IL25251A

IL25251A - Aqueous ophthalmic compositions based on hydroxyethylcellulose and method of preparation

Info

Publication number: IL25251A
Application number: IL2525166A
Authority: IL
Original assignee: Merck & Co Inc
Priority date: 1965-07-20
Filing date: 1966-02-24
Publication date: 1969-11-12
Also published as: GB1090492A; ES325333A1; FR6039M; CH468190A; NL6604206A; DK115865B; BE678695A

Description

D»oa o'i'a'j nKiBi'? ni'a'a ma yn Aqueous o i almie compositions based on hydroxyethylcellulose and method of preparation.

MBRCK & CO., IHO. 0. 24099 This invention relates to medicinal preparations for ophthalmic use and a method of their preparation. More particularly it relates to a novel aqueous base for ophthalmic medicinals and a method of preparation which ensures a resultant sterile, substantially particle free preparation.

Historically, the application of drugs to the area of the eye has been accomplished by two general methods.

Medicinals have been applied as aqueous solutions or suspensions and in the form of non-aqueous ophthalmic ointments. There are several disadvantages inherent in the use of ophthalmic solutions. Among these, difficulty of self administration, overflow and fleeting activity should be mentioned.

Ophthalmic ointments should be considered non-aqueous. Varying amounts of water may be incorporated with the aid of suitable water-in-oil emulsifying agents, however, the formulation remains essentially non-aqueous insofar as tniscibility with water is concerned. This lack of miscibility gives rise to several disadvantages inherent in the use of these products. The usual ophthalmic ointment is greasy and not readily miscible with aqueous eye fluids; it may tend to ooze from the inner lid area and normal vision becomes blurred. This latter property becomes especially disadvantageous wh'en ointments are applied to. the eye during the day. After application the vision becomes blurred and remains so for long periods of time. In addition, ophthalmic ointments usually cause a transient conjunctival erythema following instillation.

The application of medicinals to the eye is most satisfactory when all agents are in solution. This condition minimizes any possible irritation derived from solid particles which tend to cause tearing due to a foreign body effect.

At the same time the need for producing microfine solids for I suspension or dispersion is obviated. It would follow from this that an aqueous solution having physical properties similar to an ointment should be an ideal method for ophthalmic application of drugs. All solid materials would be in solution and readily miscible with aqueous eye fluids; pH and tonicity could be adjusted; spillage from the eye would not occur and duration of activity would be prolonged. Additionally, active components which must be in solution to .achieve maximum activity can be readily utilized. Moreover, such a product would be readily available for immediate absorption and have the immediate advantage of non-interference with normal vision. If necessary, the refractive index of a given formulation could be adjusted to equal that of tear fluid or other normal ophthalmic secretions.

There are several obvious difficulties in the preparation of an aqueous gel suitable for ophthalmic use.

Many gelling agents are unsatisfactory because of inverse solubility characteristics, irritation, or extremes of hydrogen ion concentration. In addition, many gel formers do not form solutions of sufficient clarity for ophthalmic use.

At best, many of these agents^ contain small amounts of insoluble fibrous material which may be a source of irritation on instillation in the eye. Moreover, any ophthalmic solution must be sterile and therefore, the preparation thereof must include an effective sterilization procedure.

It is therefore an object of this invention to provide novel compositions for ophthalmic use which avoid the inherent disadvantages known heretofore.

It is another object of this invention to provide an effective method of preparing these novel compositions for ophthalmic use. ' It has now been found that an aqueous base containing water soluble cellulose derivatives can be used to prepare effective solutions for ophthalmic use in the form of aqueous gels and sols. These gels and sols are well suited for use in and around the eye. While it is known that some cellulose derivatives do not form fiber-free aqueous solutions, a novel method has been devised for the removal of substantially all particulate matter from the resultant gels and sols.

The novel aqueous base compositions of this invention are prepared generally by forming an aqueous solution of hydroxyethylcellulose having a Brookfield relative viscosity in the range of from about 10 centipoises to about 100,000 centipoises.

