MXPA06007464A - Microemulsions for pharmaceutical compositions - Google Patents

Abstract

The invention provides microemulsion pharmaceutical compositions comprising pharmaceutical actives which are hydrotropes that facilitate formation of microemulsions. The invention further provides methods of making the compositions and utilization of the compositions in liquid fill soft shell capsules including capsules having shells of non -animal derived materials (e.g. non-ADRM).

Description

MICROEMULSIONS FOR PHARMACEUTICAL COMPOSITIONS Field of the Invention The present invention relates to the field of pharmaceutical compositions comprising mieroemulsions and to methods for preparing such microemulsions and to pharmaceutical compositions comprising such microemulsions and to drug delivery systems in soft capsules comprising such microemulsions. BACKGROUND OF THE INVENTION A number of therapeutic agents have a poor solubility in aqueous solutions. This limited solubility has an impact both on the preparation of the formulations for administration to patients and on the delivery of the therapeutic agents in physiological, aqueous environments. Methods for improving the solubility of low solubility therapeutics are particularly desirable for liquid-based preparations, such as the preparations proposed for encapsulation including, for example, encapsulation in a gel, and microencapsulation. In such compositions that include the desired amount of the therapeutic agent in a small volume, swallowing by the patient is facilitated. In addition, the pre-solubilization of the therapeutic agent in the vehicle of Ref.173954 delivery may also be desirable to improve the absorption of therapeutic agents of limited solubility. However, at least two major challenges must be faced to provide a composition with improved solubility therapeutic agents, suitable for use in encapsulations. First, a stable composition with improved solubility of the therapeutic agent of interest must be prepared and secondly the composition thus prepared must be compatible with the encapsulating delivery vehicle. Various methods have been used to prepare compositions comprising improved amounts of therapeutic agents having poor solubility in water, including oil-in-water emulsions, micelle solutions, liposomes or other multi-lamellar carrier particles. Typically, these methods involve specialized solvent systems and frequently maintenance of the therapeutic agent in the solubilized or dispersed form is problematic. Not all liquids are suitable as vehicles or carriers for use in soft gelatine capsules. Yu et al. It has specifically established that "oil / water or water / oil emulsions are not suitable for encapsulation in a soft gel because they can eventually break, releasing the water that dissolves the outer layer of gelatin." (U.S. Patent No. .360 / 615, column 1, lines 61-64). Water compositions or more generally hydrophilic compositions tend to be miscible with the gelatinous hydrophilic material typically used for the outer layers of the capsule. Examples of other hydrophilic materials besides water, which are prone to react with the outer layer of the delivery vehicles typically used for encapsulation include propylene glycol, glycerin, low molecular weight alcohols, aldehydes / ketones, acids, amines and esters. Undesirable reactions may be immediate and may prevent the formation of the encapsulated compositions or may involve more gradual processes that degrade the integrity of the delivery vehicle over time and prevent the production of an encapsulated product with a usable shelf life. Furthermore, in recent years it has become desirable to avoid the use of animal-derived materials in the preparation of pharmaceutical substances. As gelatin is a material derived from an animal, it may be desirable to use alternative materials for the formation of capsules. However, since the alternative capsule materials are typically water soluble, they also have problems similar to those described for gelatin capsules as well as problems associated with the chemical nature of the specific materials.

