Aqueous suspension of loteprednol etabonate

The conventional aqueous suspension of loteprednol etabonate is not easily amenable to production pH control and entails a pH depression on long-term storage, thus irritating the eye or the nasal mucosa on instillation. When a C2-7 aliphatic amino acid is added to an aqueous suspension of loteprednol etabonate for topical ophthalmic use, the suspension does not undergo pH depression even on prolonged storage, with the result that no irritable response is elicited in the eye or nasal mucosa.

FIELD OF THE INVENTION 
The present invention relates to an aqueous suspension of loteprednol 
etabonate and more particularly to a stable and safe aqueous suspension of 
loteprednol etabonate which does not undergo change in pH on prolonged 
storage and is not irritating to the ocular and nasal mucosa. 
BACKGROUND OF THE INVENTION 
Many steroid compounds have been used as topical therapeutic agents for eye 
inflammations. While those steroid compounds show a potent 
antiinflammatory action, they tend to cause secondary (iatrogenic) 
disorders of the eye, such as cataract and glaucoma. 
Therefore, research has been done to develop steroid compounds which do not 
cause adverse reactions even when administered topically to the eye and 
recently loteprednol etabonate (hereinafter sometimes referred to briefly 
as LE) having very satisfactory antiinflammatory activity and only a low 
risk for side effects has been developed by modification of prednisolone 
acetate (U.S. Pat. Nos. 4,716,495 and 4,996,335). 
LE is devoid of the 20-keto group in the 17.beta.-position of prednisolone 
and instead has in this 17.beta.-position an ester residue which is 
hydrolyzed in vivo to give an inert carboxylic acid metabolite which does 
not bind to the glucocorticoid receptor. Therefore, unlike many other 
steroidal agents, LE has a low incidence of side effects such as onset of 
cataract and elevation of intraocular pressure, thus being a very useful 
compound for the treatment of ocular inflammations. 
Since LE is a substantially water-insoluble crystalline substance, its 
dosage form has to be an aqueous suspension in order that it may be used 
as eye drops or nasal drops. However, when LE is formulated with an 
isotonizing agent such as sodium chloride and a buffer such as phosphoric 
acid, both of which are conventionally added in the preparation of an 
aqueous suspension, particles of LE begin to aggregate within 3 months 
and, in certain cases, within a month. 
To overcome this disadvantage, there was proposed an aqueous suspension of 
LE formulated with a nonionic suspending agent such as 
polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), etc., a nonionic 
surfactant such as tyloxapol, polysorbate 80, etc., and further an 
isotonizing agent of polyhydric alcohols such as glycerin and mannitol 
(PCT/US94-12059) with fairly successful results. However, this formulation 
makes it difficult to control pH in the preparation of the aqueous 
suspension and, moreover, when the suspension is stored for a long time, 
there occurs a pH depression despite little change in appearance so that 
it elicits an irritable response in the eye or nasal mucosa. 
SUMMARY OF THE INVENTION 
The inventors of the present invention studied a broad spectrum of 
compounds for the purpose of improving the above formulation and providing 
a more stable and safe aqueous suspension which can be easily prepared and 
even after prolonged storage does not irritate the ocular and nasal mucosa 
and found surprisingly that certain kinds of amino acids are effective in 
meeting the above purpose. The finding was followed by further research 
which has brought the present invention into being. 
The present invention, therefore, is directed to: 
(1) an aqueous suspension of loteprednol etabonate which comprises 
loteprednol etabonate and an aliphatic amino acid containing 2-7 carbon 
atoms, 
(2) the aqueous suspension (1) wherein said amino acid is one having 1 or 2 
amino groups and 1 or 2 carboxyl groups, 
(3) the aqueous suspension (2) wherein said amino acid is a neutral or 
acidic amino acid, 
(4) the aqueous suspension (3) wherein said amino acid is 
.epsilon.-aminocaproic acid, 
(5) the aqueous suspension (1) which contains 0.01-3 w/v % of loteprednol 
etabonate and 0.002-2 w/v % of said amino acid in aqueous medium, 
(6) the aqueous suspension (1) further containing a suspending agent, a 
nonionic surfactant, and an isotonizing agent, 
(7) the aqueous suspension (6) which contains 0.2-2 w/v % of the suspending 
agent, 0.05-1 w/v % of the nonionic surfactant, and 1-6 w/v % of the 
isotonizing agent in the aqueous medium, 
(8) the aqueous suspension (6) wherein said suspending agent is a 
water-soluble nonionic polymer, said nonionic surfactant is a 
polyoxyalkylene monool or polyol, and said isotonizing agent is a 
polyhydric alcohol, 
(9) the aqueous suspension (6) further containing a preservative, 
(10) the aqueous suspension (9) which contains 0.0001-0.5 w/v % of said 
preservative, 
(11) the aqueous suspension (6) which contains 0.1-5 moles of said amino 
acid, 0.01-20 moles of said suspending agent, and 0.05-1 mole of said 
nonionic surfactant per mole of loteprednol etabonate, 
(12) the aqueous suspension (1) wherein loteprednol etabonate occurs in 
finely divided form with particle diameters within the range of 0.1-30 
.mu.m, 
(13) the aqueous suspension (1), the pH of which is 4.5-7.0, and 
(14) the aqueous suspension (1), (6), or (9) which is an antiinflammatory 
agent for ophthalmic or otorhinolaryngological use. 
