MXPA97002809A - Oral cyclospor formulations - Google Patents

Abstract

Improved oral formulations of cyclosporin are disclosed, which have high bioavailability and are capable of being administered in hard capsules or in nanoparticles. In the present formulations, cyclosporin is delivered in an orally acceptable carrier, comprising at least one alkanol solvent, with 2 to 3 carbon atoms, in combination with at least one nonionic surfactant. The present formulations may further comprise at least one cosolvent, wherein cosolvents of interest include the fatty acids and the diols. The present formulations find use in immuno-suppressed therapy

Description

') ORAL CYCLOSPORINE FORMULATIONS Field of the Invention This invention relates to oral formulations of cyclosporin Background Despite efforts to prevent graft rejections through correspondence of the tissue type of a host donor, in most of the methods of transplantation, where a donor organ is introduced into a host, immunosuppressive therapy is critical to the maintained viability of the donor organ in the host. A variety of immunosuppressive agents have been used in transplant procedures, including azathioprine, methotrexate, cyclophosphamide, FK-506, rapamycin and corticosteroids. The agents that find increasing use in immunosuppressive therapy, due to their potential effect on mediated T cell reactions, are cyclosporins. 20 Cyclosporins are a class of cyclic polypeptides consisting of eleven amino acids, which are produced as a metabolite by the fungal species, Tolypocladium inflatum Gams. Cyclosporins have been observed to reversibly inhibit immunocompetent lymphocytes, particularly the T lymphocytes in the G0 or G ^ phase of the cell cycle. Cyclosporins have been observed to reversibly inhibit the production and release of lymphokine. Although a number of cyclosporins is known, Cyclosporin A is the most widely used. The use of Cyclosporin A has been reported to prolong the survival of allogeneic transplants involving the skin, heart, kidney, pancreas, bone marrow, small intestine and lung. In allogeneic transplants, Cyclosporin A has been shown to suppress humoral immunity and, to a greater extent, cell-mediated immune reactions, which include allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis and graft disease. . Guest. Although Ciclosporin A has been successful, following transplantation, the administration of the agent must be continued, since the benefits of cyclosporine therapy are reversible and graft rejection occurs once the administration of the agent is discontinued. Cyclosporin A. Although cyclosporin formulations for both oral and intravenous administration have been developed, oral administration of cyclosporine is preferred due to ease of administration and greater patient acceptance. Also, intravenous administration of ciclosporin may result in anaphylactic reactions, a side effect not seen with oral formulations. Oral formulations of cyclosporin that have been developed and are currently on the market, include formulations of soft and solution gelatin capsules, both of which are sold under the trademarks of SANDIMMUNE® and NEORAL ™. In the use of oral formulations of cyclosporine in immunosuppressive therapy, both the supplier and the manufacturer must be careful and aware of the many inherent problems. With oral cyclosporin formulations, the bioavailability of cyclosporin can be limited due to the immiscibility of cyclosporin in water and the tendency of cyclosporin to precipitate in aqueous environments. In addition, the concentration of cyclosporin present in oral formulations can be limited due to the hydrophobic nature of cyclosporin. Also, absorption of cyclosporin by the gastrointestinal tract may be erratic from one batch of the formulation to the next, which requires constant monitoring of cyclosporine levels in the blood during treatment. Finally, package stability and storage are a problem with oral formulations. For example, with formulations of soft gelatin capsules of cyclosporin, an air-tight package should be used, which is inconvenient due to the volume and high cost. Likewise, the formulations of cyclosporine may be unstable at low temperatures, since the crystallization of cyclosporin may occur. Thus, convenient oral formulations of cyclosporin will be formulations that resolve at least some of the above problems. Ideally, oral formulations will promote high bioavailability, will comprise high concentrations of cyclosporin and will be reformable for preparation in the form of hard capsules. Relevant Literature Physician's Desk Reference (1994) pages 2071-2074 describes oral formulations of cyclosporin, currently sold under the trademark of SANDIMMUNE®. Oral formulations of cyclosporin are also described in the insert of the NEORAL ™ package, (1995) (Sandoz Pharmaceuticals Corporation, East Hanover, New Jersey, 07936). Patents of E. U.A., of interest describing cyclosporins and their derivatives include Nos. 4,220,641, 4,639,434, 4,289,851 and 4,384,996. The U.A. Patent No. 5,047,396 describes an intravenous preparation for the administration of cyclosporin. The U. A. Patents, Nos. 4,388,307, 4,970,076 and 4,990,337, describe the preparation of oral formulations of cyclosporin.