However, there is a need for a practical method to provide improved solubility of the therapeutic agents, which have a low solubility in water, in the water containing the compositions, in a form that is compatible with the soft, soluble outer layers. in water, used as vehicles to supply the encapsulation. Brief Description of the Invention The invention is directed to a pharmaceutical composition for filling with a liquid of the capsules with a soft outer layer, comprising, based on the total weight of the composition, from about 15% w / w to about 50 % w / w of the hydrotropic pharmaceutical active substance; from about 10% w / w to about 65% w / w oil; and water, wherein at least a portion of the hydrotropic pharmaceutical active compound is in the form of a salt. The pharmaceutical, hydrotropic active substance can be selected from ibuprofen, naproxen, ethoprofen, salicylic acid, para-aminobenzoic acid (PABA), procaine, quincaine, resorcinol, pyrogallol, ephedrine, pseudoephedrine, phenothiazines including chlorpromazine, and promethazine, nicotinamide, and isoniazid and mixtures thereof. The oil can be selected from medium chain triglycerides and their derivatives, short chain oils, including tributyrin (C), mono and diglycerides, fatty acids, and their derivatives including fatty acid esters, long chain triglycerides, polyunsaturated oils including oil of sesame, corn oil, and soybean oil, monounsaturated oils including olive oil or canola oil, saturated oils including coconut oil and mixtures thereof. The composition may further comprise an ionization agent that reacts with the hydrotropic pharmaceutical active substance, which forms at least a portion of the hydrotropic pharmaceutical active substance in the salt form. Optionally, the composition may comprise from about 0% to about 20% by weight of the surfactant and in some embodiments from about 0% to about 14% by weight of the surfactant. The surfactant may be selected from polyoxyl castor oils, sorbitan esters, polysorbates, pegylated vegetable oil derivatives, lecithin, polyoxyethylene-polyoxypropylene block copolymers and medium chain mono / di-glycerides, or mixtures thereof. The composition of the invention can be transparent. In one embodiment, the pharmaceutical composition for filling with a liquid of soft outer layer capsules comprises, based on the total weight of the composition, from about 15% to about 50% by weight of ibuprofen; from about 15% to about 65% w / w of medium chain triglycerides, and water. A portion of the ibuprofen is present as potassium ibuprofen and the molar ratio of the potassium ibuprofen to a non-ionized ibuprofen is from about 0.3 to 0.4. Optionally, the composition may further comprise about 0 to 14% of a surfactant. The invention includes a method of manufacturing a pharmaceutical composition for filling with a capsule liquid with a soft outer layer. The method comprises obtaining a hydrotropic pharmaceutical active substance having at least a portion of the hydrotropic pharmaceutical active substance in the form of a salt; get water; get an oil; and mix the pharmaceutical agent with the water and the oil. Optionally the method may comprise adding about 0-14% of the surfactant. In one embodiment, the method may further comprise the step of mixing the hydrotropic pharmaceutical active compound with an ionization agent to form at least a portion of the hydrotropic pharmaceutical active compound in a salt form. The invention further includes a soft capsule for filling with liquid containing the pharmaceutical composition described herein. The soft capsule for filling with a liquid may have an outer layer comprised of a material other than ADRM. One embodiment of the invention includes a pharmaceutical composition for filling with a liquid of a capsule with a hard outer layer of a material other than ADRM comprising, based on the total weight of the composition, from about 15% w / w to about 50% w / w of the hydrotropic pharmaceutical active substance; from about 10% w / w to about 65% w / w oil; and water, and wherein at least a portion of the compound. Hydrotropic active pharmaceutical is in a salt form. The hard outer layer of the capsule for filling with the liquid may comprise materials other than ADRM, and portions of the capsules may be sealed. One embodiment of the invention includes a pharmaceutical composition for filling with a liquid of the soft outer layer capsules comprising, based on the weight of the composition, from about 15% w / w to about 50% w / w of the substance active hydrotropic pharmaceutical; from about 10% w / w to about 65% w / w oil; a nonionic surfactant; and a crystallization inhibitor. Approximately 15% w / w up to about 25% w / w polyvinyl pyrrolidone can be used as the crystallization inhibitor. Detailed Description of the Invention The invention provides pharmaceutical compositions comprising microemulsions and methods of preparing such microemulsions and pharmaceutical compositions comprising such microemulsions and drug delivery