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WO1996000074A1 - Pharmaceutical compositions comprising vitamin-d analogs - Google Patents

Pharmaceutical compositions comprising vitamin-d analogs Download PDF

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Publication number
WO1996000074A1
WO1996000074A1 PCT/US1995/008005 US9508005W WO9600074A1 WO 1996000074 A1 WO1996000074 A1 WO 1996000074A1 US 9508005 W US9508005 W US 9508005W WO 9600074 A1 WO9600074 A1 WO 9600074A1
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WO
WIPO (PCT)
Prior art keywords
vitamin
preparation according
cancer
matrix
analog
Prior art date
Application number
PCT/US1995/008005
Other languages
French (fr)
Inventor
Joseph Kost
Shraga Shany
Sergio A. Lamprecht
Carmen Segal
Original Assignee
Ben-Gurion University Of The Negev
Kopeika, Norman, S.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ben-Gurion University Of The Negev, Kopeika, Norman, S. filed Critical Ben-Gurion University Of The Negev
Priority to AU29980/95A priority Critical patent/AU2998095A/en
Publication of WO1996000074A1 publication Critical patent/WO1996000074A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates to the field of pharmacy. More particularly, the invention relates to novel slow-release pharmaceutical preparations containing Vitamin-D analogs.
  • Vitamin-D hormone 1,25-dihydroxyvitamin D 3
  • the Vitamin-D hormone is known to be active anti-proliferation agents which is active against a variety of cancer cells, including cells of the large intestine [A. Belelli et al., Carcinogenesis, 13, 2293-2298, 1992].
  • the activity of 1,25-dihydroxyvitamin D 3 was tested in rats colon cancer and it was found that once weekly administration for 5 weeks reduced by 50% the number of DMH-induced murine colon cancer.
  • the potentially useful therapeutic activity of 1,25- dihydroxyvitamin D 3 has so far been hampered by its high calcemic activity. Treatment of rats with higher doses of 1,25-dihydroxyvitamin D 3 , by subcutaneous injection, which could potentially be beneficial in cancer treatment, led to hypercalcemia and death.
  • the primary objects of the invention are achieved by providing controlled- release pharmaceutical preparations comprising a Vitamin-D analog in a supporting matrix, typically a polymeric matrix.
  • Fig. 1 shows the kinetics of 1,25-dihydroxyvitamin D 3 release from an EVA-based matrix, dependent on fetal calf serum concentrations
  • Fig. 2 shows the effect of 1,25-dihydroxyvitamin D 3 loading in the matrix of Fig. 1, on its released fraction;
  • Fig. 3 shows the effect of implantation site in- ⁇ i ⁇ o on the serum concentration of 1,25-dihydroxyvitamin D 3 , following two weeks post-implantation, with a load of 0.0050% of 1,25-dihydroxyvitamin D 3 ;
  • Fig. 4 shows the effect of implantation site in- ⁇ i ⁇ o on the serum concentration of Ca +2 , after two weeks post-implantation, with the same matrix as in Fig. 3;
  • Fig. 5 shows the effect of 1,25-dihydroxyvitamin D 3 released on the activity of ornithine decarboxylase (ODC) in DMH-treated rats (Example 3); and
  • Fig. 6 shows the effect of 1,25-dihydroxyvitamin D 3 released according to the invention, and injected (prior art), on the activity of ornithine decarboxylase (ODC) in DMH-treated rats.
  • ODC ornithine decarboxylase
  • the invention is directed to controlled- release pharmaceutical preparations comprising a Vitamin-D analog in a supporting matrix, alone or together with pharmaceutically acceptable additives or active agents.
  • Vitamin analogs are many, and will be recognized by the skilled person. Illustrative and non-limitative examples of such analogs include 1,25-(OH) 2 D 3 (calcitrol), 26,27-F 6 -1,25-(OH) 2 D 3 (ST-630), 1 ⁇ -(OH)D 2 , 1 ⁇ -(OH)D 3 , 1,24-(OH) 2 D 3 (TV-02), 22-oxacalcitriol (OCT), calcipotriol (MC 903), 1,25-(OH) 2 -16-ene-23-yne-D 3 (Ro 23-7553), EB 1089 and ED-71.
  • the term "analog”, in the context of the present invention, is meant to include synthetic analogs as well as Vitamin-D metabolites.
  • the matrix is a polymeric matrix.
