US 3159545 A
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Unite St res re sifii iii 3,159,545 RADHQAQTHVE QAPSULES Ralph Edward Kidwell and Edward Robert Laiton, Wauhcgan, EL, assignors to Ahhott Laboratories, North Chicage, ill., a corporation of iiiinois No Drawing. Filed (lot. t, 196%, Set. No. 6%,312 '7 Claims. till. l67--83) This invention relates to radioactive capsules and particularly to capsules wherein radioactive compounds are retained without leakage.
The use of various radioactive substances in medicine is continuously extending, and such widespread use accordingly requires additional means by which said radioactive substances can be administered. In clinical medicine, it is often desirable to administer a radioactive compound orally for both diagnostic and therapeutic purposes. Since the handling of radioactive substances presents serious contamination problems, extraordinary precautions must be taken in the handling and administration thereof. One such successful method employs a dry layer of radioactive material adsorbed on the inside surface of a gelatin capsule such as is described in US. 2,911,338. The method and practice disclosed in this patent are operable for the many radioactive compounds which can be dissolved in an organic volatile solvent. However, compounds which are not soluble in such solvents or are present in another basically dilferent physical form (an oil) are not particularly adaptable to be deposited as a dry layer within a gelatin capsule.
An oil such as glycerol trioleate has been tagged with a radioactive material and has been used as a tool in the study of fat metabolism. This radioactive isotope has been commonly deposited within a capsule and has been scaled therein by the simple step of telescoping a top capsule portion over a bottom portion of reduced diameter wherein is contained the radioactive oil. This particular embodiment has serious disadvantages in that the oil can possibly leak from the contained capsule, thereby causing serious contamination and reduction of the radioactive energy content. The possibility of such leakage is present and likely in ordinary handling, but the disadvantage is compounded many times by the necessary presence of air freight transport. Some radioactive isotopes used in clinical medicine have relatively short half lives and, consequently, time becomes the all-important factor in preparing and handling such capsules. The rapid delivery by airplane cargo shipment is a necessary factor in establishing the procedures which will secure the greatest economy of time. The use of the airplane to ship capsules containing radioactive substances in the liquid form, despite other advantages, aggravates the leakage problem because of the decreased air pressure at higher elevations. While passenger cabins are pressurized, it is seldom, if ever, that storage compartments for air freight cargoes are pressurized. It has been the unfortunate experience of persons concerned with. this art that such capsules with their contained radioactive liquids are received in a crushed or collapsed state rendering such capsules useless and a radiation hazard.
It is an object of this invention to provide capsule forms of radioactive compounds.
it is another object of this invention to provide a capsule in which radioactive compounds in the liquid form can be incorporated and retained.
It is still another object of this invention to provide capsule forms which will not leak a radioactive compound originally presented in a liquid form.
A still further object of this invention is to provide ca sules suitable for oral administration wherein a liquid form of a radioactive compound is incorporated in a waxlike vehicle.
In the accomplishment of the foregoing objects and other objects which will be apparent, it is now provided that a radioactive compound is placed in a capsule with a vehicle which is a solid at below body temperatures (37 C.) and melts at higher temperatures. It has now been found that radioactive compounds can be incorporated in those vehicles commonly employed in the suppository art. Such combined vehicle and radioactive compound can then be placed in a capsule suitable for oral ingestion and retained therein as a solid state below body temperatures. This novel article of manufacture significantly decreases any contamination hazard and eliminates the leakage of the radioactive compound from within the capsule. The radioactive compound is mixed with a suitable wax and oil of proper proportions so that the resulting mixture is a solid at temperatures lower than 37 C., but melts at temperatures at or above this level.
The novel pharmaceutical form is prepared by melting a suitable wax and oil, combining therein the desired radioactive compound, transferring the molten mixture into a capsule, allowing the molten mixture to cool into a solid form and, thereafter, encapsulating the capsule so that the solid vehicle and radioactive compound therein is entirely contained within the capsular walls. The actual volume of molten mixture which is transferred to the capsule will be determined by the degree of radioactivity desired in the final product which, in turn, is determined by the amount of activity actually in the mixture 'on the day of preparation. Since radioactive decay constantly occurs, the procedure prescribes a preliminary assay of the molten mixture containing the radioactive source and thereafter selecting an appropriate volume of said mixture in order to provide a particular range of activity in the capsule on the day of preparation. Reference to standard decay curves for the particular radioactive source incorporated will enable the practitioner to prepare capsules which will contain a desired activity at some ascertained future date of use.