systems in a soft capsule comprising such microemulsions. The microemulsions of the invention provide improved solubility of the therapeutic agents having improved compatibility with the water soluble outer layers used as encapsulation delivery vehicles. The inventors have surprisingly discovered that certain pharmaceutically active ingredients can be used to bind and stabilize the immiscible aqueous and oily phases to create clear water-in-oil (e.g., clear) microemulsions. A microemulsion means a thermodynamically and optically isotropic stable system consisting of two immiscible liquid components. The microemulsions are typically composed of a continuous phase, a dispersed phase, and an agent that stabilizes the microemulsion. Microemulsions differ from emulsions (macro or coarse) in that the dispersed phase consists of globules less than 100 nanometers (0.1 micrometers) and more particularly about 30 to about 60 nanometers in diameter. The differences between coarse emulsions and microemulsions, however, are not only the size of the dispersed phase. The microemulsions do not separate during the rest, while the rough emulsions separate, even though this only happens after a prolonged period of time. The microemulsions are also transparent because small droplets of the dispersed phase do not refract visible light. In previously known microemulsions, the stabilizing agent is typically a surfactant or a combination of surfactants. In the present invention, the dispersed phase is preferably an aqueous medium present within a continuous oily phase. The two phases are joined using a hydrotropic stabilizing agent. Hydrotropes are organic molecules that act as solubilization and binding agents to prevent the separation of phases in aqueous solubilized systems (Friberg and Branceqicz, O / W Microejections and Hydrotropes, The Coupling Action of Hydrotrope, Langmuir, 10, 1994 , 2945-2949, incorporated herein by reference). Unlike traditional surfactants, hydrotropes are small organic molecules. The hydrotropes lack long, aliphatic carbon chains typically associated with traditional surfactants. The hydrotropes typically have a structure that includes a ring and which lacks mostly aliphatic chain substituents particularly straight or branched aliphatic chains exceeding 6 carbons in length.

The therapeutic agents used in the practice of the inventions are the hydrotropes referred to herein as pharmaceutically active, hydrotropic substances. (For the purpose of this description and claims, terms such as the active therapeutic substance, the therapeutic agent, the pharmaceutical agent and the drug, should be taken as being equivalent to the pharmaceutical active substance). Non-steroidal anti-inflammatory compounds (NSAIDs), such as ibuprofen and ketoprofen, are examples of such pharmaceutically active hydrotropes. Although not wishing to be bound by any operational theory, the inventors believe that the hydrotrope contributes to the properties of the surface active substance and facilitates the formulation of the microemulsion. Accordingly, it is the inventors' belief that the therapeutic agents serve the dual function of acting as the active pharmaceutical agent and as the primary binding / stabilizing agent. The continuous phase of the microemulsions of the present invention is preferably an oil such as a medium chain triglyceride, for example. The microemulsions of the invention are particularly well suited for use in encapsulated pharmaceutical preparations and offer several benefits over existing art. The microemulsion formulations of the invention have been shown, in certain embodiments, not to interfere with the sealing of the soft capsule and have shown good long-term compatibility with the hydrophilic films used for the soft capsules. Since the therapeutic agent is a surface active hydrotrope, the water / oil interface where the therapeutic agent is believed to reside can serve as a high capacity reservoir allowing high drug loading if desired. Additionally, because the microemulsions are thermodynamically stable, these formulations are physically stable under normal storage conditions. The successful formulation of a microemulsion is dependent on the proper selection of the components and the concentrations of the components. It is believed that the order of addition of the components is not critical and that the microemulsions of the present invention will form spontaneously giving a suitable combination of the components and a sufficient time. Generally, it is easier to mix the water soluble components first in the company of the hydrotropic therapeutic agent. The hydrotrope can be used in a free acid form, in a free base form, in a salt form, or as a mixture of a free acid form or a free base form and a salt form. The oily phase materials are subsequently added with mixing to create the final microemulsion composition. Occasionally, it may be desirable to gently heat the mixture to reduce the time of formation of the microemulsion. Typically, the