Trinaphthalene trisulfonic acid and mono naphthalene trisulfonic acid-dibenzene dicarboxylic acid salts of di(carbonylimino) and mono(thioureido) trisubstituted phenyl compounds useful as complement inhibitors.

DESCRIPTION OF THE INVENTION 
This invention is concerned with compounds of the formula: 
##STR1## 
wherein R.sub.1 is selected from the group consisting of 
##STR2## 
wherein R.sub.2 is selected from the group consisting of alkali metal; and 
the pharmaceutically acceptable salts thereof 
A preferred embodiment of the instant invention consists of these compounds 
wherein R.sub.1 is selected from the group consisting of 
##STR3## 
wherein R.sub.2 is as previously defined. 
The compounds of the present invention may be prepared by treating 
8,8'-[(5-amino-m-phenylene)bis(carbonylimino)]di-1,3,6-naphthalenetrisulfo 
nic acid hexaalkali metal salt with 
8-isothiocyanato-1,3,6-naphthalenetrisulfonic acid trialkali metal salt in 
water for 23 hours. The product is isolated as the nonaalkali metal salt 
from 80% aqueous ethanol. Additionally, 
5,5'-[5-amino-1,3-phenylenebis(carbonylimino)]diisophthalic acid 
tetraalkali metal salt is treated by stirring with 
8-isothiocyanato-1,3,6-naphthalenetrisulfonic acid trialkali metal salt in 
water for 18 hours. The product is isolated as the heptaalkali metal salt 
from 66% aqueous ethanol. 
The term "complement" refers to a complex group of proteins in body fluids 
that, working together with antibodies or other factors, play an important 
role as mediators of immune, allergic, immunochemical and/or 
immunopathological reactions. The reactions in which complement 
participates take place in blood serum or in other body fluids, and hence 
are considered to be humoral reactions. 
With regard to human blood, there are at present more than 11 proteins in 
the complement system. These complement proteins are designated by the 
letter C and by number: C1, C2, C3 and so on up to C9. The complement 
protein C1 is actually an assembly of subunits designated C1q, C1r and 
C1s. The numbers assigned to the complement proteins reflect the sequence 
in which they become active, with the exception of complement protein C4, 
which reacts after C1 and before C2. The numerical assignments for the 
proteins in the complement system were made before the reaction sequence 
was fully understood. A more detailed discussion of the complement system 
and its role in body processes can be found in, for example, Bull. World 
Health Org., 39, 935-938 (1968); Ann. Rev. Medicine, 19, 1-24 (1968); The 
John Hopkins Med. J., 128, 57-74 (1971); Harvey Lectures, 66, 75-104 
(1972); The New England Journal of Medicine, 287, 452-454; 489-495; 
545-549; 592-596; 642-646 (1972); Scientific American, 229, (No. 5), 54-66 
(1973); Federation Proceedings, 32, 134-137 (1973); Medical World News, 
October 11, 1974, pp. 53-58; 64-66; J. Allergy Clin. Immunol., 53, 298-302 
(1974); Cold Spring Harbor Conf. Cell Proliferation 2/Proteases Biol. 
Control/229-241 (1975); Annals of Internal Medicine, 84, 580-593 (1976); 
"Complement: Mechanisms and Functions," Prentice-Hall, Englewood Cliffs, 
N.J. (1976). 
The complement system can be considered to consist of three sub-systems: 
(1) a recognition unit (C1q) which enables it to combine with antibody 
molecules that have detected a foreign invader; (2) an activation unit 
(C1r, C1s, C2, C4, C3) which prepares a site on the neighboring membrane; 
and (3) and attack unit (C5, C6, C7, C8 and C9) which creates a "hole" in 
the membrane. The membrane attack unit is non-specific; it destroys 
invaders only because it is generated in their neighborhood. In order to 
minimize damage to the host's own cells, its activity must be limited in 
time. This limitation is accomplished partly by the spontaneous decay of 
activated complement and partly by interference by inhibitors and 
destructive enzymes. The control of complement, however, is not perfect, 
and there are times when damage is done to the host's cells. Immunity is 
therefore a double-edged sword. 