Example 1 Aqueous Gel Base An aqueous solution is prepared by adding to water 0.2 V -propiolactone as a freshly prepared % solution and 1.25% W/V hydroxyethylcellulose (Cellosize-Union Carbide QP 100M) , and the solution agitated until gelation occurs. Clarification to render the gel solution substantially fiber-free is accomplished by centrifuging in an open type Sharpies T-l centrifuge at 23,000 r.p.m. and a flow rate of 4 liters per hour. Air or nitrogen under pressure is used to deliver the gel to the centrifuge.

After clarification, the solution is subdivided asep'tically into polyethylene containers for ophthalmic use. In a matter of a few days of standing at room temperature the finished gel as subdivided into the final container is 'sterilized in situ by the^ -propiolactone , which then itself is decomposed into harmless inert ingredients. The finished gel base has flow characteristics similar to petrolatum.

Example 2 Aqueous Gel Base An aqueous solution is prepared by adding to water 0.2 W/V^ -propiolactone as a freshly prepared % solution and 2.5% W/V hydroxyethylcellulose (Cellosize.-Union Carbide QP 4400) , and the solution agitated until gelation occurs. Clarification to render the gel solution substantially fiber-free is accomplished by centrifugihg in an open type Sharpies T-l centrifuge at 23,000 r.p.m. and a flow rate of 4 liters per hour. Air or nitrogen under pressure is used to deliver the gel to the centrifuge. After clarification, the solution is subdivided aseptically into polyethylene containers for ophthalmic use. In a matter of a few days of standing at room temperature the finished gel as subdivided into the final container is sterilized in situ by the -propiolactone, which then itself is decomposed into harmless inert ingredients. The finished gel base has flow characteristics similar to petrolatum.

Aqueous gel base compositions such as those shown in Examples 1 and 2 may be compounded aseptically with a desired medicinal at the time of administration, or a stable preparation may be prepared in accordance with any of the following Examples 3, 4, 5, 13, 14, 17, 18, 21 or 22.

Example 3 Aqueous Gel Containing Pilocarpine Nitrate Ingredient % W Example 4 Aqueous Gel Containing Pilocarpine Nitrate Ingredient Pilocarpine nitrate Sorbitol (70% aqueous sol.) Sodium citrate Ethylenediaminetetraacetic acid disodium salt (E.D.T.A. disodium) Chlorobutanol Hydroxyethylcellulose (Cellosize- Λ Union Carbide QP 4400) & -Propiolactone Water Example 5 Aqueous Gel Containing Pilocarpine Nitrate Ingredient % W/V Water In formulating the compositions of Examples 3, 4 and 5, the sorbitol solution, Έ.Ό.Τ.A. disodiu , chlorobutanol and pilocarpine nitrate are first dissolved in 70 parts of water for injection. Then a freshly prepared 10% solution of the ^-propiolactone is added and dissolved followed by the addition of the hydroxyethylcellulose . The sodium citrate is then dissolved in 20 parts of water for injection and added to the bulk while agitating. The formula is brought to volume with water for injection and agitated until gelation occurs. Clarification to render the gel solution fiber-free is accomplished by centrifuging in an open type Sharpies T-l centrifuge at 23,000 r.'p.m. and a flow rate of 4 liters per hour. Air or nitrogen under pressure is used to deliver the gel to the centrifuge. After clarification, the solution is subdivided aseptically into polyethylene containers for ophthalmic use. It is important that the sodium citrate be added to the solution after the addition of j -propiolactone since pilocarpine nitrate is destroyed very rapidly in alkaline solution.

Nonetheless, in a matter of a few days of standing' at room temperature the finished gel as subdivided in the final container is sterilized by the ^^-propiolactone, which then itself is decomposed into harmless inert ingredients. Formulations prepared in accordance with Examples 3, 4 and 5 give assay recoveries of pilocarpine nitrate having excellent values after 6 months storage at 25-50°C.

Example 6 Aqueous Sol Base I ! An aqueous solution is prepared by adding to water 0.2% W/V -propiolactone as a freshly prepared 10% solution and 1.0% W/V hydroxyethylcellulose (Cellosize- Union Carbide QP 4400), and agitating the solution.

Clarification to render the solution substantially fiber- free is accomplished by filtration through, any of the following media: 1. Sharpies centrifuge 2. Sintered glass filter-coarse 3. Unglazed porcelain candle XFF 4. Stainless steel Fulflo filter cartridge . Stainless steel 200 mesh disc.

