CA1181687A - Diagnostic adn therapeutic capsules and method of producing - Google Patents
Diagnostic adn therapeutic capsules and method of producingInfo
- Publication number
- CA1181687A CA1181687A CA000375428A CA375428A CA1181687A CA 1181687 A CA1181687 A CA 1181687A CA 000375428 A CA000375428 A CA 000375428A CA 375428 A CA375428 A CA 375428A CA 1181687 A CA1181687 A CA 1181687A
- Authority
- CA
- Canada
- Prior art keywords
- capsule
- filler material
- filler
- radioactive
- article
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired
Links
- 239000002775 capsule Substances 0.000 title claims abstract description 81
- 238000000034 method Methods 0.000 title claims abstract description 17
- 230000001225 therapeutic effect Effects 0.000 title abstract description 6
- 239000000945 filler Substances 0.000 claims abstract description 43
- 239000000463 material Substances 0.000 claims abstract description 37
- 230000002285 radioactive effect Effects 0.000 claims abstract description 35
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000011049 filling Methods 0.000 claims abstract description 10
- 231100000252 nontoxic Toxicity 0.000 claims abstract description 6
- 230000003000 nontoxic effect Effects 0.000 claims abstract description 6
- 210000001035 gastrointestinal tract Anatomy 0.000 claims abstract description 5
- 239000002195 soluble material Substances 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 239000012530 fluid Substances 0.000 claims abstract 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 24
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical group [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 12
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- 239000011630 iodine Substances 0.000 claims description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 8
- 239000002202 Polyethylene glycol Substances 0.000 claims description 7
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 5
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 5
- 235000010265 sodium sulphite Nutrition 0.000 claims description 4
- ZCYVEMRRCGMTRW-AHCXROLUSA-N Iodine-123 Chemical compound [123I] ZCYVEMRRCGMTRW-AHCXROLUSA-N 0.000 claims description 3
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 229920000609 methyl cellulose Polymers 0.000 claims description 2
- 239000001923 methylcellulose Substances 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 2
- 229940124024 weight reducing agent Drugs 0.000 claims 4
- PNDPGZBMCMUPRI-HVTJNCQCSA-N 10043-66-0 Chemical group [131I][131I] PNDPGZBMCMUPRI-HVTJNCQCSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- 229910052708 sodium Inorganic materials 0.000 description 15
- 239000000203 mixture Substances 0.000 description 8
- 239000007903 gelatin capsule Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 101100283604 Caenorhabditis elegans pigk-1 gene Proteins 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229940068917 polyethylene glycols Drugs 0.000 description 2
- 230000036515 potency Effects 0.000 description 2
- 239000012857 radioactive material Substances 0.000 description 2
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 239000008364 bulk solution Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- -1 polyethylene Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229940068984 polyvinyl alcohol Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 239000004416 thermosoftening plastic Substances 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
- A61K51/1262—Capsules
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
Abstract
DIAGNOSTIC AND THERAPEUTIC CAPSULES
AND METHOD OF PRODUCING
Abstract An article of manufacture comprising a pharmaceu-tical radioactive capsule formed essentially of a non-toxic, water soluble material adapted to being ingested and rapidly disintegrating on contact with fluids of the gastro-intestinal tract, and having a filler material supporting a pharmaceutically useful radioactive com-pound absorbable from the gastro-intestinal tract said filler material being supported by said capsule. And a method of filling a pharmaceutical radioactive capsule comprising providing filler material supporting a phar-maceutically useful radioactive compound and transporting said filler material carrying a pharmaceutically useful radioactive compound into the chamber of said capsule.
AND METHOD OF PRODUCING
Abstract An article of manufacture comprising a pharmaceu-tical radioactive capsule formed essentially of a non-toxic, water soluble material adapted to being ingested and rapidly disintegrating on contact with fluids of the gastro-intestinal tract, and having a filler material supporting a pharmaceutically useful radioactive com-pound absorbable from the gastro-intestinal tract said filler material being supported by said capsule. And a method of filling a pharmaceutical radioactive capsule comprising providing filler material supporting a phar-maceutically useful radioactive compound and transporting said filler material carrying a pharmaceutically useful radioactive compound into the chamber of said capsule.
Description
DIAGNOSTIC AND THER~PEUT~C CAPSULES
__ AND METHOD OF PRODUCING
The prese~t inven-tion relates to a new diagnostic and 5 therapeutic form of radioactive compounds and more p~rticularly to an improved encapsuled form of diagnostically and therapeutically useful radioactive compounds.
Radioactive compounds, such as sodium radioactive iodide (I - 131), have been dispensed by measuring out~
- 10 usually by remote control suitable volumes of a radio-active compound in an aqueous medium. For diag-nostic uses in particular, most of the radioactive material is given orally and for such use it was custom-ary to measure or pipette the aqueous solution of the 15 radioactive compound into a cup or glass immediately prior to administering orally to the patient. The fore-going method of administering radioactlve materials resulted in serious contamination of glassware and other equipment as ~ell as the mouth and esophagus of the patient.
