MXPA00007802A - Mixed micellar pharmaceutical delivery system and method of preparation - Google Patents

Abstract

A mixed micellar pharmaceutical formulation includes a micellar proteinic pharmaceutical agent, an alkali metal C8 to C22 alkyl sulphate, alkali metal salicylate, a pharmaceutically acceptable edetate and at least one absorption enhancing compounds. The absorption enhancing compounds are selected from the group consisting of lecithin, hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linolenic acid, borage oil, evening primrose oil, trihydroxy oxo cholanylglycine, glycerin, polyglycerin, lysine, polylysine, triolein and mixtures thereof. The amount of each absorption enhancing compound is present in a concentration of from 1 to 10 wt./wt.%of the total formulation, and the total concentration of absorption enhancing compounds are less than 50 wt./wt.%of the formulation.

Description

MIXED MICELLAR PHARMACEUTICAL SUPPLY SYSTEM. AND METHOD FOR YOUR PREPARATION FIELD OF THE INVENTION The present invention relates to an improved delivery system for the administration of large molecule pharmaceuticals, for example, peptide drugs, vaccines and hormones. In particular, it refers to pharmaceutical products that can be administered through the oral and nasal membranes.

BACKGROUND OF THE INVENTION Despite significant efforts in academic and commercial laboratories, no significant advances have been made in the oral formulation of peptides and proteins. Relatively small progress has been made in achieving the goal of safe and effective oral formulations for peptides and proteins. The main barriers in the development of oral formulations for proteins and peptides include poor intrinsic permeability, cellular and lumenal enzymatic degradation, rapid excretion and chemical stability in the gastrointestinal tract. The pharmaceutical proposals to face these barriers, which have been satisfactory with the molecules of small, traditional organic drugs, have not been easily transferred to the formulations of peptides and proteins, effective. Although the challenges are important, the potential therapeutic benefits remain high, especially in the field of the treatment of diabetes with insulin. Scientists have explored different routes of administration, different from injection, for proteins and peptides. These routes include the oral, intranasal, rectal, vaginal cavities for the effective delivery of large molecules. Of the four routes mentioned above, the oral and nasal cavities have been of maximum interest to scientists. Both the oral and nasal membranes offer advantages over other routes of administration. For example, drugs administered through these membranes have a rapid onset of action, provide therapeutic levels in the plasma, prevent the first-pass effect of hepatic metabolism and prevent drug exposure to the hostile gastrointestinal environment. Other advantages include easy access to the membrane sites, so that the drug can be easily applied, located and removed. In addition, there is good potential for the prolonged delivery of large molecules through these membranes. The oral routes have received much more attention than the other routes. The sublingual mucosa includes the ventral surface membrane of the tongue and the floor of the mouth, while the buccal mucosa forms the lining of the cheeks. The sublingual mucosa is relatively permeable, resulting in rapid absorption and acceptable bioavailability for many drugs. Additionally, the sublingual method is convenient, acceptable and easily accessible. This route has been investigated clinically for the delivery of a substantial amount of drugs. The possibility that the molecules penetrate through the oral mucosa seems to be related to the size of the molecule, to the solubility in the lipids and to the ionization of the peptide protein. Small molecules, less than 1,000 Dalton, seem to cross the mucosa rapidly. As the size of the molecule increases, permeability rapidly decreases. Lipid-soluble compounds are more permeable than molecules that are not soluble in lipids. The maximum absorption occurs when the molecules are not ionized or have neutral electrical charges. Therefore, charged molecules present the greatest challenges for absorption through the oral mucosae. Most protein drug molecules are extremely large molecules, with molecular weights that exceed 6,000 daltons. These large molecules have very poor solubility in lipids and are practically impermeable. Substances that facilitate the absorption or transport of large molecules (>2, 000 dalton) through biological membranes are known as enhancers (Lee and coauthors, Critical Reviews in Therapeutic Drug Carrier Systems, 8, 91, 1991; Lee and co-authors, Critical Reviews in Therapeutic Drug Carrier Systems, 8, 115 , 1991, 1992). The enhancers can be characterized as: chelators, bile salts, fatty acids, synthetic hydrophilic and hydrophobic compounds, and biodegradable polymeric compounds. Several mechanisms of action of the increasers have been proposed. Those mechanisms of action, at least for protein and peptide drugs, include: (1) reduction of the viscosity and / or elasticity of the mucosal layer; (2) ease of transcellular transport, by increasing the fluidity of the lipid bilayer of membranes; and (3) increase in the thermodynamic activity of the drugs (Critical Rev., 117-125, 1991, 1992). Many growth hormones have been tried thus far, and some have been found to be effective in facilitating the mucosal administration of large molecule drugs. However, almost no penetration-increasing product has reached the market. The reasons for this include the lack of a satisfactory safety profile in terms of irritation, decreased barrier function and damage to the protective mechanism of mucociliary excretion. The main factor to consider in the use of the enhancers, especially the bile salts and some protein solubilizing agents, is the extremely bitter and unpleasant taste. This makes its use almost impossible for human consumption, on a daily basis. Several proposals have been used to improve the taste of bile salt-based delivery systems; but none of them is commercially acceptable for human consumption, until now. The proposals used include the patches for the buccal mucosa, the double layer tablets, the controlled release tablets, the use of protease inhibitors, the film patch devices, administered buccally, and various polymeric matrices. The basic problem associated with the above technologies is the use of large amounts of bile acids and their salts to promote the transport of large molecules through membranes, in the form of localized delivery systems using patches or tablets. Despite the use of protease inhibitors and polymer coatings, the technologies failed to deliver the protein drugs at the required therapeutic concentrations. In addition, the problem is complicated by the effect of the patch on the localized site, which results in severe damage to the tissue of the mouth. The majority of attempts have been made to deliver large molecules through the oral, nasal, rectal and vaginal routes, using individual bile acids or individual enhancing agents, in combination with protease inhibitors and biodegradable polymeric materials. However, it is extremely difficult to obtain therapeutic levels of the protein drugs using those formulations. The individual enhancing agents do not loosen the compact cell joints in the oral, nasal, rectal and vaginal cavities for a period of time necessary to allow the passage of large molecules through the mucosal membranes, without further degradation. This problem makes the use of the systems mentioned above not practical for a commercial purpose. In order to solve the aforementioned problem, the bitter taste, the irritation and the penetration of large molecules through the sublingual, buccal and mucosal coating of the gastrointestinal tract (Gl), a system has now been designed in which the protein drug is encapsulated. in mixed micelles, constituted by a combination of increments, for example, yolk proteins (lecithins). This system allows to open the paracellular joints (compact joints) in the oral membranes, as well as in the gastrointestinal tract, by means of the movement of Gl motility, preserving a high degree of protease activity; and protects the molecules against premature degradation in the hostile, acidic and proteolytic Gl environment. It is believed that mixed micelles encapsulate molecules with a high degree of efficiency (more than 90% encapsulation). These mixed micelles are extremely small in size (1 nm to 10 nm), and are smaller than the pores of the membranes in the oral cavity or in the gastrointestinal tract. Accordingly, it is believed that the extremely small size of the mixed micelles helps the encapsulated molecules penetrate sufficiently through the mucosal membranes of the oral cavity. It is believed that the absorption of proteins and peptides is increased by the diffusion of the large molecules trapped in the mixed micellar form, through the aqueous pores and by the perturbation of the cellular structure of the compact paracellular joints. The amount of physiologically active peptide or protein, in the compositions of this invention is typically an amount that provides an effective amount of the drug, to produce the physiological activity (the therapeutic level in the plasma) for which the peptide or peptide is being administered. protein. In consideration of the fact that the bioavailability of any active substance can never be 100%, that is, that the administered dose of the active drug is not completely absorbed, it is preferred to incorporate a quantity slightly higher than the desired dose. When the dosage form is a spray (aerosol) or the like, which is supplied repeatedly from the same container, it is recommended that the unit dose be slightly higher than the desired dose. It should be understood that the dose should vary with the species of warm-blooded animals, such as man, domestic animals; and with the weight of his body. The composition of this invention is prepared as microfine droplets (from 1 to 10 nm or less) by virtue of the preparation methods and the characteristics of suitable combinations of the incrementing compounds used. Spray or aerosol spray devices (metered dose inhalers or nebulizers) may be useful to effect a sufficient reduction in particle size for effective inhalation from the nasal or oral cavity; so that the drug can be absorbed satisfactorily or can reach the specific site. The therapeutic composition of the present invention can be stored at room temperature or at cold temperatures. It is preferred to store the proteinaceous drugs at cold temperatures, to prevent their degradation and to prolong their shelf life. The mixed micellar therapeutic composition of the invention is applied to the mucous membranes; and the administration sites may be the same as those used for the usual mucosal therapeutic preparations. In general, oral, transdermal and nasal sites are preferred; but the composition can be applied to the rectal mucosa and vaginal mucosa. According to the physiologically active peptide or protein, with the dosage form and the administration site, a specific administration method can be selected. The term "edetate" is used herein to refer to pharmaceutically acceptable salts of ethylenediaminetetraacetic acid. It has also been found that improvements in the penetration and absorption of mixed micellar formulations can be achieved by mixing the mixed micellar formulation with propellants, such as tetrafluoroethane, heptafluoroethane, dimethylfluoropropane, tetrafluoropropane, butane, isobutane, dimethyl ether and other propellants that are not chlorofluorocarbons ( CFC) and that they are. It is preferred that they be supplied through metered dose spraying devices. It is known to use metered dose inhalers, which are a popular form of pulmonary drug delivery, for some drugs. The present formulation, including the propellant, is intended to improve the quality of absorption, the stability and operation of many formulations. The compositions have been selected to increase the penetration through the pores and facilitate the absorption of the drugs so that they reach the therapeutic levels in the plasma. The formulation herein can be absorbed buccally, ensuring that the person will not inhale the formulation as it is sprayed. One of the other benefits of using an atomizer or inhaler is that the potential for contamination is kept to a minimum, because the devices are self-contained.