microemulsions thus prepared are clear. Such microemulsions can be prepared with amounts of active pharmaceutical ingredients substantially larger than the amount of the active pharmaceutical ingredient that can be dissolved in an equivalent volume of water. A microemulsion thus prepared can be used in the preparation of pharmaceutical compositions (e.g., compositions capable of consumption by an individual in need of treatment) and are particularly well suited for use in encapsulated pharmaceutical preparations. Hydrotropes are typically used at relatively high concentrations in the compositions of the invention to provide the characteristic stabilizing and binding properties. A number of pharmaceutical active agents are hydrotropes. Hydrotropic pharmaceutical active substances that can be used in the practice of the invention include but are not limited to non-steroidal anti-inflammatory drugs including ibuprofen, naproxen, ketoprofen, salicylic acid; Para-aminobenzoic acid (PABA), procaine. fivecaine, resorcinol, pyrogallol, ephedrine, pseudoephedrine, phenothiazines including chlorpromazine, and promethazine; nicotinamide, and isoniazid. The hydrotrope is preferably used in an amount of about 15% to about 50% w / w (percent by weight of the hydrotrope with respect to the total weight of the microemulsion composition) and more preferably used in an amount of 25% up to about 45% p / p. Preferred oils in the microemulsion compositions of the invention are medium chain triglycerides. Medium chain triglycerides are defined as triglycerides having carbon chain substituents in which each of the substituent carbon chains is from about 6 to 12 carbons in length and preferably from about 8 to about 10 carbons in length. The three carbon chains substituents of a given triglyceride may be the same or different, and when used in the compositions of the invention, the triglyceride oil may comprise a single type of medium chain triglyceride or a mixture of medium chain triglycerides. The medium chain triglyceride carbon chains can be saturated, unsaturated or a mixture thereof. The commercially available medium chain triglyceride composition commercialized as Captex ™ 355 EP, produced by Abitec Corporation, Columbus, Ohio has been found to be useful in the practice of the invention, for example. Medium chain triglycerides and their derivatives are the preferred oils. However, other suitable oils include short chain oils, such as tributyrin (C); mono and diglycerides; fatty acids, fatty acid derivatives such as esters of fatty acids; long chain triglycerides; polyunsaturated oils such as sesame oil, corn oil, and soybean oil; monounsaturated oils such as olive oil or canola oil; and saturated oils such as coconut oil. The oils can be mixtures of compounds with similar structures and / or mixtures of different types of oils such as mixtures of medium and long chain triglycerides, for example. The oils are preferably present in an amount of about 15% to about 65% w / w and more preferably in an amount of about 15% to about 55% w / w. In the present invention, the aqueous phase is typically the dispersed phase within the microemulsion. In addition to water, other suitable aqueous soluble components may be included in some embodiments to help solubilize the hydrotrope, additionally stabilize the microemulsion, and / or alter the viscosity of the microemulsion. These additional components may include, but are not limited to, polyethylene glycols, cellulose derivatives, propylene glycol, propylene carbonate, glycerin, sorbitol, mannitol, and trehalose. Optionally, preservatives can also be incorporated into the aqueous phase. Optionally, a surfactant can be added to the microemulsion to additionally stabilize the microemulsion. Preferred surfactants include surfactant, nonionic polyoxyl ricino oils, such as Cre aphors ™, sorbitan esters such as Spans ™, polysorbates such as T eens ™, pegylated vegetable oil derivatives such as Tagats ™, lecithin, block copolymers of polyoxyethylene-polyoxypropylene and mono / diglycerides of medium chain. This is an exemplary list of surfactants and other nonionic surfactants and ionic surfactants are believed to be also suitable for use in the microemulsion of the invention. The surfactants are preferably used in amounts of about 0% to about 20%, and more preferably in amounts of about 0% to about 14%. It should be noted that the amount of the surfactant used is consistent with the amount of the surfactant typically used as co-surfactants. In the modalities that use a surfactant, the amounts of surfactant are reduced when compared with the known compositions due to the use of the hydrotropic pharmaceutical active substance, which facilitates the formation of the microemulsion. In some embodiments, it may be desirable to use a form of the hydrotrope salt or a partial salt, for example a composition in which a portion of the hydrotrope is in a salt form and a portion of the hydrotrope is in a different form from the hydrotrope. Salt. The salt