The foregoing disadvantages were in part over-come by adding an aqueous solution of a radioactive com-pound to a geiatin capsule which is filled with sodium phosphat~, the latter serving to remove part or all of the water to form a hydrate with the result that the 25 radioactive material is disposed on a fine, fluffy pow-der confined within the interior of the said capsule.
Experience showed that the latter capsules were not well suited for this purpose because the ac-tion oE the water on the gelatin capsules during filling causes the 30 development of irregular areas in the capsules. More-over, when the capsules are damaged or broken, the remaining capsules and adjacent container becomes seri-ously radioactively contamina-ted. The la-tter contamina-tion is even more serious if -the brea;;aye of the capsules occurs during the handling of the capsules while being given to the patient.
Tabern et al. in V. S. Patent No. 2,911,338 dis-closes providing a gelatin capsule c-r capsule of other thermoplastic, water soluble, non-toxic material which has disposed in-teriorally as an integral part thereof or adsorbed on the interior wall a therapeutic or diagnostic dose of an organic or inorganic radioactive compound, such as sodium radioactive iodide. Tabern dis-closes that it is possible to provide a capsule composed of a non-toxic therapeutic water soluble material having interiorally disposed as an in-tegral part thereof a therapeutic or diagnostic dose of a radioactive compound - by orming a solution of the said radioactive comFound in a relatively volatile essentially non-aqueous or~anic .
solvent, deposlting a carefully measured volume of the said solution in an empty capsule or half thereof, ~nd completely removing the solvent to leave the radio~ tive compound adsorbed on the inner walls of the capsule as a firmly attached integral part thereof.
The present invention provideS a pharmaceutical radioactive capsule of improved shelf life.
The pharmaceutical radioactive capsule of the present invention is formed of a nontoxic water soluble material ada"ted to be ingested and rapidly disintegrat-ing on contact withfluidsof the gastro-intestinal tract Each capsule is provided with filler material supporting a pharmaceutically useful radioacti~e compound absorb-5 able from the gastro-intesti~al tract. The filler mat-erial is supported by the capsule.
The filler material preEerably is polyethylene glycol. ~ost preferably the polyethylene glycol is Carbowax 1000 to 4000. The radioactive compound is preferably iodine i.e. I-131 or I-123. The capsule is preferably formed from methyl cellulose, polyvinyl - alcohol or gelatin.
The capsule may also contain a reducing agent.
Preferably the reducing agent sodium sulfite, sodium bisulfite or sodium thiosulfate. Especially preferred is sodium thiosulfate.
The pharmaceutical radioactive capsule may be filled by providing filler material supporting a phar-maceutically useful radioactive compound. Then trans-~orting the filler material carrying the pharmaceutical-ly useful radioactive compound into the chamber of the capsule. Also the filler material may support a reducing agent.
The filler material prior to being transported into the capsule chamber may be dissolved in a solvent or heated. Preferably the solvent is ethanol and the preferred tempera~ure range for the heating method is 45 to 55C.
One method of filling the capsules involves dispensing dissolved filler for example Carbowax (that * Trade Mark L ~
is solid at room temperature) i.e. any o~ the polyethy-lene glycols from 1000 to 4000) in a solvent such as ethanol together with a reducing agent, preferably sodium thiosulEate ln a solvent such as water, and -the radioactive compound for example I-131 or I-123, into the capsules. Then xemoving the solvents by evaporation in a drying chamber but preferably in a temperature con-trolled vacuum dryer. Capsules made with this method maintained a radiochemical puxity of above 99% for a period o 76 days. These capsules were impervious to deyradation caused by a high humidity atmosphere (up to 75~ relative humidity) over a period of 38 days.
Another method of making the capsule product of the present invention is to add a pharmaceutically use-ful radioactive compound to molten filler material.Then filling the capsules. An advantage of molten filler over solvent filler is that a drying cycle is not requir-ed. The molten filler solidifies as it cools within the capsule and therefore can be encapsulated with the top half immediateiy after filling. The solvent-filler pref-erably undergoes at least a 1 hour drying period in a temperature controlled vacuum drying chamber. Preferably, a base is provided in the heated filler. Where the pharmaceutically useful radioactive compound is iodine, heating may cause radioiodination of the filler. The presence of a base controls pH and minimizes any radio-iodination. Since heat is not used in the solvent filler a base preferably would not be included therein.
In the carbowax radioactive iodire embodiments some peroxide may be present in tht carbowax. The peroxide may react with the radioactive iodine to produce gaseous iodine. To prevent this,reducing a~ents may be added. Preferred reducing agents are sodium sulfite, sodium bisulfite and sodium thiosulfate.
Especially preferred is sodium thiosulfate.
A fundamental function of the filler material is to maintain the pharmaceutically use-ful compound separ-ate from the inner wall of the capsule. When thepharmaceutically useful compound is in contact wi-th the capsule wall the pharmaceutically useful compound may combine wi-th the material of the capsule wall _hus lowerin~ the effective amount of pharmaceutically use-ful compound in the capsule.
