 INJECTABLE PHARMACEUTICAL COMPOSITION, ITS METHOD OF PRODUCTION AND USE, AS WELL AS METHOD OF CONSER
专利摘要:
abstract methods of preserving injectable pharmaceutical compositions comprising a cyclodextrin and a hydrophobic drug the invention is related to injectable pharmaceutical compositions, methods of use and formulation, where the compositions comprise: one or more water-soluble complexes, with each complex comprising a cyclodextrin or its derivative and a hydrophobic drug; at least one preservative; and at least one cosolvent. the compositions are effectively preserved according to the european pharmacopeia 2011, test for efficacy of antimicrobial preservation, satisfying at least criterion b for parenteral drugs, and with american pharmacopeia 2011, guidelines for antimicrobial effectiveness testing, satisfying the criterion for category products 1 (injectable). 公开号:BR112014012985B1 申请号:R112014012985-1 申请日:2012-11-27 公开日:2020-05-12 发明作者:Kirby Shawn Pasloske；Lau Kai；Sarah Jane Richardson；Amanda Aileen Willis 申请人:Jurox Pty Ltd； IPC主号:
专利说明:
INJECTABLE PHARMACEUTICAL COMPOSITION, ITS METHOD OF PRODUCTION AND USE, AS WELL AS METHOD OF CONSERVING AN INJECTABLE PHARMACEUTICAL COMPOSITION AND USE OF AT LEAST ONE CO-SOLVENT AND AT LEAST ONE CONSERVATIVE Cross Reference to Related Applications [001] This application claims priority for Australian Provisional Patent Application No. 2011904970, filed on November 29, 2011 and Australian Provisional Patent Application No. 2012904962, filed on November 9, 2012, whose content is incorporated into the present invention as a reference. Technical field [002] The invention relates to injectable pharmaceutical compositions that are effectively preserved according to the European Pharmacopoeia Antimicrobial Conservation Effectiveness Test 2011, meeting at least criterion B for parenteral drugs, and the Antimicrobial Efficiency Test Guidelines of the American Pharmacopoeia 2011, for products of category 1 (injectable). The compositions can be stored in containers of suitable size that allow the use of a single or multiple doses. In addition, the invention offers methods for making and using the compositions defined in the present description. Background of the invention [003] Cyclodextrins are cyclic oligosaccharides that have a toroidal structure and central hydrophobic / lipophilic cavities and hydrophilic outer surfaces. A number of different cyclodextrin structures exist in nature, with a predominance of α 2/69 cyclodextrin, β-cyclodextrin and γ-cyclodextrin, which consist of 6, 7 and 8 glycopyranose units, respectively. [004] Cyclodextrins are known to increase the solubility of drugs and pharmaceutical products that are insoluble or have little solubility in water. The use of cyclodextrins and their derivatives helps to stabilize drugs through the reversible formation of water-soluble complexes. The formation of these complexes can prohibit or reduce the occurrence of parallel reactions that occur between the drug and other species present in a solution. The drug molecule, partially or totally, is located inside the central cavity of the cyclodextrin, or is derived from the cyclodextrin to produce an inclusion complex. Consequently, several cyclodextrins and their derivatives have been found safe for use in pharmaceutical excipients, for example, in Alfaxan® (WO 01/70234). [005] Generally, β-cyclodextrin and its derivatives are used in the manufacture of medicines. This occurs due to several reasons that include the size of the lipophilic cavity, the commercial availability, the low cost of the molecules, among other favorable aspects. [006] An important derivative is 2-hydroxypropyl — βcyclodextrin which has been shown to be more water-soluble and more toxic when compared to α-, β- and γ- cyclodextrin. In addition, in several studies, this derivative has been shown to be well tolerated by many species including rats, mice and dogs (S. Gould et al., Food and Chemical Technology, 43, 1451-1459, 2005). 3/69 [007] When cyclodextrins and their derivatives are used to solubilize materials in an aqueous medium, competition may occur between the various species present in the solution to occupy the central cavities of the cyclodextrin molecules. This means that one compound may be more soluble than others that may be present. This is an important point to be considered when solubilizing pharmaceutical compounds with cyclodextrins, because it is the active compound, for example, a drug molecule, which is incorporated into the cyclodextrin and not any of the other excipients that may be present in the composition. For example, preservatives can be introduced into a liquid pharmaceutical composition to eliminate any bacteria, yeast or mold that may be accidentally introduced into the composition. These species of preservatives can displace the drug molecule from the hydrophobic cavity of the cyclodextrin or cyclodextrin derivative, where the drug is unable to remain solubilized in the liquid medium and precipitate into the solution. This displacement of the drug molecule can lead to the formation of particles, compromising safety when the pharmaceutical composition is administered via injection. [008] The displacement of the drug means that the pharmaceutically active compound, for example, a hydrophobic drug, is not completely solubilized. This causes a reduction in efficacy, where the drug cannot perform its function and induce the necessary pharmacological and physiological response. In addition, for the preservative (s) to be effective in relation to bacteria, yeast and mold, it (s) should preferably remain unbound 4/69 the solution and not complexed in cyclodextrin guest molecules. If the preservative (s) forms (s) complexes with the cyclodextrins in the solution, the pharmaceutical composition may not be in accordance with conservation standards or prescribed drug standards. [009] Loftsson et al. (Drug Development and Industrial Pharmacy, 18 (13), 1477-1484, 1992) conducted several researches with 2-hydroxypropyl-p-cyclodextrin and its interactions with a selection of preservatives, including chlorobutanol, methylparaben and propylparaben, which are commonly used in multidose pharmaceutical products. The interactions were shown to be double. First, the chlorobutanol, methylparaben and propylparaben molecules are capable of displacing the drug molecules from the cyclodextrin cavity, preventing the effectiveness of cyclodextrin in solubilizing the hydrophobic drug. Second, the antimicrobial activities of the preservatives chlorobutanol, methylparaben and propylparaben have been reduced or completely prevented in the presence of 2-hydroxypropyl — β-cyclodextrin, due to the sequestration of the preservatives. [010] A number of patents use cyclodextrins to increase the solubility of drugs to improve their supply, albeit to a limited extent. [011] WO 01/70234 describes a pharmaceutical composition comprising a water-soluble cyclodextrin or a derivative thereof and alphaxalone. The composition is stable and can be administered, in an effective amount as an anesthetic, to warm-blooded animals, including birds and mammals, reptiles, fish and amphibians. Although the invention can be 5/69 used with an anesthetic effect, the patent does not describe or suggest a composition comprising a co-solvent and a preservative. [012] US 6358935 and US 6723353 describe pharmaceutically acceptable compositions that include a liquid medium, a cyclodextrin component, a chlorite present in a conservation effective amount and a pharmaceutically active component. The formulations do not include a cosolvent. [013] WO 2005/082416 describes formulations comprising β-cyclodextrin, a pharmaceutically acceptable preservative, where preservatives are limited to meta-cresol, phenol or thimerosal, or combinations thereof, and a neurokinin receptor antagonist as the active pharmaceutical component . The invention is based on the binding value of the active pharmaceutical component with the β-cyclodextrins, which is greater than the preservatives with the equivalent β-cyclodextrin molecule. An optimum balance between the concentrations of cyclodextrin and the antimicrobial preservative is necessary for the composition to comply with conservation standards and obtain acceptable injection sites. The patent does not describe aqueous formulations that comprise at least one preservative and at least one co-solvent. [014] Any discussion of documents, acts, materials, devices, articles or the like, which have been included in this specification, should not be considered as part of prior art or as general general knowledge in the field of the present invention as they exist before the priority date of each 6/69 claiming this request. [015] Throughout this specification, the word comprise or variations such as comprise or comprise must be understood by including the specified element, number or step, or group of elements, numbers or steps, and not the exclusion of any other element, number or step, or group of elements, numbers or steps. Summary of the invention [016] Although pharmaceutical compositions can be stored and sealed for an extended period in an inert medium, for example, over a nitrogen blanket in a bottle, as the seal is broken and the composition is exposed to a medium germs, microbes and other pathogens can be introduced, rendering the composition unsuitable for use as a medicine. [017] Pharmaceutical compositions can be stored in a sterile medium without the presence of preservatives, but with the perforation of the container that holds the composition, any accidental introduction of microorganisms can render the contents unsuitable for use. Therefore, it is important for the effective conservation of pharmaceutical content, especially when pharmaceutical products are stored in large volumes. If a container with a large volume of a pharmaceutical composition is punctured, the lack of a preservative can mean that most of the contents will be lost. [018] Preservatives can be introduced into a pharmaceutical solution to kill bacteria, yeasts and mold. Bacteria, yeast and mold can be introduced 7/69 accidentally when multiple quantities are removed from a container containing multiple doses of a drug. Unfortunately, problems can arise when added preservatives interact negatively with other components within the composition, reducing the effectiveness of pharmaceutical components, and / or preservation. This can be seen in pharmaceutical compositions that contain preservatives and cyclodextrins or their derivatives. [019] In the search for injectable pharmaceutical compositions that comply with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, meeting at least criterion B for parenterals, and according to the American Pharmacopoeia 2011 Test for Efficacy of Antimicrobial, satisfying the criteria for category 1 (injectable) products, the inventors have established a new technique that allows injectable compositions to be produced and used where a hydrophobic drug or hydrophobic drugs is / are solubilized in water by forming inclusion complexes with cyclodextrin or molecules of their derivatives , in the presence of at least one preservative and at least one co-solvent, without loss of drug efficacy or conservation effect. [020] The present invention addresses problems encountered in the use of preservatives combined with cyclodextrins or their derivatives and hydrophobic drugs, that is, the competition between preservatives and hydrophobic drugs to occupy the cyclodextrin or cyclodextrin derivative, in the central cavity. 