Pharmaceutical formulation and process for its preparation

A pharmaceutical formulation for the parenteral, in particular intravenous, administration of sparingly soluble substances is obtained when the very finely ground substance, with a maximum particle diameter of 3 .mu.m, is dispersed in an oil phase which contains emulsifier, and this mixture is emulsified with water for injection, is rendered isotonic and is homogenized using a high-pressure homogenizer, so that the resultant product is a solid/liquid/liquid disperse system.

The invention relates to a pharmaceutical formulation for the parenteral 
administration of substances which are very sparingly soluble in 
physiologically tolerated hydrophilic and lipophilic media, which 
formulation is prepared by dispersing the substance, which has been very 
finely ground, in the oil phase, followed by emulsification and 
homogenization. 
The preparation of emulsions which can be administered parenterally is 
described by, for example, Hansrani (P. K. Hansrani, S. S. Davis, M. J. 
Groves, J. Parenter, Sci. Technol., 37, 145 (1983)). This entails a 
vegetable oil being emulsified in water, using an emulsifier, usually 
lecithin, and high-pressure homogenization being used to obtain a particle 
size of less than one micrometer. The final product in this process is in 
the form of a liquid/liquid system. 
Numerous formulations for the intravenous administration of sparingly 
soluble substances have been described. For example, it is possible for 
these substances to be induced to dissolve using cosolvents or to be 
solubilized in micelles (Techniques of Solubilizing Drugs, S. H. Yalkowski 
ed., 1981, Marcel Dekker, New York, pages 15-134). These two possibilities 
have, in respect of tolerability, distinct disadvantages compared with the 
emulsion formulations which contain the active compound, for example 
diazepam (commercial product Diazemuls.RTM., Kabivitrum, FRG marketed 
since Jan. 1, 1983) dissolved in the oil phase (A. S. Olesen, M. S. 
Huttel, Br. J. Anaesth. 52, 609, 1980)). 
Other processes make use of parenteral nutrient emulsions as vehicles and 
add the substance dissolved in a cosolvent, which may give rise to 
complications on intravenous administration (A. J. Repta, Topics in 
Pharmaceutical Sciences, D. D. Breimer and P. Speiser ed., 1981, page 131, 
Elsevier/North-Holland Biomedical Acss.). 
The methods to date for the intravenous administration of particles using 
colloidal pharmaceutical vehicles, such as Liposomes or nanocapsules, have 
the disadvantage that they allow the administration of only small amounts 
of substance, and some of them are composed of materials which can be only 
slowly biotransformed, such as cyanoacrylates. 
The invention has the object of developing, for substances which are very 
sparingly soluble in physiologically tolerated hydrophilic and lipophilic 
media, a formulation which is well tolerated, allows intravenous 
administration of high doses, can be employed for as many substances as 
possible, and is stable, at least in the short term. 
The object is achieved according to the invention by a pharmaceutical 
formulation which is composed of a solid/liquid/liquid disperse system 
with a maximum particle size of 5 .mu.m and which is obtained by 
dispersing up to 1.5% by weight of very finely ground (for example by wet 
grinding in a stirred ball mill) substance with a particle size not 
exceeding 3 .mu.m in 8-30% by weight of oil phase which contains 1.0-4.5% 
by weight of emulsifier, based on the total mixture, and emulsifying this 
mixture with 64-90% by weight of water for injection, rendering isotonic, 
and homogenizing using a high-pressure homogenizer. 
Suitable for the processing according to the invention are substances which 
are poorly soluble in oily and aqueous media, such as, for example, 
certain cytostatics, antibiotics and spironolactone. The amounts which are 
to be used depend on a variety of factors, including the efficacy of the 
substance and range of indications. Thus, it is difficult to make a 
general statement of them. 
However, in most cases it will be preferred to use more than 0.03% by 
weight and not more than 1.5% by weight of substance. 
It is possible to use as oil phase all lipophilic media which can be used 
pharmaceutically for injection products, such as, for example, cottonseed 
oil, arachis oil, ethyl oleate, isopropyl myristate, corn oil, medium 
chain-length triglycerides, olive oil, castor oil, soybean oil and 
hydrogenated liquid vegetable oils. Miglyol.RTM. 812 (saturated 
triglycerides with C.sub.8 -C.sub.12 fatty acids) is preferably used in 
amounts of, preferably, 9 to 20% by weight of the total formulation. 
