Cyclosporiine particles

Details Cyclosporiine particles Cyclosporiine particles

2000-12-29

2002-10-15

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S486000, C514S772400

Reexamination Certificate

active

06465016

ABSTRACT:

This invention relates to compositions and procedures that yield sub-micron and micron stable particles of solid water-insoluble or solid poorly soluble drugs such as cyclic oligopeptide cyclosporine or other industrially useful insoluble compounds. The compositions of this invention include combinations of natural or synthetic phospholipids, and one or more non-ionic, anionic or cationic second surfactants, which are also referred to interchangeably herein as second surface modifiers, coated or adhered onto the surfaces of the water-insoluble-compound particles, each of which contains a core of solid compound. The combination of phospholipids and one or more second surfactants (or second surface modifiers) allows the formation and stabilization of the sub-micron and micron size compound particles via hydrophilic, lipophilic and electrostatic interactions and therefore prevents these particles from aggregation or flocculation.
BACKGROUND OF THE INVENTION
Cyclic oligopeptide cyclosporine, a drug, is a potent immunosuppressive agent that in animals prolongs survival of allogeneic transplants involving skin, kidney, liver, heart, pancreas, bone marrow, small intestine, and lung. Cyclosporine has been demonstrated to suppress some humoral immunity and to a greater extent, cell-mediated immune reactions such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant arthritis, and graft vs. host disease in many animal species for a variety of organs. Cyclosporin is useful in these and other indications. For example, cyclosporine is useful as an immunosuppressive agent in humans. Cyclosporine has been used in immunosuppressive therapy and management of organ transplant recipients to prevent rejection of transplanted organs (e.g., skin, pancreas, bone marrow, small intestine, lung, kidney, liver, heart), in immunosuppressive therapy and management of rheumatoid arthritis, and immunosuppressive therapy and management of psoriasis.
The oral bioavailability of cyclosporine in human patients in available cyclosporine dosage forms is not complete, varies among patients in a patient population, and varies with the formulation, varies when food is taken by a patient proximal to the time of administration of a cyclosporine dosage form to or by the patient. When the level of cyclosporine received by a patient is not well controlled, the patient can experience undesired side effects that include organ rejection when concentrations achieved are too low. When the level of cyclosporine received by a patient is too high, renal dysfunction, nephrotoxicity, hepatotoxicity, and systemic hypertension can result.
Cyclosporines are generally cyclic oligopeptides, and examples of this class of drug are described in The Merck Index, Twelfth Edition, page 464-465 which is herein incorporated by reference. Cyclosporins are a group of nonpolar cyclic oligopeptides with immunosuppressant activity. Cyclosporins can be naturally derived such as produced by and isolated from fungi, or they can be prepared synthetically. The solid cyclic oligopeptide cyclosporin A is a white solid which in one crystalline form appears as white prismatic needles with a melting point of 148-152° C. when crystallized from acetone. This cyclic oligopeptide cyclosporine A is soluble in alcohol but is poorly soluble in water and aliphatic hydrocarbons, and it does not have an affinity for either water or aliphatic hydrocarbons.
Cyclosporine A is commercially available in alcohol solution as Neoral® soft gelatin capsules and as Neoral® oral solution, oral formulations of cyclosporine that rapidly form microemulsions in an aqueous environment. Currently available Neoral® Soft Gelatin cyclosporine capsules for microemulsion are available in 25 mg and 100 mg strengths that contain 11.9% v/v (9.5% wt/vol) alcohol, USP dehydrated. Inactive ingredients in the formulation include corn-oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil NF, DL-(alpha)-tocopherol USP, gelatin NF, glycerol, iron oxide black, propylene glycol USP, titanium dioxide USP, and carmine. Currently available Neoral® cyclosporine oral solution for microemulsion is available in 50 mL bottles with each milliliter containing 100 mg/mL cyclosporine and 11.9% v/v (9.5% wt/vol.) alcohol, USP dehydrated. Inactive ingredients include corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil NF, DL-(alpha)-tocopherol USP, and propylene glycol USP.
Cyclosporine is also commercially available in alcohol solution as Sandimmune® soft gelatin capsules, as Sandimmune® oral solution, USP, and as Sandimmune® injection. Inactive ingredients present in these formulations include corn oil, olive oil, gelatin, glycerol, Labrafil M 2125 CS (polyoxyethylated glycolysed glycerides), Labrafil M 1944 CS (polyoxyethylated oleic glycerides), sorbitol, and Cremophor EL (polyoxyethylated castor oil). Cremophor® EL (polyoxyethylated castor oil) is known to cause hyperlipemia and electrophoretic abnormalities of lipoproteins. Cremophor® EL (polyoxyethylated castor oil) contained in currently available concentrate for intravenous infusion can cause phthalate stripping from PVC.
When currently available formulations are compared, Neoral® dosage forms exhibit increased bioavailability of cyclosporine in comparison to Sandimmune® dosage forms. These currently available dosage forms are not bioequivalent and thus cannot be used interchangeably. For a given trough concentration, cyclosporine exposure will be greater with Neoral® than with Sandimmune®.
Neoral dosage forms can carry up to about 100 mg/mL of cyclosporine and the dosage form can be relatively large.
The absolute bioavailability of cyclosporine administered as Sandimmune® is dependent on the patient population, and is estimated to be less than 10% in liver transplant patients and as great as 89% in some renal transplant patients for which cyclosporine therapy is indicated. In studies of renal transplant, rheumatoid arthritis and psoriasis patients, the mean cyclosporine AUC is known to be approximately 20% to 50% greater and the peak blood cyclosporine concentration (C
max
) approximately 40% to 106% greater following administration of Neoral® compared to following administration of Sandimmune®. The dose normalized AUC in de novo liver transplant patients administered Neoral® 28 days after transplantation is known to be 50% greater and C
max
90% greater than in those patients administered Sandimmune®. In another indication for cyclosporine therapy, AUC and C
max
are also increased (Neoral® relative to Sandimmune®) in heart transplant patients.
Following oral administration of Neoral®, the time to peak blood cyclosporine concentrations (T
max
) currently ranges from 1.5-2.0 hours. The administration of food with Neoral® is known to decrease the cyclosporine AUC and C
max
. A high fat meal (669 kcal, 45 grams fat) consumed within one-half hour before Neoral® administration is known to decrease the AUC by 13% and C
max
by 33%. The effects of a low fat meal (667 kcal, 15 grams fat) are known to be similar.
A number of drugs are known to increase in vivo levels of cyclosporine when administered to a patient at a time proximal to administration of cyclosporin. These include diltiazem, danazol, nicardipine, bromocriptine, verapamil, metoclopramide, erythromycin, methylprednisolone, ketoconazole, fluconazole, and itraconazole.
A number of drugs are known to decrease in vivo levels of cyclosporine when administered to a patient at a time proximal to administration of cyclosporin. These include rifampin, phenobarbital, phenytoin and carbamazepine.
It would be useful to have a dosage formulation of cyclic oligopeptide cyclosporine that provides an amount of cyclic oligopeptide cyclosporine to a patient in need of treatment by cyclic oligopeptide cyclosporine who has recently ingested a high fat meal or a low fat meal that is comparable to the amount of cyclic oligopeptide cyclosporine provided to the same patient in a fasted state. Preferably, these fed-fasted comparable amounts

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