MXPA00011651A - Preparations for the application of anti-inflammatory, especially antiseptic agents and/or agents promoting the healing of wounds, to the upper respiratory tract and/or the ear - Google Patents

Abstract

Use of anti-inflammatory agents such as povidone iodine for the preparation of a pharmaceutical composition for the treatment of diseases of the upper respiratory tract and/or the ear which are susceptible to the administration of such agents.

Description

PREPARATIONS FOR THE APPLICATION OF ANTI-INFLAMMATORY AGENTS, ESPECIALLY ANTISEPTIC AND / OR AGENTS PROMOTERS OF WOUND HEALING, IN THE HIGH RESPIRATORY ROUTES AND / OR THE HEARING FIELD OF THE INVENTION The invention relates to preparations for the application of agents with anti-inflammatory properties, especially antiseptic and / or that promote wound healing, in the upper respiratory tract and / or the ear. The preparations are specifically applied to wounds, skin, mucous membranes and epithelial tissue without keratinizing mucosal type, especially ciliary epithelial tissue in the upper respiratory tract and / or the ears of humans and animals. In addition, the invention relates to a method for preventing or treating infections by the application of a pharmaceutical preparation.

BACKGROUND OF THE INVENTION A plurality of different antibiotic and antiseptic agents are known for the topical treatment of infectious diseases. A decisive disadvantage of the antibiotic agent is that the infectious bacterium has primary resistances and it is possible that it acquires secondary resistances against these agents. In addition, antibiotics quite often can lead to patient sensitization. The use, for example, of antiseptics that release halogen, such as povidone iodine, also known as iodine polyvidone or iodine-PVP, ie the iodine-poly (l-vinyl-2-pyrrolidin-2-one) complex, can prevent the resistances. Also, compared to antibiotics, antiseptic agents are very rarely allergenic. Currently, infectious diseases of the respiratory tract are treated with antibiotics. The application of antibiotic agents through the respiratory tract has been subject to several reviews and articles, however, with emphasis on the lower respiratory tract. Ramsey et al., For example, describes the intermittent administration of inhaled tobramycin in patients with cystic fibrosis, in "The New England Journal of Medicine", Volume 340, Number 1, 1999, p. 23-30. The aerosolization of imipenem / cilastatin to prevent acute lung injury induced by pseudomonas has been investigated by Wiener-Kronish in "Aerosolization of imipenem / cilastatin prevents pseudomonas-induced acute lung injury" (Journal of Antimicrobial Chemotherapy (1996) 38, p. 809-818).

