US3646201A

US3646201A - Salicylate carbonate compounds

Info

Publication number: US3646201A
Application number: US846596A
Authority: US
Inventors: Andrew G Kallianos; James D Mold; Melvyn I Simpson
Original assignee: Liggett and Myers Inc
Current assignee: Liggett Group LLC
Priority date: 1969-07-31
Filing date: 1969-07-31
Publication date: 1972-02-29
Anticipated expiration: 1989-02-28
Also published as: GB1303141A

Abstract

THIS INVENTION RELATES TO NOVEL CARBONATE ANHYDRIDE ESTERS OF ACETYLSALICYLIC ACID HAVING THE GENERAL FORMULA;

1-(CH3-COO-),2-(R-OOC-OOC-)BENZENE
WHEREIN R IS A RADICAL SELECTED FROM THE GROUP CONSISTING OF BRANCHED AND STRAIGHT-CHAINED, SATURATED AND UNSATURATED, ALIPHATIC AND ALICYCLIC ALCOHOLS HAVING FROM 2 TO 30 CARBON ATOMS AND POLYHYDROXY COMPOUNDS AND MIXTURES THEREOF.

Description

United States Patent O 3,646,201 SALICYLATE CARBONATE COMPOUNDS Andrew G. Kallianos, James D. Mold, and Melvyn I. Simpson, Durham, NC, assignors to Liggett & Myers Incorporated, New York, N.Y. No Drawing. Filed July 31, 1969, Ser. No. 846,596 Int. Cl. AOln 9/24; A61k 27/00; A611 13/00 US. Cl. 424-230 8 Claims ABSTRACT OF THE DISCLOSURE This invention relates to novel carbonate anhydride esters of acetylsalicylic acid having the general formula:

wherein R is a radical selected from the group consisting of branched and straight-chained, saturated and unsaturated, aliphatic and alicyclic alcohols having from 2 to 30 carbon atoms and polyhydroxy compounds and mixtures thereof.

BACKGROUND Frequently it has been found desirable to prolong the action of a single dose of some drugs. In the case of aspirin formulations the ability to prolong activity at a more uniform dosage, while the patient is asleep, and the advantage of less frequent dosage at other times have been the primary reasons. In addition, there are other shortcomings inherent in frequent aspirin medication. Continuous high dosage of salicylates required for the treatment of rheumatoid arthritis and similar conditions results in gastro-intestinal irritation which may result in acute intestinal bleeding. There are numerous reports of massive gastrointestinal haemorrhage precipitated by aspirin, particularly in patients with peptic ulcer disease. Scott and coworkers (Scott, J. T., et al.: Studies of Gastrointestinal Bleeding Caused by Corticosteroids, salicylates and Other Analgesics, Quart. J. Med., 30 (1961) 167-188) have reported fecal blood loss in nearly 70% of patients taking repeated doses of aspirin, but in most instances the loss is small. More recently, aspirin has been described as being probably the most common cause of gastrointestinal tract bleeding in man (Quick, A. 1.: Gastrointestinal Bleeding and Aspirin, J.A.M.A., 208 (1969') 534).

While there is no argument about the irritation properties of aspirin, there has been some controversy on the mechanism leading to gastrointestinal bleeding. Whether it is injury of the gastric mucosa by high local concentrations of acetylsalicylic acid (Davenport, H. W.: Gastric Mucosal Injury by Fatty and Acetylsalicylic Acids, Gastroenterolog 46 (1964) 245-253; Menguy, R.: Gastric Mucosal Injury by Aspirin, Gastroenterology, 51 (1966') 430-432) or through systemic effects of the drug on hemostasis (Anonym: Aspirin and Gastrointestinal Bleeding, J.A.M.A., 207 (1969) 24302431), it is considered that both elfects coexist, although the extent to which each contributes is not known.

In view of the shortcomings of aspirin and the fact that it is consumed in considerable quantity, several attempts have been made over the years to overcome the irritation properties of this drug. The formation of the sodium salt of acetylsalicylic acid and the use of bufiering agents are two well known approaches. Neither has met with considerable success (Menguy, R.: Gastric Mucosal ice Injury by Aspirin. Gastroenterology, 51 (1966) 430-432). More recently, efforts have been directed toward the formation of so-called prodrugs of salicylic acid. Dittert and coworkers (Dittert, L. W., et 'al., Carbonate Ester Prodrugs of Salicylic Acid. J. Pharm. Sci., 51 01968) 828- 831) describe the synthesis of carbonate esters formed between the phenolic hydroxyl group of salicylic acid and ethyl, n-butyl, n-hexyl, and trichloroethyl alcohols. In addition to non-enzymatic hydrolysis data, these authors reported in vitro enzyme hydrolysis studies suggesting that free salicylate might be released at different rates following oral administration. Results of the average total salicylate plasma levels in dogs following oral administration of aspirin and the carbonate ester prodrugs of salicylic acid resulted in similar curves. All curves reached a peak at 2 hrs. and then decreased at about the same rate. Furthere pharmacological evaluation of the mixed carbonate ester of n-hexyl alcohol and salicylic acid in rats failed to demonstrate prolonged action of the prodrug (Misher, A., et al.: Pharmacology of Hexylcarbonate of Salicylic Acid. J. Pharm. Sci., 57 (1968) 1128-1131). The tests did show that the acute toxicity of the prodrug was less than that of aspirin, and its gastric irritation potential was markedly lower.