BRIEF DESCRIPTION OF THE INVENTION Accordingly, the present invention provides a mixed micellar pharmaceutical formulation, comprising a proteinaceous pharmaceutical agent in micellar form, water, an alkali metal lauryl sulfate in a concentration of 1 to 10% w / w of the total formulation; a pharmaceutically acceptable edetate, in a concentration of 1 to 10% w / w of the total formulation; at least one alkali metal salicylate, at a concentration of 1 to 10% w / w of the total formulation, and at least one absorption enhancing compound, selected from the group consisting of lecithin, hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linolenic acid, borage oil, evening primrose oil, trihydroxy-oxo-colanylglycine, glycerin, polyglycerin, lysine, polylysine, triolein , and mixtures of them; wherein the amount of each absorption-increasing compound is present in a concentration of 1 to 10% w / w of the total formulation, and the total concentration of absorption-increasing compounds is less than 50% w / w of the formulation. In one embodiment, each of the alkali metal lauryl sulfate, the edetate and the alkali metal salicylate are at a concentration of 2 to 5% w / w of the total formulation. In one embodiment, the edetate is an alkaline metal edetate. The alkali metal edetate, preferably, is selected from the group consisting of disodium edetate, dipotassium edetate and combinations thereof. In another embodiment, the alkali metal lauryl sulfate is sodium lauryl sulfate. In another embodiment, the alkali metal salicylate is sodium salicylate. In another embodiment, lecithin is selected from the group consisting of saturated phospholipid, for example, Phospholipon-H (registered trademark), a saturated phospholipid, unsaturated phospholipid, for example, the unsaturated phospholipid Phospholipon-G (trademark), phosphatidylcholine, phosphatidylserine, sphingomyelin, phosphatidylethanolamine, cephalin and lysolecithin. In one embodiment, one of the absorption enhancing compounds is selected from the group consisting of hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, and mixtures thereof; the concentration of said absorption enhancing compound being about 1 to 5% w / w. In another embodiment, suitable for delivery through the nasal passages, the mixed micellar pharmaceutical formulation is adequately diluted, to avoid irritation of the nasal passages. Another aspect of the present invention provides a mixed micellar pharmaceutical formulation, suitable for delivery by means of an aerosol, and comprising a pharmaceutical agent in micellar form, water, an alkyl sulphate of 8 to 22 carbon atoms, of alkali metal, to a concentration of 1 to 10% w / w of the total formulation; a pharmaceutically acceptable edetate at a concentration of 1 to 10% w / w of the total formulation, at least one alkali metal salicylate in a concentration of 1 to 10% w / w of the total formulation, and at least one an absorption enhancing compound, selected from the group consisting of lecithin, hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linolenic acid, borage oil, evening primrose oil, menthol, trihydroxy-oxo-colanylglycine and its pharmaceutically acceptable salts, glycerin, polyglycerin, lysine, polylysine, alkyl ethers of polidocanol and their analogues; triolein and its mixtures; wherein each absorption enhancing compound is present at a concentration of 1 to 10% w / w of the total formulation, and the total concentration of the absorption enhancing compounds is less than 50% w / w of the formulation. Yet another aspect of the present invention provides that the aerosol, mycelial, mixed pharmaceutical formulation further comprises: i) a phenol, selected from the group consisting of phenol and methylphenol, at a concentration of 1 to 10% w / w of the total formulation; and ii) a propellant selected from the group consisting of dialkyl ether of 1 to 2 carbon atoms, butanes, fluorocarbon propellant, fluorocarbon propellant containing hydrogen, chlorofluorocarbon propellant, hydrogen-containing chlorofluorocarbon propellant, and mixtures thereof. In one embodiment, the alkyl sulfate of 8 to 22 carbon atoms of alkali metal is at a concentration of 2 to 5% w / w of the total formulation. In another embodiment, the alkyl sulfate of 8 to 22 carbon atoms of alkali metal is sodium lauryl sulfate. In another embodiment, the lecithin is saturated or unsaturated, preferably selected from the group consisting of phosphatidylcholine, phosphatidylserine. sphingomyelin, phosphatidylethanolamine, cephalin and lysolecithin. In still another embodiment, one of the absorption enhancing compounds of the group consisting of: hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, alkyl ethers of polidocanol, trihydroxy-oxo-colanylglycine, polyoxyethylene ethers, and mixtures thereof; the concentration of that absorption enhancing compound being about 1 to 5% w / w. In yet another embodiment, the formulation comprises a combination selected from the group consisting of: i) sodium lauryl sulfate, sodium salicylate, disodium edetate, saturated phospholipid and sodium hyaluronate; ii) sodium lauryl sulfate, sodium salicylate, disodium edetate, lecithin and sodium hyaluronate; iii) sodium lauryl sulphate, sodium salicylate, disodium edetate, sodium hyaluronate and evening vesperine oil; iv) sodium lauryl sulfate, sodium salicylate, disodium edetate, saturated phospholipid and bacitracin; v) sodium lauryl sulfate, sodium salicylate, disodium edetate, saturated phospholipid, sodium hyaluronate and bacitracin; vi) sodium lauryl sulfate, sodium salicylate, disodium edetate, sodium hyaluronate, oleic acid and gamma-linoleic acid; vii) sodium lauryl sulfate, sodium salicylate, disodium edetate, saturated phospholipid and glycolic acid; and (viii) sodium lauryl sulfate, sodium salicylate, disodium edetate, saturated phospholipid, glycolic acid, and lactic acid. It is preferred that the ratio of pharmaceutical agent, e.g., insulin, to the propellant, be from 1:19 to 1: 3. In another embodiment, the propellant of the group consisting of tetrafluoroethane, tetrafluoropropane, dimethylfluoropropane, heptafluoropropane, dimethyl ether, n-butane and isobutane is selected. In yet another embodiment, the mixed micellar pharmaceutical formulation is contained in an aerosol dispenser. For formulations containing insulin and some others, the formulation may also contain at least one inorganic salt that opens channels in the gastrointestinal tract, and may provide additional stimulation for the release of insulin. Non-limiting examples of the inorganic salts are the sodium, potassium, calcium and zinc salts; in particular: sodium chloride, potassium chloride, calcium chloride, zinc chloride and sodium bicarbonate. Those skilled in the art will recognize that for many pharmaceutical formulations it is usual to add at least one antioxidant to prevent degradation and oxidation of the pharmaceutically active ingredients. Those skilled in the art will also understand that colorants, flavoring agents and non-therapeutic amounts of other compounds may be included in the formulation. Typical flavoring agents are menthol and sorbitol. In one embodiment, the antioxidant is selected from the group consisting of: tocopherol, deteroxime mesylate, methyl paraben, ethyl paraben and ascorbic acid, and mixtures thereof. A preferred antioxidant is tocopherol. In preferred embodiments, at least one protease inhibitor is added to the formulation to inhibit the degradation of the pharmaceutical agent by the action of proteolytic enzymes. Of the known protease inhibitors, most are effective at concentrations of 1 to 3% w / w of the formulation. Non-limiting examples of effective protease inhibitors are bacitracin, soy trypsin, aprotinin and bacitracin derivatives, for example, bacitracin methylendisalicylate. Bacitracin is the most effective of those named, when used at concentrations of 1.5 to 2% w / w. Soybean trypsin and aprotinin can be used in approximate concentrations of 1 to 2% w / w of the formulation. The formulation suitable for delivery through the oral mucous membranes may be in chewable form, in which case it will be necessary to add suitable ingredients for that form. These ingredients include: guar gum, acacia powder, carrageenan, beeswax and xanthan gum. The pharmaceutical agent can be selected from a wide variety of macromolecular agents, depending on the disorder being treated; in general, with molecular weights above about 1,000 and, especially, between about 1,000 and 2,000,000. Preferred pharmaceutical agents are selected from the group consisting of insulin, heparin, low molecular weight heparin, hirulog, hirugen, huridin, interferons, interleukins, cytokines, monoclonal and polyclonal antibodies, immunoglobulins, chemotherapeutic agents, vaccines, glycoproteins, bacterial toxoids, hormones, calcitonins, insulin-like growth factors (IGF), glucagon-like peptides (GLP-1, Glucagon Like Peptides), antibiotics large molecule, thrombolytic compounds based on protein, platelet inhibitors, DNA, RNA, gene therapeutics and oligonucleotides of opposite direction; and small molecule drugs, for example, opioids, narcotics, analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, hypnotics, pharmaceutical preparations for