DETAILED DESCRIPTION OF THE INVENTION 
The particle size of LE suited for preparation of the aqueous suspension of 
the present invention is generally 0.1-30 .mu.m, preferably 1-20 .mu.m, 
and more preferably 2-10 .mu.m. It is also preferable that the LE should 
be produced by a sterile procedure and has a purity of not less than 98 
weight %. The concentration of LE in the aqueous suspension need only be 
therapeutically effective in the treatment of inflammations and is 
generally 0.01-3 w/v %, preferably 0.05-2 w/v %, and more preferably 0.2-1 
w/v %. 
The aqueous suspension of the present invention contains an aliphatic amino 
acid of 2 to 7 carbon atoms, preferably 3-5 carbon atoms, not reckoning 
the carboxyl group carbon, as a buffer. The number of amino groups in this 
amino acid is preferably 1 or 2 and more preferably 1. The preferred 
number of carboxyl groups is 1 or 2. Such amino acid includes neutral 
amino acids such as alanine, .beta.-aminopropionic acid, 
.gamma.-aminobutyric acid, .epsilon.-aminocaproic acid, etc. and acidic 
amino acids such as aspartic acid, glutamic acid, etc. Particularly 
preferred are .epsilon.-aminocaproic acid and glutamic acid. 
The above amino acid in an aqueous suspension of LE serves to prevent a pH 
depression of the suspension, and it is likely that this is why the 
irritation of the ocular and nasal mucosa is alleviated. 
The concentration of said amino acid in the aqueous suspension is generally 
0.002-2.0 w/v %, preferably 0.01-0.5 w/v %, and more preferably 0.04-0.2 
w/v %. 
To provide a stable aqueous suspension in accordance with the present 
invention, a suspending agent, a nonionic surfactant, an isotonizing 
agent, and, where necessary, a preservative and other additives are 
incorporated. 
The suspending agent need only be a water-soluble polymer and is otherwise 
not critical in kind. Thus, for example, polyvinylpyrrolidone (PVP), 
polyvinyl alcohol (PVA), carboxymethylcellulose sodium (CMC. Na), dextrin, 
cyclodextrin, etc. can be mentioned. Among them, nonionic polymers such as 
PVP are preferred. The formulating amount of said suspending agent in the 
aqueous suspension is generally 0.2-2 w/v % and preferably 0.4-1 w/v %. 
The nonionic surfactant as well as said suspending agent serves to maintain 
the active ingredient loteprednol etabonate in evenly suspended state for 
a long time. The nonionic surfactant that can be used includes 
polyoxyalkylene monools or polyols which are obtainable by 
addition-polymerizing 1 or 2 different alkylene oxides, e.g. ethylene 
oxide and propylene oxide, to an organic compound containing 1 or a 
plurality of hydroxyl groups per molecule, their esters, and mixtures 
thereof. 
The useful nonionic surfactant includes but is not limited to polysorbate 
80, tyloxapol and poloxamers. Among them, tyloxapol and polysorbate 80 are 
preferred. The formulating amount of the nonionic surfactant is generally 
0.05-1 w/v % and preferably 0.1-0.6 w/v % 
The isotonizing agent is preferably an aliphatic polyhydric alcohol, 
particularly an aliphatic polyol containing 2-6 carbon atoms, such as 
glycerol and mannitol. 
The formulating amount of the isotonizing agent in the aqueous suspension 
is generally 1-6 w/v % and preferably 1.5-4 w/v %. Where necessary, a 
preservative may be incorporated. The preservative that can be used 
includes benzalkonium chloride and/or sodium edetate, among others. The 
formulating amount of the preservative in the aqueous suspension is 
generally 0.0001-0.5 w/v % and preferably 0.001-0.2 w/v %. 
The aqueous suspension of the present invention may further contain 
therapeutically effective amounts of other drugs such as an antiglaucoma 
drug, a steroidal or nonsteroidal antiinflammatory agent, an antiallergic 
agent, an antibacterial agent, and a vasoconstrictor. 
The antiglaucoma drug includes but is not limited to betaxolol, atenolol, 
levobunolol, epinephrine, dipivefrin hydrochloride, pilocarpine 
hydrochloride, physostigmine salicylate, distigmine bromide, ecothiopate 
iodide, carteolol hydrochloride, and methazolamide. 