The preparation of hard capsules for the oral delivery of pharmaceutical formulations is described in the patents of U. U. A., Nos. 4,822,618, 4,576,284, 5,120,710 and 4,894,235. COMPENDIUM OF THE INVENTION Oral formulations of cyclosporin and methods for their use in immunosuppressive therapy are disclosed. In the present formulations, cyclosporin is present in an orally acceptable carrier, comprising at least one alkanol solvent having 2 to 3 carbon atoms, in combination with at least one nonionic surfactant. The present formulations may also comprise one or more co-solvents, where these cosolvents of interest are the esters of fatty acids and diols. Cyclosporin formulations can be packaged as hard capsules. By the inclusion of a polyoxyalkylene surfactant, by diluting the stable dispersion in an aqueous medium, bioavailable, amorphous cyclosporin nanoparticles are supplied in an aqueous medium. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 provides the peak concentration of cyclosporin (Cma?) Achieved in rats for various oral formulations according to the present invention, where Cm £? Is it shown as a relative value compared to the Cma? achieved with the formulation SANDIMMUNE® ORAL (SO).

Figure 2 provides the time (Tmax) in which the Cmax occurred for each of the formulations shown in Figure 1, where the Tmax is given as a relative value compared to the Tma? of the formulation SANDIMMUNE® ORAL (SO). Figure 3 provides the relative area under the blood-time concentration curve (AUC) of the formulations shown in Figure 1, where the AUC is provided as a relative value, compared to the value of the AUC for the SANDIMMUNE® formulation. ORAL (SO). Figure 4 provides the peak concentration of cyclosporin (Cma?) Achieved in humans in various oral formulations, according to the present invention, as well as the SANDIMMUNE® ORAL solution ("Sand in the figure.) Figure 5 provides the time (Tma) in which Cmax occurs for each formulation shown in Figure 4. Figure 6 provides the area under the blood-time concentration curve (AUC) for each of the formulations shown in Figure 4. DESCRIPTION OF SPECIFIC MODALITIES Oral formulations of cyclosporin are provided, which promote bioavailability and can be formulated as capsules, particularly hard capsules In the present formulations, cyclosporin is present in an orally acceptable carrier, comprising at least one solvent of alkanol of 2 03 carbon atoms, in combination with at least one nonionic surfactant agent. comprising at least one cosolvent, where these cosolvents of interest include the esters of fatty acids and the diols. Each of the components of the present formulations are pharmaceutically acceptable. In addition to providing high bioavailability, the present formulations provide a reproducible absorption of cyclosporin, from one batch of a particular formulation, to the next. These formulations find use in immunosuppressive therapy. A number of cyclosporins are known in the art which exhibit an immunosuppressive activity and can be delivered in the oral formulations present. Cyclosporins that can be administered in the present formulations include Cyclosporin A, Cyclosporin B, Cyclosporin C, Cyclosporin D and Cyclosporin G, as well as their synthetic analogues. See the Merck index (1989) 2759. The present oral formulations are particularly suitable for the delivery of Cyclosporin A. When delivered in the present formulations, Cyclosporin A will be present in concentrations ranging from 50 to 150 mg / ml, usually from 100 to 150 mg / ml, based on the volume of the vehicle component of the formulation.

The carrier component of the present formulations will include an alkanol solvent, wherein this alkanol solvent component will comprise at least one alkanol and usually no more than three different alkanols, more usually no more than two different alkanols, wherein the alkanols will usually have 2 or more. 3 carbon atoms, and 1 or 2 hydroxy groups, so that there is no more than 1 hydroxy group per 1.5 carbon atoms. Suitable alkanols include ethanol and propylene glycol. The total amount of the alkanol solvent in the formulation will be at least about Q% (v / v), usually at least 3% (v / v), and can be as high as 95% (v / v), but will generally vary from about 5 to 75% (v / v), usually around 5 to 60% (v / v) and more usually around 10 to 60 % of the formulation. When ethanol is present in the formulation as an alkanol solvent, the amount of this ethanol may vary from 5 to 20% (v / v), usually from about 5 to 15% (v / v) of the formulation, while , when propylene glycol is present as an alkanol solvent, the amount of this propylene glycol in the present formulation can vary from about 5 to 90% (v / v), usually from about 5 to 85% (v. / v), more usually about 10 to 50% (v / v) of the formulation.