  • Polymeric materials and matrices useful in drug delivery systems are well known in the art, and need not be discussed in detail.
  • Rea detailed discussion of such systems reference is made to Robert Langer, SCIENCE, Vol. 249, pp. 1527-1533, 28 September, 1990, and to Richard L. Dunn, "Polymeric Matrices", in POLYMERIC DRUG AND DRUG DELIVERY SYSTEMS, R. L. Dunn and R. M. Ottenbrite Eds., American Chemical Society, Washington, D.C., 1991.
  • the polymeric matrix may be of a variety of types.
  • water-soluble polymers may be employed, such as polyethylene glycol, poly (vinyl alcohol), poly (vinyl pyrrolidone), poly(2- hydroxymethyl methacrylate), poly(acrylamide), hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, gelatin, starch, dextran, sodium alginate, poly(acrylic acid), poly(methacrylic acid), poly(maleic acid half esters), poly(sodium styrene sulfonate), poly(dimethylaminoethyl methacrylate), poly(vinyl pyridine), cellulose acetate N,N-diethylaminoacetate; other suitable polymers include biodegradable polymers, such as poly(meleic anhydride copolymers), gelatine-formaldehyde, acrylamide-N,N'-methylenebisacrylamide, fumaric acid/polyethylene glycol-N-vinyl-pyrrolidone, poly(vin
  • polymeric matrix is a matrix based on a poly-ethylene-vinyl-acetate copolymer.
  • This matrix will be used in the examples to follow, it being understood that this is only an illustrative matrix and the invention is in no way limited to this or any other matrix.
  • the inventors have found that, in order to obtain an optimal release effect of the vitamin-D analog, it is important that release from the polymeric matrix be effected through the formation of a complex between the vitamin-D analog and the vitamin-D binding protein (DBP) which is found in body fluids. Only the complex is substantially soluble in aqueous media, and thus only the complex is immediately and gradually bioavailable.
  • the pharmaceutical preparation is such that the release of the Vitamin-D analog is permitted or promoted by the presence of the Vitamin-D binding protein (DBP).
  • the invention also encompasses preparations wherein the DBP is provided in the polymeric matrix, to overcome a DBP deficiency at the site of administration, or to promote vitamin-D - DBP complex release.
  • Vitamin-D analog to be used in conjunction with the invention is 1,25-dihydroxyvitamin D 3 .
  • the invention is in no way meant to be hmited to this specific compound, and any other suitable and pharmaceutically valuable analog thereof can be used.
  • the invention is also directed to a pharmaceutical composition for the treatment of cancer, comprising an effective amount of a preparation according to the invention. While the invention is useful in the treatment of a variety of cancers, one particularly difficultly treated cancer, which can be treated according to the invention, is colon cancer.
  • the invention provides a method of treating a cancer patient, comprising administering to the patient in need thereof an anti-cancer effective amount of a preparation as described herein.
  • the slow-release pharmaceutical preparations of the invention may be administered orally, transdermally or by implantation. Suitable slow-release compositions of the type described above will be recognized by the skilled person.
  • the pharmaceutical composition is implanted. Preferably, but non limitatively, the implantation is effected intraperitoneal.
  • the invention further provides a method of treating patients suffering from imbalanced mineral homeostasis, who need constant correction of their serum vitamin D levels.
  • An example is the group of uremic patients, but of course the invention is not limited to this group.
  • Drug delivery matrices based on poly(ethylene-vinyl-acetate) copolymer (EVA) were prepared by solvent casting as described by Rhine et al. [J. of Pharmaceutical Sciences, 69, 265-270, 1980].
  • 1,25-dihydroxyvitamin D 3 - ethanol solution was added to the EVA-methylene chloride solution and casted on dry ice. Loading was calculated as dry weight of 1,25- dihydroxyvitamin D 3 to dry weight of the matrix.
  • Part of the 1,25- dihydroxyvitamin D 3 (1:70,000) was radiolabeled as 1,25-dihydroxy[26,27- methyl- 3 H]cholecalciferol. This was used in the in ⁇ itro experiments. Radiolabeled 1,25-dihydroxyvitamin D 3 was not included in matrices used in in ⁇ i ⁇ o experiments.
  • the release of the radiolabeled 1,25-dihydroxy[26,27-methyl- 3 H]cholecalciferol was detected by ⁇ -counter as a function of time.