In a preferred embodiment of the invention thefiller material is supported by the inner surface of the capsule and the capsule has a central axis and the filler material extends radially across the cen-tral axis of the ccpsule. The filler material sup-ports a major port cn of the radioactive compound within the interior of the filler material so that the major portion of the radioactive compound does not contact the inner surface of the capsule. Preferably, a major portion of the volume within and defined by said inner surface of said capsule contains said filler material.
Preferably a major portion of the volume within and defined by the inner surface of the cap-sule contains the filler material.
3~
Carbowax has been added to a preferred formula-tion to act as a support media for the Sod~um Radio-iodide, thus preventiny its interaction wi-th the yela-tin of the capsule. One method of manufacture is automatic filling of the capsules with small volumes of an alcoholic-aqueous solution containing the formula excipients and selective removal of the mobile liquid from the capsules in a drying chamber using heat and vacuum.
Example 1 shows the raw material per batch of 1000 capsules of the invention. Examples 2 7 and 10 show formulations per capsule of the invention.
- Examples 8 - 10 are methods of making the capsules and are within the scope of the invention.
In the examples ~Ci is micro curies; I-131 is radioactive iodine having an isotope weight of 131.
Carbowax 4000 and 1000 are polyethylene glycols made by Union Carbide having average molecular weights of 4000 and looo -RB5g Example 1 per 50.0 mCi Batch*
Sodium Radioiodide I-131 Concentra':e Solution 50.0 mCi Sodium Thiosulfate U.S.P. 0.093 grams Polyethylene Glycol, 1540 N.F. 33.64 grams Water for Injection 15.9 ml.
Alcohol (Ethanol) U.S.P. 84.1 ml.
Gelatin Capsules 1000 * Smaller or larger batches may be manufactured by decreasing or increasing the raw ma-terials proportion-ately.
Example 2 -Per Capsule Sodium Radioiodide I-131 Concentrate Solution 50 ~Ci*
Sodium Thiosulfate U.S.P. 0.093 mg Polyethylene glycol, 1540 N.F. 33.64 mg Alcohol (Ethanol) U. S. P. 0.084 ml**
Water for Injection 0.016 ml**
Gelatin Capsule * Activity on date of Calibration. Higher or lower potencies may be made by incIeasing or decreasing the radioactivity respectively o ~llowing higher potencies to decay.
** Removed by evaporation prior -to sealing the Capsule.
25 ~
- Example 3 Per Capsule Sodium Radioiodide I-131 50 ~Ci Carbowax 4000 0.09 (ml) NaHSO3- 0.25 mg Example 4 Per Capsule Sodium Radioiodide I-131 50 ~Ci Carbowax 1540 10 mg Na2S3 0.1 mg Ethanol 0.1 ml Example 5 Per Capsule Sodium Radioiodide I-131 50 ~Ci Carbowax 1540 94 mg NaHSO3 0.02 mg K~HPO4 0.176 mg Water 0.01 ml, Example 6 Per Capsule Sodium Radioiodide I-131 50 ~Ci Carbowax 1540 40 mg Ethanol 0.1 ml Example 7 Per Capsule Sodium Radioiodide I-131 50 ~Ci Carbowax 4000 94 mg K~HPO4 0.175 mg 0.01 ml Water g .
Example 8 RB58 - A formulation used ~o fill the capsules is as ~ollows:
90 ml of a 40% solution of Carbowax 1000 in ethanol.
5 ml of a 20% solution of Na2S2O .
5 ml of H2O containing the I-131~
A volume of 0.1 ml of the above solution was dispensed into each capsule. A melt tray holding the capsules in a platter is placed in a Heat-Vacuum drying chamber. Heat is applied to the base of the chamber by circulating water constantly maintained at 70C through the base. The vacuum is brought down to 27" of Hg by bleeding N2 gas into the system.
A platter is dried for one hour to two hours under the above conditions.
The chromatograms resulting from a stability study show a single sharp peak throughout seventy-six days.
Example 9 This procedure is for making 100 ml of bulk filling solution using vacuum chambexs as are known in the art. Larger or smaller volumes can be made by proportionating the ingredients.
