US 2493202 A
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Patented Jan. 3, 1950 UNITED STATES PATENT OFFICE V 2 ,493,2c2' v p u I rnoonss :oE---MAKiNo 1r iLUI-n oiL-BEns- WAX VEHIGLE1FOR THE-:PARENTERAL VADMINISTRATION F DRUGS Thomas .I. Macek, irvington; N. a ssig'norto Merck &-Co., Inc., Rahway, N. J., a corporation of New Jersey No Drawing Application June 7, 1946, Serial No. 675,312
1 Claim. (01. iar-'82) This invention relates to the preparation of a new pharmaceutical vehicle. More particularly, it is concerned with the parenteral admin; istration of certain pharmaceutical preparations, which preparations include in addition to the therapeutic substance, a mixture of materials which prolongs the duration of an efiective level of the therapeutic compound in theblood.
The primary method for administering many therapeutic, substances, such as penicillin,strep tomycin. and many of the hormonesa has been by parenteral injections. For this purposefaqueous, saline or glucose solutions of the therapeutic compound have been injected. Because of, the rapid rate of absorption of the therapeutic compound into the blood stream and the rapid rate of excretion from the body through the urine, it has frequently been necessary to repeat the injections at various intervals to maintain therapeutically-effective blood concentrations for sufficiently long periods of time I u u w I Attempts were therefore made to provide a vehicle for administration along with therapeutic substances which would decrease the rate of absorption of the therapeutic substance thus prolonging the duration of an effective level inthe blood and which would be of gninimum inconvenience to the patient. It has been-recently reported that a beeswax-peanut oil vehicle prolonged the activity of penicillin in the blood when parenterally administered.
These vehicles have the serious disadvantage of solidifying at normal injection temperatures. In order to obtain a fluid suspension, it is necessary to warm the mixture to approximately 70 C. or to break up the latticework of wax crystals by stirring the mixture mechanically or shaking vigorously. Even after shaking, numerous masses of aggregates, large particles and coarse crystals are present which render such a suspension unsuitable for use as a vehicle for many pharma ceutical preparations and difiicult to handle through a hypodermic needle. Such suspensions are not gelatinous in structure and the Wax particles settle out of the oil suspension on standing. A beeswax-peanut oil mixture containing penicillin must be heated to about 70 C. until it becomes fluid prior to injection. It is also necessary to use a preheated hypodermic needle and syringe in administering the preparation. During this heating thepenicillin tends to settle from the Warm beeswax-peanut oil mixture and, upon cooling, a. non-homogeneous preparation often results. Repeated heating and cooling also tends to affect the stability of the penicillin in such a preparation. 7
It is the primary object of this invention to provide a suspension of beeswax and peanut oil Whichis homogeneous and fluid at room tom,- perature, of a uniform, finely-divided particle size and which has a characteristic gelatinous structure from which thewax particles do not rapidly separate onstanding. i I .It is a further object of this invention to proyide a pharmaceutical vehicle which being fluid and. homogeneousacan be easily administered parenterally without. resorting to heating the vehicle and the hypodermic needle.
It ,is ,a still further object of my invention to provide suspensions of beeswax. and peanut oil havingthese characteristics without mlllingor technical processing requiring special equipment. Regarded incertain of its broader aspects the process in accordance with the present invention comprises heating a mixture of beeswax and peanut oil for from I to 4 hours at a temperature between about,150-180,C. and rapidly cooling the resulting mixture thereby. forming an improved pharmaceutical vehicle, said vehicle being anhydrous, of fine particle size and gelatinous at room temperature- Pharmaceutical vehicles prepared in accordance with my invention are useful as carriers for therapeutic substances such as penicillin, streptomycin and hormones.
In accordance with a preferred embodiment of my invention an improved pharmaceutical vehicle is prepared by heating a mixture of beeswax and peanut oil in the ratio of 4.8 gms. of beeswax to cc. of the mixture at a temperature from about to C. for from 1 to 4 hours. This mixture is rapidly cooled to room temperature with constant agitation. During the heating process some change occurs through which the physical characteristics of the suspension are altered. The cooled suspension is fluid, homogeneous in nature, of a fine particle size, free of aggregates, large particles and coarse crystals and has a characteristic gelatinous structure which suspensions made by the usual means do not possess. It is therefore superior 3 to these suspensions. It is likely that during the heating process certain fractions of beeswax are extracted by the hot peanut oil and on cooling do not crystallize with the unextracted wax but impart a gelatinous character to the suspension.
Although I have obtained best results with a mixture of beeswax and peanut oil in the ratio of 4.8 gms. of beeswax to 100 cc. of the mixture this ratio can be varied to about 5 gms. of beeswax in 100 cc. of the mixture.
When suspensions of penicillin in a beeswaxpeanut oil vehicle prepared in accordance with my invention is injected into humans, the beeswax-peanut oil vehicle delays penicillin absorption and maintains a level in the blood for six to seven hours. The patient suffers no local pain or irritation in the region where the beeswaxpeanut oil mixture has been injected and. in certain treatments only one injection is necessary.
The following examples are given by way of illustration.
Example 1 4.8 gm. of bleached beeswax are added to enough peanut oil to make 100 cc. and the mixture is warmed to about 70 C. When the beeswax has liquified, the mixture is stirred. The mixture contained in an Erlenmeyer flask is then heated at 165 C. for two hours. The flask is removed from the oven and the mixture is rapidly cooled and agitated by rotating the flask in a bath of water and ice. When cooled to room temperature, this mixture is a homogeneous, fluid, gelatinous suspension of beeswax in peanut oil and is free of aggregates, large particles and coarse crystals.
Example 2 of this vehicle is then triturated under sterile conditions with the required weight of sterile calcium penicillin, previously ground to pass through a 200 mesh sieve. The suspension of calcium penicillin in the oil and wax vehicle is then subdivided into sterilized ampul vials and stoppered. Because the beeswax-peanut oil vehicle was heated to a high temperature it is anhydrous and is more suitable for the preparation of stable penicillin suspensions.
Example 3 A mixture consisting of 4.8%, weight to volume, of bleached beeswax in refined peanut oil is melted by heating to C. While liquid it is filtered free of fibers, etc. through a warmed, coarse, sintered-glass filter. The clear filtrate is then heated for 2 hours at C. The mixture is rapidly cooled and agitated by rotating the container in a bath of water and ice. The cooled vehicle is a sterilized, fluid, homogeneous, gelatinous suspension of finely-divided particles of beeswax in peanut oil. The required quantity of this vehicle is then triturated under sterile conditions with the required Weight of sterile streptomycin hydrochloride, previously ground to pass through a 200 mesh sieve. The suspension of streptomycin hydrochloride in the oil and wax vehicle is then subdivided into sterilized ampul vials and stoppered.
Various changes and modifications may be made in my process, certain preferred embodiments of which are described herein, which changes and modifications would, nevertheless, be within the scope of my invention. It is my intention that such changes and modifications, to the extent that they are within the scope of the appended claim, shall be considered as part of my invention.
The process for producing an improved pharmaceutical vehicle for parenteral administration which comprises heating a mixture of 4.8 weight to volume of beeswax in peanut oil for from 1 to 4 hours at a temperature between 150 and C. and rapidly cooling the mixture with constant agitation thereby forming a vehicle consisting of a homogeneous suspension of finely divided particles of beeswax in peanut oil, said vehicle being fluid at room temperature.
THOMAS J. MACEK.
REFERENCES CITED The following references are of record in the file of this patent:
Penicillin, Its Practical Application, by
. Fleming (July 1946), page 52.