the treatment of chronic pain , morphine and the like. The present invention also provides a process for forming a pharmaceutical formulation suitable for delivery through transdermal membranes, comprising: a) preparing a pharmaceutical agent composition, protein, in micellar form, in an aqueous medium having a metal salicylate alkali in a concentration of 1 to 10% w / w of the total formulation; an alkali metal lauryl sulfate, at a concentration of 1 to 10% w / w of the total formulation, and a pharmaceutically acceptable edetate, at a concentration of 1 to 10% w / w of the total formulation; b) Slowly add the micellar composition of the proteinaceous pharmaceutical agent to at least one absorption enhancing compound, selected from the group consisting of: lecithin, hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile, cucumber extract, oleic acid, linolenic acid, borage oil, evening primrose oil, trihydroxy-oxo-colanylglycine, glycerin, polyglycerin, lysine, polylysine, triolein, and mixtures thereof; while vigorously mixing, to form a mixed micellar formulation, wherein each of the absorption enhancing compounds is present at a concentration of 1 to 10% w / w of the total formulation, and the total concentration of the metal salicylate alkaline, alkali metal lauryl sulfate, edetate and absorption-increasing compounds, is less than 50% w / w of the formulation. In one embodiment, the process provides an additional step of adding, while continuing to vigorously mix, at least one absorption enhancing compound, different from that added in step b), selected from the group consisting of: lecithin, hyaluronic acid, salts pharmaceutically acceptable of hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linolenic acid, borage oil, evening primrose, trihydroxy-oxo-colanylglycine, glycerin, polyglycerin, lysine, polylysine, triolein and mixtures of them. In one embodiment, the alkali metal lauryl sulfate is sodium lauryl sulfate. In another embodiment, the alkali metal salicylate is sodium salicylate. In yet another embodiment, the alkali metal edetate may be selected from the group consisting of disodium edetate and dipotassium edetate. In yet another embodiment, the formulation has a combination selected from the group consisting of: i) saturated phospholipid and sodium hyaluronate; ii) saturated phospholipid and glycolic acid; iii) sodium lecithin and hyaluronate; iv) saturated phospholipid, glycolic acid and lactic acid; v) sodium hyaluronate and evening velvet oil; vi) saturated phospholipid and bacitracin; vii) saturated phospholipid, sodium hyaluronate and bacitracin; and viii) sodium hyaluronate, oleic acid and gamma-linoleic acid. The present invention also provides a process for preparing a micellar, mixed pharmaceutical composition suitable for delivery by means of an aerosol, comprising: a) preparing a pharmaceutical agent composition in micellar form, in an aqueous medium having an alkyl sulphate of 8 at 22 carbon atoms of alkali metal, at a concentration of 1 to 10% w / w of the total formulation; a pharmaceutically acceptable edetate, at a concentration of 1 to 10% w / w of the total formulation, at least one alkali metal salicylate at a concentration of 1 to 10% w / w of the total formulation; b) slowly add the composition of micellar protein pharmaceutical agent to at least one absorption enhancing compound, selected from the group consisting of lecithin, hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile extract , cucumber extract, oleic acid, linolenic acid, borage oil, evening candle oil, menthol, trihydroxy-oxo-colanylglycine and its pharmaceutically acceptable salts, glycerin, polyglycerin, lysine, polylysine, alkyl ethers of polidocanol and its analogs, triolein and their mixtures, while mixing vigorously, to form a mixed micellar formulation; and, optionally, c) a further step of adding, while continuing to vigorously mix, at least one micelle-forming compound, different from that added in step b), selected from the group consisting of lecithin, hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linolenic acid, monooiein, borage oil, evening primrose oil, glycerin, polyglycerin, lysine, polylysine, triolein, polyoxyethylene ethers, and their analogs, alkyl ethers of polidocanol and their analogs, and mixtures thereof; d) mixing the mixed micellar formulation resulting from steps a) to c) with a phenol selected from the group consisting of phenol, m-cresol and mixtures thereof; and, subsequently, e) placing the formulation in an aerosol dispenser and loading the dispenser with a propellant; wherein each of the absorption enhancing compounds is present at a concentration of 1 to 10% w / w of the total formulation, and the total concentration of alkali metal salicylate, alkyl sulfate of 8 to 22 carbon atoms of alkali metal, edetate and absorption-increasing compounds is less than 50% w / w of the formulation. Vigorous mixing can be achieved using high speed agitators, for example, magnetic stirrers or propeller agitators, or by means of sonic treatment. In one embodiment, the mixed micellar formulation is formed by sonically treating the micellar, aqueous pharmaceutical agent composition in the presence of lecithin.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The present invention provides an improved method for delivering macromolecular (high molecular weight) pharmaceutical agents, in particular through the membranes of the nose, mouth, vagina or rectum. The preferred supply is made through the oral and nasal cavities. Pharmaceutical agents cover a broad spectrum of agents, including proteins, peptides, hormones, vaccines and drugs. The molecular weights of the macromolecular pharmaceutical agents are preferably greater than 1,000, especially between 1,000 and 2,000,000. For example, hormones that can be administered with the present invention include: thyroids, androgens, estrogens, prostaglandins, somatotropins, gonadotropins, erythropoietin, interferons, interleukins, steroids and cytokines. Vaccines that can be administered with the present invention include bacterial and viral vaccines, such as vaccines for hepatitis, influenza, tuberculosis, yellow rash, varicella, measles, mumps, rubella, pneumonia, GCG, HIV and AIDS. Bacterial toxoids that can be administered using the present invention include: diphtheria, tetanus, Pseudomonas and mycobacterial tuberculosis. Examples of specific cardiovascular or thrombolytic agents include: heparin, hirugen, hirulos and hirudin. Large molecules, usefully administered with the present invention include: monoclonal antibodies, polyclonal antibodies and immunoglobulins. As will be understood, the concentration of the pharmaceutical agent is an amount sufficient to be effective in the treatment or prevention of a disorder or to regulate a physiological condition in an animal or in a human. The concentration or amount of pharmaceutical agent administered will depend on the parameters determined for the agent, and the method of administration; for example, oral, nasal. For example, nasal formulations tend to require much lower concentrations of some ingredients, in order to avoid irritation or burning of the nasal passages. Sometimes it is convenient to dilute an oral formulation up to 10 to 100 times, in order to provide an adequate nasal formulation. The mixed micellar formulation is prepared by first preparing a first micellar composition, containing the pharmaceutically active agents, alkali metal alkyl sulfate, 8 to 22 carbon atoms, edetate and alkali metal salicylate. For those compositions that are intended to be administered through the nasal, oral, vaginal or rectal cavities, the first micellar composition is then added to at least one of the absorption enhancing compounds to form a mixed micellar composition. Subsequently, at least one other absorption enhancing compound can also be added. It is preferred that the first absorption enhancing compound be lecithin. When the aerosol formulation is prepared, the phenol and / or m-cresol and / or isotonic agent is then added. The formulation is then placed in an aerosol dispenser and the dispenser is loaded with propellant. The preferred propellants are chlorofluorocarbons containing hydrogen, fluorocarbons containing hydrogen; dimethyl ether and diethyl ether. Still more preferred is hydrofluoroalkane (HFA) 134a- (1,1,1,2-tetrafluoroethane). Although the present invention has said broad application capacity, it is described in the following the invention with particular reference to insulin and its analogues, which are used for the treatment of diabetes. As indicated hereinabove, the compositions of the present invention require that the pharmaceutical formulation be in mixed micellar form. In the case of insulin, which is intended to be administered through the nasal or oral cavities, the first micellar solution can be made by adding a buffer solution to the insulin powder, and then stirring until the powder dissolves and get a clear solution. A typical buffer solution is an aqueous solution of sodium salicylate and sodium lauryl sulfate and sodium edetate. The typical concentration of sodium salicylate and sodium lauryl sulfate in the aqueous solution is approximately 1 to 10% w / w, of each compound, in the solution.