  • the matrices were immersed in fetal calf serum (FCS) medium, containing the Vitamin-D binding protein (DBP).
  • FCS fetal calf serum
  • DBP Vitamin-D binding protein
  • Figs. 1 and 2 show the effect of serum concentration in the medium. It can easily be seen that virtually no 1,25-dihydroxyvitamin D 3 release occurs in the absence of DBP (buffer and FCS 0%), and that the release rate increases with increasing FCS (and hence DBP) concentrations.
  • Fig. 2 shows the percentage of released 1,25-dihydroxyvitamin D 3 as a function of its load in the matrix (at 50% FCS). At high loads a lower percentage is released, in contrast to known diffusion dependent EVA systems, and suggesting that the release of 1,25(OH) 2 D 3 depends on the ratio between DBP and 1,25(OH) 2 D 3 .
  • the rats were treated with 1,2-dimethylhydrazine (DMH), after 2 weeks, according to the procedure of Belleli et al., to induce colon cancer.
  • DMH 1,2-dimethylhydrazine
  • the matrices were implanted i.p.. Blood samples were withdrawn after two weeks, and the concentration of 1,25-dihydroxyvitamin D 3 and of Ca +2 were measured. In all cases EVA matrices were used, with a load of 0.0050% of 1,25-dihydroxyvitamin D 3 .
  • ODC activity is believed to be associated with the initiation stage of colon carcinogenesis. [D.H. Russell et al., Drug. Metab. Rev., 16, 1-88, 1981. G.D. Luk et al., Cancer Res., 46, 4449-4452, 1986]. If so, the ODC activity peak may serve as a reliable marker for colon carcinogenesis.
  • a radiometric technique which measures the amount of 14 CO 2 stoichiometrically released from labeled ornitine substrate during the decarboxylation reaction was used. The matrix was implanted i.p. two weeks before DMH induction.
  • Example 3 was repeated, but additionally two additional rat groups were treated with DMH for another 4 weeks until frank colon cancer.
  • the 1st group served as control and the 2nd group consisted of animals with implanted EVAc matrices (about 0.1g) loaded with 0.0050% 1,25-(OH) 2 D 3 .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A controlled-release pharmaceutical preparation comprises a Vitamin-D analog in a supporting matrix, alone or together with pharmaceutically acceptable additives or active agents.

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING VITAMIN-D
ANALOGS
Field of The Invention
The present invention relates to the field of pharmacy. More particularly, the invention relates to novel slow-release pharmaceutical preparations containing Vitamin-D analogs.
BACKGROUND OF THE INVENTION
The Vitamin-D hormone, 1,25-dihydroxyvitamin D3, is known to be active anti-proliferation agents which is active against a variety of cancer cells, including cells of the large intestine [A. Belelli et al., Carcinogenesis, 13, 2293-2298, 1992]. The activity of 1,25-dihydroxyvitamin D3 was tested in rats colon cancer and it was found that once weekly administration for 5 weeks reduced by 50% the number of DMH-induced murine colon cancer. However, the potentially useful therapeutic activity of 1,25- dihydroxyvitamin D3 has so far been hampered by its high calcemic activity. Treatment of rats with higher doses of 1,25-dihydroxyvitamin D3, by subcutaneous injection, which could potentially be beneficial in cancer treatment, led to hypercalcemia and death.
The Prior Art
A variety of vitamin-D hormone analogs have been developed [G. Jones and M. Calverly, TEM Vol. 4, No. 9, 297-303, 1993], mainly searching for noncalcemic, but still anticancer-effective analogs, but with no success. Most analogs known so far have either maintained their high calcemic activity, or have lost their effectiveness or stability.
Therefore, the great therapeutic potential of 1,25-dihydroxyvitamin D3 and its analogs has remained so-far unexploited.
Summary of the Invention
It is an object of the present invention to provide pharmaceutical preparations comprising 1,25-dihydroxyvitamin D3 or other vitamin D analogs thereof, which can be used to treat patients without leading to substantial hypercalcemia effects.
It is another object of the invention to provide slow-release pharmaceutical preparations comprising 1,25-dihydroxyvitamin D3 or other vitamin D analogs thereof, as an active ingredient.
It is a further object of the invention to provide pharmaceutical preparations which can be used to supply highly bioavailable amounts of 1,25-dihydroxyvitamin D3 or analogs thereof, in a controlled manner.