Dissolve 0.292 grams of Sodium Thiosulfate, in Water for Injection and adjust the total volume to 50 mls. Liquify 40.0 grams of Carbowax 1540, in a suitable receptacle by warming at a temperature not to exceed 70 C. Remove from warming chamber and, while still li~uid, add ethanol, up to 100 ml with stirring. Make final ~djustment to 100 ml with the ethanol when room temperature has been reached. Mix well. As a first step mix 84.1 ml of the Ethanolic Carbowax Solution Wit' 15.9 ml of the Sodium Thiosulfate Solution in a suitable container. All or part of the 15.9 ml of the Sodium Thiosulfate Solution may be used to transfer and wash the sodium radioiodide into the container. Alternative-ly, all or part of the combined solutions may be used to transfer and wash the sodium radioiodide into the container. Following the transfer into -the bulk filling container, mix by stirr: g, then assay. If the assay is low by not more than ~0%, sodium radioiodide can be added to adjust the radioconcentration. If the assay is too high, the ethanolic Carbowax 15~0 solution can be combined with the Thiosulfate Solution in the same ratio stipulated above, and used to dilute - the bulk solution. Fill up to 0.1 ml of the bulk fil-ling solution into the body of Gelatin Capsules. Seal the vacuum chambers and apply .Jq.~ 3~7 full vacuum. Determine the maximum vacuum at-tainable a-t the time and record. It should be 27 inches minimum.
Shut off the vacuum valve, allow the chambers to equil-ibrate to atmospheric condi-tions. Open the special chambers, place the plates containing the Eilled capsule bottoms on the polyethylene spacing rods, seal -the chambers with the lids. Fully open N2 bleed valve to chamber then fully open the vacuum. Gradually close the N2 bleed valve until the vacuum gauge reading is 1 to 1.5 inches lower than the value obtained above. Dry the capsules for a period of at least one hour under the above conditions but not to exceed one hour and twenty minutes. Seal the capsules with the Capsule top.
f,3~t,;j,1 Example 10 A product of the following composi-tion per cap-s~le is made by the procedure below:
Per Capsules Sodium Radioiodide I-13150 ~Ci Sodium Thiosulfate Penta~ydrate 0.628 mg Diphotassium Phosphate Anhydrous 0.175 mg Carbowax 4000 94.05 mg Water for Injection 10.45 mg First melt 54 g of Carbowa~ 4000 in a suitable 1~ glass container within a hot water bath. Then transfer to the dispenser xeservoir preheated to 60C - 3C.
Dissolve 6.28 g of Na2S2O3.5H2O up to 100 ml with a 0.1 M K2HPO4 solution. Use 6 ml of the thiosulfate/potassi-um phosphate solution to dilute and transfer the sodium radioiodide to the dispenser reservoir. Allow 1/2 hour for the solutions to completely mix by bubbliny N2 through the solutions. Dispense 0.1 ml (4 drops) into each bottom half of the gelatin capsules.
__ AND METHOD OF PRODUCING
The prese~t inven-tion relates to a new diagnostic and 5 therapeutic form of radioactive compounds and more p~rticularly to an improved encapsuled form of diagnostically and therapeutically useful radioactive compounds.
Radioactive compounds, such as sodium radioactive iodide (I - 131), have been dispensed by measuring out~
- 10 usually by remote control suitable volumes of a radio-active compound in an aqueous medium. For diag-nostic uses in particular, most of the radioactive material is given orally and for such use it was custom-ary to measure or pipette the aqueous solution of the 15 radioactive compound into a cup or glass immediately prior to administering orally to the patient. The fore-going method of administering radioactlve materials resulted in serious contamination of glassware and other equipment as ~ell as the mouth and esophagus of the patient.
The foregoing disadvantages were in part over-come by adding an aqueous solution of a radioactive com-pound to a geiatin capsule which is filled with sodium phosphat~, the latter serving to remove part or all of the water to form a hydrate with the result that the 25 radioactive material is disposed on a fine, fluffy pow-der confined within the interior of the said capsule.
Experience showed that the latter capsules were not well suited for this purpose because the ac-tion oE the water on the gelatin capsules during filling causes the 30 development of irregular areas in the capsules. More-over, when the capsules are damaged or broken, the remaining capsules and adjacent container becomes seri-ously radioactively contamina-ted. The la-tter contamina-tion is even more serious if -the brea;;aye of the capsules occurs during the handling of the capsules while being given to the patient.
Tabern et al. in V. S. Patent No. 2,911,338 dis-closes providing a gelatin capsule c-r capsule of other thermoplastic, water soluble, non-toxic material which has disposed in-teriorally as an integral part thereof or adsorbed on the interior wall a therapeutic or diagnostic dose of an organic or inorganic radioactive compound, such as sodium radioactive iodide. Tabern dis-closes that it is possible to provide a capsule composed of a non-toxic therapeutic water soluble material having interiorally disposed as an in-tegral part thereof a therapeutic or diagnostic dose of a radioactive compound - by orming a solution of the said radioactive comFound in a relatively volatile essentially non-aqueous or~anic .
solvent, deposlting a carefully measured volume of the said solution in an empty capsule or half thereof, ~nd completely removing the solvent to leave the radio~ tive compound adsorbed on the inner walls of the capsule as a firmly attached integral part thereof.
The present invention provideS a pharmaceutical radioactive capsule of improved shelf life.
The pharmaceutical radioactive capsule of the present invention is formed of a nontoxic water soluble material ada"ted to be ingested and rapidly disintegrat-ing on contact withfluidsof the gastro-intestinal tract Each capsule is provided with filler material supporting a pharmaceutically useful radioacti~e compound absorb-5 able from the gastro-intesti~al tract. The filler mat-erial is supported by the capsule.
