Method and adsorbant composition for 82 Rb generation.

The present invention relates to a composition comprising ⁸²Sr and an adsorbant.selected from tin oxide, hydrated tin oxide, poly antimonic acid, titanium oxide, hydrated titanium oxide, ferric oxide and hydrated ferric oxide. This invention also provides a low ⁸²Sr breakthrough method of generating ⁸²Rb comprising eluting the ⁸²Rb from the ⁸²Sr charged adsorbant as described above.

Rubidium -82, a positron emitter with a half-life of 75-sec is readily obtainable from the parent Sr-82 (Tl/2 = 25 days). Rubidium can be used as a diffusible flow tracer for the myocardium and kidney, and as a nondiffusible tracer for brain blood flow. Serial injections of Rb-82 can be administered every 5 to 10 minutes by eluting (milking) Rb-82 from its 25-day Sr-82 parent. The advantages of Rb-82 are low radiation dose, ability to provide for repeated examinations every 5 minutes without constraints from body background, and a convenient and economical supply of a short-half-life positron emitter. (Yano et al., The Journal of Nuclear Medicine 20:961-966, 1979.)

Significant quantities of ⁸²Sr are available for clinical investigation. The short-lived daughter, 75- second ⁸²Rb, is of value in biomedicine for circulation and perfusion studies as well as for myocardial imaging as mentioned in U. S. Patent Number 3,953,567.

Loc'h et al. J. Nucl. Med. 21: 171-173, 1980 disclose a tindioxide (SnO₂)/HCl Ga-68 generator.

Arino et al. Int. J. Appl. Radiat. Isot. 29: 117-120, 1978 disclose a ⁶⁸_Ge/⁶⁸_Ga radioisotope generator system which uses polyantimonic acid to selectively adsorb Ge and not Ga. The adsorption was speculated to be due to a dehydration reaction forming chemical bonding between Sb and Ge through oxygen.

Neirinckx et al. disclose titanium oxide in a generator for ionic gallium-68, see second International Symposium on Radiopharmaceutical Chemistry MRC. Oxford, 1978, p. 109.

Kopecky et al. Int. J. Appl. Radiat. Isot. 25: 263-268, 1974 disclose a ⁶⁸Ge/⁶⁸Ga generator for the production of ⁶⁸Ga in an ionic form. Aspects of the adsorption of carrier-free ⁶⁸Ge and ⁶⁸_Ga on a_lumia, Al(OH)₃ and Fe(OH)₃ are discussed.

The present invention provides a composition comprising ⁸²Sr and an adsorbant selected from tin oxide, hydrated tin oxide, polyantimonic acid, titanium oxide, hydrated titanium oxide, ferric oxide and hydrated ferric oxide, and also provides a low ⁸²Sr breakthrough method of generating ⁸²Rb which comprises eluting such ⁸²Sr charged adsorbant. The eluent can be physiological s.aline or a buffered isotonic solution. The yields of ⁸²_Rb are high.

The method and compositions of the present invention result in eluates which are useful in positron imaging and in the subsequent measurement of blood flow through the myocardium, brain and kidneys. The present invention provides a small bolus size of 2-3 ml which is advantageous for lower volume per unit time infusion while maintaining an effective amount of activity to monitor the patient.

The present invention is based on the discovery that breakthrough of Sr may be lowered by providing a particular adsorbant as described above, and preferably, tin oxide or hydrated tin oxide.

Hydrated tin oxide includes hydrated stannic oxide, hydrated stannous oxide, and mixtures of hydrated stannic oxide and hydrated stannous oxide. Preferably the hydrated tin oxide is amorphous. Tin oxide includes stannic oxide, stannous oxide and mixtures of stannous oxide and stannic oxide. Most preferably an amorphous mixture comprising tin oxide and a substantial amount (more than 10% by weight) of hydrated stannic oxide is used as the adsorbant.

The preferred adsorbant is in the form of chromatographic particles having an average diameter of 0.01 to 0.9 mm, and preferably, 0.05 to 0.1 mm.

The eluent may be isotonic saline or isotonic saline buffered at physiological pH and may contain bacteriostat. Preferably a buffered eluent is used wherein the buffer may be a phosphate salt or a carbonate salt, preferably a phosphate salt. Most preferably, isotonic saline at physiological pH is used. Bacteriostats may be beneficially added to the eluent. Preferred bacteriostats are those which are pharmaceutically acceptable buffers, for example parabens.

The eluent is buffered at a pharmaceutically acceptable pH, preferably from ^pH 6.0 to pH 10 and most preferably, from pH 7.0 to pH 7.5.. The concentration of the buffer in the,eluent preferably is from .01 mmol to 200 mmol per liter of eluent solution.

The saline concentration of the eluent is a pharmaceutically acceptable concentration. Preferably the saline is isotonic (0.9%).

Phosphate salts include alkali phosphates, alkaline earth phosphates, alkali metal hydrogen phosphates, alkaline earth hydrogen phosphates as well as hydrates of phosphate salts. Also phosphate salts include all phosphorous oxides which form phosphates upon addition to water.