It should be appreciated that aspirin is a very complex drug in its action and is believed to have three principal forms of action (OReagan, T.: Prolonged Release Aspirin. Drug and Cosmetic Indust., 98 (1966) 35-36, 164); an analgesic one, which appears to be primarily related to blood or tissue acetylsalicylic acid, since other salicylates are not as eifecti ve on an equivalent weight basis; an antiinflammatory activity, which appears to be related more to the total salicylate blood levels; and an antipyretic activity requiring some of the acetylated derivative as well as total salicylate in the blood. (see also: M. J. H. Smith and Paul K. Smith: The salicylates-A Critical Bibliographic Review, John-Wiley and Sons, Inc., New York, 1966). Obviously then, if the acetyl derivative is necessary for effective pharmacological activity, preparations incorporating the non-acetylated salicylic acid would not be suitable substitutes.

THE INVENTION This invention relates to carbonate anhydride esters of acetylsalicylic acid and more particularly to pharmaceutical preparations of these compounds which permit sustained release of acetylsalicylic acid in the body.

The carbonate anhydride esters of this invention have the formula:

wherein R is a radical selected from the group consisting of branched and straight-chained, saturated and unsaturated, aliphatic and 'alicyclic alcohols having from 2 to 30 carbon atoms including polyhydroxy compounds.

Among the aliphatic alcohols which may be utilized to form the esters of this invention are ethyl, hexyl and cetyl alcohols as well as higher molecular weight alcohols, branched chain, or unsaturated alcohols such as oleyl alcohol. Also alicyclic alcohols such as menthol, cholesterol and the like may be employed. Among the polyhydroxy compounds which may be utilized are compounds such as diisopropylidene glucose and isopropylidene glycerol.

The mixed carbonate anhydride esters of acetylsalicylic acid are generally prepared by reacting acetylsalicylic acid dissolved in a solvent such as acetone and a cooled solution of the chloroformate of the hydroxy compound. The reaction preferably involves the use of a catalyst such as pyridine, triethylamine, etc. The reaction of the acetylsalicylic acid with the chloroformate of the hydroxy compound generally takes place by first dissolving the chloroformate in a solvent such as ethyl ether. The chloroformate is then added to a cooled flask containing a catalyst and solvent. The flask is generally maintained at a temperature of about l to +5 C. preferably at 0' C. and the chloroformate is added over a period of about 50 to 60 minutes. A solution of the acetylsalicylic acid in acetone is then slowly added over a period of 30 to 35 minutes while the temperature of the reaction is maintained at about 0 C. The mixture is then stirred for about to 60 minutes and the solid residue is removed from the reaction mixture which is then worked up by conventional techniques. Alternatively the reaction may be run by addition of a solution of the chloroformate in tetrahydrofuran to a solution of triethylammonium acetylsalicylate, prepared in situ, at 40 to -l0 C., preferably at C.

Generally the preparation of the chloroformate takes place at reduced temperatures and involves a reaction between the appropriate alcohol in a solvent such as tetrahydrofuran. The alcohol is slowly added to phosgene over a period of from about 1 to 3 hours and upon completion of the addition the reaction mixture is allowed to reach room temperature where it is agitated over a period of 8 to 24 hours (generally overnight is satisfactory) until the reaction is complete.

The carbonate anhydride esters of this invention have been found to be relatively stable in acidic pH media but will decompose at a rate which can be controlled by adjustment of the pH. Thus, by proper selection of the hydroxyl compound it has been found that carbonate anhydride esters may be maintained in a relatively stable condition to the acidic pH found in the stomach.

Studies in the in vitro sustained release of acetylsalicylic acid by some of these preparations at various pH levels have shown a definite degree of slow decomposition at low pH levels with notable increases in the rate of decomposition as the pH level increases. It has been found that the nature of the product, its solubility in various solvents, its partition between aqueous and lipophilic solvents, as well as its stability in acidic media and slow decomposition at pH levels approaching physiologically neutral values are influenced by the nature of the R group in the above formula. Enzymes present in the gastrointestinal tract or in the blood may also participate in effecting hydrolysis of these compounds. In this case as well, the nature of the R group would likely play a role on the rate of hydrolysis. By proper selection of the size and shape of this group there is permitted considerable flexibility in preparing the most suitable compound for maximum pharmacological benefit.

The following examples illustrate the preparation of the compounds of this invention and their utilization. These examples are for illustrative purposes only and the invention is not intended to be limited thereby, but only by the appended claims.

EXAMPLE 1 Acetylsalicyloyl cetyl carbonate (a) Cetyl chloroformate.-In a 500 milliliter, 3-neck round-bottom flask fitted with a magnetic stirrer, Dry-Ice condenser, dropping funnel, and cooling bath, was placed approximately 25 g. (0.25 mole) of phosgene at a bath temperature of --10 to -20 C. A solution of g. (0.124 mole) of cetyl alcohol in 120' milliliters of tetrahydrofuran was added with stirring at 0 to -10 C.

over a period of 1.5 hours. The reaction mixture was then allowed to reach room temperature and to stir overnight.

