Increasing the choroidal blood flow

A method for increasing the choroidal blood flow which comprises administering to a subject in need of such increasing a 13,14-dihydro-15-keto-20-ethyl-prostaglandin F, a pharmaceutically acceptable salt thereof or a lower alkyl ester thereof.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The present invention relates to a treatment for increasing the choroidal 
blood flow using 13,14-dihydro-15-keto-20-ethyl-prostaglandin Fs, salts or 
lower alkyl esters thereof. 
2. Background Information 
The compounds used in the present invention, i.e. 
13,14-dihydro-15-keto-20-ethyl-prostaglandin Fs, salts or lower alkyl 
esters thereof are known compounds and described in EP-A-289349 
(particularly in Examples 7, 11, 12, 13, 14 and 24) and EP-A-308135 
(particularly in Example 8). In the former publication, the compounds are 
described as having a blood pressure increasing activity and in the latter 
publication, the compounds are described as having an ocular hypotensive 
activity. Nothing has been reported, however, about an activity of the 
above compounds on the choroidal blood flow. As a result of a study about 
the biological activity of 13,14-dihydro-15-keto-20-ethyl-prostaglandin 
Fs, salts or lower alkyl esters thereof, it has now been discovered that 
these compounds have an activity of increasing choroidal blood flow. 
SUMMARY OF THE INVENTION 
In a first aspect, the present invention provides a method for increasing 
the choroidal blood flow which comprises administering to a subject in 
need of such increasing a 13,14-dihydro-15-keto-20-ethyl-prostaglandin F, 
a pharmaceutically acceptable salt thereof or a lower alkyl ester thereof. 
In a second aspect, the present invention provides a use of a 
13,14-dihydro-15-keto-20-ethyl-prostaglandin F, a pharmaceutically 
acceptable salt thereof or a lower alkyl ester thereof for the manufacture 
of a medicament for increasing choroidal blood flow. 
In a third aspect, the present invention provides a pharmaceutical 
composition for increasing choroidal blood flow comprising a 
13,14-dihydro-15-keto-20-ethyl-prostaglandin F, a pharmaceutically 
acceptable salt thereof or a lower alkyl ester thereof in association with 
a pharmaceutically acceptable carrier, diluent or excipient. 
The present invention also provides a process for preparing the medicament 
or the pharmaceutical composition which comprises combining a 
13,14-dihydro-15-keto-20-ethyl-prostaglandin F, a pharmaceutically 
acceptable salt thereof or a lower alkyl ester thereof with a 
pharmaceutically acceptable carrier, diluent or excipient.

DETAILED DESCRIPTION OF THE INVENTION 
The compounds used as the active ingredient in the present invention are 
compounds having basic structure of the natural prostaglandin F and having 
a saturated carbon to carbon bond between positions 13 and 14, lacking the 
hydroxyl group at position 15, having an oxo group instead of said hydroxy 
group at position 15 and having an omega chain elongated by combining an 
ethyl group at position 20 (i.e. the terminal of the omega chain), and 
salts or lower alkyl esters thereof. 
The term "prostaglandin F" herein includes prostaglandin F.sub.1 .alpha., 
F.sub.2 .alpha. and F.sub.3 .alpha.. 
The salts of 13,14-dihydro-15-keto-20-ethyl-prostaglandin Fs are 
conveniently pharmaceutically acceptable salts. 
Suitable "pharmaceutically acceptable salts" includes conventional 
non-toxic salts, and may be a salt with an inorganic base, for example a 
metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, 
etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, 
etc.), ammonium salt, a salt with an organic base, for example, an amine 
salt (e.g. methylamine salt, dimethylamine salt, cyclohexylamine salt, 
benzylamine salt, piperidine salt, ethylenediamine salt, ethanolamine 
salt, diethanolamine salt, triethanolamine salt, 
tris(hydroxymethylamino)ethane salt, monomethyl-monoethanolamine salt, 
procaine salt, caffeine salt, etc.), a basic amino acid salt (e.g. 
arginine salt, lysine salt, etc.), tetraalkylammonium salt and the like. 
These salts can be prepared by the conventional process, for example from 
the corresponding acid and base or by salt interchange. 
The term "lower alkyl" in lower alkyl esters means alkyl groups having 1 to 
6, preferably 1 to 4 carbon atoms, and include for example, methyl, ethyl, 
propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl etc. 
Among the compounds used in the present invention, methods for the 
preparation of 13,14-dihydro-15-keto-20-ethyl-prostaglandin F.sub.2 
.alpha. and its methyl ester, ethyl ester, isopropyl ester and n-butyl 
ester are described in Examples 24, 7, 11, 12 and 13 of EP-A-289,349, 
respectively. A method for the preparation of the isopropyl ester is also 
described in Example 7 of EP-A-30,135. A method for the preparation of 
13,14-dihydro-15-keto-20-ethyl-prostaglandin F.sub.1 .alpha. methyl ester 
is described in Example 14 of EP-A-289,349. Other compounds can be 
prepared analogously taking into consideration the other processes known 
for the preparation of prostaglandin compounds. 