After clarification, the solution is subdivided aceptically into polyethylene containers for ophthalmic use. In a matter of a few days of standing at room temperature the finished. sol as subdivided into the final container is sterilized in situ by the^ -propiolactone , which then itself is decomposed into harmless inert ingredients.

The finished sol base has flow characteristics similar to glycerin.

Example 7 Aqueous Sol Base An aqueous solution is prepared by adding to water 0 0..22%% --pprrooppiioollaaccttoonnee aass aa ffrreesshhllyy pprreeppaarreedd 1100%% ssoolluuttiioonn aanndd 00..33%% WW//VV hhyyddrrooxxyyeetthhyyllcceelllluulloossee ((CCeelllloossiizzee-- UUnniioonn CCaarrbbiiddee QQPP 110000 MM)) ,, aanndd aaggiittaattiinngg tthhee ssoolluuttiioonn.. 7884 Clarification to render the solution substantially fiber- free is accomplished by filtration through any of the following media: 1. Sharpies centrifuge 2. Sintered glass filter-coarse 3. Unglazed porcelain candle XFF 4. Stainless steel Fulflo filter cartridge . Stainless steel 200 mesh disc.

After clarification, the solution is subdivided aseptically into polyethylene containers for ophthalmic use. In a matter of a few days of standing at room temperature the finished sol, as subdivided into the final container is sterilized in situ by the , which then itself is decomposed into harmless inert ingredients.

The. finished sol base has flow characteristics similar to glycerin.

Aqueous sol base compositions such as those shown in Examples 6 and 7 may be compounded aseptically with a desired medicinal at the time of administration,, or a stable preparation may be prepared in accordance with any of the following Examples 8, 9, 10, 11, 12, 15, 16, 19, 20, 23, 24 or 25.