Activation of the complement system also accelerates blood clotting. This 
action comes about by way of the complement-mediated release of a clotting 
factor from platelets. The biologically active complement fragments and 
complexes can become involved in reactions that damage the host's cells, 
and these pathogenic reactions can result in the development of 
immune-complex diseases. For example, in some forms of nephritis, 
complement damages the basal membrane of the kidney, resulting in the 
escape of protein from the blood into the urine. The disease disseminated 
lupus erythematosus belongs in this category; its symptoms include 
nephritis, visceral lesions and skin eruptions. The treatment of 
diphtheria or tetanus with the injection of large amounts of antitoxin 
sometimes results in serum sickness, an immune-complex disease. Rheumatoid 
arthritis also involves immune complexes. Like disseminated lupus 
erythematosus, it is an autoimmune disease in which the disease symptoms 
are caused by pathological effects of the immune system in the host's 
tissues. In summary, the complement system has been shown to be involved 
with inflammation, coagulation, fibrinolysis, antibody-antigen reactions 
and other metabolic processes. 
In the presence of antibody-antigen complexes the complement proteins are 
involved in a series of reactions which may lead to irreversible membrane 
damage if they occur in the vicinity of biological membranes. Thus, while 
complement constitutes a part of the body's defense mechanism against 
infection it also results in inflammation and tissue damage in the 
immunopathological process. The nature of certain of the complement 
proteins, suggestions regarding the mode of complement binding to 
biological membranes and the manner in which complement effects membrane 
damage are discussed in Annual Review in Biochemistry, 38, 389 (1969). 
A variety of substances have been disclosed as inhibiting the complement 
system, i.e., as complement inhibitors. For example, the compounds 
3,3'-ureylenebis-[6-(2-amino-8-hydroxy-6-sulfo-1-naphthylazo)]benzenesulfo 
nic acid, tetrasodium salt (chlorazol fast pink), heparin and a sulphated 
dextran have been reported to have an anticomplementary effect, British 
Journal of Experimental Pathology, 33, 327-339 (1952). The compound 
8-(3-benzamido-4-methylbenzamido)naphthalene-1, 3,5-trisulfonic acid 
(Suramin) is described as a competitive inhibitor of the complement 
system, Clin. Exp. Immunol., 10, 127-138 (1972). German Pat. No. 2,254,893 
or South African Pat. No. 727,923 discloses certain 1-(diphenylmethyl)-4 
-(3-phenylallyl)piperazines useful as complement inhibitors. Other 
chemical compounds having complement inhibiting activity are disclosed in, 
for example, Journal of Medicinal Chemistry, 12, 415-419; 902-905; 
1049-1052; 1053-1056 (1969); Canadian Journal of Biochemistry, 47, 547-552 
(1969); The Journal of Immunology, 93, 629-640 (1964); The Journal of 
Immunology, 104, 279-288 (1970); The Journal of Immunology, 106, 241-245 
(1971); and The Journal of Immunology, 111, 1061-1066 (1973). 
It has been reported that the known complement inhibitors 
epsilon-aminocaproic acid, Suramin and tranexamic acid all have been used 
with success in the treatment of hereditary angioneurotic edema, a disease 
state resulting from an inherited deficiency or lack of function of the 
serum inhibitor of the activated first component of complement (C1 
inhibitor), The New England Journal of Medicine, 286, 808-812 (1972). It 
has also been reported that the drug, pentosan-poly-sulfoester, has an 
anticomplementary activity on human serum both in vitro and in vivo, as 
judged by the reduction in the total hemolytic complement activity; 
Pathologie Biologie, 25, 33-36 (1977). 