The tetrahydrofuran, hydrgoen chloride and excess phosgene were removed on a rotary evaporator leaving 38.3 g. of a yellow oil. The infrared spectrum showed peaks at 5.64 and 8.72 microns, characteristic for a chloroformate. Mass spectrum: parent peaks at 304 and 306 (ratio 3:1, in agreement with the natural distribution of chlorine isotopes C1 and C1 M.W. 304.5). The product crystallized when stored in the refrigerator.

(b) Acetylsalicyloyl cetyl carbonate.-A 500 milliliter, 3-neck round-bottom flask, equipped with a stirrer, condenser, dropping funnel, and ice-bath, was charged with 1.02 g. (0.013 mole) of pyridine and 50- milliliters of ethyl ether. After cooling the flask to 0 C., a solution of 4.0 g. (0.013 mole) of cetyl chloroformate in 50 milliliters of ethyl ether was added with stirring over a period of one hour. To this suspension was added, at 0 C. over a period of 35 minutes, a solution of 2.36 g. (0.013 mole) of acetylsalicylic acid in 50 milliliters of acetone. The mixture was stirred an additional 10 minutes at 0 C., filtered to remove approximately 1.5 g. of pyridinium chloride, and concentrated on a rotary evaporator to give a semicrystalline residue, which solidified in the refrigerator overnight. Concentration of the solution followed by cooling in the refrigerator gave a solid material. This was dissolved in pentane, filtered, the solution was concentrated and placed in the refrigerator. The white solid obtained melted at 44-47 C.

The product, when measured in CCL, solution, had infrared absorption bands at 5.71 and 5.52 microns, characteristic of the benzoyl carbonyl and the carbonate carbonyl stretching vibrations observed for mixed carboxylic-carbonic anhydrides of this type (D. S. Tarbell and E. I. Longosz, J. Org. Chem, 24 (1959) 774), and exhibited bands at 5.64 and 8.41 microns characteristic of the acetate group present in acetylsalicylate.

Mass spectrum: m/e 404 (M+CO the parent peak was not observed because of the high temperature required to volatilize the sample), 163, 138, 121, 120, 43.

Nuclear magnetic resonance spectrum: 7:7.69 (singlet), 1.88-2.98 (multiplet), 5.70 (triplet), 8.0-9.5 (envelop).

Elemental analysis gave (percent): C, 69.47; H, 9.02. Calculated for C H O (percent): C, 69.61; H, 8.99.

EXAMPLE 2 Acetylsalicyloyl cholesteryl carbonate To a solution of 8.98 g. (0.02 mole) of cholesteryl chloroformate in milliliters of dry tetrahydrofuran was added, dropwise with stirring at 0 C., a solution of 2.02 g. (0.02 mole) of triethylamine in 15 milliliters of tetrahydrofuran. The mixture was stirred for an additional 1-0 minutes and a solution of 3.6 g. (0.02 mole) of acetylsalicylic acid was added with stirring while the reaction mixture was maintained at 0 C.

After addition was complete, the cooling bath was removed and stirring was continued for a half hours. The triethylamine hydrochloride was then removed by filtration and the solvent was removed on the rotary evaporator. Refrigerating at about 4 C. overnight gave a white solid which was recrystallized from ether; yield 10 g. (84%); melting point 98l00.5 C.

The product, when measured in G01 solution, had infrared absorption bands at 5.70 and 5.52 microns, characteristic of the benzoyl carbonyl and the carbonate carbonyl stretching vibrations observed for mixed carboxylic-carbonic anhydrides of this type, and exhibited bands at 5.60 and 8.4 microns characteristic of the acetate group present in acetylsalicylate.

Nuclear magnetic resonance spectrum: -r=7.39.75 (multiplet), l.832.98 (multiplet), 4.43-4.70 (multiplet), 5.0-5.7 (broad).

Elemental analysis gave (percent): C, 75.04; H, 9.13. Calculated for C H O (percent): C, 74.96; H, 8.84.

EXAMPLE 3 Acetylsalicyloyl methyl carbonate To a solution of 8.5 g. (0.039 mole) of methyl chloroformate in 70 milliliters of dry tetrahydrofuran was added, dropwise with stirring at C., a solution of 3.94 g. (0.039 mole) of triethylamine in 20 milliliters of tetrahydrofuran. To the cooled solution was added with stirring 7.0 g. (0.039 mole) of acetylsalicylic acid in 50 milliliters of tetrahydrofuran. After addition was complete, the cooling bath was removed and stirring was continued for one hour. The triethylamine hydrochloride was removed by filtration. The solvent was then evaporated under vacuum yielding 11.0 g. of a yellow oil. This was dissolved in ether and the solution placed in the refrigerator, whereupon after four days some crystals were found deposited in the container. The crystals were removed by filtration and under examination were proved to be acetylsalicylic anhydride. Evaporation of the solvent from the filtrate yielded 10.0 g. of a pale yellow oil.

The product, when measured in CCl solution, had infrared absorption bands at 5.71 and 5.56 microns, characteristic of the benzoyl carbonyl and the carbonate carbonyl stretching vibrations observed for mixed carboxylic-carbonic anhydrides of this type, and exhibited bands at 5.61 and 8.41 microns characteristic of the acetate group present in acetylsalicylate.

