Title:  Oral cyclosporin formulations

United States Patent:  6,254,885

Assignee:  SangStat Medical Corporation (Menlo Park, CA); The University of North Carolina at Chapel Hill (Chapel Hill, NC)

Filed:  March 9, 1998

Improved oral cyclosporin formulations which have high bioavailability and are capable of admiration in hard capsules are provided. In the subject formations, cyclosporin is delivered in an orally acceptable vehicle comprising at least one alkanol solvent of from 2 to 3 carbon atoms in combination with at least one non-ionic surfactant. The subject formalations may further comprise at least one cosolvent, where cosolvents of interest include fatty acids and diols. The subject formulations find use in immuno-suppressive therapy.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

Oral cyclosporin formulations are provided which promote bioavailability and can be formulated as capsules, particularly hard capsules. In the subject formulations, cyclosporin is present in an orally acceptable vehicle comprising at least one alkanol solvent of from 2 to 3 carbon atoms in combination with at least one non-ionic surfactant. The subject formulations may father comprise at least one cosolvent, where cosolvents of interest include fatty acid esters and diols. Each of the components of the subject formulations are pharmaceutically acceptable. In addition to providing for high bioavailability, the subject formulations provide for reproducible cyclosporin absorption from one batch of a particular formulation to the next. The subject formulations find use in immunosuppressive therapy.

A number of cyclosporins are known in the art to exhibit immunosuppressive activity and may be delivered in the subject oral formulations. Cyclosporins that may be administered in the subject formulations include Cyclosporin A, Cyclosporin B, Cyclosporin C, Cyclosporin D and Cyclosporin G, as well as synthetic analogs thereof See Merck Index (1989) 2759. The subject oral formulations are particularly suited for the delivery of Cyclosporin A. When delivered in the subject formulations, Cyclosporin A will be present in concentrations ranging from 50 to 150 mg/ml, usually 100 to 150 mg/ml, based on the volume of the vehicle component of the formulation.

The vehicle component of the subject formulations will include an alkanol solvent component, where the alkanol solvent component will comprise at least one alkanol and usual no more than three different alkanols, more usually no more than two different alkanols, where the alkanols will usual be from 2 to 3 carbon atoms, and from 1 to 2 hydroxy groups, such 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 alkanol solvent in the formulation will be at least about 1% (v/v), usually at least about 3% (v/v) and may be as high as 95% (v/v), but will generally range from about 5 to 75% (v/v), by from about 5 to 60% (v/v), and more usually from about 10 to 60% (v/v) of the formulation. When ethanol is present in the formulation as an alkanol solvent, the amount of ethanol may range 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 propylene glycol in the subject formulation may range from about 5 to 90% (v/v), usually from about 5 to 85% (v/v), more usually from about 10 to 50% (v/v) of the formulation.

Also present in the orally acceptable vehicle will be at least one non-ionic polyoxyalkylene surfactant, usually not more than two polyoxyalkylene non-ionic surfactants. The polyoxyalkylene surfactants will have a hydrophilic-lipophilic-balance (HLB) of from about 5 to 20, usually from about 8 to 16. Preferably, the polyoxyalkylene non-ionic surfactants employed in the subject formulations will be polyoxyethylene compounds. Polyoxyethylene compounds of interest include: ethoxylated alcohols, i.e. polyoxyethylene alcohols or ethoxylated fatty alcohols, where the alcohol moieties are generally of from 10 to 18, usually from 10 to 14 carbon atoms, as well as ether and ester substituents thereof and polyoxyethylene derivatives of fatty acid partial esters, usually monoesters, of polyols of from 4 to 6 carbon atoms, usually 6 carbon atoms, where the polyols may be polyol anhydrides e.g. sorbitan. The fatty acid moieties of the subject surfactant will typically range from 10 to 18 carbon atoms. The number of ethylenoxide groups will generally be in the range of 2 to 30, usually in the range from about 2 to 25. Preferred surfactants are polyoxyethylene (4) lauryl ether (BRIJ 30.RTM.) and polyoxyethylene (20) mono sorbitan mono-oleate (TWEEN 80.RTM.. The total amount of non-ionic surfactants present in the subject formulations will range from 5 to 65%, usually from about 5 to 60% (v/v) of the formulation. Where TWEEN 80.RTM. is present in the formulation, it will usually be present in amounts ranging from 5 to 60%, more usually from about 10 to 50% (v/v) of the formulation. When BRIJ 30.RTM. is present in the subject formulation, it will usually be present in amounts ranging from 10 to 45%, more usual from about 15 to 40% (v/v) of the formulation.