The compounds of the present invention may be administered internally, 
e.g., orally, intra-articularly or parenterally e.g., intra-articular, to 
a warm-blooded animal to inhibit complement in the body fluid of the 
animal, such inhibition being useful in the amelioration or prevention of 
those reactions dependent upon the function of complement, such as 
inflammatory process and cell membrane damage induced by antigen-antibody 
complexes. A range of doses may be employed depending on the mode of 
administration, the condition being treated and the particular compound 
being used. For example, for intravenous or subcutaneous use from about 5 
to about 50 mg/kg/day, or every 6 hours for more rapidly excreted salts, 
may be used. For intra-articular use for large joints such as the knee, 
from about 2 to about 20 mg/joint per week may be used, with 
proportionally smaller doses for smaller joints. The dosage range is to be 
adjusted to provide optimum therapeutic response in the warm-blooded 
animal being treated. In general, the amount of compound administered can 
vary over a wide range to provide from about 5 mg/kg to about 100 mg/kg of 
body weight of animal per day. The usual daily dosage for a 70 kg subject 
may vary from about 350 mg to about 3.5 g. Unit doses of the acid or salt 
can contain from about 0.5 mg to about 500 mg. 
While in general the sodium salts of the acids of the invention are 
suitable for parenteral use, other salts may also be prepared, such as 
those of primary amines, e.g., ethylamine; secondary amines, e.g., 
diethylamine or diethanol amine; tertiary amines, e.g., pyridine or 
triethylamine or 2-dimethylaminomethyl-dibenzofuran; aliphatic diamines, 
e.g., decamethylenediamine; and aromatic diamines, can be prepared. Some 
of these are soluble in water, others are soluble in saline solution, and 
still others are insoluble and can be used for purposes of preparing 
suspensions for injection. Furthermore as well as the sodium salt, those 
of the alkali metals, such as potassium and lithium; of ammonia; and of 
the alkaline earth metals, such as calcium or magnesium, may be employed. 
It will be apparent, therefore, that these salts embrace, in general 
derivatives of salt-forming cations. 
In therapeutic use, the compounds of this invention may be administered in 
the form of conventional pharmaceutical compositions. Such compositions 
may be formulated so as to be suitable for oral or parenteral 
administration. The active ingredient may be combined in admixture with a 
pharmaceutically acceptable carrier, which carrier may take a wide variety 
of forms depending on the form of preparation desired for administration, 
i.e., oral or parenteral. The compounds can be used in compositions such 
as tablets. Here, the principal active ingredient is mixed with 
conventional tabletting ingredients such as corn starch, lactose, sucrose, 
sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, 
gums, or similar materials as non-toxic pharmaceutically acceptable 
diluents or carriers. The tablets or pills of the novel compositions can 
be laminated or otherwise compounded to provide a dosage form affording 
the advantage of prolonged or delayed action or predetermined successive 
action of the enclosed medication. For example, the tablet or pill can 
comprise an inner dosage and an outer dosage component, the latter being 
in the form of an envelope over the former. The two components can be 
separated by an enteric layer which serves to resist disintegration in the 
stomach and permits the inner component to pass intact into the duodenum 
or to be delayed in release. A variety of materials can be used for such 
enteric layers or coatings, such materials including a number of polymeric 
acids or mixtures or polymeric acids with such materials as shellac, 
shellac and cetyl alcohol, cellulose acetate and the like. A particularly 
advantageous enteric coating comprises a styrene maleic acid copolymer 
together with known materials contributing to the enteric properties of 
the coating. The tablet or pill may be colored through the use of an 
appropriate non-toxic dye, so as to provide a pleasing appearance. 
The liquid forms in which the novel compositions of the present invention 
may be incorporated for administration include suitable flavored emulsions 
with edible oils, such as, cottonseed oil, sesame oil, coconut oil, peanut 
oil, and the like, as well as elixirs and similar pharmaceutical vehicles. 
Sterile suspensions or solutions can be prepared for parenteral use. 