Choroid (Chorioidea) is the tissue present between the sciera and the 
retina with rich pigment and vascular, extending from the optic disk to 
the ora serrata. It is composed of four layers: supra-choroid (Stratum 
perichorioideum), layer of vessels (Lamina vasculosa), choriocapillaries 
(Lamina choriocapillaris) and Bruch's membrane (Lamina vitrea). 
Since the compounds used in the invention have an activity of increasing 
choroidal blood flow, the compounds used in the invention, or medicaments 
or pharmaceutical compositions comprising said compounds, are useful in 
the treatment of, for example, ischemic disorder of choroid such as 
ischemic choroidal syndrome. 
Such activity can be measured by the conventional pharmacological assays 
which have been used for evaluating the blood flow. The term "treatment" 
herein refers to any means of control of a disease including preventing 
the disease, curing the disease, relieving the disease and arresting or 
relieving the development of the disease. 
The compounds used in the present invention may be used as a medicine for 
animals and human beings and usually applied systemically or locally by 
such methods as ophthalmic administration, oral administration, 
intravenous injection (including instillation), subcutaneous injection, 
suppository and the like. While the dosage will vary depending on the 
particular animal or human patient, age, body weight, symptom to be 
treated, desired therapeutic effect, administration route, term of 
treatment and the like, satisfactory effects will be obtained with the 
dosage of 0.01-100 .mu.g/eye administered locally or 0.001-500 mg/kg 
administered systemically in 2 to 4 divided doses a day or as a sustained 
form. 
The ophthalmic composition used according to the invention includes 
ophthalmic solution, ophthalmic ointment and the like. The ophthalmic 
solution can be prepared by dissolving an active ingredient in a sterile 
aqueous solution such as a physiological saline or a buffered solution, or 
as a combination of a solid and a solution for dissolving said solid to 
make a ready-to-use preparation. The ophthalmic ointment can be prepared 
by mixing an active ingredient with an ointment base. 
The solid composition for oral administration used according to the 
invention includes tablets, troches, buccals, capsules, pills, powders, 
granules and the like. The solid composition contains one or more active 
substances in admixture with at least an inactive diluent, e.g. lactose, 
mannitol, glucose, hydrocypropyl cellulose, fine crystalline cellulose, 
starch, polyvinyl pyrolidone, magnesium aluminate metasilicate. The 
composition may contain additives, in addition to the inactive diluent, 
for example, lubricants e.g., magnesium stearate, a disintegrator e.g. 
cellulose calcium gluconates, stabilizers e.g. .alpha.-, .beta.-, or 
.gamma.-cyclodextrins, etherated cyclodextrins (e.g. dimethyl-.alpha.-, 
dimethyl-.beta.-, trimethyl-.beta.-, or 
hydroxypropyl-.beta.-cyclodextrins), branched cyclodextrins (e.g. 
glucosyl- or maltosyl-cyclodextrins), formyl cyclodextrins, 
sulfur-containing cyclodextrins, misoprotols or phospholipids. Such 
cyclodextrins may increase the stability of the compounds by forming an 
inclusion compounds. The stability may be often increased by forming 
lyposome with phospholipids. Tablets and pills may be coated with an 
enteric or gastroenteric film e.g. white sugar, gelatin, 
hydroxypropylcellulose, hydroxypropylmethylcellulose phthalates and the 
like, if necessary, and furthermore they may be covered with two or more 
layers. Additionally, the composition may be in the form of capsules made 
of substance easily absorbed e.g. gelatin. The composition may be in the 
form of buccals, when an immediate effect is desired. For this purpose, 
base e.g. glycerine, lactose may be used. 
Liquid compositions for oral administration include pharmaceutically 
acceptable emulsions, solutions, suspensions, syrups, elixirs and the like 
and contain a commonly used inactive diluent e.g. purified water or ethyl 
alcohol. The composition may contain additives e.g. wetting agents, 
suspending agents, sweeteners, flavors, perfumes and preservatives. 
The composition of the present invention may be in the form of sprays which 
may contain one or more active ingredients and which can be prepared 
according to a well known methods. 
An injection of this invention for non-oral administration includes sterile 
aqueous or nonaqueous solutions, suspensions, and emulsions. Diluents for 
the aqueous solution or suspension include, for example, distilled water 
for injection, physiological saline and Ringer's solution. Diluents for 
the nonaqueous solution and suspension include, for example, propylene 
glycol, polyethylene glycol, vegetable oils e.g. olive oil, alcohols, e.g. 
ethanol and polysorbates. The composition may contain other additives, 
e.g. preservatives, wetting agents, emulsifying agents, dispersing agents 
and the like. These are sterilized by filtration through, e.g. a bacteria- 
retaining filter, compounding with a sterilizer, gas sterilization or 
radiation sterilization. These can be prepared by producing a sterilized 
water or a sterilized solvent for injection before use. 