Example 8 Aqueous Sol Containing Pilocarpine Nitrate Ingredient % W Pilocarpine nitrate 1.0 Sorbitol ('70 aqueous sol.) 1.0 ' Sodium citrate 1.0 E.D.T.A. disodium 0.05 Chlorobutanol 0.5 Hydroxyethylcellulose (Cellosize- Union Carbide QP 4400) 1.0 & -Propiolactone ^ 0.2 Water 7884 Example 9 Aqueous Sol Containing Pilocarpine Nitrate Ingredient % W/sf Pilocarpine nitrate 2.0 Sorbitol {70% aqueous sol.) 1.0 Sodium citrate 1.0 E.D.T.A. disodium 0.05 Chlorobutanol 0.5 Hydroxyethylcellulose (Cellosize- Union Carbide QP 4400) 1.0 -Propiolactone , . 0.2 Water Example 10 Aqueous Sol Containing Pilocarpine Nitrate Ingredient - % W/V Pilocarpine nitrate 4.0 Sorbitol {70% aqueous sol.) 1.0 Sodium citrate 1.0 E.D.T.A. disodium " 0.05 Chlorobutanol 0.5 Hydroxyethylcellulose (Cellosize- Union Carbide QP 100 M) 0.3 > -Propiolactone 0.2 Water The compositions of Examples 8, 9 and 10 are formulated in the same manner as those of Examples 3, 4 and 5 except that since the resultant solutions are sols rather than gels, the clarification to remove fibers and other extraneous material thereof is accomplished by filtration through any of the following media: 1. Sharpies centrifuge 2. Sintered glass filter-coarse 3. Unglazed porcelain candle XFF '4. Stainless steel Fulflo filter cartridge . Stainless steel 200 mesh disc 7884 Example 11 Aqueous Sol Containing Dexamethasone Phosphate Disodium Ingredient % W/V Dexamethasone phosphate disodium 0.10 (as free acid) Sorbitol (70% aqueous sol.) 1.0 E.D.T.A. disodium 0.05 Creatinine 0.5 Polyoxyethylene sorbitan mono- oleate 0.2 Benzalkonium chloride 0.02 Sodium citrate > 0.5 Hydroxyethylcellulose (Cellosize - Union Carbide QP 100 M) 0.3 Water Example 12 Aqueous Sol Containing examethas'one Phosphate Disodium Ingredient % WV Dexamethasone phosphate disodium 0.10 (as free acid) Sorbitol (70% aqueous sol.) 1.0 E.D.T.A. disodium 0.05 Creatinine 0.5 Polyoxyethylene sorbitan mono- oleate 0.2 Benzalkonium chloride 0.02 Sodium citrate 0.5 Hydroxyethylcellulose (Cellosize- Union Carbide QP 4400) 1.0 Water The compositions of Examples 11 and 12 are formulated by dissolving the sorbitol solution, E.D.T. A. disodium, creatinine, polyoxyethylene sorbitan mono-oleate, sodium citrate, benzalkonium chloride and hydroxyethylcellulose in 80 parts of water for injection. This solution is then sterilized by autoclaving. Separately, the dexamethasone phosphate disodium is dissolved in 15 parts of water for injection. This solution is sterilized by filtration 7884 through a sterilizing filter directly into the autoclaved substantially fiber-free vehicle. The total formulation is cooled to room temperature and brought to volume by passing water for injection through the sterilizing filter described above. The solution is rendered fiber-free as described by any of the methods in Example 10. In these formulations, sterilization by autoclaving may be eliminated by the addition of either ^ -propiolactone or propylene oxide as in situ sterilizing agents. In these cases, formulation is by simple solution of all of the ingredients in sufficient water for injection to yield the formula volume. However, when^-propiolactone is employed, sufficient sodium hydroxide must be added to maintain a pH of 7-7.5. Formulations in accordance with Examples 11 and 12 as thus prepared have excellent physical and chemical stability in polyethylene containers for ophthalmic uae after 6 months at temperatures between 5° and 50° C Example 13 Aqueous Gel Containing "Dexamethasone Phosphate Disodium Ingredient % W/V Dexamethasone phosphate disodium 0 .10 (as free a Sorbitol (70 aqueous sol.) 1 .0 E.D.T.A. disodium 0 .05 Creatinine 0 .5 Polyoxyethylene sorbitan mono- oleate 0 .2 Benzalkonium chloride 0 .02 Sodium citrate 0 .5 Hydroxyethylcellulose (Cellosize- Union Carbide QP 4400) 2.5 Sodium hydroxide or: hydrochloric acid q . s . pH 7.5 -propiolactone \ 0.2 'Water 7884 Example 14 , Aqueous Gel Containing "Dexamethasone Phosphate Disodium Ingredient % W/V Dexamethasone phosphate disodium 0.10 (as free acid) Sorbitol (70 aqueous sol.) 1.0 E.D.T.A. disodium 0.05 Creatinine 0.5 Polyoxyethylene sorbitan mono- oleate 0.2 2 . pH 7.5 Wate The compositions of Examples 13 and 14 are formulated in an identical way with those of Examples 3, 4 and 5, and the pH is adjusted to 7.5 with the sodium hydroxide "and hydrochloric acid as necessary.

Example 15 Aqueous Sol Containing Dexamethasone Phosphate Disodium and Neomycin Sulfate .

Ingredient % wA Dexamethasone phosphate disodium 0.10 (as free acid) Neomycin sulfate 0.50 Creatinine 0.50 E.D.T.A. disodium 0.05 Sodium citrate 0.75 Sodium bisulfite 0.10 Polyoxyethylene sorbitan monooleate 0.20 Benzalkonium chloride 0.02 Hydroxyethylcellulose (Cellosize- Union Carbide QP 100 M) 0.30 Water v 7884 Example 16 Aqueous Sol Containing Dexamethasone Phosphate Disodium and Neomycin Sulfate Ingredient % W Dexamethasone phosphate disodium 0.10 (as free acid) Neomycin sulfate- 0.50 Creatinine 0.50 E.D.T.A. disodium 0.05 Sodium citrate 0.75 Sodium bisulfite 0.10 Polyoxyethylene sorbitan monoo'leate 0.20 Benzalkonium chloride 0.02 Hydroxyethylcellulose (Cellosize- ' Union Carbide QP 4400) 1.0 Water The compositions of Examples 15 and 16 are formulated by dissolving the creatinine, E.D.T.A. disodium, sodium citrate, polyoxyethylene sorbitan mono-oleate, benzalkonium chloride and the hydroxyethylcellulose in 60 parts of water of injection. This solution is auto-claved to sterilize the composition and cooled to room temperature. The neomycin sulfate and sodium bisulfite are dissolved separately in 10 parts of water for injection.