The subject formulations may further comprise one or more cosolvents, usually not more than three different cosolvents, more usually not more than two different cosolvents, where suitable cosolvents include fatty acid esters and diols, where the cosolvent may be 100% fatty acid ester, 100% diol, or combination thereof. The total amount of cosolvent present in the formulation may range from about 20 to 80% (v/v) and will usually range from about 25 to 75% (v/v). When present in the formulation, the ratio of cosolvent to solvent in the subject formulations may range from about 1:1 to 15:1, but will usually range from about 1:1 to 13:1.

Fatty acid esters which may serve as cosolvents in the subject formulations are those fatty acid esters where the hydrocarbon chain of the fatty acid is from 12 to 18, usually 14 to 18 carbon atoms in length, where the fatty acid ester will be a mono-ester of a lower alkanol. Suitable fatty acid esters will generally comprise an even numbered fatty acid chain, where the hydrocarbon chain may be saturated or unsaturated, usually having not 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 mono-ester will be a lower alkanol of from 2 to 4 carbon atoms in length, usually 2 to 3 carbon atoms in length, with or without branches. Fatty acid esters of particular interest are isopropyl myristate and ethyl oleate. Isopropyl myristate, when present, will range from about 55 to 75% (v/v), and ethyl oleate, when present, will range from about 35 to 75% (v/v) ofthe total formulation. Usually the fatty acid ester will be present in an amount at least about equal (v/v) and up to 8 times the amount of surfactant in the formulation, usually not greater than 5 times the amount of surfactant in the formulation (v/v).

Diols may also be present in the subject formulations, where the diols may be present in addition to, or in lieu of, the fatty acid ester cosolvent. Diols of interest as cosolvents are generally liquids at physiologic temperatures and include diols of from 8 to 28 carbon atoms, usually 16 to 20 carbon atoms, where the diol may be a polyoxyalkylene diol, where alkylene is of from 2 to 3 carbon atoms. Suitable diols for use as cosolvents may range from about 200 to 800 daltons, usually from about 200 to 650 daltons. Diols of particular interest include polyethylene glycols, particularly polyethylene glycol 200 (PEG₂₀₀), polyethylene glycol 400 (PEG₄₀₀), polyethylene glycol 600 (PEG₆₀₀), and the like, with PEG₄₀₀ being preferred. When present as cosolvents in the subject formulations, the diols will range from about 5 to 60% (v/v), usually from 5 to 55% (v/v) of the formulation.

In the subject formulations, the cosolvents themselves may impart desirable physical properties to the formulation, such as viscosity, stability and the like. Where desired, the formulation may further comprise additional agents which impart desired physical properties to the formulation, such as thickening agents, suspending agents, solidifying agents, and the like, where such agents include acacia, carboxymethylcellulose, hydroxypropylcellulose, lecithin, methyl cellulose, high molecular weight polyethylene glycols, e.g those polyethylene glycols with molecular weights ranging from about 1000 to 6000, usually 1000 to 5000 daltons, povidone, sodium alginate, tragacanth, and the like. Also present in the subject formulations may be a number of minor components which provide various functions, such as enzyme inhibitors, preservatives, antioxidants, antimicrobial agents, stabilizers and the like. The total amount of these thickening agents and other additives, when present in the formulation, will normally not be greater than 5 weight %, usually 2 weight %, more usually 1 weight % of the formulation. A number of excipients may also be present in the subject formulations, as is known in the art.

The subject formulations are stable over a wide range of temperatures, where by stable is meant that the physical integrity of the formulation is not comprised, e.g. crystallization of the cyclosporin active agent does not occur. Included within the temperature range over which the subject formulations are stable are lower temperatures, such as those employed in refrigerated storage, where such lower temperatures typically range from about 0 to 15^oC., more typically from about 2 to 8^oC.