8/69 [021] When more than one hydrophobic drug is present in a pharmaceutical composition of the invention, each hydrophobic drug is capable of forming a water-soluble complex with a cyclodextrin or cyclodextrin derivative present in the composition, even in the presence of at least one preservative , when at least one co-solvent is added. [022] In one aspect, the invention offers an injectable pharmaceutical composition that complies with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, meeting at least criterion B for parenterals, and according to the American Pharmacopoeia 2011 Test for Efficacy of Antimicrobial, satisfying the criterion for category 1 (injectable) products comprising: - Water, - one or more water-soluble complexes, each comprising a cyclodextrin or a derivative thereof and a hydrophobic drug, - at least one preservative, - at least one co-solvent and - optionally an effective buffer to offer a pH in the composition in the range of about 4.0 to about 9.0. [023] In this specification, the phrase one or more water-soluble complexes, with each comprising a cyclodextrin or a derivative and a hydrophobic drug "means that the pharmaceutical composition may comprise one or more hydrophobic drugs, where each is capable of forming a water-soluble complex with a cyclodextrin or cyclodextrin derivative present in the composition. Therefore, the invention allows the pharmaceutical composition to understand 9/69 a type of water-soluble complex, when only one hydrophobic drug is included in a composition of the invention, or more than one type of water-soluble complex, when more than one hydrophobic drug is included in a composition of the invention invention. [024] In a preferred embodiment, the composition pharmaceutical injectable features a efficiency antimicrobial of the flask perforated 7 days and preferably one effectiveness of 28 days or more. [025] In one embodiment, a hydrophobic drug is present in the injectable pharmaceutical composition according to the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least criterion B for parenterals, and according to the American Pharmacopoeia 2011 Test for Efficacy of Antimicrobial, satisfying the criterion for category 1 (injectable) products, where the hydrophobic drug is capable of forming a water-soluble complex with a cyclodextrin or cyclodextrin derivative present in the composition. [026] In one embodiment, more than one hydrophobic drug is present in the injectable pharmaceutical composition according to the European Pharmacopeia 2011 Test for Efficacy of Antimicrobial Preservation, meeting at least criterion B for parenterals, and according to the American Pharmacopoeia 2011 Test for Efficacy of Antimicrobial, satisfying the criterion for category 1 (injectable) products, where each hydrophobic drug is capable of forming a water-soluble complex with a cyclodextrin or cyclodextrin derivative present in the composition. [027] In one embodiment, the pharmaceutical composition 10/69 injectable according to the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least criterion B for parenterals, and according to the American Pharmacopoeia 2011 Test for Efficacy of Antimicrobial for category 1 products (injectable), it comprises in at least one hydrophobic drug, where each is capable of forming a water-soluble complex with a cyclodextrin or cyclodextrin derivative present in the composition, and also comprises at least one hydrophilic drug. [028] The present invention produces an injectable pharmaceutical composition, where the composition stored in an appropriate sealed container remains viable for administration via injection and with no negative effect observed with the drug or hydrophobic drugs for an extended period of at least 7 days, preferably 2 8 days or more, once the container is opened and stored at room temperature. [029] The invention allows pharmaceutical compositions to be effectively preserved even after opening the container, for a period of at least 7 days, preferably 28 days or more, when stored in a suitable container, in volumes for a single dose or for multiple doses. In addition, pharmaceutical compositions can be stored at room temperature even after perforation and do not require a refrigerated medium, although the invention is not limited to their exclusion. [030] The possibility of storing a pharmaceutical composition at room temperature is advantageous. Usually an individual, for example, a veterinarian, to 11/69 administering an injectable composition that has been stored in cold temperatures, you need to wait for the composition to reach room temperature before administering the drug, avoiding possible discomfort to the patient and facilitating its administration, that is, viscosity. The ability to store an open bottle at room temperature is more convenient as it avoids the need to heat the composition before use. [031] The present invention is directed to a preservative that presents a water-soluble hydrophobic drug comprising a cyclodextrin or a cyclodextrin derivative and a hydrophobic drug by introducing at least one co-solvent into a pharmaceutical composition. The use of a co-solvent or co-solvents allows at least one preservative to be present without any harmful effect in relation to the hydrophobic drug present in the water-soluble complex and in the preservative, that is, the pharmaceutical composition maintains the desired therapeutic effect and the composition complies with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least criterion B for parenterals, and in accordance with the American Pharmacopoeia 2011 Test for Efficacy of Antimicrobial for category 1 (injectable) products. [032] The link between the hydrophobic drug and the cyclodextrin or cyclodextrin derivative is reversible. Therefore, the invention offers a pharmaceutical composition that administered by injection allows the hydrophobic drug to be released from the cyclodextrin molecule or cyclodextrin derivative to offer the desired treatment and / or 12/69 induce the pharmacological response and / or physiological result. [033] A 7-day limit is the minimum period of time in which the composition remains viable after opening, that is, the pharmaceutical composition is effectively preserved, and the drug or complex hydrophobic drugs administered by injection, are capable of inducing the desired pharmacological and physiological response. Preferably, the time period is 28 days or more. [034] The present invention allows injectable pharmaceutical compositions to be stored in a container of appropriate size that contains sufficient quantity of the composition for a single dose of a medicine, where the composition is effectively preserved for a period of at least 7 days, preferably 28 days or more when the container is punctured. In addition, the present invention also allows injectable pharmaceutical compositions to be stored in a container of appropriate size that holds a sufficient amount of the composition for multiple doses of the drug, where the composition is effectively preserved for a period of at least 7 days, from preferably 28 days or more when the container is punctured. Multiple doses or portions of the composition can be removed from the container without any detrimental effect on the preservatives or the hydrophobic drug for a period of at least 7 days, preferably 28 days or more, that is, the composition is effectively preserved for at least 7 days, preferably 28 days or more. [035] In another aspect, the invention offers a method for producing an injectable pharmaceutical composition of 13/69 according to the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least criterion B for parenterals, and according to the American Pharmacopoeia 2011 Test for Efficacy of Antimicrobial for category 1 (injectable) products, where the method comprises : - preparation of a first composition through: a) dissolving the cyclodextrin or cyclodextrin derivative or a mixture of these in water; b) adding one or more hydrophobic drugs to the solution; c) optional introduction of additional water to completely dissolve cyclodextrin or cyclodextrin derivatives and one or more hydrophobic drugs; d) optional addition of buffered salts; e) optional pH adjustment; - preparation of a second composition by dissolving at least one preservative in one or more cosolvents; - and formation of the injectable pharmaceutical composition by: a) combination of the first and the second composition; b) optional addition of water to increase the combined composition to a required volume; and c) sterilization of the combined composition. [036] In a preferred embodiment, the method of producing an injectable pharmaceutical composition offers an injectable pharmaceutical composition having a minimum antimicrobial efficacy of the open bottle of 7 days, preferably 28 days or more. 14/69 [037] In another embodiment, the method of producing a pharmaceutical composition also comprises at least one hydrophilic drug, where it is added to produce the first composition, the second composition, or to form the injectable pharmaceutical composition. [038] In one embodiment, in the preparation of the first composition, the pH is adjusted by adding an acidic aqueous solution. In another embodiment, the aqueous acidic solution is hydrochloric acid. [039] In another embodiment, in the preparation of the first composition, the pH is adjusted by the addition of a basic aqueous solution. In another embodiment, the basic aqueous solution is sodium hydroxide. [040] In another embodiment, one or more additional preservatives are incorporated into an injectable pharmaceutical composition. Any additional preservatives can be added to the first composition along with the optional buffered salts. [041] In another embodiment, one or more additional co-solvents can be included in the injectable pharmaceutical composition. Any additional co-solvents can be included after adjusting the optional pH in the first composition and before mixing the first and second compositions to form the injectable pharmaceutical composition. [042] In one embodiment, the injectable pharmaceutical composition can be sterilized by moist heat, including sterilization by autoclave, or by aseptic sterilization through filtration or sterilization by radiation. 15/69 [043] In another aspect, the invention offers a method of preserving an injectable pharmaceutical composition comprising: - Water, - one or more water-soluble complexes , with each one understanding an cyclodextrin or derivative in cyclodextrin is hydrophobic drug and - optionally an effective buffer for offer a pH in the composition in a range of about 4.0 to about 9.0, including an effective amount of at least one preservative and at least one co-solvent in the composition. [044] In a preferred embodiment, the method of preserving an injectable pharmaceutical composition offers an injectable pharmaceutical composition with a minimum effectiveness of the open bottle of 7 days, preferably 28 days or more. [045] The effective amount of at least one preservative and at least one co-solvent in the injectable pharmaceutical composition means that the concentration of at least one preservative and the concentration of at least one co-solvent is sufficient for the injectable pharmaceutical composition have a minimum effectiveness of the open bottle of 7 days, preferably 28 days or more. [046] In another modality, the method of preserving an injectable pharmaceutical composition offers a composition that complies with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least criterion B for parenterals, and according to the Pharmacopoeia Americana 2011 Test for Efficacy of Antimicrobial for category 1 products (injectable). 16/69 [047] In another embodiment for the method of preserving a pharmaceutical composition, the injectable pharmaceutical composition comprises a hydrophobic drug. [048] In another embodiment for the preservation method and a pharmaceutical composition, the injectable pharmaceutical composition comprises more than one hydrophobic drug. [049] In another embodiment for the method of preserving a pharmaceutical composition, the injectable pharmaceutical composition comprises at least one hydrophobic drug and also comprises at least one hydrophilic drug. [050] In another aspect, the invention offers the use of at least one co-solvent and at least one preservative to preserve the injectable pharmaceutical composition comprising: - Water, - one or more water-soluble complexes , with each one understanding an cyclodextrin or derivative in cyclodextrin is hydrophobic drug and - optionally an effective buffer for offer a pH in the composition in a range of about 4.0 to about 9.0, including an effective amount of at least one preservative and at least one co-solvent in the composition. [051] In a preferred embodiment, the use of at least one co-solvent and at least one preservative to preserve an injectable pharmaceutical composition offers an injectable pharmaceutical composition with a minimum effectiveness of the open bottle of 7 days, preferably 28 days or more. [052] In another modality, the use of at least one cosolvent and at least one preservative to conserve a 17/69 injectable pharmaceutical composition offers a composition that complies with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, satisfying at least criterion B for parenterals, and according to the American Pharmacopoeia 2011 Test for Efficacy of Antimicrobial for category products 1 (injectable). [053] In another embodiment, the invention offers the use of at least one co-solvent and at least one preservative to preserve an injectable pharmaceutical composition, according to the present invention, where the injectable pharmaceutical composition comprises a hydrophobic drug. [054] In another embodiment, the invention provides the use of at least one co-solvent and at least one preservative to preserve an injectable pharmaceutical composition, as described in the present invention, where this composition comprises more than one hydrophobic drug. [055] In another embodiment, the invention provides the use of at least one co-solvent and at least one preservative to preserve an injectable pharmaceutical composition, as described in the present invention, where this composition comprises at least one hydrophobic drug, and also comprises at least one hydrophilic drug. [056] In another aspect, the invention offers an injectable pharmaceutical composition of the invention for treating an animal. In one embodiment, the treatment has at least one of the following objectives: anesthetize the animal, relieve pain or improve inflammation. [057] In the present invention the term animal includes: warm-blooded animals, including mammals 18/69 (including, but not limited to, dogs, cats, cattle, pigs, sheep and horses), reptiles, fish and amphibians. [058] In another aspect, the invention offers an injectable pharmaceutical composition of the invention for treating humans. In one embodiment, treatment is used to anesthetize a human. [059] In another aspect, the invention offers a method of treating an animal, comprising administering an injectable pharmaceutical composition of the invention to an animal. In one embodiment, the treatment aims to at least anesthetize the animal, relieve pain or inflammation. [060] In another aspect, the invention offers a method of treating a human, comprising administering an injectable pharmaceutical composition of the invention to a human. In one embodiment, the treatment aims to anesthetize humans. [061] In another aspect, the invention offers a use of an injectable pharmaceutical composition of the invention, in the preparation of a medicament for treating an animal. In one embodiment, the treatment includes at least the following treatments: anesthesia of the animal, relief of pain or inflammation. [062] The invention also offers a use of a pharmaceutically injectable composition in the preparation of a medicine for treatment of a human. In a modality, the treatment has the goal in numb humans. [063] Description of Drawings [064] Figure 1 - describes the concentration gives alfaxalone 19/69 in plasma (mg / L) in relation to the time after IV administration of alfaxan® or formulation W (table 1) in dogs (n = 12 per time point). [065] Figure 2 - describes the concentration of alfaxalone in plasma (mg / L) in relation to the time after IV administration of alfaxan® or formulation W (table 1) in cats (n = 12 per time point). Detailed Description of the Invention Buffer [066] In a preferred embodiment, the invention optionally comprises a buffer effective to stabilize the drug or hydrophobic drugs in the injectable pharmaceutical composition, and offers a pH in the range of about 4.0 to about 9.0. [067] In another embodiment, the buffer, if present, can be chosen from the group comprising: phosphate-based, acid-phosphate-based and citrate-based buffers. [068] In another modality O plug, if gift, is base phosphate.