form, in some embodiments, may increase the solubility of the hydrotrope in the aqueous or dispersed phase. The inventors believe, without wishing to be bound by any theory, that the ionization of the hydrotrope with an ionization agent can impart a polar character to a portion of the hydrotrope molecule and improve its coupling and stabilizing effect. When a partial salt is used, the preferred partial salt is the product of a reaction of an acid hydrotrope with a strong base as the ionization agent. For example, with hydrotropes that are weak acids, similar to ibuprofen, strong bases such as NaOH or KOH are preferred. However, bases such as ammonia or basic amino acids such as arginine or Usin can be used. For hydrotropes that are weak bases, strong or weak acids are preferred as ionization agents. If a weak base is used, a weak base with a pKa above 7.2 is preferred. In some embodiments, it may be desirable to provide cushioning to maintain a desirable pH. It is not necessary to use a complete salt, for example, to completely convert the hydrotrope to a salt. Indeed, in some embodiments, a partial salt of the hydrotrope is preferable. The preformed salts of the hydrotrope can be used or alternatively the salts can be made during the formulation by ionization of the hydrotrope with a solution of the appropriate acid or base. The ionization agent is typically provided in a relatively concentrated solution. For example, a 50% w / w KOH solution (KOH in water) can be used with ibuprofen. In the embodiments in which the ibuprofen is the hydrotrope, the amount of the base used will preferably be sufficient to give a mixture in a molar ratio of potassium ibuprofen to un-ionized ibuprofen of from about 0.3 to about 0.4. As an alternative to the use of an ionization agent, the hydrotropic pharmaceutical active substance can be made more soluble in the aqueous phase or dispersed by melting the hydrotropic pharmaceutical active substance in the presence of a crystallization inhibitor. Suitable crystallization inhibitors include, for example, polyvinyl pyrrolidone (PVP) in the range of about 15% to about 25% w / w. The microemulsions of the invention can be incorporated into pharmaceutical preparations for administration to patients. The microemulsions are capable of being incorporated into a wide range of delivery vehicles, including but not limited to liquid pharmaceutical preparations, soft gel pharmaceutical preparations, pharmaceutical preparations in gel form, soft capsule preparations for filling with a liquid, sealed hard capsule preparations, and pharmaceutical film preparations. The amounts of microemulsions included in the pharmaceutical preparation are amounts consistent with an effective dosage of the pharmaceutical active ingredient (or "pharmaceutical active substance") of the composition. In an exemplary embodiment, an effective dosage of ibuprofen can be administered in about 0.4 ml to about 1 ml of the microemulsion, for example. The amounts of microemulsion necessary to supply the desired dosage may vary depending on the level of dosage desired, the proposed patient (dosing for child versus dosing for adult, for example) and / or the nature of the active pharmaceutical substances. The pharmaceutical preparations thus prepared are administered to individuals in need of treatment by methods well known to those skilled in the art of using practices consistent with the established practices for the use of the pharmaceutical active substances of the composition. The use of a delivery system comprising the microemulsion of this invention in a soft outer layer capsule is particularly desirable. A soft outer layer capsule is a single unit solid dosage form, consisting of a liquid or semi-solid filler wrapped in an elastic, sealed outer layer in one piece. In one embodiment, soft outer layer capsules can be formed from two strips of elastic outer layer material that are filled and sealed in a continuous operation employing, for example, a rotary matrix process to form the sealed elastic outer layer in one piece. Soft outer layer capsules suitable for use in a drug delivery system with the microemulsion described herein include soft gelatine-based capsules as well as capsules that are not gelatin-based. The outer layers of the gelatin-based capsule typically have a composition comprising gelatin, a plasticizer and water. Other additives may be included to modify the physical properties of the outer layer such as dyes and / or opacity modifiers, for example. In an exemplary embodiment of a gel-based outer layer, the gelatin has a gel strength of about 150-200 degrees of bloom, a viscosity (60 ° C / 6 2/3% w / w in water) of about 2.8 -4.5 m Pas, a well controlled degree of viscosity rupture, a well-defined particle size and a broad molecular weight distribution. Gelatin can be obtained from any of a variety of animal sources or a combination of animal sources. Typical plasticizers include but are not limited to glycerol, non-crystallizing aqueous sorbitol or