It is still another object of the invention to provide a method for treating a patient suffering from an illness which responds to vitamin D-analogs treatment, particularly cancer patients, psoriasis patients or patients with unbalanced mineral homeostasis, by administration of slow-release active compositions. The primary objects of the invention are achieved by providing controlled- release pharmaceutical preparations comprising a Vitamin-D analog in a supporting matrix, typically a polymeric matrix.
Other objects of the invention will become apparent as the description proceeds.
Brief Description of the Drawings
In the drawings:
Fig. 1 shows the kinetics of 1,25-dihydroxyvitamin D3 release from an EVA-based matrix, dependent on fetal calf serum concentrations;
Fig. 2 shows the effect of 1,25-dihydroxyvitamin D3 loading in the matrix of Fig. 1, on its released fraction;
Fig. 3 shows the effect of implantation site in-υiυo on the serum concentration of 1,25-dihydroxyvitamin D3, following two weeks post- implantation, with a load of 0.0050% of 1,25-dihydroxyvitamin D3;
Fig. 4 shows the effect of implantation site in-υiυo on the serum concentration of Ca+2, after two weeks post-implantation, with the same matrix as in Fig. 3; Fig. 5 shows the effect of 1,25-dihydroxyvitamin D3 released on the activity of ornithine decarboxylase (ODC) in DMH-treated rats (Example 3); and
Fig. 6 shows the effect of 1,25-dihydroxyvitamin D3 released according to the invention, and injected (prior art), on the activity of ornithine decarboxylase (ODC) in DMH-treated rats.
Detailed Description of The Invention
As stated above, in one aspect the invention is directed to controlled- release pharmaceutical preparations comprising a Vitamin-D analog in a supporting matrix, alone or together with pharmaceutically acceptable additives or active agents. Vitamin analogs are many, and will be recognized by the skilled person. Illustrative and non-limitative examples of such analogs include 1,25-(OH)2D3 (calcitrol), 26,27-F6-1,25-(OH)2D3 (ST-630), 1α-(OH)D2, 1α-(OH)D3, 1,24-(OH)2D3 (TV-02), 22-oxacalcitriol (OCT), calcipotriol (MC 903), 1,25-(OH)2-16-ene-23-yne-D3 (Ro 23-7553), EB 1089 and ED-71. The term "analog", in the context of the present invention, is meant to include synthetic analogs as well as Vitamin-D metabolites.
According to a preferred embodiment of the invention the matrix is a polymeric matrix. Polymeric materials and matrices useful in drug delivery systems are well known in the art, and need not be discussed in detail. For a detailed discussion of such systems reference is made to Robert Langer, SCIENCE, Vol. 249, pp. 1527-1533, 28 September, 1990, and to Richard L. Dunn, "Polymeric Matrices", in POLYMERIC DRUG AND DRUG DELIVERY SYSTEMS, R. L. Dunn and R. M. Ottenbrite Eds., American Chemical Society, Washington, D.C., 1991. As will be apparent to the skilled person, the polymeric matrix may be of a variety of types. For instance, water-soluble polymers may be employed, such as polyethylene glycol, poly (vinyl alcohol), poly (vinyl pyrrolidone), poly(2- hydroxymethyl methacrylate), poly(acrylamide), hydroxypropyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethyl cellulose, gelatin, starch, dextran, sodium alginate, poly(acrylic acid), poly(methacrylic acid), poly(maleic acid half esters), poly(sodium styrene sulfonate), poly(dimethylaminoethyl methacrylate), poly(vinyl pyridine), cellulose acetate N,N-diethylaminoacetate; other suitable polymers include biodegradable polymers, such as poly(meleic anhydride copolymers), gelatine-formaldehyde, acrylamide-N,N'-methylenebisacrylamide, fumaric acid/polyethylene glycol-N-vinyl-pyrrolidone, polylactic acid, polyglycolic acid, polycaprolactone, polyhydroxybutyrate, polyhydroxyvalerate, polyanhydrides, polyorthoesters, poly(amino acids), and polyphosphazenes; or nonbiodegradable polymers, such as silicones, poly(ethylene vinyl acetate), poly(methyl methacrylate), polyethylene, polyurethanes, polyisobutylene, cellulose acetate, poly(ethyl methacrylate) and poly (butyl methacrylate). Other suitable polymers will be recognized by the skilled person.