[069] In anotheracid-phosphate. modality O plug, if gift, is base [070] In another modality O plug, if gift, is base citrate.[071] In another modality O plug, if gift, is an combination of phosphate and citrate based buffers. Preservatives [072] In the present invention, at least one preservative is present in the injectable pharmaceutical composition. [073] A number of preservatives are available that can kill or prevent the growth of contaminants 20/69 commonly found; these contaminants include, but are not limited to, P. aeruginosa, E. coli and S. aureus bacteria; yeasts C. albicans; and A. brasiliensis mold. [074] The presence of at least one preservative allows the injectable pharmaceutical composition to be used for a period of at least 7 days, preferably 28 days or more, once the container with the composition is opened. The injectable pharmaceutical composition of the open container has a minimum antimicrobial effectiveness of 7 days, and preferably 28 days or more. 7 days is the minimum duration, after opening the bottle, for the effectiveness of the preservative / preservatives present and to allow the viability of the pharmaceutical composition for use and / or treatment beyond this period. [075] The incorporation of a preservative or preservatives into a pharmaceutical composition does not impair the solubility of the drug or hydrophobic drugs, and the final compositions are capable of undergoing a test method according to the European Pharmacopoeia Antimicrobial Conservation Test 2011, satisfying at least criterion B for parenteral drugs, and the American Pharmacopoeia Antimicrobial Efficiency Test Guidelines 2011, for category 1 (injectable) products, when the compositions comprise at least one co-solvent and one or more water-soluble complexes , with each complex containing a cyclodextrin or cyclodextrin derivative, and a hydrophobic drug. The presence of an optional buffer, effective to stabilize the drug or hydrophobic drugs and offer a pH in the composition in the range of about 4.0 to about 9.0, impairs the passage of 21/69 preservative hair tests needed applied to composition.[076] In an modality preferred, at least one preservative is present in the pharmaceutical composition and can be selected from a group comprising, but not limited to: m-cresol, chlorocresol, parabens including, but not limited to methylparaben, ethylparaben, propylparaben, butylparaben, its derivatives and salts; chlorobutanol, quaternary ammonium compounds, their derivatives and salts including benzethonium chloride and benzalkonium chloride, boric acid, benzyl alcohol, cetylpyridinium chloride, cetrimide, phenol, phenylethanol, phenoxyethanol and mixtures thereof. [077] The preservative or preservatives are present in an amount that is effective to provide the desired characteristics of the preservative and allow the final composition to comply with the European Pharmacopoeia Antimicrobial Conservation Effectiveness Test 2011, meeting at least criterion B for parenteral drugs, and the 2011 American Pharmacopoeia Antimicrobial Efficiency Test Guidelines for category 1 (injectable) products. [078] In one embodiment, the injectable pharmaceutical composition comprises m-cresol, where m-cresol is present in an amount in the range of about 0.1 to about 1% w / v, preferably in a range of about 0.1 to about 0.5% w / v, more preferably in a range of about 0.1 to about 0.2% w / v. [079] In one embodiment, the injectable pharmaceutical composition comprises chlorocresol, present in a 22/69 amount in a range of about 0.1 to about 1% w / v, preferably in a range of about 0.1 to about 0.5% w / v, more preferably in a range from about 0.1 to about 0.2% w / v. [080] In one embodiment, the injectable pharmaceutical composition comprises methyl-, ethyl-, propyl- or butylparaben, where methyl-, ethyl-, propyl- or butyl-paraben are present in an amount in the range of about 0.005 to about 1% w / v, preferably in the range of about 0.01 to about 0.5% w / v, more preferably in the range of about 0.01 to about 0.2% w / v / v. [081] In another embodiment, the injectable pharmaceutical composition comprises chlorobutanol, where chlorobutanol is present in an amount in the range of about 0.05 to about 1% w / v, preferably in the range of about 0, 05 to about 0.5% w / v, more preferably in a range of about 0.1 to about 0.5% w / v. [082] In one embodiment, the injectable pharmaceutical composition comprises benzethonium chloride, where benzethonium chloride is present in an amount in the range of about 0.05 to about 1% w / v, preferably in a range of about 0.005 to about 0.1% w / v, most preferably in a range of about 0.005 to about 0.05% w / v. [083] In another embodiment, the injectable pharmaceutical composition comprises benzalkonium chloride, where benzalkonium chloride is present in an amount in the range of about 0.001 to about 1% w / v, preferably in the range of about 0.001 to about 0.5% w / v, with greater 23/69 preferably in a range of about 0.001 to about 0.05% w / v. [084] In another embodiment, the injectable pharmaceutical composition comprises boric acid, where boric acid is present in an amount in the range of about 0.25 to about 5% w / v, preferably in the range of about 0.25 to about 2% w / v, most preferably in the range of about 0.25 to about 1% w / v. [085] In another embodiment, the injectable pharmaceutical composition comprises benzyl alcohol, where benzyl alcohol is present in an amount in the range of about 0.1 to about 5% w / v, preferably in the range of about 0.1 to about 2% w / v, more preferably in a range of about 0.1 to about 1% w / v. [086] In another embodiment, the injectable pharmaceutical composition comprises cetylpyridinium chloride, where cetylpyridinium chloride is present in an amount in the range of about 0.0001 to about 0.5% w / v, preferably in a a range of about 0.0001 to about 0.01% w / v, most preferably in a range of about 0.0001 to about 0.01% w / v. [087] In another embodiment, the injectable pharmaceutical composition comprises cetrimide, where cetrimide is present in an amount in the range of about 0.001 to about 1% w / v, preferably in the range of about 0.001 to about 0.5% w / v, most preferably in a range of about 0.001 to about 0.01% w / v. [088] In another embodiment, the injectable pharmaceutical composition comprises phenol, where phenol is present in an amount in the range of about 0.05 to about 1% 24/69 w / v, preferably in a range of about 0.05 to about 0.5% w / v, more preferably in a range of about 0.05 to about 0.1% w / v v. [089] In another embodiment, the injectable pharmaceutical composition comprises phenylethanol, where phenylethanol is present in an amount in the range of about 0.1 to about 2% w / v, preferably in the range of about 0, 1 to about 1.5% w / v, more preferably in a range of about 0.1 to about 1.0% w / v. [090] In another embodiment, the injectable pharmaceutical composition comprises phenoxyethanol, where phenoxyethanol is present in an amount in the range of about 0.1 to about 2% w / v, preferably in the range of about 0, 1 to about 1.5% w / v, more preferably in a range of about 0.1 to about 1.0% w / v. [091] In yet another embodiment, the injectable pharmaceutical composition comprises a mixture of any of the preservatives described here, where each is present in an amount specified in the ranges described here. Solvent [092] In the present invention, the solvent is water. In a preferred embodiment, the water is pharmaceutically quality purified water. In another preferred embodiment, the pharmaceutical composition contains sufficient water to produce a composition of the invention in the desired dosage. Co-solvents [093] The present invention covers at least one cosolvent in the injectable pharmaceutical composition. 25/69 [094] In a preferred embodiment, the co-solvent or co-solvents are miscible in water. [095] The invention offers at least one co-solvent in the injectable pharmaceutical composition, which allows a hydrophobic drug to remain in the hydrophobic cavity of a cyclodextrin or cyclodextrin derivative in the presence of at least one preservative. [096] When more than one hydrophobic drug is present in the injectable pharmaceutical composition, the presence of at least one co-solvent means that each hydrophobic drug is able to remain in the hydrophobic cavity of a cyclodextrin or cyclodextrin derivative in the presence of at least one preservative. [097] In a preferred embodiment, the co-solvent or co-solvents may be selected from the group comprising, but not limited to: ethanol, glycerin, propylene glycol, isopropyl alcohol, formal glycerol, tetraglycol, polyethylene glycol and mixtures thereof . [098] The co-solvent or co-solvents are present in the composition in a pharmaceutically acceptable amount that does not impair the compliance of the preservative or preservatives with the European Pharmacopoeia Antimicrobial Conservation Effectiveness Test 2011, meeting at least criterion B for medicines parenterals, and the 2011 American Pharmacopoeia Antimicrobial Efficiency Test Guidelines for category 1 (injectable) products. [099] In another embodiment, the injectable pharmaceutical composition comprises ethanol, present in an amount in the range of about 1 to about 30% w / v, 26/69 in preference in a track in about 1 the fence in 25% p / v , with greater preference in a track of fence in 1 to about 20% w / v. [100] In another modality, the composition injectable pharmaceutical product comprises glycerin, present in an amount in the range of about 1 to about 30% w / v, preferably in the range of about 1 to about 25% w / v, most preferably in a range from about 1 to about 20% w / v. [101] In another embodiment, the injectable pharmaceutical composition comprises propylene glycol, present in an amount in the range of about 1 to about 30% w / v, preferably in the range of about 1 to about 25% w / v, most preferably in a range of about 1 to about 20% w / v. [102] In another embodiment, the injectable pharmaceutical composition comprises isopropyl alcohol, where isopropyl alcohol is present in an amount in the range of about 1 to about 30% w / v, preferably in the range of about 1 to about 25% w / v, more preferably in a range of about 1 to about 20% w / v. [103] In another embodiment, the injectable pharmaceutical composition comprises formal glycerol, where formal glycerol is present in an amount in the range of about 1 to about 30% w / v, preferably in the range of about 1 to about 25% w / v, more preferably in a range of about 1 to about 20% w / v. [104] In another embodiment, the injectable pharmaceutical composition comprises tetraglycol, where tetraglycol is present in an amount in a range of 27/69 about 1 to about 30% w / v, preferably in a range of about 1 to about 25% w / v, more preferably in a range of about 1 to about 20% w / v v. [105] In another embodiment, the injectable pharmaceutical composition comprises polyethylene glycol, where polyethylene glycol is present in an amount in the range of about 1 to about 30% w / v, preferably in the range of about 1 to about 25% w / v, more preferably in a range of about 1 to about 20% w / v. [106] In yet another embodiment, the injectable pharmaceutical composition comprises a mixture of any of the preservatives described, where each is present in an amount specified in the ranges described in the present invention. Cyclodextrin and Cyclodextrin Derivatives [107] The present invention offers an injectable pharmaceutical composition comprising one or more water-soluble complexes, with each complex containing a cyclodextrin or cyclodextrin derivative and a hydrophobic drug. [108] The cyclodextrin or cyclodextrin derivative is chosen to improve the solubility of a hydrophobic drug in water by the formation of a water-soluble complex. [109] The hydrophobic drug and cyclodextrin or cyclodextrin derivative form a host-host complex where the hydrophobic drug is the guest and cyclodextrin or cyclodextrin derivative is the host. [110] The invention allows the presence of one or more hydrophilic drugs in the pharmaceutical