Topical bioadhesive formulations

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DESCRIPTION

Topical bioadhesive formulations.

The present invention relates to precursor formulations (preformulations) for the in situ generation of controlled release lipid compositions. In particular, the invention relates to preformulations in the form of low viscosity mixtures (such as molecular solutions) of amphiphilic components and optionally at least one bioactive agent which are subjected to at least one phase transition when exposed to aqueous liquids, such as body fluids, thereby forming a bioadhesive matrix.

Many bioactive agents, including pharmaceuticals, nutrients, vitamins, and others, have a "functional window." That is, there is a range of concentrations above which it can be observed that these agents provide a certain biological effect. When the concentration in the appropriate part of the body (eg locally, as demonstrated by the concentration in the serum) falls below a certain level, no beneficial effect can be attributed to the agent. Similarly, there is generally a higher concentration level above which no additional advantage is achieved by increasing the concentration. In some cases, increasing the concentration above a certain level results in undesirable or even dangerous effects.

Some bioactive agents have a long biological half-life and / or a wide functional window and therefore can be administered occasionally, maintaining a functional biological concentration above a substantial period of time (eg, from 6 hours to several days). In other cases, the clearance rate is high and / or the functional window is narrow, and therefore regular (or even continuous) doses of small amounts are necessary to maintain a biological concentration within this window. This can be especially difficult when non-oral routes of administration are desirable (eg, parenteral administration). Furthermore, in some cases, such as in implant coupling (eg, joint replacements or oral implants), the desired area of ​​action may not remain accessible for repeated administration. In these cases a single administration should provide therapeutically active agent throughout the entire period during which the activity is required.

Similarly, in the case where the effect of the bioactive agent is required locally, it may be difficult or undesirable to administer sufficient amount of said agent to achieve the effective level in the entire body of the subject. This may be due to undesirable effects of the agent itself (for example, anti-inflammatory steroids) or it may be because the agent is used to locally counteract an undesirable characteristic of a systemic treatment (such as chemotherapy) but which would reduce the effects of the treatment. primary if used extensively.

A major difficulty with topically applied compositions, however, is their duration of action. These compositions are by their nature applied to body surfaces that may be prone to abrasion, washing and the action of body fluids or applied to the body, such as tears, sweat or mucus. An especially difficult situation for the use of topical preparations is found in body cavities such as the digestive tract. The reason for this is that these cavities are typically lined with a mucous membrane that is non-adherent and rapidly transforming. In addition, thick and viscous preparations can be difficult to apply effectively to the mouth / throat or rectal portion of the lower gastrointestinal tract and are difficult to manufacture because the high viscosity prevents sterile filtration. However, existing compounds are typically low-viscosity and short-lived or long-lived with the counterweight of high viscosity. Furthermore, existing topical compositions are frequently capable of containing only a low level of active agent, due to poor compatibility between the base composition and the active agent. This results in a composition that quickly loses its effectiveness as it begins to dissipate from the site of action. Therefore, it would be of great value to present bioadherent topical formulations, even on mucosal surfaces, and that could be formulated in the form of low viscosity preformulations that will become adherent when contacting the desired surface. Furthermore, it would be a significant advantage if the formulation is protective, non-irritating and shows considerable resistance to contact and exposure to an aqueous environment. WO2005 / 046642 and US5807573 disclose certain lipid compositions but not bioadhesive compositions.

The present inventors have discovered that by providing preformulations comprising certain amphiphilic components, at least one bioactive agent and a biologically tolerable solvent, especially in a low viscosity phase, such as a molecular solution, a preformulation can be generated that solves many of the drawbacks of the previous formulations. In particular, the preformulation is easy to manufacture, can be sterile filtered, has low viscosity (allows quick and easy administration) and / or allows the incorporation of a high level of bioactive agent (thus allowing the use of a smaller amount of the composition and / or providing a long effective shelf life The compositions are formed from non-toxic, biotolerable and biodegradable materials. They are suitable for application to sensitive areas such as sensitive parts of the body and places where inflammation occurs, and comprise lipids that are part of natural protective surface coatings, eg phospholipids. Furthermore, due to the combination of bioadhesive characteristics and extremely low solubility in water of the main constituents of the compositions, the composition applied according to the invention is stable on exposure to aqueous media and on contact.

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The compound further provides a sustained release of a wide range of active ingredients with an adaptable duration window. Preformulation is therefore very suitable for the formation of depot compositions that follow non-parenteral (eg topical) administration to body and / or surface cavities of the body or elsewhere, and which are formed on the basis of lipids. which can provide intrinsic advantages in themselves, in addition to forming very effective supports and topical reservoirs for the active agents.

In a first aspect, the present invention provides a preformulation as defined in the appended claims.

Generally, the aqueous fluid will be a body fluid such as a mucosal surface fluid, tears, sweat, saliva, gastrointestinal fluid, extravascular fluid, extracellular fluid, interstitial fluid, or plasma, and the preformulation will form a liquid crystalline phase structure. when it comes into contact with a body surface, area or cavity (eg, in vivo) after coming into contact with aqueous body fluid. The preformulation of the invention will generally not contain any significant amount of water prior to administration.

In a second aspect of the invention, a method is also envisaged for the delivery of a cosmetic bioactive agent to the body of a human or a non-human animal (preferably a mammal), as indicated in the appended claims.

The method of administration suitable for the indicated method of the invention will be an appropriate method for the condition to be treated and the bioactive agent used. A non-parenteral bioadhesive depot compound (eg, topical) can be formed by administration to the surface of the skin, mucous membranes and / or nails, to ophthalmic, nasal, oral or internal surfaces or to cavities such as the nasal cavities, rectals , vaginal or buccal, periodontal pocket or cavities formed after the extraction of a natural or implanted structure or before the insertion of an implant (for example, a joint, "stent", cosmetic implant, tooth, dental fillings or other implants).

In yet another aspect, the present invention provides the use of a low viscosity blend of:

a) at least one neutral lipid diacyl and / or one tocopherol;

b) at least one phospholipid;

c) at least one biocompatible organic solvent (preferably containing oxygen);

wherein at least one bioactive agent is dissolved or dispersed in the low viscosity mixture in the manufacture of a preformulation for use in the continued local administration of said active agent, such that said preformulation is capable of forming, as minimum, a liquid crystalline phase structure on contact with an aqueous liquid.

According to another aspect, the present invention discloses the use of a compound, according to the present invention, in therapy and in particular for the use of a composition, according to the present invention, optionally including an active agent in the manufacture of a medicament. for the treatment of inflammation and / or irritation, especially on a body surface and / or in a body cavity such as the gastrointestinal tract.

The use of non-lamellar phase structures (such as liquid crystalline phases) in the delivery of bioactive agents is currently relatively well established. These structures form when an amphiphilic compound is exposed to a solvent because amphiphilic has polar and apolar groups that come together to form polar and apolar regions. These regions can effectively solubilize both polar compounds and apolar compounds. Furthermore, many of the structures formed by amphiphilics in polar and / or apolar solvents have a very considerable polar / apolar boundary area in which other amphiphilic compounds can be absorbed and stabilized. Amphiphilic compounds can also be formulated to protect active agents, at least to some extent, against aggressive biological environments, including enzymes, and thus provide advantageous control over the stability and release of the active agent.

The formation of non-laminar regions in amphiphilic / water, amphiphilic / oil and amphiphilic / oil / water phase diagrams is a well-known phenomenon. These phases comprise liquid crystalline phases, such as cubic P, cubic D, cubic G and hexagonal phases, which are liquid at the molecular level but show a significantly low rank order and the L3 phase comprising a bicontinuous lattice interconnected in multiple ways. bilayer sheets that are not laminar but lack the long rank order of liquid crystalline phases. Depending on the curvature of the amphiphilic sheets, these phases can be described as normal (mean curvature towards the apolar region) or inverse (mean curvature towards the polar region).

The crystalline non-lamellar liquid phases and L3 are thermodynamically stable systems. That is, they are not simply a meta-stable state that will separate and / or reform into layers, lamellar phases or the like, but are stable thermodynamic forms of the lipid / solvent mixture.

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As used in this description, the term "low viscosity mixture" is used to indicate a mixture that can be easily administered to a subject and in particular easily administered by means of a standard syringe and needle or a pump / sprayer. aerosol. This may be indicated, for example, by the ability to dispense from a 1 ml single use syringe via a 22 awg (or 23 gauge) needle by hand pressure. In an especially preferred embodiment, the low viscosity mixture should be a mixture capable of passing through a standard sterile filter membrane, such as a 0.22 pm syringe filter. In other preferred embodiments, a similar function of appropriate viscosity can be defined as the viscosity of a preformulation that can be sprayed using a compression pump device or pressure spray device using conventional spray equipment. A typical range of suitable viscosities would be, for example 0.1 to 5,000 mPas, preferably 1 to 1,000 mPas at 20 ° C.

It has been found that by adding small amounts of a low viscosity solvent, as indicated in this description, a very significant change in viscosity can be achieved. As indicated in Figure 2, for example, the addition of 5% solvent can only reduce the viscosity 100 times and the addition of 10% can reduce the viscosity up to 10,000 times. In order to achieve this synergistic nonlinear viscosity lowering effect it is important to use a solvent with appropriate low viscosity and proper polarity. These solvents include those described below.

Particularly preferred examples of low-viscosity mixtures are molecular solutions and / or isotropic phases such as L2 and / or L3 phases. As described, the L3 phase is a non-lamellar phase of interconnected sheets that has a certain phase structure but lacks the long rank order of a liquid crystalline phase. Unlike the liquid crystalline phases that are generally highly viscous, the L3 phases are of low viscosity. Obviously, mixtures of an L3 phase solution and molecular solution and / or L3 phase particles suspended in a bulk molecular solution of one or more components are also suitable. The L2 phase is the so-called "reverse micellar" or microemulsion phase. Most preferably, the low viscosity mixtures are molecular solutions, L3 phases, and mixtures thereof. Phases L2 are less preferred except in the case of expanded phases L described below.

The present invention provides a preformulation comprising components (a, b, c) and optionally and preferably, at least, one bioactive agent, as indicated in the description itself. One of the considerable advantages of the preformulations of the present invention is that components (a) and (b) can be formulated within a wide range of proportions. In particular, it is possible to prepare and use preformulations of the present invention that have a much higher ratio of phospholipids to neutral diacyl lipid and / or tocophenol than previously achievable without risk of unacceptably phase separation and / or viscosities. elevated preformulation. The weight ratios of the a: b components can be anything from 5:95 to 95: 5. Preferred ratios would generally be between 90:10 and 20:80 and more preferably between 85:15 and 30:70. In a preferred embodiment of the invention there is a higher proportion of component b than component a. That is, the a: b weight ratio is below 50:50, for example below 48:52 to 2:98, preferably 40:60 to 10:90 and more preferably 35:65 a 20:80.

The amount of component c in the preformulations of the invention will be, at a minimum, sufficient to provide a low viscosity mixture (e.g., a molecular solution, as above) of components a, b, and c and will be readily determined for any specific combination of components by standard methods. The phase behavior itself can be analyzed by techniques such as visual observation in combination with polarized light microscopy, nuclear magnetic resonance and cryotransmission electron microscopy (cryoTEM) to look for solutions, L2 or L3 phases, or liquid crystalline phases. Viscosity can be measured directly by the standard method. As described above, a suitable practical viscosity is one that can be effectively applied by syringe and especially filtered to sterile and / or sprayed by a pressure pump or sprayer. This will be easily evaluated as indicated in this description. The maximum amount of component ca to include will depend on the exact application of the preformulation, but in general the desired properties will be achieved in any amount that forms a low viscosity mixture (for example, a molecular solution, as described) and / or a solution with a sufficiently low viscosity.

Since the administration of unnecessarily large amounts of solvent to a subject is generally undesirable, the amount of component c may be limited in one embodiment to no more than ten times (eg, three times) the minimum amount required to form a low viscosity mixture, preferably not more than five times and more preferably not more than twice.

Higher proportions of solvent can also be used for non-parenteral (e.g. topical) applications of the invention, however, especially when applying the outer surfaces of the body, where the solvent will evaporate rather than be absorbed by the body. For these applications, up to 100 times the minimum amount of solvent can be used (for example, up to 95% by weight of the compound, preferably up to 80% by weight and more preferably up to 50% by weight), especially in the case in where a non-parenteral reservoir with a very thin layer is desired.

