JPS6059885B2 - Ophthalmic aqueous gel formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates generally to compositions for treating ocular diseases and methods for treating ocular diseases.

More particularly, the present invention relates to a time-retaining topical ophthalmic gel containing an ophthalmic drug. Ocular DiseasesA variety of ophthalmic drugs have been developed that have therapeutic effects when used to treat eye diseases.

Such ophthalmic drugs include, for example, pilocarpine, epinephrine, tetracycline, corticosteroids and carbachol. A problem with the use of such ophthalmic drugs is maintaining the drug in contact with the ocular surface for a sufficient period of time to produce the desired therapeutic effect. Various methods have been tried to prolong the time that ophthalmic drugs remain in contact with the eye. For example, U.S. Pat. No. 3,828,777 discloses an ophthalmic device for controlling and continuously administering a predetermined amount of a drug to the eye. It is a microporous drug release rate adjusting material that is insoluble in liquids. The pores of this drug release rate controlling material are filled with a medium that allows the drug to percolate through diffusion. The drug release rate modulating material body further includes a reservoir of drug formulation entrapped within the material body. have The reservoir has low solubility in the medium and has a shape suitable for insertion and retention in the conjunctival sac. The material body continues to release a therapeutically effective amount of drug to the eye and surrounding tissues at a predetermined rate over an extended period of time. Ophthalmic inserts are well known and are used for the purpose of prolonging the effects of drugs contained therein.

U.S. Patent No. 3811444, U.S. Patent No. 382625
Specification No. 8 and No. 378681? The specification discloses the ophthalmic insert. US Pat. No. 3,845,201 and US Pat. No. 3,914,404 disclose conventional solid drug dosage forms. Conventional drug-containing ointments are either opaque and therefore obstruct the vision of the eye or are rapidly removed by the normal function of the eye and are therefore unable to reduce the rate of drug release. It was not effective in treating eye diseases. U.S. Pat. No. 4,003,991 discloses a relatively low viscosity ophthalmic ointment containing a water-soluble polymer and an active ingredient.
Accordingly, a first object of the present invention is to provide compositions and methods for treating eye diseases.

Another object of the present invention is to provide compositions and methods for topical ophthalmic administration that provide long-acting, detentive gel formulations containing ophthalmic drugs. Another object of the present invention is to provide compositions and methods for the treatment of eye diseases comprising reacting an ophthalmic drug with a polymer to form a complex and/or salt suitable for topical administration to the eye. Then, the ophthalmic drug is slowly released from the complex and/or salt. The foregoing and other objects of the present invention will become more apparent from the detailed description of the invention.

In summary, the present invention provides a method for forming highly viscous gels, which can be used to increase the duration of action of ophthalmic drugs when the gel is administered to the conjunctival sac of the eye. Concerning aqueous dispersions with molecular weight polymers.

Sustained action of the ophthalmic drug is achieved by slowly releasing the ophthalmic drug from the gel matrix and/or by slowly eroding the gel surface. The ophthalmic drug-containing gel composition of the present invention remains in the eye for a long period of time and, as a result, remains in contact with the ocular surface for a long period of time. High molecular weight polymers useful in the present invention have a molecular weight of about 1 million to about 6 million.

The polymers are characterized by having carboxyl or carboxylic anhydride functional groups and preferably contain from 2 to 7 carbon atoms per functional group. The gel formed during the preparation of the ophthalmic drug/polymer dispersion is
5 rpm (NO.7 spindle). RVTB type viscometer (RVTBrOOkfjeldViscOmeter)
It has a viscosity of from about 40,000 to about 300,000 CPS, preferably from about 75,000 to about 2,000,001 PS as measured at . The viscosity of the gel is NO. Too high to measure with 3 spindles. The gel was further measured using a Ferr'Anti-Shirey Viscometer.
Approximately 5,000 to approximately 20 at 25°C (Ometer)
It is characterized by having a descending value of 000dyne1cr1 or more. The high molecular weight polymers used in the compositions of the present invention not only increase the viscosity of the composition to form a gel, but also provide a special type of viscosity or rheology, namely plastic viscosity.