Nuclear magnetic resonance spectrum: 1-=1.94-3.07 (multiplet), 5.13-5.68 (broad), 7.75 (singlet), 7.9-9.6 (multiplet) EXAMPLE 4 Acetylsalicyloyl hexyl carbonate In a reaction flask was placed 7.0 g. (0.039 mole) of acetylsalicylic acid in 70 milliliters of dry tetrahydrofuran and 3.94 g. (0.039 mole) of triethylamine. The flask and contents were cooled to 10 C. To the cold solution was added with stirring a solution of 6.4 g. of hexyl chloroformate in 20 milliliters of tetrahyd'rofuran. The reaction mixture was allowed to reach room temperature and the product was recovered in the same manner as set forth in Example 3. The product was a pale yellow oil.

The product, when measured in CCl, solution, had infrared absorption bands at 5.71 and 5.53 microns, characteristic of the benzoyl carbonyl and the carbonate carbonyl stretching vibrations observed for mixed carboxylic-carbonic anhydrides of this type, and exhibited bands at 5.62 and 8.43 microns characteristic of the acetate group present in acetylsalicylate.

Mass spectrum: m/e 308 (M+), 163, 138, 121, 120, 43.

Nuclear magnetic resonance spectrum: =7.73 (singlet), 1.93-3.06 (multiplet), 5.76 (triplet), 8.0-9.33 (multiplet).

EXAMPLE Acetylsalicyloyl ethyl carbonate A solution of tirethylammonium acetylsalicylate was prepared by addition of 5.05 g. (0.05 mole) of triethylamine to a cold solution of 9.0 g. (0.05 mole) of acetylsalicylic acid in 50 milliliters of tetrahydrofuran. To this solution, cooled to -l0 C., was added dropwise with stirring a solution of 5.43 g. (0.05 mole) of ethyl chloroformate in 20 milliliters of tetrahydrofuran. The reaction mixture was then allowed to reach room temperature and the product was recovered in the same manner as set forth in Example 3. The solvent was evaporated under vacuum yielding 12.1 g. of pale pink oil.

The product, when measured in CCl, solution, had infrared adsorption bands at 5.71 and 5.52 microns, characteristic of the benzoyl carbonyl and the carbonate carbonyl stretching vibrations observed for mixed carboxylic-carbonic anhydrides of this type, and exhibited bands at 5.63 and 8.42 microns characteristic of the acetate group present in acetylsalicylate.

Mass spectrum: m/e 252 (M+), 163, 138, 121, 120, 43.

Nuclear magnetic resonance spectrum: 'r=7.77 (singlet), 1.94-3.07 (multiplet), 5.13-5.68 (broad), 7.9-9.6 (multiplet).

Elemental analysis gave (percent): C, 57.03; H, 4.99. Calculated for C H O (percent): C, 57.14; H, 4.80.

EXAMPLE 6 Acetylsalicyloyl 1,2-isopropylideneglyceryl carbonate (a) 1,2 isopropylideneglycerol.1,2 isopropylideneglycerol was prepared according to the procedure of Hibbert and Morazain (H. Hibbert and J. G. Morazain, Can. J. Res., 2 (1930) 35); BR 8990/25 mm. The infrared spectrum of the compound, when measured in CCL, solution, showed peaks at 2.77, 2.86, 8.23, 9.38, 9.53, and 11.29 microns.

(b) 1,2-isopropylideneglyceryl chloroformate. Approximately 22 g. (0.67 mole) of 1,2-isopropylideneglycerol in milliliters of anhydrous tetrahydrofuran was added With stirring over a period of 1 hour to approximately 36 g. (0.36 mole) of phosgene in a 500-milliliter, 3-neck round-bottom flask equipped with a magnetic stirrer, Dry-Ice condenser and sodium hydroxide solution trap. The reaction mixture was maintained at a temperature of 10 to 20 during addition. After addition was complete, the solution was allowed to reach room temperature and to stir overnight. After concentration on a rotary evaporator, distillation at -72/12 mm. gave 25.9 g. (79% yield) of a colorless liquid which was found to discolor slowly in the freezer. The infrared spectrum of the product, measured in CCl showed peaks at 5.60, 8.65, and 14.55 microns.

Mass spectrum: m/e 181, 179 (ratio 3/1) M+, 101 85, 59, 43, 41.

(c) Acetylsalicyloyl 1,2-isopropylideneglyceryl carbonnate.-A 500-milliliter, 3-neck, round-bottom flask was fitted with stirrer, condenser, dropping funnel, and cooling bath. Approximately 5 g. (0.0278 mole) of acetylsalicylic acid was added followed by 50 milliliters anhydrous tetrahydrofuran. The solution was cooled to -5 and a solution of 2.82 g. (0.0279 mole) of triethylamine in 3 milliliters of tetrahydrofuran was added. The reaction solution was then cooled to -20 and to this was added a solution of 5.4 g. (0.0278 mole) of 1,2-isopropylideneglyceryl chloroformate in 20 milliliters of tetrahydrofuran with stirring over a period of 0.5 hour. The reaction mixture was allowed to reach room temperature and to stir for an additional 0.5 hour. The triethylamine hydrochloride was removed by filtration, and the filtrate was concentrated on a rotary evaporator to give 10 g. of a pale pink oil.