Insulin is typically present in the micellar solution in an amount that will give an approximate concentration of 2 to 4% w / w of the final formulation. Typically the concentration may be about 10% w / w of the first micellar composition. The micellar solution is then added slowly to the first absorption enhancing compound, for example, lecithin, while vigorously mixing, for example, by sonic treatment, to form a liposomal solution of mixed micelle. At least one other absorption enhancing compound selected from the group consisting of lecithin, hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, acid is then added. linolenic, borage oil, evening velvet oil, trihydroxy-oxo-colanylglycine, glycerin, polyglycerin, lysine, polylysine, triolein. Mixing can be effected with a high-speed mixer or sonic treatment apparatus, to ensure uniform distribution of the micelle particle size, within the formulation. Each of the absorption enhancing compounds, when present, is present at a concentration of 1 to 10% w / w of the total formulation. Preferred hyaluronic acid salts are alkali metal hyaluronates, alkaline earth metal hyaluronate and aluminum hyaluronate. The preferred salt is sodium hyaluronate. The preferred concentration of hyaluronic acid or pharmaceutically acceptable salts of hyaluronic acid is from 1 to 5% w / w of the total formulation. A still more preferred scale is 1.5 to 3.5% w / w of the total formulation. Other ingredients can be added to the mixed micellar solution. For example, flavoring agents, antioxidants, salts, protease inhibitors or other pharmaceutically acceptable compounds may be added. In general, the size of the micelle particles in the solution is approximately 1 to 10 nm, and preferably 1 to 5 nm. Said size distribution guarantees the effective absorption of the formulation and, consequently, of the pharmaceutical agent, through the membranes; for example, the membranes of the oral and nasal cavities. The specific concentrations of the essential ingredients can be determined by relatively direct experimentation. For absorption through the nasal and oral cavities, it is often convenient to increase, for example, doubling or tripling, the dose that is normally necessary through injection or administration by the gastrointestinal tract. As will be understood, the amount of each component of the formulation will vary, depending on the pharmaceutical agent and the site of application. Preferred formulations for oral or nasal application have the following combinations: i) sodium lauryl sulfate, sodium salicylate, disodium edetate, Phospholipon-H and sodium hyaluronate; ii) sodium lauryl sulfate, sodium salicylate, disodium edetate, lecithin and sodium hyaluronate; iii) sodium lauryl sulphate, sodium salicylate, disodium edetate, sodium hyaluronate and evening vesperine oil; iv) sodium lauryl sulfate, sodium salicylate, disodium edetate, Phospholipon-H and bacitracin; v) sodium lauryl sulfate, sodium salicylate, disodium edetate, Phospholipon-H, sodium hyaluronate and bacitracin; and vi) sodium lauryl sulfate, sodium salicylate, disodium edetate, sodium hyaluronate, oleic acid and gamma-linoleic acid. For aerosol formulations, the addition of a mixture of phenol and m-cresol is preferred. Said aerosol formulation can then be placed in an aerosol dispenser and then loaded with a propellant, preferably a propellant other than CFC. The therapeutic compositions of the present invention can be stored at room temperature or at a cold temperature. Storage of protein drugs at a cold temperature is preferred to prevent degradation of the drugs and prolong their shelf life. As indicated previously, in general, oral and nasal membranes are the favorite sites for administration; but the composition can be applied to the rectal or vaginal mucosa. In accordance with the physiologically active peptide or protein used, the dosage form and the administration site, a specific administration method can be selected. The formulation of this invention is generally prepared as mixed, microfine micelle particles (from 1 to 10 nm or less) by virtue of the preparation methods and the characteristics of the appropriate combinations of the absorption enhancers used. For oral and nasal application sprays are preferable, but drops, chewable tablets, chewable gum or other suitable forms can also be used. Spray or aerosol spray devices (inhalers or metered dose nebulizers) can be used to further reduce the particle size for effective inhalation from the nasal or oral cavity, so that the drug can successfully reach the specific site and be absorbed. It is also possible to use a drug delivery system so that an enteric coating is applied to the gelatin capsule, to cause the micelles to be released only in the duodenum or in the vicinity of the large intestine, and not in the stomach. The invention is illustrated by reference to the following examples.

