WO2000016744A1

WO2000016744A1 - A pharmaceutical solution for the treatment of erectile dysfunction, prepared by sedds formulation

Info

Publication number: WO2000016744A1
Application number: PCT/KR1999/000568
Authority: WO
Inventors: Sang Soon Lee; Young Wook Choi; Sang Kil Lee; Gee Bae Park
Original assignee: Guju Pharm. Co., Ltd.
Priority date: 1998-09-23
Filing date: 1999-09-21
Publication date: 2000-03-30
Also published as: KR20000022734A; KR100350179B1

Abstract

The present invention relates to a new solution preparation containing prostanglandin E1 for the treatment of erectile dysfunction, which is prepared into a form of microemulsion preconcentrate. This preparation has a property, upon administration to a human body, of easily emulsifying or dispersing of itself and is of a system called a self-emulsifying drug delivery system (hereinafter to be referred to as 'SEDDS'), which is prepared by dispersing or dissolving a drug into a liquid mixture of oil, surfactant and cosurfactant.

Description

A PHARMACEUTICAL SOLUTION FOE THE TREATMENT OF ERECTILE

DYSFUNCTION, PREPARED BY SEDDS FORMULATION.

BACKGROUND OF THE INVENTION

Field of the invention

The present invention relates to a new pharmaceutical

composition for the treatment of erectile dysfunction. More

specifically, it relates to a mew pharmaceutical solution

composition containing prostaglandins, or prostan landin Eι{PGEι)

in particular.

Description of the prior art

Prostaglandin Ei is a bioactive compound chemically designated as

(11 a , 13E, 15S)- 11, 15-dihydroxy-9-oxaprost-13-erii-l-oic acid or

3-hydroxy-2-(3-hydroxy-l-octenyl )-5-oxo-cyclopentaneheptanoic

acid. It is odorless, white crystal which is soluble in water

and acetone, freely soluble in alcohol, very slightly soluble in

chloroform and ether, slightly soluble in ethylacetate and has a

molecular weight of 354.49. It is known to be the most stable at

pH 3—4 range in the form of an aqueous solution preparation and

at pH 5 in the form of an emulsion preparation. As such, it is

very unstable, especially in the presence of moisture, so a lot

of attempts to improve the stability of pharmaceuti al preparations containing the drug have been so far made as

described in such publications as, for example, the

specifications of US Patent No.3, 927.197, US Patent No.3, 952, 004

and 1095/11683, in which methods for freeze-drying prostaglandin

Ei and compositions of the corresponding formulations are

disclosed.

Namely, US Patent No.3, 927, 197 discloses a pharmaceutical

composition comprising a biologically active prostaglandin of

the E-series(Eι, E₂ and others) and a saturated aliphatic

tertiary alcohol having from 4 to 10 carbon atoms, said

prostaglandin being present in the amount of from about 0.005 to

0.500 * by weight, which is suitable to be processed into an

aerosol spray preparation for use in the dilation of the

bronchus. Further, US Patent No.3, 952, 04 discloses a

lyophilized pharmaceutical composition comprising a biologically

active prostaglandin of the E-series(Eι, E₂ and others) together

with a storage stabilizing amount of sodium chloride in a

weight/weight ratio of 1:1 to 1:200 and ¥095/11683 discloses a

lyophilized pharmaceutical formulation of prostaglandin Ei made

by the process comprising: a)dissolving prostaglandin Ei in a

solution of lactose and tertiary butyl alcohol; b)adjusting and

maintaining the pH of said formulation from about 3.5 to about 6 with an organic acid buffer; c)freezing said formulation to

about -50TC; and d)drying said formulation to obtain a moisture

content of less than \% by dry weight and a tertiary butyl

alcohol content of less than 3* by dry weight. Examples of these

pharmaceutical compositions that are placed for actual sales in

the market include an injectable lyophilized powder under the

brand name of Caverject by the Upjohn Company of USA and a

suppository under the brand name of MUSE by Vivas of USA, which

is administered either by injection or by insertion into the

urinary tract, respectively.

The significant defects of Caverject including pain at the time

of injection, tissue fibrosis and excessively long duration of

erection are common and well known to cause reluctance of the

patient. In contrast, MUSE is said to have overcome such defects

of the injectable preparation as it is in the form of a

pellet-type suppository that enables the drug to be absorbed

through dispersion by massaging after being inserted into the

urinary tract using an inserting device but still, it is not

free from the patient reluctance of inserting the suppository

into the urinary tract.