The product, when measured in CCL; solution, had infrared absorption bands at 5.76 and 5.52 microns, characeteristic of the benzoyl carbonyl and the carbonate carbonyl stretching vibrations observed for mixed carboxyliccarbonic anhydrides of this type, and exhibited bands at 5.64 and 8.40 microns characteristic of the acetate group present in acetylsalicylate.

Nuclear Magnetic Resonance spectrum: 7:1.80-3-01 (multiplet), 5.53-6.50 (multiplet), 7.72 (singlet), 8.66 (doublet).

Mass spectrum: m/e 338 (M+), 323, 163, 138, 121, 120.

Elemental analysis gave (percent): C,56.74; H, 5.51. Calculated for C H O (percent): C, 56.80; H, 5.36.

EXAMPLE 7 Acetylsalicyloyl oleyl carbonate (a) Oleyl chloroformate.0leyl chloroformate was prepared according to the procedure set forth in Example 6 for the synthesis of 1,2-isopropylideneglyceryl chloroformate. Approximately 20 g. (0.0746 mole) of oleyl alcohol in 65 milliliters of anhydrous tetrahydrofuran was added to approximately g. (0.15 mole) of phosgene at 10 to After workup the reaction mixture yielded g. of a yellow oil (quantitative yield). The infrared spectrum of the product, measured in CCl showed peaks at 3.31, 5.60, 8.66, and 14.49 microns.

Mass spectrum: m/e 330, 332 (ratio 3/1) M+ (molecular weight, 330.5).

(b) Acetylsalicyloyl oleyl carbonate.-The title compound was prepared according to the procedure set forth in Example 6 above for the synthesis of acetylsalicyloyl 1,2-isopropylideneglyceryl carbonate. Approximately 5 g. (0.028 mole) of acetylsalicylic acid in milliliters of anhydrous tetrahydrofuran is mixed with 2.82 g. (0.028 mole) of triethylamine in 3 milliliters of tetrahydrofuran. To this mixture, cooled at 20 to 30, is added a solution of 9.2 g. (0.028 mole) of oleyl chloroformate in 30 milliliters of tetrahydrofuran. After appropriate workup, 12.0 g. of a yellow oil was recovered.

The product, when measured in CCl solution, had infrared absorption bands at 5.76 and 5.53 microns, characteristic of the benzoyl carbonyl and the carbonate carbonyl stretching vibrations observed for mixed carboxyliccarbonic anhydrides of this type, and exhibited bands at 5.61 and 8.42 microns characteristic of the acetate group present in acetylsalicylate and at 3.27 microns, characteristic stretching vibrations of the vinyl protons.

Nuclear magnetic resonance spectrum: =1.91-3.03 (multiplet), 4.73 (olefinic triplet), 5.75 (triplet), 7.72 (singlet), 7.81-9.35 (envelope).

Mass spectrum: m/e 474 (M+), 430 (M+CO 250, 163, 138, 121, 120.

Elemental analysis gave (percent): C, 70.87; H, 8.92. Calculated for C H O (percent): C, 70.85; H, 8.94.

Studies were undertaken to determine the physicalchemical properties of some of the preparations of this invention. Dittert et al. (Dittert, L. W. et al: Carbonate Ester Prodrugs of Salicylic Acid, J. Pharm. Sci., 57 (1968) 828-831) reporting on their studies of prodru gs have indicated that the relative availability of such compounds following ingestion may be suggested by their partition coeflicients between aqueous and lipophilic solvents and by their in vitro rates of hydrolysis under physiological pH conditions.

The partition coelficients between 0.1 N hydrochloric acid and cyclohexane were determined for several of the compounds prepared by the procedures described in this application. These are shown in Table I below. In this table are shown also the t (time required for one-half of the reaction material to hydrolyze) for the non-enzymatic hydrolysis of the carbonate anhydride esters at two pH levels.

The 13,, of the in vitro hydrolysis of the carbonate anhydride esters at 38 in pH 3 and pH 8 phosphate buffers were determined by direct UV analysis. Samples of approximately 5 mg. of the compounds were dissolved in milliliters water containing 10 milliliters dioxane (dioxane was used to facilitate solubility of the materials). Aliquots of 20 milliliters of this solution were mixed with 5 milliliters of 0.1 M phosphate buffer of either pH 3 or pH 8, and shaken at 38. The progress of hydrolysis was followed by determination of the UV spectrum and measuring the absorbance at about 240 mp. of 2-milliliter aliquots of the reaction mixture, where a decrease in absorbance reflected disappearance of the carbonate anhydride ester. Readings were taken at frequent intervals of time for the first 8 hours, and a final reading was taken at 24 hours, when the reaction was considered to be apparently complete.

The time required for one-half of the reaction material to be hydrolyzed, tl/z, was determined from plots of log (A-Aoo) versus time (A==absorbance at time I; Aoo=absorbance at 24 hours, when the reaction is apparently complete).

TABLE I.-PARTITION COEFFICIENTS AND HYDROLYSIS RATES OF ACETYLSALICYLOYL ALKYL OARBONATES Time required for one-half Acetone produced by hydrolysis of the 1,2-isopropylidene group interfered with this determination.

It is clearly seen that the partition coefficient and the rate of hydrolysis of the compounds of this invention are influenced markedly by the size and complexity of the R group.