In the case where the compositions of the invention are formulated in the form of aerosol spray compositions (eg, for topical delivery of an active agent), the composition may also comprise a propellant. These compositions can also include a high proportion of solvent component c), such as

ES 2 343 641 T3 as considered above, since a large amount of the solvent will evaporate when the composition is dispensed, particularly under the action of the propellant.

Suitable propellants are volatile compounds that will be mixed with the composition of the invention under the pressure of the spray dispenser, without generating high viscosity mixtures. Obviously they must have an acceptable biocompatibility. Suitable propellants will be easily identified by simple checking and examples including hydrocarbons (especially Ci to C hydrocarbons₄), carbon dioxide and nitrogen. Volatile hydrofluorocarbons, such as HFCs 134, 134a, 227ea and / or 152a, may also be suitable.

As a general rule, the weight of component c will typically be around 0.5 to 50% of the total weight of the abc solution. This proportion can be limited to between 2 and 30% or between 5 and 20% by weight. However, as indicated above, in the case of a spray composition, especially with a propellant, the amount of c can exceed 50%.

The formulations of the invention may additionally contain small proportions of other agents, such as polymers that are soluble in the precursor. These polymers can act as a reinforcement of the expanded liquid crystalline phase, so that a film attached to a mucosal surface becomes more strongly coupled. A "reinforcement" according to the same principle could also be obtained by soaking a matrix (paper, polymer network, or the like) with the precursor. After applying this "patch" to the skin, the formulation can act itself as a glue. In contrast to conventional adhesives for coating damaged tissues, however, the formulations of the invention are adhesive even with respect to mucous membranes and are non-irritating. In many cases, they are actually soothing in their own right, as described, and may contain suitable active agents.

Component "a", as indicated in this description, is a neutral liquid component, comprising a polar "head" group and also non-polar "tail" groups. Generally, the head and tail portions of the lipid will be linked by an ester moiety, but this coupling can take place by means of an ether, an amide, a carbon-carbon bond, or other couplings. Nonionic groups are preferred polar head groups and include polyols, such as glycerol, diglycerol, and sugar moieties (such as inositol and glucosyl-based moieties) and polyol esters, such as acetate or succinate esters. Preferred polar groups are glycerol and diglycerol groups, especially glycerol.

In a preferred aspect, component a is a diacyl lipid, in that it has two non-polar "tail" groups. This is generally preferable to the use of mono-acyl ("smooth") lipids because these are typically less well tolerated in vivo. The two nonpolar groups can have the same or different number of carbon atoms and each of them can be independently saturated or unsaturated. Examples of nonpolar groups include C₆ -C₃₂ alkyl and alkali groups that are typically present as long chain carboxylic acid esters. These are frequently described with reference to the number of carbon atoms and the number of unsaturations in the carbon chain. Thus, CX: Z indicates a hydrocarbon chain having X carbon atoms and Z unsaturations. Examples include especially caproyl (C6: 0) capryloyl (C8: 0), capryl (C10: 0), lauroyl (C12: 0), myristoyl (C14: 0), palmitoyl (C16: 0), phytanoyl ( C16: 0), Palmitoleoyl (C16: 1), Stearoyl (C18: 0), Oleoyl (C18: 1), Elaidoyl (C18: 1), Linoleoyl (C18: 2), Linolenoyl (C18: 3), Arachidonoyl (C20 : 4), behenoyl (C22: 0) and lignoceroyl (C24: 9). Therefore, typical nonpolar chains are based on the natural ester lipid fatty acids, including caproic, caprylic, capric, lauric, myristic, palmitic, phytanic, palmitolic, stearic, oleic, elaidic, linoleic, linolenic, arachidonic acids, behenic or lignoceric, or the corresponding alcohols. Preferred nonpolar chains are palmitic, stearic, oleic and linoleic acid, particularly oleic acid.

Diacyl lipid, when used as all or part of component "a", can be synthetic or can be derived from purified and / or chemically modified natural sources, such as vegetable oils. Mixtures of any number of diacyl lipids can be used as component a. More preferably, this component will include at least one part of diacyl glycerol (DAG), especially glycerol dioleate (GDO). In a favorable embodiment, component a consists of the DAGs. These can be a single DAG or a mixture of several DAGs. A highly preferred example is a DAG comprising at least 50% and preferably at least 80% and even comprising substantially 100% of GDO.

An alternative or additional highly preferred class of compounds for use, all or part of component a, are tocopherols. As used in this description, the term "tocopherol" is used to indicate a non-ionic lipid tocopherol, often known as vitamin E and / or suitable salts and / or analogs thereof. Suitable analogs will be those that provide the phase behavior, lack of toxicity, and phase change upon exposure to aqueous liquids that characterize the compositions of the present invention. These analogs will not generally form liquid crystalline phase structures, such as a pure compound in water. The most preferred tocopherols are tocopherol itself having the structure indicated below. Obviously, especially in the case where it has been purified from a source of natural origin, there may be a small proportion of non-tocopherol "contaminant", but this will not be enough to alter the advantageous phase behavior or lack of toxicity. Typically, a tocopherol will contain no more than 10% non-tocopherol analogs, preferably no more than 5%, and more preferably no more than 2% by weight.

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In another advantageous embodiment of the invention, component a) consists essentially of tocopherols, in particular tocopherol, as shown.

A preferred combination of constituents for component a) is a mixture of at least one DAG (eg GDO) with a minimum of one tocopherol. These mixtures include 2:98 to 98: 2 by weight of tocopherol: GDO, for example 10:90 to 90:10 tocopherol: GDO and especially 20:80 to 80:20 of these compounds. Similar mixtures of tocopherol with other DAGs are also suitable.

Component "b" of the present invention is at least one phospholipid. Like component a, this component comprises a polar head group and at least one non-polar tail group. The difference between components a and b resides mainly in the polar group. The non-polar parts can therefore be suitably derived from fatty acids or corresponding alcohols considered and in the above for component a. This will typically be the case where the phospholipid contains two non-polar groups, although one or more constituents of this component may have a non-polar fraction. In the case where more than one non-polar group is present, they may be the same or different.

Polar phospholipid "head" groups include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol. Most preferred is phosphatidylcholine (PC). In a preferred embodiment, component b) consists of a minimum of 50% PC, preferably at least 70% PC and more preferably, at least 80% PC. Component b) can consist essentially of PC.

The phospholipid portion, even more suitably than any diacyl lipid portion, can be derived from a naturally occurring source. Suitable sources of phospholipids include eggs, heart (eg, bovine), brains, liver (eg, bovine), and plant sources, including soy. These sources can provide one or more components b, which can comprise any mixture of phospholipids.

Since the preformulations of the invention can be administered to a subject for controlled release of an active agent, it is preferable that components a and b are biocompatible. In this regard, it is preferable to use, for example, diacyl lipids and phospholipids rather than mono-acyl (smooth) compound. A notable exception to this is tocopherol which has been described above. Although it has only one alkyl chain, this is not a "smooth" lipid in the conventional sense. The nature of tocopherol, as a well tolerated essential vitamin, clearly makes it very suitable in terms of biocompatibility.

The nature of the compositions of the invention suitable for soothing and curing irritations and inflammations on the surface of the body makes the need for well-tolerated lipids very important. In particular, the lipid composition will be present in high concentration in contact with tissues that may be damaged or inflamed. As a result, a very high level of compatibility of, for example, the diacyl lipids of the present invention is significant compared to less tolerated components, such as monoacyl lipids.

In addition, it is highly preferable that the lipids and phospholipids of components a and b are of the natural type (whether derived from a source of natural origin or are of synthetic origin). Naturally occurring lipids tend to cause less inflammation and reaction from the subject's body. Not only is it more comfortable for the subject, but it can increase the residence time of the resulting depot composition, since less activity of the immune system accumulates at the site of administration and there is less tendency for the subject to alter said activity. area. However, in certain cases it may be desirable to include a part of a non-naturally derived lipid in components a and / or b. This can be, for example, a "lipid ether" in which the head and tail groups are linked by an ether bond rather than an ester. These non-natural lipids can be used, for example, to alter the degradation rate of the resulting depot compound by having a greater or lesser solubility or vulnerability to decomposition mechanisms present at the site of release of the active agent. While all proportions are within the scope of the present invention, in general at least 50% of each of components a and b will be natural lipids. This will preferably be a minimum of 75% and can go up to substantially 100%.

Two spatially preferred combinations of components a and b are GDO with PC and tocopherol with PC, especially in the range of 30-90% by weight GDO / tocopherol, 10-60% by weight PC and 1-30% solvent (especially ethanol, NMP and / or isopropanol). The most preferred combinations are 35-60% (eg 40-55) GDO with 20

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50% (for example, 25-45%) PC. These are especially suitable in combination with ethanol, in particular 525% (eg 7 to 19%).

In addition to amphiphilic compounds a and b, the preformulations of the invention may also contain additional amphiphilic components at relatively low levels. In one embodiment of the invention, the preformulation contains up to 10% (by weight of components a and b) of a charged amphiphilic, in particular an anionic amphiphilic, such as a fatty acid. Preferred fatty acids for this purpose are caproic, caprylic, capric, lauric, myristic, palmitic, phytanic, palmitolic, stearic, oleic, elaidic, linoleic, linolenic, arachidonic, behenic or linoceric acids, or the corresponding alcohols. Preferred fatty acids are palmitic, stearic, oleic and linoleic acids, in particular oleic acid. It is especially advantageous that this component is used in combination with a cationic peptide active (see below). The combination of an anionic lipid and a cationic peptide is believed to provide a sustained release composition of specific value. This may be due in part to increased protection of the peptide from degrading enzymes present in vivo.

Component c of the preformulations of the invention is an organic solvent containing oxygen. Since the preformulation is intended to generate a depot / bioadhesive composition after administration (for example, in vivo), after contact with an aqueous fluid, it is desirable that this solvent is tolerable to the subject and capable of mixing with the aqueous liquid and / or diffusing or dissolving from the preformulation into the aqueous liquid. Solvents having at least moderate solubility in water are therefore preferred.

A special case is that in which the composition of the invention is formulated as an aerosol spray composition. In this case, it will be appreciated that component c comprises the propellant, which has reduced aqueous solubility. All mixing ratios from essentially pure propellant to primarily oxygen containing organic solvents can be taken into consideration. When the formulation is administered, the propellant will evaporate to a great extent. When c is primarily the propellant, an instantaneous increase in viscosity can be observed after spraying of the formulation. This is due to the rapid evaporation of the propellant and may have the advantage of more effective initial retention at the application site and may avoid the potential disadvantage of the formulation having a low viscosity during "cure" (water absorption and transformation from phase to a liquid crystalline phase with high viscosity).

In a preferred version, the solvent is such that a relatively small addition to the composition comprising a and b, ie below 20% and more preferably below 16%, eg up to 10% or even less, provides a large reduction in viscosity of an order of magnitude or more. As described, the addition of 10% solvent can provide a reduction of two, three, or even four orders of magnitude in viscosity relative to a solvent-free composition, even if said composition is a solution. or phase L₂ containing no solvent or an unsuitable solvent, such as water (subject to the special case explained below) or glycerol.

Typical solvents suitable for use as component c include at least one solvent selected from alcohols, ketones, esters (including lactones), ethers, amides, and sulfoxides. Examples of suitable alcohols include ethanol, isopropanol, and glycerol. Monools are preferable to diols and polyols. In the case where diols or polyols are used, this is preferably carried out in combination with at least an equal amount of monool or another preferred solvent. Examples of ketones include acetone, n-methyl pyrrolidone (NMP), 2-pyrrolidone, and propylene carbonate. Suitable ethers include diethyl ether, glycofurol, diethylene glycol monoethyl ether, dimethylisobarbide, and polyethylene glycols. Suitable esters include ethyl acetate and isopropyl acetate and dimethyl sulfide as a suitable sulfide solvent. Suitable amides and sulfoxides include dimethylacetamide (DMA) and dimethylsulfoxide (DMSO), respectively. Less preferred solvents include dimethyl isosorbide, tetrahydrofurfuryl alcohol, diglyme, and ethyl lactate. The most preferred solvent comprises ethanol and in particular consists of a minimum of 80% ethanol, preferably a minimum of 90% ethanol.