The pulmonary applications of different antibiotic agents, such as benzyl penicillin, tobramycin or amikacin, for the treatment of infectious diseases, are described by Schreier in several recent reviews, for example, in "Pulmonary applications of liposomes" (Medical applications of liposomes, Papahadjopoulos and Lasic (eds.), Elsevier 1998). However, treatment with antibiotics induces the complications known to the experts. For example, patients suffering from acute or chronic laryngopharyngitis are often treated with antibiotics to relieve symptoms. Many times, this only induces resistance of the bacteria responsible for the symptoms. Many diseases of the respiratory tract are caused by viruses. A typical example, in the upper respiratory tract, is rhinitis. Antibiotics are ineffective in these cases and patients are not cured of infections. The use of antiseptics and / or wound healing promoting agents, for external application to humans and animals, is disclosed in our first patent EP 0 639 373. Specifically, it is shown therein that the liposomal preparations of iodine-PVP are applicable topically to the external part of the eye. These preparations, in general, are presented in the form of P1168 ^^^ cream, ointment, lotion, gel or a formulation of drops. Liposomes are well-known carriers for drugs and therefore the application of drugs in liposomal form has often been investigated. An overview related to the pulmonary delivery of drugs encapsulated in liposomes, in the therapy of asthma, is presented in the review "Pulmonary delivery of liposomes" (H. Schreier, in "Journal of Controlled Relay", 24, 1993, pp. 209-223). The physicochemical characterization of liposomal aerosols and also their therapeutic applications to the respiratory tract are shown in it. Drugs that have been investigated for pulmonary delivery through liposomes include, for example, anti-cancer agents, peptides, enzymes, antieismic and anti-allergenic compounds and as mentioned above, also antibiotics. The formulation of liposomal aerosols or aerosols of liposome powders, using for example a dry powder inhaler have also been described by H. Schreier in "Formulation and in vitro perfomance of liposome powder aerosols" (STP Pharma Sciences 4, 1994, p. 38-44). Although much attention has been paid to liposomes as drug carriers, as can be seen from the documents cited, it seems P1168 - - - - * - * * - * • - * »that there is no prior art related to liposomes and other particulates as carriers of anti-inflammatory agents, especially antiseptics and / or wound healing promoters, for applications in the body, especially in the upper respiratory tract, including the mouth, throat and nose and in the ear. Most of the prior art mentioned above is related to liposomal preparations. It should be understood that there are alternative drug carriers, of a similarly particulate type. These drug carriers can often be used and also in the context of this invention, instead of liposomes and include microspheres (usually comprise lipophilic polymers), nanoparticles, "Large Porous Particles" and molecules of drug substances coated individually, for example, made using pulse laser deposition (PLD) techniques. These PLD methods can be used to apply coatings to powdered drugs and to modify the surface properties and release rate in a variety of drug systems. Hereinafter, when reference is made to liposome or particulate carriers, it will be understood that this is to incorporate said alternative carriers, as well. It is known in the art that the administration of particles susceptible to inhalation through the respiratory tract can be carried out by nebulization or aerosolization of preparations of liposomes, microspheres, Large Porous Particles, PLD or nanoparticles or by inhalation of the dry powder of the preparation. respective. Apparently there is a notable lack of interest in the technique, to apply disinfectants to the inner parts of the body, except perhaps in extreme cases of septic complications that endanger life. In general, it seems that antibiotic preparations are preferred, even considering their disadvantages discussed above. An object of the present invention is to provide an anti-inflammatory, especially antiseptic or wound healing promoter preparation, that is well tolerated, easily applicable, that provides prolonged release and a prolonged topical effect of the active agent in the lower respiratory tract. According to the invention, this object is achieved since the preparation comprises at least one anti-inflammatory agent, especially antiseptic and / or wound healing promoting agent, in the form of a preparation P11S8 particulate carrier, as defined in independent claim 1. The invention further comprises a method of treating the upper respiratory tract, in humans and 5 animals, as defined in independent claim 25. The dependent claims further define advantageous embodiments of the invention. In the context of the invention, it is considered that the upper respiratory tract generally includes the mouth, nose and throat areas, the larynx and the area below it and exclude areas of the external facial skin of the upper respiratory tract. mouth and nose The upper respiratory tract thus includes those parts that can be considered within the body. In the same context, it is generally considered that the ear includes those parts that remain inside the skull, but that are accessible from the outside of the skull. In general, they will include the passages of the outer ear and in some cases the middle ear, 20 but will exclude the inner ear and also the parts of the outer ear that surround the ear orifice, on the outside of the skull. In the context of this invention, it is understood that anti-inflammatory agents include antiseptic agents, antibiotic agents, corticosteroids and P1168 jM-MMi-fc -. ^ - ^^^ *. . . . . , - «-, - ^^ - - ... ..., ¡. .. < .-... i. , »Ata,, > -. wound healing agents, as defined below. In the context of this invention, antiseptic agents are understood to include those disinfectants which are pharmaceutically acceptable and suitable for the treatment of the upper respiratory tract, to the extent that they can be formulated according to the invention. More specifically, antiseptic agents include, among others, compounds that release oxygen and halogens; metal compounds, for example, silver and mercury compounds; organic disinfectants including formaldehyde releasing compounds, alcohols, phenols including alkyl- and arylphenols, as well as halogenated phenols, quinolines and acridines, hexahydropyrimidines, quaternary ammonium compounds and iminium salts and guanidines. Wound healing agents comprise agents that promote granulation and epithelization, for example, dexpanthenol, allantoins, azulenes, tannins and vitamin B type compounds. The precedent precedent of the invention is that particulate carriers, especially liposomes, although also the microspheres, nanoparticles and molecules of coated drug substances are quite suitable as carriers for antiseptic agents, especially for povidone iodine and agents that promote wound healing, for application in the upper respiratory tract. The preparations according to this invention allow the prolonged release of the agent or agents and provide a prolonged and topical activity at the desired site of action, by interaction with cell surfaces. In another aspect, the invention is based on a surprising and unexpected additional fact. It is well known in the art that the formation of new body tissue can cause problems. Thus, it is known that the repair of the body tissue can be accompanied by the formation of scar tissue, which can be detrimental from a functional and / or cosmetic point of view or at least undesirable. Hyperkeratosis and the uncontrolled proliferation of tissue can cause serious damage that leads to dysfunctions and, of course, can also be cosmetically undesirable. After infections and inflammations, the recovery or scarring of tissue can cause neoplasms and intergrowth. It is well known in the art that in the cure of diseases, proper remodeling of tissue is not only desirable, but in fact necessary.

P1168 ^^^^^ ^^^^^ gSggsg ^ Now, it has been found with surprise that the use of anti-inflammatory agents, alone or in combination with other agents of this type, leads to a markedly less formation of undesirable body tissue in the course of tissue repair and other tissue growth processes. In this way, the formation of scar tissue is reduced, in the skin and also in the mucosa and in other tissues, such as muscle tissue or that of internal organs. Hyperkeratosis can be completely suppressed and the intergrowth or formation of neoplasm in the cure of non-infectious diseases is also greatly reduced. An object that is achieved by the invention is therefore related to an improved tissue repair in the body. This is achieved by the invention through the application of anti-inflammatory agents, in the form of a particulate carrier preparation as defined in the independent claims. The anti-inflammatory, antiseptic and / or wound healing promoter preparation can be administered to the respiratory tract by means of a nebulizing agent charged in the particulate carrier preparation or by inhalation of dry powder of the respective preparation. For example, a liposome preparation can be made by loading liposomes with PVP iodine by a conventional procedure. It is also possible to compress the charged liposomes, optionally together with auxiliary materials, such as low molecular weight sugars, preferably lactose, into a strongly compressed solid drug reservoir. This stock of medicament can then be rubbed or micronized or otherwise treated to give the powder in the form of a particle. The resulting liposome preparation can be administered by inhalation of the preparation in the form of an aerosol powder, for example as described in "Acute Effects of Liposome Aerosol Inhalation on Pulmonary Function in Helathy Human Volunteers" (Thomas et al., Preliminary report , Volume 99, 1991, p.1268-1270). The pressures for preparing the stock of strongly compressed solid medicament are preferably in the range between 50 and 500 MPa. Said drug pool is described in WO 94/14490 and a device for administration is disclosed in WO 93/24165. In general, the nature or constitution of liposomes is not critical. The liposome preparation, for example as described in EP 0 639 373, can be administered to the nose or throat as an aerosol, for example, a pump spray. For applications in the oral cavity, the preparations of the invention, of P1168 preference is formulated as a spray with pump, a gel or a rinse solution. The disclosure of EP 0 639 373 is considered part of the present, for reference. The preparations according to this invention apparently do not contain only the active agent, such as povidone iodine, encapsulated in the particulate carrier, especially in liposomes. It seems that there is also some amount of agent that is not contained within the carrier. The preparations according to the invention often show a marked initial effect which is observed in addition to the slower prolonged release of the active agent from the carrier. This effect is observed especially when the carrier contains liposomes. Without wishing to be limited to a theoretical explanation, it is now assumed that in addition to the active agent encapsulated within the liposomes, some active agent is present outside the liposomes and probably in a dispersed form adhered to the outer surfaces of the liposomes. This may be due to the association of the active agent molecules with the liposome membrane or the active agent molecules that form a layer on the liposome surface, this layer partially or even completely coats the liposome externally. The type and quantity of this initial effect of the agent may be influenced, for example, by the choice of concentration parameters.