Isotonic preparations containing suitable preservatives are also desirable 
for injection use. 
The term dosage form, as described herein, refers to physically discrete 
units suitable as unitary dosage for warm-blooded animal subjects, each 
unit containing a predetermined quantity of active component calculated to 
produce the desired therapeutic effect in association with the required 
pharmaceutical diluent, carrier or vehicle. The specification for the 
novel dosage forms of this invention are indicated by characteristics of 
the active component and the particular therapeutic effect to be achieved 
or the limitations inherent in the art of compounding such an active 
component for therapeutic use in warm-blooded animals as disclosed in this 
specification. Examples of suitable oral dosage forms in accord with this 
invention are tablets, capsules, pills, powder packets, granules, wafers, 
cachets, teaspoonfuls, dropperfuls, ampules, vials, segregated multiples 
of any of the foregoing and other forms as herein described. 
The complement inhibiting activity of the compounds of this invention has 
been demonstrated by one or more of the following identified tests: (i) 
Test, Code 026 (C1 inhibitor) -- This test measures the ability of 
activated human C1 to destroy fluid phase human C2 in the presence of C4 
and appropriate dilutions of the test compound. An active inhibitor 
protects C2 from C1 and C4; (ii) Test, Code 035 (C3-C9 inhibitor) -- This 
test determines the ability of the late components of human complement 
(C3-C9) to lyse EAC 142 in the presence of appropriate dilutions of the 
test compound. An active inhibitor protects EAC 142 from lysis by human 
C3-C9; (iii) Test, Code 036 (C-Shunt inhibitor) -- In this test human 
erythrocytes rendered fragile are lysed in autologous serum via the shunt 
pathway activated by cobra venom factor in the presence of appropriate 
dilutions of the test compound. Inhibition of the shunt pathway results in 
failure of lysis; (iv) Forssman Vasculitis Test -- Here, the well known 
complement dependent lesion, Forssman vasculitis, is produced in guinea 
pigs by intradermal injection of rabbit anti-Forssman antiserum. The 
lesion is measured in terms of diameter, edema and hemorrhage and the 
extent to which a combined index of these is inhibited by prior 
intraperitoneal injection of the test compound at 200 mg/kg is then 
reported, unless otherwise stated; (v) Forssman Shock Test -- Lethal shock 
is produced in guinea pigs by an i.v. injection of anti-Forssman antiserum 
and the harmonic mean death time of treated guinea pigs is compared with 
that of simultaneous controls; (vi) Complement Level Reduction Test -- In 
this test, the above dosed guinea pigs, or others, are bled for serum and 
the complement level is determined in undiluted serum by the capillary 
tube method of U.S. Pat. No. 3,876,376 and compared to undosed control 
guinea pigs; and (vii) Cap 50 Test -- Here, appropriate amounts of the 
test compound are added to a pool of guinea pig serum in vitro, after 
which the undiluted serum capillary tube assay referred to above is run. 
The concentration of compound inhibiting 50 % is reported. 
With reference to Table I, guinea pigs weighing about 300 g were dosed 
intravenously (i.v.) or intraperitoneally (i.p.) with 200 mg/kg of the 
test compound dissolved in saline and adjusted to pH 7-8. One hour after 
dosing, the guinea pigs were decapitated, blood was collected and the 
serum separated. The serum was tested for whole complement using the 
capillary tube assay. Percent inhibition was calculated by comparison with 
simultaneous controls. The results appear in Table I together with results 
of tests, code 026, 035, 036, Cap 50, % inhibition and Forssman shock. 
Table I shows that the compounds of the invention possess highly 
significant in vitro and in vivo, complement inhibiting activity in 
warm-blooded animals. 