Also present in the orally acceptable carrier will be at least one nonionic polyoxyalkylene surfactant, usually not more than two nonionic polyoxyalkylene surfactants. These polyoxyalkylene surfactants will have a hydrophilic-lipophilic balance ("HLB") of about 5 to 20, usually about 8 to 16. Preferably, the nonionic polyoxyalkylene surfactants employed in the present formulations will be the polyoxyethylene compounds. These polyoxyethylene compounds of interest include: the ethoxylated alcohols, ie the polyoxyethylene alcohols or ethoxylated fatty alcohols, wherein the alcohol portions generally have from 10 to 18, usually from 10 to 14 carbon atoms, as well as their substituents of ether and ester; and polyoxyethylene derivatives of partial fatty acid esters, usually the monoesters, of polyols with 4 to 6 carbon atoms, usually of 6 carbon atoms, where these polyols can be polyol anhydrides, for example sorbitan. The fatty acid portions of the surfactant people will typically vary from 10 to 18 carbon atoms, the number of ethylene oxide groups will generally be in the range of 2 to 30, usually in the range of about 2 to 25. Preferred surfactants they are the polyoxyethylene (4) -lauryl ether (BRIJ 30® and the polyoxyethylene (20) mono-sorbitan-monmo-oleate (TWEEN 80®). The total amount of the non-ionic surfactants present in the present formulations will vary from to 65%, usually around 5 to 60% (v / v) of the formulation When TWEEN 80® is present in the formulation, it will usually be present in amounts ranging from 5 to 60%, more usually around 10 to 50% (v / v) of the formulation When BRIJ 30® is present in the present formulation, it will usually be present in amounts ranging from 10 to 45%, more usually from about 15 to 40% (v / v) of the formulation The present f Ormulations may further comprise one or more cosolvents, usually no more than three different cosolvents, more usually no more than two different cosolvents, where suitable cosolvents include the fatty acid esters and the diols, wherein the cosolvent may be 100% of the fatty acid, 100% diol, or combinations thereof. The total amount of the cosolvent present in the formulation can vary from about 20 to 80% (v / v) and will usually vary from about 25 to 75% (v / v). When present in the formulation, the ratio of the cosolvent to the solvent in the present formulation may vary from about 1: 1 to 15: 1, but will usually vary from about 1: 1 to 13: 1.