The subject formulations are suitable for administration in capsule form, e.g. hard and soft capsules. Methods of producing hard capsules comprising liquid formulations are known in the art and described in U.S. Pat. Nos. 4,822,618 and 4,576,284, the disclosures of which are herein incorporated by reference. Generally, hard capsules that find use with the subject formulations will comprise two parts: a shell component and a cap component. The shell and cap components fit together to produce an enclosed cavity of defined volume sealed in a hard capsule shell. The shell and cap components may be fabricated from a bydrophilic polymer, such as starch or gelatin. In preparing the hard capsules, the liquid formulation will be poured into the shell component and then the capsule will be sealed by fitting the cap component over the shell component. The seal between the two components may be secured, thereby preventing leakage of the enclosed formulation from the capsule, by using a sealant as described in EP 116744, the disclosure of which is herein incorporated by reference. To avoid degradation in the stomach, capsules comprising the subject formulations may be coated with an enteric coating which inhibits degradation of the capsule in the acidic environment of the stomach. A variety of enteric coatings are known in the art. See for example, U.S. Pat. No. 5,206,219, the disclosure of which is herein incorporated by reference.

The subject formulations find use in immunosuppressive therapy. Immunosuppressive therapy is indicated in a wide variety of diseases, including idiopathic nephrotic syndrome, type I insulin-dependent diabetes, Behcet's syndrome, active Crohn's disease, a plastic anemia, severe corticosteroid-dependent asthma, psoriasis, rheumatoid arthritis, and other diseases where the immune system may play a pathogenic role. Of particular interest is the use of the subject formulations in transplant situations, including both allogeneic and xenogeneic organ, tissue or cell transplantation, where immunosuppression is desired to ensure maintained viability of the transplanted organ or tissue or cell following transplantation, i.e. to prevent graft rejection or prevent graft vs. host disease, e.g. following bone marrow transplantation.

In using the subject formulations to provide immunosuppressive therapy to a host, an effective amount of cyclosporin will be orally administered to achieve the desired level of immunosuppression in the host, depending on the particular condition to be treated. With transplantation, usually an initial dosage of cyclosporin will be administered prior to operation. Following transplantation of the donor organ to the host, the cyclosporin will be administered repeatedly, i.e. chronically, to the host to maintain immunosuppression. The initial dosage will be administered 4 to 12 hours prior to transplantation and may range from 10 to 18 mg/kg host, usually 10 to 15 mg/kg host. Following the operation, the initial dosage will usually be continued on a daily basis for a period of 1 to 3 weeks, usually 1 to 2 weeks. The dosage may then be tapered to a maintenance dosage of 3 to 10 mg/kg per day, usually 3 to 6 mg/kg per day. The rate at which the dosage is tapered to the maintenance level may range from 3 to 8% per week and will usually be about 5% per week. The dosage will typically be adjusted based on trough blood levels to maintain a concentration of 150 to 250 ng/ml, as measured by HPLC, RIA, ELISA or TDx assay. The subject formulations may be administered in conjunction with additional agents, where adjunct therapy is recommended and is known in the art. For example, the subject formulations may be administered in conjunction with adrenal corticosteroids, azathioprine and the like.

Administration of the subject formulations in conjunction with transplantation of a donor organ to a host will result in a prolongation of the viability of the donor organ in the host as a result of suppression of the host's 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 than it would have had immunosuppressive therapy not been employed in conjunction with the transplantation. Thus, prolongation of viability includes maintenance of viability for an indefinite period of time. A donor organ is considered viable as long as it maintains functionality in the host environment.

Claim 1 of 17 Claims

What is claimed is:

1. A cyclosporin formulation consisting essentially of:

cyclosporin;

at least one alkanol solvent of from 2 to 3 carbon atoms;

at least one non-ionic polyoxyalkylene surfactant, wherein said surfactant is selected from the group consisting of polyoxyethylene alcohols and fatty acid monoesters of ethoxylated polyols of from 4 to 6 carbon atoms; and

at least one cosolvent, wherein said cosolvent is selected from the group consisting of mono-esters of a lower alkanol and a fatty acid of from 14 to 18 carbon atoms and diols of from 8 to 28 carbon atoms.

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