The filler material preEerably is polyethylene glycol. ~ost preferably the polyethylene glycol is Carbowax 1000 to 4000. The radioactive compound is preferably iodine i.e. I-131 or I-123. The capsule is preferably formed from methyl cellulose, polyvinyl - alcohol or gelatin.
The capsule may also contain a reducing agent.
Preferably the reducing agent sodium sulfite, sodium bisulfite or sodium thiosulfate. Especially preferred is sodium thiosulfate.
The pharmaceutical radioactive capsule may be filled by providing filler material supporting a phar-maceutically useful radioactive compound. Then trans-~orting the filler material carrying the pharmaceutical-ly useful radioactive compound into the chamber of the capsule. Also the filler material may support a reducing agent.
The filler material prior to being transported into the capsule chamber may be dissolved in a solvent or heated. Preferably the solvent is ethanol and the preferred tempera~ure range for the heating method is 45 to 55C.
One method of filling the capsules involves dispensing dissolved filler for example Carbowax (that * Trade Mark L ~
is solid at room temperature) i.e. any o~ the polyethy-lene glycols from 1000 to 4000) in a solvent such as ethanol together with a reducing agent, preferably sodium thiosulEate ln a solvent such as water, and -the radioactive compound for example I-131 or I-123, into the capsules. Then xemoving the solvents by evaporation in a drying chamber but preferably in a temperature con-trolled vacuum dryer. Capsules made with this method maintained a radiochemical puxity of above 99% for a period o 76 days. These capsules were impervious to deyradation caused by a high humidity atmosphere (up to 75~ relative humidity) over a period of 38 days.
Another method of making the capsule product of the present invention is to add a pharmaceutically use-ful radioactive compound to molten filler material.Then filling the capsules. An advantage of molten filler over solvent filler is that a drying cycle is not requir-ed. The molten filler solidifies as it cools within the capsule and therefore can be encapsulated with the top half immediateiy after filling. The solvent-filler pref-erably undergoes at least a 1 hour drying period in a temperature controlled vacuum drying chamber. Preferably, a base is provided in the heated filler. Where the pharmaceutically useful radioactive compound is iodine, heating may cause radioiodination of the filler. The presence of a base controls pH and minimizes any radio-iodination. Since heat is not used in the solvent filler a base preferably would not be included therein.
In the carbowax radioactive iodire embodiments some peroxide may be present in tht carbowax. The peroxide may react with the radioactive iodine to produce gaseous iodine. To prevent this,reducing a~ents may be added. Preferred reducing agents are sodium sulfite, sodium bisulfite and sodium thiosulfate.
Especially preferred is sodium thiosulfate.
A fundamental function of the filler material is to maintain the pharmaceutically use-ful compound separ-ate from the inner wall of the capsule. When thepharmaceutically useful compound is in contact wi-th the capsule wall the pharmaceutically useful compound may combine wi-th the material of the capsule wall _hus lowerin~ the effective amount of pharmaceutically use-ful compound in the capsule.
In a preferred embodiment of the invention thefiller material is supported by the inner surface of the capsule and the capsule has a central axis and the filler material extends radially across the cen-tral axis of the ccpsule. The filler material sup-ports a major port cn of the radioactive compound within the interior of the filler material so that the major portion of the radioactive compound does not contact the inner surface of the capsule. Preferably, a major portion of the volume within and defined by said inner surface of said capsule contains said filler material.
Preferably a major portion of the volume within and defined by the inner surface of the cap-sule contains the filler material.
3~
Carbowax has been added to a preferred formula-tion to act as a support media for the Sod~um Radio-iodide, thus preventiny its interaction wi-th the yela-tin of the capsule. One method of manufacture is automatic filling of the capsules with small volumes of an alcoholic-aqueous solution containing the formula excipients and selective removal of the mobile liquid from the capsules in a drying chamber using heat and vacuum.
Example 1 shows the raw material per batch of 1000 capsules of the invention. Examples 2 7 and 10 show formulations per capsule of the invention.
- Examples 8 - 10 are methods of making the capsules and are within the scope of the invention.
In the examples ~Ci is micro curies; I-131 is radioactive iodine having an isotope weight of 131.
Carbowax 4000 and 1000 are polyethylene glycols made by Union Carbide having average molecular weights of 4000 and looo -RB5g Example 1 per 50.0 mCi Batch*
Sodium Radioiodide I-131 Concentra':e Solution 50.0 mCi Sodium Thiosulfate U.S.P. 0.093 grams Polyethylene Glycol, 1540 N.F. 33.64 grams Water for Injection 15.9 ml.
Alcohol (Ethanol) U.S.P. 84.1 ml.
Gelatin Capsules 1000 * Smaller or larger batches may be manufactured by decreasing or increasing the raw ma-terials proportion-ately.