It has been found that one particularly convenient polymeric matrix is a matrix based on a poly-ethylene-vinyl-acetate copolymer. This matrix will be used in the examples to follow, it being understood that this is only an illustrative matrix and the invention is in no way limited to this or any other matrix.
The inventors have found that, in order to obtain an optimal release effect of the vitamin-D analog, it is important that release from the polymeric matrix be effected through the formation of a complex between the vitamin-D analog and the vitamin-D binding protein (DBP) which is found in body fluids. Only the complex is substantially soluble in aqueous media, and thus only the complex is immediately and gradually bioavailable. Thus, according to a preferred embodiment of the invention the pharmaceutical preparation is such that the release of the Vitamin-D analog is permitted or promoted by the presence of the Vitamin-D binding protein (DBP).
While, as stated, the DBP is normally provided by body fluids, the invention also encompasses preparations wherein the DBP is provided in the polymeric matrix, to overcome a DBP deficiency at the site of administration, or to promote vitamin-D - DBP complex release.
A preferred Vitamin-D analog to be used in conjunction with the invention is 1,25-dihydroxyvitamin D3. However, the invention is in no way meant to be hmited to this specific compound, and any other suitable and pharmaceutically valuable analog thereof can be used.
The invention is also directed to a pharmaceutical composition for the treatment of cancer, comprising an effective amount of a preparation according to the invention. While the invention is useful in the treatment of a variety of cancers, one particularly difficultly treated cancer, which can be treated according to the invention, is colon cancer.
Thus the invention provides a method of treating a cancer patient, comprising administering to the patient in need thereof an anti-cancer effective amount of a preparation as described herein. The slow-release pharmaceutical preparations of the invention may be administered orally, transdermally or by implantation. Suitable slow-release compositions of the type described above will be recognized by the skilled person. According to a preferred embodiment of the invention the pharmaceutical composition is implanted. Preferably, but non limitatively, the implantation is effected intraperitoneal.
The invention further provides a method of treating patients suffering from imbalanced mineral homeostasis, who need constant correction of their serum vitamin D levels. An example is the group of uremic patients, but of course the invention is not limited to this group.
All the above and other characteristics and advantages of the invention will be better understood through the following illustrative and non- limitative examples. Preparation A
Matrix Preparation
Drug delivery matrices, based on poly(ethylene-vinyl-acetate) copolymer (EVA) were prepared by solvent casting as described by Rhine et al. [J. of Pharmaceutical Sciences, 69, 265-270, 1980]. 1,25-dihydroxyvitamin D3 - ethanol solution was added to the EVA-methylene chloride solution and casted on dry ice. Loading was calculated as dry weight of 1,25- dihydroxyvitamin D3 to dry weight of the matrix. Part of the 1,25- dihydroxyvitamin D3 (1:70,000) was radiolabeled as 1,25-dihydroxy[26,27- methyl-3H]cholecalciferol. This was used in the in υitro experiments. Radiolabeled 1,25-dihydroxyvitamin D3 was not included in matrices used in in υiυo experiments.
Example 1
In Vitro Release
The release of the radiolabeled 1,25-dihydroxy[26,27-methyl- 3H]cholecalciferol was detected by β-counter as a function of time. The matrices were immersed in fetal calf serum (FCS) medium, containing the Vitamin-D binding protein (DBP).
1,25-Dihydroxyvitamin D3 release was studied in a Backman LS 1800 Series Liquid Scintillation System. The results are shown in Figs. 1 and 2. Fig. 1 shows the effect of serum concentration in the medium. It can easily be seen that virtually no 1,25-dihydroxyvitamin D3 release occurs in the absence of DBP (buffer and FCS 0%), and that the release rate increases with increasing FCS (and hence DBP) concentrations.
Fig. 2 shows the percentage of released 1,25-dihydroxyvitamin D3 as a function of its load in the matrix (at 50% FCS). At high loads a lower percentage is released, in contrast to known diffusion dependent EVA systems, and suggesting that the release of 1,25(OH)2D3 depends on the ratio between DBP and 1,25(OH)2D3.
Example 2
Effect of Implantation Site
Tumor induction experiments with rats were carried out according to the procedures described in the aforementioned Belleli et al. article, and their description is incorporated herein by reference, for the sake of brevity. 12 rats were used in the experiment, according to the following groups:
1) 8 rats as a control group, were given the EVA matrix without any 1,25-dihydroxyvitamin D3;
2) 4 rats were given implants of about 0.1 gr of 0.0050% 1,25- dihydroxyvitamin D3 in an EVA matrix.
