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

Definitions

• the present invention relates to solutions of chloramphenicol in aqueous liquids, and to a process of preparing such solutions.
• the antibiotic chloramphenicol is readily absorbed by the body on oral administration. For this reason it is usually given per os, for instance, in the form of gelatine capsules or dragees. In some instances, however, oral administration cannot be used or is ineffective because the patient is not able to swallow the drug, respectively, to absorb it. It is also frequently necessary for medical reasons to avoid the passage of the drug through the digestive tract, for instance, during or before an operation. In some cases it is desirable to achieve a rapid increase of the antibiotic level in the blood. Thus, there is a considerable demand for injectable solution of this valuable antibiotic. However, the preparation of such solutions meets with great difficulties.
• Chloramphen-icol is soluble in water at room temperature only up to 0.4%. This concentration is by far insufiicient for administration by intramuscular or intravenous injection. It has been found that non-aqeous solvents for chloramphenicol, which have been used for the preparation of more concentrated solutions, cause severe damage to the tissue in the form of painful swellings and frequently of serious necroses, even if the solvent as such is physiologically inert. This disadvantage is especially encountered on intramuscular injection. The same applies to aqueous mixtures with said solvents because the solvent content required to provide stable solutions by far exceeds the limit of compatibility.
• esters for instance, the preferably investigated 3-succinate, are water-soluble in the form of their neutral salts, such as their sodium salts. Their solutions may be injected almost without causing harmful reactions. However, the biological efiiciency test shows that, for instance, the succinate produces a much lower blood level than the same amount of chloramphenicol. This is probably due to the poor hydrolysis of the succinate within the body to produce the effective chloramphenicol.
• Another object of the present invention is to provide a simple and effective process of producing such highly concentrated chloramphenicol solutions.
• a further object of the present invention is to provide phenicol is increased considerably by the addition of lower chloramphenicol esters. Solutions of chloramphenicol containing such esters can be diluted with water without precipitation of chloramphenicol.
• the application of this principle permits parenteral administration of chloramphenicol, preferably intramuscular administration thereof, which, in .many' cases, is highly desirable, in an amount sufficient to produce the desired antibiotic eifects without causing damage to the body, such as necrotic changes of the tissue.
• esters indica-ta esters having a maximum of 10 carbon atoms Within the ester group and will be used hereinafter and in the claims annexed hereto. With higher esters a significant decrease in antibiotic efiiciency is observed.
• Suitable esters are not only the mono-esters of chloramphenicol but also the di-esters and mixtures thereof.
• the esters may be esters of monoor polyvalent organic acids and their substitution products as well as of inorganic acids, such as nitric acid, hydrochloric acid, phosphoric acid, and the like.
• Especially effective esters are the following esters of organic acids:
• esters of lower aliphatic monoor'polycarboxylic acids such as the following esters:
• esters of esterified and etherified hydroxy lower fatty acids such as the following esters:
• solubility increasing and stabilizing effect of such esters is apparently not principally connected with their, own solubility in wateror, respectively, with the solubility of their salts in water; most of them are, in fact, only difliculty soluble therein.
• solvents'must be inert to chloramphenicol and its esters.
• Polyethylene glycol ethers such as diethylene glycol dimethyl ether
• N,N-di-(lower alkyl) lower alkanoic acid amides such as dimethyl formamide, dimethyl acetamide, diethyl formamide, diethyl acetamide;
• solubilizing or, respectively, stabilizing ester as such.
• the ester may also be formed-and this is the preferred method in some cases-when preparing the chloramphenicol solution, whereby, of course, an excess of chloramphenicol is used.
• the corresponding acid anhydride is added to the mixture of solvent and chloramphenicol.
• esters of acids which contain a salt-forming group, it is the preferred procedure to form the salt by adding an equivalent amount of an alkali hydroxide or another basic substance, for instance, of a physiologically inert amine.
• solubilizing agent to cause further stabilization of the resulting solution, such as urea or its substitution products, or urethanes.