The fatty acid esters which can serve as co-solvents in the present formulations are those fatty acid esters wherein the hydrocarbon chain of the fatty acid has from 12 to 18, usually from 14 to 18 carbon atoms in length, where the acid ester Fatty will be a monoester of a lower alkanol. Suitable fatty acid esters will generally comprise an even number fatty acid chain where the hydrocarbon chain can be saturated or unsaturated, usually with no more than two sites of unsaturation. Fatty acids of interest will generally be of plant or mammalian origin, and include palmitate, stearate, palmitoleate, linoleate, linolenate and the like, particularly myristate and oleate. The alcohol of the fatty acid monoster will be a lower alkanol of 2 to 4 carbon atoms in length, usually 2 or 3 carbon atoms in length, with or without branches. The fatty acid esters of particular interest are isopropyl myristate and ethyl oleate. The isopropyl myristate, when present, will vary from about 55 to 75% (v (v)) and the ethyl oleate, when present, will vary from about 35 to 75% (v / v) of the total formulation. , the fatty acid ester will be present in an amount of at least equal (v / v) and up to 8 times the amount of the surfactant in the formulation, usually not more than 5 times the amount of the surfactant in the formulation (v. / v) Diols may also be present in the present formulations, in which these diols may be present in addition to, or in place of, the fatty acid ester cosolvent The diols of interest as cosolvents are generally liquid at temperatures physiological and include diols of 8 to 28 carbon atoms, usually of 16 to 20 carbon atoms, where this diol can be a polyoxyalkylene diol, in which the alkylene has 2 or 3 carbon atoms. Diols suitable for use as solvents can n vary from 200 to 800 Daltons, usually from 200 to 650 Daltons. Diols of particular interest include polyethylene glycols, particularly polyethylene glycol 200 (PEG 200), polyethylene glycol 400 (PEG 400), polyethylene glycol 600 (PEG 600, and the like, with PEG 400 being preferred. are present as co-solvents in the present formulations, the diols will vary from 5 to 60% (v / v), usually around 5 to 55% (v / v) of the formulation For the formation of amorphous nanoparticles, conveniently in In the formulation, the total amount of the lower alkanol will generally be in the range of about 25 to 60 weight percent, more usually in the approximate range of 30 to 50 weight percent.The total amount of the one or more alkylenoxy compounds generally will be in the range of about 20 to 50 weight percent, more usually in the approximate range of 25 to 40 weight percent.When combinations of the polyoxyalkylene compounds are employed, the amount of the grade acid ester will generally range from about 25 to 100% of the polyoxyalkylene compounds. In the present formulations, the cosolvents themselves can impart the physical properties suitable for the formulation, such as viscosity, stability and the like. When desired, the formulation may further comprise additional agents imparting the desired physical properties to the formulation, such as thickening agents, suspending agents, solidifying agents, and the like, where these agents include acacia, carboxymethyl cellulose, hydroxypropyl cellulose , lecithin, methyl cellulose, high molecular weight polyethylene glycols, for example those polyethylene glycols with molecular weights ranging from about 1000 to 6000, usually from 1000 to 5000 Daltons, povidone, sodium alginate, gum tragacanth, and Similar. A number of minor components which provide various functions may also be present in the present formulations., such as enzyme inhibitors, preservatives, antioxidants, antimicrobial agents, stabilizers and the like. The total amount of these thickening agents and other additives, if present in the formulation, will normally not be greater than 5% by weight,. usually 2% by weight, more usually 1% by weight of the formulation. A number of excipients may also be present in the present formulations, as is known in the art. The present formulations are stable over a wide range of temperatures, whereby stable it is understood that the physical integrity of the formulation is not understood, for example, crystallization of the cyclosporin active agent will not occur. Included within the temperature range in which the present formulations are stable are lower temperatures, such as those employed in refrigerated storage, where these lower temperatures typically range from 0 to 15ac, more typically from 2 to 8SC, approximately. The present formulations are suitable for administration in the form of capsules, for example, hard and soft capsules. Methods for producing hard capsules comprising liquid formulations are known in the art and are described in the patents of E. U. A., Nos. 4,822,618 and 4,576,284, the disclosures of which are incorporated herein by reference. In general, the hard capsules which find use with the present formulations will comprise two parts: a cover component and a cover component. The cover and lid components are adapted together to produce an enclosed cavity of defined volume, sealed in a hard capsule shell. The cover and lid components can be made of a hydrophilic polymer, such as starch or gelatin. In the preparation of the hard capsules, the liquid formulation will be emptied into the cover component and then the capsule will be sealed by fitting the lid component on the cover component. The