical reaction (s), which is (are) is (are) either identical or somewhat modified, by, for example, the use of a lower reaction temperature or the addition to a greater degree of one or more of the start substance (s) previously summarized, compared to the reaction (s) performed initially. For some biologically active agents it is preferred to prepare a supersaturated composition shortly before the administration thereof. In fact, the present composition is useful for such preparations in addition to being suitable for the supersaturated compositions proposed for long-term storage and application. As for the selection of an adequate degree of supersaturation of the biologically active agent in the present composition, it is known from the laws of thermodynamics that within a given period of time the danger of precipitation increases with the degree of supersaturation. Still, the present composition is also suitable in these particular preparations where a very high degree of supersaturation is desirable, despite the somewhat increased risk of precipitation.

The scope of the invention is not limited to the specific embodiments described above, and the invention described may optionally be combined with methods i) -vii) (vide supra) in any suitable manner, if deemed necessary in any particular case. As a non-limiting example, the pH of the composition prepared according to the invention can be optionally modified subsequently by the inclusion of an appropriate acidic or basic compound, if useful in a particular context. The following non-limiting example will further illustrate the present invention.

Brief description of the accompanying diagrams Diagram 1 shows the amount of metronidazole permeate as a function of time for a subsaturated composition Ao, a saturated composition C and the supersaturated compositions Bi and B2. Diagram 2 shows the amount of metronidazole permeate of the compositions X1-X4 and Yl-Y4.

Experimental part Example 1; demonstration of a thermodynamic potential, increased by the use of the method of the present invention. The degree of supersaturation was characterized by the permeation rate of the biologically active agent through a membrane (Silastic sheeting NRV, 0.0127 centimeters (0.005 inches), series # HH055353) by the use of a Franz diffusion cell (FDC-400). Crown Glass Company) with a cell opening area of 2.011 cm2. All measurements of the permeation rate were made at 25 ° C and deaerated H20 was used as an acceptor phase on the opposite side of the membrane. The donor and acceptor phase both were sealed with the parafilicle, and each experiment was done in triplicate. Additional substances: citric acid (CiAc) and propylene glycol. Four parts of CiAc and six parts of propylene glycol were added to a sealable container at room temperature, after which the container was sealed. The resulting mixture was stirred with a magnetic stirrer and the temperature was raised to and maintained at 80 ° C until all the CiAc was dissolved, after which the solution was allowed to reach room temperature. This solution was symbolized A. Then solid metronidazole was added to solution A at a ratio of 5:95 (w / w), after which the metronidazole was dissolved by magnetic stirring at room temperature. The solution prepared in this way was then divided into two solutions symbolized A0 and B, respectively. As a reference, a solution of 4 parts of CiAc and 6 parts of propylene glycol was prepared as above. Solid metronidazole was added in a ratio of 7.5: 92.5 (w / w), and the mixture was stirred at room temperature for three days. After the centrifugation resulted in the sedimentation of undissolved metronidazole, the obtained supernatant consisted in this way of a saturated metronidazole composition, symbolized C. The final ratio, obtained between metronidazole and CiAc / propylene glycol was 7:93 (p. / p). The fundamental principles behind the compositions A-C were the following: Ao is a sub-saturated mixture of a pharmaceutically active agent and starting carrier substances which are not actively subject to polymerization; in B, the starting substances are subjected to the polymerization conditions in the presence of a pharmaceutically acceptable agent; and in C, the permeation rate for a saturated solution of a pharmaceutically active agent in a matrix of the starting carrier substances is illustrated. Compositions B and C were then treated as follows: B was divided into two compositions, which were stored at 70 ° C for one month (Bi) and two months (B2), respectively, after which the time period of Permeation rate measurements were performed on the formed compositions Bi and B2, respectively. The compositions Ao and C were used directly after the preparation thereof. The measured permeation velocity is shown in the attached diagram 1. Diagram 1 shows that a considerably higher permeation rate is obtained in the compositions Bi and B2, compared to any of compositions A or C. This increased permeation rate is in turn a r evidence that the thermodynamic potential of metronidazole is significantly higher in compositions Bi and B2 as compared to any of compositions A0 or C. In the present, it is important to note that the compositions Ao and B are initially the same. In summary, this example shows that the supersaturation of the initially subsaturated composition is achieved in the polymerization. In fact, the additional polymerization results in an even higher permeation rate, that is, a higher thermodynamic potential, as illustrated by Bi and B2.

Example 2; demonstration of the precipitation prevention properties of the carrier matrix of the present invention: A Franz diffusion cell described above was used under conditions similar to those of example 1, unless otherwise noted. The permeation rate experiments were performed for 21 hours. As a reference, the permeation rate of saturated composition C in example 1 was determined to be 46 μg per 21 hours in a Franz diffusion cell experiment, depicted in Diagram 1. All experiments were analyzed by the use of the spectrophotometry. The results are plotted in diagram 2. In order to determine their solubility in the water, an excess of metronidazole was added to the water, after which the mixture was stirred for 3 days at room temperature. The analysis by spectrophotometry was carried out after sedimentation and centrifugation, and a resulting solubility of s = 0.82% (w / w) was obtained. Then, four solutions of supersaturated metronidazole water were prepared, each having a degree of saturation (GS = concentration / solubility) of 1.3, 1.6, 2.0 and 2.5, respectively. These were precipitated by heating the corresponding amount of metronidazole in water at 80 ° C for 30 minutes under agitation, followed by equilibrium at room temperature, to produce supersaturated solutions therefor. The time for precipitation of metronidazole (tp) to occur at storage at room temperature was monitored by visual inspection and the results are shown in Table 1.