Plastic viscosity is a measure of a material that will not flow until the force or stress exceeds a certain value. This is called the descending value. Without wishing to be bound by theory, it appears that the prolongation of the duration of action of the ophthalmic drug in the gel composition of the present invention is not only related to the apparent viscosity (thickness), but also to the desiccation value. It will be done. The gel compositions of the present invention also exhibit thixotropic rheological parameters associated with disruption and recovery of gel structure. As the gel composition is sheared above the shedding value and begins to flow, the gel structure is destroyed. However, upon removal of the shear, the gel structure is restored and initial high viscosity and descending values can be reached. High molecular weight polymers useful in the ophthalmic compositions of the present invention are those capable of providing high viscosity and high dropout value rheological properties at the levels described above.

Suitable polymers useful in the present invention include carboxypropyl methylene, carboxyvinyl polymer (B.F.GOO
It is commercially available from drich Company under the trade name 4°C ArbOpOPl.

) and ethylene maleic anhydride (MOnsantOC
It is commercially available from Ompany under the trade name ``EMN''. ) etc. The polymers are present in the gel composition at about 2
Wt% ~ approx.? Use at the % level. The compositions and treatment methods of the invention can be used with any ophthalmically active drug.

In particular, it can be used with known amine drugs for the treatment of eye diseases. Examples of such ophthalmic drugs include pilocarpine, epinephrine, tetracycline,
Phenylephrine, serine, phosphorine iodide, demecarium bromide, cyclobentrate, hematropine, scopolamine, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, gentamicin, penicillin, erythromycin, carbachol, sulfur Cetamidine, polymyxin B1 idoxulurisine,
Isofluorofate, fluoromethalone, dexamethasone, hydrocortisone, hydrocortisone acetate, dexamethasone utorinate, fluorocinolone, medrysone,
These include prednisolone, methylprednisolone, prednisolone utrate, prednisolone acetate, betamethasone, and triamcinolone. The ophthalmic drug is incorporated into the gel composition of the present invention in an amount effective to treat the disease.

The usual dosage of ophthalmic drugs is about 0.0 based on the weight of the gel composition.
It is within the range of 3 wt% to about 15 wt%. - The present invention is particularly suitable for prolonging the action of pilocarpine.

This has been the goal of the field of eye disease treatment in ophthalmology for many years. Accordingly, various embodiments of the invention are detailed below with reference to the use of pilocarpine as the ophthalmic drug in the compositions of the invention. Several methods are used to produce the ophthalmic drug/polymer compositions of the present invention.

The first method (hereinafter referred to as "Method A") consists of dispersing the polymer in water followed by the addition of a basic ophthalmic drug to neutralize the polymer. Upon neutralization, a hydrogel complex of ophthalmic drug and polymer is produced. Final P
H depends on the basicity of the ophthalmic drug and the amount used. If the drug is not sufficiently basic, the pH of the hydrogel can be adjusted to the desired pH by adding basic substances such as ammonium hydroxide, sodium hydroxide, ethanolamine or other basic compounds. Preferably, the ophthalmic drug/polymer gel formulation has a pH of about 4.5 to about 8.5. Similarly, it was confirmed that any ophthalmic drug can be added to the hydrogel. That is, the basic drug (non-pharmaceutical) is first added to the polymer to form a hydrogel, followed by the addition of the ophthalmic drug at any desired concentration. The second method (hereinafter referred to as "Method B").

) produces salts of ophthalmic drugs and polymers. Ophthalmic drug salts are prepared by dispersing the polymer in an inert organic solvent such as hexane, benzene or chloroform to form a slurry. Thereafter, a solvent solution of the ophthalmic drug is added to the slurry. Acid-base neutralization reactions occur which precipitate the polymeric ophthalmic drug product from the solvent. After removing the solvent, a finely divided solid remains. In the case of ophthalmic drugs such as carbachol, the neutralization reaction produces a solid mass. The various solid lumps can be made into fine powder by a crushing operation. Thereafter, a gel is produced by dispersing the finely divided product in water. A third method (hereinafter referred to as "Method C") uses an acid salt form of the drug.
A non-pharmaceutical base such as sodium hydroxide is used to neutralize the aqueous dispersion of the polymer and form a gel, followed by addition of the acid salt form of the drug. The duration of action of the ophthalmic drug-containing gel formulations prepared by all three methods described above is at least twice that of commercially available ophthalmic drug formulations.

