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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
  • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
  • B65B3/00—Packaging plastic material, semiliquids, liquids or mixed solids and liquids, in individual containers or receptacles, e.g. bags, sacks, boxes, cartons, cans, or jars
  • B65B3/003—Filling medical containers such as ampoules, vials, syringes or the like
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• This .invention relates to the.;filling of definite quantities f solid materials into containers, and more particularly to such dispensing involving small quantities.
• Thi'sis because many therapeutic agents have such potent therapeutic value that a few milligrams will be-sufiicient fora single dosage, and a larger dosage may be injurious.
• the original form of the solid is to be preserved.
• penicillin is very stable in crystallineiform but not as an amorphous powder; when theliquid in which it is dissolved is removed, the penicillin appears as an amor- Even though lyophilization is resorted to as the only practical means of drying a penicillin-containing solution, the penicillin is left as an amorphous Moreover,
• the present invention obviates the many difiiculties
• the invention consists in the dispensing of solid materials by suspending them in a liquid in which the-solid material is insoluble and not chemically reactive, the liquid further having a specific gravity which is the same as or very close to that of the suspended solid.
• the suspension so prepared is filled intocontainers by transferring a measured amount of the suspension into individual containers.
• the suspending medium then may be removed by methods known to the art for accelerated conversion to a vapor as, for instance, evaporation, which includes evaporation both above and below theboiling point of the liquid used, and also sublimation.
• This method completely eliminates the difliculties in-
• the desired material is not altered in .form from itsoriginal state, it is not subjected to the type-of decomposition (hydrolysis, oxidation) that so many sensitive materials undergo in solution, and it eliminates the search for a suitable solvent in those cases in which'the material does not exhibit appreciable solubility in any conventional solvent (riboflavin).
• the difiiculties inherent in dry weighing also are overcome since even minute-quantities of material are easily handled by this invention. The danger of allergic or chemical irritation to personnel caused by fine dust during dry filling cannot occur in this method. Moreover, the precision is very great, being limited only to those errors involved vin measuring out an amount of liquid, inasmuch as .the concentration of the suspension can be varied over a wide range.
• the suspending liquid of the invention process may be of a single molecular structure-or it may be amixture of two or moret liquids of different density inorder to have the desired final composite density.
• the liquids sethe vials assayed 1760 units per milligram. penicillin was crystalline, free of any trace of the suspendlected for the mixture should be miscible with each other and none should be a solvent or impair the properties of the solid material to be suspended therein.
• the concentration of the solid in the suspending liquid is not critical. If the amount of solid to be filled is to be in micrograms, a greater accuracy is obtainable if the concentration is very low, but this of course requires an increased time for subsequent removal of the large amount of liquid. If the amount of solid to be filled is to be in grams or large fractions thereof, the concentration may be the maximum obtainable compatible with pouring or other case of handling.
• the suspending liquid be of a volatile nature so that it may be removed easily, leaving the solid material in the container.
• the liquid may be removed by ordinary evaporation or by boiling, either at atmospheric or reduced pressure.
• the suspending liquid can be removed by a lyophilization process as well.
• a controlled reduction of pressure in the vacuum chamber for example, over a period of approximately one hour, may be found to be important to eliminate bumping within the container.
• Another suitable means of removing the liquid suspending the penicillin is to place the filled vials in a vacuum chamber and to evacuate the chamber over a period of approximately one hour to a pressure of about mm. of mercury. This pressure is then maintained for a period of from approximately two to twenty-four hours to complete removal of the suspending medium.
• the time required can be varied by variance of the temperature and pressure at which the process is carried out.