The steroidal antiinflammatory agent includes beclomethasone, 
dexamethasone, betamethasone, fluocinolone, fluorometholone, etc. and the 
nonsteroidal antiinflammatory agent includes piroxicam, indomethacin, 
naproxen, phenylbutazone, ibuprofen, and diclofenac sodium, among others. 
The antiallergic agent includes but is not limited to sodium cromoglycate, 
tranilast, ketotifen fumarate, diphenhydramine hydrochloride, etc. and the 
antibacterial agent includes but is not limited to idoxuridine, 
erythromycin, sulfisoxazole, tobramycin, and gentamicin. The 
vasoconstrictor includes naphazoline hydrochloride, among others. 
The molar ratio of LE and the above-defined amino acid, suspending agent 
and nonionic surfactant in the aqueous suspension of the present invention 
is generally 1:0.1:0.01:0.05 through 1:5:20:1. 
The viscosity of the aqueous suspension of the present invention is 
preferably not over 100 cps. Moreover, the pH of the suspension is 
preferably within the range of 4.5-7.0 and more preferably within the 
range of 5.0-6.5. 
The aqueous suspension of the present invention can be prepared by the per 
se known production technology for aqueous suspensions in general. A 
typical procedure comprises dissolving the suspending agent in water, 
adding the surfactant, buffer, isotonizing agent, preservative, and other 
additives sequentially, sterilizing the mixture by filtration or 
autoclaving, adding pre-sterilized LE, and agitating the whole mixture 
with a stirrer to provide an aqueous suspension of LE. 
The aqueous suspension of LE thus prepared can be used as an 
ophthalmological or otorhinolaryngological aqueous LE suspension in the 
prevention and treatment of various inflammations of the eye, ear, nose, 
or throat. 
Taking an ophthalmic aqueous suspension containing 0.5 w/v % of LE 
according to the present invention as an example, various ocular 
inflammatory diseases such as allergic conjunctivitis and trachoma can be 
treated by instilling 0.05-0.1 ml of the suspension in the eye 3 to 10 
times daily for one day to one week.

EXAMPLES 
The following working and experimental examples are intended to describe 
the present invention in further detail and should by no means be 
construed as defining the scope of the invention. 
Example 1 
Using the routine production procedure for eye drops, eye drops A of the 
following formulation (Table 1) was prepared. 
TABLE 1 
______________________________________ 
Formula Eye drops A 
______________________________________ 
Loteprednol etabonate 0.5 g 
Concentrated glycerin 2.6 g 
.epsilon.-Aminocaproic acid 
0.1 g 
Tyloxapol 0.3 g 
Polyvinylpyrrolidone (K* - 30) 
0.6 g 
Sodiuin edetate 0.01 g 
Benzalkonium chloride (10 w/v %) 
0.05 ml 
Hydrochloric acid q.s. 
Sterilized pure water 
to make 100 ml 
pH 5.53 
______________________________________ 
*K stands for intrinsic viscosity. 
Stability Test 
Eye drops A according to Example 1 and Eye drops B of the composition 
available on elimination of .epsilon.-aminocaproic acid from the 
composition used in Example 1 were respectively dispensed into colorless 
polypropylene bottles and stored at 40.degree. C. and 75% RH for 6 months. 
Then, the description and pH of each preparation and the mean particle 
diameter of loteprednol etabonate were evaluated and determined. The 
results are presented in Table 2. Eye Irritation Study 
Method 
In this eye irritation test, 0.05-0.1 ml each of Eye drops A and Eye drops 
B after 6 months of storage at 40.degree. C. and 75% RH were respectively 
instilled into the eyes of volunteers. 
Results 
The results of the test are shown in Table 2. 
TABLE 2 
______________________________________ 
Eye drops A 
Eye drops B 
______________________________________ 
Subject a - - 
b - + 
c - + 
d - + 
e - + 
pH Immediately 
5.53 5.51 
after pre- 
paration 
After 6 5.11 3.85 
months of 
storage 
(40.degree. C., 
75% RH) 
Mean Immediately 
3.052 3.783 
particle 
after pre- 
diameter 
paration 
(.mu.m) After 6 Substantially 
Substantially 
months of unchanged from 
unchanged trom 
storage the particle the particle 
(40.degree. C., 
diameter re- diameter re- 
75% RH) corded immedi- 
corded immedi- 
ately after ately after 
preparation preparation 
______________________________________ 
#: pain 
+: foreign sensation 
-: no irritation 
It was found that the eye drops containing .epsilon.-aminocaproic acid does 
not cause an irritable response in the eye and can be used safely even 
after 6 month s of storage at 40.degree. C. and 75% RH. 
EFFECT OF THE INVENTION 
The aqueous suspension of loteprednol etabonate containing a C2-7 aliphatic 
amino acid according to the present invention has the advantage that it is 
amenable to production pH control and remains stable without pH depression 
even on long-term (i.e. 6-month or longer) storage. Therefore, it does not 
irritate the ocular or nasal mucosa on instillation and hence can be 
safely administered as eye drops or nasal drops.