seal between the two components can be secured, thus preventing leakage of the formulation enclosed from the capsule, using a sealant, as described in patent EP 116744, the disclosure of which is incorporated herein by reference. To avoid degradation in the stomach, the capsules comprising the present formulations can be coated with an enteric coating, which inhibits the degradation of the capsule in the acid medium of the stomach. A variety of enteric coatings are known in the art. See, for example, U.S. Patent No. 5,206,219, the disclosure of which is incorporated herein by reference. The compositions, particularly the nanoparticles that produce the formulation, can be prepared by dissolving the cyclosporin in the lower alkanol, where a small proportion of the polyoxyalkylene compound can also be included, generally less than 50 percent by weight of the composition used for the composition. dissolve cyclosporin. An elevated temperature can be used, usually in the approximate range of 60 to 90 ° C. After dissolving the cyclosporin, the major proportion of the polyalkylenoxy compound can be added and the total formulation is brought to the desired ratios by the addition of the appropriate components. In general, cyclosporin can be dissolved in the lower alkanol (optionally includes a portion of the polyalkylenoxy compound) in a weight ratio of about 1: 1.5-5, more usually 1: 2-4. The present formulations find use in immunosuppressive therapy. This immunosuppressive therapy is indicated in a wide variety of diseases, including idiopathic nephrotic syndrome, insulin-dependent diabetes type I, Behcet's syndrome, active Crohn's disease, aplastic anemia, severe corticosteroid-dependent asthma, psoriasis. , rheumatoid arthritis and other diseases, where the immune system can play a pathogenic role. Of particular interest is the use of the present formulations in transplant situations, which include the transplants of organs, tissues or allogeneic and xenogeneic cells, where immunosuppression is convenient to ensure the continued viability of the transplanted organ, tissue or cell, following the transplant, that is, preventing the rejection of the graft or preventing the disease of the graft vs host, for example, following transplantation of the bone marrow. In using the present formulations to deliver immunosuppressive therapy to a host, an effective amount of the cyclosporin will be administered orally to achieve the desired level of immunosuppression in the host, depending on the particular condition to be treated. With transplants, usually an initial dose of ciclosporin will be administered preoperatively. Following transplantation from the donor organ to the host, cyclosporin will be administered repeatedly, i.e. chronically, to the host to maintain immunosuppression. The initial dose will be administered 4 to 12 hours before transplantation and may vary from 10 to 18 mg / kg of the host, usually 10 to 15 mg / kg of the host. Following the operation, the initial dose will usually continue on a daily basis, for a period of 1 to 3 weeks, usually 1 to 2 weeks. The dose can then be reduced to a maintenance dose of 3 to 10 mg / kg per day, usually 3 to 6 mg / kg per day. The regimen at which the dose is reduced to the maintenance level may vary from 3 to 8% per week and will usually be 5% per week. The dose will typically be adjusted based on blood levels to maintain a concentration of 150 to 250 mg / ml, as measured by HPLC, RIA, ELISA or TDx assays. The present formulations can be administered in conjunction with additional agents, when auxiliary therapy is recommended and is known in the art. For example, the present formulations can be administered in conjunction with adrenal corticosteroids, azathioprine and the like. The administration of the present formulations in conjunction with the transplantation of a donor organ to a host, will result in an extension of the viability of the donor organ in the host as a result of the suppression of the host immune response to the presence of the donor organ. . By "prolongation of viability" is meant that the donor organ remains viable in the host for a longer period of time if the immunosuppressive therapy has not been used in conjunction with the transplant. Thus, an extension of the viability includes the maintenance of this viability for an indefinite period of time. A donor organ is considered viable as long as it maintains functionality in the host environment. For convenience of the user, equipment is provided having the appropriate amount of the cyclosporin, one or more dose levels and the cosolvents, ie the lower alkanols and the polyalkylenoxy compounds, for example at least one of the ethanol and the propylene glycol , and at least one of polysorbate 80 and PEG 400. The following examples are offered in the form of illustration and in no way limitation. EXPERIMENTAL EXAMPLE Several oral formulations of cyclosporin, according to the present invention, were prepared. The bioavailability of cyclosporin in the prepared formulations was then observed in rats and in humans. I Oral Formulations of Ciclosporin The following oral formulations of Cyclosporin A were prepared. In each case, 100 mg of CsA, the indicated amount of the surfactant, and the indicated amount of ethanol or propylene glycol, were added to a flask. 1.0 mL volumetric, and the final volume of 1.0 mL was achieved by the addition of an appropriate volume of fatty acid ester and / or diol.