Example 2 -Per Capsule Sodium Radioiodide I-131 Concentrate Solution 50 ~Ci*
Sodium Thiosulfate U.S.P. 0.093 mg Polyethylene glycol, 1540 N.F. 33.64 mg Alcohol (Ethanol) U. S. P. 0.084 ml**
Water for Injection 0.016 ml**
Gelatin Capsule * Activity on date of Calibration. Higher or lower potencies may be made by incIeasing or decreasing the radioactivity respectively o ~llowing higher potencies to decay.
** Removed by evaporation prior -to sealing the Capsule.
25 ~
- Example 3 Per Capsule Sodium Radioiodide I-131 50 ~Ci Carbowax 4000 0.09 (ml) NaHSO3- 0.25 mg Example 4 Per Capsule Sodium Radioiodide I-131 50 ~Ci Carbowax 1540 10 mg Na2S3 0.1 mg Ethanol 0.1 ml Example 5 Per Capsule Sodium Radioiodide I-131 50 ~Ci Carbowax 1540 94 mg NaHSO3 0.02 mg K~HPO4 0.176 mg Water 0.01 ml, Example 6 Per Capsule Sodium Radioiodide I-131 50 ~Ci Carbowax 1540 40 mg Ethanol 0.1 ml Example 7 Per Capsule Sodium Radioiodide I-131 50 ~Ci Carbowax 4000 94 mg K~HPO4 0.175 mg 0.01 ml Water g .
Example 8 RB58 - A formulation used ~o fill the capsules is as ~ollows:
90 ml of a 40% solution of Carbowax 1000 in ethanol.
5 ml of a 20% solution of Na2S2O .
5 ml of H2O containing the I-131~
A volume of 0.1 ml of the above solution was dispensed into each capsule. A melt tray holding the capsules in a platter is placed in a Heat-Vacuum drying chamber. Heat is applied to the base of the chamber by circulating water constantly maintained at 70C through the base. The vacuum is brought down to 27" of Hg by bleeding N2 gas into the system.
A platter is dried for one hour to two hours under the above conditions.
The chromatograms resulting from a stability study show a single sharp peak throughout seventy-six days.
Example 9 This procedure is for making 100 ml of bulk filling solution using vacuum chambexs as are known in the art. Larger or smaller volumes can be made by proportionating the ingredients.
Dissolve 0.292 grams of Sodium Thiosulfate, in Water for Injection and adjust the total volume to 50 mls. Liquify 40.0 grams of Carbowax 1540, in a suitable receptacle by warming at a temperature not to exceed 70 C. Remove from warming chamber and, while still li~uid, add ethanol, up to 100 ml with stirring. Make final ~djustment to 100 ml with the ethanol when room temperature has been reached. Mix well. As a first step mix 84.1 ml of the Ethanolic Carbowax Solution Wit' 15.9 ml of the Sodium Thiosulfate Solution in a suitable container. All or part of the 15.9 ml of the Sodium Thiosulfate Solution may be used to transfer and wash the sodium radioiodide into the container. Alternative-ly, all or part of the combined solutions may be used to transfer and wash the sodium radioiodide into the container. Following the transfer into -the bulk filling container, mix by stirr: g, then assay. If the assay is low by not more than ~0%, sodium radioiodide can be added to adjust the radioconcentration. If the assay is too high, the ethanolic Carbowax 15~0 solution can be combined with the Thiosulfate Solution in the same ratio stipulated above, and used to dilute - the bulk solution. Fill up to 0.1 ml of the bulk fil-ling solution into the body of Gelatin Capsules. Seal the vacuum chambers and apply .Jq.~ 3~7 full vacuum. Determine the maximum vacuum at-tainable a-t the time and record. It should be 27 inches minimum.
Shut off the vacuum valve, allow the chambers to equil-ibrate to atmospheric condi-tions. Open the special chambers, place the plates containing the Eilled capsule bottoms on the polyethylene spacing rods, seal -the chambers with the lids. Fully open N2 bleed valve to chamber then fully open the vacuum. Gradually close the N2 bleed valve until the vacuum gauge reading is 1 to 1.5 inches lower than the value obtained above. Dry the capsules for a period of at least one hour under the above conditions but not to exceed one hour and twenty minutes. Seal the capsules with the Capsule top.
f,3~t,;j,1 Example 10 A product of the following composi-tion per cap-s~le is made by the procedure below:
Per Capsules Sodium Radioiodide I-13150 ~Ci Sodium Thiosulfate Penta~ydrate 0.628 mg Diphotassium Phosphate Anhydrous 0.175 mg Carbowax 4000 94.05 mg Water for Injection 10.45 mg First melt 54 g of Carbowa~ 4000 in a suitable 1~ glass container within a hot water bath. Then transfer to the dispenser xeservoir preheated to 60C - 3C.
Dissolve 6.28 g of Na2S2O3.5H2O up to 100 ml with a 0.1 M K2HPO4 solution. Use 6 ml of the thiosulfate/potassi-um phosphate solution to dilute and transfer the sodium radioiodide to the dispenser reservoir. Allow 1/2 hour for the solutions to completely mix by bubbliny N2 through the solutions. Dispense 0.1 ml (4 drops) into each bottom half of the gelatin capsules.