Table 1. Time for the precipitation of metronidazole from a supersaturated solution thereof in water. Solution% conc. (p / p) GS 'of metronidazole 1 1.06 1. 3 5 days < tp < 14 days 2 1.31 1. 6 2 h < tD < 17 h 3 1.65 2. 0 3 h < tD < 3 . 5 h 4 2.05 2. fifty . 5 h < tp < 1 hour * GS = 1 equal 0.82% (w / w) of metronidazole in water (vide supra), determined by spectrophotometry A composition X was prepared by mixing 4 parts of CiAc and 6 parts of propylene glycol (starting substances) at room temperature in a glass vessel which was subsequently sealed. The temperature was raised to and maintained at 80 ° C under agitation for about 45 minutes. The resulting solution was maintained at room temperature for about 3 minutes, then divided into 4 separate solutions. An appropriate amount of metronidazole (see Table 2) was subsequently added to each solution, followed by heating the mixture at 80 ° C for about 40 minutes, after which the resulting compositions were allowed to reach room temperature, to produce due to that the supersaturated compositions X1-X4. Directly after its preparation, compositions X1-X4 were investigated by measurements of Franz diffusion cells (see example 3). A sample of each respective composition X1-X4 was taken. These four samples were each kept at 70 ° C for 3 weeks, to produce the compositions Y1-Y4 (see Table 2). The compositions Y1-Y4 were also examined in the Franz diffusion cell experiments (see example 3).

Table 2. Saturation degree of metronidazole in compositions X1-X4 and Y1-Y4. % conc. (p / p) Composition GS * Composition GS * of me ronidazo 1 8.0 XI 1.16 Yl 1.62 9.0 X2 1.23 Y2 1.86 10.0 X3 1.54 Y3 2.02 11.0 X4 1.59 Y4 2.18 * The saturation permeation rate was assumed to be 46 μg during 21 hours.

The GS values shown in Table 2 were obtained by the use of Franz diffusion cell measurements, and for a person skilled in the art, it is well known that the rate of permeation of a compound through a membrane Silastic in a Franz cell diffusion cell experiment is a direct measure of the thermodynamic potential of the compound. further, a direct correlation between the thermodynamic potential and the degree of saturation (GS) can often be assumed. Therefore, the equation GS = permeation velocity / permeation velocity at saturation, therefore, was assumed to be valid when GS values were estimated. The tp values for compositions Yl-Y4 according to the present invention were then investigated in the same manner as described above. These investigations showed that the value of tp for all compositions Y1-Y4 exceeds 6 weeks. At the time of the presentation of the present application, precipitation has not yet been observed. In fact, the precipitation prevention properties of the carrier matrix according to the present invention were clearly maintained, particularly in comparison with the tp values represented in Table 1 above.

Example 3; Further evidence of the thermodynamic potential, increased achieved in accordance with the present invention: These experiments were performed in order to further check the degree of saturation of metronidazole in compositions X1-X4 and Y1-Y4. The Franz diffusion cell experiments were performed under the same conditions as in Example 1 (vide supra), and the results are shown in Diagram 2. Diagram 2. Amount of permeate metronidazole of compositions X1-X4 and Y1- Y4 As depicted above, Diagram 2 shows that the chemical operation subjected to the compositions X1-X4 in the preparation of the compositions Y1-Y4 resulted in an increased, thermodynamic potential of metronidazole, as is tested directly through the speed of increased permeation. The permeation rate for a composition Y has increased approximately 40% compared to its corresponding composition X. In summary, it is clearly understood that biologically active compositions which are prepared or obtainable according to the present invention are useful as medicaments. In addition, the biologically active compositions according to the invention are also useful in a non-medical context, such as in cosmetic products for the skin. More specifically, the compositions must be highly efficient in dermal application to a mammal, preferably man, as well as in the general application where a biological barrier must be penetrated by a biologically active agent.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following claims is claimed as property.

Claims (27)

1. A biologically active composition, characterized in that it comprises a biologically active agent to be released therefrom, the biologically active agent that is dissolved and / or dispersed in a carrier therefor, wherein the carrier is a non-crystalline, liquid matrix and / or or solid in which the biologically active agent is present in a supersaturated state, the supersaturated state that can be obtained by holding one or more carrier substance (s) from start to chemical operation (s) such ) that the carrier, non-crystalline, liquid and / or solid matrix is provided in which the saturation degree of the biologically active agent is greater than in the carrier substance (s) of initiation, the biologically active agent which is added before the chemical operation (s) has been completed.