TABLE I 
__________________________________________________________________________ 
Biological Activities 
In Vivo Activity (Guinea Pig) 
% Inhibition 
Cl C-Late 
Shunt Inhi- 
Intraperitoneal 
Intravenous 
026* 
035* bition 036* 
Time (min) 
Time (min) 
Compound Wells 
Wells 
Wells Cap 50* 
30 60 120 
2 30 120 
__________________________________________________________________________ 
8-3-[3,5-Bis(3,6,8-trisulfo-1-naph- 
+7** 
+1** +1** 78 -50 
-57 
-74 
-97 
-79 
-58 
thylcarbamoyl)phenyl]-2-thioureido- 
+6 +1 +3 
1,3,6-naphthalenetrisulfonic acid 
nonasodium salt 
5,5'-5-[2-Thio-3-(3,6,8-trisulfo- 
1-naphthyl)ureido]-1,3-phenylene- 
+5 N +1 
bis(carbonylimino) diisophthalic 
acid heptasodium salt 
__________________________________________________________________________ 
*Code designation for tests employed as referred herein. 
**Activity in wells a serial dilution assay. Higher well number indicates 
higher activity. The serial dilutions are two-fold. 
N=Negative

EXAMPLE 1 
8-{3-[3,5-Bis(3,6,8-trisulfo-1-naphthylcarbamoyl)phenyl] 
-2-thioureido}-1,3,6-naphthalenetrisulfonic acid nonasodium salt 
To a stirred solution of 32.0 g of 8-amino-1,3,6-naphthalenetrisulfonic 
acid trisodium salt in 350 ml of water plus 7.0 ml of concentrated 
hydrochloric acid, at room temperature, is added 10 g of thiophosgene. The 
mixture is stirred for 21/2 hours, and treated with activated charcoal and 
filtered through diatomaceous earth. The filtrate is neutralized with 46 
ml of 5N sodium hydroxide then is concentrated, cooled to room temperature 
and filtered. The product is washed with a small amount of ice-water, then 
acetone and ether to give 13.7 g of material. Further concentration of the 
filtrate yields another 13.8 of product. The product fractions (27.5 g) 
are combined and recrystallized from 40 ml of water. The product is 
collected, washed with ice-water, acetone and ether and dried by 
conventional means to give 11.2 g of 
8-isothiocyanato-1,3,6-naphthalenetrisulfonic acid trisodium salt. 
A mixture of 60.0 g of 5-nitroisophthalic acid, 300 ml of thionyl chloride 
and one ml of dimethylformamide is stirred at room temperature for 30 
minutes, then is refluxed for one hour. The resulting clear solution is 
allowed to stand 24 hours then is evaporated to a small volume in vacuo. 
The evaporation step is then repeated with toluene and the resulting 
liquid is diluted with 250 ml of hexane. The mixture is stirred and cooled 
until the resulting oil is solidified. The product is ground to a powder 
and is recrystallized twice from carbon tetrachloride to give 47.4 g of 
5-nitroisophthaloyl chloride. 
To a solution of 13.75 g of 8-amino-1,3,6-naphthalenetrisulfonic acid 
trisodium salt and 4.6 g of sodium acetate trihydrate in 100 ml of water 
in a 500 ml baffle flask is added 4.10 g of powdered 5-nitroisophthaloyl 
chloride. The mixture is stirred vigorously at room temperature for one 
hour then is filtered through diatomaceous earth. The filtrate is 
concentrated to 50 ml, then warmed, acidified with 0.5 ml of concentrated 
hydrochloric acid and diluted with 50 ml of hot ethanol. The product is 
crystallized on cooling with scratching and is collected by filtration, 
then washed with 25 ml of 55% aqueous ethanol and 60 ml of ethanol. 
Additional product is obtained from the filtrate in the same manner. The 
total product is dried by conventional means to give 13.8 g of 
8,8'-[(5-nitro-1,3-phenylene)bis(carbonylimino)]-di-1,3,6-naphthalenetrisu 
lfonic acid hexasodium salt. 