The dexamethasone phosphate disodium is dissolved separately in 10 parts of water for injection. Each of these two separate solutions is sterilized individually by filtration through a sterilizing filter directly into the autoclaved vehicle. The formula is brought to volume by filtration of water for injection through the sterilizing filter, and polyethylene containers for cphthaJjmc use are filled aseptically after clarification. Alternately, sterilization of the compositions of Examples 15 and 16 may i¾e accomplished by incorporating therein 0. Q W/V^'-propiolactone , but a ·;: . - :. i : i 7884 different formulation procedure must be observed. In this case, all of the ingredients except the neomycin sulfate and the sodium bisulfite are dissolved in 80 parts of water for injection, including 0.2# and sufficient sodium hydroxide to obtain a final formulation pH of 6.80. This solution is stored for 24-48 hours to allow for dissipation of the ft -propiolactone . Then the neomycin sulfate and sodium bisulfite are dissolved in parts of water for injection and this solution is added - aseptically to the ^-propiolactone sterilized vehicle while sterilizing through a suitable sterilizing filter -such as an 015 Selas candle. The sterilizing filter is rinsed with water for injection to reach the formula volume. The sol is clarified as before and ; sub-divided aseptically.

The stability of the formulations in accordance with Examples 15 and 16 have been demonstrated by analysis of samples stored up to 6 months ' at a temperature of between 5°C .' -50°C .

Example 17 Aqueous Gel Containing Dexamethasone Phosphate Disodium and Neomycin Sulfate ■ Ingredient % W Dexamethasone phosphate disodium 0.10 (as free acid) Neomycin sulfate 0.50 Creatinine 0.50 E.D.T.A. disodium 0.05 Sodium citrate ■ - . 0.75 Sodium bisulfite 0.10 Polyoxyethylene sorbitan monooleate 0.20 Benzalkonium chloride 0.02 Hydroxyethylcellulose (Cellosize - Union Carbide QP 4400) f 2.5 Sodium hydroxide or..', hydrochloric acid q.s. pH 7.5 J -propiolactone 0.2 'Water 7884 Example 18 Aqueous Gel Containing Dexamethasone Phosphate Disodium and Neomycin Sulfate Ingredient % W/V Dexamethasone phosphate disodium 0.10 (as free acid) Neomycin sulfate 0.50 Creatinine 0.50 E.D.T.A. disodium : 0.05 Sodium citrate 0.75 Sodium bisulfite 0.10 Polyoxyethylene sorbitan monoqleate 0.20 Benzalkonium chloride 0.02 Hydroxyethylcellulose (Cellosize- Union Carbide QP 100 M) 1.25 •Sodium hydroxide or hydrochloric acid q;s. pH 7.5 /*9 -propiolactone 0.2 Water The compositions of Examples 17 and 18 are formulated in the same manner as those of Examples 15 and 16, except that the clarifying procedure of Examples 3, 4 and must be used (and the pH is adjusted to 7.5 with the sodium hydroxide o ! hydrochloric acid as necessary) and the vehicle containing the ί rpropiolactone must be clari- fied before dissipation of the sterilizing agent. The neomycin sulfate is then added as a-sterile solution after dissipation of the^ -propiolactone .

Example 19 Aqueous Sol Containing Dexamethasone Phosphate- Disodium and Sulfisoxazole Ingredient % WA ' Dexamethasone phosphate disodium 0..0 (as free acid) Sulfisoxazole 4.0 Diethano'lamine 1.66 Sodium thiosulfate 0.2 Sodium bisulfite 0.1 Sodium citrate / 0.5 E.D.T.A. disodium 0.05 Creatinine 0.5 Sorbitol (70% aqueous sol.) 1.0 Polyoxyethylene sorbitan monooleate 0.20 7884 Example 20 Aqueous Sol Containing Dexamethasone Phosphate Disodium and Sulfisoxazole Ingredient % W/V Dexamethasone phosphate disodium 0.10 (as free acid) Sulfisoxazole 4.0 Diethanolamine 1.66 Sodium thiosulfate 0.2 Sodium bisulfite :; 0.1 Sodium citrate ' 0.5' E.D.T.A. disodium , 0.05" Creatinine - 0.5 Sorbitol {l0% aqueous sol.) 1.0 Polyoxyethylene sorbitan monooleate 0.20 Benzalkonium chloride 0.02 Hydroxyethylcellulose (Cellosize- Union Carbide QP 4400) 1.0 Sodium hydroxide or' hydrochloric acid q.s. pH 7.5 Water (Note: Sulfisoxazole is 3,4-dime thyl-5 sulfanil- amdoisoxazole ) The compositions of Examples 19 and 20 are formulated by dissolving the sodium thiosulfate, sodium citrate, -E.D.T.A. disodium, Creatinine, Sorbitol solution, polyoxyethylene sorbitan monooleate, benzalkonium chloride and hydroxyethylcellulose in sufficient water to obtain % of the formula volume. This solution is sterilized by autoclaving, followed by cooling to room temperature.