It is possible to use as emulsifier, or component of an emulsifier mixture, 
emulsifiers which are tolerated on parenteral administration, such as egg 
lecithins, soybean lecithins, hydrogenated egg lecithins, hydrogenated 
soybean lecithins, cholesterol, acetylated monoglycerides and polyethylene 
glycol/polypropylene glycol block polymers. Soybean lecithins are 
preferably used in amounts of, preferably, 1.3 to 3.0% by weight of the 
total formulation. 
For rendering isotonic, use is made of not only preferably monovalent 
electrolytes, for example NaCl, but also non-ionic additives such as, for 
example, glycerol, mannitol, sorbitol and xylitol. NaCl is preferably 
used, and the amount which is preferably used is between 0.5 and 0.81% by 
weight of the total formulation. 
In principle, all processes with which a particle fineness of less than 5 
.mu.m can be achieved without the solid particles leaving the oil phase 
are suitable for the homogenization. Since, on the industrial scale, 
parenteral emulsions are brought to the necessary particle fineness by 
high-pressure homogenization, and there is a risk of decomposition of the 
active compounds or auxiliaries on exposure to ultrasound, use is 
preferably made of high-pressure homogenization. 
It has been shown that the combination of the additive for rendering 
isotonic and the emulsifier has an effect on whether the active compound 
particles remain in the oil phase. Thus, it has emerged that on use of, 
preferably, monovalent electrolytes, for example NaCl, as additive for 
rendering isotonic, and of lecithin or lecithin and cholesterol as 
emulsifier, the solid particles do not leave the oil phase, and the 
particles are, despite the addition of electrolyte, in the size range of 
smaller than 5 .mu.m which is required for emulsions for intravenous 
administration, although--as is known from the literature--emulsions 
stabilized with lecithin may be destabilized by electrolytes (C. D. Black, 
N. G. Popovich, Drug Intell. Clin. Pharm., 15, 185 (1981)). On the other 
hand, where hydrogenated lecithin, preferably Epikuron.RTM. 200H, was 
used, the addition of a non-ionic agent for rendering isotonic was more 
favorable. Hence, the emulsifier and the substance for rendering isotonic 
are preferably used in the formulation according to the invention in such 
a way that electrolytes are combined with lecithin or lecithin and 
cholesterol, and non-ionic agents for rendering isotonic are combined with 
hydrogenated lecithin. 
The particular advantages of the formulation according to the invention are 
that it is well tolerated owing to the exclusive use of substances which 
are well tolerated physiologically, that there is no exposure of the 
substances to heat during the preparation, and there is prevention of 
decomposition reactions in the aqueous phase (A. J. Repta, Topics in 
Pharmaceutical Sciences, D. D. Breimer and P. Speiser ed. 1981, page 131, 
Elsevier/North-Holland Biomedical Press). 
The general basic formulation which can be used is: 
Active compound: up to 1.5% by weight, preferably up to 0.5% by weight 
Oil phase: 8-30% by weight, preferably 9-20% by weight 
Emulsifier: 1-4.5% by weight, preferably 1.3-3% by weight 
Aqueous phase: 64-90% by weight, preferably 76.5-89.7% by weight. 
It is possible for the preparation according to the invention to process 
both lecithins with a high proportion of unsaturated fatty acids, 
preferably Epikuron.RTM. 170 (a specially purified soybean lecithin), but 
in this case preferably with addition of electrolyte, as well as those 
with a proportion of only 10-30% of unsaturated fatty acids. The former 
have the advantage that emulsification and homogenization are less 
problematical. 
Active compounds which are incorporated in the formulation according to the 
invention show a clearly measurable effect after one parenteral 
administration. The extent of release depends on the composition of the 
emulsifier. Intravenous administration of the particles is well tolerated, 
and thus the formulation is also suitable for parenteral administration 
for screening purposes in animal experiments.

The preparation of the formulation according to the invention is 
illustrated in detail in the examples which follow: 
EXAMPLE 1 
______________________________________ 
Batch size (g) 
______________________________________ 
Dihydroxyanthraquinone 
0.200 
Miglyol .RTM. 812 
3.800 
Epikuron .RTM. 170 
0.480 
Cholesterol 0.048 
0.9% NaCl 35.472 
40.000 
______________________________________ 
A 10% strength suspension of dihydroxyanthraquinone in Miglyol.RTM. 812 was 
ground to a particle size of less than 3 .mu.m in a Dyno-Mill type KDL 
(continuous operation, circumferential speed 10 m/s, time 60 min, 0.3 mm 
glass beads). An amount of the suspension containing the necessary amount 
of dihydroxyanthraquinone was mixed with Miglyol.RTM. 812 in an Erlenmeyer 
flask to produce one half of the total oil phase, and the mixture was made 
up with a 24% strength solution of the lecithin in Miglyol.RTM. 812. 