Such capsules can be handled with greater assurance of freedom from radioactive contamination and can be quickly transported by air or other means without the extraordinary handling precautions which were necessary prior hereto in order to guard against leakage. Air transportation is now an added advantage because the lower temperatures of air flight make the wax-like vehicle harder, therefore, providing greater resistance to the damaged effects of lowered pressure. The great advantages obtained in the handling of such capsules are worthwhile because the pharmaceutical form is beneficially absorbed and utilized by the human. The attending clinician administers such a capsule to the patient and once the capsule reaches the stomach of the patient, the capsule material is disintegrated, the solid vehicle melts and the radioactive compound is absorbed.
The capsules comprising an element disclosed herein are composed of a non-toxic, therapeutic, water-soluble material such as gelatin, methyl cellulose, polyvinyl alcohol or other thermoplastic, water-soluble, non-toxic materials which are therapeutically acceptable. The vehicle for the radioactive compounds is basically composed of a solid wax generally having melting points materially in excess of 37 C. and a solid oil which is of a lower melting point, but when mixed with the foregoing waxes in proper proportions results in a solid form which melts 1 larger amount of solid oil which melts at a lower level in order to obtain the resultant solid form at temperatures lower than 37 C. The choice of the waxes and solid oils is within the ordinary skill of the man in the art, once he is apprised of the teachings of this invention.
The skilled practitioner will first select solid oils and Waxes which are non-toxic and compatible with the human organism. He will next compound the oil and wax in the proper proportion to obtain a solid having the melting characteristics described herein. Representative and useful oils are theobroma oil (cocoa butter), hydrogenated or partially hydrogenated vegetable and plant oils such as corn, palm kernel, cottonseed, peanut, saffiower, olive and other operable solid oils. Suitable waxes are carbowax, spermaceti, glycerol monostearate, beeswax, cetyl alcohol and other suitable low or highmelting, non-toxic, pharmaceutical waxes.
It is a purpose of this invention to provide a vehicle which melts at about 37 C., but is a solid at lower temperatures. The amount of solid oil and wax which must be combined to obtain a solid melting at about 37 C. is determined by the allegation method. The allegation method is Widely known and practiced among skilled pharmacists; it is represented by the following schematic formula:
ALLEGATION M.P Parts oil c x 37 1 011 Q 37z wax wax y J r) parts The above schematic formula states that an oil of known melting point and a wax of known melting point can be combined to prepare a solid melting at 37 C. by as many parts of the oil as are equal to the ditferenceof the melting point between the wax and 37 C.; and as many parts of the wax as are equal to the difference of the melting point of the wax and 37 C. Thus, with, for example, theobroma oil melting at 33 C. and spermaceti mel ing at 46 C., the parts required to make a solid melting at 37 C. would be determined by the following allegation.
theobroma oil 33 C.
Parts 9 theobroma oil 4 spermaceti 13 total parts spermaccti The principles of allegation are also applicable in the event more than two ingredients are intended for combination. An example would be the combination of two solid oils of differing melting points with a solid wax of still another melting point. Recourse may be made to standard pharmaceutical texts in order to ascertain the method for combining such mixtures into a final composition melting at about 37 C.
The radioactive compounds suitable for incorporation in the combination of the present invention are those compounds which have a known use after oral administration to the human. Such uses may either be diagnostic or therapeutic. Radioactive compounds which have been administered orally to the human for numerous purposes are radioactive iodine, glycerol trioleate, oleic acid, triiodothyronine and others. The radioisotopes which have a particular utility and which are prescribed orally can be determined by current recourse to the state of this dynamic art, for the new compounds which are tagged with radioactive atoms are constantly increasing in number and in application. If a particular radioisotope has been described in the art as an orally useful agent, then such compound can be incorporated in the novel combination disclosed herein.