composition. Each drug Hydrophobic 28/69 is capable of forming a water-soluble complex with a cyclodextrin or cyclodextrin derivative present in the pharmaceutical composition. [111] In a preferred embodiment, the cyclodextrin or cyclodextrin derivative can be chosen from a group comprising, but not limited to: α-cyclodextrin, βcyclodextrin, γ-cyclodextrin, substituted methyl cyclodextrins, substituted ethyl cyclodextrins, substituted cyclohextrins, hydroxyalkyls including 2-hydroxypropyl— β-cyclodextrin, alkyl ether cyclodextrins, branched cyclodextrins, cationic cyclodextrins, quaternary ammonium cyclodextrins, anionic cyclodextrins, amphoteric cyclodextrins, sulfoalkyl ether β cyclodextrins, or modified forms or mixtures thereof. [112] The specific cyclodextrin or its derivative is chosen to form a water-soluble complex with a hydrophobic drug that can be used in an injectable pharmaceutical composition according to the European Pharmacopoeia Antimicrobial Conservation Efficacy Test 2011, meeting at least criterion B for parenteral drugs, and the 2011 American Pharmacopoeia Antimicrobial Efficiency Test Guidelines for category 1 (injectable) products. The composition also comprises water, at least one co-solvent, at least one preservative, and optionally an effective buffer to stabilize the drug or hydrophobic drugs, and to offer a pH in the composition in the range of about 4.0 to about 9 , 0. [113] Cyclodextrin or cyclodextrin derivative is chosen to form water-soluble complexes with one drug or hydrophobic drugs when more than one drug 29/69 hydrophobic is present, where the complexes are stable in water and where, once the pharmaceutical composition is supplied via injection, the hydrophobic drug is removed from the cyclodextrin or cyclodextrin derivative to provide the desired pharmacological and physiological response. [114] In a preferred embodiment, the binding of a hydrophobic drug to the cavity of a cyclodextrin or cyclodextrin derivative in a water-soluble complex is reversible, allowing the displacement of the hydrophobic drug from the cyclodextrin or cyclodextrin derivative in the injection of the composition that incorporates the water-soluble complexes. [115] The amount of cyclodextrin or cyclodextrin derivative in the invention is sufficient to solubilize the drug or hydrophobic drugs, if more than one hydrophobic drug is present, selected to form stable water-soluble complexes. [116] In one embodiment, the cyclodextrin derivative is preferably 2-hydroxypropyl — β-cyclodextrin. [117] In one embodiment, the injectable pharmaceutical composition comprises a cyclodextrin or cyclodextrin derivative, where the cyclodextrin or cyclodextrin derivative is present in a range of about 1 to about 50% w / v, preferably in a range of about 1 to about 40% w / v, more preferably in a range of about 5 to about 25% w / v. [118] In yet another preferred embodiment, the injectable pharmaceutical composition comprises 2-hydroxypropyl— βcyclodextrin, where the 2-hydroxypropyl— βcyclodextrin derivative is present in an amount ranging from 1 to about 50% w / v, preferably in a range About 1 to about 40% w / v, more preferably in a range of about 5 to about 25% w / v. Hydrophobic drugs [119] The invention describes the solubilization and preservation of a hydrophobic drug or drugs, contained within the complexes, with each complex comprising a cyclodextrin or a cyclodextrin derivative, for a period of at least 7 days, preferably 28 days or furthermore, where the drug (s) remains active and viable for treatment in a patient for at least 7 days, preferably 28 days or more in the presence of at least one preservative and at least one co-solvent, once the bottle has been opened. [120] The invention allows one or more hydrophobic drugs to be present in the pharmaceutical composition. Each hydrophobic drug is capable of forming a water-soluble complex with a cyclodextrin or cyclodextrin derivative present in the pharmaceutical composition. [121] The invention can also comprise at least one hydrophilic drug. [122] In a preferred embodiment, the hydrophobic drug or drugs are / are selected so that they can be delivered via injection. [123] The hydrophobic drug or drugs are / are combined (s) with a cyclodextrin or cyclodextrin derivative to form a water-soluble complex that is included in a pharmaceutical composition that also comprises: water, at least one preservative, at least one co- solvent and optionally an effective buffer to stabilize the hydrophobic drug and offer a pH in the composition in a range of 31/69 about 4.0 to about 9.0, where the composition can be provided via injection, and where the injectable pharmaceutical composition is in accordance with the European Pharmacopoeia Antimicrobial Conservation Test for 2011, satisfying at least the criterion B for parenteral drugs, and the 2011 American Pharmacopoeia Antimicrobial Efficiency Test Guidelines for category 1 (injectable) products. [124] The drug or hydrophobic drugs is / are conserved (s) after opening the container for at least 7 days, preferably 28 days or more in an injectable pharmaceutical composition and stored (s) as a medicine in volumes suitable for single doses or multiple. [125] The hydrophobic drug or drugs is / are combined (s) with a properly selected cyclodextrin or cyclodextrin derivative to form a water-soluble complex that once administered via injection, the hydrophobic drug or drugs is / are released from the central cavity of the cyclodextrin or cyclodextrin derivative inducing the necessary physiological and pharmacological response. [126] The hydrophobic drug or drugs are / are stable since they have been / have been complexed with cyclodextrin or an appropriate cyclodextrin derivative to form water-soluble complexes, in the presence of at least one co-solvent and at least one preservative, where the co-solvent or cosolvents and preservatives are properly chosen, before being administered via injection. [127] In a preferred embodiment, the hydrophobic drug or drugs can (m) be chosen from a group that comprises, but is not limited to: 32/69 - steroids, their derivatives and salts including alfaxalone, prednisolone, hydrocortisone, alfadolone, alopregnanolone, alfadolone acetate and their prodrugs. - NSAIDs - oxicam, its derivatives and salts including meloxicam, piroxicam and its pro-drugs. - propionic acid, its derivatives and salts including carprofen, ibuprofen, naproxen and its prodrugs. - phenols, their derivatives and salts including propofol and its prodrugs. - benzimidazoles, their derivatives and salts including albendazole, triclabendazole and their prodrugs. - hexahydropyrazines, their derivatives and salts including praziquantel and its prodrugs. - beta-lactams, their derivatives and salts including ampicillin, penicillin, cefixime and their prodrugs. - sulfonamides, their derivatives and salts and their prodrugs. - pyridines and pyrimidine, their derivatives and salts and their prodrugs. - oxazolidones, their derivatives and salts, and their prodrugs. - ansamycins, their derivatives and salts, and their prodrugs. - glycopeptides, their derivatives and salts, and their prodrugs. - benzodiazepines, their derivatives and salts, including diazepam and its prodrugs. - hormones, their derivatives and salts including estradiol and their prodrugs. 33/69 - aminoamides, their derivatives and salts including lidocaine, and its pro-drugs.- barbiturates, their derivatives and salts including thiopental and its pro-drugs.- salicylates, their derivatives and salts including aspirin and its pro-drugs.- salicylanilides, their derivatives and salts including closantel and its pro-drugs. [128] The drug or hydrophobic drugs is / are present in an amount sufficient to induce the necessary therapeutic effect (s) in a patient when administered via injection. [129] In one embodiment, the hydrophobic drug or drugs is / are appropriately chosen by a specialist in the field, as being effective in treating an animal in the group comprising: warm-blooded animals, including birds and mammals, reptiles , fish and amphibians. [130] In another embodiment, the drug or hydrophobic drugs is / are appropriately chosen (s) by a specialist in the field, as being effective in treating an animal in the group comprising: dogs, cats, cattle, pig, sheep and horses . [131] In one embodiment, the hydrophobic drug or drugs are / are appropriately chosen (s) by an expert in the field, to be effective in human treatment. [132] In one embodiment, the hydrophobic drug is an anesthetic. [133] In another embodiment, the hydrophobic drug is an anesthetic for animals including: blood animals 34/69 hot, including birds and mammals, reptiles, fish and amphibians. [134] In another embodiment, the hydrophobic drug is an anesthetic for a human. [135] In another embodiment, a hydrophobic drug is present in the injectable pharmaceutical composition, where a hydrophobic drug is selected from alfaxalone, meloxicam, propofol or carprofen. [136] In another modality, more of a drug hydrophobic it is present in composition pharmaceutical injectable, Where at least one hydrophobic drug is selected in alfaxalone, meloxicam, propofol or carprofen. [137] In another modality, the hydrophobic drug is alfaxalone, Where the alphaxalone is present in a quantity in one fence strip from 1 to fence 100 mg / mL, preferably was going to about 1 to about 75 mg / mL, and with greater preference from about 1 to about 50 mg / ml. [138] In another embodiment, the hydrophobic drug is propofol, where propofol is present in an amount ranging from about 1 to about 100 mg / mL, preferably from about 1 to about 75 mg / mL, and more preferably from about 1 to about 50 mg / ml. [139] In another embodiment, the hydrophobic drug is meloxicam, where meloxicam is present in a range of about 1 to about 100 mg / ml, preferably about 1 to about 75 mg / ml, and most preferably from about 1 to about 50 mg / ml. [140] In another embodiment, the hydrophobic drug is carprofen, where carprofen is present in a range of 35/69 about 1 to about 100 mg / ml, preferably about 1 to about 75 mg / ml, and more preferably about 1 to about 50 mg / ml. [141] In another embodiment, a composition of the invention may also comprise a compound that increases the solubility of a hydrophobic drug or drugs, as described in the present invention. Examples of compounds that improve the solubility of meloxicam in a composition of the invention can be selected from the group that comprises, but is not limited to, N-vinylpyrrolidone polymers. [142] In another embodiment, Nvinylpyrrolidone polymers have a molecular formula of (C6H9NO) n, where n is in a range of about 20 to about 27000 polymers with molecular weights of about 2220 g mol -1 to about 3108000 g mol -1 . [143] In another embodiment, Nvinylpyrrolidone polymers, if present in a composition of the invention, are included in a concentration of about 1% w / v to about 20% w / v, preferably about 1% w / v about 10% w / v, and more preferably about 1% w / v to about 5% w / v. [144] In another embodiment, a compound that improves the solubility of a hydrophobic drug or drugs, as described in a composition of the invention, can also modify the viscosity of said composition. Hydrophilic Drugs [145] The invention offers an injectable pharmaceutical composition optionally comprising at least one hydrophilic drug. 36/69 [14 6] In one embodiment, the hydrophilic drug may be chosen from the group that comprises, but is not limited to: opioids, including, but not limited to tramadol and its metabolites M1, buprenophrine, opioid-like substances, and α-adrenergic agonists, including, but not limited to medetomidine. [147] In one embodiment, the injectable pharmaceutical composition comprises tramadol and its metabolite M1, where tramadol and its metabolite M1 are present in an amount in the range of about 1 to about 200 mg / mL, preferably in a range from about 10 to about 100 mg / ml, more preferably in a range of about 25 to about 75 mg / ml. [148] In one embodiment, the injectable pharmaceutical composition comprises buprenorphine, where buprenorphine is present in a range of about 0.01 to about 5 mg / ml, preferably about 0.1 to about 1 mg / ml , and more preferably from about 0.1 to about 0.5 mg / ml. [149] In one embodiment, the injectable pharmaceutical composition comprises medetomidine, where medetomidine is present in a range of about 0.01 to about 10 mg / mL, preferably about 0.05 to about 5 mg / mL , and more preferably from about 0.1 to about 2 mg / ml. [150] In one embodiment, the injectable pharmaceutical composition comprises one or more hydrophobic drugs, as described in the present invention, and also comprises at least one hydrophilic drug, where one or more hydrophobic drugs form a water-soluble complex with a cyclodextrin or cyclodextrin derivative appropriately chosen. At least one hydrophilic drug, as 37/69 described in the present invention, is present in an amount sufficient to induce the necessary pharmacological and physiological response. [151] In another embodiment, the injectable pharmaceutical composition comprises one or more hydrophobic drugs, where at least one hydrophobic drug is selected from alfaxalone, meloxicam, propofol or carprofen, and also comprises at least one hydrophilic drug, as described in the present invention, where one or more hydrophobic drugs form a water-soluble complex with an appropriately chosen cyclodextrin or cyclodextrin derivative. At least one hydrophilic drug is present in an amount sufficient to induce the necessary pharmacological and physiological response. [152] In another embodiment, the injectable pharmaceutical composition allows for the combination of analgesic injections comprising oxycam-type NSAIDs and opioids and / or opioid-like substances, as described in the present invention. [153] In one embodiment, the hydrophilic drug or drugs is / are appropriately chosen by an expert in the field, to be effective in treating an animal in the group comprising: warm-blooded animals, including birds and mammals, reptiles , fish and amphibians. [154] In another embodiment, the hydrophilic drug or drugs is / are appropriately chosen by a specialist in the field, as being effective in the treatment of an animal in the group comprising: dogs, cats, cattle, pig, sheep and horses . 