Thus, in order to overcome the problem of instability and other defects of existing pharmaceutical preparations containing

prostaglandins, the inventors of the present invention have made

strenuous efforts with a view to develop a new formulation of

prostaglandin, based on the concept of self-emulsi ying drug

delivery system(SEDDS), which can be easily administered as it

is in the form of a solution instead of a solid, rapidly absorbed

from the urethral mucus and of which the carrier can have such a

property to form a microemulsion to facilitate rapid excretion

and to minimize the feeling of foreignness upon urination as

well as being able to easily form a gel upon contact with the

body fluid to secure retention of the drug in the urinary tract.

We have tested and confirmed that the pharmaceutical solution

preparation of the present invention possesses such favorable

features as the followings:

a)Stability is much increased as the drug is dispersed in oil.

b)Easy to administer as it is in a solution form.

c)Upon contact with moisture, it tends to obtain viscosity or

form a gel which, in turn, increases retention in the urinary

tract facilitating closer contacts with the urethral mucus and,

subsequently, rapid absorption of the drug.

d)As it is prepared adopting the SEDDS concept, the residues

remaining after the drug has been absorbed and utilized can be easily excreted into the urine by forming a microemulsion.

Now that we have succeeded in preparation of an urethral

solution containing prostaglandin Ei which is useful for the

treatment of erectile dysfunction and has advantages as

described above, we hereby apply for a patent on it.

Summary of the invention

An object of the present invention is to provide a new urethral

solution containing prostaglandin Ei. The present invention

relates to a new solution preparation containiing prostanglandin

Ei for the treatment of erectile dysfunction, which is prepared

into a form of microemulsion preconcentrate.

This preparation has a property, upon administration to a human

body, of easily emulsifying or dispersing of itself and is of a

system called a self-emulsi ying drug delivery system

(hereinafter to be referred to as "SEDDS^*), tthich is prepared by

dispersing or dissolving a drug into a liquid mixture of oil,

surface active agent(surfactant) and auxiliary surface active

agent(cosurfactant).

The characteristic features of the preparation include such facts that it is capable to overcome instability of the drug to

moisture as it does not contain water and that it can easily be

administered into the urinary tract as it is in the form of a

solution. Moreover, it facilitates absorption of the drug as it

allows closer contact of the drug with the urethral mucus and

increases drug retention in the urinary tract by forming gels or

by increasing viscosity upon contact with a small amount of

water after being administered. Besides, the residues remaining

after absorption of the drug will be easily excreted into the

urine by self-emulsification upon contact with the body fluid.

Brief description of the drawings

Figure la is a diagram of phase equilibria for systems

containing Labrafac CC, where the relative ratios of surfactant

over cosurfactant are 3.0, 2.5, 2.0 and 1.5, respectively and

which also illustrates the relative concentrations of the three

components of the composition of the present invention. Further,

it represents Examples 1-1 through 1-24 of the present

invention.

Figure lb is a diagram of phase equilibria for systems

containing Labrafac lipophile and represents Examples 2-1

through 2-8 of the present invention.

Figure lc is a diagram of phase equilibria for systems containing Labrafil M1944CS and represents Examples 3-1 through

3-24 of the present invention.

Figure Id is a diagram of phase equilibria for systems

containing Labrafil WL2609BS and represents Examples 4-1 through

4-6 of the present invention.

Figure le is a diagram of phase equilibria, for systems

containing Maisine and represents Examples 5-1 through 5-6 of

the present invention.

Figures 2aa and 2ab show the distribution patterns of particle

sizes of the microemulsion prepared according to a

representative Example 1-17.

Figure 2b represents changes in the mean diameter of particles

in relation to the increases in the contents of oil in a

microemulsion prepared according to the present invention while

the ratio of surfactant to cosurfactant is controlled at 2.5.

(#; eight, O: number)

Figure 2c represents changes in the mean diameter of particles

in relation to the increases in the contents of oil in a

microemulsion prepared according to the present invention while

the ratio of surfactant to cosurfactant is controlled at 2.

(©'.weight, O^number)

Figure 3 represents changes in the viscosity in relation to the

increases in the contents of water in Examples 1-17(0), 1-21 (•) and l-24( r).

Figure 4a is a graph showing stabilities of the drug in Example

1-17 at the respective temperatures [4^*C(©), 20t:(O), 30t!(V),

40O(V) and Figure 4b is an Arrhenius plot showing k-value, or

the rate constant of drug degradation at respective temperatures

which demonstrate temperature-dependence of the degradation of

the drug.