Amphiphilic substances known generally in the prior art to form liposomal membranes may be used in the context of the invention, provided that they are pharmaceutically acceptable for the intended application. At present, liposome-forming systems comprising lecithin are preferred. Such systems may comprise hydrogenated soy lecithin in addition to disodium cholesterol succinate hexahydrate; it is specifically preferred to use hydrogenated soy lecithin as the sole membrane forming agent. The methods known in the prior art for forming liposomal structures are described in the documents cited above and can generally be used in the context of the invention. In general terms, these methods comprise mechanical agitation of a suitable mixture containing the membrane-forming substance and water or an aqueous solution. Filtration through suitable membranes is preferred to form a practically uniform liposome size. The average size of the liposomes according to this invention can vary over a wide range, usually from about 1 to 20,000 nm. Liposomes with diameters in the range of about 50 to 4,000 nm are preferred. The liposomes with P1168 diameters of approximately 1000 nm are actually the most preferred, for example for gel applications. For solutions, the smallest average diameters are the most suitable. When alternative particulate carriers are used, they are usually prepared as is known in the art. In this way, microspheres that are used to deliver a very wide range of therapeutic or cosmetic agents are made in the manner described, for example, in WO 95/15118. In some cases nanoparticles may be used, with the proviso that they can be loaded with a sufficient amount of active agent and can be administered to the lower respiratory tract, according to this invention. They can be prepared according to methods known in the art, such as those described by Heyder (GSF München) in "Drugs delivered to the lung, Abstracts IV, Hilton Head Island Conference, May 1998. Methods using a deposition apparatus by pulse laser (PLD) and a polymeric target to apply coatings to powdered drugs in a non-aqueous short process, they are also suitable for the formation of particulate preparations according to this invention, which have been described, for example, by Taiton et al. ., "Novel Coating Method for Improved Dry Delivery", Univ. Of Florida P1168 UF 1887 (1998). Another suitable supply system employs Large Porous Particles such as those exhibited by David A.

Edwards et al. in "Large Porous Particles for Pulmonary Drug Delivery" (Science, 20, June 1997, Vol. 276, pp. 1868-1871). Preferred anti-inflammatory agents comprise antiseptic agents, antibiotics, corticosteroids and wound healing promoters, as substances alone or in combination with each other. Preferred antiseptic agents comprise the well-known pharmaceutical substances that provide rapid effect, a wide range of activity, low systemic toxicity and good tissue compatibility. They may be selected, for example, from the group comprising metal compounds, phenolic compounds, detergents, iodine and iodine complexes. A preferred antiseptic agent is povidone iodine. Preferred wound healing promoting agents comprise substances which for said application are described in the literature. These preferred agents include substances that are known to promote epithelization. These include vitamins, specifically B vitamins, allantoin, some sugars, etc.

Some presently preferred embodiments of the invention comprise anti-inflammatory agents or combinations thereof that show positive effects in tissue repair, especially with respect to the remodeling of functional and cosmetic tissue. In these modalities, the active agent is often an antiseptic, such as iodine-PVP or an antibiotic. In preferred embodiments, the preparations of the invention containing anti-inflammatory, especially Antiseptics and / or wound healing promoting agents may also comprise agents of the anesthetic type. The preparations of the invention may also contain other commonly used agents, including adjuvants and additives, antioxidants, preservatives or consistency-forming agents as additives for adjusting viscosity, emulsifiers, etc. In general, the concentrations in the preparation, particle sizes, active agent loads, etc., in the case of alternative carriers, are will be selected so that they basically correspond to the parameters discussed herein with respect to liposomal preparations. Selecting and providing these parameters, among others, based on a simple experimentation, is within the reach of a person with ordinary experience in this technique.