A preferred phosphate salt is Na₂HPO₄ which may be added to the eluent as Na₂HPO₄ 7H₂O. In the saline eluent it forms Na⁺ and PO₄^-3 HPO₄^-2 H₂PO₄⊖. Upon addition of NaOH some of the H₂PO₄⊖ would be used up in the formation of HPO₄^-2. The balanced equation being: NaH₂PO₄ + NaOH <img file="EP0043650A2_D0001.tif" /> Na₂HPO₄ + ^H₂^0.

When acid is added for example HC1; some H₂PO₄⊖ is formed. The balanced equation being: Na₂HP0₄ + HCl <img file="EP0043650A2_D0002.tif" /> NaH₂PO₄ + NaCl .

Carbonate salts include water soluble carbonate salts such as alkali metal carbonates and alkali metal hydrogen carbonates for example NaHCO₃. In water NaHCO₃ forms Na⁺ and CO₃^-2<img file="EP0043650A2_D0003.tif" /> H CO₃⊖ <img file="EP0043650A2_D0004.tif" /> H₂CO₃. Upon addition of NaOH; HCO₃^-1 and H₂CO₃ are used up and CO₃^-2 and HCO₃^-1 respectively are formed. Upon addition of HCl; CO₃^-2 and HCO₃^- are used up and HCO₃^- and H₂CO₃ respectively are formed.

A column containing adsorbant is charged with ⁸²Sr. Preferably the adsorbant is hydrated tin oxide or polyantimonic acid, and most preferably, hydrated tin oxide. The column is then eluted with the eluent. Elution rates of 5-10 ml per minute or higher are useful.

At clinically useful flow rates of about 20 ml per minute, ⁸²Sr breakthroughs of 10^-9 per ml of eluate are obtained by the present invention. Breakthrough is the ratio of microcuries of ⁸²Sr in the eluate to the microcuries of ⁸²Sr on the adsorber.

⁸²_Rb yields of 90% of theoretical maximum and high radioactive concentration in the eluate (90% elution yield in 5-10 cc) as well as low ⁸²Sr breakthroughs of 10^-9/ml are obtained using the present invention. These yields may be obtained over a 0.1 minute interval using an eluent flow rate of 30 ml/min.

The procedure used in examples 1-4 is as follows: 50 mg amounts of one of Ti(OH)₄, polyantimonic acid, SnO₂ (hydrated) or ferric oxide (hydrated) are shaken with 5 ml of liquid phase. The liquid phase is either isotonic saline (0.9% NaCl) or saline and phosphate salt solution. The phosphate concentrations are 0.25% and 0.025%. 0.02 ml of Sr-85 or Rb-83 is added. After one hour of equilibration, 1 ml fractions are pipetted. The activity in each fraction is measured and the K_D calculated.

The SnO₂ (hydrated) used in Example 3 is sold by Applied Research,Rue Hercoliers, Brussels, Belgium as oxide d'etain hydrate', (which is French for hydrated tin oxide); OXTAIN (Trademark). This material is a chromatographic amorphous mixture comprising tin oxide and a substantial amount of hydrated stannic oxide. Upon heating, this material looses most of its Sr-Rb separation ability. Thus, there is a loss of activity with the loss of hydration of tin oxide. <tables id="tabl0001" num="0001"><img file="EP0043650A2_D0005.tif" /></tables>

In Examples 1-4 the difference in K_D values for ⁸²Sr and ⁸²Rb shows the amount of separation. The high K_D values for ⁸²Sr and the low K_D values for ⁸²Rb show that ⁸²Sr is strongly adsorbed while ⁸²Rb is only slightly adsorbed. Thus, while a Sr loaded column of the adsorbants in Examples 1-4 is eluted the Sr remains adsorbed strongly with very minute breakthrough into the eluate. The daughter ⁸²Rb is only slightly adsorbed and passes out into the eluate in yields of about 90%.

The bolus volume is the amount of eluent needed to elute the available ⁸²Rb.

Example 5

Into a column 2 inches long and one fourth inch in diameter is placed 1.5cc of SnO₂ (hydrated)

particles having diameters of from .05 to O.lmm. Pre-equilibrium is done by washing the SnO₂ (hydrated) with saline three times. 2 ml of Sr-82 in saline solution having a pH of about 11 is loaded onto the SnO₂ (hydrated) particles by gravity in about one minute. The column is eluted at 12 ml per minute. The multi scaler mode on a multi channel analyzer was used to determine the elution profile. The bolus volume is about 3.4 ml.

The column is allowed to equilibrate and then counted for 777 KeV(Rb-82) with a Ge(Li) detector.

Table 1 shows the eluent composition volumes and the breakthrough fraction of ⁸²Sr for each volume eluted.

Table 2 shows a Summary of Characteristics of ⁸²Rb Generator Systems using inorganic adsorbers. At the bottom of the table are shown the characteristics of the SnO₂ (hydrated) adsorbant of the present invention. <tables id="tabl0002" num="0002"><img file="EP0043650A2_D0006.tif" /></tables><tables id="tabl0003" num="0003"><img file="EP0043650A2_D0007.tif" /></tables>