• Example 1 A suspension of crystalline sodium penicillin G, assaying 1690 units per milligram, was suspended in a medium composed of equal parts of methylene chloride and chloroform so that two milliliters of the suspension represented sixty milligrams of penicillin. Two milliliters of this suspension were filled into several vials and the vials and contents were then subjected to vacuum. The pressure of the vacuum chamber was reduced over a period of approximately one hour to about ten millimeters of mercury and this pressure was maintained for twenty hours. The vacuum was then released, the vials capped and then assayed for penicillin activity. The penicillin in The filled ing medium and of essentially the same color, potency and appearance as before filling.
• One of the vials was subjected to an accelerated stability test consisting of being exposed to a temperature of C. for four days and then was assayed.
• the penicillin assayed 1770 units per milligram showing no deterioration in antibiotic activity.
• Example 2 -Crystalline sodium penicillin G assaying 1690 units per milligram was suspended in a medium consisting of equal parts of methylene chloride and chloroform such that each milliliter contained milligrams of penicillin. Five mls. of this suspension was filled into vials and the vials then put under vacuum. The pressure of the vacuum chamber was reduced over a period of approximately one hour to about ten millimeters of mercury and the vacuum maintained for approximately 24 hours. The vacuum was released and the vials of penicillin stoppered. A sample of the penicillin in the vial assayed 1840 units per milligram. The filled penicillin was crystalline, free of any trace of the suspending medium and of essentially the same color, potency and appearance as before filling.
• the penicillin in a sample vial assayed 1830 units per milligram.
• Example 4 Crystalline sodium penicillin G assaying 1690 units per milligram was suspended in a medium consisting of four parts of ethylene chloride and six parts of chloroform such that each milliliter of the suspension represented milligrams of penicillin. Five milliliters of this suspension was measured into vials, and the vials subjected to vacuum. The pressure in the vacuum chamber was reduced over a period of approximately one hour to approximately ten millimeters of mercury and the vacuum maintained for approximately twenty-four hours. The vacuum was released, the vials capped and assayed. A sample vial assayed 1810 units per milligram. The filled penicillin was crystalline, free of any trace of the suspending medium and of essentially the same color, potency and appearance as before filling.
• Example 5 -Crystalline sodium penicillin G assaying 1623 units per milligram was suspended in a medium consisting of six parts of chloroform and four parts ethylene chloride in such quantity that each two milliliters of the suspension represented 100,000 units of penicillin. Two milliliters of this suspension was filled into a number of containers and the containers were subjected to vacuum. The pressure in the vacuum chamber was reduced over a period of approximately one hour to about ten milliliters of mercury and the vacuum maintained for twenty-four hours. The vacuum was then released and the containers stoppered and assayed. Assay of 10% of the vials (10 vials) gave an'average of penicillin content per vial of 112,100 units. The filled penicillin was crystalline, free of any trace of the suspending medium and of essentially the same color, potency and appearance as before filling.
• Example 6 Crystalline sodium penicillin G assaying 1650 units per milligram was suspended in a mixture of two parts ethylene chloride and three parts of chloroform such that each milliliter of the suspension represented 50,000 units of penicillin. Two milliliters of this suspen sion were filled into various containers and the containers then placed in an oven at 100 C. for approximately one hour. At the end of one hour the temperature was raised to 150 C. in order to sterilize the vials, all of the solvent having been removed during the first hour of heating. After exposure at 150 C. for one hour, the vials were stoppered and assayed for penicillin content and tested for sterility. All the vials were sterile and the penicillin content averaged 94,000 units per vial.
• Example 7 Example 6 was repeated using a suspending medium consisting of four parts of carbon tetrachloride and one part n-hexane. Substantially similar results-were obtained.
• Example 8 Example 6 was repeated using a suspending medium consisting of 20 parts carbon tetrachloride and seven parts benzene. Substantially similar results were obtained.