P1168 ** Byyy-ry & t? Á m & amp; & amp; At present, a rather preferred use of the liposomal preparations of the invention is the local treatment of nose, mouth and throat infections, especially when the liposomal preparations contain povidone iodine. Also in this indication, the antiseptic preparations of the invention, especially those containing iodine PVP, have the great advantage of not causing resistances and of inducing much less allergic reactions, while permitting a very cost-effective therapy with an effect of spread spectrum. A povidone iodine liposomal preparation according to this invention is effective, for example, against viruses such as herpes simplex. This effect is not provided by the antibiotic agents. In addition a liposomal preparation of a microbicidal agent such as povidone iodine, provides prolonged release of the agent from the liposomes, in the nasal or oral mucosa. This leads to a prolonged effect of the antimicrobial substance and thus to a less frequent application, in comparison with the preparations of antiseptic solution in common use. The present invention is also useful in the treatment of infectious diseases or for the relief of diseases such as HIV infections that are accompanied by opportunistic infections. Also patients who have suppressed the immune system, for example, after organ transplantation, can be treated according to the invention. In particular, chronic laryngopharyngitis and angina can be treated with the povidone iodine preparation according to the invention. Another rather preferred use is in tissue repair, especially in the remodeling of functional and cosmetic tissue. The preparations according to this invention may have a variety of forms, which are suitable for administration through the upper respiratory tract and the ear, including solid or liquid pharmaceutically acceptable formulations. The preparations according to this invention can therefore be in the form of an aerosol (powder) or in the form of a compressed solid drug reservoir, preferably a circular tablet, more preferably a gelatin capsule, a powder, a spray, an emulsion , a dispersion, a suspension or a solution containing the carrier and the agent or agents. They can be in the form of a gel or some other form of semisolid, viscous or solid application, for application, for example, in the buccal cavity. In general, the amount of active agents in a preparation of the invention will be determined on the one hand by the effect desired and on the other by the transport capacity of the carrier preparation for the P1168 agent. For preparations of the invention having large amounts of active agents or high doses of active agent, solid, liquid or gel preparations are often preferred for nebulized preparations or aerosols or for powdered powders or aerosols. In general terms, the amount of active agent in the carrier preparation of the invention can vary in concentrations between the lower limit of effectiveness of the agent and the maximum load of the agent in the respective carrier preparation. More specifically, for an antiseptic agent, such as povidone iodine, a solution or dispersion in a carrier preparation of the invention, especially when the carrier is a liposomal preparation, may contain between 0.1 and 10 g of agent in 100 g of preparation. Such preparation will normally have a content between 1 and 5 g of liposomal membrane-forming substance, especially lecithin, per 100 g of preparation. In a lotion, which may be a hydrophilic or lipophilic lotion, a typical range of active agent will be between 0.5 and 10 g of agent and between 1 and 5 g, preferably about 4 g of agent; Liposomal membrane former, such as hydrogenated soy lecithin, per 100 g of lotion. In the case of a hydrophilic lotion, electrolyte solution will often be used to P1168 prepare the lotion containing the liposomes. A lipophilic lotion will generally be made from the agent, the membrane forming substance and lipophilic forming agents, for example medium length chain triglycerides, etc. A hydrophilic cream comprising a liposomal preparation of the invention, will generally comprise between 0.1 and 10 g of agent, such as povidone iodine, together with approximately between 1 and 10 g of membrane forming substance and other typical oil / water cream-forming additives, per 100 g of cream. A comparable amphiphilic cream according to the invention will have similar contents of agent and membrane forming substance such as lecithin and will usually have the additional additives typical of an amphiphilic cream. A hydrophilic ointment according to the invention, in general terms can comprise between 0.1 and 10 g of Agent and between 1 and 10 g of membrane-forming substance such as lecithin, together with typical ointment base substances of the prior art, such as Macogrol (MR, registered trademark) and water, in 100 g of ointment. A non-alcoholic hydrogel according to the invention, in General can comprise between 1 and 5 g of eigen as the P1168 povidone iodine, approximately 2 g of lecithin and gel-forming substances such as Carbopol (MR), with pH and water regulating agents to form 100 g of hydrogel. An aerosol or spray preparation of the invention will often comprise up to 50 mg, although it could comprise up to 100 mg and more of liposomal active agent formulation, per spray dose unit. The spray preparation will generally comprise at least 10% by weight of active agent such as PVP-Iodine in the charged liposomes (or alternative carrier particles), but can comprise up to 50% by weight or even more of active agent. When the active agent is iodine-PVP, the amount of available iodine will generally be approximately 10% by weight (based on the Iodine-PVP). From the examples of modalities, more specific formulations will be evident. The features and advantages of this invention will be seen in greater detail from the subsequent description of the preferred embodiments. In these embodiments that include the best form, povidone iodine is exemplified as an antiseptic agent and the liposomes are selected as carrier. However, this should not be considered as a restriction of this invention to antiseptic agents or among antiseptic agents, to the P1168 povidone iodine and / or liposomes as the carrier, although such preparations are specifically preferred. A preferred method for producing the liposomes of the invention, can generally be described as follows: The lipid membrane-forming components, for example, lecithin, are dissolved in a suitable solvent, for example, chloroform or a mixture 2: 1 of methanol and chloroform and filtered under sterile conditions. Then, a lipid film is produced on a sterile substrate of high surface area, for example glass beads, by controlled evaporation of the solvent. In some cases, it may be sufficient to form the film on the inner surface of the container used to evaporate the solvent, without having to use a specific substrate to increase the surface. An aqueous system is prepared from electrolyte components and the active agent (one or more) to be incorporated into the liposome preparation. An aqueous system of this type may comprise, for example, 10 mmol / l of hydrogenated sodium phosphate and 0.9% of sodium chloride at pH 7.4; the aqueous system will furthermore comprise at least the desired amount of the active agent, which in the exemplary embodiments is povidone iodine. Many times, the aqueous system will comprise a P1168 ^^ ¡^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ ^^^^ * ^ ^ excess amount of agent or agents. In general, liposomes are formed by agitating the aqueous system in the presence of the film formed by the lipid components. In this stage, other additives can be added to improve liposome formation; for example, sodium cholate can be added. The formation of liposomes can also be influenced by mechanical action, such as pressure filtration, for example, through polycarbo membranes or centrifugation. In general, the base liposomal dispersion will be subjected to washing, for example, with electrolyte solution as used to prepare the active agent solution described above. When the liposomes with the required size distribution have been obtained, they can be redispersed in an electrolyte solution such as the one already described, which often comprises sugars, such as sucrose or a suitable sugar substitute. The dispersion can be dried by freezing and lyophilized. Before use, it can be reconstituted by the addition of water and suitable mechanical stirring at the transition temperature of the lipid component, which for hydroged soy lecithin is, for example, 55 ° C. In the following Examples, hydroged soy lecithin (EPIKURONMR) 200 SH was used P1168 L by Lukas Meyer, Germany or PHOSPOLIPONMR 90 H available from Nattermann Phospholipid GmbH, Germany). However, instead of lecithin, other pharmaceutically acceptable liposome membrane forming substances can be used and it will be easy for the person skilled in the art to select alternative liposome forming systems, from what is described in the prior art.