Thereafter, first cholesterol and then water for injection was added, 
stirring continuously, and when emulsification was complete the sodium 
chloride was added. The high-pressure homogenization was carried out in a 
French pressure cell (Millner, Lawrence, French, Science, 3, 633, 1950) 
which was additionally equipped with a fine control valve. 
The homogenization was carried out under a pressure of 550 bar and with a 
slit width of 35 .mu.m. 
EXAMPLE 2 
______________________________________ 
Batch size (g) 
______________________________________ 
S830544 0.0124 
Miglyol .RTM. 812 
3.9876 
Epikuron .RTM. 0.48 
Cholesterol 0.048 
NaCl (0.9%) 35.472 
40.000 
______________________________________ 
The chemical name of S830544 is 1,4-bis(dl-2,3-oxidopropoxy)anthraquinone. 
Preparation as for Example 1. Homogenization with 320 bar, 150 .mu.m slit 
and 3 passages. 
An animal test was carried out to investigate the cytostatic action of the 
substance. Test groups each comprising 6 BDF1 mice (18-20 g) were formed, 
and the mice received 10.sup.6 L1210 Leukemia cells by i.p. administration 
one day before the start of the test. Each group received i.p. 
administration of a particular dose once a day during the 5-day test. 
The median survival time (MST) in the individual test groups was evaluated. 
The percentage prolongation of life was obtained by dividing by the median 
survival time in the control group without administration of substance, 
multiplied by 100. Figures above 125% indicated a cytostatic action. The 
occurrence or absence of ascites was used to assess the cause of death. 
The occurrence of ascites was caused by the L1210 leukemia cells, and thus 
it was possible to differentiate between the toxicity of the test 
substance and that of the tumor. 
______________________________________ 
Dosage MST/contr. % 
Ascites 
______________________________________ 
7.75 mg/kg body weight 
114 4 of 6 
4.65 mg/kg body weight 
143 5 of 6 
1.55 mg/kg body weight 
129 6 of 6 
______________________________________ 
The results show that the formulation according to the invention makes it 
possible straightforwardly and without difficulty to administer 
therapeutically relevant amounts of substance, and that the incorporated 
substance is released in therapeutically relevant concentrations from the 
formulation according to the invention. The prolongation of life found 
with the middle dosage clearly exceeded the criterion of efficacy. As the 
dose increases the significance of the toxicity of the substance increases 
in comparison with that of the tumor. 
Comparison of the results obtained with those of earlier tests reveals that 
the onset of action takes place at much lower doses with the formulation 
according to the invention. 
______________________________________ 
Dosage MST/contr. % 
Ascites 
______________________________________ 
1 .times. 1000 mg/kg body weight 
81 1 of 6 
1 .times. 800 mg/kg body weight 
81 3 of 6 
1 .times. 600 mg/kg body weight 
95 6 of 6 
1 .times. 400 mg/kg body weight 
95 6 of 6 
1 .times. 200 mg/kg body weight 
100 6 of 6 
______________________________________ 
To carry out these tests, before the i.p. administration of the substance 
it was dispersed in a surfactant-containing medium and homogenized with 
ultrasound. 
EXAMPLE 3 
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Batch size (g) 
______________________________________ 
S827942 0.128 
Miglyol .RTM. 812 
3.872 
Epikuron .RTM. 0.48 
Cholesterol 0.048 
NaCl 0.9% 35.472 
40.000 
______________________________________ 
The chemical name of S827942 is 
3-methyl-9-((2-methoxy-4-methylsulfonylamino)anilino)thieno[3,2-b]quinolin 
e lactate. Preparation, homogenization conditions and substance testing in 
analogy to Example 2. 
______________________________________ 
Dosage MST/contr. % 
Ascites 
______________________________________ 
80 mg/kg body weight 
157 0 of 6 
48 mg/kg body weight 
157 0 of 6 
16 mg/kg body weight 
157 6 of 6 
8 mg/kg body weight 
129 6 of 6 
1.6 mg/kg body weight 
129 6 of 6 
______________________________________ 
Example 3 likewise demonstrates that the incorporated substance is released 
in effective concentrations. Comparison of these results with those of 
earlier tests shows that the cytostatic action on preparation according to 
the invention is detectable at far lower doses. 