Biological evaluation of some of these carbonate anhydride esters was undertaken to determine their pharmacological properties. Male, Spraque-Dawley (Charles River-CD) strain rats weighing 101-118 grams W I: 111.8 grams) were administered a single oral dosage of each compound at levels of or 300 mg. per kilogram of body weight based on acetylsalicylic acid content.

All rats were assigned numbers and randomized as to the dosage each would receive. Animals were housed individually in wire cages and fasted overnight with only water available prior to oral dosage. Control samples of plasma were collected from each animal 24 hours prior to dosage. During the test period a minimum of 0.5 milliliter of pooled plasma was collected from the orbital sinus at 0, 2 (1, 2, 3), 4, and 8 hours, and about 2 milliliters from the inferior vena cava at sacrifice 12 hours after dosage. About equal quantities of blood were pooled from each of the 3-6 rats comprising a test group.

Free salicylic acid in the plasma samples was determined by a modification of published methods (Routh, J. L, et al.: Method for the Determination of Acetylsalicylic Acid in the Blood, Clinical Chemistry, 13 (1967) 734-743; Williams, L. A., Linn, R. A., and Zak, B.: Differential Ultraviolet Spectrophotometric Determination of Serum Salicylates, J. Lab and Clinical Medicine, 53 (1969) 156-162). Briefly, this entailed acidification of the collected plasma with a small amount of concentrated hydrochloric acid, extraction with chloroform, back extraction of the chloroform phase with sodium bicarbonate solution and UV spectrophotometric analysis of the aqueous phase.

Results of the free salicylic acid levels in plasma samples pooled from rats treated with the compounds of this invention or aspirin are shown in Table II below.

TABLE II.FREE SALICYLIC ACID LEVELS IN RAT PLASMA ASA oral Hours after dosage dosage, M body N0. rats Compound mgJkg. wt. gms sampled 0 1, 2, 3 4 B 1 2 Aspirin 150 110. 2 6 0 21.6 17. 2 13. 8 6. 6 Ethyl acetylsalicyloyl carbonate 150 112. 2 6 0 15.8 11. 7 11. 6 8. 3 Hexyl acetylsalicyloyl carbonate 150 113.6 5 0 13. 7 l7. 8 14. 5 9. 3 Cetyl ecetylsalicyloyl carbonate 150 112. 2 5 0 12. 5 12. 3 9. 3 6. 7 Oholesteryi acetylsallcyloyl carbonate- 150 111.2 4 0 1. 8 0.9 1. 3 1.0 Aspirin 300 112. 0 5 0 34. 9 33. 0 26,0 15. 7 Cetyl aeetylsalicyloyl carbonate 300 110.7 3 0. 3 19.5 19. 3 17. 16.

1 Each value represents the free salicylic acid (SA) in one pooled plasma sample from number 01 rats indicated (3-6). Ind ependent values are corrected for apparent SA levels in blanks (Time 0) and for recovery of control SA levels. Values in mg. percent can be converted to ug./ml. by multiplying by 10.

2 Samples from one or two rats at each time of 1, 2, and 3 hours pooled prior to analysis.

The free salicylic acid recovery of the method was determined as follows: a weighed amount of salicylic acid is added to a volume of rat plasma. This plasma is then submitted to the analytical procedure and the recovery of salicylic acid determined. A control recovery experiment, which serves as a check on the method, was included with each set of plasma samples resulting from the treatment of rats with each dose of the compounds tested. The values of the experimental results shown in Table II are corrected for apparent salicylic acid levels in blanks (time and for recovery which averaged 97.4% (standard deviation, 3.5).

The data on plasma levels of salicylate after administration of the test compounds indicate that the size of alkyl group markedly effects the magnitude and time course of release of salicylic acid in the blood stream of the rat. This may be seen more clearly from the data in Table III, where comparison of plasma salicylic acid levels at various times after dosage with the compounds of this invention or aspirin is made.

of this invention. Male, Sprague-DaWley (Charles River- CD) strain rats weighing about 93.3 grams (88.5-97.5) were administered a single oral dosage of each compound at a level of 300 mg. per kilogram of body weight based on acetylsalicylic acid content.

Forty-five rats were assigned numbers and randomized as to the sampling times and dosage each group of nine rats would receive. A sample of control plasma from each of the rats was collected 72 hours prior to closing. Animals were housed individually in wire cages and fasted overnight with only water available prior to oral dosage. During the test period a minimum of 0.5 milliliters of pooled plasma was collected from the orbital sinus at 0, 2 (1, 2, 3), 4, 8, 12, 16 and 20 hours, and about 2 milliliters from the inferior vena cava at sacrifice 12 or 24 hours after dosage. About equal quantities of blood were pooled from each of the 8-9 rats comprising a test group. Blood was drawn from each rat five times during the test period and the blood sampling site (orbital sinus) was clotted immediately. One animal died approximately TABLE TIL-COMPARISON OF PLASMA SALICYLIC ACID (SA) LEVELS AT VARIOUS TIMES AFTER DOSAGE WITH ACETYLSALICYLOYL ALKYL CARBONATES OR ASPIRIN Test compound SA level/ Maximum SA level persisting (percent of aspirin SA level hours ASA oral SA level max. level) hours after dosage after dosage dosage, detected, Compound mg./kg. mg. percent 1,2,3 2 4 8 12 2 4 8 12 Aspirin 150 21.6 100 80 64 31 Ethyl acetylsalicyloyl carbonate 150 15. 8 100 74 73 52 0.73 0.68 0.85 1. 26 Hexyl acetylsalicyloyl carbonate, 150 17. 8 77 100 82 52 0.63 1. 04 1.05 1. 41 Cetyl acetylsalicyloyl carbonate. 150 12. 5 100 98 74 54 0.58 0. 72 0.67 1.02 Cholesteryl acetylsalicyloyl carbonate. 150 1. 8 100 72 56 0.08 0.05 0.09 0.15 Aspirin 300 34. 9 100 95 74 45 Cetyl acetylsalicyloyl carbonate 300 19. 5 100 99 92 84 0.56 0.58 0. 69 1, 04