Eiemplificative Mode I In a 1000 ml glass flask, equipped with glass beads to increase the surface area, 51.9 m of cholesterol and 213 mg of hydrogenated soy lecithin were dissolved in a sufficient quantity of a mixture of methanol and chloroform in the proportion of 2: 1 Then, the solvent was evaporated in vacuo, until a film formed on the inner surface of the flask and on the glass beads. Separately 2.4 g of PVP iodine (containing about 10% available iodine) were dissolved in 12 ml of water. Again in a separate vessel, 8.77 g of sodium chloride and 1.78 g of Na2HP04.2H20 were dissolved in 400 ml of water. More water was added until a total volume of 980 ml was added and then added P1168 approximately 12 ml of IN hydrochloric acid to adjust the pH to 7.4. Water was added to this solution until it had exactly 1000 ml. In a fourth vessel, 900 mg of sucrose and 57 mg of disodium succinate were dissolved in 12 ml of water. The PVP iodine solution was then added to the lipid film in the flask and the mixture was stirred until the film dissolved. This resulted in the formation of liposomes from the hydrated lipids in the flask. The product was centrifuged and the supernatant liquid discarded. The 12 ml of the sucrose solution was added and the product was centrifuged again. Then, the supernatant liquid was discarded again. In this step, an additional washing step can be performed, using the sucrose solution or the sodium chloride buffer solution. After the last centrifugation step and the supernatant was discarded, sodium chloride buffer was added to make up 12 ml and the liposomes were homogeneously distributed therein. The product was divided into vials, given one with a content of 2 ml of liposome dispersion, and subjected to a freeze drying step. After freeze drying, each vial comprised approximately 40 mg of solids.

P1168 The method of the Exemplary Modality I has a minor disadvantage, since the PVP iodine solution used, due to the high percentage of solids, is more viscous and thus more difficult to handle.

Modality E? II In a 2000 ml flask fitted with glass beads to increase the surface, 173 mg of hydrogenated soy lecithin and 90 mg of disodium succinate were dissolved in approximately 60 ml of a methanol / chloroform mixture in a ratio of 2: 1 . The solvent was removed in vacuo until a film formed. 4 g of PVP iodine (10% of available iodine) were dissolved in 40 ml of the sodium chloride buffer solution described in Exemplary Modality I and added to the lipid film in the flask. Then the flask was shaken until the film dissolved and the liposomes formed. The product was centrifuged and the supernatant liquid discarded. To the liposomal peliet produced in this manner, sodium chloride buffer solution was added to make up 40 ml and the centrifugation step was repeated. Again the supernatant was discarded. At this stage, the washing step could be repeated, if P1168 necessary. After the final centrifugation and decantation steps, sodium chloride buffer was again added to the precipitated liposomes, until 40 ml was completed. The homogeneous dispersion was then distributed in vials, each vial with a content of approximately 2 ml of liposome dispersion and they were subjected to a freeze drying step. This produced approximately 200 mg of frozen dried solids, per vial. From the frozen dried solids of Examples I and II, additional preparations were made as described in the Exemplary Modalities and the following Test Reports. As in the Exemplary Modality I, the aforementioned method uses a hydration step after film formation in the presence of organic solvents and reaches inclusion rates of 5 to 15%. These methods usually produce larger and often multilamellar liposomes. The aforementioned methods can be modified by a high pressure filtration step through a suitable membrane, for example, a polycarbonate membrane after the polycarbonate membranes have been formed.

P1168 crude liposomes or after one of the subsequent washing steps or directly using high pressure homogenization. This produces much smaller unilamellar liposomes with respect to increased amounts of encapsulated agent. Instead of high pressure homogenization, other methods of the prior art known to provide uniform small size liposomes may be employed.

Emulsifying Modality III A hydrophilic cream (oil / water) was prepared from 10 g of hydrogenated soy lecithin / PVP iodine liposomes such as those described in Exemplary Modality II; these were mixed with 4 g of Polysorbate ™ 40, 8 g of cetylstearyl alcohol, 8 g of glycerol, 24 g of white petrolatum and water of up to 100 g.

Eiemplificative Modality IV An amphiphilic cream was prepared from 10 g of hydrogenated soy lecithin / povidone iodine liposomes as described in Exemplary Modality II; 7.5 g of triglycerides of medium chain length, 7 g of polyoxyethylene glycerol monostearate, 6 g of cetylstearyl alcohol, 8 g of propylene glycol, 25 g of white petrolatum and water of up to 100 g.