• solubilizing aids alone do not produce any substantial increase in solubility of chloramphenicol in aqueous liquids.
• the injectable liquids according to the present invention are quite stable. However, due to the sensitivity of most esters against hydrolysis, it is advisable to first prepare a solution containing the chloramphenicol and the ester and, if necessary, the solubilizing aid in an anhydrous organic solvent of the above mentioned type.
• This solution which can be stored for an unlimited period of time, represents the stock solution. It is diluted with water shortly before its use. The physician may prepare the final dilution. Further handling of the injectable solutions according to the present invention, for instance, adjustment of its pH-value, sterilization, and the like is effected with the usual care.
• Example 1 A suspension containing 4 g. of chloramphenicol in a solution of 5.5 g. of chloramphenicol-Ownccinate in the form of its sodium salt in 100 cc. of water is caused to dissolve by heating for a short period of time. The resulting solution remains clear after cooling whereas a solution of 0.6 g. of chloramphenicol in 100 cc. of warm water shows immediate precipitation of crystals when cooled.
• Example 2 When a solution containing 1.0 g. of chloramphenicol in 2.0 cc. of dimethyl sulfoxide is diluted with cc. of water, chloramphenicol precipitates immediately. However, if 1.4 g. of the sodium salt of chloramphenicol-O succinate are added to the starting solution, a clear solution results on the addition of the same amount of water. This solution does not precipitate even after several days.
• Example 3 A solution containing 1.89 g. of chloramphenicol, 2.0 g. of dimethyl urea, and 0.15 g. of chloramphencol-O methoxy ethoxy acetate in 2 cc. of dimethyl sulfoxide remains clear after dilution with water whereas, without the addition of the chloramphenicol ester, the chloramphenicol is precipitated by the addition of water.
• Example 4 500 mg. of chloramphenicol and 635 mg. of chloram- PhBIIlCOl-O -SUCClHQlfi are dissolved in a mixture of 0.4 cc. of dimethyl sulfoxide and 0.2 cc. of diethylene glycol dimethyl ether. Upon addition of 160 mg. of sodium carbonate and distilled water in an amount sufiicient to yield a volume of 4 cc., a clear solution containing 25% of chloramphenicol is obtained.
• Example 5 10 g. of chloramphenicol and 13.8 g. of the sodium salt of chloramphenicol-O -succinate are dissolved in 16 cc. of tetrahydrofurfuryl methyl ether. In order to obtain a 25% chloramphenicol solution, water is added to a volume of cc.
• Example 6 A solution containing 2.0 g. of chloramphenicol and 0.206 g. of succinic acid anhydride in 1.4 cc. of N,N- dimethyl methoxy acetamide is heated at 110 C. for 60 minutes. Upon adding 5.1 cc. of a 4.3% sodium carbonate solution, a clear solution is obtained with a total chloramphenicol content of 25
• Example 7 A solution of 2.0 g. of chloramphenicol in 1.6 cc. of diethylene glycol dimethyl ether sold under the trademark Diglyme is mixed with 0.3 g. of succinic acid anhydride. The resulting mixture is heated to 110 C. for minutes. By adding a solution of 350 mg. of sodium carbonate in 4.9 cc. of water thereto, a clear solution is obtained.
• Example 8 A solution of 2.0 g. of chloramphenicol in 0.9 cc. of diethylene glycol dimethyl ether and 0.5 cc. of dimethyl acetamide is mixed with 0.25 g. of maleic acid anhydride. The mixture is heated to C. for 60 minutes. By adding a solution of 300 mg. of sodium carbonate in 5.1 cc. of water, a clear solution is obtained.
• Example 9 0.5 g. of chloramphenicol and 0.69 g. of chloramphenicol-3-N,N-dimethy1 glycinate hydrochloride correspond ing to 0.5 g. of chloramphenicol, are dissolved in 1.0 cc. of dimethyl methoxy acetamide. The resulting solution is diluted with water to a volume of 4 cc. A clear solution with a total chloramphenicol content of 25% is obtained.
• chloramphenicol- 3-glycinate sulfate or chloramphenicol-3-betainate hydrochloride are used in place of chloramphenicol-LEN- dimethyl glycinate hydrochloride.
• esters of acids which contain a salt-forming group
• alkali hydroxides or carbonates can be used but also ammonia or organic amines, e.g. butyl amine, methoxy propyl amine etc;

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• Health & Medical Sciences (AREA)
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• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Citations (4)

• 1958
  • 1958-11-25 GB GB37986/58A patent/GB844431A/en not_active Expired
  • 1958-11-28 CH CH6672758A patent/CH400454A/de unknown
  • 1958-11-29 DK DK441258AA patent/DK90234C/da active
  • 1958-12-02 US US777602A patent/US3044936A/en not_active Expired - Lifetime
  • 1958-12-03 BE BE573551A patent/BE573551A/fr unknown

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