38/69 [155] In one embodiment, the drug or hydrophilic drugs is / are appropriately chosen (s) by a specialist in the field, to be effective in human treatment. Isotonic Agent [156] The injectable pharmaceutical compositions of the invention, as described in the present invention, can also comprise an isotonic agent. Examples of isotonic agents include, but are not limited to, sodium chloride and dextrose. [157] In one embodiment, the isotonic agent is sodium chloride or dextrose, where sodium chloride or dextrose is present in a composition of the invention in an amount that makes the composition isotonic with the blood of the individual being treated. [158] In another embodiment, the isotonic agent is sodium chloride, which is present in an amount of about 0.9% w / v. [159] In another embodiment, the isotonic agent is dextrose, which is present in an amount of about 5% w / v. Stability [160] The stability of injectable compositions is very important. In general terms, the compositions described in the present invention remain physically and chemically stable for at least 3 months, when stored at a temperature below 30 ° C, preferably at least 6 months when stored at a temperature below 30 ° C, more preferably at least 1 year when stored below 30 ° C, and even more preferably 39/69 at least 3 years when stored at temperatures below 30 ° C. Examples of modalities A. Injectable pharmaceutical composition according to the European Pharmacopoeia Antimicrobial Preservation Effectiveness Test 2011, meeting at least criterion B for parenteral drugs, and the American Pharmacopoeia Antimicrobial Efficiency Test Guidelines 2011, for category 1 products (injectables ) comprising: - Water - one or more water-soluble complexes, each comprising a cyclodextrin or cyclodextrin derivative and a hydrophobic drug, - at least one preservative, - at least one co-solvent and - optionally an effective buffer to offer a pH in the composition in a range of about 4.0 to about 9.0. B. Injectable pharmaceutical composition, according to modality A, where at least one hydrophobic drug is selected from a group comprising: alfaxalone, propofol, meloxicam and carprofen. C. Injectable pharmaceutical composition, according to modality B, where: - alphaxalone is present in an amount in a banner in about 1 The about 100 mg / mL, of preference in fence in 1 the fence in 75 mg / mL, and with greater preference in fence in 1 the fence in 50 mg / ml; and/ or - propofol is present in an amount in the range of about 1 to about 100 mg / mL, preferably 40/69 about 1 to about 75 mg / ml, and more preferably about 1 to about 50 mg / ml; and / or meloxicam is present in a range of about 1 to about 100 mg / ml, preferably about 1 to about 75 mg / ml, and most preferably about 1 to about 50 mg / ml; and / or - carprofen is present in a range of about 1 to about 100 mg / ml, preferably about 1 to about 75 mg / ml, and most preferably about 1 to about 50 mg / ml. D. Injectable pharmaceutical composition, according to any of modalities A to C, where the cyclodextrin or cyclodextrin derivative is selected from a group comprising: α-cyclodextrin, β-cyclodextrin, γcyclodextrins, substituted methyl cyclodextrins, substituted ethyl cyclodextrins, substituted hydroxyalkyl cyclodextrins, 2-hydroxypropyl - β cyclodextrin, alkyl ether cyclodextrins, branched cyclodextrins, cationic cyclodextrins, quaternary ammonium cyclodextrins, anionic cyclodextrins, amphoteric cyclodextrins, sulfoalkyl ether and a modified cyclodextrins. E. Injectable pharmaceutical composition, according to any of the modalities A to D, where the cyclodextrin or cyclodextrin derivative is 2 - hydroxypropyl - β cyclodextrin. F. Injectable pharmaceutical composition, according to any of modalities A to E, where at least one preservative is selected from a group comprising: mcresol, chlorocresol, parabens (including, but not limited to 41/69 a: methylparaben, ethylparaben, propylparaben or butylparaben), their derivatives and salts, chlorobutanol, benzethonium chloride, benzalkonium chloride, boric acid, benzyl alcohol, cetylpyridinium chloride, cetrimide, phenol, phenylethanol, phenoxyethanol and their mixtures. G. Injectable pharmaceutical composition, according to any of the modalities A to F, where at least one cosolvent is selected from a group comprising: ethanol, glycerin, propylene glycol, isopropyl alcohol, formal glycerol, tetraglycol and their mixtures. H. Injectable pharmaceutical composition, according to any of modalities A to G, where the buffer effective to stabilize the hydrophobic drug and provide a pH in the composition in the range of about 4.0 to about 9.0 is selected from one group of buffers comprising: phosphate-based, acid-phosphate and citrate-based buffers. I. Injectable pharmaceutical composition, according to any of the modalities A to H, where it also comprises at least one hydrophilic drug. J. Method for producing an injectable pharmaceutical composition according to the European Pharmacopoeia Antimicrobial Conservation Efficacy Test 2011, meeting at least criterion B for parenteral drugs, and the American Pharmacopoeia Antimicrobial Efficiency Test Guidelines 2011 for category 1 (injectable), comprising: - preparation of a first composition by: a) dissolving a cyclodextrin or cyclodextrin derivative or a mixture of these in water; 42/69 b) adding one or more hydrophobic drugs to the solution; c) optional introduction of additional water to completely dissolve the cyclodextrin or cyclodextrin derivative and one or more hydrophobic drugs; d) optional addition of buffered salts; e) optional pH adjustment; - preparation of a second composition by: dissolving at least one preservative in one or more co-solvents; and formation of the injectable pharmaceutical composition by: a) combination of the first and second compositions; b) optional addition of additional water to obtain the desired volume of the combined composition; and c) sterilization of the combined composition. K. Method according to modality J where the cyclodextrin or cyclodextrin derivative is selected from the group comprising: α-cyclodextrin, β-cyclodextrin, γcyclodextrins, methyl substituted cyclodextrins, substituted ethyl cyclodextrins, substituted hydroxyalkyl cyclodextrins, 2-hydroxyextrin - 2-hydroxyextrin - β , alkyl ether cyclodextrins, branched cyclodextrins, cationic cyclodextrins, quaternary ammonium cyclodextrins, anionic cyclodextrins, amphoteric cyclodextrins, sulfoalkyl ether β cyclodextrins or a modified form, and mixtures thereof. L. Method, according to modality J or K, where at least one hydrophobic drug is selected from a group comprising: alfaxalone, propofol, meloxicam and carprofen. 43/69 M. Method, according to any of the modalities J to L where: - alfaxalone it is gift in a quantity in one banner in about 1 The about 100 mg / mL, in preference in fence in 1 the fence in 75 mg / mL, and with greater preference in fence in 1 the fence in 50 mg / ml; and/ or - propofol is present in an amount in a banner in about 1 The about 100 mg / mL, of preference in fence in 1 the fence in 75 mg / mL, and with greater preference in fence in 1 the fence in 50 mg / ml; and/ or meloxicam is present in a range of about 1 to about 100 mg / ml, preferably about 1 to about 75 mg / ml, and most preferably about 1 to about 50 mg / ml; and / or - carprofen is present in a range of about 1 to about 100 mg / ml, preferably about 1 to about 75 mg / ml, and most preferably about 1 to about 50 mg / ml. N. Method, according to any of the modalities J to M, where at least one preservative is selected from a group comprising: m-cresol, chlorocresol, parabens, including, but not limited to methylparaben, ethylparaben, propylparaben, butylparaben, its derivatives and salts, including benzethonium chloride and benzalkonium chloride, boric acid, benzyl alcohol, cetylpyridinium chloride, cetrimide, phenol, phenylethanol, phenoxyethanol and mixtures thereof. O. Method, according to any of the modalities J to N, where one or more co-solvents are selected from a group comprising: ethanol, glycerin, propylene glycol, 44/69 isopropyl alcohol, formal glycerol, tetraglycol and mixtures thereof. P. Method, according to any of the already O modalities, where the buffer is effective to stabilize the hydrophobic drug and provide a pH in the first composition in the range of about 4.0 to about 9.0 and is selected from one group of buffers comprising: phosphate-based, acid-phosphate and citrate-based buffers. Q. Method, according to any of the modalities J to P, where the injectable pharmaceutical composition is sterilized by autoclave. R. Method, according to any of the modalities J to Q, where the pharmaceutical composition also comprises at least one hydrophilic drug, where at least one hydrophilic drug is added in the production of the first, second or in the formation of the injectable pharmaceutical composition. S. Method of preserving an injectable pharmaceutical composition comprising: - Water, - one or more water-soluble complexes, each comprising a cyclodextrin or a derivative thereof and a hydrophobic drug, and - optionally an effective buffer to provide a pH in the composition in the range of about 4.0 to about 9.0, including an effective amount of at least one preservative and at least one co-solvent in the composition. T. Method according to modality S, where the cyclodextrin or cyclodextrin derivative is selected from the group comprising: α-cyclodextrin, β-cyclodextrin, γ- 45/69 cyclodextrins methyl substituted cyclodextrins, substituted ethyl cyclodextrins, substituted hydroxyalkyl cyclodextrins, 2-hydroxypropyl - β cyclodextrin, alkyl ether cyclodextrins, branched cyclodextrins, cationic cyclodextrins, cyclodextrins, anhydrous, quaternary, cyclodextrins, anhydrous, quaternary, cyclodextrins modified form, and their mixtures. U. Method, according to the S or T modality, where at least one hydrophobic drug is selected from a group comprising: alfaxalone, propofol, meloxicam and carprofen. V. Method, according to any of the modalities S to U, where: - alphaxalone is present in an amount in the range of about 1 to about 100 mg / ml, preferably about 1 to about 75 mg / ml, and most preferably about 1 to about 50 mg / ml / mL; and / or - propofol is present in an amount ranging from about 1 to about 100 mg / ml, preferably from about 1 to about 75 mg / ml, and most preferably from about 1 to about 50 mg / ml mL; and / or meloxicam is present in a range of about 1 to about 100 mg / ml, preferably about 1 to about 75 mg / ml, and most preferably about 1 to about 50 mg / ml; and / or - carprofen is present in a range of about 1 to about 100 mg / ml, preferably about 1 to about 75 mg / ml, and most preferably about 1 to about 50 mg / ml. W. Method, according to any of the modalities 46/69 S to V, where at least one preservative is selected from the group comprising: m-cresol, chlorocresol, parabens (including, but not limited to methylparaben, ethylparaben, propylparaben or butylparaben), their derivatives and salts, chlorobutanol, quaternary ammonium compounds , its derivatives and salts including benzethonium chloride, benzalkonium chloride, boric acid, benzyl alcohol, cetylpyridinium chloride, cetrimide, phenol, phenylethanol, phenoxyethanol, and mixtures thereof. X. Method, according to any of the modalities S to W, where at least one co-solvent is selected from a group comprising: ethanol, glycerin, propylene glycol, isopropyl alcohol, formal glycerol, tetraglycol and mixtures thereof. Y. Method, according to any of the modalities S to X, where the buffer is effective to stabilize the hydrophobic drug and provide a pH in the first composition in the range of about 4.0 to about 9.0 and be selected from a group of buffers comprising: phosphate-based, acid-phosphate-based and citrate-based buffers. Z. Method, according to any of the modalities S to Y, where the injectable pharmaceutical composition is in accordance with the European Pharmacopoeia Antimicrobial Conservation Effectiveness Test 2011, meeting at least criterion B for parenteral drugs, and the Guidelines for American Pharmacopoeia Antimicrobial Efficiency Test 2011, for category 1 products (injectable). 