PG = propylene glycol; EtOH = Brij 30 ethanol = polyoxyethylene (4) - lauryl ether Tween 80 = polyoxyethylene (29) -monosorbitan-mono-oleate IO = isopropyl-myristate EO = ethyl oleate.

II. Bioavailability studies in vivo for Formulations 19-24 and 33-42. The bioavailability of cyclosporin in formulations 19-24 and 33-42 was studied as follows. As a measure of bioavailability, the following akinetic parameters were determined: (a) the peak concentration in the blood of cyclosporin (Cmax); (b) the time (tm?) to obtain the Cmax; and the area under the concentration curve in the blood - time (AUC). In addition to formulations 19-24 and 33-42, the bioavailability of cyclosporin in an oral solution (SO) of SANDIMMUNE®, under analogous conditions, was observed for comparison purposes. For each of the above formulations, Sprague-Dawley rats, of natural CsA, weighing 250-350 g, were fed standard pellet feed (Agway® 3000, Granville Mili, Greensboro, NC) and water ad libitum. One day before the experiment, a silicone rubber cannula was inserted into the right jugular veins and right femoral veins under mild ether anesthesia. After fasting during the night, CsA was administered by priming. Following administration, blood samples of 200 μl of the jugular vein were collected in 0.5 ml polypropylene microcentrifuge tubes, containing 0.3 mg of freeze-dried Na EDTA and subjected to shaking immediately for 10 seconds. The sampling times for the animals submitted to the oral formulations were 0, 0.5, 1, 2, 4, 8, 12, 24, 36, 48 and 72 hours, after the administration. CsA, which includes some of its metabolites, was determined in the whole blood by the fluorescence polarization immunoassay (FPI) (TDx, Abbott Lab.). In brief, 150 μl of the whole blood sample was transferred quantitatively to a 1.5 ml microcentrifuge tube. The cells were lysed and dissolved with 50 μl of a solubilizing reagent containing a surfactant. The proteins were then precipitated and separated with 300 μl of acetonitrile. After centrifugation, the supernatant was subjected to the FPI assay on a TDx autoanalyzer, followed by the procedure recommended by Abbott Diagnostics. Since the TDx assay was originally developed for human blood, some of the recommended procedures were modified as follows. A series of standard solutions of known CsA concentration were prepared by adding a known amount of CsA to the blood of the rat treated with EDTA. When the concentration of CsA in a sample is expected to be greater than 1.0 μg / ml, the blood sample was diluted 10 times in a 0.1M phosphate buffer, pH 7.0. For diluted samples, another calibration curve was obtained using a series of standard solutions containing known amounts of CsA, which in the blood of the rats is 10% by volume and 90% of the phosphate buffer. The descriptive far acoynnetic parameters were obtained for the non-compartmental analysis. The peak concentration (Cmax) and the time (Tmax) in which this peak concentration occurred were estimated by the inspection of the concentration-time profile, untreated. The area under the blood-time concentration curve (AUC), from time 0 to the last data point (AUCg-t) was calculated according to the linear trapezoidal procedure. The residual area under the end of the blood-time concentration curve (AUC ^ -oo) was estimated as the ratio of the final concentration observed (C *) to a constant first order regime, associated with the terminal elimination phase. of the concentration-time profile (? z). The contact regime? Z was determined by the log-linear regression of the concentration-time data in the apparent terminal log-linear phase of the concentration-time profile (ie the final points 3 to 5)., depending on the profile under analysis). The total AUC (AUC-t-8) was taken as the sum of AUC0_t and AUC-t-8 The results for each formulation were compared with the results obtained for SO2 and are given in Figures 1-3. These results demonstrate that, for most formulations, the greater bioavailability of cyclosporin is achieved with the present formulations compared to the oral solution (SO) SANDIMMUNE®, as indicated by the higher AUC values of the present formulations. III. Human bioavailability in vivo of Formulations 35, 43-46 and 48-52. 48 healthy male people, aged between 19 and 55 years and no more than 20% deviation from ideal weight, were used as the test subjects. A crossed study of three routes, double-blind, randomized, fasting, with a single dose. The 48 subjects formed 6 groups of 8 subjects at random. Each group received a single dose of 300 mg of the ciclosporin of the previous formulations, or the oral solution (SO) of SANDIMMUNE®, on three different occasions, where each occasion was separated by a recovery period of 7 days. Subjects were required to fast 10 hours before, and 4 hours after, dosing. Water was allowed ad libitum during the study, except for a period of 1 hour before and 2 hours after dosing. Prior to dosing, a sample of 15 ml of blood was drawn. For administrations, 3 ml aliquots of the formulation (300 mg) were combined with 200 ml of milk with chocolate and ingested orally. 10 ml of blood samples were taken at t = 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 20 and 24 hours. A blood sample of 15 ml was also taken in a subsequent study. The concentrations of cyclosporin A in the whole blood samples were tested using TDx (Abbott Diagnostics, N. Chicago, IL), according to the manufacturer's instructions. Non-compartmental pharmacokinetics were derived using standard methods. The maximum total blood concentration (Cma?) And the time (Tmax) of its occurrence were compiled from the concentration-time data. The area under the blood-time concentration curve (AUC) was calculated by the linear trapezoidal rule at the last blood concentration above the limit of sensitivity (25 mg / ml) and extrapolated to infinity. The observed values of Cmax, Tmax and AUC for each formulation were averaged. The average values of each formulation were given in Figures 4 to 6. The results show that for each formulation tested, the max occurred at least twice as fast as with the oral solution (SO) SANDIMMUNE® under the same conditions. Also, the AUC observed for the test formulations was at least 2000 ng-hour / ml greater than that observed for the oral solution (SO) SANDIMMUNE® under the same conditions. Based on these results, formulations 35, 43-46 and 48-52 provided greater bioavailability compared to the oral solution (SO) SANDIMMUNE®. Formulations were prepared for the formation of amorphous nanoparticles in the dilution in an aqueous medium. IV Nanoparticle Formulations A. 5 g of cyclosporin A were added to 5 ml of ethanol. The mixture was stirred to complete the dissolution of cyclosporin A. To the resulting solution was added 25 g of polysorbate 80 and the volume was completed to 50 ml by 1,2-propylene glycol. The mixture was sufficiently stirred at room temperature until a homogeneous solution formed.

