WO2004054593A1

WO2004054593A1 - Ophthalmic compositions containing bile products from animal

Info

Publication number: WO2004054593A1
Application number: PCT/KR2003/002687
Authority: WO
Inventors: Geeyoung Kim; Jeongsook Park
Original assignee: Geeyoung Kim; Jeongsook Park
Priority date: 2002-12-18
Filing date: 2003-12-09
Publication date: 2004-07-01
Also published as: AU2003303053A1; KR100518276B1; KR20040054180A

Abstract

The present invention relates to ophthalmic compositions containing bile products from animal as an effective component and the treatment method therewith. More particularly, this invention relates to the topically applying ophthalmic compositions containing bile products from bears, cows, pigs, wild boars, badgers or snakes as an effective component. The topical application of this compositions is useful in the treatment or prophylaxis of various disorder connected with ocular disease.

Description

[Specification] [Title of the invention]

OPHTHALMIC COMPOSITIONS CONTAINING BILE PRODUCTS FROM ANIMAL [Field of the invention]

The present invention relates to ophthalmic compositions containing bile products from animal and the treatment method for ocular diseases therewith.

More particularly, the present invention relates to the topically applying ophthalmic compositions containing bile products from bears, cows, pigs, wild boars, badgers or snakes as an effective ingredient. The compositions are useful in the treatment or prophylaxis of various diseases associated with eyes through topical administration thereto.

[Technical background]

In general, one of the most common ocular diseases is keratitis or conjunctivitis caused by viral or bacterial infection or allegic. Even without these external causes, people suffer from the ocular diseases such as cataract or glaucoma associated with the abnormality of eye lens or optic nerve arisen from a result of other physical troubles or aging.

Furthermore, people suffer from eye fatigue, redness and ocular pain and also undergo many kinds of ocular diseases and troubles of weakened visual power because of the long use of computers and the increasing stress as getting civilized.

However, a concern is that the commercially available topical formulations, such as artificial tears, antibiotics, steroid agents, anti-inflammatory agents and so on, cannot have enough efficacy and give rise to side-effects as long applying.

Therefore, it was in urgent need of the topical ocular agent being scarcely causes side-effects and having long-term safety. The object of this invention is to provide the topical ophthalmic formulations which are useful in treating or preventing ocular diseases, what is more, is proven to be safe since they contains an effective ingredient which is oriented from natural products and have been used for a folk remedy.

According to Chinese herb medicine, bear's gall has been taken in for treating many kinds of disorder such as convulsion, lymphatic tuberculosis, some cerebral disorders, cholelithiasis, eye disorders, febrile diseases, stomach cramps, toothache, bruise, pneumonia and so on, and has been utilized for anti-seizure, analgesia, anti- inflammation, antidote and antipyretic. The gall from other animals has also been used for similar activity. Though gall from animals has been known as being biologically effective, it has not been tried to provide bile-containing topical formulations for treating ocular disease.

These inventors prepared a composition containing bile products, topically administered the composition to rabbit's eyes where conjunctivitis had been induced, and as a result proved the composition to have efficacy against conjunctivitis. [Detailed description of the invention]

The present invention relates to ophthalmic compositions containing bile products from animal.

The present invention also relates to ophthalmic compositions containing bile products from animal and ophthalmologically acceptable carriers.

Further, the present invention provides a treatment or prophylaxis method which comprises of topically applying an ophthalmic composition containing bile products from animal to eye in an amount effective to treat or prevent ocular diseases.

Bile acids are produced in the liver, collected in the gallbladder and then flows through bile duct to the duodenum, and there helps fat absorption by emulsification. The pH of bile is in the range of from 7.8 to 8.6, and the main compounds of bile are bile salts and bile pigment.

The suitable bile products of this invention is one or more of bile products from bears, cows, pigs, wild boars, badgers and snakes, but not limited thereto. The bile product of bears is the most preferable. The bile products of animals may be obtained through many routes of, such as extraction from the nature, genetic engineering, artificial synthesis and so on, and the present invention would not restrict the route.

The preferable route of the present invention may be purchasing commercially available bile products which are dried after drawn the gallbladder from the animal or dried after extracted from the gallbladder.