Claims (10)
1. An article of manufacture comprising, a pharma-ceutical capsule formed substantially of a nontoxic, water soluble material adapted to being ingested and rapidly dis-integrating on contact with fluids of the gastro-intestinal tract and a polyethylene glycol filler material having a pharmaceutically useful radioactive iodine and a reducing agent dispersed therein, said capsule having a central axis and an inner surface, said inner surface defining a volume within said capsule, said filler material being supported by said inner surface of said capsule, a major portion of said volume within said capsule containing said filler mat-erial, said filler material having a shape which is coex-tensive with the inner surface of said capsule, said filler material extending radially across the central axis of said capsule, said filler material containing a major portion of said radioactive iodine within the interior of said filler material, whereby said major portion of said radioactive compound does not contact said inner surface of said capsule.
2. The article of claim 1 wherein said radioactive iodine is iodine 131 or iodine 123.
3. The article of claim 1 wherein said capsule is methyl cellulose, polyvinyl alcohol or gelatin.
4. The article of claim 1, 2 or 3 wherein said reduc-ing agent is sodium thiosulfate, sodium sulfite or sodium bisulfite.
5. The article of claim 1, 2 or 3 further comprising a base dispersed throughout said filler material, and said reducing agent is sodium thiosulfate, sodium sulfite or sodium bisulfite.
6. A method of filling a pharmaceutical capsule hav-ing an inner surface defining a volume within said capsule, said capsule being formed substantially of a nontoxic, water soluble material adapted to being ingested and rapidly dis-integrating on contact with fluids in the gastro-intestinal tract comprising providing a polyethylene glycol filler mat-erial having a pharmaceutically useful radioactive iodine and a reducing agent dispersed therein and transporting said fil-ler material into said capsule, whereby a major portion of said volume within said capsule is filled with filler material.
7. The method of claim 6 wherein said filler material is heated prior to said transporting and said filler material further has a base dispersed therein.
8. The method of claim 7 wherein said filler is heated to 50° to 60°C prior to said transporting, and said polyethylene glycol additionally has a base dispersed throughout said filler.
9. The method of claim 6 wherein said filler material is dissolved in a solvent prior to said transporting and both said filler material and said solvent are transported into said capsule.
10. The method of claim 9 further comprising removing said solvent from said capsule.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US140,341 | 1980-04-14 | ||
| US06/140,341 US4349529A (en) | 1980-04-14 | 1980-04-14 | Diagnostic and therapeutic capsules and method of producing |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1181687A true CA1181687A (en) | 1985-01-29 |
Family
ID=22490796
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000375428A Expired CA1181687A (en) | 1980-04-14 | 1981-04-14 | Diagnostic adn therapeutic capsules and method of producing |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US4349529A (en) |
| JP (1) | JPS56161052A (en) |
| AU (1) | AU553720B2 (en) |
| BE (1) | BE888396A (en) |
| CA (1) | CA1181687A (en) |
| CH (1) | CH661872A5 (en) |
| DE (1) | DE3115053C2 (en) |
| FR (1) | FR2480124A1 (en) |
| GB (1) | GB2073589B (en) |
| IT (1) | IT1137544B (en) |
| ZA (1) | ZA812305B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4610868A (en) * | 1984-03-20 | 1986-09-09 | The Liposome Company, Inc. | Lipid matrix carriers for use in drug delivery systems |
| US5456663A (en) * | 1984-05-25 | 1995-10-10 | Lemelson; Jerome H. | Drugs and methods for treating diseases |
| US4702228A (en) * | 1985-01-24 | 1987-10-27 | Theragenics Corporation | X-ray-emitting interstitial implants |
| WO1989012305A1 (en) * | 1988-06-07 | 1989-12-14 | Nutech, Inc. | Method for decontaminating specially selected and conventional plastic materials which have become radioactively contaminated, and articles |
| US4936074A (en) * | 1988-11-17 | 1990-06-26 | D. M. Graham Laboratories, Inc. | Process for preparing solid encapsulated medicament |