The radioactive forms which are particularly useful for the present embodiment are those which occur as oils,
such as glycerol trioleate and oleic acid. These comall pounds are liquid oils and, therefore, are particularly adaptable to being incorporated directly in the oil-wax combination which comprises the solid vehicle. The foregoing oils have unsaturated bonds in their chains which are suitably tagged with radioactive iodine Other oils with double bonds can also be tagged with such radioactive isotopes, e.g., corn oil, sai'llower oil and the like.
Unsaturated oils tagged at their double bonds will not become solidified oils. It is to be remembered that only a minute number of oil molecules are tagged with iodine an any given operable volume of oil. A specific activity of about 1-2 millicuries per ml. of oil is sufficient to meet most diagnostic and therapeutic requirements, but such activity corresponds to a saturation of very few double bonds in a 1 ml. volume of said oil.
The foregoing oils tagged with radioactive iodine can be combined in equal volumes with the solid oil-wax combination which has been compounded to melt at 37 C. as set out hereinbefore. The combination of an equal volume of oil with the solid vehicle compounded to melt at 37 C. does not significantly alter such melting point. For radioactive substances which occur naturally as oils, another inert oil can be employed as a diluent such as peanut oil or other vegetable oils. It is preferred to use an equal volume of the oil alone or diluted with another oil, which is to be combined with the solid vehicle because such volumes are easy to handle, easy to calculate and do not alter the melting point of the final composition. If the amount of oil added to the vehicle base is substantially greater than an equal volume, the resulting mixture tends not to form a firm solid melting in the desired range. Therefore, it is a preferred and well-advised practice to incorporate at least an equal volume of the vehicle base to the oil. Of course, lesser volumes of the oil will not significantly affect the desired melting point range even though the mass tends to become more firm.
it should be understood that radioactive materials which are not oils can also be incorporated in the wax-like vehicle to obtain similar advantages from the invention. Such radioactive substances can be either a dry powder form which carries the radioactive compounds or suspensions and emulsions thereof.
Dry crystalline and powder forms can be incorporated directly into the wax-like vehicle by a mixing step. A prepared vehicle base which melts at substantially 37 C., as illustrated hcreinbefore, is melted or softened by heat, and the dry radioactive form is placed therein and mixed. It is apparent that incorporating such dry forms into the present embodiments attains advantages in the subsequent handling and administration of the radioactive materials. Hazards of contamination from capsular leakage or damage are virtually eliminated while, concurrently, an elegant pharmaceutical form for oral administration is provided.
It is also intended that suspensions and emulsions of radioactive carriers can be incorporated into the embodiments of the present invention. A practitioner may desire to employ suspensions rather than placing a waterinsoiuble material directly into the vehicle base as described hereinbefore. Such suspensions can be prepared by conforming with the conventional procedures provided by that art and, thereafter, mixing said suspensions with the melted vehicle base.
The following examples are presented to illustrate the preparation of the novel capsule combinations, but it should be understood that such examples are meant to be representative and illustrative without implying any limitations which are not warranted by the disclosure presented herein.
Example I Ingredient: Amount Theobroma oil 4.753 gms. 8 1 Spermaceti 2.334 gms.
Glycerol triole'ate, 1 tagged (1-2 mc./ml.)
The theobroma oil and spermaceti are melted on a steam bath at temperatures not exceeding 75 C. The glycerol trioleate is added to this mixture and thoroughly mixed. The combined volume of the theobroma and spermaceti is 8 ml. which results in a vehicle melting at about 37 C. When this vehicle is combined with the equal volume of 1 tagged glycerol trioleate, the melting point of the final composition is not altered from 37 C. A volume of approximately 0.2 ml. of this melted mixture is removed by a pipette and transferred into a bottom half of a gelatin capsule while taking the conventional precautions against radiation hazards. The upper half of the gelatin capsule is telescoped over the bottom portion and the melted mixture within the capsule is allowed to solidify. The foregoing formulation provides a sufiicient amount of melted material to prepare about 80 gelatin capsules. The solidified mixture melts in the range of 3436 C. Each capsule contains an activity of about 50-100 ,uc. as calibrated to a future date of use or approximately 120 ,uC. of 1 activity as of day of preparation.