The rats were treated with 1,2-dimethylhydrazine (DMH), after 2 weeks, according to the procedure of Belleli et al., to induce colon cancer.
The matrices were implanted i.p.. Blood samples were withdrawn after two weeks, and the concentration of 1,25-dihydroxyvitamin D3 and of Ca+2 were measured. In all cases EVA matrices were used, with a load of 0.0050% of 1,25-dihydroxyvitamin D3.
The results are shown in Fig. 3, for 1,25-dihydroxyvitamin D3, and in Fig. 4 for Ca+2. The control was as specified above.
From the results it is evident that implantation in the peritoneum is substantially more effective than subcutaneous implantation. Without wishing to be bound by any particular theory, the inventors believe that this difference may derive from the fact that body fluids are abundant in the peritoneum, and therefore DBP is more readily available there, to release 1,25-dihydroxyvitamin D3 from the polymeric matrix. The 1,25- dihydroxyvitamin D3 released is biologically active, as expressed by the increase in serum calcium levels (Fig. 4).
Example 3
Early Stage Inhibition
The activity level of ODC in DMH-treated rats were measured, at 48 hours after DMH induction. ODC activity is believed to be associated with the initiation stage of colon carcinogenesis. [D.H. Russell et al., Drug. Metab. Rev., 16, 1-88, 1981. G.D. Luk et al., Cancer Res., 46, 4449-4452, 1986]. If so, the ODC activity peak may serve as a reliable marker for colon carcinogenesis. A radiometric technique which measures the amount of 14CO2 stoichiometrically released from labeled ornitine substrate during the decarboxylation reaction was used. The matrix was implanted i.p. two weeks before DMH induction.
The results are shown in Fig. 5. The values shown in the figure have the following meanings:
"vehicle" - control rats without DMH induction,
"control" - matrix without the drug with DMH.
"Vit.D3 low" - 0.0025% loading of Vitamin-D analog with DMH
"Vit.D3 high" - 0.0050% loading of Vitamin-D analog with DMH
The results indicate that the ODC activity obtained with a Vit.D3 loading of 0.0050% approaches that of the vehicle. It therefore appears that the preparation of the invention interferes with early stages of colon carcinogenesis.
Example 4
Example 3 was repeated, but additionally two additional rat groups were treated with DMH for another 4 weeks until frank colon cancer. The 1st group served as control and the 2nd group consisted of animals with implanted EVAc matrices (about 0.1g) loaded with 0.0050% 1,25-(OH)2D3.
16 weeks after the 1st DMH treatment the rats were killed and the number and distribution of the grossly visible tumors were independently scored by at least two observers. In the control group (5 rats) colonic tumors were present - average, 5 tumors/rat. By contrast, in the 1,25- (OH)2D3 treated rats (4 rats) no tumors were observed. The results obtained 48 hours after the first DMH injection are shown in Fig. 6. These results are seen to be in agreement with those of Fig. 5.
All the above has been provided for the purpose of illustration, and is not intended to limit the invention in any way. Many modifications are possible, as will be appreciated by the skilled person, in the various active ingredients, matrices and administration methods. For instance, additional beneficial agents can be incorporated in the matrix, which can be released together with the vitamin-D analog, or at different times, various implantation locations are possible, as well as different administration methods, e.g., by ingestion, all without exceeding the scope of the invention.

Claims

1. A controlled-release pharmaceutical preparation comprising a Vitamin- D analog in a supporting matrix, alone or together with pharmaceutically acceptable additives or active agents.
2. A pharmaceutical preparation according to claim 1, wherein the matrix is a polymeric matrix.
3. A pharmaceutical preparation according to claim 2. wherein the polymeric matrix is based on a poly-ethylene-vinyl-acetate copolymer.
4. A pharmaceutical preparation according to any one of claims 1 to 3, wherein the release of the Vitamin-D analog is permitted or promoted by the presence of the Vitamin-D binding protein (DBP).
5. A pharmaceutical preparation according to claim 4, wherein the DBP is provided by body fluids.
6. A pharmaceutical preparation according to claim 4, wherein the DBP is provided in the polymeric matrix.
7. A pharmaceutical preparation according to any one of claims 1 to 6, wherein the Vitamin-D analog is 1,25-dihydroxyvitamin D3.
