Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 9,10-seco- cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2001-05-22
2003-12-16
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
9,10-seco- cyclopentanohydrophenanthrene ring system doai
C514S560000
Reexamination Certificate
active
06664246
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention is concerned with pharmaceutical compositions suitable for the treatment of cancer, and in particular, with pharmaceutical compositions containing vitamin D or a precursor, analogue or metabolite thereof and the use of these compositions in the treatment of a tumor in a subject.
Vitamin D is an isoprenoid compound made up of activated 5-carbon units. The most abundant form of vitamin D is vitamin D
3
, or cholecalciferol. Vitamin D
3
arises from biosynthesis of 7-dehydrocholesterol, an intermediate in cholesterol biosynthesis. Vitamin D
3
is metabolised in the liver to 25-hydroxycholecalciferol [25(OH)D
3
] which is a major form of Vitamin D circulating in the blood compartment 25(OH)D
3
is converted by the kidney to produce two principal dihydroxylated metabolites, namely, 1,25-dihydroxycholecalciferol [1,25(OH)
2
D
3
] and 24,25-dihydroxycholecalciferol [24R,25(OH)
2
D
3
].
1,25(OH)
2
D
3
is the most biologically active naturally occurring form of vitamin D
3
and is transported in the bloodstream to its major site of action in the mucosal cells of the intestine, where calcium absorption is stimulated. Thus vitamin D
3
may be regarded as a prohormone because it is converted to a metabolite that acts analogously to a steroid hormone. It regulates calcium and phosphorous metabolism particularly in the synthesis of the inorganic matrix of bones.
Systemic administration of high doses of vitamin D
3
or its metabolites is limited by the production of hypercalcaemia. This has led to the development of analogues of activated vitamin D (D
3
) which have a greater effect on cell growth than on calcium metabolism. These compounds have been found to be effective in the inhibition of growth of breast, rectal, colorectal and prostate cancer cells.
DISCLOSURE OF THE INVENTION
We have found that tumors in certain organs, for example, primary and secondary tumors in the liver, can be treated by regional delivery of high concentrations of 1,25(OH)
2
D
3
to the affected organ without giving rise to hypercalcaemia. Applicant's co-pending International Application No. PCT/AU98/00440, the disclosure of which is incorporated herein by reference, discloses a method for the treatment of liver cancer by means of regional delivery of vitamin D or its metabolite or analogues to the liver.
The effect on tumors is very dose dependent and there is therefore advantage in delivering higher concentrations of vitamin D compounds such as 1,25(OH)
2
D
3
. However, the limited solubility of vitamin D and its precursors, analogues and metabolites in a conventional carrier such as water places an upper limit on the concentration of the compound that can be delivered to the organ. Delivery of vitamin D
3
intra-arterially in a conventional carrier limits the vitamin D
3
concentration in the blood going to the liver to at most 10
−7
mole per liter.
We have found that very high concentrations of vitamin D compound such as 1,25(OH)
2
D
3
can be achieved by dissolving 1,25(OH)
2
D
3
in a lipid, for example, an iodised or non-iodised oil. A further advantage of using an oil as the carrier for the vitamin D compound is that some oils are concentrated in certain cancers allowing the achievement of very high tumor concentrations of vitamin D
3
. Moreover, we believe that the use of a lipid as the carrier for the vitamin D compound results in a sustained antiproliferative activity of the vitamin D compound and the compound is retained for considerably longer periods within the tumor.
Accordingly, in a first aspect, the present invention provides a pharmaceutical composition suitable for use in the treatment of cancer cells in an organ by regional delivery of the composition to the organ, the composition including a vitamin D compound and a pharmaceutically acceptable lipid, wherein the concentration of the vitamin D compound in the composition is greater than about 1×10
−7
mole per liter.
By the term “vitamin D compound” we include the biologically active and inactive forms of vitamin D. The vitamin D compound may be a precursor, metabolite or analogue of vitamin D. The vitamin D compound may be any analogue having anti-tumor properties. The vitamin D compound maybe cholecalciferol, 25(OH)D
3
or 1,25(OH)
2
D
3
. Examples of analogues of vitamin D include, but are not restricted to, EB1089, OCT (22-oxa-1,25(OH)
2
D
3
), 1&agr;25(OH)
2
, 22,24 diene, 24, 26, 27 trihomo D
3
, MC903 (calcipotriol) and KH1060, 1,25(OH)
2
-16
-ene 23-yne vitamin D
2
and its hexadeutero form. The vitamin D compound may be vitamin D
5
or an analogue thereof.
Preferably the concentration of vitamin D compound in the composition of the invention is at least about 1×10
−6
mole per liter. The concentration of vitamin D compound may be at least about 1×10
−5
mole per liter. The concentration may be at least about 1×10
−4
mole per liter. The concentration may be at least 1×10
−'
mole per liter. A preferred concentration of the vitamin D compound is about 1×10
−6
to 50×10
−5
mole per liter.
Preferably the lipid used is one for which the tumor is avid so that high concentrations of the vitamin D compound are delivered to the tumor. To determine whether the tumor being treated is lipid avid or not a-small dose of lipid may be given into the hepatic artery by a percutaneous or surgically placed catheter. A tumor that is not lipid avid is unlikely to benefit from the treatment to the same extent as a tumor that is avid to the the lipid used.
The pharmaceutically acceptable lipid may be an oil. A non-iodised oil is preferred. The non-iodised oil may be any pharmaceutically acceptable oil in which the vitamin D compound is soluble. The non-iodised oil may be a vegetable oil. The oil may be, for example, poppy seed oil, soybean oil, sesame oil, safflower oil, peanut oil, cremophore, Liposyn or Intralipid. The oil may be derived from shark liver oil including squalane and squalene. The lipid may be medium chain triglycerides (MCT).
An iodised oil such as iodised poppy seed oil (lipiodol) can be used, however, the iodine has the effect of making the vitamin D compound more light sensitive.
The lipid may be in the form of an emulsion of these oils prepared with pharmaceutically acceptable emulsifying agents including, but not limited to, natural and synthetic phospholipids, Spans, Tweens or Pluronics,
We have found that very high concentrations of activated vitamin D
3
in lipiodol can be achieved. For example, 2 mg of 1,25(OH)
2
D
3
can be readily dissolved in one ml of iodised poppy seed oil.
Apart from providing a composition that is more effective in the treatment of tumors, the higher concentrations of vitamin D compounds achievable in the composition of the invention provide a reservoir of the vitamin D compound, which is released over time, thus allowing for “one shot” administration of the composition.
Furthermore, because the composition of the invention is capable of providing higher concentrations of vitamin D, even non-active forms of vitamin D may be used to treat tumors. Although at low concentrations these non-active forms may not be effective treating tumors, at very high concentrations they may become effective.
The composition of the invention may further include one or more other components. The present composition may contain a component that is capable of increasing vitamin D receptor expression. The composition may include an estrogen, estrogen-like compound or estrogen antagonist. The component may be tamoxifen.
The composition may be used to treat primary or secondary tumors in any organ to which the composition can be administered by regional delivery.
Accordingly, the present invention further extends to a method for the treatment of a tumor in an organ in a subject, the method including regional administration to the organ of a composition in accordance with the present invention.
The regional delivery, may be by means of intra-arterial de
Criares Theodore J.
Kim Jennifer
MRC Holdings PTY Limited
Nixon & Vanderhye
LandOfFree
Pharmaceutical composition does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Pharmaceutical composition, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Pharmaceutical composition will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3119807