2. A composition according to claim 1, characterized in that the highest degree of saturation is the result of such chemical operation (s) that the solubility of the biologically active agent in the matrix is lower than the solubility of the same in the starting carrier substance (s).

3. A composition according to any of claims 1 and 2, characterized in that the highest degree of saturation is the result of such chemical operation (s) that the degree of dissociation, aggregation and / or degree of The protonation of the biologically active agent is different from the degree of dissociation, aggregation and / or the degree of protonation of the agent in the initiating carrier substance (s).

4. A composition according to any of claims 1-3, characterized in that the biologically active agent is added before the chemical operation (s) has been initiated (s).

5. A composition according to any of claims 1-3, characterized in that the biologically active agent is added at a predetermined time point after the chemical operation (s) has been initiated (s). ), the composition obtained in this way is then subjected additionally to the chemical operation (s).

6. A composition according to claim 5, characterized in that the predetermined time point is from 1 minute to 6 months, preferably 0.5 hours to 4 months after the operation (s) has been initiated (s). is) chemistry (s).

7. A composition according to claim 6, characterized in that the composition is further subjected to the chemical operation (s) for a period of time from about 1 minute to 6 months, preferably from 0.5 hours to 4 hours. months

8. A composition according to any of claims 1-7, characterized in that the starting substance (s), or the non-crystalline matrix formed, act (s) as a solvent or dispersion medium.

9. A composition according to any of claims 1-8, characterized in that the biologically active agent is added as a solid and / or liquid which subsequently dissolves in the carrier.

10. A composition according to any of claims 1-8, characterized in that the biologically active agent is added in the form of a solution or a dispersion.

11. A composition according to any of claims 1-10, characterized in that the biologically active agent is added above or at about room temperature.

12. A composition according to any of claims 1-11, characterized in that the chemical operation (s) comprises (s) one or more chemical reactions.

13. A composition according to claim 12, characterized in that the chemical reaction (s) comprise the reactions of etherification, esterification, hydrolysis, substitution, addition, elimination, oligomerization and / or polymerization.

14. A composition according to claim 13, characterized in that the chemical reaction (s) is (are) selected and (n) performed to provide an optimum delivery rate of the biologically active agent.

15. A composition according to any of claims 1-14, characterized in that the chemical operation (s) involve (s) holding the starting carrier substance (s) at a temperature of about -50 ° C to about 300 ° C, preferably about 0-150 ° C.

16. A composition according to any of claims 1-15, characterized in that the chemical operation (s) is conducted for a period of time from 1 minute to 6 months, preferably 0.5 hours. to 4 months.

17. A composition according to any of claims 1-16, characterized in that the starting carrier substance, or a mixture of two or more different starting carrier substances, are selected from monomers, acids, such as mono-, di- or triazides or higher acids, alcohols, including mono-, di- or triols, ketones, aldehydes, amines, amides, anhydrides, lactides, glycolides, saccharides and derivatives thereof, acrylic or acrylamide-type compounds such as methyl methacrylate, PEO-diacrylate monomers, cyanoacrylate, acrylate saccharides, including acrylate starch, acrylate lactate, acrylate glycolate, isocyanates, ethylene oxide, propylene oxide, pyrrolidone, PEO-diacrylate, ethylene vinyl acetate, siloxane monomers organic and oligomers, polymers or prepolymers thereof.

18. A composition according to claim 17, characterized in that the acid is a monomeric acid and the alcohol is a monomeric alcohol, the non-crystalline matrix comprises an ester and / or polyester thereof.

19. A composition according to claim 18, characterized in that • the monomeric acid is citric acid.

20. A composition according to any of claims 18 and 19, characterized in that the monomeric alcohol is propylene glycol.

21. A composition according to any of the preceding claims, characterized in that it consists solely of a liquid or solid phase.

22. A composition according to any of the preceding claims, characterized in that the biologically active agent is a pharmaceutically active agent.

23. A composition according to claim 22, characterized in that the pharmaceutically active agent is selected from the group consisting of guanosides, corticosteroids, psychopharmaceutical hormones, oxicams, peptides, proteins, antibiotics, antivirals, antimicrobials, anticancer agents, antifungals, estrogens, anti-inflammatory agents , neuroleptic agents, melanocyte stimulants and gland stimulants, preferentially stimulators of zebra and pilo-sebaceous glands and agents with an effect on the secretion of mast cells or maztzelle.

24. A composition according to any of claims 22 and 23, characterized in that it is for the use of a medicament.

25. A composition according to any of the preceding claims, characterized in that it is for topical application, preferably the dermal application to a mammal, preferably man.

26. A method for the preparation of a biologically active composition comprising a biologically active agent dissolved and / or dispersed in a carrier therefor, characterized in that a starting carrier substance, or a mixture of two or more different starting carrier substances, subject (s) to chemical operation (s) such that a carrier matrix is formed, non-crystalline, liquid and / or solid, in which the degree of saturation of the biologically active agent is greater than in the (s) carrier substance (s) of initiation, the biologically active agent that is added before the chemical operation (s) has been completed and in such an amount that a supersaturated state is obtained.

27. A method according to claim 26, characterized in that the composition is as defined in any of claims 2-25.