EXAMPLE 1 A first experiment was carried out to provide data for comparative purposes. This example is not within the scope of the present invention. A solution was prepared using 0.5 g of sodium lauryl sulfate, 0.5 g of sodium salicylate and 0.25 g of disodium edetate, dissolved in 10 ml of water. To this solution was added 40 mg (1,000 units) of insulin and completely dissolved, while stirring, to give approximately 100 units / ml of insulin solution.

In a test series, five healthy, non-diabetic human volunteers were tested with insulin, by injection. In another series of tests, volunteers were tested with insulin, taken orally. The volunteers were fasting from the previous night, prior to the test; without taking food during the four hours of the study. On the first day, volunteers received 10 units of insulin by injection (fast-acting, regular insulin, available from Eli Lilly). On the second day, the volunteers received 100 units (volume of 1 ml per drop, approximately 20 drops) of the oral insulin prepared above (10 times the injection dose). In both tests blood glucose levels were monitored every 15 minutes, using the Bayer Elite glucometer. The average results for the five volunteers of the first day trial (subcutaneous injection with 10 units) were as follows: TABLE I Time * 0 15 30 60 75 90 120 150 180 Average 5.8 5.8 5.4 5.0 4.6 4.3 3.8 3.6 3.4 Time * 210 240 Average 4.2 4.5 * Time, in minutes. The results for each of the five volunteers, from the second day trial (oral drops, with 100 units) were as follows: TABLE II Time * 0 15 30 60 75 90 120 150 180 Subjects No: 1 6.2 5.8 5.2 5.0 4.9 5.0 5.0 4.8 4.7 2 5.8 5.4 5.0 4.7 4.9 4.3 5.0 5.5 5.2 3 4.8 4.6 4.3 4.3 4.4 4.6 4.8 4.7 5.2 4 6.6 6.1 5.8 5.5 5.1 4.9 5.0 5.0 5.9 Time 210 240 Subjects No: 1 5.5 6.0 2 5.8 6.1 3 5.5 5.1 4 6.2 6.8 5 5.9 6.7 * time in minutes These tests indicate that, compared to the injection method, oral insulin gives a faster onset of action and levels lower blood glucose, without creating hypoglycemic condition. Due to the production of hepatic glucose, there was a rebound effect. It is believed that this is due to incomplete absorption of insulin.

EXAMPLE 2 Another experiment was carried out, neither within the scope of the present invention, for comparative purposes. 100 units of oral insulin were formulated in 10 mg of Phospholipon-H, without any absorption enhancer of sodium lauryl sulfate, sodium salicylate, edetate or other absorption enhancers, to evaluate its effectiveness in lowering blood glucose, in a fasted state, in healthy volunteers. The volunteers were asked to remain fasted during the night and not to take any breakfast before the dose. Volunteers were asked to take this oral insulin formulation in their mouth and sow it. Blood glucose levels were monitored every 15 minutes, using Bayer's Elite glucometer for three hours, and the average results for the five volunteers are shown in Table III: TABLE III Time * 0 15 30 45 60 75 90 120 150 180 Average: 5.6 5.8 5.8 5.7 5.7 5.8 5.7 5.7 5.8 5.7 * Time in minutes This indicates that insulin administered orally with lecithin alone has no effect on the decrease in blood glucose.

EXAMPLE 3 Yet another experiment was carried out, neither within the scope of the present invention, for comparative purposes. 100 units of oral insulin were formulated with sodium salicylate and alkaline metal edetate (both 5% by weight), to evaluate its efficacy in lowering blood glucose, in the fasted state, in healthy volunteers. The volunteers were asked to remain fasting during the night and not to take any breakfast before dosing. Volunteers were asked to take this oral insulin formulation in their mouth and sow it. Blood glucose levels were monitored every 15 minutes, using the Bayer Elite glucometer, for three hours, and the average results for the five volunteers are shown in table IV.

TABLE IV Time * 0 15 30 45 60 75 90 120 150 180 Average: 5.8 5.8 5.8 5.9 5.8 5.9 5.7 5.9 6.2 6.0 * Time in minutes This indicates that insulin administered orally with sodium salicylate and alkaline metal edetate alone has no effect on the decrease in blood glucose. In addition, this formulation caused irritation and a burning sensation, which lasted several hours.

EXAMPLE 4 Another experiment was carried out, neither within the scope of the present invention, for comparative purposes. 100 units of oral insulin were formulated using sodium salicylate and alkaline metal edetate (both 5% by weight), with 10 mg of Phospholipon-H, and tested in healthy subjects. Blood glucose levels were monitored every 15 minutes, using the Bayer Elite glucometer, for three hours, and the results are shown in Table V.

TABLE V Time * 0 15 30 45 60 90 120 180 Average: 5.3 5.3 5.3 5.4 5.6 5.7 5.7 5.8 * Time in minutes. This indicates that insulin administered orally with sodium salicylate, alkaline metal edetate and Phospholipon-H has no effect on the decrease of blood glucose.

EXAMPLE 5 Another experiment was carried out, neither within the scope of the present invention, for comparative purposes. 50 units of oral insulin were formulated using only alkali metal lauryl sulfate (5% by weight). Blood glucose levels were monitored every 15 minutes, using Bayer's Elite glucometer for three hours, and average results for four volunteers are shown in Table VI.

TABLE VI Time * 0 15 30 60 90 120 180 Average: 5.8 5.6 5.4 5.3 5.4 5.4 5.6 * Time in minutes These data show that insulin administered orally, only with alkaline metal lauryl sulfate, has little metabolic effect on the decrease in glucose in the blood. blood, in healthy subjects. This formulation caused a feeling of substantial burning and irritation in the subjects, which lasted two days.

EXAMPLE 6 Another experiment was carried out within the scope of the present invention. 50 units of mixed micellar oral insulin were formulated, using alkali metal lauryl sulfate and sodium salicylate (both at 4.4% by weight) and alkaline metal edetate (2.2% by weight) with 10 mg of Phospholipon-H and tested in healthy volunteers The method involved mixing the sodium lauryl sulfate, the sodium salicylate and the alkaline metal edetate with water in a beaker, with a magnetic stirrer, at medium speed, until the ingredients are dissolved, to form the buffer solution. Insulin powder was placed in a beaker and the buffer solution was added to this powder. The solution was continuously stirred using a magnetic stir bar until all of the insulin powder dissolved and a clear solution was obtained. The micellar solution thus formed was stored in clean glass bottles and refrigerated. The mixed micellar liposomal insulin was then prepared in a beaker, in which the Phospholipon-H and a small amount of isopropyl alcohol were placed. The mixture was stirred at high speed (1000 r.p.m.) for about 10 minutes to ensure complete dissolution of Phospholipon-H. The micellar insulin solution was added to this solution, very slowly, dropwise, using a glass dropper, with continuous stirring, at high speed. The solution was stirred continuously for another 30 minutes at high speed, to ensure a uniform distribution of micellar particle sizes. The volunteers orally took samples of the mixed micellar solution. Blood glucose levels were monitored every 15 minutes using the Bayer Elite glucometer for three hours and the average results for five volunteers are shown in Table VII.

TABLE VII Time * 0 15 30 45 60 90 120 150 180 Average 6.5 6.1 5.5 5.3 5.3 5.4 5.5 5.5 5.5 * Time in minutes. These data show that insulin administered orally with alkali metal lauryl sulfate combined with sodium salicylate and alkaline metal edetate, with Phospholipon-H, has a small metabolic effect on blood glucose levels in healthy volunteers.

EXAMPLE 7 An experiment was carried out within the scope of the present invention. In this example the formulation was for oral administration. 50 units of oral insulin were formulated using alkali metal lauryl sulfate and sodium salicylate (both 4.4% by weight) and alkaline metal edetate (2.2% by weight) with 10 mg Phosph oolliippoon-H and sodium hyaluronate ( 1.1% by weight). HE He tested this formulation on healthy subjects, under fasting conditions. The method involved mixing the sodium lauryl sulfate, the sodium salicylate and the alkaline metal edetate with water, in a beaker, with a magnetic stirrer, at medium speed, until the ingredients were dissolved, to form a buffer solution. The insulin powder was placed in a beaker and the buffer solution was added to that powder. The solution was continuously stirred using a magnetic stir bar, until all the insulin powder dissolved and a clear solution was obtained. The micellar solution thus formed was stored in clean glass bottles, and refrigerated. Then the mixed micellar liposomal insulin was prepared in a glass beaker, in which the Phospholipon-H and a small amount of isopropyl alcohol were placed. The mixture was stirred at high speed (1000 r.p.m.) for about 10 minutes to ensure complete dissolution of Phospholipon-H. The micellar insulin solution was added to this solution, very slowly, dropwise, using a glass dropper, with continuous stirring, at high speed. The solution was continuously stirred for another 30 minutes at high speed, to ensure a uniform distribution of micellar particle size. Then the hyaluronate and small amounts of menthol and sorbitol were added, with continuous agitation. The volunteers orally took samples of mixed micellar solution. Blood glucose levels were monitored every 15 minutes using the Bayer Elite glucometer for three hours, and the average results for five volunteers are shown in Table VIII.