47/69 AA. Method, according to any of the modalities S to Z, where the pharmaceutical composition comprises at least one hydrophilic drug. AB. Use of at least one co-solvent and at least one preservative to preserve an injectable pharmaceutical composition comprising: - Water, - one or more water-soluble complexes, each comprising a cyclodextrin or a derivative thereof and a hydrophobic drug, and - optionally an effective buffer to provide a pH in the composition in the range of about 4.0 to about 9.0, including an effective amount of at least one preservative and at least one co-solvent in the composition. B.C. Use, according to the AB modality, where the cyclodextrin or cyclodextrin derivative is selected from the group comprising: α-cyclodextrin, β-cyclodextrin, γcyclodextrins methyl substituted cyclodextrins, substituted ethyl cyclodextrins, substituted hydroxylalkyl cyclodextrins, 2-hydroxypropyl - 2-hydroxypropyl , alkyl ether cyclodextrins, branched cyclodextrins, cationic cyclodextrins, quaternary ammonium cyclodextrins, anionic cyclodextrins, amphoteric cyclodextrins, sulfoalkyl ether β cyclodextrins or a modified form, and mixtures thereof. AD. Use, according to the AB or AC modality, where at least one hydrophobic drug is selected from a group comprising: alfaxalone, propofol, meloxicam and carprofen. AE. Use, according to any of the AB to AD modalities, where: 48/69 - alphaxalone is present in an amount in a banner in about 1 The about 100 mg / ml, preferably in fence in 1 the fence in 75 mg / mL, and most preferably in fence in 1 the fence in 50 mg / ml; and / or propofol is present in a quantity in one banner in about 1 The about 100 mg / ml, preferably in fence in 1 the fence in 75 mg / mL, and most preferably in fence in 1 the fence in 50 mg / ml; and / or meloxicam is present in a range of about 1 to about 100 mg / ml, preferably about 1 to about 75 mg / ml, and most preferably about 1 to about 50 mg / ml; and / or - carprofen is present in a range of about 1 to about 100 mg / ml, preferably about 1 to about 75 mg / ml, and most preferably about 1 to about 50 mg / ml. AF. Use, according to any of the AB to AE modalities, where at least one preservative is selected from the group comprising: m-cresol, chlorocresol, parabens (including, but not limited to methylparaben, ethylparaben, propylparaben or butylparaben); its derivatives and salts, chlorobutanol, quaternary ammonium compounds, its derivatives and salts including benzethonium chloride, benzalkonium chloride, boric acid, benzyl alcohol, cetylpyridinium chloride, cetrimide, phenol, phenylethanol, phenoxyethanol, and mixtures thereof. AG. Use, according to any of the modalities AB to AF, where at least one co-solvent is selected from a group comprising: ethanol, glycerin, propylene glycol, 49/69 isopropyl alcohol, formal glycerol, tetraglycol and mixtures thereof. AH. Use, according to any of the modalities AB to AG, where the buffer is effective to stabilize the hydrophobic drug and provide a pH in the first composition in the range of about 4.0 to about 9.0 and is selected from a group of buffers comprising: phosphate-based, acid-phosphate-based and citrate-based buffers. THERE. Use, according to any of the AB to AH modalities, where the injectable pharmaceutical composition is in accordance with the European Pharmacopoeia Antimicrobial Conservation Effectiveness Test 2011, meeting at least criterion B for parenteral drugs, and the Guidelines for Testing American Pharmacopoeia Antimicrobial Efficiency 2011, for category 1 products (injectable). AJ. Use, according to any of the modalities AB to AI, where the pharmaceutical composition comprises at least one hydrophilic drug. AK. Injectable pharmaceutical composition according to the European Pharmacopoeia Antimicrobial Conservation Effectiveness Test 2011, meeting at least criterion B for parenteral drugs, and the American Pharmacopoeia Antimicrobial Efficiency Test Guidelines 2011, for category 1 (injectable) products comprising : - Water - one or more water-soluble complexes, each comprising a cyclodextrin or cyclodextrin derivative and a hydrophobic drug, 50/69 - at least one preservative, - at least one co-solvent and - optionally an effective buffer to offer a pH in the composition in a range of about 4.0 to about 9.0, to treat an animal. AL. Composition, according to the AK modality, where the treatment of the animal has at least the objective of: anesthetizing the animal, improving pain or inflammation. AM. Injectable pharmaceutical composition according to the European Pharmacopoeia Antimicrobial Conservation Effectiveness Test 2011, meeting at least criterion B for parenteral drugs, and the American Pharmacopoeia Antimicrobial Efficiency Test Guidelines 2011, for category 1 (injectable) products comprising : - Water - one or more water-soluble complexes, each comprising a cyclodextrin or cyclodextrin derivative and a hydrophobic drug, - at least one preservative, - at least one co-solvent and - optionally an effective buffer to offer a pH in the composition in a range of about 4.0 to about 9.0, to treat a human. AN. Composition, according to the AM modality, where treatment in humans is used for anesthesia. TO. Method for treating an animal comprising administering an injectable pharmaceutical composition according to the European Pharmacopoeia Antimicrobial Conservation Test 2011, satisfying 51/69 at least criterion B for parenteral drugs, and the American Pharmacopoeia Antimicrobial Efficiency Test Guidelines 2011, for category 1 (injectable) products, and comprising: - Water, - one or more water-soluble complexes, each comprising a cyclodextrin or cyclodextrin derivative and a hydrophobic drug, - at least one preservative, - at least one co-solvent and - optionally an effective buffer to offer a pH in the composition in a range of about 4.0 to about 9.0. AP. Method, according to the AO modality, where the treatment of an animal has at least the objective of: anesthetizing the animal, improving pain or inflammation. AQ. Method for treating a human comprising administration of an injectable pharmaceutical composition according to the European Pharmacopoeia Antimicrobial Conservation Efficacy Test 2011, meeting at least criterion B for parenteral drugs, and the American Pharmacopoeia Antimicrobial Efficiency Test Guidelines 2011, for category 1 (injectable) products, and comprising: - Water, - one or more water-soluble complexes, each comprising a cyclodextrin or cyclodextrin derivative and a hydrophobic drug, - at least one preservative, - at least one co-solvent and 52/69 - optionally an effective buffer to offer a pH in the composition in a range of about 4.0 to about 9.0. AIR. Method, according to the AQ modality, where the human treatment method is used for anesthesia. AT. Use of an injectable pharmaceutical composition according to the European Pharmacopoeia Antimicrobial Conservation Effectiveness Test 2011, meeting at least criterion B for parenteral drugs, and the 2011 American Pharmacopoeia Antimicrobial Efficiency Test Guidelines for category 1 products ( injectables), comprising: - Water, - one or more water-soluble complexes, each comprising a cyclodextrin or cyclodextrin derivative and a hydrophobic drug, - at least one preservative, - at least one co-solvent and - optionally an effective buffer to offer a pH in the composition in a range of about 4.0 to about of 9.0,on one in preparation in a medicine for treatment animal. AT. Use, in according to the AS modality, where the treatment of animal is at least with the objective of: anesthetize the animal, improve pain or inflammation. AU. Use of an injectable pharmaceutical composition according to the European Pharmacopoeia Antimicrobial Conservation Effectiveness Test 2011, meeting at least criterion B for parenteral drugs, and the American Pharmacopoeia Antimicrobial Efficiency Test Guidelines 2011 for category 1 products 53/69 (injectable) comprising: - Water, - one or more water-soluble complexes, each comprising a cyclodextrin or cyclodextrin derivative and a hydrophobic drug, - at least one preservative, - at least one co-solvent and - optionally an effective buffer to offer a pH in the composition in a range of about 4.0 to about 9.0, in the preparation of a medicine for treating a human. AV. Use, according to the AU modality, where treatment in humans is used for anesthesia. Examples [161] To better understand the nature of this invention, a number of illustrative examples will be described. [162] The scope of the invention is not limited to the examples provided below. The examples demonstrate the effectiveness of the invention. Example 1: Compositions of the invention comprising alfaxalone [163] Synthesis of pharmaceutical compositions containing alfaxalone [164] Six different formulations: S, V, W, X, Y and Z are shown in table 1. All six formulations comprise alfaxalone, but are composed of several [165] solvents and preservatives in different amounts. Table 1. Six examples of formulations, exemplifying the invention, comprising alfaxalone as the drug 54/69 hydrophobic. Component Formulations FormulationV FormulationW FormulationX FormulationY FormulationZ alfaxalone 10 g 10 g 10 g 10 g 10 g 10 g 2hydroxypropylβcyclodextrin 80 g 80 g 80 g 80 g 80 g 80 g Sodium chloride (NaCl) 8_ ^ 8_ ^8_ ^ Disodium phosphate, anhydrous (Na 2 HPO 4 ) 94 0 mg 940 mg 940 mg 940 mg 940 mg 940 mg Potassium dihydrogen phosphate (KH 2 PO 4 ) 4 50 mg 450 mg 450 mg 450 mg 450 mg 450 mg Glycerin - - - - - 100 g Ethanol(denatured) 150 g 150 g 150 g 100 g 100 g 100 g Chlorocresol 1.2 g 1 g 1.5 g 1 g 1 g 1 g Benzethonium chloride - 200 mg 200 mg - 200 mg 200 mg Water for injection (WFI) q.s. 1 L q.s. 1 L q.s. 1 L q.s. 1 L q.s. 1 L q.s. 1 L [166] The formulations in Table 1 were prepared according to the following standard procedure which is based on formulation X: 1. 200 mL of WFI was heated to a temperature of 45 ° C -50 ° C. During mixing, 2-hydroxypropyl-βcyclodextrin was added slowly. The solution was mixed until all the solid had dissolved. 2. Alphafaxone was added to the solution from step 1. The solution was mixed until transparent. 3. The solution was made up to 400 mL using WFI. 4. During stirring, NaCl, Na 2 HPO 4 and KH 2 PO 4 were added. The solution was mixed until the salts were completely dissolved. 5. The pH of the solution was checked and adjusted to specification (6.0- 7.5), using 10% HCL and 10% NaOH, 55/69 as needed. 6. Ethanol was transferred to a separate container. During stirring, chlorocresol was added slowly. It was mixed until the solid dissolved completely. 7. The solution from step 6 was transferred to the loading solution. 8. The solution was produced to the volume of 1L using WFI and mixed well. [167] When benzethonium chloride has been incorporated into a formula, it is added in step 4 together with the buffered salts. [168] When glycerin was included in the formula, it was added after adjusting the pH (step 5) and before adding chlorocresol in ethanol. Stability tests for X, Y and Z formulations [169] Formulations submitted to the autoclave for 20 minutes, at 121 ° C, did not show any significant reduction in the concentration of alphaxalone, and the increase in degradation products was comparable to that contained in WO 01/70234, without preservative after the autoclave. [170] Storage of the formulations at -20 ° C and 0 ° C for 3 months had no detrimental effect on the active content or preservative. There was no precipitation in the formulations. [171] Storage of the formulations for 12 months, at a temperature of 25 ° C / relative humidity (RH) 60%, at a temperature of 30 ° C / RH 65%, and at a temperature of 40 ° C / RH 75%, does not had a detrimental effect on the active content and preservative. 56/69 [172] The inventors found that the addition of chlorocresol in the absence of a co-solvent caused the precipitation of alfaxalone from a solution of water-soluble complexes of alfaxalone and 2-hydroxypropyl-pciclodextrin. Similar effects were observed with benzyl alcohol, parabens, phenol and phenylethanol. The titrations carried out with benzyl alcohol showed significant precipitation with a benzyl alcohol content from 0.2% w / v upstream to 1% w / v (characteristic content). Conservation studies for formulations X, Y, Z, V and S [173] Formulations X, Y and Z were examined for three microorganisms: Pseudomonas aeruginosa (P. aeruginosa) (bacteria, gram negative), Escherichia coli (E coli) (gram negative bacteria) and Candida albicans (C. albicans) (yeast). Formulations S and V were examined for five microorganisms: Pseudomonas aeruginosa (P. aeruginosa) (gram negative bacteria), Escherichia coli (E. coli) (gram negative bacteria), Staphylococcus aureus (S. aureus) (bacteria, gram positive) ), Candida albicans (C. albicans) (yeast) and Aspergillus brasiliensis (A. brasiliensis) (mold). The Standards for the European Pharmacopoeia Antimicrobial Conservation Test for 2011 efficacy, meeting at least criterion B for parenteral drugs, and the 2011 American Pharmacopoeia Antimicrobial Efficiency Test Guidelines for category 1 (injectable) products are shown in table 2 Antimicrobial tests for formulations X, Y and Z according to these criteria are shown in table 3. Antimicrobial tests for 57/69 formulations S and V according to these criteria are shown in table 4. Table 2. The standards required for injectable compositions according to the European Pharmacopoeia Antimicrobial Conservation Effectiveness Test 2011, meeting at least criterion B for parenteral drugs, and the American Pharmacopoeia Antimicrobial Efficiency Test Guidelines 2011, for products category 1 (injectable). Bacteria Log reduction a) Standards 6 hours 24 hours 7 days 14 days 28 days Criterion A 2 3 NR b) Criterion B1 3NR c) USP d)1 3 NR c) Fungus 1 ) / Yeast & Mold f) Log reduction a) Standards 6 hours 24 hours 7 days 14 days 28 days Criterion A 2NR c) Criterion B 1 NR c) USP d)NI d) NI d) NR d) a) Numerical values related to the minimum log reduction required in relation to the initial readings / counts; b) NR = without recovery; c) NI = no increase in