8. A pharmaceutical composition for the treatment of cancer, comprising an effective amount of a preparation according to any one of claims 1 to 7.
9. A pharmaceutical composition according to claim 8, wherein the cancer is colon cancer.
10. A method of treating a cancer patient, comprising administering to the patient in need thereof an anti-cancer effective amount of a preparation according to any one of claims 1 to 7.
11. A method according to claim 10. wherein the cancer is colon cancer.
12. A pharmaceutical composition for the treatment of illnesses associated with low serum vitamin D levels, or which respond to vitamin D treatment, comprising an effective amount of a preparation according to any one of claims 1 to 7.
13. A pharmaceutical composition according to claim 12, wherein the illness is imbalanced mineral homeostasis.
14. A pharmaceutical composition according to claim 12, wherein the illness is psoriasis.
15. A method of increasing serum vitamin D or vitamin D-analog levels, comprising administering to the patient in need thereof an effective amount of a preparation according to any one of claims 1 to 7.
16. A method according to claim 15, wherein the pharmaceutical composition is implanted.
17. A method according to claim 16, wherein the implantation is effected intraperitoneal.
18. A pharmaceutical preparation according to any one of claims 1 to 14, which is suitable for oral administration.
19. A pharmaceutical preparation according to any one of claims 1 to 14, which is suitable for transdermal administration.
20. Use of a Vitamin-D analog-containing matrix, for the preparation of a medicament.
21. A controUed-release pharmaceutical preparation, substantially as described.
PCT/US1995/008005 1994-06-24 1995-06-22 Pharmaceutical compositions comprising vitamin-d analogs WO1996000074A1 (en)

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US6521608B1 (en) 1998-03-27 2003-02-18 Oregon Health & Science University Vitamin D and its analogs in the treatment of tumors and other hyperproliferative disorders
WO2004012743A1 (en) * 2002-08-01 2004-02-12 Chugai Seiyaku Kabushiki Kaisha Antipsoriatic agent
WO2004028515A1 (en) * 2002-09-26 2004-04-08 Young-Kweon Choi Matrix type patch for transdermal administration of vitamin d analog and the use thereof
KR100438254B1 (en) * 2001-03-29 2004-07-02 아이큐어 주식회사 Matrix form of preparation for transdermal administration of vitamin d analog
WO2006120682A3 (en) * 2005-05-10 2007-01-25 Dermipsor Ltd Compositions and methods for treating hyperproliferative epidermal diseases
CN100345547C (en) * 1996-12-30 2007-10-31 骨疗国际公司 Method of treating prostatic disease using delayed and/or sustained release vitamin D formulations
US20080234239A1 (en) * 2007-03-15 2008-09-25 Derek Wheeler Topical composition
US8207149B2 (en) 2007-04-25 2012-06-26 Cytochroma, Inc. Method for treating secondary hyperparathyroidism in CKD
US8329677B2 (en) 2006-06-21 2012-12-11 Cytochroma, Inc. Method of treating and preventing secondary hyperparathyroidism
US8426391B2 (en) 2006-02-03 2013-04-23 Proventiv Therapeutics, Llc Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
US8592401B2 (en) 2007-04-25 2013-11-26 Proventiv Therapeutics, Llc Methods and compounds for vitamin D therapy
WO2014143941A1 (en) * 2013-03-15 2014-09-18 Opko IP Holdings II, Inc. Stabilized modified release vitamin d formulation and method of administring same
US20160038514A1 (en) * 2014-08-07 2016-02-11 Opko Ireland Global Holdings, Ltd. Adjunctive Therapy With 25-Hydroxyvitamin D and Articles Therefor
US20160184329A1 (en) * 2013-07-13 2016-06-30 Aphios Corporation Formulations and Compositions of Vitamin D Analogs for Treating and Preventing Cancer and other Diseases
US9610245B2 (en) 2011-03-14 2017-04-04 Drug Delivery Solutions Limited Ophthalmic composition
US10302660B2 (en) 2008-04-02 2019-05-28 Opko Renal, Llc Methods useful for vitamin D deficiency and related disorders
US11173168B2 (en) 2016-03-28 2021-11-16 Eirgen Pharma Ltd. Methods of treating vitamin D insufficiency in chronic kidney disease