TABLE VIII Time * 0 15 30 45 60 90 120 150 180 Average 6.5 5.9 5.6 5.4 4.9 5.0 4.9 5.2 5.4 * Time in minutes. These data show that insulin administered orally, with alkali metal lauryl sulfate, sodium salicylate, alkaline metal edetate, Phospholipon-H and sodium hyaluronate, has resulted in the decrease of blood glucose levels in healthy subjects, better than the formulations mentioned above.

EXAMPLE 8 Another experiment was carried out within the scope of the present invention. In this example the formulation was for oral administration. A buffer solution was prepared using 0.5 g of sodium lauryl sulfate, 0.5 g of sodium salicylate and 0.25 g of disodium edetate, dissolved in 10 ml of water. The solution was added to insulin and mixed to form micellar insulin. 100 mg of powdered phosphatidylcholine-H was separately added to a glass beaker and 10 ml of 50% ethanol was added to that powder. The powder completely dissolved. Slowly, with vigorous stirring, 16 mg (400 units) of micellar insulin solution in 3 ml of the buffer was added to this solution to give a solution of 30 units / ml of insulin to form a micellar solution mixed To this was added 0.6 ml of sodium hyaluronate and 0.2 ml of 2% menthol solution containing 3% sorbitol. Ten human diabetic type II volunteers were studied in a series of tests, who took insulin, by injection, three times a day. In another series of tests, the volunteers were tested with insulin, taken orally. The volunteers were left fasting from midnight before the test, without taking food during the four hours of study. On the first day, the volunteers received 10 units of insulin by injection (regular rapid-acting insulin, available from Eli Lilly). On the second day, the volunteers received 30 units (volume of 1 ml per drop, approximately 20 drops) of the oral insulin prepared above (three times the injection dose). In both tests blood glucose levels were monitored every 15 minutes, using the Bayer Elite glucometer. The results, which show the average for the ten volunteers, were as shown below: TABLE IX GLUCOSE LEVELS IN THE BLOOD (mmol / L) The results show that the oral insulin formulation of the present invention, at a dose three times greater than the injected level, is comparable with the injected insulin.

EXAMPLE 9 This example illustrates a method for preparing a mixed micellar formulation according to the present invention. In a glass beaker, with a capacity of 250 ml, was added 5 g of sodium lauryl sulfate, 5 g of sodium salicylate and 2.5 g of edetate. The beaker was placed on the hot plate, with magnetic stirrer. To this dry powder mixture was added 100 ml of distilled water and the mixture was stirred, using the magnetic stir bar, at a medium speed, until all the powder was dissolved. The buffer solution was stored in a clean glass bottle at room temperature (pH 6.5). A solution of micellar insulin was then prepared in a glass beaker with a capacity of 50 ml, in which 11.54 mg of insulin powder was placed. 10 ml of the buffer solution was added to that powder. The solution was continuously stirred using a magnetic stirring bar, until all the insulin powder dissolved and a clear solution was obtained. The micellar solution thus formed was stored in clean glass bottles and refrigerated. Then a 2% menthol solution was prepared from 100 mg of menthol crystals, dissolved in 5 ml of ethanol. To that solution was added 5 mg of blue dye FD &C. The solution was stirred for 10 minutes and stored in a glass bottle at room temperature. The mixed micellar liposomal insulin was then prepared in a 50 ml glass beaker, in which 100 mg of phosphatidylcholine (Sigma, type I = EH, hydrogenated) was placed. 10 ml of isopropyl alcohol was added to that powder. The mixture was stirred at high speed (1000 r.p.m.) for about 10 minutes, to ensure complete dissolution of the phosphatidylcholine. To this solution, very slowly, dropwise, using a dropper of glass, the solution of micellar insulin, with continuous stirring, at high speed was added. The solution was stirred continuously for another 30 minutes at high speed, to ensure the uniform distribution of micellar particle size. To this solution was added 1 ml of the 2% menthol solution and 50 mg of sodium hyaluronate. The mixed micellar solution of liposomal insulin, half-shell, translucent, light blue in color (final volume 15 ml) was stored in a clear glass bottle and refrigerated. The solution had a pH of 6.5. If the phosphatidylcholine powder does not dissolve completely, then it may be necessary to heat up to about 45 ° C, for example, by the use of a water bath. It has been found that if the micellar insulin composition is not added slowly, then the mixed micellar formulation will not form and the formulation will be gelatinous and sticky.

EXAMPLE 10 The formulation of Example 9 was tested in a manner similar to that indicated in Example 8, except that the formulation of the present invention was administered nasally. On the first day, each of the ten volunteers received ten units of insulin per injection (regular fast action, Eli Lilly). On the second day, the volunteers received 20 units of the "oral" insulin from example 9 (twice the injection dose). The "oral" insulin was administered as drops (volume of 0.4 ml per drop, approximately 4 large drops in total, ie, two drops in each nostril). The results, which show the average for the ten volunteers, are shown in the following: TABLE X GLUCOSE LEVELS IN THE BLOOD (mmol / L) The results show that the nasal insulin formulation of the present invention, at a dose twice the level injected, is comparable with the injected insulin.

EXAMPLE 11 The formula of Example 9 was taken and tests were carried out to determine the action of insulin on glucose with food in healthy volunteers. Usually diabetic patients receive an insulin injection 30 minutes before a meal, because the injected insulin takes a long time to provide its effect. Injected insulin is slowly absorbed into the bloodstream within 60 minutes and has a metabolic effect on glucose levels with food. The mixed micellar formulation of Example 9 was tested in healthy volunteers, under controlled conditions, to determine the effect of oral insulin on glucose with food, when compared to the injected insulin. In a series of tests, ten healthy, non-diabetic human volunteers were tested with insulin, by injection. In another series of tests, volunteers were tested with insulin taken orally. The volunteers were left fasting from midnight before the tests, taking food 30 minutes after the dose. The food was 240 ml of the liquid diet Sastacal, normal, approved by the Society of Diabetics, which contains 400 calories. On the first day, the volunteers received 10 units of insulin by injection (fast-acting, regular insulin, available from Eli Lilly). On the second day, the volunteers received 30 units of oral insulin, prepared above (three times the injection dose). In both tests the blood glucose levels were monitored every 15 minutes, by means of the Bayer Elite glucometer. The results are shown below: TABLE XI GLUCOSE LEVELS IN THE BLOOD (mmol / L) The results indicate that oral insulin helps control glucose levels with food in healthy volunteers, when compared to injected insulin.

EXAMPLE 12 The mixed micellar formulation of Example 9 was tested in diabetic volunteers, under controlled conditions, to determine the effect of oral insulin on glucose with food, when compared to injected insulin. In a series of tests, ten human diabetic type II volunteers were studied, who received insulin by injection three times a day. In another series of tests, volunteers were tested with insulin, taken orally. The volunteers were left fasting from midnight before the tests, taking food 30 minutes after the dose. The foods were 240 ml of normal Sastacal liquid diet, approved by the Diabetic Society, which contains 400 calories. On the first day, the volunteers received 10 units of insulin per injection (regular rapid-acting insulin, available from Eli Lilly). On the second day, the volunteers received 30 units of the oral insulin prepared above (three times the injection dose). In both tests blood glucose levels were monitored every 15 minutes, using the Bayer Elite glucometer. The average results for the ten volunteers were the following: TABLE XII GLUCOSE LEVELS IN THE BLOOD (mmol / L) The results indicate that oral insulin helps control glucose levels in diabetic patients when compared to injected insulin.