Since the preformulations have to be administered to a living individual, it is necessary that the solvent component c is sufficiently biocompatible. The degree of this biocompatibility will depend on the method of application and since component c can be any mixture of solvents, a certain amount of solvent may be present which would not be acceptable in large quantities. In general, however, the solvent or mixture that forms component c should not cause unacceptable reactions from the subject to which it is administered. Generally, these solvents will be hydrocarbons or preferably oxygen-containing hydrocarbons, both optionally with other substituents, such as nitrogen-containing groups. It is preferable that little or no amount of component c contains hydrocarbons substituted by halogens, since these tend to have a lower biocompatibility. In the case where a part of halogenated solvent is necessary, such as dichloromethane or chloroform, this proportion will be generally minimized. Obviously, the range of suitable solvents will be greater in formulations for application to external sound surfaces than to sensitive and / or damaged internal surfaces where only the most biocompatible agents are acceptable. Furthermore, in the case of aerosol sprayable compositions, halogenated hydrocarbons can also be considered as a propellant, since it will evaporate to a great extent during administration.

Component c used in this invention may be a single solvent or a mixture of suitable solvents, but will generally have a low viscosity. This is important because one of the key aspects of this in

The invention is that it provides preformulations having low viscosity and a basic role of a suitable solvent which consists in reducing this viscosity. This reduction will be a combination of the low viscosity effect of the solvent and the effect of molecular interactions between the composition of the solvent and the lipid. An observation of the present inventors is that the low viscosity oxygen-containing solvents described have many unexpected advantages and molecular interactions with the liquid parts of the compound, thus providing a non-linear reduction in viscosity with the addition of a small volume of solvent.

The viscosity of the "low viscosity" solvent component c (single solvent or mixed solvent) should not be typically greater than 18 mPas at 20 ° C. Preferably it will not be more than 15 mPas, more preferably not more than 10 mPas and more preferably not more than 7 mPas at 20 ° C.

Solvent component c will generally be at least partially lost in the formation of the reservoir / bioadhesive composition upon contact with a surface (eg, a body surface or the surface of an implant) or will be diluted by absorption. water from the environment and / or tissues. Therefore, it is preferable that component c is at least to some extent miscible and / or dispersible in water and at least should not repel water to such an extent that absorption of water is prevented. Also, in this regard, oxygen-containing solvents with a relatively small number of carbon atoms (eg, up to 10 carbon atoms, preferably up to 8 carbon atoms) are preferable. As is evident, in the case where a greater number of oxygen atoms are present, the solvent will tend to remain soluble in water with a large number of carbon atoms. The ratio of carbon to heteroatom (eg N, O, preferably oxygen) will therefore frequently be about 1: 1 to 6: 1, preferably 2: 1 to 4: 1. In case a solvent is used with a proportion that is outside one of these preferred ranges, then it will preferably be not more than 75%, preferably not more than 50% in combination with a preferred solvent (such as ethanol). This can be used, for example, to decrease the rate of evaporation of the solvent from the preformulation in order to control the rate of formation of the liquid crystalline deposit.

Another advantage of the preformulations of the present invention is that a higher level of bioactive agent can be incorporated into the system. In particular by the appropriate choice of ac components (especially c) high levels of active agent can be dissolved or suspended in the preformulations. In general, the lipid components in the absence of water are relatively poorly solubilized but in the presence of water they form phases too viscous to be easily administered. Higher proportions of bioactive agent can be included by using appropriate solvents as component c and this level will dissolve in the depot compound as it is formed in situ or can form microdroplets or microcrystals that gradually dissolve and release active agent. A suitable choice of solvent will be possible through routine experimentation within the standards disclosed in this description. In particular, the present inventors have discovered that the combination of a low molecular weight alcohol solvent (such as ethanol or isopropanol) with the lipid components of the present invention is unexpectedly effective in solubilizing a wide number of drugs and other molecules. active.

The preformulations of the present invention typically do not contain significant amounts of water. Since it is basically impossible to remove any trace of water from a lipid composition, it is to be taken as an indication that there is only a minimal trace of water that cannot be easily removed. This amount will generally be less than 1% by weight, preferably less than 0.5% by weight of the preformulation. In a preferred aspect, the preformulations of the invention will not contain glycerol, ethylene glycol or propylene glycol and will contain only traces of water, as described.

In some cases, the composition may contain traces of water (or a polar solvent with similar characteristics) such that they form a phase with rather low viscosity L2 (reverse miscellar). This can also help to solubilize certain active ingredients in the formulation, particularly those that are only soluble in water.

However, there is a certain embodiment of the present invention in which higher proportions of water can be tolerated. This is the case where water is present as part of the solvent component in combination with an additional water-miscible component c (single solvent or mixture). In this embodiment, up to 10% by weight of water may be present assuming that at least 3% by weight is also present, preferably a minimum of 5% and more preferably a minimum of 7% by weight of component. c, said component c being miscible in water and that the resulting preformulation remains non-viscous and therefore does not form a liquid crystalline phase. Generally, there will be a greater amount of component c by weight than the weight of water included in the preformulation. The most suitable solvents for use with water in this aspect of the invention include ethanol, isopropyl alcohol, NMP, acetone, and ethyl acetate.

The preformulations of the present invention contain one or more bioactive agents (equivalently described as "active agents"). The active agents can be any compound that has the desired biological or physiological effect, such as a protein, drug, antigen, nutrient, cosmetic, fragrance, flavor, diagnostic, pharmaceutical agent, vitamin or dietary agent and will be formulated as level sufficient to provide an in vivo concentration and a functional level (which is generally a local concentration for topical compositions).

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Drug agents that can be delivered by the present invention include drugs that act on cells and receptors, such as peripheral nerves, adrenergic receptors and cholinergic receptors, skeletal muscles, cardiovascular system, smooth muscles, blood circulation system, endocrine system and of hormones, blood circulatory system, synoptic sites, neuroeffector joint sites, immune system, reproductive system, skeletal system, autacoid system, alimentary and secretory systems, histamine system and central nervous system. Drug agents intended for local stimulatory or inhibitory effects on enzymes or proteins can also be provided by the present invention. The effect of the delivered drug agent can also be associated with direct effects on DNA or RNA synthesis, such as transcription, translation, or post-translational modification. Also these effects can be stimulatory and inhibitory.

Examples of drugs to be delivered by the compound of the present invention include, but are not limited to: antibacterial agents, such as β-lactams or macrocyclic peptide antibiotics, antifungal agents, such as polyene macrolides (for example, amphotericin B) or azole antifungals, anticancer and / or antiviral drugs, such as nucleotide analogs, pacitaxel and derivatives thereof , anti-inflammatory drugs, such as non-steroidal anti-inflammatory drugs and corticosteroids, cardiovascular drugs such as agents for the increase or reduction of blood pressure (especially local action), analgesics and prostaglandins and derivatives. Diagnostic agents include radionuclide-labeled compounds and contrast agents including X-ray, ultrasound and MRI contrast enhancers (especially for application to an internal surface of a body cavity). Nutrients include vitamins, coenzymes, diet supplements, etc. which can be used, for example, for recovery of the effects of a systemic medicament, such as recovery by folate from a folate analog, such as methotrexate.

Particularly suitable active agents include those that would normally have a short residence time in the body due to their rapid decomposition or secretion and those that have a low oral bioavailability, especially if their effect can be provided by topical treatment. , thus deriving systemic absorption. These include peptides, proteins and active agents based on nucleic acids, hormones and other natural agents in their original or modified forms. By administering such agents in the form of bioadhesive depot compositions, formed from the preformulation of the present invention, the agents are received at a continuous level over a long period of time despite having rapid systemic clearance rates. This offers obvious advantages in terms of stability and patient adaptation over dosing multiple times each day for the same period. In a preferred embodiment, the active agent has a biological half-life (after entry into the bloodstream) of less than 1 day, preferably less than 12 hours, and more preferably less than 6 hours. In some cases, this can be as low as 1-3 hours or less. Suitable agents are also those that have a reduced oral bioavailability compared to that achieved by injection, for the case in which the active agent also or alternatively has a bioavailability of less than 0.1%, especially less than 0.05%. in oral formulations. Similarly, some agents would be inappropriate or undesirable when administered systemically, but can be administered locally, particularly to external surfaces.

Active agents based on peptides and proteins are highly suitable for inclusion in surface applied depot compositions according to the invention. These agents can be included for their local effect or they can be applied to a surface for their systemic action. Active agents suitable for local or systemic effect include human and veterinary drugs selected from the group consisting of adrenocorticotropic hormone (ACTH) and its fragments, angiotensin and its related peptides, antibodies and its fragments, antigens and its fragments, atrial natriuretic peptides, bioadhesive peptides, bradykinins and their corresponding peptides, calcitonins and their corresponding peptides, cell surface receptor protein fragments, chemotactic peptides, cyclosporins, cytokines, dinorphins and their corresponding peptides, endorphin and P-lidotropin fragments, enkephalin and their corresponding proteins, enzyme inhibitors, immunostimulating peptides and polyamino acids, fibronectin fragments and their peptides corresponding, gastrointestinal peptides, gonadotropin-releasing hormone (GnRH) agonists and antagonists, glucagon-like peptides, growth hormone-releasing peptides, immunostimulating peptides, insulin-like and insulin-like growth factors, interleukins, luteinizing hormone-releasing hormones (LHRH) and their corresponding peptides, melanocyte-stimulating hormones and their corresponding peptides, peptides related to nuclear signal localization, neurotensins and their corresponding peptides, neurotransmitter peptides, opioid peptides, oxytokines, vasopressins and their corresponding peptides, parathyroid hormones and their fragments, protein kinase and their corresponding peptides, somatostatins and their corresponding peptides, substance P and their corresponding peptides, transforming growth factors (TGF) and their corresponding peptides, factor fragments of tumor necrosis, toxins and functional toxoids and peptides, such as anticancer peptides including angiostatins, antihypertension peptides, blood anticoagulation peptides and antimicrobial peptides; selected from the group consisting of proteins, such as immunoglobulins, angiogenins, bone morphogenic proteins, chemokines, colony stimulating factors (CSF), cytokines, growth factors, interferons (type I and II), interleukins, lectins, inhibitory factors of leukemia, stem cell factors, transforming growth factors and tumor necrosis factors.

Another considerable advantage of the reservoir compositions of the present invention is that the active agents are released gradually over extended periods of time without the need for repeated doses. The COM

ES 2 343 641 T3 position is therefore very suitable for children or people whose lifestyle is incompatible with a reliable or repeated dosing regimen. Also for "lifestyle" activities where the inconvenience of repeated dosing could outweigh the benefits of the active agent.

Cationic peptides are particularly suitable for use where a part of the preformulation comprises an anionic amphiphilic agent, such as a fatty acid. In this embodiment, preferred peptides include octreotide, lanreotide, calcitonin, oxytocin, beta and gamma interferon, interleukins 4, 5, 7, and 8, and other peptides that have an isoelectric point above pH 7, especially above pH 8.

In a preferred aspect of the present invention the compound of the invention is such that a phase (I2), or a mixed phase including phase (I2), is formed on exposure to aqueous fluids and a polar active agent is included in the composition. Particularly suitable polar active agents include active peptides and proteins, oligo nucleotides, and agents with low water solubility, including those listed above. Of particular interest in this regard are the octreotide peptide and other peptides related to somatostatin, alpha and beta interferons, glucagon type 1 and 2 peptides and their receptor agonists, luprorelin and other GnRH agonists, abarelix and other GnRH antagonists, alpha and beta interferon. , zolendronate and ibandronate and other bisphosphonates and polar active chlorhexidine (eg, chlorhexidine digluconate or chlorhexidine dihydrochloride). Considerations for Exclusion. Most of those that have been indicated as especially interesting are intended for parenteral dosing, except for chlorhexidine.

The amount of bioactive agent to be formulated with the preformulations of the present invention will depend on the functional dose and the period during which the depot compound formed after administration must provide sustained release. Typically, the formulated dose for a specific agent will be around the equivalent of the normal individual dose multiplied by the number of times the expected duration of action that the formulation should provide. Obviously, this amount should be adapted to take into account any adverse effects of a large dose at the beginning of treatment and, therefore, generally this will be the maximum dose used. The precise amount suitable in each case will easily be determined by proper experimentation.