B. 5 g of cyclosporin A were added to 5 ml of ethanol. The mixture was stirred until complete dissolution of cyclosporin A. To the resulting solution was added 15 g of polysorbate 80 and the volume was completed to 50 ml by a mixture of 1,2-propylene glycol and polyethylene glycol 400. The mixture was sufficiently stirred at room temperature to form a homogeneous solution. C. 1 ml of the solution obtained in Example 1 was added to 50 ml of water with a glass syringe, as recommended for the oral administration of concentrated emulsions or microemulsions in humans. The addition of the solution was followed by a rapid dissolution and a white suspension of fine particles, having a blue reflection, was obtained as colloidal suspensions (Tyndall effect). After centrifugation at 26,000 G for 5 hours, the pellet was washed with water and then centrifuged at 26,000 G for 24 hours. The washing and centrifugation processes were repeated twice under the same conditions. After drying, an X-ray diagram of the powder was made. The solid was exclusively in an amorphous form. The sediment was examined by scanning electron microscopy. The sediment consisted of amorphous spherical nanoparticles with a diameter between 200 and 400 nm, with the presence of some aggregates.

D. 2 ml of the solution obtained in Example 1 was added to 100 ml of water and the colloidal suspension was examined 10 minutes and 1 hour after dilution by the diffraction / diffusion laser granulometer (Malvern SB.OD) After Within 1 hour, two groups of particles were observed: one representing 70% of the weight of cyclosporin A, with an average diameter of 300 nm, and the second representing 30% of the weight of cyclosporin A, with an average diameter of 20 μm, probably constituting aggregates of nanoparticles. E. ml of the solution obtained in Example 1 was added to 50 ml of water and the colloidal suspension was stirred for 10 minutes. The suspension was then added to 200 ml of artificial acid gastric juice and heated to 37 ° C. The homogeneous colloidal suspension was examined by laser diffraction / diffusion granulometry (Malvern SB.OD). The suspension was composed exclusively of nanoparticles with an average diameter of 600 nm. F. 1 ml of the solution obtained in Example 1 was added directly to 200 ml of artificial acid gastric juice. The homogeneous suspension was heated to 37 ° C and examined rapidly by laser diffraction / diffusion granulometry (Malvern SB.OD). The suspension was composed exclusively of nanoparticles with an average diameter of 350 nm. From the above results and discussion, it is evident that novel formulations of cyclosporin have a high bioavailability. The present formulations are capable of comprising high concentrations of cyclosporins and are stable during storage over a wide range of temperatures, including low temperatures. commonly used in refrigeration. The present formulations are capable of being delivered in the form of capsules, which include the form of hard capsules, providing easy storage and handling. The formulations also provide nanoparticles, which result in increased bioavailability of cyclosporin. All publications and patent applications cited in the specification are incorporated herein by reference as if each publication or individual patent application was specifically and individually indicated to be incorporated by reference. Although the above invention has been described in some detail in the form of illustration and example, for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art, in light of the teachings of this invention, that certain changes and modifications in it without departing from the spirit or scope of the appended claims.