P1168 ^^^^^^^^^^^^ _ B ^ _ ^ _ ^^^^^^^^^^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^ B ^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^^ _ ^ _ ^^^ _ ^^^ _ ^ _ ^ _ ^^ _ ^ _ ^ _ ^ _ ^ _ ^ _ ^^^^ ¿^^ _ ^ _ ^^ L ^^^^^^^^ Eiemplificative Mode V A hydrophilic ointment was prepared, which can be rinsed with water, using liposome PVP iodine as described in Exemplary Modality II, 55 g of Macogrol ™ 400, 25 g of Macogrol ™ 4000 and water up to 100 9- Eiemplificative Modality VI A hydrogel was prepared from 4 g of liposomal PVP iodine as described in Exemplary Modality II, 0.5 g of Carbopol® 980 NF, sodium hydroxide to pH 7 and water to 100 g. Further modifications to the aforementioned modalities are conceived. In this way, the creams of leis Modalities Exemplary III and IV may have an additional content of a known agent to promote wound healing, such as allantoin. Said agent will be added to a pharmaceutically useful concentration, in the case of allantoin, in the range between 0.1 and 0.5 g per 100 g of cream. The wound healing agent can be incorporated into the base cream, in this case a large part will be outside the liposomes. However, it can be partially or completely incorporated in the liposomes, in which case it will be added at the appropriate stage P1168 corresponding to the method of preparing the liposomes. Similar alternatives are easily conceived based on the additional Exemplary Modalities. It is also possible to prepare modalities similar to those mentioned above, comprising an agent having the ability to promote wound healing, instead of the antiseptic agent and not in addition to it, for example, of the povidone iodine described in the Exemplary Modalities. previously mentioned 10. At present, however, it is preferred to use a wound healing promoting agent (if any) in addition to the antiseptic agent. For the application of the preparations of the invention to a patient, the known systems 15 can be used, such as applicators with pneumatic pumps, two-chamber gas pressure gaskets, aerosol spray dispensers, etc. In a pneumatic pump applicator, a bellows device is disposed between a water valve 20 upstream and a downstream valve, the two valves operate in a way in the same direction. A pharmaceutical preparation supply, for example ointment or gel, is contained in a reservoir upstream of the valve and bellows device. 25 When the bellows is compressed, the water valve P1168 ^ jaa »fa ^ aM¡jÉjMlllgjgMttM ^^ j ^^ | ^^ b < i | j ^^^^^^^ MM ^^ Mumiii ii ii - * * "* *" • - * 1"* - * '< > * j-wWM-ftJt ^ below opens and allows A dosed amount of preparation comes out of the device for application When the bellows extends, this valve closes and prevents the preparation from re-entering. At the same time, the upstream valve opens and allows the preparation of the reservoir to enter the bellows, so that it is released through the downstream valve, in the next compression step of the bellows. The reservoir is sealed by a closure element that can move through the reservoir as a piston moves in a cylinder. By emptying the reservoir step by step, this closing element is absorbed in the reservoir, so that the remaining amount of pharmaceutical preparation in it is always enclosed, while at the same time the reservoir can be emptied. A device of this type is useful for pasty preparations, creams, ointments, etc. In a two-chamber gas pressure package, the pharmaceutical preparation is contained in a bag of flexible plastic film material. Frequently, this is high pressure polyethylene. The bag is contained inside a gas tight pressure vessel, which also contains a supply of pressurization gas, many P1168 times an inert gas compressed as nitrogen or air. The plastic film bag has only one outlet, which is airtight to the passage of gas connected to the inner wall of the pressure vessel, which surrounds only one opening thereof. The pressurized gas in the container tends to compress the bag, directing the pharmaceutical preparation into the bag out of the opening of the bag and thus through the opening of the container. A valve and, if applicable, a sprinkler, are provided in the mouth of the container. By operating the valve, a spray mist, a jet of liquid or a portion of solid with ease to flow, for example, cream, is released. Using a system of this type it is possible to dose and apply solutions, emulsions, creams, ointments and gels. Using the preparations of the invention, efficiency tests were carried out, in the following manner: Test I This was an in vi tro test of the bactericidal effect provided by a liposomal povidone iodine preparation of the invention. The test was based on the quantitative suspension test as described in "Richtiinien der Deutschen Gesellschaft für Hygiene und P1168 ^ píhpni -mifiaittflÉlftí- nimßáí ..

Mikrobiologie ", 1989. In this test, the bactericidal agent is used to kill staphylococcus aureus (ATCC 29213), an important problem in the hygiene of hospitals.

Exemplary Modality I. At different contact times between 1 and 120 minutes, the minimum concentration of the preparation in water that had the ability to kill staphylococci was determined. These results are shown in Table 1. TABLE 1 Contact Time (Minutes) Bactericidal Concentration 1, 2, 3, 4 > 0.060% 5, 30, 60 > 0.015% 120 > 0.007% The results show that at short contact times (between 1 and 4 minutes) the bactericidal concentration is as low as 0.06% and that at long contact times (120 minutes) the bactericidal concentration can be as low as 0.007%.

Test II The virucidal and chlamydial activity of liposomal iodine PVP has been studied in cell cultures by P1168 Wutzler et al., 9th European Congress of Clinical Microbiology and Infectious Diseases, Berlin, March 1999. In cell cultures, liposomal iodine-PVP is quite effective against herpes simplex virus type I and adenovirus type 8, whereas Long-term cytotoxicity experiments indicated that the liposome form is more tolerated than aqueous iodine-PVP by most of the cell lines that were tested. Iodine-PVP in liposomal form is not genotoxic.

Test III A 3% iodine-PVP hydrogel liposomal preparation was compared to a 3% PVP-iodine ointment in which the active agent was not in liposomal form. The agent was applied to standardized in vitro cultures of rat skin and peritoneal explants, such as tapping for tissue compatibility of the skin and anti-infective for wounds. The growth rate of the cultured explants was studied after 30 minutes of exposure and incubation with a test substance. Again, the considerably good tolerance of the liposome preparation was clearly demonstrated with the results, in terms of peritoneal growth rate and skin growth rate.

P1168 ^^^^^^^^^ ij ¡sÉ With the ointment, the peritoneal growth rate reached 85% and the skin growth rate reached 90%; with the liposomal hydrogel formulation, the peritoneal growth rate was 96% and the skin growth rate was 108%; these values were compared with 100% values in a control test using Ringer's solution as the agent.