EXAMPLE 13 An insulin formulation, such as chewable gum, was prepared by vigorously stirring the mixed micellar solution of liposomal insulin of Example 9 while adding guar gum, beeswax, acacia powder, oleic acid, gamma-linoleic acid and sorbitol. For each 30 units of insulin the mixture contained 100 mg of guar gum, 50 mg of beeswax, 50 mg of acacia powder, 100 mg of oleic acid, 100 mg of gamma-linoleic acid and 1 ml of 3-sorbitol. % in ethanolic solution. The mixture was then poured into a flat tray lined with polytetrafluoroethylene, until the mixture was approximately 10 mm deep. The mixture then solidified and after solidification was cut into tablets of approximately 1 cm by 3 cm. Each tablet contained approximately 30 units of insulin. The mixed micellar formulation in chewable tablet form was tested in diabetic volunteers under controlled conditions to determine the effect of oral insulin on glucose with food, compared to injected insulin. Five human volunteers type II diabetics, who took insulin by injection three times a day. In another series of tests the volunteers were tested with insulin in chewable gum, taken orally. The volunteers were left fasting from midnight before the tests, taking food 30 minutes after the dose. The food was 240 ml of normal Sastacal liquid diet, approved by the Diabetic Society, which contained 400 calories. On the first day the volunteers received 10 units of insulin by injection (fast-acting, regular insulin, obtainable from Eli Lilly). On the second day, volunteers received 30 units of oral insulin in chewable gum, prepared above (triple the dose per injection). In both tests the blood glucose levels were monitored every 15 minutes, by means of the Bayer Elite glucometer. The results averaged for the five volunteers were as follows: TABLE XIII LEVELS OF GLUCOSE IN THE BLOOD EXAMPLE 14 Another experiment was carried out, within the scope of the present invention. In this example the formulation was for oral administration. A buffer solution was prepared using 0.5 g of sodium lauryl sulfate, 0.5 g of sodium salicylate and 0.25 g of disodium edetate, dissolved in 10 ml of water. The solution was added to 8 mg (200 units) of insulin and mixed to form micellar insulin. 0.2 g of bacitracin and 0.5 g of evening vesoril oil were added to this micellar solution and the solution was mixed vigorously to form a mixed micellar insulin solution (approximately 20 units / ml). Six human volunteers were studied. The volunteers were fasted from midnight before the test, without taking food during the four-hour study. On the first day, the volunteers received 10 units of insulin by injection (regular rapid-acting insulin, available from Eli Lilly). On the second day, the volunteers received 20 units of the oral insulin prepared above (twice the dose per injection). In both tests, blood glucose levels were monitored at intervals, using the Bayer Elite glucometer. The results, which show the average for the six volunteers, were as follows: TABLE XIV GLUCOSE LEVELS IN THE BLOOD (mmol / L) The results show that the oral insulin formulation of the present invention, at a dose twice the level injected, is comparable with the injected insulin.

EXAMPLE 15 Another experiment was carried out to show another method for effecting the mixed micellar formulation of the present invention. In a 250 ml round bottom flask, 100 mg of saturated lecithin powder (Phospholipon-90H), purchased from American Lecithin Co., was added. 5 ml of absolute ethanol (USP grade) was added to this powder. The flask was then fixed to a rotary evaporator with a vacuum pump and admission for nitrogen, to maintain the condition of an inert atmosphere in order to minimize the oxidation of the lecithin. The flask was rotated at 100-150 r.p.m. to the vacuum The solution in the flask was heated to 60 ° C by means of a water bath, to completely dissolve the powder. After complete dissolution of the powder the heating was stopped and the rotation speed was increased to 300 rpm, under vacuum under a nitrogen atmosphere, until the alcohol was completely evaporated, which left a uniform film on the side of the flask. The rotation was continued for at least 30 minutes to ensure uniform coating of the film on the wall and complete the removal of the solvent. After 30 minutes the rotation was stopped and the vacuum was relieved. The micellar insulin solution, which had been prepared from an aqueous solution of insulin, sodium lauryl sulfate, sodium salicylate and disodium edetate, was added to this flask. He shook the flask with the help of a shaking plate. Shaking was continued for at least 30 minutes and then the solution was sonically treated with a sonic treatment probe, high frequency, for another 60 minutes, in order to form uniform, small mixed micelles. The mixed micelles thus obtained were analyzed by means of a Malvern Zeta (registered trademark) particle size distribution measuring equipment equipped with the laser light diffraction device. The particle size distribution of the mixed micelles, obtained by this method, was between 2 and 9 nm. To this solution was added 1 ml of a 2% menthol solution and 50 mg of sodium hyaluronate. The translucent, light blue, semi-glazed solution (final volume 10 ml) was stored in a clean glass bottle and refrigerated. The solution had a pH of 6.5.

EXAMPLE 16 Another experiment was carried out within the scope of the present invention. A buffer solution was prepared using 0.5 g of sodium lauryl sulfate, 0.5 g of sodium salicylate and 0.25 g of disodium edetate, dissolved in 10 ml of water. The solution was added to 8 mg (200 units) of insulin and mixed to form micellar insulin.

To this micellar solution was added 0.5 g of borage oil and the solution was vigorously mixed to form a mixed micellar insulin solution (approximately 20 units / ml).

Claims (9)