Bile products of this invention can be incorporated into various types of ophthalmic formulations for delivery to eye, e.g., topically, intracamerally or via implant. In order to improve bioavailablity, it is preferred that the compositions of this invention containing bile products and ophthalmologically acceptable carrier are formulated into topical ophthalmic formulations, not oral formulations.

The composition of the invention can be utilized as safe topical formulations because of comprising of natural-oriented bile products as an effective ingredient.

The composition of this invention may be formulated into gels (including thermogel), solutions, suspensions or ointments for topical administration to eye. Also, it is possible that the compositions are incorporated into ophthalmic drug delivery system such as liposome, microsphere, gel-phase protein, collagen, curative contact lens or intraocular lens.

More particular, the topical ophthalmic formulations of this invention may comprise of additives such as buffers, tonicity agents, preservatives, solubility enhancers (stabilizers), pH adjusters, viscosity enhancers, not as long as impairing the purpose of this invention. Examples of the buffers include phosphate buffer, borate buffer, citrate buffer, tartrate buffer, acetate buffer and amino acid, but not limited thereto. Acetate buffer as like sodium acetate is preferable.

As suitable tonicity agent, there are saccharides such as sorbitol, glucose and mannitol; polyalcohols such as glycerin, polyethyleneglycol and propyleneglycol; and salts such as sodium acetate. Polyethyleneglycol is preferable.

Examples of preservatives include, but not limited to, p-hydroxybenzoic esters such as benzalkonium chloride, benzethonium chloride, methylp-hydroxy benzoic acid, ethylp-hydroxy benzoic acid; benzyl alcohol; phenethyl alcohol; sorbic acid and derivatives thereof; thimerosal and chlorobutanol.

Examples of solubility enhancers (stabilizers) include, but not limited to, soluble polymer such as cyclodextrins and derivatives thereof, polyvinylpyrrolidone; and surfactants. Polyvinylpyrrolidone or cyclodextrin is preferable.

Examples of pH adjusters include, but not limited to, hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide and potassium hydroxide. Hydrochloric acid is preferable.

Examples of viscosity enhancers include, but not limited to, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethyl cellulose and derivatives thereof.

When the compositions of this invention are formulated into ophthalmic ointments, bases of the ointments such as purified lanolin, vaseline, plastibase, liquid paraffin and polyethyleneglycol are utilized, but not limited thereto. The pH of the ophthalmic formulations may be adjusted to the range of generally 4.5 to 8.5, preferably 5.0 to 8.0, and more preferably 6.0 to 7.0.

The ophthalmic formulations of this invention may comprise the additional effective ingredients but bile products from animal, not as long as impairing the purpose of the invention. The topical ophthalmic formulations of this invention can be prepared according to preparation method well known in the pertinent art. The present invention provides a treatment or prophylaxis method which comprises of topically applying an ophthalmic composition containing bile products from animal to eye in an amount effective to treat or prevent ocular diseases.

The ocular disease includes ocular infections and also glaucoma, cataract, eye fatigue, redness, ocular pain, weakened visual power, etc., wherein the ocular infections include conjunctivitis, trachoma, keratohelcosis, keratitis, endophthalmitis, infective uvetitis and combinations thereof.

In order to determine therapeutic effect of the ocular formulations, the inventors prepared a composition containing bile products, topically administered the composition to rabbit's eyes where conjunctivitis had been induced. As a result, redness and swelling following inflammation were disappeared and tearing and exudation were reduced as time goes by.

Further, the composition has been topically administered to eyes of volunteers who are in teens or twenties. As a result, it is proven that symptom of eye fatigues was reduced and eyesight was strengthened.

In case of male volunteer in sixties suffering from cataract, the symptoms got better. When the composition was topically administered to the volunteer after cataract surgery, his eyesight was getting clear.

Also, intraocular pressure of glaucoma went down as topical applying. Many cases showed that redness and/or pain of eyes were generally reduced and discharge was inhibited.

Accordingly, ocular diseases can be treated or prevented through topical applying the ophthalmic formulation of this invention to eyes in an amount effective to treat or prevent ocular diseases.

The administration of the topical ophthalmic formulations is preferably useful to treat or prevent pre-bulbar inflammation, glaucoma, cataract, fatigue, redness, weakening visual power, more preferably to treat infective disease as like traumatic inflammation.