l When the maximum level measured is the average of 1, 2, and 3 hour blood samples, it is likely to be lower than the actual maximum reached.

3 Samples from one or two rats at each time of 1, 2, and 3 hours pooled prior to analysis.

In evaluating the results of these tests, we consider that the ability of a preparation to reach and maintain a relatively high level of salicylate in the plasma of the animals over an extended period of time is an indication of its potential as a sustained release preparation. The results clearly show that the compounds of this invention can serve as a source of salicylate in the animal and more importantly that they provide a more constant level of medication over longer periods of time than free aspirin.

one hour after oral dosing, leaving eight rather than nine test animals in the group which was monitored for 24 hours after dosage with the cetyl acetylsalicyloyl carbonate.

Free salicylic acid in the plasma samples was determined by the differential ultraviolet spectrophotometric method described above. The results of these analyses are shown in Table IV below. The values are corrected for apparent salicylic acid levels in blanks (time 0) and for By comparison with the other materials tested, the 54) recovery of control salicylic acid levels.

TABLE IV.FREE SALICYLIC ACID LEVELS 1 IN PLASMA OF RATS DOSED WITH ASPIRIN AND ACETYLSALICYLOYL ALKYL CARBONATES Salicylic acid levels in mg. percent, hours after ASA oral dosagedosage, No. rats Compound mgJkg sampled 0 1, 2, 3 2 4 8 12 16 20 24 Aspirin 300 9 0 1 Acetylsalicyloyl ethyl carbonate. 300 9 0,0 Do 300 9 0,1 Acetylsalicyloyl cetyl carbonate. 3 300 9 0. 3 Do 3 300 8 0 0 1 Each value represents the tree salicylic acid (SA) in one pooled plasma sample from number of rats indicated (8-9). Independent values are corrected for apparent SA levels in blanks (Time 0) and for recovery of control SA levels. Values in mg. percent can be converted to ugJml. by multiplying by 10.

2 Samples from two or three rats at each time of 1, 2, and 3 hours hours pooled prior to analysis.

3 Actual dosage was determined to be about 10% lower (270 mg./kg.).

The results from the second study essentially confirmed our findings of the earlier study for the first 12 hours after dosing. In addition, data from this study show that both of the compounds tested, especially the ethyl acetylsalicyloyl carbonate, sustain a higher level of salicylate in the blood than free aspirin. This can be seen more clearly by comparison of plasma salicylic acid levels at various times after dosage with the compounds of this invention or aspirin when the results are presented as percent of maximum level, as shown in Table V.

12 volume was immersed in the mercury bath. The deflection was adjusted so that a calibration factor of 0.0739 ml./ cm. was obtained with range 50, and 0.0296 mL/cm. at

TABLE V.-COMPARISON OF PLASMA SALICYLIG ACID (SA) LEVELS AT VARIOUS TIMES AFTER DOSAGE WITH ACETYLSALICYLOYL ALKYL CARBONATES OR ASPIRIN Time max. Maximum SA level SA level persisting (percent of max. level) ASA oral SA level detected, hours after dosage dosage, detected, hours alter Compound rug/kg. mg. percent dosage l, 2, 3 4. 8 12 16 20 24 300 27.2 l-3 100 48.2 34.2 23.5 300 19. 9 1-3 100 93.0 91. 90.0 0 300 25.0 1-3 10 88.4 73.2 48.8 38.4 Acetylsalicyloyl cetyl carbonate 3 300 24.6 1-3 100 84.6 80. 5 68. 3 Do 300 24.6 1-3 100 77.2 58.1 46.8 36.2

1 When the maximum level measured is the average of 1, 2, and 3 hour blood samples, it is likely to be lower than the actual maximum reached.

3 Actual dosage was determined to be about 10% lower (270 mg.[kg.).

A major shortcoming of free aspirin medication is that free aspirin produces a very high peak in the concentration of plasma salicylate in about 2 hours after administration and a rapid fall thereafter. The compounds of this invention, on the other hand, reduce to a minimum this overdosing peak and sustain a slower decline in plasma salicylate with time. Thus by allowing only a limited amount of free salicylate to be available to the subject at any one time, the preparation of this invention would allow good control of a sustained dosage level. This would have the added advantage in that it would eliminate high initial concentrations of free salicylate at any one locale and thereby effect a reduction in irritations of the mucosa with a concomitant reduction in gastrointestinal bleeding.