the number of viable microorganisms compared to the previous reading; d) NI = no increase in the number of viable microorganisms compared to the initial reading; e) category 1 criterion, applicable for injections; f) the term Fungi is used in the Test for the effectiveness of European Pharmacopoeia Antimicrobial Conservation 2011; the phrase Yeast & Mold is in accordance with the Pharmacopoeia Antimicrobial Efficiency Test Guidelines American 2011. Table 3. Assessing the antimicrobial effects of formulations X, Y and Z on P. aeruginosa, E.coli and C. albicans. When the test meets criterion A 58/69 for parenterals of the European Pharmacopoeia Antimicrobial Conservation Efficacy Test 2011, and with the American Pharmacopoeia Antimicrobial Efficiency Test Guidelines 2011 for category 1 (injectable) products, the term of agreement ”is demonstrated. Formulation Preservative (s) Cosolvent (s) Defying microorganism Results of the compliance criterion Reduction [log] of inoculation 24 hours 7 days X Chlorocresol0.1% 10% Ethanol P. aeruginosa 6.0 (according) AT E. coli 6.1 (according) AT C. albicans AT 4.2 (according) Y 0.1% chlorocresol + 0.02% benzethonium chloride 10% Ethanol P. aeruginosa 6.0 (according) AT E. coli 6.1 (according) AT C. albicans AT 5.2 (according) Z 0.1% chlorocresol + 0.02% benzethonium chloride Glycerin 10% + ethanol 10% P. aeruginosa 6.0 (according) AT [174] The results in Table 3 demonstrated that formulations X, Y and Z are in accordance with the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, criterion A for parenterals, and the American Pharmacopoeia Antimicrobial Efficiency Test Guidelines 2011 , for category 1 (injectable) products, for category 1 (injectable) products, and the European Pharmacopoeia Antimicrobial Conservation Effectiveness Test 2011, criterion B for parenterals. The conformity of formulations X, Y and Z was only evaluated in 3 of 5 microorganisms with 24 hours (P. aeruginosa and E. coli) and 7 days (C. albicans), different from formulation S and V that were evaluated using all necessary microorganisms, 6 h after inoculation at 28 days, with a life time of 28 days after the initial opening of the product. 59/69 Table 4. Assessing the antimicrobial effects of formulations S and V in P. aeruginosa, E.coli, S. aureus, C. albicans and A. brasiliensis. When the test meets criterion A for parenterals according to the European Pharmacopoeia Antimicrobial Conservation Efficacy Test 2011, and category 1 (injectable) criteria, according to the Pharmacopoeia Antimicrobial Efficiency Test Guidelines American 2011, the term of agreement ”is demonstrated. 60/69 Formulation Preservative(s) Co-solvent(s) Defying microorganism Results of the compliance criterion Reduction [log] of inoculation 6 hours 24 hours 7 days 14 days 28 days s Chlorocresol0.1% 15% Ethanol P. aeruginosa 5.3 (according) 5.3 (according) AT AT 5.3 (* according) E. coli 5.2 (according) 5.2 (according) AT AT 5.2 (* according) S. aureus 3.2 (according) 5.8 (according) 5.8 (according) AT 5.8 (* according) C. albicans AT AT 5.8 (according 5.8 (according) 5.8 ( agreement) THE.Brasiliensis AT AT 3.4 (according) 5.1 (according) 5.1 ( agreement) V 0.1% chlorocresol + 0.02% benzethonium chloride 15% Ethanol P. aeruginosa 5.9 (according) 5.9 (according) AT AT 5.9 (* according) E. coli 5.8 (according) 5.8 (according) AT AT 5.8 (* according) S. aureus 3.0 (according) 6.0 (according) 6.0 (according) AT 6.0 (* according) C. albicans AT AT 5.8 (according) 5.8 (according) 5.8 ( agreement) THE.Brasiliensis AT AT 3.9 (according) 4.7(according) 4.7 (í according) * No recovery (NR) of microorganisms 28 days after inoculation (EP-A). : No increase (NI) in microbial concentration from 7 to 28 days after inoculation (EP-A). 61/69 [175] The results of table 4 - Test of the effectiveness of formulations S and V demonstrate that both formulations are within the requirements of the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, criterion A for an ophthalmic or parenteral product with in relation to microorganisms: Pseudomonas aerginosa, Escherichia coli, Staphylococcus aureus, Candida albicans and Aspergillus brasiliensis, at 6 and 24 hours, and 7, 14 and 28 days after inoculation. Therefore, formulations S and V are also in accordance with the American Pharmacopoeia 2011 Guidelines for Antimicrobial Effectiveness Testing, for category 1 (injectable) products and the European Pharmacopoeia 2011 Test for Efficacy of Antimicrobial Preservation, criterion B for parenterals . Example 2: Compositions of the invention comprising Meloxicam Synthesis of pharmaceutical compositions containing meloxicam Table 5. An example composition of the invention containing meloxicam, formulation U. Component Quantity (g / L) Meloxicam 5.0 2-hydroxypropyl- β cyclodextrin 21.0 Plasdone® K25 5.0 Ethanol 150.0 Chlorocresol 1.0 Sodium chloride 9.0 Water for injection (WFI) q.s. 1L [176] Formulation U was prepared according to the following procedure: 1. 600 mL of WFI was transferred to a beaker. While stirring, sodium chloride was added and the solution was mixed until all of the solid was 62/69 dissolved. 2. During stirring, 2-hydroxypropyl-p-cyclodextrin and Plasdone® K25 (obtained from International Specialty Products Inc. (ISP)) were added slowly. The solution was mixed until the solid dissolved completely. 3. Meloxicam was added to the solution from step 1. The solution was mixed until complete suspension of the solid. 4. O solution pH has been adjusted to 12.0-12.5, using solutions hydroxide sodium according required . The solution was agitated The thesis become transparent. 5. The pH of the clear solution was adjusted for 8-9 using acid solution hydrochloric. 6. Ethanol was transferred to a separate container. During stirring, chlorocresol was added slowly. It was mixed until the solid dissolved completely. 7. The solution from step 6 was transferred to the loading solution. 8. The solution was produced to the volume of 1L using WFI and mixed well. Stability tests [177] Formulation U showed no significant change in active or preservative content during 6 months storage at 30 ° C / 65% RH. Conservation studies [178] The conservation effectiveness test of formulation U proved to be in accordance with the requirements of USP 2011, Antimicrobial Preservation Effectiveness Test, for an ophthalmic or parenteral product with respect to 63/69 microorganisms: Staphylococcus brasiliensis, 7, Pseudomonas aeruginosa, Escherichia coli, aureus, Candida albicans and Aspergillus and 28 days after inoculation. 64/69 Table 6. Preservative Effectiveness Test - American Pharmacopoeia 2011 Parenteral & Ophthalmic Formulation U. a) Time point S. aureusAMS 027 (ATCC 6538) P. aeruginosaAMS 095 (ATCC 9027) E. coliAMS 006 (ATCC 8739) C. albicansAMS 003 (ATCC 10231) A. nigerAMS 032 (ATCC 16404) Inoculation cfu / mL 9.1 x 10 5 4.0 x 105 7.4 x 105 8.9 x 105 1.6 x 105 0 day 8.5 x 105 2.8 x 105 6.4 x 105 6.7 x 105 1.7 x 105 7 days <10 <10 <10 <10 <10 14 days <10 <10 <10 <10 <10 28 days <10 <10 <10 <10 <10 All the results were expressed as cfu (colony forming unit and) per ml. 65/69 Example 3: Compositions of the invention comprising carprofen Synthesis of pharmaceutical compositions containing carprofen Table 7. An example of the composition of the invention containing carprofen, formulation T. Component Formulation T Carprofen 50 g 2-hydroxypropyl- β cyclodextrin 2 0 0g Sodium hydroxide (NaOH) 12 g Hydrochloric acid (10 M) 11 g Non-denatured ethanol 100 g Chlorocresol 1 g Water for injection (WFI) q.s. 1L [179] Formulation T was prepared according to the following procedure: 1. 400 mL of WFI was transferred to a beaker. During stirring, 2-hydroxypropyl-p-cyclodextrin was added slowly and the solution heated to 50 ° C until all the solid was completely dissolved. 2. Sodium hydroxide was added to the solution. The solution was mixed until the solid dissolved completely. 3. Carprofen was added to the solution in step 2. The solution was mixed until the solid was completely suspended. 4. The pH of the solution was adjusted to 7.5-8.0, using a hydrochloric acid solution. 5. The ethanol was transferred to a separate container. During stirring, chlorocresol was added slowly. It was mixed until the solid dissolved completely. 6. The solution from step 5 was transferred to the loading solution after reaching room temperature. 66/69 7. The solution was produced to the volume of 1L using WFI and mixed well. Stability tests for formulation T [180] Formulation T showed no significant change in active content or preservative during 6 months storage at 40 ° C / 75% RH. Conservation studies for formulation T [181] The conservation effectiveness test for formulation T has been found to comply with the European Pharmacopoeia, Test for Efficacy of Antimicrobial Preservation, criterion A, and with the American Pharmacopoeia 2011, Guidelines requirements for efficacy of Anti-Microbial Preservation with respect to five reference microorganisms: Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Candida albicans and Aspergillus brasiliensis, with 0, 6 and 24 hours, 7, and 14 28 days for a parenteral or ophthalmic product. Example 4: Animal studies [182] Effectiveness and safety of formulation Y in mice: [183] JX9604.08-K012 A study in mice investigating the comparative anesthetic efficacy and safety of Jurox formulations RD0304 and Alfaxan® at a clinical dose rate ”. The animal phase of this study was completed on February 21, 2012. Blind studies were created for treatment groups. [184] The study demonstrated the following: 1. Treatment of mice with Alfaxan® and formulation Y (RD0304) did not cause any morbidity or mortality. 67/69 2. The anesthetic efficacy of formulation Y of the test article was comparable to that of Alfaxan® of the reference article in the test conditions of this study. 3. Both formulations were well tolerated and had comparable duration and quality of anesthesia. Safety and efficacy of W formulation in dogs [185] JX9604.08-K013 The comparative safety and efficacy of Alfaxan® plus preservatives versus Alfaxan® at a dose rate of 2 mg alfaxalone / kg body weight as an intravenous anesthetic induction agent in dogs ” . The animal phase of this study was completed on May 10, 2012. Blind studies with treatment groups were created. [186] It was a two-period crossover study involving twelve mixed-breed dogs. The assessment instruments were concentration of alfaxalone over time with measurements of clearance, quality and duration of anesthesia, and physiological variables such as heart rate, respiratory rate, oxygen saturation of hemoglobin concentration, final tidal CO 2 and non-blood pressure invasive. [187] The results of the study demonstrate the following: 1. The treatment of mice with Alfaxan® and formulation W (RD0307) did not cause any morbidity or mortality. 2. The secondary pharmacokinetics produced by the plasma alphaxalone concentration over time (figure 1) demonstrated that two pivotal parameters for bioequivalence (ie the area under the curve [AUC] and the maximum blood concentration [Cmax]) were similar. 68/69 3. The quality of anesthesia was similar between Alfaxan® and Formulation W. 4. The physiological variables measured during anesthesia remained within the clinically acceptable limits for both Alfaxan® and formulation W. Anesthetic induction, anesthesia and recovery time were also comparable between formulations. [188] Figure 1 describes the plasma concentration of alfaxalone (mg / L) in relation to time after IV administration of alfaxan or formulation W to dogs (n = 12 per time point). Safety and efficacy of formulation W in cats [189] JX9604.08-K014 The comparative safety and efficacy of Alfaxan® plus preservatives versus Alfaxan® at a dose rate of 5 mg alfaxalone / kg body weight as an intravenous anesthetic induction agent in cats ” . The animal phase of this study was completed on June 27, 2012. Blind studies with treatment groups were created. [190] It was a crossover study with two periods involving twelve domestic shorthaired cats. The assessment instruments were concentration of alfaxalone over time with measurements of clearance, quality and duration of anesthesia, and physiological variables such as heart rate, respiratory rate, oxygen saturation of hemoglobin concentration, final tidal CO 2 and non-blood pressure invasive. [191] The results of the study demonstrate the following: 1. The treatment of cats with Alfaxan® and formulation W (RD0307) did not cause any morbidity or mortality. 2. The secondary pharmacokinetics produced by 69/69 plasma alphaxalone concentration over time (figure 2) demonstrated that two pivotal parameters for bioequivalence (ie the area under the curve [AUC]) and the maximum blood concentration [Cmax] were similar. 3. The quality of anesthesia was similar between Alfaxan® and Formulation W. 4. The physiological variables measured during anesthesia remained within the clinically acceptable limits for both Alfaxan® and formulation W. Anesthetic induction, anesthesia and recovery time were also comparable between formulations. [192] Figure 2 describes the plasma concentration of alfaxalone (mg / L) in relation to time after IV administration of alfaxan or formulation W to cats (n = 12 per time point). [193] It will be considered by experts in the field that numerous variations and / or modifications can be made to the invention, as demonstrated in the specific modalities, without departing from the scope of the invention. The modalities are, therefore, considered as illustrative and not restrictive.