The formulations of the present invention can form non-parenteral reservoirs in which the active agent is slowly released onto a body surface. It is particularly significant that the compounds generated from the preformulations are bioadhesive because this allows local release of the active agent over a continuous period of time. This means that the compositions must coat the surface to which they are applied and / or on which they form in an appropriate manner and must remain even when this surface is subjected to air or liquid flow and / or abrasion. It is particularly preferable that the liquid crystalline depot compositions formed should be stable to washing with water. For example, a small volume (eg, 100 µl) of a depot precursor can be applied to a body surface and can be exposed to a flow of 500 times its own volume of water per minute for 5 minutes. After this treatment, the composition can be considered bioadhesive if less than 50% of the composition or the bioactive agent has been lost. Preferably, this level of losses will be achieved when a volume of water equal to 1,000 times, and more preferably 10,000 times the volume of the composition is passed through per minute, for 5 or, preferably, 10 minutes.

Another advantageous characteristic of the compositions of the invention is that the film generated after administration can act not only as a reservoir system. This film can also have the advantage of reducing the evaporation of water from damaged areas or areas affected by a certain medical condition (in which the barrier properties of the skin are reduced). Therefore, these compositions may have additional advantageous characteristics by themselves showing additive advantages and / or synergistic advantages in combination with active agents, for example, for the prophylaxis of inflammatory or allergic dermatoses and for the care and reestablishment of sensitive skin or stressed.

While the non-parenteral depot compositions of the present invention can absorb some or all of the water necessary to form a liquid crystalline phase structure from biological surfaces with which they come in contact, some additional water can be also absorbed from the surrounding air. In particular, in the case where a thin layer of large surface area is formed, then the affinity of the composition for water may be sufficient to form a liquid crystalline phase structure upon contact with water in the air. The "aqueous fluid" referred to in this description is, at least partially, air containing a portion of moisture in this embodiment.

Non-parenteral depot compositions will typically be generated by applying the preformulation topically to a body surface (external or within a naturally or artificially generated body cavity) and / or to the surface of an implant. This application can take place for direct liquid application such as spraying, dipping, washing, application of a mat or rolling roller, intracavity injection (for example, to an open cavity with or without use of a needle), painting, application of drops (especially in the eyes), patch application, and similar methods. A highly effective method is aerosol or pump spraying and this obviously requires that the viscosity of the preformulation be as low as possible and therefore very suitable for the compositions of the invention. However, non-parenteral reservoirs cannot be used to deliver systemic agents, eg, transmucosally or transdermally.

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In the case that the formulation is administered in the form of a patch, this can be based on the "tail" function of the composition. The "glue property" can be beneficial to the tissues in contact with the formulation, since the compositions can be soothing and rehydrating, as indicated. This is in contrast to previously known patches where the adhesive is at best inert.

Conditions especially suitable for causal or symptomatic treatment by topical bioadhesive depot compositions according to the present invention include skin conditions (such as irritations resulting from any cause including chapping, scratching, and skin conditions including eczema. and herpes), eye conditions, genital inflammations (including those due to genital infection such as genital herpes), infections and conditions of the fingers and / or toe nails (such as bacterial or fungal infections of the nails, such as onychomycosis or poronychia) and in particular inflammation and / or irritation of any body surface. Two especially suitable states that can be improved by using the composition of the invention s mucositis and infectious diseases of the intestine (eg Crohn's disease or ulcerative colitis). Topical bioadhesive formulations can also be used to deliver active systemic agents (eg, medication), particularly by skin adsorption, oral, transdermal or rectal route. A preferred example is travel sickness medication, such as nicotine (for example, in anti-smoking aids). Where context permits, the terms "topical application" referred to in this description include systemic agents applied non-parenterally to a specific region of the body.

Periodontal infections are especially suitable for treatment by the compositions of the present invention. In particular, known compositions for the treatment of periodontal infection are difficult to apply or are generally ineffective. The most widely used periodontal depot composition comprises the insertion of a collagen "chip" into the periodontal space, from which an anti-infective agent is released. This chip is difficult to insert and is not shaped to accommodate the shape and volume of the periodontal space, so pockets of infection can remain untreated. In contrast to this, the compositions of the present invention, applied in the form of a low viscosity preformulation, can be easily and rapidly injected into the periodontal space and will flow precisely adapting to said space filling the available volume. The compositions then rapidly absorb water to form a consistent gel that is resistant to aqueous conditions in the mouth. The only known prior attempt at such injectable periodontal treatment relied on relatively high viscosity dispersions that were difficult to apply and subject to undesirable phase separation. All these drawbacks are solved by the compositions of the present invention, as described. Suitably high activities for periodontal administration are anti-antibacterial, antibiotic, anti-inflammatory and local analgesic agents, in particular benzdamine, tramadol and particularly chlorhexidine.

Non-parenteral depot compositions are also especially advantageous in combination with non-pharmaceutical active agents, such as cosmetic active agents, fragrances, essential oils, etc. These non-pharmaceutical reservoirs will maintain the important bioadhesion and sustained release aspects providing long-lasting cosmetic effects, but can be easily applied by spraying or wiping. This is additionally applicable to agents that have cosmetic and medical (especially prophylactic) effects such as sunscreen agents. Since topical depot compounds provide consistent, water-resistant barriers that can solubilize high levels of active agents, they are especially suitable for sunscreens and sun-blocking agents in combination with ultraviolet light (UV, e.g., UVa, UVb, and / O UVc), absorbing and / or dispersing agents, particularly where high levels of protection are desirable. The compositions are also highly biocompatible and can act to moisturize and soothe the skin during sun exposure. Compositions of the invention containing soothing agents, such as aloe vera, are also highly suitable for soothing and moisturizing application after exposure to sunlight, or to dry, inflamed or damaged skin due, for example, to irritation, burns or abrasion.

Active agents especially suitable for administration as a suitable non-parenteral (eg topical) depot, including intraoral, buccal, nasal, ophthalmic, dermal, rectal and vaginal routes, include antibacterials such as chlorhexidine, chloralphenicol, triclosan, tetracycline , terbinafine, tobramycin, sodium fusidate, butenafine, metronidazole (the latter particularly for the treatment (eg symptomatic) of acne rosacea, adult acne or vaginal infections), antivirals including acyclovir, anti-infectives such as bibrocatol, ciprofloxacin, levofloxacin, local pain relievers such as benzydamine, lidocaine, prilocaine, xylocaine, bupivacaine, pain relievers such as tramadol, fentanyl, sufentanilorph, morphine oxycodone, codeine, aspirin, acetaminophen, NSAIDS such as ibuprofen, flurbiprofen, naproxen, ketoprofen, fenoprofen, diclofenac, etodalac, diflunisal, oxaproxin, piroxicam, indomethasine, sulindac, tolmetin, salicylic acids such as salicylamide and diflunisal, Cox1 or Cox2 inhibitors such as celecoxib, rofecoxib, or valdecoxib, corticosteroids, anticancer and immunostimulatory agents (for example, methylaminolevulon alpha hydrochloride), interferon alfa and beta hydrochloride, and beta-interferon hydrochloride (for example, tiagabine or gabapentin topiramate), hormones (such as testosterone and testosterone undecanoate, medroxyprogesterone, estradiol), growth hormones (such as human growth hormone) and growth factors (factors such as granulocyte macrophage colony-stimulating factor), immunosuppressants (cyclosporine, sirolimus, tacrolimus), nicotine and antivirals (eg, acyclovir), vitamin D3 and derivatives thereof.

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Other especially suitable active agents include:

Acetaminophen, Ibuprofen, Propoxyphene, Codeine, Dihydrocodeine, Hydrocodone, Oxycodone, Nalbuphine, Meperidine, Leverorphanol, Hydromorphone, Oxymorphone, Alfentanil, Fentanyl and Sefentanil.

Some specific active agents discovered by the inventors to form highly effective deposits, according to the present invention, include the following:

For topical bioadhesive, controlled release products for intraoral administration (including buccal and periodontal);

i. benzydamine (local pain reliever, anti-inflammatory) or other local pain reliever, analgesic, anti-inflammatory, antibacterial, antifungal, or a combination thereof. The composition provides a sustained effect on intraoral mucosa, in particular on damaged, sensitized, infected mucosa, for example, in patients suffering from oral mucositis (induced, for example, by chemotherapy and radiotherapy). In particular, for the treatment of oral mucositis.

ii. tramadol (pain reliever). Provides a composition with a continuous systemic analgesic effect.

iii. Chlorhexidine gluconate (antibacterial) for the treatment of periodontal and topical infections. In particular for prolonged effect on the periodontal pocket. The compositions result in deposits that release chlorhexidine for more than 1 hr, preferably more than 6 hr, more preferably more than 24 hr, when applied as a liquid, forming a bioadhesive gel in situ. The surface gel formation time has been found to be between 1 second and 5 minutes.

Deposits ia iii can be formed with a high level of incorporation of active agent and a high degree of resistance to its washout. Preformulations in liquid form, administered as a spray or rinse / wash liquid for i and ii and gel-forming liquid for iii in which the liquid is applied to the periodontal pocket, eg, by injection.

For controlled release products for nasal administration, non-parenteral bioadhesives (eg, topical or systemic);

i. fentanyl (analgesic) provides rapid onset and sustained duration of analgesic effect when administered by nasal spray or into the oral cavity ii. diazepam (anti-anxiety) provides non-parenteral, nasal or oral cavity depot with systemic effect, providing a rapid onset and continued duration. It is administered as a spray.

For topical bioadhesive, controlled release products for ophthalmic administration;

i. diclofenac (NSAID) with continuous duration. Administered as phase-forming liquid in situ ii. pilocarpine (parasympathomimetic, cholinergic agonist) for treatment of glaucoma.

iii. Levocabastine Hydrochloride, Ketotifen fumarate that provides a liquid for eye drops to provide long-lasting relief from allergic conjunctivitis with a long period for re-application.

iv. Pilocarpine hydrochloride for treatment of Sjogrens syndrome

v. dexamethasone (corticosteroid) vi. chloramphenicol (mainly bacteriostatic anti-infective) vii. indomethacin (NSAID).

Deposits ia vii formulated in the form of a liquid spray or more preferably drops for direct application to the surface of the eye and to provide an in situ deposit formation with high resistance to washout by tear action and blink contact / eye massage. The composition of the invention shows excellent compatibility for ophthalmic application. Safety studies in rabbits as a model show no irritation or blurred vision effects. Are they appropriate in this case?

Other suitable activities for ophthalmic compositions include antihistamines, stem cell stabilizers, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids (for example, for the treatment of allergic conjunctivitis), antiglaucoma active agents including suppressing / inhibiting agents (beta-blocking agents: timolol , betaxolol, carteolol, levobunolol, etc., topical carbonic anhydrase inhibitors: dorzolamide, brinzolamide, sympathomimetics: epinephrine, dipivephrine, clonidine, apraclonidine, brimonidine), agents that facilitate exit (parasympathomimetics (cholinergic agonists): pilocarpine, prostaglandin analogs and related compounds: atanoprost, travoprost, bimatoprost, unoprostone).

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For non-parenteral bioadhesive (eg, topical or systemic) controlled release products for dermatological administration;

i. acyclovir (antiviral). The compound generates a bioadhesive, long-lasting film-forming product. Applied as a spray or liquid ii. testosterone undecanoate or testosterone ethanate (hormonal deficiency). Bioadhesive, long lasting film-forming compound. It can be applied as an aerosol or spray pump or as a liquid.

Especially suitable applications of dermatological formulations are anti-infective dermatological bioadhesive deposits for protection in environments where contact with infectious agents is likely (eg human or veterinary surgery, slaughterhouse work, certain types of cleaning, etc.). Bioadhesive deposits generated by compounds of the invention provide effective and sustained user protection. Compositions with anti-infective agents can also be used in situations where the sterile nature of the user's skin is important to the health of others, such as nurses or doctors visiting multiple patients in hospitals, where infections must be avoided. crusades. A prior coating with a composition of the present invention may serve to provide resistance against the uptake of infectious agents from one area thereby preventing transmission to another.