Example II Ingredient: Amount Glycerol monostearate 4 parts 1 Theobroma oil parts Glycerol trioleate, 1 tagged 4 ml.
The procedure steps outlined in Example I are followed to prepare 40 gelatin capsules wherein each capsule contains an activity of about 50-100 [10. as calibrated to a future date of use.
Example III Ingredient: Amount Theobroma oil 4.753 gms.} 1 Spermaceti 2.334 gms.
Oleic acid, 1 tagged (l-2 mc./m1.) 8 ml.
The theobroma and spermaceti are melted and combined with the oleic acid by process steps as described in Example I. The combined melted mixture is placed in a syringe which is aflixed to a syringe microburet, Model SE22, manufactured by the Micro-metric Instrument Co. of Cleveland, Ohio. A heating tape, attached to a rheostat temperature control, is wrapped around the syringe to keep the waxes and oils in a molten state. The syringe microburet has a manually motivated plunger arm which terminates at a position flush against the plunger arm of the syringe. A dial is connected to the plunger systems whereby the desired volume of expelled molten solids can be determined. Volumes of approximately 0.2 ml. of expelled into each of the bottom portions of the gelatin capsules. The opening of the top portion of the gelatin capsule is dipped in an alcoholic solution of polyvinylpyrrolidone and then telescoped over the bottom portion of the capsule containing the melted composition. The alcoholic solution of polyvinylpyrrolidone serves to seal the capsule portions. The foregoing formulation provides a suflicient amount of melted mate- 6 rial to prepare about gelatin capsules. The solidified mixture melts in the range of 3234 C. Each capsule contains an activity of about 50-100 ,uC. as calibrated to a future date of use.
()thers may practice the invention in any of the numerous ways which will be suggested by this disclosure to one skilled in the art. All such practice of the invention is considered to be a part hereof provided it falls Within the scope of the appended claims.
1. An article of manufacture comprising a pharmaceutical capsule formed of a non-toxic, water-soluble, thermoplastic material and a radioactive composition compounded from pharmaceutical oils and waxes within said capsule, said radioactive composition being a liquid at about 37 C. and remaining a solid at lower temperatures.
2. An article of manufacture comprising a pharmaceutical capsule formed of a non-toxic, Water-soluble thermoplastic material containing therein a radioactive composition compounded from pharmaceutical oils and waxes, said composition containing a radioactive material that is liquid, said radioactive composition melting at about normal body temperatures and remaining substantially a solid at lower temperatures.
3. An article of manufacture according to claim 2 wherein the composition melting at body temperature is mixed with no more than an equal volume of Oil labeled with radioisotopes.
4. An article of manufacture :according to claim 2 wherein the capsule is made of gelatin and the radioactive composition is compounded from theobroma oil and spermaceti wax.
5. An article of manufacture according to claim 2 wherein said capsule is formed of gelatin and said radioactive composition is compounded from theobroma oil, spermaccti wax and glyceryl trioleate.
6. An article of manufacture according to claim 2 wherein said capsule is essentially composed of gelatin and said composition comprises theobroma oil, spermaceti wax and radioactive oleic acid.
7. An article of manufacture according to claim 2 wherein said capsule is formed of gelatin and said composition is compounded from theobroma oil and spermaceti wax, and the radioactive material is introduced therein as an oil.
References flited in the file of this patent UNITED STATES PATENTS 2,780,355 Palermo et a1. Feb. 5, 1957 2,830,010 Valentine et al Apr. 8, 1958 2,911,338 Tabern et al. Nov. 3, 1959 2,956,926 Greif Oct. 18, 1960 2,969,331 Brynko et a1 "Jan. 24, 1961 2,973,301 Klotz Feb. 28, 1961 OTHER REFERENCES J.A.P.A., Sci. Ed., volume 39, No. 11, November 1950, pages 607-609.
Citations de brevets