| US5188837A (en) * | 1989-11-13 | 1993-02-23 | Nova Pharmaceutical Corporation | Lipsopheres for controlled delivery of substances |
| US5227165A (en) * | 1989-11-13 | 1993-07-13 | Nova Pharmaceutical Corporation | Liposphere delivery systems for local anesthetics |
| IE904098A1 (en) * | 1989-11-13 | 1991-05-22 | Nova Pharm Corp | Lipospheres for controlled delivery of substances |
| US5221535A (en) * | 1989-11-13 | 1993-06-22 | Nova Pharmaceutical Corporation | Sustained release formulations of insect repellent |
| US5314678A (en) * | 1992-01-28 | 1994-05-24 | Mallinckrodt Medical, Inc. | Sodium iodide 131 I capsules |
| US6537518B1 (en) | 1994-01-21 | 2003-03-25 | Sirtex Medical Limited | Particulate material |
| JP3770906B2 (en) * | 1994-01-21 | 2006-04-26 | シルテックス、メディカル、リミテッド | Granular material |
| US5993374A (en) * | 1997-06-17 | 1999-11-30 | Radiance Medical Systems, Inc. | Microcapsules for site-specific delivery |
| JP2005538993A (en) * | 2002-07-31 | 2005-12-22 | ファルマシア・コーポレーション | Gelatin capsule that does not easily form a thin film |
| US20040081689A1 (en) * | 2002-10-24 | 2004-04-29 | Dunfield John Stephen | Pharmaceutical dosage form and method of making |
| US8733274B2 (en) * | 2006-10-20 | 2014-05-27 | Hewlett-Packard Development Company, L.P. | Tube mounted inkjet printhead die |
| US7867548B2 (en) * | 2006-10-27 | 2011-01-11 | Hewlett-Packard Development Company, L.P. | Thermal ejection of solution having solute onto device medium |
| WO2009073698A1 (en) * | 2007-12-04 | 2009-06-11 | Bracco Imaging S.P.A. | Homogenization of a radiopharmaceutical using sonification and/or rotor-stator technology to produce a homogenous suspension, emulsion, mixture or solid suspension of immiscible ingredients |
| US10299745B2 (en) | 2014-12-29 | 2019-05-28 | Loyola University Of Chicago | Traceable devices for gastrointestinal use and methods of use and manufacturing the same |
| CN113750260B (en) * | 2021-07-29 | 2023-03-31 | 原子高科股份有限公司 | Radioactive iodine [ I-131] sodium iodide capsule for treatment and preparation method thereof |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US1683466A (en) * | 1927-05-09 | 1928-09-04 | Joseph A Horigan | Capsule |
| US2911338A (en) * | 1954-03-09 | 1959-11-03 | Abbott Lab | Capsules and method of producing |
| NL269886A (en) * | 1960-10-04 | |||
| NL270593A (en) * | 1960-10-26 | |||
| DE2140177A1 (en) * | 1971-08-11 | 1973-02-22 | Hoechst Ag | Radioactive iodine capsules - for thyroid function tests |
| US3780170A (en) * | 1972-07-03 | 1973-12-18 | Warner Lambert Co | Tasteless methenamine mandelate |
| JPS5653351Y2 (en) * | 1976-09-06 | 1981-12-11 | ||
| JPS5345344U (en) * | 1976-09-22 | 1978-04-18 | ||
| JPS5398949U (en) * | 1977-01-14 | 1978-08-10 | ||
| JPS52128952A (en) * | 1977-04-02 | 1977-10-28 | Yoshino Kogyosho Co Ltd | Method of molding decorated synthetic resin container body or cap |
| US4235871A (en) * | 1978-02-24 | 1980-11-25 | Papahadjopoulos Demetrios P | Method of encapsulating biologically active materials in lipid vesicles |
-
1980
- 1980-04-14 US US06/140,341 patent/US4349529A/en not_active Expired - Lifetime
-
1981
- 1981-04-03 AU AU69087/81A patent/AU553720B2/en not_active Ceased
- 1981-04-07 ZA ZA00812305A patent/ZA812305B/en unknown
- 1981-04-08 FR FR8107076A patent/FR2480124A1/en active Granted
- 1981-04-10 IT IT21084/81A patent/IT1137544B/en active
- 1981-04-13 BE BE0/204467A patent/BE888396A/en not_active IP Right Cessation
- 1981-04-13 CH CH2451/81A patent/CH661872A5/en not_active IP Right Cessation
- 1981-04-13 GB GB8111673A patent/GB2073589B/en not_active Expired
- 1981-04-14 CA CA000375428A patent/CA1181687A/en not_active Expired
- 1981-04-14 JP JP5686881A patent/JPS56161052A/en active Granted
- 1981-04-14 DE DE3115053A patent/DE3115053C2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| AU6908781A (en) | 1981-10-22 |
| AU553720B2 (en) | 1986-07-24 |
| CH661872A5 (en) | 1987-08-31 |
| GB2073589B (en) | 1985-01-16 |
| IT8121084A1 (en) | 1982-10-10 |
| JPS56161052A (en) | 1981-12-11 |
| FR2480124B1 (en) | 1983-07-18 |
| ZA812305B (en) | 1982-04-28 |
| IT8121084A0 (en) | 1981-04-10 |
| JPH0379326B2 (en) | 1991-12-18 |
| DE3115053C2 (en) | 1994-07-28 |
| BE888396A (en) | 1981-10-13 |
| US4349529A (en) | 1982-09-14 |
| IT1137544B (en) | 1986-09-10 |
| GB2073589A (en) | 1981-10-21 |
| DE3115053A1 (en) | 1982-02-18 |
| FR2480124A1 (en) | 1981-10-16 |
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