Detailed description of the invention

The new urethral solution of the present invention having the

above-mentioned advantages is a pharmaceutical composition

containing prostaglandins such as PGEi as the active ingredient

in an oily carrier medium consisting of the components described

under (1) through (3) below.

(l)At least one or more of the cosurfactant selected from

a group of lower alcohols capable to enhance penetration through

the skin, consisting of ethanol, isopropyl alcohol and benzyl

alcohol.

(2)A kind of oil selected from a group consisting of

natural oils, glycerides, polyglycol ized glycerides, mineral oil

and isopropyl myristate.

(3)A hydrophilic surfactant selected from a group

consisting of those with an hydrophile-lipophile balance (HLB) value of 10 or higher.

The word, "pharmaceutical composition, used in the specification

and the claims of the present application is defined as a

composition consisting of ingredients or components which are

all pharmaceutically allowable, for example, those being

applicable and less irritant to the urethral mucus.

Prostaglandins utilizable for embodiment of the pharmaceutical

composition of the present invention can be any prostaglandin

known to the related fields of arts as far as it possesses

certain pharmacological usefulness, for example, being useful

for the treatment of erectile dysfunction, or more specifically,

being prostaglandin Ei. Moreover, lower alcohols or Component

(1), utilizable for embodiment of the pharmaceutical composition

of the present invention can be any one or two kinds of alcohols

combined by selecting from a group consisting of ethanol,

isopropyl alcohol and benzyl alcohol. Oils or Component (2),

utilizable for embodiment of the pharmaceutical composition of

the present invention can include a mixture of monoglycerides,

diglycerides and triglycerides of fatty acids with the number of

carbon atoms from 6 to 14, more preferably, a mixture of

monoglycerides, diglycerides and triglycerides of fatty acids

with the number of carbon atoms from 8 to 10. Further, in said _j mixture of monoglycerides, diglycerides and triglycerides of

fatty acids, the fatty acid portion can include both saturated

and unsaturated fatty acid residues. Preferably, however, the

fatty acid portion will include saturated fatty acid residues,

c more specifically, the residues of the saturated fatty acids

with the number of carbon atoms of 8 and 10, for example,

caprylic acid and capric acid. Component (2) will suitably

contain at least 90*. preferably 95* or more,, by weight of the

saturated fatty acids with the number of carbon atoms from 8 to

Q 10. Or, conversely, Component (2) ?/ill contain 1 * at maximum,

preferably 5* or less, by weight of lauric acid or myristic

acid. For more desired embodiment of the pharmaceutical

composition of the present invention, Component (2) will

preferably contain tryglycerides as one of the principal

_jr components, in an amount of at least 90*. for example 95* or

more, by weight of the total weight of Component (2).

Besides, some specific examples of the oils or Component (2)

suitable for the present invention include the followings.

20

Natural oils

(2.1)A corn oil which is a triglyceride consisting of fatty acid

esters of glycerol, contains five major fatty acids(58.9* of 1 linoleic acid, 25.8* of oleic acid, 11.0* of palmitic acid, 1.7*

of stearic acid and 1.1* of linolenic acid) and has an iodine

value of about 102 to 130 and a saponification value of about 187

to 193. c (2,2)A castor oil which is a glyceryl-tri-12-hydroxystearate and

has an acid value of less than 4, an iodine value of about 83 to

88, a refractive index( η O²⁵) between 1.473 and 1.477 and a

saponification value of about 176 to 182.

(2.3)Labrafac CC which contains triglycerides of caprylic acid

and capric acid as the principal components and monoglycerides,

diglycerides and triglycerides of lauric acid and myristic acid

as the auxiliary components and has an acid value of 0.2 at

maximum, an iodine value of 0.1 and a saponification value of

about 336.

_jc (2.4)Labrafac lipophile WL1349 having an acid value of less than

0.2, a saponification value between 310 and 360 and an iodine

value of less than 1.

(2.5)Maisine 35-1 having an acid value of less than 2, a

saponification value between 160 and 180, an iodine value

0 between 100 and 120 and with concentrations of free glycerol at

less than 1*. 1-monoglycerides 30—39*, palmitic acid(Clβ) 4—

20*. stearic acid(Clβ) 1-6*. oleic acid(C18:l) 24-34*.

linoleic acid(Cl8:2) 53—63* and linolenic acid(Cl8:3) less than 3*.

(2.6)Peceol having an acid value of 2.6(3 at maximum), a

saponification value between 155 and 170, an iodine value

between 69 and 85 and with concentrations of free glycerol at

less than 7*. 1-monoglycerides more than 35* and total

mono-esters 40—55*.