solutions of sorbitol / sorbitan, propylene glycol and polyethylene glycol. The outer layers of the soft capsules other than gelatin can be used in the practice of the invention. Hydrocolloid plant-derived materials such as carrageenan, modified starches or starches such as hydroxypropyl starch, methylcellulose and hydroxypropylmethyl cellulose and combinations thereof are examples of plant derived materials that can be used as the base material to form capsules soft gelatin free. Synthetic polymers such as polyvinyl alcohol (PVA) for example, can also be used for soft outer layers. Alternatively, combinations of plant materials and synthetic materials can be used, such as, for example, the use of a combination of PVA and starch for an outer layer of the capsule. In addition to the base material, the outer layers of the non-gelatin capsule may include plasticizers. (See international patent applications WO 9735537, WO 0103677 and WO 0137817 incorporated herein by reference to the extent that their description is consistent with the present disclosure). The main criteria for the selection of a material other than gelatin for the formation of outer layers of the capsule include the ability of the material to form a deformable, machinable film; the ability to effectively seal the material to prevent leakage or loss of the fill material from the finished capsule, and biocompatibility including but not limited to toxicological acceptability and an acceptable impact if any impact on the bioavailability profile of the substance Active pharmaceutical filling in the capsule delivery system is expected. The outer layers of the capsule on synthetic polymers and / or materials derived from plants are considered to be non-animal derived materials (eg, different from ADRM) and have the advantage of avoiding issues related to ingestion of materials derived from animals. In another exemplary embodiment, a hard outer layer capsule of a plant material, gelatinous, a synthetic material or combinations thereof, may be employed. Preferably, a different ADRM material (s) is (are) used for the outer layer. If a hard outer layer of the capsule is used, the portions of the capsule must be sealed after filling with the microemulsion composition. Example 1 The exemplary microemulsion modalities of the invention using ibuprofen / potassium ibuprofen as the hydrotrope, are provided in Tables 1, 2 and 3. In these examples, the potassium ibuprofen was prepared by mixing a concentrated aqueous solution of sodium hydroxide. potassium with ibuprofen. The microemulsion is typically prepared by first mixing the aqueous soluble components. The medium chain triglycerides are then added and the clear microemulsion is formed spontaneously. Ibuprofen is often not fully solubilized until the oil is added and the microemulsion begins to form. The formation time of the microemulsion can be reduced by heating the mixture to 40-60 ° C for a short time interval (typically 30 minutes).

Table 1 Table 2 Table 3 EXAMPLE II The water microemulsions in ibuprofen oil, exemplary, prepared from the free acid ibuprofen, are provided in table 4. For the preparation of the compositions, the ibuprofen was heated in Cremaphor RH 40, PEG 600 and Povidone K17 . The molten material was combined with the oily component to form the microemulsion compositions. Table 4 It will be understood that the specific embodiments of the invention shown and described herein are exemplary only. Numerous variations, changes, substitutions and equivalents will be appreciated by those skilled in the art without departing from the spirit and scope of the present invention. In particular, the terms used in this application should be read widely in view of their similar terms used in related applications. Accordingly, it is proposed that all subject matter described herein and shown in the accompanying drawings be considered as illustrative only and not in a limiting sense, and that the scope of the invention be determined only by the appended claims. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (23)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property. A pharmaceutical composition for filling the capsules with a soft outer layer with a liquid, characterized in that it comprises, based on the total weight of the composition: from about 15% w / w to about 50% w / w of the pharmaceutical active substance hydrotropic; from about 10% w / w to about 65% w / w oil; and water, wherein at least a portion of the hydrotropic pharmaceutical active substance is in a salt form. The composition according to claim 1, characterized in that the hydrotropic pharmaceutical active substance is selected from the group consisting of ibuprofen, naproxen, ketoprofen, salicylic acid; para-aminobenzoic acid (PABA), procaine, quincaine, resorcinol, pyrogallol, ephedrine, pseudoephedrine, phenothiazines including chlorpromazine, and pro-etazine, nicotinamide, and isoniazid and mixtures thereof. 