In the treatment methods according to the present invention and also in the corresponding use as drug therapy and application, an active agent is not always necessary. In particular, lipids, particularly phospholipids, such as PC, have been implicated as highly beneficial for the treatment of certain conditions (including those described below). Without wishing to be bound by theory, it is believed that suitable lipids, such as those in the formulations of the present invention, are naturally present in protective layers on top of and around many structures in the body, such as coatings of many body cavities and joint contact surfaces. These layers can serve as protection against the adhesion and attack of a wide variety of chemical and biological agents (such as gastric surfaces and in the lining of the digestive tract), they can act as lubricants (particularly in joints but also crucially in coatings and membranes that surround many internal structures, such as the heart and lungs), and many may further contribute to cell wall repair by allowing lipid exchange and dilution of undesirable membrane-bound and membrane-soluble agents. The lipid nature of the compositions also forms a non-harmful substrate for unwanted inflammatory lipase enzymes including phospholipases, such as phospholipase A₂ (PLA₂).

In an alternative embodiment of the treatment methods and corresponding uses of the present invention, suitable active agents may be included as the sole beneficial agent or to complement the effect of suitable lipid components. These active agents will typically be suitable for treating inflammation and / or irritation, such as locally steroidal and non-steroidal anti-inflammatory drugs and immune modulators. Examples of such agents are known and many have been mentioned elsewhere in this description. They include cis-urocanic acid, corticosteroids, such as prednisone, methylprednisolone, and hydrocortisone, and derivatives of non-steroidal anti-inflammatory compounds, such as benzydamine, paracetamol, ibuprofen, and salicylic acid derivatives, including acetyl salicylate and 5-amino salicylates. Also suitable are local inhibitors of inflammatory pathways including antigen recognition suppressors, methotrexate, azathioprine or 6-mercaptopurine and phospholipase inhibitors, such as PLA inhibitors.₂.

The preformulations of the present invention provide non-laminar liquid crystalline reservoir compositions upon exposure to aqueous fluids, especially in contact with body surfaces. As used in this description, the term "non-laminar" is used to indicate a normal or reverse liquid crystalline phase (such as cubic or hexagonal phase) or the L3 phase or any combination thereof. The term "crystalline liquid" indicates all the hexagonal liquid crystalline phases, all the cubic crystalline phases and / or all their mixtures. The term "hexagonal" used in this description indicates "normal" or "reverse" hexagonal (preferably reverse) and "cubic" indicates any cubic liquid crystalline phase unless otherwise indicated. By using the preformulations of the present invention, it is possible to generate any phase structure present in the phase diagram of components a and b with water. The reason for this is that preformulations can be generated with a wider range of corresponding component concentrations than in previously known lipid reservoir systems without risks of phase separation or resulting in highly viscous injection solutions. In particular, the present invention provides for the use of phospholipid concentrations above 50% with respect to the total amphiphilic content. This allows access to only appreciated phases with high phospholipid concentrations, particularly the hexagonal liquid crystalline phases.

For many lipid combinations, only certain non-laminar phases exist or exist in any stable state. It is a surprising feature of the present invention that compositions described in this description frequently show non-lamellar phases that are not present with many other combinations of components. In an especially advantageous embodiment, therefore, the present invention relates to compositions having a combination of components for which the phase I reaction exists.₂ and / or L₂when diluted with an aqueous solvent. The presence or absence of these regions can easily be verified for any specific combination by simply diluting the composition with aqueous solvent and studying the resulting phase structures by the methods described.

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In a very advantageous embodiment, the compositions of the invention can form a phase I₂ or a mixed phase including phase I₂ when they make contact with water. Phase I₂ it is an inverse cubic liquid crystalline phase having discontinuous aqueous regions. This phase is particularly advantageous in the controlled release of active agents and especially in combination with polar active agents, such as water-soluble active agents, because the discontinuous polar domains prevent the rapid diffusion of the active principles. Deposition precursors in phase L2 are very effective in combination with a deposit formation in phase I2. The reason for this is that the L2 phase is the so-called "reverse micellar" phase which has a continuous hydrophobic region surrounding discrete polar nuclei. L₂ It therefore has similar advantages with hydrophilic active ingredients.

In transient stages after contact with body fluids, the composition may comprise multiple phases, since the formation of an initial surface phase will delay the passage of solvent into the core of the reservoir. Without wishing to be bound by theory, it is believed that this transient formation of a surface phase, especially a liquid crystalline surface phase, serves to markedly reduce the "burst / lag" profile of the present combinations when immediately limit the rate of exchange between the composition and the surrounding medium. Transient phases can include (generally in this order from the outside to the center of the reservoir): H_h or L_to, I₂, L₂, and liquid (solution). It is highly preferred that the composition of the invention is capable of forming at least two, and more preferably at least three, of these phases simultaneously in transient stages after contact with water at physiological temperatures. In particular, it is highly preferred that one of the phases formed, at least transiently, is phase I₂.

It is important to note that the preformulations of the present invention are low in viscosity. As a result, these preformulations should not be in any bulk liquid crystalline phase, since all liquid crystalline phases have significantly higher viscosity than could be delivered by a syringe or spray dispenser. The preformulations of the present invention will therefore be in a non-liquid crystalline state, such as a solution, phase L₂ or L₃, particularly solution or L₂. Phase L₂As used in this description, it is preferably an "expanded" L2 phase containing about 10% by weight or more of solvent (component c) with a viscosity reducing effect. This is in contrast to a "concentrated" or "unexpanded" L2 phase that does not contain a solvent or a minor amount of solvent or that contains a solvent (or mixture thereof) that does not provide the viscosity decrease associated with low viscosity solvents. containing oxygen, specified in this description.

In one embodiment, a small proportion (eg, less than 5% by weight) of a reinforcing polymer can be added to the formulation.

After administration, the preformulations of the present invention undergo a phase structure transition from a low viscosity mixture to a high viscosity depot (tissue adherent) composition. Generally, this will be a transition from an expanded molecular mixture L₂ and / or phase L₃ to one or more liquid crystalline phases (high viscosity) such as normal or reversed hexagonal or cubic liquid phases or mixtures thereof. As indicated above, other phase transitions can also take place after administration. Obviously, a complete phase transition is not necessary for the operation of the invention, but at least a surface layer of the administered mixture will form a liquid crystalline structure. Generally, this transition will be rapid for at least the surface region of the administered formulation (the part in direct contact with air, body surfaces and / or body fluids). This will preferably last a few seconds or minutes (eg, up to 30 minutes, preferably up to 10 minutes, more preferably 5 minutes or less). The remainder of the composition can phase change to a liquid crystalline phase more slowly by diffusion and / or by dispersing the surface region.

In a preferred embodiment, the present invention therefore provides a preformulation, as described, of which at least a part forms a hexagonal liquid crystalline phase on contact with an aqueous fluid. The hexagonal phase formed in this way may gradually disperse, releasing the active agent, or it may subsequently become a cubic liquid crystalline phase which in turn gradually disperses. It is believed that the hexagonal phase will provide a more rapid release of the active agent, in particular a hydrophilic active agent, than the cubic phase structure, especially the I2 and L2 phase. Therefore, when the hexagonal phase forms before the cubic phase, this will result in an initial release of the active agent to bring the concentration to an effective level quickly, followed by the gradual release of a "maintenance dose." as the cubic phase degrades. In this way, the release profile can be controlled.

Without limitation by theory, it is believed that upon exposure (eg to body fluids) the preformulations of the invention lose a portion of all organic solvent, included therein (eg, by diffusion and / or evaporation) and adsorbs aqueous fluid from the body's surrounding environment (for example, moist air close to the body or in the environment in vivo) such that at least a part of the formulation generates a non-laminar liquid crystalline phase structure. In most cases, these non-lamellar structures are highly viscous and do not readily dissolve or disperse in the surrounding medium in vivo and are bioadhesive and therefore are not easily removed by washing or rinsing. Furthermore, since the non-laminar structure has large polar, apolar and boundary regions, it is very effective in solubilizing and stabilizing many types of active agents and protecting them from degradation mechanisms. As the depot composition formulated from the preformulation progressively degrades over a period of hours or days, or even weeks or months (depending on the nature and place of application), the active agent is released.

ES 2 343 641 T3 gradually and / or diffuses from the composition. Since the environment within the depot composition is relatively protected, the preformulations of the invention are well suited for active agents with a relatively low biological half-life (see above).

In a further aspect of the invention, topical compositions can be used to provide a physical barrier on body surfaces in the absence of any active agent. In particular because of the very high bioadhesion of the compositions, "barrier" coatings formed by spraying or applying liquid can be formed with the present compositions in order to reduce contact with potentially infective or irritating agents or to reduce soiling of surfaces of the body. The stable nature of the compositions and resistance to washout provide advantageous characteristics for these barriers that could conveniently be applied as a liquid or by spray. Without limitation by theory, it is believed that the stability and contact resistance of the applied topical compositions are due to specific phase transitions of the composition upon exposure to aqueous fluid / moisture and its bioadhesion in combination with the low solubility. aqueous of the building blocks of diacyl lipid.

The formulations, compositions and methods of the invention relating to the treatment of inflammation or irritation are especially suitable for combating inflammation and / or irritation in a body cavity. Administration to a bodily activity is therefore very suitable in this regard and will be carried out by a method suitable for the cavity under treatment. For example, mouthwashes may be suitable for the oral or buccal cavities, while other parts of the digestive tract may be adequately treated by oral formulations, including dry dispersions and preformulations, and rectal formulations, such as enemas or suppositories. Rinses and pessaries are equally suitable for vaginal delivery.

The compositions of the present invention are highly suitable for treating body cavity inflammations because of the highly bioadhesive nature of the non-laminar phase and the resulting long-lasting effects. The inherently calming and highly biocompatible nature of the constituents is also important and can play a passive or active role in treating inflammation.

The treatment methods and corresponding uses of the present invention are therefore most applicable to inflammatory diseases and inflammations caused, for example, by wounds, abrasion or reaction to aggressive therapies, such as radiation and / or chemotherapy. Inflammatory diseases that affect at least one body cavity are especially suitable. Diseases of the digestive tract are well suited for treatment with the compositions of the present invention, particularly inflammatory bowel diseases including Crohn's disease and ulcerative colitis, as well as oral inflammation, such as oral mucositis. Similarly, application to a body cavity during surgery can also be used to take advantage of the characteristics of the formulations. In this way they can be applied directly, for example, by spraying or application by painting, soothing inflammation resulting from surgery or exposure during surgery and also to reduce the tendency of surgically manipulated tissues to "stick" and / or form adhesions. / bridges in unwanted places.

The invention especially provides a method of treating an inflammatory disease (eg Crohn's disease, ulcerative colitis or oral mucositis), said method comprising administering a preformulation of the present invention in the absence of an active agent or comprising, at a minimum , an anti-inflammatory or anti-infective active agent, such as an agent selected from corticosteroids, such as prednisone, methylprednisolone and hydrocortisone, and derivatives of non-steroidal anti-inflammatory compounds, such as benzydamine, paracetamol, ibuprofen, and derivatives of salicylic acids, including acetyl salicylate and 5-amino salicylates. Also suitable are local inhibitors of inflammatory pathways including the antigen recognition suppressors methotrexate, azathioprine or 6-mercaptopurine and phospholipase inhibitors, such as PLA2 inhibitors. Other suitable active agents include glutamine, antioxidants such as ascorbate, beta-carrothin, vitamin E, oxypentifylline, azelastine hydrochloride, allopurinol, chlorhexidine, povidone iodide, nystatin, clotrimazole, polymyxin E, tobramycin, amphotericin B, acyclovir, colony-stimulating factor granulocytes (G-CSF), macrophage-granulocyte stimulating factor (GM-CSF), cytokines, and cytokine inducers / suppressors.

An especially preferred method and corresponding use is a method for the treatment of oral mucositis in a human or an animal subject (especially a subject in need thereof) by means of a composition of the present invention (comprising especially preferred combinations of components a, b and c), comprising at least a local analgesic or an anti-inflammatory agent, especially benzydamine or a derivative thereof. These can optionally be combined with one or more of the active agents indicated for the treatment of inflammation and / or topical anesthetics, such as lignocaine, cocaine, diphendramine, or particularly dichlonine HCl.