1. - A process for preparing a protein pharmaceutical formulation, suitable for delivery through mucosal membranes, characterized in that it comprises: a) preparing a proteinic pharmaceutical agent composition in micellar form, in an aqueous medium having an alkali metal salicylate, at a concentration of 1 to 10% w / w of the total formulation; an alkali metal alkyl sulphate of 8 to 22 carbon atoms, at a concentration of 1 to 10% w / w of the total formulation; and a pharmaceutically acceptable edetate, at a concentration of 1 to 10% w / w of the total formulation; b) slowly add the composition of micellar protein pharmaceutical agent, while mixing, to at least one absorption enhancing compound, while continuing. mixing vigorously; said absorption-enhancing compound is selected from the group consisting of lecithin, hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linolenic acid, borage oil, oil of evening vesicle, menthol, trihydroxy-oxo-colanylglycine and their pharmaceutically acceptable salts; glycerin, polyglycerin, lysine, polylysine, alkyl ethers of polidocanol and their analogues; triolein and its mixtures; wherein the amount of each absorption enhancing compound is present in a concentration of 1 to 10% w / w of the total formulation, and the total concentration of the alkali metal salicylate, alkali metal alkyl sulfate, of 8 to 22 carbon atoms , edetate and absorption enhancing compounds, is less than 50% w / w of the formulation. 2 - A process according to claim 1, further characterized in that there is a further step of adding, while continuing to mix, at least one absorption enhancing compound, different from that added in step b), selected from the group consisting of lecithin, hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile extract, cucumber extract, oleic acid, linolenic acid, borage oil, evening primrose oil, trihydroxy-oxo-colanylglycine, glycerin , polyglycerin, lysine, polylysine, triolein and mixtures thereof. 3. A process according to claim 1, further characterized in that the absorption enhancing compound of step b) is selected from the group consisting of saturated phospholipid, unsaturated phospholipid, phosphatidylcholine, phosphatidylserine, sphingomyelin, phosphatidylethanolamine, cephalin, lecithin, lysolecithin and mixtures of them. 4. A process according to claim 1, further characterized in that one of the absorption-enhancing compounds is lecithin, and another absorption-enhancing compound is selected from the group consisting of hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid and mixtures thereof. they; the concentration of the other absorption enhancing compound being about 1 to 5% w / w. 5. - A process according to claim 1, further characterized in that the absorption-enhancing compounds comprise combinations selected from the group consisting of: i) saturated phospholipid and sodium hyaluronate; ii) saturated phospholipid and glycolic acid; iii) sodium lecithin and hyaluronate; iv) saturated phospholipid, glycolic acid and lactic acid; v) sodium hyaluronate and evening velvet oil; vi) saturated phospholipid and bacitracin; vii) saturated phospholipid, sodium hyaluronate and bacitracin; and viii) sodium hyaluronate, oleic acid and gamma-linoleic acid. 6. - A process according to claim 1, further characterized in that the protein pharmaceutical agent is selected from the group consisting of insulin, heparin, the so-called low molecular weight heparin, hirulog, hirugen, huridin, interferons, interleukins, cytokines, monoclonal antibodies and polyclonal antibodies, chemotherapeutic agents, vaccines, glycoproteins, bacterial toxoids, hormones, calcitonins, insulin-like growth factors (IGF), glucagon-like peptides (GLP-1), large-molecule antibiotics, protein-based thrombolytic compounds, platelet inhibitors, DNA, RNA, genetic therapeutics, opposite-sense oligonucleotides, opioids, narcotics, analgesics, NSAIDS , steroids, hypnotics, pharmaceutical preparations for the treatment of chronic pain and morphine. 7. A process according to claim 1, further characterized in that, in step b), the composition of micellar protein pharmaceutical agent is added to lecithin, with sonic treatment, to form a mixed micellar formulation; and c) while continuing to mix, add at least one absorption enhancing compound, selected from the group consisting of hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile act, cucumber act, acid oleic acid, linolenic acid, borage oil, evening primrose oil, trihydroxy-oxo-colanylglycine, glycerin, polyglycerin, lysine, polylysine, triolein and mixtures thereof; wherein the amount of each of the lecithin and the absorption enhancing compound is present at a concentration of 1 to 10% w / w of the total formulation; and the total concentration of the alkali metal salicylate, alkali metal alkyl sulfate, 8 to 22 carbon atoms, edetate and absorption enhancing compounds is less than 50% w / w of the formulation. 8. A process according to claim 1, further characterized in that the absorption enhancing compound is formed to a film, before adding the composition of micellar pharmaceutical agent. 9. A process according to claim 1, further characterized in that after the addition of the micellar pharmaceutical agent composition a second absorption enhancing compound is added; the second absorption enhancing compound of the first absorption enhancing compound previously used being different. 10. A process according to claim 1, further characterized in that a phenol selected from the group consisting of phenol, methylphenol and mixtures thereof is added to the mixed micellar formulation; and the resulting formulation is placed in a container, and the container is subsequently loaded with a propellant. 11. A process according to claim 10, further characterized in that the propellant is selected from the group consisting of tetrafluoroethane, tetrafluoropropane, dimethylfluoropropane, heptafluoropropane, dimethyl ether, n-butane and isobutane. 1

2. A process according to claim 1, further characterized in that the pharmaceutical agent is insulin. 1

3. A process according to claim 11, further characterized in that the pharmaceutical agent is insulin. 1

4. A mixed micellar protein pharmaceutical formulation, characterized in that it comprises a proteinaceous pharmaceutical agent in micellar form; water, an alkali metal alkyl sulphate, of 8 to 22 carbon atoms, at a concentration of 1 to 10% w / w of the total formulation; a pharmaceutically acceptable edetate, at a concentration of 1 to 10% w / w of the total formulation; at least one alkali metal salicylate, at a concentration of 1 to 10% w / w of the total formulation, and at least one absorption enhancing compound; the absorption enhancing compounds of the group consisting of lecithin, hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, octylphenoxypolyethoxyethanol, glycolic acid, lactic acid, chamomile act, cucumber act, oleic acid, linolenic acid, borage oil, oil are selected of evening vesicle, menthol, trihydroxy-oxo-colanylglycine, and their pharmaceutically acceptable salts; glycerin, polyglycerin, lysine, polylysine, alkyl ethers of potidocanol and its analogues; triolein and its mixtures; wherein the amount of each absorption enhancing compound is present at a concentration of 1 to 10% w / w of the total formulation, and the concentration of alkali metal salicylate, alkali metal alkyl sulfate, of 8 to 22 carbon atoms, edetate and absorption-increasing compounds is less than 50% w / w of the formulation. 1

5. A mixed micellar pharmaceutical formulation according to claim 14, further characterized in that it comprises lecithin. 1

6. A formulation according to claim 14, further characterized in that the alkali metal alkyl sulfate, of 8 to 22 carbon atoms, is sodium lauryl sulfate.; and the alkali metal salicylate is sodium salicylate. 1

7. A formulation according to claim 15, further characterized in that the lecithin is selected from the group consisting of: saturated phospholipid, unsaturated phospholipid, phosphatidylcholine, phosphatidylserine, sphingomyelin, phosphoryl I-ethanolamine, cephalin, lysolecithin, and mixtures of them. 1

8. A formulation according to claim 15, further characterized in that it comprises a second absorption enhancing compound, selected from the group consisting of: hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, and mixtures thereof; the concentration of the second absorption enhancing compound being about 1 to 5% w / w of the total formulation. 1

9. A formulation according to claim 14, further characterized in that it comprises a combination selected from the group consisting of: i) sodium lauryl sulfate, sodium salicylate, disodium edetate, saturated phospholipid and sodium hyaluronate; ii) sodium lauryl sulphonate, sodium salicylate, disodium edetate, lecithin and sodium hyaluronate; iii) sodium lauryl sulphate, sodium salicylate, disodium edetate, sodium hyaluronate and evening vesperine oil; iv) sodium lauryl sulfate, sodium salicylate, disodium edetate, saturated phospholipid and bacitracin; v) sodium lauryl sulfate, sodium salicylate, disodium edetate, saturated phospholipid, sodium hyaluronate and bacitracin; vi) sodium lauryl sulfate, sodium salicylate, disodium edetate, sodium hyaluronate, oleic acid and gamma-linoleic acid; vii) sodium lauryl sulfate, sodium salicylate, disodium edetate, saturated phospholipid and glycolic acid; and viii) sodium lauryl sulfate, sodium salicylate, disodium edetate, saturated phospholipid, glycolic acid and lactic acid. 20. A formulation according to claim 14, further characterized in that the pharmaceutical agent is selected from the group consisting of insulin, heparin, the so-called low molecular weight heparin, hirulog, hirugen, huridine, interferons, interleukins, cytokines, antibodies monoclonal and polyclonal, chemotherapeutic agents, vaccines, glycoproteins, bacterial toxoids, hormones, calcitonins, insulin-like growth factors (IGF), glucagon-like peptides (GLP-1), large-molecule antibiotics, thrombolytic compounds based on proteins, inhibitors of platelets, DNA, RNA, genetic therapeutics, oligonucleotides of opposite direction, opioids, narcotics, analgesics, NSAIDs, steroids, hypnotics, pharmaceutical preparations for the treatment of chronic pain, and morphine. 21. A formulation according to claim 14, further characterized in that the pharmaceutical agent is insulin. 22. A formulation according to claim 21, further characterized in that the absorption-enhancing compounds are lecithin; and a second absorption enhancing compound, selected from the group consisting of hyaluronic acid, pharmaceutically acceptable salts of hyaluronic acid, and mixtures thereof. 23.- A formulation in accordance with the claim 14, further characterized in that the formulation further comprises a phenol selected from the group consisting of phenol, methylphenol and mixtures thereof. 24. A formulation according to claim 23, further characterized in that the formulation is contained in an aerosol container and the container is loaded with a propellant. 25.- A formulation in accordance with the claim 24, further characterized in that the propellant is selected from the group consisting of tetrafluoroethane, tetrafluoropropane, dimethylfluoropropane, heptafluoropropane, dimethyl ether, n-butane and isobutane.