Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-09-09
2003-12-02
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S501000, C424S502000, C514S011400
Reexamination Certificate
active
06656504
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to nanoparticulate compositions comprising amorphous cyclosporine, or a mixture of amorphous and crystalline cyclosporine, and methods of making and using such compositions.
BACKGROUND OF THE INVENTION
Cyclosporine is a hydrophobic, cyclic, undecapeptide that exerts immunosuppressive, antiinflammatory, antifungal, and antiparasitic activities. Immunosuppressive medications play a large part of the management of many pediatric illnesses. Cyclosporine is the primary tool used to prevent rejection following solid organ and bone marrow transplantation; the drug helped revolutionize transplantation by improving transplant survival, reducing hospitalization, and reducing patient morbidity. It has been estimated that cyclosporine is given to more than 90% of children who have received a kidney transplant in the United States. Cyclosporine also has been effective in various other autoimmune conditions such as uveitis, psoriasis, type I diabetes mellitus, rheumatoid arthritis, inflammatory bowel disease, certain nephropathies, refractory Crohn's disease, ulcerative colitis, biliary cirrhosis, aplastic anemia, rheumatoid arthritis, myasthenia gravis, and dermatomyositis.
Cyclosporine is in clinical use worldwide under the trade names SANDIMMUNE® (Novartis), NEORAL® (Novartis), and SANGCYA® (SangStat). SANDIMMUNE®, introduced in 1983, suffered from poor and widely variable absorption rates. This prompted development of a second generation cyclosporine formulation, NEORAL®, which is a microemulsion formulation having better absorption than SANDIMUNE®-both in quantity and consistency. Since 1995, when NEORAL® was introduced, about 70% of patients have switched from SANDIMMUNE® to NEORAL®, indicating the severity of poor and inconsistent absorption of cyclosporine. SANGCYA®, which is a modified oral solution bioequivalent to NEORAL®, was introduced in 1998.
Cyclosporine is administered orally and intravenously (IV). After oral administration, roughly 20 to 50% is absorbed, although absorption is highly variable. First-pass metabolism, mode of administration, and drug interactions all affect cyclosporine absorption. Food decreases the absorption of NEORAL® and SANGCYA®.
Cyclosporine is extremely hydrophobic. The IV formulation contains 33% alcohol and a castor oil vehicle to solubilize the drug, which is believed to account for occasionally severe hypersensitivity reactions. Oral preparations can contain corn, castor or olive oil and ethanol, but in lower concentrations. The dose normalized area under the curve (AUC) is 23% greater for NEORAL® or SANGCYA® as compared to SANDIMUNE® in renal transplant, rheumatoid arthritis, and psoriasis patients, and 50% greater in liver transplant patients. Data for cardiac transplant patients is limited, but similar increases have been noted. Increases in peak blood cyclosporine concentrations (NEORAL® and SANGCYA® related to SANDIMMUNE®) range from 40 to 106% for renal transplant patients and 90% for liver transplant patients.
While NEORAL® and SANGCYA® are an improvement over SANDIMMUNE®, the conventional cyclosporine formulations suffer from poor bioavailability because, among other things, cyclosporine is poorly water soluble. Moreover, currently marketed cyclosporine formulations are known to have disadvantageous “intersubject variability,” i.e., it has been found that, given the same dosage amount, actual blood levels of cyclosporine vary significantly from patient to patient. See
Physicians' Desk Reference
(1998) at 1882 et seq. This represents an important shortcoming of these drugs. Specifically, because cyclosporine has a narrow therapeutic index (a narrow range between an effective dosage and a harmful dosage), the inability to predict drug absorption requires that physicians closely monitor each patient to establish baseline absorption levels. Such monitoring is expensive and time consuming. In addition, the poor absorption and patient variability of known cyclosporine formulations can make dosage formulation difficult. Proper dosage formulation for cyclosporine is critical because the drug is a general immunosuppressive. Therefore, the drug can result in an increased susceptibility to infection. Too much drug can result in uncontrolled infection while too little can result in organ rejection.
One drug delivery method that can result in increasing the bioavailability, increasing the absorption rate, quantity, and consistency, and decreasing the toxicity of a drug is formulation of the drug into a nanoparticulate composition. Nanoparticulate compositions, first described in U.S. Pat. No. 5,145,684 (“the '684 patent”), are particles consisting of a poorly soluble crystalline therapeutic or diagnostic agent onto which are adsorbed a non-crosslinked surface stabilizer. Nanoparticulate compositions comprising cyclosporine are not described by the '684 patent. Nanoparticulate compositions containing crystalline, but not amorphous, cyclosporine are disclosed in U.S. Pat. Nos. 5,494,683 and 5,399,363.
Conventional large particle sized amorphous cyclosporine compositions are described in U.S. Pat. Nos. 5,389,382 (“the '382 patent”) and 5,827,822 (“the '822 patent”). These disclosures suffer from various deficiencies. For example, the '382 patent describes hydrosols of cyclosporine in an intravenous applicable, stabilized, pharmaceutically acceptable form, which is suspended or dry. The hydrosol formulations are obtained by controlled precipitation methods. Such methods are disadvantageous in that they result in solid dose formulations having a low drug to surface stabilizer ratio, and liquid dispersion formulations having a low solid content. This is because controlled precipitation methods require an excess amount of surface stabilizer and water to produce small-sized precipitated particles. The excess of surface stabilizer produces solid dose compositions having a large quantity of surface stabilizer and a small quantity of drug, and the excess of water produces a liquid dispersion formulation having a low solids content and, therefore, a low drug content.
A high drug content for a solid dose or liquid dispersion formulation is preferred because it produces a more concentrated dosage formulation. Concentrated dosage forms of cyclosporine are particularly desirable because the dosage for this drug is relatively high, i.e., about 100 mg a day or more. A dosage formulation having a low drug content, but requiring a high daily dosage, results in either a large pill, capsule, or quantity of fluid, or multiple doses of such formulations, to be administered to the patient. In contrast, a concentrated dosage form allows minimization of the size of the orally administered pill or capsule or number of daily administrations.
The '822 patent is directed to aqueous suspension formulations of amorphous cyclosporin A containing lower alkanols as solubilizing agents and a polyoxyalkylene surfactant. The addition of alcohol solubilizing agents is frequently undesirable because they can an trigger an allergic response in a patient. Such solubilizing agents are often required for prior art cyclosporine compositions to increase the solubility of the cyclosporine. A drug must be absorbed by a patient prior to taking effect. Thus, often pharmaceutical formulations of highly insoluble drugs additionally contain solubilizing agents to aid in absorption of the drug following administration.
There remains a need in the art for cyclosporine formulations that can be delivered in high dosage formulations, that exhibit consistent and effective absorption, that have decreased toxicity as compared to known cyclosporine formulations, and which do not require the presence of alcohol solubilizing agents. The present invention satisfies these needs.
SUMMARY OF THE INVENTION
The present invention is directed to nanoparticulate compositions of amorphous cyclosporine and, adsorbed to the surface of the cyclosporine, at least one non-crosslinked surface stabilizer. The cyclosporine particles
Bosch H. William
Hovey Douglas C.
Ostrander Kevin D.
Elan Pharma International Ltd.
Pulliam Amy E
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