The invention will be further explained with reference to the following non-limiting examples and the attached figures, in which:

Figure 1 shows the cumulative release of methylene blue (MB) from a depot formulation comprising PC / GDO / EtOH (45/45/10% by weight) when injected with excess water;

Figure 2 shows the non-linear decrease in viscosity of the preformulation with the addition of N-methyl pyrolidinone (NMP) and EtOH;

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Figure 3 shows the in vitro release in excess of aqueous phase of chlorhexidine from a depot formulation comprising PC / GDO / EtOH (36/54/10% by weight), containing 50 mg of chlorhexidine / g of corresponding formulation at a 5% drug load.

Examples

Example 1

Availability of several liquid crystalline phases in the tank by choice of composition

Injectable formulations containing different proportions of phosphatidyl choline ("PC" -Epikuron 200) and glycerol dioleate (GDO) were prepared with EtOH as solvent to show that different liquid crystalline phases can be achieved after equilibrating the depot precursor formulation with water in excess.

Appropriate amounts of PC and EtOH were weighed into glass vials and the mixture was placed on a shaker until the PC was completely dissolved into a clear liquid solution. Next, GDO was added to form a homogeneous injectable solution.

Each of the formulations was injected into a vial and equilibrated with excess water. The behavior of the phase was evaluated visually and between cross polarizations at 25 ° C. The results are shown in Table 1.

TABLE 1

<td>Formulation</td><td>Pc (% in weigh)</td><td>GDO (% in weigh)</td><td>EtOH (% in weigh)</td><td>Phase</td><td>in H₂OR</td>

<td>TO</td><td> 22,5</td><td> 67,5</td><td> 10,0</td><td>L₂</td><td></td>

<td>B</td><td> 28,8</td><td> 61,2</td><td> 10,0</td><td>i₂</td><td></td>

<td>C</td><td> 45,0</td><td> 45,0</td><td> 10,0</td><td>H</td><td></td>

<td>D</td><td> 63,0</td><td> 27,0</td><td> 10,0</td><td>H</td><td>/ L_to</td>

<td>l₂</td><td>= phase</td><td>reverse micellar</td><td></td>

<td>I₂</td><td>= phase</td><td>liquid crystalline</td><td>inverse cubic</td>

<td>H</td><td>= phase</td><td>liquid crystalline</td><td>reverse hex</td>

<td></td><td>= phase</td><td>laminate</td><td></td>

Example 2

In Vitro Release of Water-soluble Substances

A water soluble dye, methylene blue (MB) was dispersed in formulation C (see example 1) to a concentration of 11 mg / g formulation. When 0.5 g of the formulation was injected into 100 ml of water, a rigid reverse hexagonal phase H formed. The absorbance of MB released to the aqueous phase was monitored at 664 nm over a period of 10 days. The release study was carried out in an Erlenmeyer flask at 37 ° C and with reduced magnetic stirring.

The MB release profile (see Figure 1) from the hexagonal phase indicates that these formulations (and the like) are promising depot systems. Furthermore, the formulation appears to provide a low initial release and the release profile indicates that the substance can be released over several weeks; only about 50% of MB is released after 10 days.

Example 3

Viscosity in PC / GDO (6: 4) or PC / GDO (3: 7) in the addition of solvent (EtOH, PG and NMP)

A PC / GDO / EtOH mixture was prepared according to the procedure of Example 1. All or almost all of EtOH was removed from the mixture with a rotary evaporator (in vacuo, 40 ° C, 1 h) and the mixture The resulting solid was weighed into a glass vial, after which 2, 5, 10 or 20% of a solvent (EtOH, propylene glycol (PG) or n-methyl pyrrolidone (NMP)) were added. Samples were allowed to equilibrate for several days before measuring viscosity with 0.1s shear.^-1 with a Physica UDS 200 rheometer at 25 ° C.

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This example clearly shows the need for solvents with certain depot precursors in order to obtain an injectable formulation (see figure 2). The viscosity of solvent-free PC / GDO mixtures increases with increasing PC ratio. Systems with a low PC / GDO ratio (more GDO) are injectable with a lower concentration of solvent.

Example 4

Composition and in vitro phase study

The formulations were manufactured according to a method described in example 1 with compositions according to table 2. An active substance (peptide), salmon calcitonin (sCT), was added to each formulation with a concentration of 500 pg sCT / g formulation. The formulations were prepared as homogeneous suspensions for parenteral administration (requiring mixing shortly before use since the drug is not fully dissolved in the PC / GDO / EtOH system).

The phase study in this example is carried out in an excess of rat serum at 37 ° C in order to simulate an in vivo situation. Table 2 shows the same phases as those formed in water (compare table 1).

TABLE 2

<td></td><td>Pc</td><td>GDO</td><td>OA</td><td>EtOH</td><td>Phase in</td>

<td>Formulation</td><td>(% in</td><td>(% in</td><td>(% in</td><td>(% in</td><td>serum</td>

<td></td><td>weight)</td><td>weight)</td><td>weight)</td><td>weight)</td><td>rat</td>

<td>AND</td><td> 18</td><td> 72</td><td> -</td><td> 10</td><td>L₂</td>

<td>F</td><td> 36</td><td> 54</td><td> -</td><td> 10</td><td>I₂</td>

<td>G</td><td> 34</td><td> 51</td><td> 5</td><td> 10</td><td>I₂</td>

<td>H</td><td> 54</td><td> 36</td><td> -</td><td> 10</td><td>H</td>

<td>I</td><td> 72</td><td> 18</td><td> -</td><td> 10</td><td>Hh / L · »</td>

<td>OA = acid</td><td>oleic</td><td></td><td></td><td></td><td></td>

Example 5

Sterile filtration of formulations with reduced viscosity

Reducing the viscosity with different solvents is necessary in some cases, in order to obtain an injectable formulation and to be able to administer the system with a normal syringe (see example 3). Another important effect of the viscosity reducing solvent is that the formulations can be filter sterilized.

The EI formulations of Example 4 were studied in a filter sterilization test using a 0.22 pm filter (before adding the active substance). Formulations EH were filtered satisfactorily, but with formulation I this was not achieved, since the viscosity was too high. Therefore, an aseptic manufacturing process was required for this formulation.

Example 6

Preparation of depot precursor compositions with different solvents

Depending on the composition of the formulation and the nature and concentration of the active substance, certain solvents may be preferable.

The depot precursor formulations (solvent / PC / GDO (36/54/10)) were prepared with various solvents; NMP, PG, PEG400, glycerol / EtOH (90/10) by the method of Example 1. All depot precursor compositions were solutions of a homogeneous phase with a viscosity that allowed injection via syringe (23 G, i.e. 23 gauge needle; 0.6mm x 30mm). After injecting formulation precursors into excess water, a highly viscous monolith liquid crystalline phase rapidly formed with precursors containing NMP and PG. The liquid crystalline phase had an inverse cubic micellar structure (I2). With PEG400 glycerol / EtOH (90/10) the viscosification / solidification process was much slower and initially the liquid precursor became a somewhat sticky soft material. The difference in appearance probably reflects the slower dissolution of PEG400 and glycerol with respect to the excess aqueous phase compared to that of EtOH, NMP and PG.

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Example 7

Preparation of a depot composition containing benzydamine

Benzydamine is a non-steroidal anti-inflammatory drug and is widely used as a topical drug in states of inflammation.

g of depot formulation containing 1.5 mg of benzydamine was prepared by dissolving the active substance in a mixture of PC / GDO / EtOH (36/54/10) prepared as described in Example 1. The depot compound was stable against crystallization during storage at 25 ° C for a minimum of two weeks. Equilibration of the formulation precursor with excess water resulted in a highly viscous monolithic liquid crystalline phase (structure I₂).

Example 8

Behavioral stability of the formulation against variations in the quality of the excipient

Depot precursor formulations with several different grades of GDO (supplied by Danisco, Dk), Table 3, were prepared using the procedure of Example 1. Final depot precursors contained 36% by weight PC, 54% by weight GDO and 10 % by weight of EtOH. The appearance of the deposit precursors was insensitive to the variation of the quality used and after contact with excess water a monolithic body with reverse micellar cubic phase behavior (structure I2) was formed.

TABLE 3

Proven GDO qualities

<td>GDO quality</td><td>Monoglyceride (% by weight)</td><td>Diglyceride (% by weight)</td><td>Triglyceride (% by weight)</td>

<td>TO</td><td> 10,9</td><td> 87,5</td><td> 1,6</td>

<td>B</td><td> 4,8</td><td> 93,6</td><td> 1,6</td>

<td>C</td><td> 1,0</td><td> 97,3</td><td> 1,7</td>

<td>D</td><td> 10,1</td><td> 80,8</td><td> 10,1</td>

<td>AND</td><td> 2,9</td><td> 88,9</td><td> 8,2</td>

<td>F</td><td> 0,9</td><td> 89,0</td><td> 10,1</td>

Example 9

Preparation of a reservoir composition containing saturated PC (Epikuron 200SH)

Depot precursor formulations with various amounts of PC comprising saturated hydrocarbon chains were prepared by adding Epikuron 200SH directly to a PC / GDO / EtOH mixture prepared as in Example 1. The formulations are shown in Table 4. All formulations are shown in Table 4. Precursor formulations were homogeneous one-phase samples at RT, although they became more viscous with an increase in the amount of Epikuron 200SH. Injection of the deposit precursor into excess water provided a monolith comprising a reverse cubic micellar structure (I2). Monoliths formed from samples containing higher amounts of Epikuron 200SH became cloudy, possibly indicating segregation between Epikuron 200SH and the other components when exposure to water and phase I2 formation occurred.

TABLE 4

Reservoir compound containing saturated PC

<td></td><td>Saturated PC,</td><td>Epikuron</td><td>PC (% in</td><td>GDO (% in</td><td>EtOH (% in</td>

<td>Formulation</td><td>200SH (% in</td><td>weight)</td><td>weight)</td><td>weight)</td><td>weight)</td>

<td>G1</td><td> 3,9</td><td></td><td> 34,6</td><td> 51,9</td><td> 9,6</td>

<td>G2</td><td> 7,0</td><td></td><td> 33,5</td><td> 50,2</td><td> 9,3</td>

<td>G3</td><td> 14,3</td><td></td><td> 30,8</td><td> 46,3</td><td> 8,6</td>

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Example 10

Bioadhesive spraying of a depot precursor formulation

A pump spray bottle was found to be a convenient way to apply the formulation topically, for example to the skin or oral mucosa.

A depot precursor formulation prepared as in Example 1 (36% by weight PC, 54% by weight GDO and 10% by weight EtOH) was sprayed with a pump spray bottle on the skin and oral mucosa. A film with marked mechanical characteristics was formed shortly after application.

Example 11

Stability of a topical film

After applying the depot precursor formulation, as described in Example 10 (36% by weight PC, 54% by weight GDO and 10% by weight EtOH) to the skin, the applied formulation was subjected to a bath of water (10 ml / min) for 10 minutes. The formulation showed excellent bioadhesive characteristics and resistance against washing and showed no loss of the formulation.

Example 12

Formulation of a cubic phase with stable characteristics after exposure of the deposition precursor formulation to air

After exposing a depot precursor formulation prepared as described in Example 1 (36% by weight PC, 54% by weight GDO and 10% by weight EtOH) to air (RT, 40% relative humidity) for a minimum of 3 hours, a solid cubic phase was formed. This cubic phase structure formation demonstrates that the topical film acquires non-laminar deposition characteristics in bulk after application without the need for direct exposure to excess aqueous fluid.

Example 13

Formulation to treat periodontitis or perimplantitis

In order to treat periodontitis or perimplantitis, an antibacterial formulation was injected into the periodontal pocket, normally desiring a prolonged effect of the formulation.

100 µl of the formulation were prepared as in example 1, with the addition of the antibiotic chlorhexidine (PC / GDO / EtOH / chlorhexidine (35/53/10/2)), and injected through a syringe into a rat periodontal bag . The injected composition is observed in its transformation from a low viscosity formulation that initially spreads filling the voids to form a solid mass by absorption of gingival fluid. An antibacterial reservoir system is thus achieved.

Chlorhexidine remains at clinically effective levels (MIC 125 pg / ml) in the GCF of periodontal pockets for more than a week. The reservoir system is completely degraded by enzymes within 7-10 days and does not need to be removed.