Polyglycolized glycerides

(2.7)Labrafil M1944CS having an acid value of less than 2, a

saponification value between 155 and 169, an iodine value

between 79 and 89 and with concentrations of free glycerol at

less than 3*. palmitic acid 4—20*. stearic acid 1—6*, oleic

acid 58-68*. linoleic acid 22-32*. linolenic acid(C18:3) less

than 3* and arachidonic acid(C20) less than 3%.

(2.8)Labrafil WL2609BS having an acid value of less than 2, a

saponification value between 124 and 138, an iodine value

between 81 and 91 and with concentrations of monoglycerides at

12* at maximum, palmitic acid(C16) 4—20*. stearic acid(C18) 1 —

6*. oleic acid(C18:l) 24-34*. linoleic acid(C18:2) 53-63*.

linolenic acid 3* at maximum and archidonic acid(C20) 3* at

maximum.

(2.9)Labrafil M 2125 CS. Liquid paraffin

Isopropyl myristate(acid value of less than 1, saponification

value 202—212, iodine value less than 1)

Component (3) of the pharmaceutical composition of the present

invention will preferably be a hydrophilic surfactant having an

HLB value of 10 or higher. Examples of Component (3) suitable

for the present invention include products of reaction of

natural or hydrogenated castor oil with ethylene oxide and, more

specifically, such commercially available tensides as sold

under the brand names like Cremophor EL, Cremophor ELP,

Cremophor RH 40, Cremophor RH 60, etc. and, in particular,

Cremophor EL having a molecular weight of about 1,630, a

saponification value between about 65 and 70, an acid value of

2, an iodine value between about 28 and 32 and a refractive

index( η O ) of about 1.471 or Cremophor ELP containing moisture

at less than 0.5*. ethylene oxide less than 1 ppm, free fatty

acids(Ci2~Ciε) less than 1*, ricinoleic acid less than 0.2*,

oleic acid and palmitic acid less than 1*. respectively but

Cremophor ELP is more preferable.

Components (1), (2) and (3) of the present invention should

better exist at a relative ratio which will be favorable for the pharmaceutical composition of the present invention to form a

microemulsion preconcentrate. The pharmaceutical composition of

the present invention should preferably be of SEDDS, or.

specifically, should be in the form of a microemulsion of oil in

water(o/w) type. In addition to Components (1), (2) and (3), the

pharmaceutical composition of the present invention contains

water(4) and the dosage forms according to the present invention

should be understood to also include those in the forms of a

microemulsion and a viscous dispersion. In the afore-said

microemulsion preconcentrate(SEDDS), Component (1) will exist in

an amount of 5—35*. preferably 10—25*. Component (2) will

exist in an amount of 10—50*, preferably 20—40* or 15—30* for

example, and Component (3) will preferably exist in an amount of

50—60* by weight against the total weight of the mass

[Component ( 1 )+Component (2)+Component (3)].

Besides, the pharmaceutical composition of the present invention

contains prostaglandin Ei in an amount in the usual dose range

per single-use urethral solution. Speci ically, the volume of

single-use urethral solution is in the range from 0.1 to 1.0 ml,

preferably from 0.1 to 0.5 ml or more preferably, from 0.1 to 0.3

ml and the usual dosage range of prostaglandin Ei is between 250

μ g and 1,000 zg. In the pharmaceutical composition of the present invention, the

relative ratios of Components (1), (2) and (3) will be properly

determined at a point in the two areas(Gel area or viscous

liquid area and microemulsion area), shown in Figure la. Figures

la through le show diagrams of phase equilibria obtained with a

variety of oils and Figures 2aa and 2ab show distribution

patterns of the particle sizes of the representative Example

1-17, presented later on. As shown in the figures, particle

sizes of the microemulsions obtained are uniform in the

distribution pattern. Moreover, it was observed that the

microemulsions of the preparations according to the SEDDS method

of the present invention were spontaneously formed upon light

stirring.

Figures 2b and 2c represent changes of the particle sizes in

relation to the increase in the ratio of oil. According to them,

the average particle size is in the range of 20—300 nm and it is

confirmed that microemulsions stable for several weeks can be

prepared.

Further, as it is represented in Figure 3„ viscosity of the

preparation will increase with the increase in the ratio of

water and it is expected that, after being administered to the urethral, absorption of the drug will be facilitated due to the

intimate adherence to the mucus as well as the reflux phenomenon

of the solution will be overcomed.

