Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
1999-12-10
2002-08-20
Travers, Russell (Department: 1619)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C424S464000, C514S506000, C514S937000
Reexamination Certificate
active
06436430
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a pharmaceutical composition comprising a lipophilic drug, which is substantially non-soluble in water.
BACKGROUND OF THE INVENTION
Many of the drugs in pharmaceutical compositions are lipophilic, i.e., substantially insoluble in aqueous solution. As a result, there are several problems associated with administration thereof to a patient, such as a mammal. These problems are best illustrated with a representative lipophilic drug, the cyclosporins.
The Cyclosporins comprise a class of structurally distinctive, cyclic, poly-N-Methylated undecapeptides, commonly possessing pharmacological, in particular immunosuppressive, anti-inflammatory and/or anti-parasitic (in particular anti-protozoal, e.g. anti-malarial) activity. The first of the Cyclosporins to be isolated was the naturally occurring fungal metabolite Ciclosporin or Cyclosporine, also known as cyclosporin A and commercially available under the Registered Trademark SANDIMMUN® or SANDIMMUNE®.
Cyclosporin is highly lipophillic and hydrophobic. Therefore, cyclosporin is sparingly soluble in water, but dissolves readily in organic solvents, such as methanol, chloroform and the like. Due to its limited solubility in water, the bioavailability of orally administered cyclosporin is extremely low and may be highly dependent on the condition of the patient. Accordingly, it is very difficult to retain an effective therapeutic concentration. Cyclosporin can thus be formulated into a preparation for oral administration only with great difficulty. Accordingly, numerous studies have been extensively conducted to find a cyclosporin preparation effective for oral administration, that is, a preparation which provides both uniform dosage and bioavailability of the active component.
In the prior art preparations of cyclosporin suitable for oral administration, sparingly water-soluble cyclosporin has been usually formulated in the form of an emulsion by combining cyclosporin with a surfactant, an oil and a co-surfactant. For example, U.S. Pat. No. 4,388,307 discloses a liquid formulation of cyclosporin that includes at least one of the following components: (a) a transesterification product of a natural or hydrogenated vegetable oil and a polyalkylene polyol; (b) a saturated fatty acid triglyceride; or (c) a monoor diglyceride. Component (a) is formed by the transesterification of a triglyceride, e.g., a triglycerides from a vegetable oil, with polyethylene glycol. Component (b) may be obtained by esterifying a triglyceride with saturated fatty acid while component (c) is a mono- or di-glyceride, or a mono- or di-fatty acid glyceride. In these prior art formulations, it is preferred that ethanol be further used as a solubilizing agent. However, since this liquid formulation is administered as an aqueous solution, it is both inconvenient and difficult to administer in an uniform dosage as a result of its limited solubility in water.
In order to mitigate the inconvenience of diluting a cyclosporin liquid composition with water prior to oral administration, a liquid composition has been formulated into a soft capsule preparation, which is now commercially available as SANDIMMUN®. In this preparation, the cyclosporin soft capsule contains a large amount of ethanol as a cosurfactant in order to solubilize the cyclosporin. However, since ethanol permeates the gelatin shell of the capsule and is volatile even at normal temperatures, the constitutional ratio of the contents of the soft capsules may greatly vary during storage. The resulting reduced ethanol content may in turn result in crystallization of the cyclosporin and thus results in a significant variation in the bioavailability of cyclosporin. The variation in cyclosporin concentration in this formulation makes it quite difficult to determine the dosage needed to provide a desired therapeutic effect.
Belgian Patent No. 895,724, which relates to the use of Cyclosporin in the treatment of multiple sclerosis, also describes two oral formulations suitable for the administration of this particular compound. Both of these are based on the commercial Cyclosporin (SANDIMMUN®) drink-solution, with adaption to suit the particular cyclosporin active ingredient. The first comprises 5-10% Cyclosporin, 10-12% ethanol, 30-40% MAISINE®, about 4% CREMOPHORE® and 51-30% LABRAFIL®. This corresponds to the composition of the liquid oral formulation of SANDIMMUN®, but with the replacement of the natural vegetable oil component with MAISINE® and the introduction of a minor percentage of the tenside CREMOPHORE®. MAISINE® is a trans-esterification product of corn oil with glycerol. The ratio of Cyclosporin: tenside in the disclosed composition is 1:0.4-0.8. Inasmuch as ethanol is a key component of the formulation, it does not make any suggestion to replace ethanol as co-solvent/cosurfactant.
U.S. Pat. No. 5,342,625 discloses cyclosporin in association with a hydrophilic phase, lipophilic phase and a surfactant. The hydrophilic phase comprises 1,2-propylene glycol or R
1
—[O—(CH
2
)
x
]—OR
2
, where R
1
is alkyl containing 1-5 carbon atoms or tetrahydrofuryl, R
2
is hydrogen, alkyl containing 1-5 carbon atoms or tetrahydrofurfuryl and x is 1-6. Such ethers are commercially available under the trade name of Transcutol and Glycofurol; in addition, it may contain C
1-5
alkanols, such as ethanols.
However, the use of ethanol as well as other hydrophilic solvents such as 1,2-propylene glycol or liquid polyethylene glycols in these sorts of systems creates several problems. Since ethanol permeates the gelatin shell of the capsule and is volatile, even at room temperature, the constitutional ratio of the contents of the soft capsules may greatly vary during storage. The resulting reduced ethanol content may in turn result in crystallization of the cyclosporin, and this results in a significant variation in the bioavailability of cyclosporin when administered to an animal. The variation in cyclosporin concentrate in these types of formulations makes it quite difficult to determine the dosage needed to provide a desired therapeutic effect. Moreover, when solvents such as ethanol, 1,2-propylene glycol and liquid polyethylene glycols are utilized in gelatin capsules, these solvents have a tendency to absorb moisture, thereby rendering brittle the shell walls, especially those in hard gelatin capsules, and thereby resulting in leakage of the contents of the capsules during storage or shipment. Moreover, one of the biggest drawbacks using hydrophilic components, as in U.S. Pat. No. 5,342,625, has been the potential of reprecipitation of the drug from the formulation when it comes into contact with aqueous systems, such as in the stomach or intestine after ingestion by the mammal.
Moreover, the complexity of the ternary formulations as in U.S. Pat. No. 5,342,625 makes them costly and difficult to manufacture. Moreover, U.S. Pat. No. 5,342,625 suggests the use of solvents such as Glycofurol and Transcutol which are restricted for pharmaceutical use by several regulatory agencies worldwide, including the FDA, because they are not considered “Generally Recognized As Safe” (GRAS) for oral use. Further, with hydrophilic solvents there is always an added risk of precipitation of the cyclosporin on exposure to gastrointestinal fluids in vivo, thereby further affecting bioavailability.
U.S. Pat. No. 4,970,076 discloses the use of GLA (gamma linoleic acid) and DGLA (dihomogammalinolenic acid) and their derivatives as active components in pharmaceutical compositions to counter the adverse side effects of cyclosporin, such as nephrotoxicity and renal side effects. It, however, does not teach or even recognize the use of the lipophilic materials for enhancing the solubility, bioavailability, emulsion or microemulsion capability.
A couple of very recent patents, U.S. Pat. Nos. 5,759,997 and 5,858,401, disclose the use of a mixture of mono-,di-and triglycerides as a carrier for cyclosporin formulations. The formulations therein do not contain a hydrophilic component, such as al
Pharmasolutions, Inc.
Scully Scott Murphy & Presser
Travers Russell
Wells Lauren Q.
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