Test IV Tolerance of liposomal iodine-PVP solutions in nasal applications was studied by investigating the influence of different test substances on cells of ciliated epithelium, the most sensitive cells of the mucous membrane. Cytotoxic damage of these cells that would cause a restriction of mucociliary clearance could be determined by a detectable decrease in ciliary vibration. Human ciliated epithelial cells were analyzed by an in vitro method that allows the determination of ciliary activity or ciliary vibration. The corresponding cells were exposed and incubated with 100 μl of test substance at a temperature of 37 ° C. After the incubation period of 5 minutes the ciliary vibration was measured. Using this in vitro method, a P1168 nutrient solution (Dulbeco) as standard, a 0.2% chlorhexidine solution (typical antiseptic agent), conventional polyvidone iodine solutions (Betaisodona®) of different concentrations (iodine-PVP at 5.0%, 2.5% and 1.25%) and a liposomal solution with a iodine-PVP content of 4.5%. The considerably good tolerance of the liposome preparation was clearly demonstrated with the following results: if the ciliated epithelial cells were exposed to the Betaisodona solutions containing 5.0% or 2.5% iodine-PVP, it was not possible to observe ciliary activity after the incubation period. The treatment of the cells with a chlorhexidine solution led to a decrease in the measured ciliary vibration compared to the standard (nutrient solution). The solution of Betaisodona little concentrated that contained iodine-PVP at 1.25%, did not cause a decrease in ciliary activity susceptible to be detected. With respect to the measured ciliary vibration, differences with the standard (nutrient solution) could not be determined by exposing the human ciliated epithelial cells to the concentrated liposome solution of 4.5% iodine-PVP. The results indicate that the liposomal formulation is well tolerated for nasal application and has advantages with regard, for example, to the P1168 , -AI ttufcjj '-' - * -? - rp ~ &S Chlorhexidine or conventional Betaisodone solutions. P11S8

Claims (47)