Example 14

Alternative antibacterial formulation to treat periodontitis or perimplantitis

An alternative antibacterial formulation is achieved by a formulation prepared, as described in Example 1, and containing the antibacterial detergent Gardol (glycine, N-methyl-N- (1-oxododecyl) -, sodium salt) (PC / GDO / EtOH / Gardol (34/51/10/5)). This formulation is injected into the periodontal pouch of the rat.

Gardol is observed to remain at clinically effective levels in the GCF of the periodontal pockets for a prolonged period of time (several days). The reservoir system is completely degraded by the action of enzymes within a period of 7 to 10 days and does not need to be removed.

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Example 15

Adhesion of the formulation to high energy surfaces

In order to treat perimplantitis, adherence not only to biological surfaces, but also to high-energy surfaces such as gold or titanium implants is important. It is also important that the formulation adheres to ceramic and plastic surfaces.

A formulation (PC / GDO / EtOH (36/54/10)) prepared as in Example 1 was applied to various surfaces in the oral cavity. The composition showed excellent adhesion to ceramic, plastic, gold and also to the normal tooth surface and could not be rinsed out by excess aqueous fluid. The resulting deposit of the composition remained in place in the oral cavity where it was applied for a minimum of 6 hours.

Example 16

Bioadhesive sustained release formulation of sodium fluoride for use on teeth

Fluoride compounds are frequently required to counteract caries attack and a precursor of a bioadhesive formulation with depot effect was prepared as indicated in Example 1 from a mixture of PC / GDO / EtOH / sodium fluoride (35/53 / 10/2). The formulation was a sodium fluoride dispersion since it could not be dissolved in the precursor. The liquid formulation was applied to the following with the help of a brush. Upon absorption of saliva, the formulation solidified and formed a deposit that provided sustained release of sodium fluoride over a prolonged period (several hours).

Example 17

Oral Cavity Spray Deposition Composition

To achieve its suitability as a topical deposit system in the oral cavity, the mechanical characteristics of the system were adjusted by reducing the PC / GDO ratio.

A mixture containing PC / GDO / EtOH (27/63/10) was prepared according to example 1. A drop of patent blue was added to visualize the formulation after application. About 300 µl of the formulation was sprayed into the oral cavity via a pump spray bottle. Shortly after application, the formulation became viscous / solidified as it underwent phase transformation by absorption of aqueous fluid (saliva) and loss of solvent (EtOH). The formulation had excellent bioadherence to keratinized surfaces such as the hard palate and gums. In this case, the film lasted several hours despite saliva secretion and mechanical tongue contact. On soft mucosal surfaces, the duration was much shorter (minutes).

Example 18

Composition of liquid reservoir for oral cavity

To be suitable for pipetting into the oral cavity, solidification / viscosification of the formulation has to be delayed relative to the spray formulation. This is to allow the formulation to be conveniently distributed with the tongue forming a thin film in the oral cavity after application.

Propylene glycol (PG) and EtOH were added to the formulation prepared as in example 1 with the final composition PC / GDO / EtOH / PG (24/56/10/10). 300 µl of the formulation was conveniently pipetted into the oral cavity and distributed with the tongue forming a thin film in the oral cavity. After about 20 seconds, the viscosification of the formulation began as it underwent a phase transformation by absorption of aqueous fluid (exit) and loss of solvent (EtOH and PG). After about a minute the solidification / viscosification seemed to be finished. The formulation had excellent bioadherence to keratinized surfaces such as the hard palate and gums. In this case, the film lasted several hours despite the secretion of saliva and mechanical wear produced by the tongue. On soft mucosal surfaces, the duration was much shorter (minutes).

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Example 19

Bioadhesive deposit for nails

The mixture from Example 18 was sprayed onto the nail bed and between the toes. The formulation solidifies / viscosifies slowly by absorption of aqueous fluids (sweat). Solidification can be accelerated by adding water after application of the spray. The formulation had excellent bioadhesive characteristics and a shelf life of several hours.

Example 20

Loading capacity of benzydamine as a bioactive agent in formulation precursors

Formulations with the compositions specified in Table 5 were prepared using the method of Example 1. An excess amount of benzydamine (50 mg) was added to 0.5 g of the formulations. The vials were placed on a shaker at 15 ° C for three days, after which the solutions were filtered through a filter (0.45 pg) to remove undissolved benzydamine crystals. The benzydamine concentration of each formulation was determined by reverse phase gradient HPLC and UV detection at 306 nm and the results are indicated in Table 5.

TABLE 5

<img file="ES2343641T3_D0002.tif" />

Example 21

Compositions containing PC and tocopherol

Depot precursor formulations with several different PC / α-tocopherol compositions were prepared using the method of Example 1 (PC was first dissolved in the appropriate amount of EtOH and then α-tocopherol was added to achieve clear homogeneous solutions).

Each of the formulations was injected into a vial and equilibrated with excess water. The behavior of the phase was evaluated visually and between cross polarizations at 25 ° C. The results are indicated in Table 6.

TABLE 6

<img file="ES2343641T3_D0003.tif" />

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Example 22

In Vitro Release of Water Soluble Disodium Fluorescein

A water soluble dye, disodium fluorescein (Fluo), was dissolved in a formulation containing PC / atocopherol / Ethanol (27/63/10% by weight) to a formulation concentration of 5 mg Fluo / g. When 0.1 g of the formulation was injected into 2 ml of a phosphate buffered solution (PBS), a reverse miscellar phase (I₂). The absorbance of Fluo released to the aqueous phase was followed at 490 nm over a period of 3 days. The release study was carried out in a 3 ml vial closed with a completely breakable aluminum cap at 37 ° C. The vial was placed on a shaking table at 150 rpm.

The release of Fluo from the PC / α-tocopherol formulation (see Table 7) indicates that these formulations (and others like them) are promising depot systems. Furthermore, the absence of a discharge effect is noteworthy, and the release indicates that the substance can be released over a period of several weeks to months; only 0.4% of Fluo is released after 3 days.

TABLE 7

<td>Formulation</td><td>% release 24 h</td><td>ion (37 ° C) 72 h</td>

<td>PC / a-tocopherol / EtOH: 27/63/10% by weight</td><td> &lt;0,1*</td><td> 0,43</td>

<td colspan="3">* Release below the detection limit of the absorbance test</td>

Example 23

Anti-inflammatory analgesic / benzydamine formulations

Formulations were prepared as in example 1, mixing benzydamine with a mixture of GDO, PC, ethanol and optionally PG / AP in the following proportions.

<td>Formulation</td><td>BZD</td><td>GDO</td><td>Pc</td><td>EtOH</td><td>PG</td><td>AP</td>

<td> 1</td><td> 3,0</td><td> 53,3</td><td> 28,7</td><td> 10,0</td><td> 5,0</td><td> 0,01</td>

<td> 2</td><td> 3,0</td><td> 53,3</td><td> 28,7</td><td> 15,0</td><td> 0</td><td> 0,01</td>

<td> 3</td><td> 3,0</td><td> 57,4</td><td> 24,6</td><td> 10,0</td><td> 5,0</td><td> 0,01</td>

<td> 4</td><td> 3,0</td><td> 49,2</td><td> 32,8</td><td> 10,0</td><td> 5,0</td><td> 0,01</td>

where BZD is benzydamine, EtOH is ethanol, PC is LIPOID S100 soy phosphatidylcholine, GDO is glycerol dioleate, PG is propylene glycol, and AP is ascorbyl palmitate.

All formulations are low viscosity liquids that generate liquid crystalline phase compositions when exposed to aqueous conditions.

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Example 24

Fentanyl nasal formulation

Formulations were prepared as in example 1, mixing the narcotic analgesic fentanyl with a mixture of GDO, PC, Ethanol and optionally PG in the following proportions.

<td>Formulation</td><td>Fentanyl</td><td>Pc</td><td>GDO</td><td>EtOH</td><td>PG</td>

<td> 1</td><td> 0, 05</td><td> 34</td><td> 51</td><td> 10</td><td> 5</td>

<td> 2</td><td> 0, 05</td><td> 36</td><td> 54</td><td> 10</td><td> -</td>

<td> 3</td><td> 0 , 05</td><td> 42</td><td> 43</td><td> 10</td><td> 5</td>

<td> 4</td><td> 0 , 05</td><td> 45</td><td> 45</td><td> 10</td><td> -</td>

<td> 5</td><td> 0,15</td><td> 34</td><td> 51</td><td> 10</td><td> 5</td>

<td> 6</td><td> 0,15</td><td> 36</td><td> 54</td><td> 10</td><td> -</td>

<td> 7</td><td> 0 , 05</td><td> 30</td><td> 45</td><td> 15</td><td> 10</td>

<td> 8</td><td> 0,15</td><td> 30</td><td> 45</td><td> 15</td><td> 10</td>

wherein EtOH is ethanol, PC is LIPOID S100 soy phosphatidylcholine, GDO is glycerol dioleate, and PG is propylene glycol.

All formulations are low viscosity liquids suitable for nasal spray administration, which generate liquid crystalline phase compositions on exposure to aqueous conditions.

Example 25

Diazepam nasal formulation

Formulations were prepared as in the previous examples by mixing the benzodiazepine anti-anxiety agent Diazepam with a mixture of GDO, PC, ethanol and optionally PG in the following proportions.

<td>Formulation</td><td>Diazepam</td><td>Pc</td><td>GDO</td><td>EtOH</td><td>PG</td>

<td> 1</td><td> 5</td><td> 32</td><td> 48</td><td> 10</td><td> 5</td>

<td> 2</td><td> 5</td><td> 34</td><td> 51</td><td> 10</td><td> -</td>

<td> 3</td><td> 10</td><td> 37</td><td> 38</td><td> 10</td><td> 5</td>

<td> 4</td><td> 10</td><td> 40</td><td> 40</td><td> 10</td><td> -</td>

<td> 5</td><td> 10</td><td> 30</td><td> 45</td><td> 10</td><td> 5</td>

<td> 6</td><td> 10</td><td> 32</td><td> 48</td><td> 10</td><td> -</td>

<td> 7</td><td> 10</td><td> 26</td><td> 39</td><td> 15</td><td> 10</td>

<td> 8</td><td> 10</td><td> 30</td><td> 45</td><td> 15</td><td> -</td>

wherein EtOH is ethanol, PC is LIPOID S100 soy phosphatidylcholine, GDO is glycerol dioleate, and PG is propylene glycol.

All formulations are low viscosity liquids suitable for nasal spray administration, which generate liquid crystalline phase compositions on exposure to aqueous conditions.

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Example 26

Formulations with Clindamycin for acne

Formulations were prepared as in the previous examples by mixing the semisynthetic antibiotic clindamycin (free base or salt) with a mixture of GDO, PC, ethanol and PG in the following proportions (by weight).

<td>Formulation</td><td>Clindamycin HC1</td><td>Pc</td><td>GDO</td><td>EtOH</td><td>PG</td>

<td> 1</td><td> 1</td><td> 30</td><td> 54</td><td> 10</td><td> 5</td>

<td> 2</td><td> 2</td><td> 29</td><td> 54</td><td> 10</td><td> 5</td>

<td> 3</td><td> 1</td><td> 34</td><td> 50</td><td> 10</td><td> 5</td>

<td> 4</td><td> 2</td><td> 33</td><td> 50</td><td> 10</td><td> 5</td>

<td> 5</td><td> 1</td><td> 30</td><td> 54</td><td> 10</td><td> 5</td>

<td> 6</td><td> 2</td><td> 29</td><td> 54</td><td> 10</td><td> 5</td>

<td> 7</td><td> 1</td><td> 33</td><td> 54</td><td> 2</td><td> 10</td>

<td> 8</td><td> 2</td><td> 32</td><td> 54</td><td> 2</td><td> 10</td>

The resulting preformulations are low viscosity liquids which, after application, are resistant to water, sweat, etc. The formulations are applied locally to the skin as a gel or by spraying and are bioadhesive with good film-forming characteristics.

Example 27

Other examples of viscosity in PC / GDO mixtures when adding a co-solvent

PC / GDO and co-solvent mixtures were prepared according to the methods of Examples 1 and 3 in the proportions indicated in the following table.

The samples were allowed to equilibrate for several days before carrying out viscosity measurements using a Physica UDS 200 rheometer at 25 ° C.