Studies of pilocarpine formulations complexed with carboxypolymethylene by Method A demonstrated the special properties of these gel formulations. The peculiarity is that these gel formulations remain in the conjunctival sac of rabbits for 4 to 8 hours. It has been found that conventional formulations such as petrolatum ointments or suspensions of slightly soluble salts of pilocarpine are flushed out of rabbit eyes within 15 to 3 doses. In another embodiment of the invention, microparticles of the polymeric ophthalmic drug salt produced by Method B are suspended in a non-aqueous vehicle of stabilizing oil, such as mineral oil, vegetable oil, and liquid silicone. The suspended particles are then administered directly to the eye. The particles react with the tears in the eye and immediately form a gel in the eye. The pilocarpine salt of carboxypolymethylene, containing 2 m9 of pilocarpine for each dose, caused rabbit eyes to remain miotic for H hours, whereas the aqueous solution of pilocarpine caused only 4 to 6 hours of miosis. There was only a period of miosis. In yet another embodiment, the ophthalmic drug salt particles are administered directly into the eye by any suitable method. You can also do it.

The particles then gel in situ in the eye by reacting with the eye's tears. The present invention will be explained in more detail below with reference to Examples.

The following examples are intended to illustrate various aspects of the invention and are intended to limit the scope of the invention. It's not a thing. Example 1 Salt of carboxypolymethylene and pilocarpine was prepared using method B.
Generated by.

B. F. From GOOdrIch ゜゜Carb0p01
Carboxypolymethylene 6y, commercially available under the trade name 940゛, was stirred in 30 ml of hexane. Pilocarpine 49 was dissolved in 30 ml of hexane. The pilocarpine solution was then mixed with a suspension of carboxypolymethylene. An acid-base neutralization reaction occurred to form a salt of pilocarpine and carboxypolymethylene. A finely powdered salt form of carboxypolymethylene pilocarpine containing about 35 to 40 wt % of pilocarpine was recovered from the hexane carrier. A gel formulation containing pilocarpine/carboxypolymethylene salt was prepared.

The gel formulation contained the ingredients in the amounts shown in Table 1 below. Benzalkonium chloride was added to 80V of purified water to produce 100y of final gel. The benzalkonium chloride solution was stirred while the carboxypolymethylene/pilocarpine salt powder was rapidly added. The solution was stirred vigorously for about 1-2 minutes to infiltrate as much of the salt powder as possible before forming a gel. Stirring was continued until no more visible hydration occurred. Then, a sufficient amount of sodium hydroxide was added little by little to adjust the pH to a desired level. Purified water was then added into the gel to give a final gel weight of 100y. Gel formulation 120
Autoclave for 2 minutes at ℃ followed by rapid degassing. The final gel may contain air bubbles, which can be removed by centrifugation. The following conditions: (a)
3X Switch Position (SwjtchPOsitiOn) (
b) sweep between 6 [strains]; (c) medium cone; and (d) using a Ferrantj-Shirley viscometer with a spring constant of 100 r'Pm;
The following viscosity measurements were obtained.

50 doses of Formulation A and Formulation B in the left eye of 9 healthy subjects.
Human miosis data were obtained by administering μe.

The untreated right eye was used as a control. Prescription A1 Prescription B
and a control formulation of standard pilocarpine solution contained the equivalent of 2 wt% pilocarpine. The data shown in Table 3 below was obtained. The greater pupil diameter difference after 1 hour for compositions A and B compared to the control 2% pilocarpine solution indicates the longer duration of the gel composition of the present invention. Example 2 Three additional formulations were prepared and used to obtain miosis data in rabbits.

The formulation contained the ingredients in the amounts shown in Table 4 below. Formulation C in Table 4 was prepared as described in Example 1 above.

Therefore, Formulation C is the same as Formulation A of Example 1. Table 4
Formulation A was produced as follows.

Pilocarpine hydrochloride and benzalkonium chloride were dissolved in 80f of purified water. While stirring the solution vigorously, carboxypolymethylene was slowly added into the stirring vortex. Stirring was continued until a cloudy solution without lumps was obtained. After the stirring was stopped, the trapped air was degassed.