Even though a suitable dose of the topical ophthalmic formulation is dependant on age, weight or condition of patients, state of disease and the like, it is preferred that the topical ophthalmic solutions would comprise of effective ingredient of 0.001 ~ 5.0 w/v%, more preferably of 0.05 ~ 1.0 w/v%, and 1 - 2 drops of the solutions would be topically applied to eye 2-6 times per day.

In case of topical ophthalmic ointment, it is preferred that the ointment comprises of effective ingredient of 0.001 ~ 10.0 w/v%, more preferably of 0.05 — 1.0 w/v%, and would be topically applied 2-6 times per day. [Preferred embodiments]

The present invention will be described by the following examples in more detail.

However, the examples shown below are provided solely to illustrate the invention; the scope of the invention should not be construed to be limited thereto.

Preparation of the ophthalmic aqueous solution An ophthalmic aqueous solution of pH 6.0 was prepared as following formula; Ingredients weight (g)

Bear bile 0.1

Mannitol 5.0

Sodium hydrogen phosphate 0.1

Methyl p-hydroxy benzoic acid 0.02

Propyl p-hydroxy benzoic acid 0.01

Diluted hydrochloric acid q.s.

D.D.W. to make 100ml

Preparation of the ophthalmic aqueous solution

An ophthalmic aqueous solution of pH 6.0 was prepared as following formula;

Ingredients weight (g) Bear bile 0.2

Boric acid 2.0

Benzalkonium chloride 0.005

Sodium hydroxide q.s.

D.D.W. to make 100ml

Preparation of the ophthalmic aqueous solution An ophthalmic aqueous solution of pH 4.5 was prepared as following formula; Ingredients weight (g)

Bear bile 0.3

Concentrated glycerin 2.6

Sodium acetate 0.1 α-cyclodextrin 0.1 methyl p-hydroxy benzoic acid 0.02 propyl p-hydroxy benzoic acid 0.01

Diluted hydrochloric acid q.s.

D.D.W. to make 100ml

Preparation of the ophthalmic aqueous solution

An ophthalmic aqueous solution of pH 6.0 was prepared as following formula; Ingredients weight (g)

Bear bile 0.4

Concentrated glycerin 2.6

Sodium acetate 0.1

Benzalkonium chloride 0.005

Diluted hydrochloric acid q.s.

D.D.W. to make 100ml <Example 5>

Preparation of the ophthalmic aqueous solution

An ophthalmic aqueous solution of pH 5.5 was prepared as following fomiula; Ingredients weight (g)

Bear bile 0.5

Concentrated glycerin 2.6

Sodium acetate 0.1

Polyvinylpyrrolidone 0.5

Benzalkonium chloride 0.005

Diluted hydrochloric acid q.s.

D.D.W. to make 100ml

Preparation of the ophthalmic aqueous solution An ophthalmic aqueous solution of pH 4.0 was prepared as following formula;

Ingredients weight (g)

Bear bile 0.1

Concentrated glycerin 2.6

Sodium hydrogen phosphate 0.1 Polyvinylpyrrolidone 1.0

Sodium edetate 0.05

Benzalkonium chloride 0.005 Sodium hydroxide q.s.

D.D.W. to make 100ml

Preparation of the ophthalmic aqueous solution

An ophthalmic aqueous solution of pH 5.0 was prepared as following formula; Ingredients weight (g)

Bear bile 2.0

Concentrated glycerin 0.1

Sodium acetate 2.6

Polyvinylpyrrolidone 0.1

Benzalkonium chloride 0.005

Diluted hydrochloric acid q.s.

D.D.W. to make 100ml

Preparation of the ophthalmic ointment

An ophthalmic ointment was prepared as following formula; Ingredients weight (g) Bear bile 0.5

Liquid paraffin 1.0

White petrolatum to make lOOg <Example 9>

Preparation of the ophthalmic ointment

An ophthalmic ointment was prepared as following formula; Ingredients weight (g)

Bear bile 1.0

Liquid paraffin 1.0

White petrolatum to make lOOg

Experimental Example 1>

Determination of therapeutic effect against conjunctivitis of white rabbit

<1-1> Preparation of acute conjunctivitis model

Acute conjunctivitis was artificially induced to the eyes of test animals which were male white rabbits weigh of 2.3 - 3.0 Kg (Samyook Animal Center, Kyoungi-do KR.)

