Preparation of pharmaceutical compositions

Details Preparation of pharmaceutical compositions Preparation of pharmaceutical compositions

1999-12-17

2003-07-29

Kishore, Gollamudi S. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Capsules

C424S400000, C424S464000, C424S489000, C514S009100, C514S763000

Reexamination Certificate

active

06599527

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the preparation of carriers for lipophilic materials in general. More specifically it relates to the formation of an improved carrier for these compounds which disperses in the presence of the aqueous contents of the gastro-intestinal tract (GI) to form drug-carrying lipid aggregates. The invention is particularly suitable for oral applications but can be readily adapted for other uses. The invention especially relates to novel phospholipid-cyclosporin formulations having improved bio-availability, increased efficacy and reduced toxicity and to a process of manufacture of such formulations.
BACKGROUND TO THE INVENTION
Cyclosporins are fungal metabolites. They are hydrophobic neutral cyclic peptides and have essentially similar chemical and physical properties. Cyclosporin A (CyA) is representative and is the best known example. It is widely used in organ transplants to prevent rejection and as an immunosupressive agent in the treatment of systemic and local autoimmune disorders in which T cells play a major role. CyA has also been used to treat chronic conditions such as rheumatoid arthritis, asthma and non-malignant skin disorders. Derivatives of CyA are also known to prevent multi-drug resistance from developing during treatment with cytotoxic drugs.
The clinical use of CyA in oral and intravenous dosage forms to prevent organ rejection was approved by the FDA in 1983. It has dramatically improved long-term survival rates in transplant patients. Most patients, however, still need to be maintained on life-long CyA therapy. This is normally provided in an oral form but may involve intravenous injection when it is necessary to obtain an adequate blood concentration quickly or oral therapy proves ineffective. Unfortunately, there are two major problems associated with oral therapy. Firstly, since the drug is lipophilic, its absorption from the GI tract is variable and incomplete, and bioavailability can range from 6% to 60%. This results in variable or inadequate blood concentrations which can bring about graft rejection and failure Secondly, use of CyA is associated with nephrotoxicity. Impairment in kidney function is dose-related and increases with prolonged exposure, again emphasising the importance of controllable and predictable bioavailability.
There are few therapeutic compounds that have received more extensive and exhaustive pharmacodynamic and pharmacokinetic examination than CyA. Investigations have shown that CyA has a narrow therapeutic index and that drug absorption takes place across an absorption window located along the upper part of the small intestine. Little absorption takes place in the stomach or colon.
The first CyA oral formulation introduced into clinical use (Sandimmune) comprised a solution of CyA dissolved in a solvent system of olive oil and ethanol (Patentschrift (Switz.) CH 64I 356, Feb. 29, 1984, Appl. 79/1949. Feb. 27, 1979). The oil was emulsified in water using a polyethoxylated oleic glyceride surfactant to give a coarse O/W emulsion. This system was found to be inherently thermodynamically unstable. It is markedly affected by external conditions such as pH, temperature, diluting medium surrounding medium As a result, drug tended to precipitate out of solution, and thus not be absorbed. The release of CyA from the oil-droplets and its subsequent absorption was also found to be highly dependent on the prevailing conditions in the GI tract e.g. composition of food and presence of bile and pancreatic enzymes. This formulation thus gave erratic inter- and intra-patient bioavailability.
Although these problems were widely recognised, Sandimmune was relied upon exclusively by transplant patients for a number of years. It is only recently that a new oral formulation of CyA called Neoral with improved pharmacokinetics has been introduced to address these problems. This formulation was introduced as a ‘high-technology’ microemulsion system in which the CyA is dissolved in a solvent consisting of a mixed lipophilic (corn oil mono-, di- and triglycerides) and hydrophilic (propylene glycol) solvent stabilised by an appropriate amount of a powerful surfactant, polyoxyl-40 hydrogenated castor oil (Kovarik et al, J. Pharm Sciences, 83, 444 (1994), and Hall, Inpharm, 10 December p 13 (1994)). This new formulation is reported to have self-emulsifying properties and immediately forms a transparent microemulsion in aqueous fluids. The CyA is dissolved in colloidal oil droplets (10-100 nm diameter) stabilised by the surfactant and can be diluted without precipitation, having similar properties to a real aqueous solution.
Neoral is at present the only known oral formulation generally available that gives consistent absorption, independent of bile and food. Clearly, in view of the number of patients world-wide who need to be on long-term CyA maintainance and their individual circumstances, it would be most desirable for there to be a comparable bioequivalent formulation that does not rely on the presence of potentially harmful synthetic surfactants.
A number of alternative approaches to the solubilisation of CyA and the development of formulations that avoid the dual problems of variable bioavailabilty and incomplete absorption from the GI tract have been described in the prior art.
Polyvinyl pyrollidone (PVP) with molecular weights of 40,000 and 17,000, have been used as solubilising agent to carry the drug (Yonish-Rouach et al Journal of Immunological Methods 135, 147-153 (1990)). It was demonstrated that CyA can be solubillsed and retain its activity (in vitro) in aqueous solutions of PVP. However, no evidence that the formulation would work in vivo was presented.
Co-administration of d-alphatocopheryl polyethylene glycol succinate (TPGS) which can form micelles has been reported to lead to an improvement of CyA absorption in children after liver transplantation (Sokol et al., The Lancet 338, 212-215, (1991)).
In order to counter the poor solubility of CyA, Guzman et al., have immobdilsed the drug in nanoparticles of polymeric nanomatrix composed of either isobutyl-2-cyanoacrylate monomer or poly-E-caprolactone, in the presence of Pluronic F-68 (Journal of Pharmaceutical Sciences 82, 498-502 (1993)). However, the drug-free nanoparticles also exhibited immunosupressive activity suggesting that they are unlikely to be a suitable vector for carrying CyA.
The enhancement of the intestinal absorption of a cyclosporine derivative (used as a model for CyA) by using milk fat globule membrane (MFGM) as an emulsifier of lipophilic cyclopeptides has been reported (Biol. Pharm. Bull. 17, 1526-1528(1994)).
In cases, where it is necessary to administer CyA intraveneously, it is normally formulated in an injectable form using a solvent consisting of ethanol and Cremophor EL, a tri-ricinoleate ester of ethoxylated castor oil. This solubiliser frequently gives rise to anaphylatic reactions and is itself known to cause nephrotoxicity exacerbating problems associated with the inherent renal toxicity of CyA.
A well-recognised approach to the formulation of lipophilic drugs is liposome encapsulation in which the drug is intercalated into the lipid bilayer(s) of the liposome. Compositions, methods of preparation, applications, advantages and disadvantages of liposomes have all been extensively reported, and there are more than 30 publications describing liposomal entrapment of CyA mainly for intravenous and systemic use.
From purely pharmaceutical considerations, there is general consensus that liposome entrapment significantly reduces nephrotoxicity. However, there is less certainty about whether the reduced nephrotoxicity reported with intravenous liposomal formulations is in fact due to altered pharmacokinetics of liposome encapsulated CyA or the non-specific, physical binding of the drug to other lipids present in the system. Some reports claim that CyA pharmacolknetics depend on such factors as liposome charge, size and composition. Fahr (Pharmaceutical Research, 12, 1189-1198 (1995)), however, dismisses this idea and cit

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