A solution 10y containing about 95% of the required molar amount of sodium hydroxide was slowly added to the non-clear solution with stirring. When stirring was continued for 10 to 2 minutes, a gel was rapidly formed. The gel was stored overnight in the refrigerator to complete hydration and equilibrate the pH. The final pH of the finished gel was adjusted by adding sodium hydroxide dropwise, mixing thoroughly after each drop addition. Purified water was then added to the gel to make the final weight of the gel 100y. If the finished gel contained air bubbles, the air bubbles were removed by centrifugation.
Formulation B in Table 4 was prepared as follows.

Bengalkonium chloride was dissolved in 80 y of purified water. While stirring the solution vigorously, carboxypolymethylene was slowly added to the stirring vortex. Stirring was continued until a clear suspension without lumps was obtained. After the stirring was stopped, the air trapped in the liquid was degassed. Pilocarpine-containing solution 1
0y was prepared and slowly added to the carboxypolymethylene solution with stirring. A gel formed quickly. Stirring was continued for 0 to 2 minutes.

The pH of the gel was adjusted to within the desired pH range of 0.1-0.2 PH by adding sodium hydroxide dropwise and stirring thoroughly after each drop of sodium hydroxide. The gel was stored in the refrigerator overnight to allow the pH to equilibrate. The final pH was adjusted to 5.4. Purified water was added to the gel to bring the final weight of the gel to 100V.
If the finished gel contained air bubbles, they were removed by centrifugation. The final pH of Formulation A and Formulation B was measured.

Both were 5.35. Rheograms were measured using a Ferranti-Shirley viscometer with the following conditions: (a) 2X switch position; (b) 6-line sweep; (c) medium cone; and (d) 100 r'Pm spring constant.

The viscosity measurements shown in Table 5 below were obtained. Miosis-time data were obtained using six white rabbits for each formulation in Table 4 and for the control formulation of pilocarpine solution described in Table 1 above.

Miosis data is shown in Table 6 below. The ophthalmic gel compositions of the present invention for topical administration provide therapeutic compositions that are retentive and provide sustained release of the active ingredient.

The "compositions can be used in the eye in various disease states. If the active ingredient is pilocarpine, epinephrine or carbachol, they can be used in particular in glaucoma. Previously known ophthalmic compositions with sustained release properties can be used in solid inserts. , flakes or steroid preparations of various compositions and designs, either in suspension or ointment dosage forms.Ointment dosage forms contain primarily petrolatum, with additional amounts of lanolin or derivatives thereof. Another known ointment dosage form consists of polyethylene containing liquid paraffin entrapped in the matrix. Conventional ointment dosage forms are substantially greasy and cosmetically unappealing because the Ointments are sticky and obscure vision. Furthermore, they have been found to last only about 25% longer therapeutic or pharmacological effects compared to water-based preparations. The ophthalmic drug/polymer gel composition of the present invention has a sustained action that is 2 to 3 times longer than that of an aqueous solution.Furthermore, the gel composition of the present invention has approximately 95 wt% water incorporated into the polymer matrix. and is not sticky.The vision is clear and the refractive index is similar to that of tears.Example 3 Pilocarpine in the form of an acid salt was prepared by method C. Ethylene maleic anhydride (EMA-9 from MOnsantO)
It is commercially available under the trade name 1.

) was mixed into the gel produced from Two gel formulations were prepared. These contained the ingredients in the amounts shown in Table 7 below. Ethylene maleic anhydride was added into a vortex of 25 ml of water that was vigorously stirred using a high speed mixer to make 100 Da of the final gel.

1 to completely infiltrate and disperse the polymer.
Mixing for a minute was sufficient. Ammonium hydroxide was added to the dispersion and mixed for 1-2 minutes until a hard gel was formed. Pilocarpine hydrochloride, mannitol and benzalkonium chloride were dissolved in 15 ml of purified water and added to the gel. This mixture was stirred for 4 minutes. PH is 5.1
It was hot. No. An RVTB type viscosity with a 7 spindle at 20 rpm was used and the following conditions were used: (a) 3X switch position; (b) 6@ sweep; (c) medium cone; and (d) Ferranti-Shjrley with 100 rpm spring constant. A viscometer was similarly used to obtain the viscosity measurements shown in Table 8 below.