Another formulation according to the present invention is a rectal or 
vaginal suppository. This can be prepared by mixing at lest one active 
compound according to the invention with a suppository base e.g. cacao 
butter and optionally containing nonionic surfactant for improving 
absorption. 
A more complete understanding of the present invention can be obtained by 
reference to the following Formulation Examples and Test Examples which 
are provided herein for purpose of illustration only and are not intended 
to limit the scope of the invention. 
FORMULATION EXAMPLE 1 
Powders for injection 
______________________________________ 
(Parts by weight) 
______________________________________ 
13,14-dihydro-15-keto-20- 
1 
ethyl-prostaglandin F.sub.2 .alpha. 
mannitol 5 
distilled water 0.4 
______________________________________ 
The above ingredients are mixed, stirred, sterilized, filtered and 
lyophilized to give powders for injection. 
FORMULATION EXAMPLE 2 
Injectable solution 
______________________________________ 
(Parts by weight) 
______________________________________ 
13,14-dihydro-15-keto-20- 
0.2 
ethyl-prostaglandin F.sub.2 .alpha. methyl ester 
nonion surfactant 2 
distilled water 98 
______________________________________ 
The above ingredients are mixed and sterilized to give and injectable 
solution. 
FORMULATION EXAMPLE 3 
Powders for oral administration 
______________________________________ 
(Parts by weight) 
______________________________________ 
13,14-dihydro-15-keto-20- 
5 
ethyl-prostaglandin F.sub.2 .alpha. ethyl ester 
light anhydrous silicic acid 
5 
Abicel .TM. 20 
lactose 70 
______________________________________ 
The above ingredients are mixed to give powders for oral administration. 
FORMULATION EXAMPLE 4 
Soft gelatin capsules 
______________________________________ 
(Parts by weight) 
______________________________________ 
13,14-dihydro-15-keto-20- 
1 
ethyl-prostaglandin F.sub.2 .alpha. propyl ester 
Panasate .TM. 899 
______________________________________ 
The above ingredients are mixed and filled in soft gelatine capsules. 
FORMULATION EXAMPLE 5 
Ophthalmic solution 
______________________________________ 
(Parts by weight) 
______________________________________ 
13,14-dihydro-15-keto-20- 
1 
ethyl-prostaglandin F.sub.2 .alpha. isopropyl ester 
Physiological saline 10 
______________________________________ 
The above ingredients are placed in separate vials. The vials are combined 
for preparing a solution on actual use. 
In the above formulation Examples, the active ingredient can be replaced by 
any other compound within the compounds used in the invention. 
TEST EXAMPLE 1 
Six normal white rabbits (weight: 2.1-3.2 kg) were anesthetized by 
intraperitoneal administration of urethane (1.3 mg/kg). After 2 hours, 
experiments were conducted under stable depth of anesthesia (room 
temperature : 25.degree. C). The blood flow was measured by a heat 
gradient tissue blood flowmeter (thermostromuhr ?) BTG-221 (Biomedical 
Science). Thus, an embedding type thermodiffusion sensor TGD-8R was fixed 
on the underlying membrane of Tenon capsule at a position between the 
medial rectus muscle and the superior rectus muscle and distanced by 10 mm 
from the Dimbus. The tissue blood flow was measured continuously by an 
amplifier TGA-2. One eye was used as the treating eye and the other was 
used an the control. The treating eye received 50 .mu.l of 0.06% aqueous 
solution of 13,14-dihydro-15-keto-20-ethyl-prostaglandin F.sub.2 .alpha. 
isopropyl ester and the control eye received 50 .mu.l of the physiological 
saline. Change in the tissue blood flow was measured over 5 hours. 
The results are shown in Table 1 and also plotted in the Figure, wherein * 
denotes p&lt;0.05 and ** denotes p&lt;0.01, according to the paired t-test (n=6, 
vs. control eye). 
TABLE 1 
______________________________________ 
Time Rabbit 
(min.) A B C D E F 
______________________________________ 
(Treating eye) 
30 100 103 97 102 104 102 
60 108 108 103 108 111 109 
90 114 112 107 110 113 111 
120 113 110 108 107 110 107 
150 116 108 107 108 113 110 
180 117 105 105 106 110 107 
210 112 103 102 105 108 106 
240 111 103 101 105 107 104 
270 105 101 101 105 106 103 
300 100 98 99 104 103 101 
(control eye) 
30 102 98 97 98 101 98 
60 105 98 96 99 102 98 
90 104 100 99 101 102 101 
120 110 99 98 100 103 101 
150 112 100 98 101 102 103 
180 105 97 94 97 98 99 
210 108 98 96 100 97 102 
240 108 96 95 98 96 99 
270 104 96 95 98 97 98 
300 102 95 95 96 96 95 
______________________________________ 
(Values are shown in % taking the value at 0 minute as 100%.) 
The above results clearly show that the compound used in the present 
invention had as activity increasing choroidal blood flow.