A mixture of 4.45 g of the preceding compound, 0.5 g of 10% palladium on 
carbon catalyst and 50 ml of water is hydrogenated in a Parr shaker at 
room temperature for one hour. The mixture is filtered through 
diatomaceous earth and the filtrate containing 
8,8'-[(5-amino-m-phenylene)bis(carbonylimino)]-di-1,3,6-naphthalenetrisulf 
onic acid hexasodium salt is concentrated to 25 ml. To this solution is 
added 2.04 g of 8-isothiocyanato-1,3,6-naphthalenetrisulfonic acid 
trisodium salt with standing for 23 hours. The solution is diluted with 
100 ml of ethanol to give a precipitate which is filtered and washed with 
80% aqueous ethanol, ethanol and ether, then is dried overnight by 
conventional means to give 5.8 g of the product of the example as a yellow 
powder. 
EXAMPLE 2 
5,5'-{{5-[2-Thio-3-(3,6,8-trisulfo-1-naphthyl)ureido]-1,3-phenylene}bis(car 
bonylimino)}diisophthalic acid heptasodium salt 
A mixture of 21.1 g of 5-nitroisophthalic acid, 40.5 ml of 5N sodium 
hydroxide and 2.0 g of 10% palladium on carbon catalyst in 110 ml of water 
is hydrogenated at room temperature for 1 hour and then filtered through 
diatomaceous earth. To the solution of 5-aminoisophthalic acid disodium 
salt is added 9.2 g of sodium bicarbonate followed by 13.65 g of powdered 
5-nitroisophthaloyl chloride (prepared as described in Example 1). The 
solution is cooled in a water bath and stirred vigorously in a baffle 
flask for 1 hour and 15 minutes. The mixture is filtered, the filtrate is 
concentrated to approximately 125 ml and 200 ml of ethanol is added to 
give a yellow precipitate. The mixture is filtered and the product is 
washed with 66% aqueous ethanol, ethanol and ether. The material is dried, 
then dissolved in 200 ml of water. The solution is filtered through 
diatomaceous earth and diluted slowly with stirring and warming with 300 
ml of ethanol. The precipitate formed is collected and washed with 100 ml 
of 60% aqueous ethanol, 400 ml of ethanol and ether. The product is dried 
by conventional means to give 27.8 g of 
5,5'-[5-nitro-1,3-phenylenebis(carbonylimino)]diisophthalic acid 
tetrasodium salt. 
A mixture of 25.0 g of the product above and 2.5 g of 10% palladium on 
carbon catalyst in 150 ml of water is hydrogenated in a Parr shaker at 
room temperature for 11/2 hours. The resulting mixture is filtered through 
diatomaceous earth. The filter is washed with 25-30 ml of water and the 
filtrate is diluted with 300 ml of ethanol with vigorous stirring. The 
precipitate formed is collected by filtration, washed with 60% aqueous 
ethanol, ethanol and ether and dried by conventional means to yield 22.2 g 
of 5,5'-[5-amino-1,3-phenylenebis(carbonylimino)]diisophthalic acid 
tetrasodium salt as a pale yellow powder. 
To a solution of 2.55 g of 8-isothiocyanato-1,3,6-napththalenetrisulfonic 
acid trisodium salt (prepared as described in Example 1) in 15 ml of water 
is added 3.25 g of the preceding compound in 25 ml of water with stirring. 
Stirring is continued at room temperature for 18 hours. The solution is 
filtered and concentrated. The precipitate is dissolved in 30 ml of hot 
water and is slowly added to 60 ml of ethanol, with stirring, with 
formation of a precipitate. The mixture is allowed to cool and the 
precipitate is collected, washed with 80% aqueous ethanol, ethanol and 
ether and dried. The product is recrystallized from 40:60, water:ethanol, 
washed with ethanol and ether and dried to yield 1.7 g of the product of 
the example as a light yellow solid. 