Claims (14)

1. CLAIMS 1. A cyclosporin formulation, which comprises: a cyclosporin, at least one alkanol solvent, having 2 or 3 carbon atoms, and at least one nonionic polyoxyalkylene surfactant, in which this surfactant is selected of the group consisting of polyoxyethylene alcohols and monoesters of fatty acids of ethoxylated polyols, with 4 to 6 carbon atoms. The formulation, according to claim 1, wherein this formulation further consists of at least one cosolvent, selected from the group consisting of monoesters of a lower alkanol and a fatty acid, having 14 to 18 carbon atoms, and diols with 8 to 28 carbon atoms. 3. The formulation according to claim 1, wherein the alkanol solvent is at about 5 to 75% (volume / volume) of the formulation, and the at least one nonionic polyoxyalkylene surfactant is at about 5 to 65% (volume / volume) of the formulation, and the at least one cosolvent is approximately 20 to 80% (volume / volume) of the formulation. 4. A formulation of cyclosporin, which consists of: Cyclosporin A; at least one alkanol solvent, selected from the group consisting of ethanol and propylene glycol, in which this alkanol solvent is in about 5 to 75% (volume / volume) of the formulation; at least one nonionic polyoxyethylene surfactant, wherein this nonionic polyoxyethylene surfactant is selected from the group consisting of polyoxyethylene alcohols and monoesters of ethoxylated sorbitans, and is approximately 5 to 65% (volume / volume) of the formulation; and at least one cosolvent, in which at least one of the cosolvents is n ester of a lower alkanol having 2 to 4 carbon atoms and a fatty acid having 14 to 18 carbon atoms, wherein this cosolvent is approximately 20 a 80% (volume / volume) of the formulation. 5. The formulation according to claim 4, wherein the nonionic surfactant is selected from the group consisting of polyoxyethylene (4) -lauryl ether and polyoxyethylene (20) - mono-sorbitan-mono-oleate, this The fatty acid ester is selected from the group consisting of isopropyl myristate and ethyl oleate, and the formulation comprises two cosolvents, in which one of the cosolvents is a diol with 8 to 28 carbon atoms. 6. An oral formulation of cyclosporin, consisting of: Cyclosporin A, at a concentration ranging from about 50 to 150 mg / ml; a solvent component of alkanol, consisting of ethanol and propylene glycol, in which this solvent component of alkanol is approximately 5 to 75% (volume / volume) of the formulation; and a monoester of an ethoxylated sorbitan, in about 10 to 50% (volume / volume) of the formulation. 7. A formulation, according to claim 6, wherein the ethanol is approximately between 5 and 20% (volume / volume) of the formulation. 8. The formulation according to claim 6, wherein the propylene glycol is approximately between 10 and 50% (volume / volume) of the formulation. 9. A cyclosporin formulation in hard capsule, which consists of: a hard capsule containing the oral formulation according to claim 1. 10. An aqueous dispersion of cyclosporin nanoparticles, in which at least 50 weight percent of the cyclosporin present in the dispersion is of particles less than about 1 μm, and cyclosporin is amorphous. A dispersion, according to claim 10, comprising, in minor amounts, a lower alkanol, and at least one polyoxyethylene surfactant. A dispersion, according to claim 11, wherein the lower alkanol is at least one of the ethanol and the propylene glycol, and the polyoxyethylene compound is the polysorbate 80. 13. An assembly comprising cyclosporine, at least one of the ethanol and the propylene glycol and at least one of the polysorbate 80 and the PEG 400. 14. A method for preparing an aqueous dispersion of cyclosporin particles, according to claim 10, this method comprises: less one of ethanol and propylene glycol with cyclosporin, to form a solution and combine the solution with a polyethyleneoxy surfactant, to form a second solution, which, when diluted with water, forms amorphous nanoparticles of cyclosporin.