The sulfisoxazole is suspended in 20 parts of water and the diethanolamine added with agitation to dissolve the sulfisoxazole. This solution is set aside. The dexamethasone phosphate disodium and the sodium bisulfite are dissolved in 5 parts of water. The pH is adjusted to 7.50 with sodium hydroxide or hydrochloric acid as necessary. 7884 The resultant solution and the sulfisoxazole solution are combined and then added to the solution in the sterile vehicle through a sterilizing filter such as a Selas 015 candle. The solution is brought to volume by passing water through the sterilizing filter. The formula is rendered substantially fiber free as described in the methods of Example 10 and then divided aseptically. Complete assay recoveries of both dexamethasone phosphate and sulfisoxazole have been obtained after 6 months storage at 5°C . -50°C . of the compositions of Examples 19: and 20.

Alternatively, sterilization by autoclaving may be eliminated by using ^ -propiolactone in a manner identical to that hereinbefore described as in situ sterilization.

Example 21 Aqueous Gel Containing Dexamethasone Phosphate Disodium and 'Sulfisoxazole Ingredient % W/V Dexamethasone phosphate 0.10 (as free acid) Sulfisoxazole 4.0 Diethanolamine 1.66 Sodium- thiosulfate 0.2 Sodium bisulfite 0.1 Sodium citrate 0.5 E.D.T.A. disodium 0.05 Creatinine 0.5 Sorbitol (70 aqueous sol.) 1.0 Polyoxyethylene sorbitan monooleate 0.20 Benzalkonium chloride 0.02 Hydroxyethylcellulose (Cellosize- Union Carbide QP 100 M-) 1.25 Sodium hydroxide or. hydrochloric acid q . s . pH 7.5 Water 7884 Example 22 Aqueous Gel Containing Dexamethasone Phosphate Disodium and Sulfisoxazole Ingredient % W/V Dexamethasone phosphate disodium 010 (as free Sulfisoxazole ' ' 4.0 Diethanolamine 1.66 Sodium thiosulfate 0.2 Sodium bisulfite 0.1 Sodium citrate < 0.5 E.D.T.A. disodium 0.05 Creatinine '· 0.5 Sorbitol (70% aqueous sol.) 1.0 Polyoxyethylene sorbitan monooleate 0.20 Benzalkonium chloride 0.02 Hydroxyethylcellulose (Cellosize- Union Carbide QP 4400 2.5 Sodium hydroxide or; hydrochloric acid q.s. pH 7.5 Water The compositions of Examples 21 and 22 are formulated in the same manner as those of Example 19 and 20, except that the clarifying procedure of Examples 3, 4 and 5 must be used.

Example 23 The procedure in accordance with Example 8 is repeated, except that 0.3% W/V citric acid is substituted for the ^'-propiolactone , and the autoclaving procedure of Examples 12 and 16 is used.

Example 24 The procedure in accordance with Example 9 is repeated, except that 0.3% Wy citric acid' is substituted for- the ^-propiolactone, and the autoclaving procedure of Examples 12 and 1β is used. 7884 ■ ■ Example 25 The procedure in accordance with Example 10 is repeated, except that 0.3% WV citric acid is substituted for the β -propiolactone , and the autoclaving procedure of Examples 32 andl6 is used.

The herein described . process of sterilization . utilizing ^-propiolactone is preferred whenever the viscosity of the ophthalmic solutions produced in accordance with the process of this invention or the susceptibility of such solutions to sterilizing temperatures renders filtration through bacteria-retentive filters or heat sterilization impractical. When thus used, the solution may be effectively sterilized in subdivided form in its final container, in situ by the simple expedient of allowing the product to stand for several days, he^-propiolactone decomposing into inert non-irritating compounds.