_c The pharmaceutical composition of the present invention is very ϋ stable as the test results are shown in Figure 4a[4O(#), 20O

(O). 30O(V), 40"C(V)]. The 120-day stability test results

were plotted in a first-order degradation equation and the rate

constant of degradationk) at 4^*C. calculated from the slope,

was 1.54X10^" /day. Using this value and calculating from the

first-order degradation equation, the shelf-life of the drug in

the microemulsion preconcentrate was determined to be about 688

days with the half-life of about 4,540 days. From these results,

the preparation was found very stable at the storage temperature

of 4O and expected to possess long-term stability of one year or 15 longer. Figure 4b represents an Arrhenius plot demonstrating a

correlation between the k-value and the temperature, determined

at different temperatures. The correlation curve is shown to

have a good linearity with the value of the correlation

coefficient γ ) at 0.975, which indicates that the stability

data presented in Figure 4a are sufficiently reliable. n the

following, Tables 1-1 and 1-2 show the comparative test results

on the time-dependent stability of the urethral solution of the 00/16744

17 present invention and a pH 3.5 buffered solution used as a

control .

Table 1-1

The urethral solution for the treatment of erectile dysfunction

of the present invention and the preparation methods using SEDDS

technology are explained further in detail with the following

examples but these examples do not have to be understood to

limit the scope of the present invention.

(Example 1 )

Preparation of SEDDS using Labrafac CC

According to the formulation given in Table 2, prostaglandin Ei 00/16744

18 in an amount equivalent to 1,000 μg in the final urethral solution of 0.1 ml is dissolved with stirring into ethanol and/or benzyl alcohol and then, to this solution, Cremophor EL or Cremophor ELP and Labrafac CC are added with stirring to prepare SEDDS.

For Examples from 1-10 to 1-15 in the table, the ratio of surfactant over cosurfactant(hereinafter to be abbreviated as "km") is 3 and for Examples from 1.-1 to 1-4 and from 1-16 to

1-19, km is 2.5. Further, for Examples from 1-5 to 1-7 and from 1-20 to 1-22, km is 2 and for Examples from 1-8 to 1-9 and from

1-23 to 1-24, km is 1.5.

(Table 2): Formulations for SEDDS using Labrafac CC(volume unit

in »1)

00/16744

19

( * : Cremophor EL)

(Example 2): Preparation of SEDDS using Labrafac lipophile

According to the formulation given in Table 3, prostaglandin Ei

in an amount equivalent to 1.000 μg in the final urethral

solution of 0.1 ml is dissolved with stirring into ethanol

and/or benzyl alcohol and then, to this solution, Cremophor EL

or Cremophor ELP and Labrafac lipophile are added with stirring

to prepare SEDDS. For Examples from 2-1 to 2-8 in the table, the

ratio of surfactant over cosurfactant is 2.5. 00/16744

20 (Table 3) Formulations for preparation of SEDDS using Labrafac

lipophile(volume unit in ml)

(Example 3): Preparation of SEDDS using Labrafil M1944CS According to the formulation given in Table 4, prostaglandin Ei

in an amount equivalent to 1,000 μg in the final urethral

solution of 0.1 ml is dissolved with stirring into ethanol

and/or benzyl alcohol at room temperature and then, to this

solution, Cremophor EL or Cremophor ELP and Labrafil M1944CS are

added with stirring to prepare SEDDS. For Examples from 3-1 to

3-24 in the table, the ratio of surfactant over cosurfactant is

2.5.

(Table 4) Formulations for preparation of SEDDS using Labrafil

M1944CS(volume unit in ml) 00/16744

21

Examples 3-19 3 20 3-21 3-22 323 3-24

Cremophor ELP 5 5 5 5 5 5

1

Ethanol 1 1 ¹ 1 1 1

Benzyl alcohol 1 1 1 1 1 I

1

Labrafil M1944CS 5.73 7 8.55 10.5 13 16.3

1

Total 12.73 7.5

! 14 15.55 1 20 23.3 (Example 4): Preparation of SEDDS using WL2609BS

According to the formulation given in Table 5, prostaglandin Ei

in an amount equivalent to 1,000 μg in the final urethral

solution of 0.1 ml is dissolved with stirring into ethanol

and/or benzyl alcohol at room temperature and then, to this

solution, Cremophor EL or Cremophor ELP and WL2609BS are added

with stirring to prepare SEDDS. For Examples from 4-1 to 4-6 in

the table, the ratio of surfactant over cosurfactant is 2.5.