1. CLAIMS; A process for the manufacture of a pharmaceutical preparation for the application of anti-inflammatories, especially antiseptic agents and / or agents that promote wound healing, in the upper respiratory tract and / or ear, characterized in that the preparation contains at least minus one of the agents combined with a particulate carrier, the preparation does not contain additional surfactants that do not form liposomes. The process according to claim 1, characterized in that the particulate carrier comprises at least one liposome preparation, a preparation of microspheres, a preparation of nanoparticles, a preparation of Large Porous Particles or a preparation of molecules coated with polymer by pulse laser . 3. The process according to claims 1 or 2, characterized in that at least the major part of the agent is encapsulated within the carrier, especially a liposome or microsphere carrier. 4. The process according to any of claims 1 to 3, characterized in that the anti-inflammatory agent is an antiseptic agent, an antibiotic, a corticosteroid or a wound healing promoting agent. P1168 5. The process according to any of claims 1 to 4, characterized in that the antiseptic agent is selected from compounds that release oxygen and halogen; metal compounds, for example, silver and mercury compounds; organic disinfectants including formaldehyde releasing compounds, alcohols, phenols including alkyl- and arylphenols as well as halogenated phenols, quinolines and acridines, hexahydropyrimidines, quaternary ammonium compounds and iminium salts and guanidines. The process according to claim 5, characterized in that the antiseptic agent is selected from the group comprising metal compounds, for example, mercury compounds, phenolic derivatives such as thymol, eugenol and hexachlorophene, iodine and iodine complexes. 7. The process according to claim 6, characterized in that the antiseptic agent is povidone iodine. The process according to any of claims 1 to 7, characterized in that the wound healing promoter agent is selected from agents that promote granulation and epithelization such as dexpanthenol, allantoins, azurenes, tannins, compounds of the vitamin B series. or agents of similar action. 9. The process according to any of the P1168 * A * preceding claims, characterized in that the preparation contains at least one antiseptic and at least one wound healing promoting agent. The process according to any of the preceding claims, characterized in that the carrier particles, especially the liposomes, have a substantially uniform size in the range between about 20 and 20,000 nm, preferably in the range between about 50 and 4,000 nm, more preferably between 500 and 2,500 nm and especially preferably a uniform size of approximately 1,000 nm in diameter. The process according to any of the preceding claims, characterized in that the carrier preparation, in particular of liposomes, releases the agent for a prolonged period of time, preferably a period of time extending to several hours in duration. The process according to claim 11, characterized in that the carrier preparation, in particular liposomes, releases the agent at approximately the same rate of release in the period of time of release. 13. The process according to any of the preceding claims, characterized in that the P1168 preparation further comprises at least one anesthetic active agent. The process according to any of the preceding claims, characterized in that the preparation contains additives and adjuvants as preservatives, antioxidants and consistency modifying additives. 15. The process according to any of claims 1 to 14, the preparation is in the form of a solution or dispersion comprising the carrier loaded with the active agent, especially in the form of liposomes, preferably in the form of a liquid pharmaceutical preparation. 16. The process according to any of claims 1 to 14, the preparation is in the form of a hydrophilic or amphiphilic cream, comprising the carrier and agent formulation in a hydrophilic or amphiphilic cream base or in the form of an oil / pharmaceutical lotion. water or water / oil. 17. The process according to any of claims 1 to 14, the preparation is in the form of a pharmaceutical ointment, containing the carrier and the agent or agents in a pharmaceutical ointment base. 18. The process according to any of claims 1 to 14, the preparation is in the form of a P1168 -. ? , 4, & pharmaceutical gel, especially an alcohol-free hydrogel containing the carrier and the agent or agents in a pharmaceutically acceptable hydrogel base. 19. The process according to any of claims 1 to 14, the preparation is in the form of a spray containing the carrier and the agent in a pharmaceutically acceptable solid or liquid sprayable formulation. 20. The process according to any of the preceding claims, the preparation is in the form of a pharmaceutical formulation in solution or dispersion, comprising: a) liposomes comprising a pharmaceutically acceptable liposomal membrane-forming substance; and b) a PVP iodine solution of 0.1 to 2% (with approximately 10% of available iodine in the PVP iodine complex) and that at least most of it is encapsulated by the liposome membranes, where the liposomes are of practically uniform size between about 50 and 4,000 nm and, where appropriate, the formulation also comprises additives, adjuvants and auxiliary substances commonly used in pharmaceutical formulations in solution or dispersion. 21. The process according to claim 20, P1168 -S ™ ^ - • --- • »* & i? and * e »* + UH * characterized in that the liposomes are of practically uniform size, with diameters of approximately 1,000 nm and the formulation is a gel. 22. The process according to any of claims 1 to 21, wherein the preparation is suitable for the treatment of infectious diseases or the alleviation of diseases such as HIV infections that are accompanied by opportunistic infections or a suppressed immune system. 23. The process according to any of claims 1 to 21, wherein the preparation is suitable for the treatment of laryngopharyngitis, angina and / or acute and / or chronic rhinitis. The process according to any of claims 1 to 21, wherein the preparation is suitable for remodeling and repair treatments of functional and cosmetic tissue. 25. A method for preventing or treating infections and / or remodeling and repairing functional and cosmetic tissue, in the upper respiratory tract and / or the ear in humans or animals, by applying, in the tract or ear, a pharmaceutical preparation comprising at least one anti-inflammatory agent, especially antiseptic and / or a wound healing promoting agent, the at least one agent is combined in the preparation with a particulate carrier and P1168 The preparation does not contain additional surfactants that do not form liposomes. 26. The method according to claim 25, wherein the carrier comprises at least one liposome preparation, a preparation of microspheres, a preparation of nanoparticles, a preparation of Large Porous Particles or a preparation of molecules coated with polymer by pulse laser. 27. The method according to claim 25, wherein at least the major part of the agent is encapsulated within the carrier, especially a liposome or microsphere carrier. The method according to claim 25, wherein the anti-inflammatory agent is selected from antiseptic agents, antibiotics, corticosteroids and wound healing promoting agents. 29. The method according to claim 25, wherein the antiseptic agent is selected from compounds that release oxygen and halogen; metal compounds, for example, silver and mercury compounds; organic disinfectants including formaldehyde releasing compounds, alcohols, phenols including alkyl- and arylphenols, as well as halogenated phenols, quinolines and acridines, hexahydropyrimidines, quaternary ammonium compounds and iminium salts and P1168 guanidines. The method according to claim 25, wherein the antiseptic agent is selected from the group comprising metal compounds, for example, mercury compounds, phenolic derivatives such as thymol, eugenol and hexachlorophene, iodine and iodine complexes. 31. The method according to claim 25, wherein the antiseptic agent is povidone iodine. 32. The method according to claim 25, wherein the wound healing promoter agent is selected from granulation and epithelization promoting agents such as dexpanthenol, allantoins, azulenes, tannins, compounds of the vitamin B series or agents of action. Similary. The method according to claim 25, wherein the preparation contains at least one antiseptic and at least one wound healing promoting agent. 34. The method according to claim 25, wherein the carrier particles, especially the liposomes, have a substantially uniform size in the range between about 20 and 20,000 nm, preferably in the range between about 50 and 4,000 nm, with greater preference between 500 and 2,500 nm and especially preferably a uniform size of P1168 approximately 1,000 nm in diameter. 35. The method according to claim 25, wherein the carrier preparation, especially liposomes, releases the agent for a prolonged period of time, preferably a period of time extending to several hours in duration. 36. The method according to claim 25, wherein the carrier preparation, especially liposomes, releases the agent at approximately the same rate of release in the time period of release. 37. The method according to claim 25, wherein the preparation further comprises at least one anesthetic active agent. 38. The method according to claim 25, wherein the preparation contains additives and adjuvants as preservatives, antioxidants and consistency modifying additives. 39. The method according to claim 25, the preparation is in the form of a solution or dispersion comprising the carrier loaded with the active agent, especially in the form of liposomes, preferably in the form of a liquid pharmaceutical preparation. 40. The method according to claim 25, the preparation is in the form of a hydrophilic or amphiphilic cream, comprising the carrier formulation and P1168 • * "* * *" *** • * - - - ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ agent in a hydrophilic or amphiphilic cream base or in the form of an oil / water or water / oil pharmaceutical lotion. 41. The method according to claim 25, the preparation is in the form of a pharmaceutical ointment, containing the carrier and the agent or agents in a pharmaceutical ointment base. 42. The method according to claim 25, the preparation is in the form of a pharmaceutical gel, especially an alcohol-free hydrogel containing the carrier and the agent or agents in a pharmaceutically acceptable hydrogel base. 43. The method according to claim 25, the preparation is in the form of a spray containing the carrier and the agent in a pharmaceutically acceptable solid or liquid sprayable formulation. 44. The method according to claim 25, the preparation is in the form of a pharmaceutical formulation in solution or dispersion, comprising: a) liposomes comprising a pharmaceutically acceptable liposomal membrane-forming substance; and b) a PVP iodine solution of 0.1 to 2% (with approximately 10% of available iodine in the PVP iodine complex) and that at least most of it is encapsulated by the liposome membranes, P1168 wherein the liposomes are of practically uniform size between approximately 50 and 4,000 nm and, where appropriate, the formulation also comprises additives, adjuvants and auxiliary substances commonly used in pharmaceutical formulations in solution or dispersion. 45. The method according to claim 25, wherein the liposomes are of substantially uniform size, with diameters of approximately 1,000 nm and the preparation is a gel. 46. The method according to claim 25, wherein the preparation is suitable for the treatment of infectious diseases or the alleviation of diseases such as HIV infections that are accompanied by opportunistic infections or a suppressed immune system. 47. The method according to claim 25, wherein the preparation is suitable for the treatment of laryngopharyngitis, angina and / or rhinitis. P1168