More particularly, ethanol(83%) of 25 μl was dropped to eyes of white rabbit. After 12 hours, conjunctival congestion and swelling being a major symptom of conjunctivitis was caused, eye mucus was generated and exudation was increased. Each group comprised of 5~7 rabbits and was divided into control group or test group. <l-2> Determination of therapeutic effect of bile-containing topical ophthalmic formulations against acute conjunctivitis

After 12 hours since the congestion was induced by ethanol, 1 to 2 drops of the ophthalmic solution according to the formula of Example 2 were administered for 2 days, 5 times with intervals of 3 hours per day, to eye of test group, while those according to the formula analogues to Example 2 except bear bile to control group.

The symptoms of conjunctivitis were observed for 72 hours after administration and the result was shown in Table 1.

[Table 1]

Determination of therapeutic effect against conjunctivitis of white rabbit

h Table 1, criteria to symptom are as follows;

(1) Congestion (restricted to conjunctiva of palpebrae and eyeball, not cornea and iris)

Normal state of capillary 0

Redness of some capillary 1

Widespread dark red, each capillary is not indicated 2

Bright red 3

(2) Conjunctival swelling Not swelling 0

Slightly swelling (including membrana nictitans) 1

Remarkable swelling with partial abduction of eyelid 2

Eyelid swelling as to cover half of eyeball 3 Eyelid swelling as to cover more than half of eyeball 4

(3) Exudation

None 0

Some exudation 1

Getting eyelash and eyelid wet 2 Getting eyelash, eyelid and somewhat surrounding wet 3

(4) Total marks (1+2+3) x 2 (Maximum=20)

(5) Decision

0 - 5 Normal (0)

6 - 10 Mild inflammation (+) 11 - 15 Middle inflammation (++)

16 - 20 Serious inflammation (+++)

It is showed from the Table 1 that when the topical ophthalmic formulations containing bile products as an effective ingredient according to the invention were administered, most of symptoms were disappeared after 12 hours, hi case of controls administered the topical ophthalmic formulations without bile products thereto, congestion, swelling and exudation were not reduced even though 12 hours went by after administration. Also the symptoms were slightly remained by after 48 hours.

That is, it is proven that the composition of the invention exhibits the efficacy of reducing congestion of eyeball and/or conjunctiva, of rapidly sedating swelling of eyelid, and of inhibiting generation of eye mucus and exudation. [Industrial Applicability]

According to the invention, the ophthalmic composition containing bile products is useful to treat or prevent redness of eyeball and/or eyelid, swelling, excessive eye mucus and so on, because of having improved therapeutic effect.

Further, the ophthalmic composition of this invention can be utilized to settle the concern associated with weakening visual power, eye fatigue, redness, ocular pain and so on caused by the long use of computers and the increasing stress as getting civilized.

It is also possible to lower or control intraocular pressure of patients suffering from glaucoma and to reduce flecked eyesight of patients suffering from cataract via the treatment method of this invention.

Claims

[Claims]

1. An ophthalmic composition containing bile products from animal as an effective ingredient and an ophthalmologically acceptable carrier.

2. The composition according to claim 1, wherein said animal is selected from the group consisting of bears, cows, pigs, wild boars, badgers and snakes.

3. The composition according to claim 1, which further contains an additional effective ingredient.

4. The composition according to one of claim 1 to claim 3, wherein said effective ingredient is contained in an amount of from 0.01 to 5.00 w/v%.

5. The composition according to claim 1, wherein said carrier is selected from the group consisting of buffers, tonicity agents, preservatives, solubility enhancer

(stabilizers), pH adjusters and viscosity enhancers.

6. The composition according to claim 1 or claim 5, which is formulated into solution, suspension, gel or ointment.

7. A treatment method comprising of topically applying an ophthalmic composition containing bile products from animal as an effective ingredient to eye for treatment or prophylaxis of ocular diseases.

8. The treatment method according to claim 7, wherein said ocular disease is selected from the group consisting of ocular infection, eye fatigue, redness, ocular pain, weakening visual power, glaucoma and cataract.

9. The treatment method according to claim 7 or claim 8, wherein said ocular infection is selected from the group consisting of conjunctivitis, trachoma, keratohelcosis, keratitis, endophthalmitis, infective uvetitis and combinations thereof.