(Table 5) Formulations for preparation of SEDDS using

L2609BS(volume unit in ml)

(Example 5): Preparation of SEDDS using Maisine

According to the formulation given in Table 6, prostaglandin Ei

in an amount equivalent to 1,000 μg in the final urethral

solution of 0.1 ml is dissolved with stirring into ethanol

and/or benzyl alcohol at room temperature and then, to this solution, Cremophor RH40 or Cremophor ELP and Maisine are added

with stirring to prepare SEDDS. For Examples from 5-1 to 5-6 in

the table, the ratio of surfactant over auxiliary cosurfactant

is 2.5.

(Table 6) Formulations for preparation of SEDDS using

Maisine(volume unit in ml)

The urethral solution for the treatment of erectile dysfunction

prepared according to the present invention is stable for one

year or more and capable to overcome instability of the drug to

moisture as it does not contain water. Moreover, it can easil

be administered into the urinary tract as it is in the form of a

solution and it facilitates absorption of the drug as it allows

closer contact with the urethral mucus and increases retention

in the urinary tract by forming gels and increasing viscosity upon contact with a small amount of water after being administered. Besides, the residues remaining after absorption

of the drug will be easily excreted into the urine by

self-emulsi fication upon contact with the body fluid. In

essence, the preparation according to the present invention is

more convenient to use than the existing preparations of

injection or suppository and thus, the present invention is

considered very useful for the industry.

Claims

(Claim 1) A pharmaceutical composition of a solution containing

prostaglandin Ei for the treatment off erectile dysfunction, which

consists essentially of;

Component (1): At least one or more of lower alcohols

selected from a group consisting off ethanol, isopropyl alcohol

and benzyl alcohol.

Component (2): A kind of oil selected from a group

consisting of natural oils, glycerides, polyglycolized

glycerides, liquid paraffin(mineral oil) and isopropyl

myristate, and,

Component (3): A carrier medium containing one surfactant

with an HLB value of 10 or higher and prostaglandin Ei as active

ingredient.

(Claim 2) The composition of claim 1 above, where said lower

alcohols of component (1) is contained in an amount of 10 to 25 *

by weight over the total weight of [component (1 )+component

(2)+comρonent (3)].

(Claim 3) The composition of claim 1 above, where said oil of

component (2) includes monoglycerides, diglycerides and

triglycerides of the fatty acids having from 8 to 10 carbon atoms.

(Claim 4) The composition of claim 3 above, where said oil of

component (2) contains about 50 to 80 * of caprylic acid(Cβ) and

about 20 to 50 * of capric acid(Cιo).

(Claim 5) The composition of any of claims 1, 3 and 4 above,

where said oil of component (2) contains Labrafac CC which

contains triglycerides of caprylic acid and capric acid as

principal component and monoglycerides, diglycerides and

triglycerides of lauric acid and myristic acid as auxiliary

component and has an acid value of 0.2 at maximum, an iodine

value of 0.1 and a saponification value of about 336.

(Claim 6) The composition of claim 1 above , where said

surfactant of component (3) includes natural or hydrogenated

castor oil or ethylene oxide.

(Claim 7) The composition of elate 6 above, where said

surfactant of component (3) is selected from either Cremophor

EL, which has a molecular weight of about 1630, a saponification

value of about 65 to 70, an acid value of about 2, an iodine

value of about 28 to 32 and a refractive index of 1.471 or, Cremophor ELP, which contains less than 0.5 * of water, less

than 1 ppm of ethylene oxide, less than 1 * of free fatty acids

with numbers of carbon atoms from 12 to 16 and less than 0. * of

ricinoleic acid.

(Claim 8) The composition of any of claims 1, 3, 4 and 5 above,

where said oil of component (2) is contained in an amount of

about 15 to 30 * by weight over the total weight of [component

( 1 )+component (2)+component (3)].

(Claim 9) The composition of any of claims 1, 6, and 7 above,

where said surfactant of component (3) is contained in an amount

of about 50 to 60 * by weight over the total weight of [component

( 1 )+component (2)+component (3)].

(Claim 10) The composition of claim 1 above, where dosage forn

of said solution is for administration into the urinary tract by

means of an infusing device and which can increase retention of

the drug in the urinary tract either by gaining viscosity or by

forming gels upon contact with a small amount of water.

(Claim 11) The composition of claim 10 above, where dosage form

of said solution contains water or an aqueous phase,

additionally and is a microemulsion or a viscous suspension.