<td>Sample</td><td>PC / GDO (weight / weight)</td><td>EtOH / wt%</td><td>Glycerol% by weight</td><td>h₂or/% in weigh</td><td>Viscosity / mPas</td>

<td> 1</td><td> 50/50</td><td> 3</td><td> -</td><td> -</td><td> 1900</td>

<td> 2</td><td> 50/50</td><td> 5</td><td> -</td><td> -</td><td> 780</td>

<td> 3</td><td> 50/50</td><td> 7</td><td> -</td><td> -</td><td> 430</td>

<td> 4</td><td> 50/50</td><td> 8</td><td> -</td><td> -</td><td> 300</td>

<td> 5</td><td> 50/50</td><td> 10</td><td> -</td><td> -</td><td> 210</td>

<td> 6</td><td> 50/50</td><td> 15</td><td> -</td><td> -</td><td> 100</td>

<td> 7</td><td> 45/55</td><td> 3</td><td> -</td><td> -</td><td> 1350</td>

<td> 8</td><td> 45/55</td><td> 5</td><td> -</td><td> -</td><td> 540</td>

<td> 9</td><td> 45/55</td><td> 7</td><td> -</td><td> -</td><td> 320</td>

<td> 10</td><td> 45/55</td><td> 8</td><td> -</td><td> -</td><td> 250</td>

<td> 11</td><td> 45/55</td><td> 10</td><td> -</td><td> -</td><td> 150</td>

<td> 12</td><td> 45/55</td><td> 15</td><td> -</td><td> -</td><td> 85</td>

<td> 13</td><td> 40/60</td><td> 3</td><td> -</td><td> -</td><td> 740</td>

<td> 14</td><td> 40/60</td><td> 5</td><td> -</td><td> -</td><td> 400</td>

<td> 15</td><td> 40/60</td><td> 7</td><td> -</td><td> -</td><td> 240</td>

<td> 16</td><td> 40/60</td><td> 8</td><td> -</td><td> -</td><td> 200</td>

<td> 17</td><td> 40/60</td><td> 10</td><td> -</td><td> -</td><td> 130</td>

<td> 18</td><td> 40/60</td><td> 15</td><td> -</td><td> -</td><td> 57</td>

<td> 19</td><td> 40/60</td><td> -</td><td> 10</td><td> -</td><td> 8*10⁶</td>

<td> 20</td><td> 40/60</td><td> -</td><td> -</td><td> 3</td><td> 2,5*10⁸</td>

<td> 21</td><td> 40/60</td><td> -</td><td> -</td><td> 5</td><td> 4*10⁷</td>

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This example further shows the need for a solvent with decreasing viscosity characteristics in order to obtain injectable formulations. Mixtures containing glycerol (sample 19) or water (samples 20 and 21) are too viscous to be injected with solvent concentrations equivalent to samples containing EtOH (compare with samples 13, 14 and 17).

Example 28

Sunscreen formulations

Formulations were prepared as in Example 1, mixing each of several UV absorbing / dispersing agents with a mixture of GDO, PC and ethanol in the following proportions (by weight)

<img file="ES2343641T3_D0004.tif" />

where TIOVEIL CM (Uniqema) comprises Cyclomethicone (and) Titanium Dioxide (and) Dimethicone Copolyol (and) Aluminum Stearate (and) Alumina, SPECTRAVEIL FIN (Uniqema) comprises Zinc Oxide (and) C12-15 Alkyl Benzoate (and) Polyhydroxystearic Acid, SOLAVEIL CT-100 (Uniqema) comprises C12-15 Alkyl Benzoate (and) Titanium Dioxide (and) Polyhydroxystearic Acid (and) Aluminum Stearate (and) Alumina (and) TIOVEIL 50 MOTG (Uniqema) comprises Titanium Dioxide (and) Caprylic / Capric Acid Triglyceride (and) Mineral Oil (and) Polyhydroxystearic Acid (and) Aluminum Stearate (and) Alumina.

The resulting formulation precursors show low viscosity after formulation and are easily applied by pump spray. On contact with the body surfaces, a UV protective layer with elastic characteristics is formed.

Example 29

Chlorhexidine periodontal deposits

Formulations were prepared as in example 1, mixing the chlorhexidine digluconate anti-infective agent with a mixture of GDO, PC and ethanol in the following proportions (by weight)

TABLE

Chlorhexidine digluconate depot formulation compositions

<td>Formulation</td><td>Chlorhexidine digluconate</td><td>Pc</td><td>GDO</td><td>EtOH</td>

<td>TO</td><td> 5</td><td> 34</td><td> 51</td><td> 10</td>

<td>B</td><td> 5</td><td> 36</td><td> 54</td><td> 5</td>

<td>C</td><td> 7</td><td> 33</td><td> 50</td><td> 10</td>

<td>D</td><td> 10</td><td> 32</td><td> 48</td><td> 10</td>

<td>AND</td><td> 15</td><td> 30</td><td> 45</td><td> 10</td>

Chlorhexidine depot preformulations have low viscosity and are easily delivered to the periodontal pocket. The compositions provide better distribution and spread of the active substance throughout the periodontal pocket when compared to known products, such as Periochip®.

ES 2 343 641 T3

The deposit formed after application provides protection against reinfection of the bag. The deposit also has excellent bioadhesive characteristics and adheres to the surfaces of the mucosa, teeth and bones.

The release of 250 mg chlorhexidine digluconate from formulation A (see above) in 0.9% NaCl in aqueous solution (500 ml) was studied. The formulation was kept in a cylindrical metal pail placed on a Teflon holder at the bottom of a USP standard release bath. The contact area between the formulation and the surrounding saline solution was 2.4 cm² and the solution was stirred by paddle at 100 rpm.

The release curve shown in Figure 3 shows the sustained and essentially uniform release of chlorhexidine from the formulation over a 24 hour period.

Example 30

Topical formulation with NSAIDs

Diclofenac sodium is a non-steroidal anti-inflammatory drug (NSAID). It belongs to the phenylacetic acid group and is used in inflammatory states of different etiologies, degenerative joint diseases and many other pain states.

A formulation for topical administration containing diclofenac sodium was prepared by first preparing a placebo formulation.

Composition of the placebo formulation

<td>Excipient</td><td>Abbreviation</td><td>Concentration (%)</td>

<td>Phosphatidyl choline (from soy)</td><td>Spc</td><td> 45,0</td>

<td>Glycerol Dioleate</td><td>GDO</td><td> 45,0</td>

<td>Ethanol 99.5%</td><td>EtOH</td><td> 10,0</td>

Diclofenac sodium at a concentration of 5% was dissolved in the placebo formulation. The resulting oily liquid was slightly yellow in color, clear, and low in viscosity.

Example 31

Formation of liquid crystalline phase

A drop of diclofenac sodium containing the formulation of Example 30 was added to 3 ml of aqueous saline with a pipette. A cohesive liquid crystalline phase was formed.

Example 32

Formation of a rigid sheet in situ

A drop of diclofenac sodium containing the formulation of Example 30 was applied to the skin of the arm of a healthy volunteer and spread forming a thin film covering an area of ​​approximately 2-4 cm². Shortly after application, the liquid formulation was transformed into a much stiffer film by absorption of small amounts of water from the skin and / or from the air.

Example 33

Improvement of the spray pattern by reducing the viscosity

A placebo formulation with the composition indicated in the table of Example 30 was filled into a standard pump spray bottle. After priming the pump with the formulation, it could be applied to the skin with a suboptimal spray pattern.

By diluting the additional formulation with EtOH, the viscosity of the formulation decreased and at a corresponding EtOH concentration of approximately 25% the formulation could be applied in the form of nebulization.

ES 2 343 641 T3 to the skin. Spraying of the formulation to the skin of the arm of a healthy volunteer resulted in the formation of a rigid film after evaporation of EtOH and absorption of small amounts of water from the skin and / or air.

Example 34

Spray pattern improvement using compression pump device

A placebo formulation with the composition indicated in Table 1 of Example 30 was filled into a standard squeeze pump bottle. This device provided a satisfactory mist / aerosol and spray pattern. Spraying of the formulation on the skin of the arm of a healthy volunteer resulted in the formation of a rigid film after absorption of small amounts of water from the skin and / or air.

Example 35

Using a pressure actuated device

A placebo formulation with the composition as indicated in the table of Example 30 was filled in a pressure-driven spray device with a hydrocarbon propellant or with a HFC134a propellant, respectively. Both propellants were found to form low viscosity homogeneous mixtures with the formulation. Spraying the formulation onto the skin of the arm of a healthy volunteer resulted in the rapid formation of a rigid sheet after absorption of small amounts of water from the skin and / or air.

Example 36

Spray formulation with very low EtOH concentration

A formulation with the composition indicated in the following table was prepared by evaporating EtOH from the placebo formulation with the composition indicated in the table of Example 30 with the aid of a rotary evaporator (vacuum, 40 ° C). The resulting formulation had a high viscosity, but when mixed with propellant (hydrocarbon propellant or HFC-134a) and filled into a spray bottle, the formulation could be sprayed onto the skin of the healthy volunteer's arm where a film was formed. rigid after absorption of small amounts of water from skin and / or air.

Composition of the placebo formulation

<td>Excipient</td><td>Abbreviation</td><td>Concentration (%)</td>

<td>Phosphatidyl choline (from soy)</td><td>Spc</td><td> 49,0</td>

<td>Glycerol Dioleate</td><td>GDO</td><td> 49,0</td>

<td>Ethanol 99.5%</td><td>EtOH</td><td> 2,0</td>

Example 37

Treatment of different surfaces by varying the composition of the formulation

By varying the PC / GDO ratio in the formulation, it was possible to adjust the duration of the formulation in different places in the oral cavity. A formulation with the PC / GDO / EtOH (36/54/10) composition has preference in terms of adhesion to hard surfaces, such as teeth, while a formulation with the PC / GDO / EtOH (27/63/10) composition it was found to be more appropriate for the upper part of the palate.

ES 2 343 641 T3

Example 38

Formation of a liquid crystalline phase from precursors with different solvent mixtures

To improve the solubility of the active substance in the precursors it may be useful to change the solvent of the formulation. A series of different solvent mixtures were used in the formulation precursors (see table) and their ability to form a liquid crystalline phase was investigated after contacting them with an excess of an aqueous solution. One drop of each formulation was added to 3 ml of aqueous saline with a pipette. Regardless of the solvent (mixture) used, a coherent liquid crystalline phase was formed.

Composition of formulations

<td>Excipients</td><td>Composition (% by weight)</td>

<td>PC / GDO / EtOH</td><td> 45/45/10</td>

<td>PC / GDO / EtOH / NMP</td><td> 45/45/5/5</td>

<td>PC / GDO / EtOH / propylene carbonate</td><td> 45/45/5/5</td>

<td>PC / GDO / EtOH / dimethyl isosorbide</td><td> 45/45/5/5</td>

<td>PC / GDO / EtOH / dimethyl acetamide</td><td> 45/45/5/5</td>

<td>PC / GDO / EtOH / ethyl acetate</td><td> 45/45/5/5</td>

Example 39

Topical formulation with Testosterone Enanthate

A topical formulation containing 2% testosterone enanthate was prepared by mixing the components indicated in the following table. Shortly after applying the liquid formulation to the skin it was transformed into a much stiffer film by absorption of small amounts of water from the skin and / or from the air.

Composition of topical formulation with Testosterone Enanthate

<td>Component</td><td>Quantity (g)</td><td>Composition (% by weight)</td>

<td>Testosterone enanthate</td><td> 0,060</td><td> 2,00</td>

<td>Phosphatidyl Soy Choline</td><td> 1,323</td><td> 44,10</td>

<td>Glycerol Dioleate</td><td> 1,323</td><td> 44,10</td>

<td>Ethanol</td><td> 0,294</td><td> 9,80</td>

Legends of the figures

Figure 1. Cumulative release of MB from a deposit that forms an H phase_N reverse hex.

Figure 2. Decrease in the viscosity of the deposit precursor to the addition of solvents. PC / GDO (6/4) is a precursor of an H phase || reverse hexagonal and PC / GDO (3/7) is a precursor of a reverse cubic I2 phase.

Figure 3. Chlorhexidine release from formulation A, see example 33.