3. The composition according to claim 1, characterized in that the oil is selected from the group consisting of medium chain triglycerides and their derivatives; short chain oils, including tributyrin (C); mono and diglycerides; fatty acids, and their derivatives including esters of fatty acids, long chain triglycerides; polyunsaturated oils including sesame oil, corn oil, and soybean oil; monounsaturated oils that include olive oil or canola oil; saturated oils including coconut oil and mixtures thereof. 4. The composition according to claim 3, characterized in that the oil is a medium chain triglyceride. 5. The composition according to claim 1, characterized in that it further comprises an ionization agent wherein the ionization agent reacts with the hydrotropic active pharmaceutical substance forming at least a portion of the hydrotropic pharmaceutical active substance in the salt form. 6. The composition according to claim 1, characterized in that it further comprises from about 0% to about 20% by weight of the surfactant. The composition according to claim 6, characterized in that it comprises from about 0% to about 14% by weight of the surfactant. 8. The composition according to claim 7, characterized in that the surfactant is selected from the group consisting of polyoxyl castor oil, sorbitan esters, polysorbates, pegylated vegetable oil derivatives, lecithin, polyoxyethylene-polyoxypropylene block copolymers and mono / medium chain di-glycerides, or mixtures thereof. The composition according to claim 1, characterized in that the hydrotropic pharmaceutical active substance is selected from the group consisting of ibuprofen, naproxen, and ketoprofen. 10. The composition according to claim 1, characterized in that the composition is transparent. 11. A pharmaceutical composition for filling with a liquid of the soft outer layer capsules, characterized in that it comprises, based on the total weight of the composition: from about 15% to about 50% by weight of the ibuprofen; from about 15% to about 65% w / w of medium chain triglycerides; and water, wherein a first portion of the ibuprofen is potassium ibuprofen and the second portion of the ibuprofen is not ionized, and the molar ratio of the first portion of potassium ibuprofen to the second portion of the non-ionized ibuprofen is from about 0.3 to 0.4. . 12. The composition according to claim 11, characterized in that it also comprises approximately 0% up to 14% of the surfactant. The components according to claim 12, characterized in that the surfactant is selected from the group consisting of sorbitan esters and polysorbates. A method of manufacturing a pharmaceutical composition for filling with a liquid of soft outer layer capsules, characterized in that it comprises: obtaining a hydrotropic pharmaceutical active substance having at least a portion of the hydrotropic pharmaceutical active ingredient in a salt form; get water; get an oil; and mix the pharmaceutical agent with the water and the oil. 15. The method according to claim 14, characterized in that it further comprises adding approximately 0% to approximately 14% of the surfactant. 16. The method of compliance with the claim 14, characterized in that the hydrotropic pharmaceutical active substance is ibuprofen. 17. The method of compliance with the claim 14, characterized in that it further comprises the step of mixing the hydrotropic pharmaceutical active substance with an ionization agent to form at least a portion of the pharmaceutical, hydrotropic active substance in a salt form. 18. A soft capsule for filling with a liquid, characterized in that it contains a composition according to any of claims 1 to 13. 19. Soft capsules for filling with a liquid according to claim 18, characterized in that the capsule soft has an outer layer comprised of a material other than ADRM. 20. A pharmaceutical composition for filling with a liquid of a capsule of a material other than ADRM in the hard outer layer, characterized in that it comprises, based on the total weight of the composition: from about 15% w / w to about 50% p / p of the hydrotropic pharmaceutical active substance; from about 10% w / w to about 65 w / w oil; and water, wherein at least a portion of the hydrotropic pharmaceutical active substance is in the form of a salt. 21. A hard capsule for filling with a liquid, containing the composition according to claim 20, characterized in that the outer layer of the capsule comprises materials other than ADRM and wherein the outer layer of the capsule has portions of the capsule which are sealed. 22. A pharmaceutical composition for filling with a liquid of a soft outer layer capsule, characterized in that it comprises, based on the total weight of the composition: from about 15% w / w to about 50% w / w of the hydrotropic pharmaceutical active substance; from about 10% w / w to about 65% w / w oil; a nonionic surfactant; and a crystallization inhibitor. 23. The composition according to claim 22, characterized in that the crystallization inhibitor is about 15% w / w to about 25% w / w polyvinyl pyrrolidone.