权利要求:
Claims (10) [1] 1. Injectable pharmaceutical composition CHARACTERIZED by the fact that it comprises: - Water; - a water-soluble complex, each comprising a cyclodextrin or a cyclodextrin derivative and a hydrophobic drug, wherein the hydrophobic drug is alfaxalone; - a preservative selected from the group consisting of: m-cresol, chlorocresol, chlorobutanol, benzotonium chloride, benzalkonium chloride, boric acid, cetylpyridinium chloride, cetrimide, phenol, phenylethanol, phenoxyethanol, and mixtures thereof; - a co-solvent selected from the group consisting of: ethanol, glycerin, propylene glycol, isopropyl alcohol, formal glycerol, tetraglycol, and mixtures thereof; and - optionally a buffer to provide a pH in the injectable pharmaceutical composition in a range of 4.0 to 9.0. [2] 2. Injectable pharmaceutical composition according to claim 1, CHARACTERIZED by the fact that the cyclodextrin or cyclodextrin derivative is selected from the group consisting of: a-cyclodextrin, β-cyclodextrin, γcyclodextrin, substituted methyl cyclodextrins, substituted cyclodextrins, cyclodextrins, cyclodextrins substituted hydroxyalkyl, 2-hydroxypropyl-eciclodextrin, alkyl ether cyclodextrins, branched cyclodextrins, cationic cyclodextrins, quaternary ammonium cyclodextrins, anionic cyclodextrins, cyclodextrins Petition 870200016100, of 02/03/2020, p. 23/53 2/5 amphoteric, sulfoalkyl ether β-cyclodextrins, and mixtures thereof. [3] Injectable pharmaceutical composition according to claim 1 or 2, CHARACTERIZED by the fact that the cyclodextrin or cyclodextrin derivative is 2-hydroxypropyl-and-cyclodextrin. [4] Injectable pharmaceutical composition according to any one of claims 1 to 3, CHARACTERIZED by the fact that the buffer to stabilize the hydrophobic drug and provide a pH in the injectable pharmaceutical composition of 4.0 to 9.0 is present and selected of the group consisting of: phosphate-based, acid-phosphate-based and citrate-based buffers. [5] 5. Injectable pharmaceutical composition, according to any one of claims 1 to 4, CHARACTERIZED by the fact that: - the cyclodextrin or cyclodextrin derivative is 2-hydroxypropyl-β-cyclodextrin; - the co-solvent is ethanol; and - the preservative is selected from the group consisting of: chlorocresol, benzethonium chloride and a mixture thereof. [6] 6. Method for producing an injectable pharmaceutical composition CHARACTERIZED by the fact that it comprises: - preparation of a first composition by: a) dissolving a cyclodextrin or cyclodextrin derivative or a mixture of these in water to form a solution; b) add alfaxalone to the solution; Petition 870200016100, of 02/03/2020, p. 24/53 3/5 c) optionally introducing additional water to completely dissolve the cyclodextrin or cyclodextrin derivative and one or more hydrophobic drugs; d) optionally add buffered salts; e) optionally adjusting the pH; - preparation of a second composition by: dissolving a preservative in a co-solvent, where co-solvent is selected from the group consisting of: ethanol, glycerin, propylene glycol, isopropyl alcohol, formal glycerol, tetraglycol, and mixtures thereof, and where the preservative is selected from the group consisting of in: m-cresol, chlorocresol, methylparaben, ethylparaben, propylparaben or butylparaben, their derivatives and salts, chlorobutanol, benzethonium chloride, benzalkonium chloride, boric acid, benzyl alcohol, cetylpyridinium chloride, cetrimide, phenol, phenoxyethanol and phenoxyethanol mixtures; and formation of the injectable pharmaceutical composition by: a) combination of the first and second compositions; b) optionally adding additional water to raise the combined composition to a desired volume; and c) sterilize the combined composition. [7] 7. Method of preserving an injectable pharmaceutical composition comprising: - Water; - one or more water-soluble complexes, each comprising a cyclodextrin or a derivative of Petition 870200016100, of 02/03/2020, p. 25/53 4/5 cyclodextrin and a hydrophobic drug, in which the hydrophobic drug is selected: alfaxalone; and - optionally a buffer to provide a pH in the composition of 4.0 to 9.0 CHARACTERIZED for including a preservative and a co-solvent in the injectable pharmaceutical composition, where: - the preservative is selected from the group consisting of: m-cresol, chlorocresol, chlorobutanol, benzotonium chloride, benzalkonium chloride, boric acid, cetylpyridinium chloride, cetrimide, phenol, phenylethanol, phenoxyethanol, and mixtures thereof; and - the co-solvent is selected from the group consisting of: ethanol, glycerin, propylene glycol, isopropyl alcohol, formal glycerol, tetraglycol, and mixtures thereof. [8] 8. Method, according to claim 7, CHARACTERIZED by the fact that the cyclodextrin or cyclodextrin derivative is selected from the group consisting of: acyclodextrin, β-cyclodextrin, γ-cyclodextrins, methyl substituted cyclodextrins, substituted ethyl cyclodextrins, hydroxylquinyl substituted cyclodextrins 2hydroxypropyl-e-cyclodextrin, alkyl ether cyclodextrins, branched cyclodextrins, cationic cyclodextrins, quaternary ammonium cyclodextrins, anionic cyclodextrins, amphoteric cyclodextrins, sulfoalkyl ether βcyclodextrins or a modified form thereof. [9] 9. Use of a co-solvent and a preservative, CHARACTERIZED by the fact that it is to preserve an injectable pharmaceutical composition comprising: Petition 870200016100, of 02/03/2020, p. 26/53 5/5 - Water, - one or more water-soluble complexes, each comprising a cyclodextrin or a derivative thereof and a hydrophobic drug in which the hydrophobic drug is: alfaxalone; and - optionally a buffer to provide a pH in the composition of 4.0 to 9.0, introducing an amount of the co-solvent and preservative in the composition, where: - the preservative is selected from the group consisting of: m-cresol, chlorocresol, benzethonium chloride, benzalkonium chloride, boric acid, benzyl alcohol, cetylpyridinium chloride, cetrimide, phenol, phenylethanol, phenoxyethanol and their mixtures; and - the co-solvent is selected from the group consisting of: ethanol, glycerin, propylene glycol, isopropyl alcohol, formal glycerol, tetraglycol, and mixtures thereof. [10] 10. Use according to claim 9, CHARACTERIZED by the fact that the cyclodextrin or cyclodextrin derivative is selected from the group consisting of: α-cyclodextrin, βcyclodextrin, γ-cyclodextrins, methyl substituted cyclodextrins, substituted ethyl cyclodextrins, hydroxylalkyls 2-hydroxypropylβ-cyclodextrin, alkyl ether cyclodextrins, branched cyclodextrins, cationic cyclodextrins, quaternary ammonium cyclodextrins, anionic cyclodextrins, amphoteric cyclodextrins, sulfoalkyl ether β-cyclodextrins or a modified form thereof.
类似技术:
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同族专利:
公开号 | 公开日 EP2785352A1|2014-10-08| US20170014428A1|2017-01-19| US9492552B2|2016-11-15| DK2785352T3|2020-05-25| JP5819005B2|2015-11-18| HK1198325A1|2015-04-02| NZ706101A|2016-03-31| BR112014012985A2|2017-06-13| TW201328721A|2013-07-16| JP2015145364A|2015-08-13| CA2852716A1|2013-06-06| SG10201506273PA|2015-09-29| ES2784629T3|2020-09-29| NZ624592A|2015-07-31| HRP20200567T1|2020-06-26| JP2014533703A|2014-12-15| EP2785352B1|2020-03-11| KR20140113629A|2014-09-24| IL232860D0|2014-07-31| ZA201402895B|2015-11-25| AR089004A1|2014-07-23| KR101922752B1|2018-11-27| CN103998046A|2014-08-20| SG11201401597TA|2014-05-29| JP6095707B2|2017-03-15| US20190125762A1|2019-05-02| EP3446692A1|2019-02-27| EP2785352A4|2015-07-29| US10188664B2|2019-01-29| CA2852716C|2015-11-17| TWI552770B|2016-10-11| IL232860A|2019-10-31| CN103998046B|2021-04-06| ES2784629T8|2020-11-23| WO2013078500A1|2013-06-06| US20140336163A1|2014-11-13| CN107261152A|2017-10-20| AU2012268889A1|2013-06-13| CN107261152B|2022-03-04| AU2012268889B2|2013-12-19| IN2014KN01341A|2015-10-16|
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法律状态:
2018-01-23| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]| 2019-04-16| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI | 2019-06-25| B06T| Formal requirements before examination [chapter 6.20 patent gazette]| 2019-11-05| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]| 2020-03-17| B09A| Decision: intention to grant [chapter 9.1 patent gazette]| 2020-05-12| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 27/11/2012, OBSERVADAS AS CONDICOES LEGAIS. |
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申请号 | 申请日 | 专利标题 AU2011904970|2011-11-29| AU2011904970A|AU2011904970A0|2011-11-29|Pharmaceutical compositions| AU2012904962|2012-11-09| AU2012904962A|AU2012904962A0|2012-11-09|Pharmaceutical compositions| PCT/AU2012/001452|WO2013078500A1|2011-11-29|2012-11-27|Methods of preserving injectable pharmaceutical compositions comprising a cyclodextrin and a hydrophobic drug| 相关专利
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