______________________________________ 
Dosage MST/contr. % 
Ascites 
______________________________________ 
1 .times. 800 mg/kg body weight 
138 4 of 10 
1 .times. 700 mg/kg body weight 
149 7 of 10 
1 .times. 600 mg/kg body weight 
154 9 of 10 
1 .times. 500 mg/kg body weight 
147 10 of 10 
1 .times. 400 mg/kg body weight 
147 10 of 10 
1 .times. 300 mg/kg body weight 
151 10 of 10 
______________________________________ 
The preparation was prepared in analogy to Example 2 by dispersion of the 
substance in a surfactant-containing medium, followed by homogenization 
with ultrasound. 
EXAMPLE 4 
______________________________________ 
Batch size (g) 
______________________________________ 
Spironolactone 0.288 
Miglyol .RTM. 812 
7.712 
Epikuron .RTM. 1.20 
Cholesterol 0.12 
0.9% NaCl 30.68 
40.000 
______________________________________ 
The preparation was carried out in analogy to Example 1. Homogenization 
with 660 bar, 150 .mu.m slit and 3 passages. 
An animal test was carried out to investigate the diuretic action of the 
preparation. Test groups each comprising 3 Lewis rats (160-180 g) were 
formed and accommodated in metabolism cages. During the 4-day test, the 
animals received food and water as required, and the amount of urine 
excreted was measured every 24 hours. Various control groups were formed 
to improve the assessment of the results: 
without administration 
blank formulation i.p. 
blank formulation i.v. 
__________________________________________________________________________ 
Dosage Urine excretion ml/rat/h 
Cumulative urine excretion 
Preparation 
mg/kg body weight 
0-24 
24-48 
48-72 
72-96 
per rat after 96 h (ml) 
__________________________________________________________________________ 
Spironolactone 
25 i.p. 0.42 
0.44 
0.28 
0.3 34.56 
Spironolactone 
50 i.p. 0.8 
0.58 
0.55 
0.56 
60.48 
Blank formulation 
1 ml i.p. 0.16 
0.2 0.25 
0.28 
21.12 
Spironolactone 
50 i.v. 0.6 
0.55 
0.39 
0.3 44.16 
Blank formulation 
1 ml i.v. 0.47 
0.36 
0.38 
0.33 
35.1 (90 h) 
Without administration 
0.33 
0.25 
0.16 
0.25 
24 
__________________________________________________________________________ 
Spironolactone is released in therapeutically relevant concentrations from 
the formulation according to the invention. The results data demonstrate 
that the diuretic action found after i.p. administration is more 
pronounced and long-lasting than after i.v. administration. The amount of 
urine excreted is about 25% higher than in the group with i.v. 
administration of the blank formulation whereas an increase of about 185% 
is detectable on i.p. administration. 
EXAMPLE 5 
______________________________________ 
Batch size (g) 
______________________________________ 
Spironolactone 0.288 
Miglyol .RTM. 812 
7.712 
Epikuron .RTM. 200H 
0.96 
Epikuron .RTM. 170 
0.24 
2.5% glycerol 30.8 
40.000 
______________________________________ 
The preparation was carried out in analogy to Example 1. Homogenization 
with 300 bar, 100 .mu.m slit width and 3 passages. 
The animal test was carried out under the same conditions as for Example 4. 
__________________________________________________________________________ 
Dosage Urine excretion ml/rat/h 
Cumulative urine excretion 
Preparation 
(mg/kg body weight) 
0-24 
24-48 
48-72 
72-90 
per rat after 90 h (ml) 
__________________________________________________________________________ 
Spironolactone 
50 i.p. 0.5 
0.42 
0.36 
0.33 
36 
Blank formulation 
1 ml i.p. 0.28 
0.31 
0.32 
0.3 27 
Spironolactone 
50 i.v. 0.44 
0.42 
0.48 
0.63 
44.1 
Blank formulation i.v. 
1 ml i.v. 0.47 
0.36 
0.36 
0.36 
35.1 
Without administration 
See Example 4 See Example 4 
__________________________________________________________________________ 
An increase in diuresis compared with the control groups is also detectable 
in Example 5. However, it is noticeable that the increase in diuresis on 
i.p. administration is distinctly lower than in Example 4, and that there 
is a delay in the occurrence of the maximum effect after i.v. 
administration. These effects are attributable to the variation in the 
lecithin component. Apparently release takes place more rapidly and 
completely the higher the content of unsaturated fatty acids in the 
lecithin component.