EXAMPLE 3 
Preparation of Compressed Tablet 
______________________________________ 
Ingredient mg/Tablet 
______________________________________ 
Active Compound 0.5-500 
Dibasic Calcium Phosphate N.F. 
qs 
Starch USP 40 
Modified Starch 10 
Magnesium Stearate USP 1-5 
______________________________________ 
EXAMPLE 4 
Preparation of Compressed Tablet -- Sustained Action 
______________________________________ 
Ingredient mg/Tablet 
______________________________________ 
Active Compound 0.5-500 (as acid 
as Aluminum Lake*, Micronized 
equivalent) 
Dibasic Calcium Phosphate N.F. 
qs 
Alginic Acid 20 
Starch USP 35 
Magnesium Stearate USP 
1-10 
______________________________________ 
*Complement inhibitor plus aluminum sulfate yields aluminum complement 
inhibitor. Complement inhibitor content in aluminum lake ranges from 
5-30%. 
EXAMPLE 5 
Preparation of Hard Shell Capsule 
______________________________________ 
Ingredient mg/Capsule 
______________________________________ 
Active Compound 0.5-500 
Lactose, Spray Dried qs 
Magnesium Stearate 1-10 
______________________________________ 
EXAMPLE 6 
Preparation of Oral Liquid (Syrup) 
______________________________________ 
Ingredient mg/Capsule 
______________________________________ 
Active Compound 0.05-5 
Liquid Sugar 75.0 
Methyl Paraben USP 0.18 
Propyl Paraben USP 0.02 
Flavoring Agent qs 
Purified Water qs ad 100.0 
______________________________________ 
EXAMPLE 7 
Preparation of Oral Liquid (Elixir) 
______________________________________ 
Ingredient % W/V 
______________________________________ 
Active Compound 0.05-5 
Alcohol USP 12.5 
Glycerin USP 45.0 
Syrup USP 20.0 
Flavoring Agent qs 
Purified Water qs ad 100.0 
______________________________________ 
EXAMPLE 8 
Preparation of Oral Suspension (Syrup) 
______________________________________ 
Ingredient % W/V 
______________________________________ 
Active Compound 0.5-5 
as Aluminum Lake, Micronized 
(acid equivalent) 
Polysorbate 80 USP 0.1 
Magnesium Aluminum Silicate, 
Colloidal 0.3 
Flavoring Agent qs 
Methyl Paraben USP 0.18 
Propyl Paraben USP 0.02 
Liquid Sugar 75.0 
Purified Water qs ad 100.0 
______________________________________ 
EXAMPLE 9 
Preparation of Injectable Solution 
______________________________________ 
Ingredient % W/V 
______________________________________ 
Active Compound 0.05-5 
Benzyl Alcohol N.F. 0.9 
Water for Injection 100.0 
______________________________________ 
EXAMPLE 10 
Preparation of Injectable Oil 
______________________________________ 
Ingredient % W/V 
______________________________________ 
Active Compound 0.05-5 
Benzyl Alcohol 1.5 
Sesame Oil qs ad 100.0 
______________________________________ 
EXAMPLE 11 
Preparation of Intra-Articular Product 
______________________________________ 
Ingredient Amount 
______________________________________ 
Active Compound 2-20 mg 
NaCl (physiological saline) 
0.9% 
Benzyl Alcohol 0.9% 
Sodium Carboxymethylcellulose 
1-5% 
pH adjusted to 5.0-7.5 
Water for Injection qs ad 
100% 
______________________________________ 
EXAMPLE 12 
Preparation of Injectable Depo Suspension 
______________________________________ 
Ingredient % W/V 
______________________________________ 
Active Compound 0.05-5 
(acid equivalent) 
Polysorbate 80 USP 0.2 
Polyethylene Glycol 4000 USP 
3.0 
Sodium Chloride USP 0.8 
Benzyl Alcohol N.F. 0.9 
HCl to pH 6-8 qs 
Water for Injection qs ad 
100.0 
______________________________________