US11672809B2 (en) 2010-03-29 2023-06-13 Eirgen Pharma Ltd. Methods and compositions for reducing parathyroid levels
US11696919B2 (en) 2018-03-19 2023-07-11 MC2 Therapeutics Limited Topical composition
US11752158B2 (en) 2007-04-25 2023-09-12 Eirgen Pharma Ltd. Method of treating vitamin D insufficiency and deficiency
US11801253B2 (en) 2007-04-25 2023-10-31 Opko Renal, Llc Method of safely and effectively treating and preventing secondary hyperparathyroidism in chronic kidney disease
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US6521608B1 (en) 1998-03-27 2003-02-18 Oregon Health & Science University Vitamin D and its analogs in the treatment of tumors and other hyperproliferative disorders
KR100438254B1 (en) * 2001-03-29 2004-07-02 아이큐어 주식회사 Matrix form of preparation for transdermal administration of vitamin d analog
WO2004012743A1 (en) * 2002-08-01 2004-02-12 Chugai Seiyaku Kabushiki Kaisha Antipsoriatic agent
WO2004028515A1 (en) * 2002-09-26 2004-04-08 Young-Kweon Choi Matrix type patch for transdermal administration of vitamin d analog and the use thereof
US9173835B2 (en) 2005-05-10 2015-11-03 Dermipsor Ltd. Compositions and methods for treating hyperproliferative epidermal diseases
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US8426391B2 (en) 2006-02-03 2013-04-23 Proventiv Therapeutics, Llc Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
US11007204B2 (en) 2006-02-03 2021-05-18 Opko Renal, Llc Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
US10213442B2 (en) 2006-02-03 2019-02-26 Opko Renal, Llc Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
US10668089B2 (en) 2006-06-21 2020-06-02 Opko Ireland Global Holdings, Ltd. Method of treating and preventing secondary hyperparathyroidism
US9402855B2 (en) 2006-06-21 2016-08-02 Opko Renal, Llc Method of treating and preventing secondary hyperparathyroidism
US8329677B2 (en) 2006-06-21 2012-12-11 Cytochroma, Inc. Method of treating and preventing secondary hyperparathyroidism
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US10265265B2 (en) * 2007-03-15 2019-04-23 Drug Delivery Solutions Limited Topical composition
US20080234239A1 (en) * 2007-03-15 2008-09-25 Derek Wheeler Topical composition
US11065195B2 (en) 2007-03-15 2021-07-20 MC2 Therapeutics Limited Topical composition
US9918940B2 (en) 2007-04-25 2018-03-20 Opko Renal, Llc Methods for controlled release oral dosage of a vitamin D compound
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US11801253B2 (en) 2007-04-25 2023-10-31 Opko Renal, Llc Method of safely and effectively treating and preventing secondary hyperparathyroidism in chronic kidney disease
US9498486B1 (en) 2007-04-25 2016-11-22 Opko Renal, Llc Method for controlled release oral dosage of a vitamin D compound
US9408858B2 (en) 2007-04-25 2016-08-09 Opko Renal, Llc Method for treating secondary hyperparathyroidism in CKD
US9925147B2 (en) 2007-04-25 2018-03-27 Opko Renal, Llc Method for treating secondary hyperparathyroidism in CKD
US8778373B2 (en) 2007-04-25 2014-07-15 Opko IP Holdings II, Inc. Methods for controlled release oral dosage of a vitamin D compound
US8592401B2 (en) 2007-04-25 2013-11-26 Proventiv Therapeutics, Llc Methods and compounds for vitamin D therapy
US11154509B2 (en) 2007-04-25 2021-10-26 Eirgen Pharma Ltd. Methods for controlled release oral dosage of a vitamin D compound
US8361488B2 (en) 2007-04-25 2013-01-29 Cytochroma Inc. Methods and compositions for controlled release oral dosage of a vitamin D compound
US10302660B2 (en) 2008-04-02 2019-05-28 Opko Renal, Llc Methods useful for vitamin D deficiency and related disorders
US11672809B2 (en) 2010-03-29 2023-06-13 Eirgen Pharma Ltd. Methods and compositions for reducing parathyroid levels
US10154959B1 (en) 2011-03-14 2018-12-18 Drug Delivery Solutions Limited Ophthalmic composition containing a polyaphron dispersion
US9610245B2 (en) 2011-03-14 2017-04-04 Drug Delivery Solutions Limited Ophthalmic composition
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IL110117A0 (en) 1994-10-07

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