The therapeutic efficacy of the preparations of this invention was demonstrated by their ability to reduce yeastrange 20 on the Sanborn Polygraph. After the normal foot volume of each rat had been determined, 0.1 ml. of Brewers yeast (20% in sterile H O) was injected into the foot pad. Exactly one hour later the volumeof the now swollen foot was again determined and the predetermined dosage of test compound was administered orally. Subsequently, the foot volume of each animal was monitored at 1, 2, 3, 4, 6, 8, 1'0, 12, 14, 16, 18, 20, 22 and 24 hours after treatment.

The efiectiveness of the various test compounds in reducing yeast-induced swelling in the foot of littermate rats is shown in Table VI. The results are presented as the mean percent change in rat paw volume at eight-hour time intervals after treatment. It is clearly evident that the two compounds of this invention tested appeared to be essentially comparable to free aspirin in this test system.

TABLE VI.MEAN PERCENTAGE CHANGE IN RAT PAW VOLUME Hours after treatment No. rats Group ASA Dosage studied 1-8 8-16 16-24 Untreated control 16 +17. 2 -6. 2 l3. 7 Procedural control- H20 (4.14 ml.) r 16 +11. 6 l0, 8 -l6 9 Positive control Aspirin mgJkg.) 16 2. 2 15. 5 18. 6

Cetyl aeetysalicyloyl carbonate (600 rug/kg.) a l6 0. 6 -17. 0 l0. 9 Test 11 r. Ethyl ecetylselicyloyl carbonate (600 mg.[kg.) r. 16 6. 4 17. 8 -20. 9

*+indicates increases in paw volume after treatment with test compound; indicates decrease in paw volume after treatment with test compound.

induced foot edema in young male littermate rats of comparable body weight. Male SpragueDaWley (Charles River-CD) strain littermate rats weighing approximately 84.2 grams (70.096.5 grams) were administered each salicylate compound orally. Each compound was administered in water at a concentration permitting a dosage of 600 mg. (based on acetylsalicyclic acid content) per kilogram body weight to be given in about 3.5 milliliters per animal, assuming an 80 gram rat.

Eighty rats from sixteen litters, each containing 5 male animals, were used in these studies. One member of each litter was assigned at random to each test compound, and the order of treatment within each litter was also randomized. All animals were housed individually in metal cages within air conditioned quarters and were fasted overnight prior to testing. Water was available at all times.

Foot volumes were determined and recorded as follows: a rats foot was immersed in a 10 ml. mercury bath to a previously inscribed line on the ankle. The bath was connected to a pressure sensitive transducer which in turn was connected to a recording galvanometer. The displacement of the foot was translated into a deflection from the base line tracing. At the beginning of the run and at the beginning of each reading period, a standard of known The sustained release agents of this invention may be used alone or mixed with other conventional binders and fillers, such as starch, gelatin and sugars. Preferably the active ingredient will be formed into waters or tablets in unit dosage forms.

It will be understood that it is intended to cover all changes and modifications of the examples of the invention herein chosen for the purpose of illustration which do not constitute departure from the spirit and scope of the invention.

What is claimed is:

1. Pharmaceutical compositions comprising a pharmaceutical carrier and as the active ingredient thereof an effective oral dosage amount, for sustaining an effective dosage level in plasma salicylate, of carbonate anhydride esters of acetylsalicylic acid having the general formula:

13 wherein R is a radical selected from the group consisting of branched and straight-chained, saturated and unsaturated, aliphatic and alicyclic alcohols and polyhydroxy compounds having from 2 to 30 carbon atoms and mixtures thereof.

2. A sustained release pharmaceutical preparation in unit dosage form according to claim 1, comprising acetylsalicyloyl cetyl carbonate as the active ingredient thereof.

3. A sustained release pharmaceutical preparation in unit dosage form according to claim 1, comprising acetylsalicyloyl cholesteryl carbonate as the active ingredient thereof.

4. A sustained release pharmaceutical preparation in unit dosage form according to claim 1, comprising acetylsalicyloyl menthyl carbonate as the active ingredient thereof.

5. A sustained release pharmaceutical preparation in unit dosage form according to claim 1, comprising acetylsalicyloyl hexyl carbonate as the active ingredient thereof.

6. A sustained release pharmaceutical preparation in unit dosage form according to claim 1, comprising acetylsalicyloyl ethyl carbonate as the active ingredient thereof.

7. A sustained release pharmaceutical preparation in unit dosage form according to claim 1, comprising acetylsalicyloyl 1,2-isopropylideneglyceryl carbonate as the active ingredient thereof.

8. A sustained release pharmaceutical preparation in unit dosage form according to claim 1, comprising acetylsalicyloyl oleyl carbonate as the active ingredient thereof.

References Cited UNITED STATES PATENTS OTHER REFERENCES Swintosky et al.: J. Pharm. Sci. 992 (1966), Carbonate Prodrugs in Formulation and Therapeutics.

Dittert et al.: J. Pharm. Sci. 57(5), 828-831, May 1968, Carbonate Ester Prodrugs of Salicylic Acid.

Misher et al.: J. Pharm. Sci. 57(7), 1128-1131, July 1968, Pharmacology of the Hexylcarbonate of Salicylic Acid.

SHEP K. ROSE, Primary Examiner US. Cl. X.R. 260-463