• Example 9 Example 9 was repeated using a suspending medium consisting of 10 parts carbon tetrachloride and four parts ethyl acetate. Substantially similar results were obtained.
• Example 10 Example 6 was repeated using a suspending medium consisting of 10 parts carbon tetrachloride and three parts of di-isopropyl ether. Substantially similar results were obtained.
• Example 11.Crystalline potassium penicillin G assaying 1580 units per milligram was suspended in a medium consisting of six parts of chloroform and four parts ethylene dichloride in such quantity that each milliliter of the suspension represented 30 milligrams of penicillin.
• Two milliliters of this suspension was filled into various vials and the vials subjected to vacuum.
• the pressure in the vacuum chamber was reduced over a period of approximately one hour to approximately 10 millimeters of mercury and the vacuum maintained for approximately 24 hours.
• the vacuum was then released, the vials capped and assayed.
• the filled penicillin was crystalline, free of any trace of the suspending medium and of essentially the same color, potency and appearance as before filling.
• Example 12 Example 6 was repeated using crystalline potassium penicillin G instead of sodium penicillin. Substantially similar results were obtained.
• Example 13 -1300 ml. of a mixture of 2% parts of carbon tetrachloride and one part acetone were added to 39.0 grams of the ground cells of S. typhosa. The specific gravity of the liquid mixture without the cells was 1.35 and the cells remained in a stable suspension.
• This suspension of cells was filtered through a 200 mesh nylon filter and then filled in 2 ml. volumes in 30 ml. vials so that each vial contained 60 milligrams of the cells.
• the vials were covered with process stoppers and placed in a vacuum chamber for removal of the filling fluid mixture. This was done by applying 60110 mm. of pressure for 35 minutes. At this time the vacuum was increased to regular lyophilizing condition (100,41. pressure) and applied for 20 hours.
• the vials were then removed, stoppered under vacuum and sealed with roll-on enclosures. The material made by this process was found to retain its Vi antigen content when tested in both mice and rabbits.
• Example 14 The process of Example 13 was carried out using S. paratyphi instead of S. typhosa and the same results were obtained.
• Example 15 The process of Example 13 was carried out using S. schoztmulleri instead of S. typhasa and the same results were obtained.
• Example 16 The process of Example 13 was carried out using an equal part mixture of the cells of S. typhosa, S. paratyphi and S. schottmulleri, and the same result was obtained as they have approximately equal densities.
• Example 17 A liquid suspension mixture was made up of 20% chloroform and ethylene dichloride, having a specific gravity of 1.280. To this was added crystalline vitamin B12 so that each milliliter of the liquid contained 250 micrograms of the vitamin B12. This was measured out by placing 2 ml. in individual ampuls and the liquid was withdrawn by subjecting to a vacuum of about 10 mm. mercury for twenty-four hours.
• Example 18 A liquid suspension mixture was made up of chloroform and 10% ethylene dichloride, having a specific gravity of 1.454. To this was added ascorbic acid so that each milliliter of the liquid contained 500 mg. of the ascorbic acid. This was measured out by placing 2 ml. in individual ampuls and the liquid was withdrawn by subjecting to a vacuum of about 10 mm. mercury for twenty-four hours.
• Example 19 To ethylene dichloride having a specific gravity of 1.250 was added the sedative, sodium S-ethyl- 5-(l-methyl-1-butenyl) barbiturate, sold under the trade name Delvinal. Each milliliter of the mixture contained 60 mg. of the Delvinal. This was measured out in 2 ml. quantities into individual ampuls and the liquid withdrawn by subjecting to a vacuum of 10 mm. mercury for twenty-four hours.

Landscapes

• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Molecular Biology (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Engineering & Computer Science (AREA)
• Mechanical Engineering (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Priority Applications (3)

Applications Claiming Priority (1)

Publications (1)

Family

ID=23206281

Family Applications (1)

Country Status (3)

Cited By (3)

Citations (5)

• 0
  • BE BE523021D patent/BE523021A/xx unknown
• 1952
  • 1952-09-24 US US311299A patent/US2727665A/en not_active Expired - Lifetime
• 1953
  • 1953-09-19 FR FR1087535D patent/FR1087535A/fr not_active Expired

Patent Citations (5)

Also Published As

Similar Documents