Miosis-time data were obtained using six white rabbits for Formulation A and Formulation B of Table 7 and the control formulation of pilocarpine hydrochloride aqueous solution.

Miosis data is shown in Table 9 below. 50μ' was administered.

EXAMPLE 4 Two tests were conducted to illustrate the dependence of residence time in the eye for high duration of gel compositions of the present invention.

The test method is summarized below. (a) Three groups of six rabbits per group were used, and they were administered 50 μe of carboxypolymethylene gel containing 1.7% pilocarpine, produced by method B.

Using a cotton sponge saturated with physiological saline, the gel was removed from the eyes of the two groups of rabbits 6 and 12 times after instillation. The rabbits were then compared to a control group in which the gel formulation was left in the eyes without being removed. The duration of miosis in the rabbits in the control group was 8. It was class time. On the other hand, the test group showed a miosis duration of 5.1 SI and 5.28 hours, corresponding to gel removal at 6 and 12 drops after instillation. Therefore, removing the gel from the rabbit's eye, even 2 hours after instillation, significantly shortens the duration of miosis. (b) Tritium-labeled pilocarpine was used to produce carboxypolymethylene pilocarpine salt according to Method B.

Tritiated pilocarpine was similarly incorporated into petrolatum. 50 μl of each formulation containing 1.7% pilocarpine was administered to the right eye of the rabbit. Groups of 6 rabbits were killed periodically. The entire conjunctival sac of each rabbit was excised and the content of tritium-labeled pilocarpine was determined in each case. Two hours after instillation, the 30% pilocarpine/carboxypolymethylene formulation remained in the rabbit's eye. However, only 30% of the pilocarpine/petrolatum formulation remained in the rabbit's eye within a few minutes after instillation.

Claims (1)

Claims: 1. An ophthalmic aqueous gel formulation for administration to the conjunctival sac of the eye, the gel comprising an ophthalmic drug and a gel-forming high molecular weight carboxyvinyl polymer, the polymer comprising
00000 or more, and the ophthalmological drug has a molecular weight of about 0.00000 or more.
03 to about 15% by weight, the polymer is present at a level of about 2 to about 8% by weight, and the gel is about 4000% by weight.
An ophthalmic aqueous gel formulation, characterized in that it has a (Bruckfield) viscosity of 0 to about 300,000 cps and a yield value of about 5,000 to about 20,000 dyn/cm^2. 2 The polymer has a molecular weight of about 1,000,000 to about 6,000,000
Claim 1 characterized in that it has a molecular weight of
The aqueous gel formulation described in Section 1. 3. The aqueous gel formulation of claim 1, wherein the gel has a (Bruckfield) viscosity of about 75,000 to about 200,000 cps. 4 The gel has about 90,000 to about 150,000 cps (
2. The aqueous gel preparation according to claim 1, which has a viscosity of 10% (Bruckfield). 5. The aqueous gel formulation of claim 1, wherein the ophthalmic drug is selected from the group consisting of idoxuridine, pilocarpine, pharmaceutically acceptable salts of pilocarpine, and carbachol. 6. The ophthalmic drug is selected from the group consisting of hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluorocinolone, medrysone, prednisolone, methylprednisolone, prednisolone 21-phosphate, prednisolone acetate, fluoromethasone, bemethasone, and triamcinolone. The aqueous gel preparation according to claim 1, which is an ophthalmic steroid. 7. The aqueous gel preparation according to claim 1, wherein the ophthalmic drug is an ophthalmic antibiotic selected from the group consisting of neomycin, polymyxin, chloramphenicol, erythromycin, tobramycin, and gentamicin. . 8. The aqueous gel preparation according to claim 1, wherein the gel has a pH of about 4.5 to about 8.5. 9. The ophthalmic drug is pilocarpine, the high molecular weight polymer is a carboxyvinyl polymer, and the gel has a (Bruckfield) viscosity of about 75,000 to about 200,000 cps and a viscosity of about 5,000 to about 20,000 dyne/
The aqueous gel preparation according to claim 1, characterized in that it has a yield value of cm^2.