The novel hydroxyethylcellulose base for active ophthalmic pharmaceuticals of this invention includes any type which in water will yield a Brookfield relative viscosity in the range of from about 10 centipoises to about 100,000 centipoises. The resultant solutions after clarification are clear, colorless and are substantially free of fiber-forming particles.

The sol compositions of the foregoing examples are fluid types having flow characteristics similar to glycerin, while the gel compositions have flow characteristics similar to petrolatum. A typical gel composition formulated in accordance with the process of this invention has a relative :' · · ,· 7884 i Brookfield viscosity o£ greater than 12,000 centipoises, while a typical sol composition so formulated has a relative Brookfield viscosity of below, 500 centipoises. Gels or sols made in accordance with this invention retain essentially their original viscosities during storage or during use over the temperature range of from about 5°C . to about 37°C . , hence the pharmaceutical forms remain reasonably f constant. Similar solutions utilizing other gum substances frequently change in viscosity :with temperature appreciably, and sometimes even markedly. This, is, of course, an undesirable characteristic in. an ophthalmic preparation.

Claims

HAVING NOW PARTICULARLY DESCRIBED AND ASCERTAINED THE NATURE OP OUR SAID INVENTION AND IN WHAT MANNER THE SAME IS TO BE PERFORMED, WE DECLARE THAT WHAT WE CLAIM ISj

1. A process for the preparation of a sterile for opht'plmic use particle free preparation comprising the steps of (1) preparing an -.aqueous solution of hydroxy- , ethyl cellulose, said solution having a Brookfield relative viscosity in. he range of from about 10 centipoises to about 100,000 centipoises, and (2) clarifying and sterilizing the resultant - solution of step (l).

2. A process for the preparation of a sterile particle free solution for ophthalmic use comprising the steps of (1) dissolving an ophthalmic medicinal in an aqueous solution of hydroxyethyl cellulose, said solution having a Brookfield relative viscosity in the range of from about 10 centipoises to about 100,000 centipoises, and (2) clarifying and sterilizing the resultant solution of step (l) .

3. The process of claims 1 and 2 wherei ' clarification is carried out by filtration.

4. . The process of claims 1 and 2 wherein clarification is carried out by centrifugation. 7884

5. The process of claims 1 and 2 wherein the resultant . solution of step (l) is a sol and clari ication is carried out by filtration.

6.. The process of claims 1 and 2 wherein the resultant solution of step (l)« is a gel and clarification is carried out by centrifugation.

7. The process of claim 2 wherein the ophthalmic medicinal is pilocarpine nitrate.

8. The process of claim 2 wherein the ophthalmic medicinal is dexamethasone phosphate disodium.

9. The process of claim 2 wherein the ophthalmic medicinal is a combination of dexamethasone phosphate disodium and 3, ½-dimethyl-5-sulfanilamidoisoxazole. 788 for onhtalmic use

10. -An aqueous preparation/consisting essentially of a sterile, substantially fiber forming particle free, aqueous solution of hydroxyethyl-cellulose having a Brookfleld relative viscosity in the range of from about 10 centipoises to about 100,000 centipoises.

11. A sterile, substantially particle free preparation for ophthalmic use consisting essentially of (1) an ophthalmic medicinal in (2) an aqueous solution of hydroxyethyl cellulose havin a Brookfleld relative viscosity in the range of from about 10 centipoises to about 100,000 centipoises.

12. The composition of claim 11 wherein the ophthalmic medicinal is pilocarpine nitrate.

13. · The composition of claim 11 wherein the ophthalmic medicinal is dexamethasone phosphate disodiura.

14. The composition of claim 11 wherein the ophthalmic medicinal is a combination of dexamethasone phosphate disodium and neomycin sulfate.

15. The composition of claim 11 wherein the ophthalmic medicinal is a combination of dexamethasone phosphate disodium and' 3 , -dimethyl-5-sulfanilamidoisoxazole .

16. The composition of claim 11 wherein the ophthalmic medicinal is a combination of dexamethasone phosphate and neomycin sulfate.

17. A preparation in accordance with claim 11, having flow characteristics similar to glycerin.

18. A preparation in accordance with claim 11, having flow θΑτεο