CA1330304C - Tissue irrigating solution - Google Patents
Tissue irrigating solutionInfo
- Publication number
- CA1330304C CA1330304C CA000608460A CA608460A CA1330304C CA 1330304 C CA1330304 C CA 1330304C CA 000608460 A CA000608460 A CA 000608460A CA 608460 A CA608460 A CA 608460A CA 1330304 C CA1330304 C CA 1330304C
- Authority
- CA
- Canada
- Prior art keywords
- solution
- irrigating
- dextrose
- ions
- glutathione
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/42—Phosphorus; Compounds thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
- A61K38/063—Glutathione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
Abstract
TISSUE IRRIGATING SOLUTION
Abstract of the Disclosure In a tissue irrigating solution of the type con-taining the combination of glutathione, bicarbonate, and Ringer solution (GBR), the chloride salts (Ringer solution) are packaged and stored in solution and the bicarbonate and glutathione are freeze-dried and packaged and separately stored in powder form until immediately preceeding the operation, at which time the bicarbonate and glutathione are dissolved directly into the solution of chloride salts. The resulting solution is mixed within 24 hours of use.
Abstract of the Disclosure In a tissue irrigating solution of the type con-taining the combination of glutathione, bicarbonate, and Ringer solution (GBR), the chloride salts (Ringer solution) are packaged and stored in solution and the bicarbonate and glutathione are freeze-dried and packaged and separately stored in powder form until immediately preceeding the operation, at which time the bicarbonate and glutathione are dissolved directly into the solution of chloride salts. The resulting solution is mixed within 24 hours of use.
Description
` 1 330304 TISSUE IRRIGATING SOLUTION
Background of the Invention The present invention is directed to tissue irri-gating solutions and, more particularly, to an improved technique for formulating and packaging the components of a tissue irrigating solution containing glutathione, bicarbonate, and Ringer solution.
During the surgical procedures, it has been found extremely important to minimize disturbance of the environment of tissue and cells as much as possible. A
traumatic change in the environment surrounding inter-nal cells may lead to the destruction of such cells or the destruction of the function of such cells. The destruction of cell function may even lead to destruc-tion of other cells which are dependent upon a proper functioning of the destroyed cells. Therefore, during surgical procedures such as, for example, intraocular ~ -surgery, it is very important that the exposed tissue be continuously irrigated with solutions which approxi-mate natural body fluids. Such solutions are called "tissue irrigating solutions". One of the earliest ~ tissue irrigating solutions for ophthalmic procedures `~' was an isotonic saline. However, it was quickly ~ - recognized that the isotonic saline was not adequate as `~ 25 an ophthalmic irrigating solution because it resulted in endothelial cell swelling, cell damage, and con-sequent corneal clouding.
Alternatively, various electrolyte solutions have i been proposed as tissue irrigating solutions, par-ticularly in ophthalmic procedures, because such solu-tions more closely resemble the aqueous humor of the eye. The earliest electrolyte solution was known as ~ Ringer's solution, which was a combination of sodium, i calcium and potassium ions along with sodium lactate.
Background of the Invention The present invention is directed to tissue irri-gating solutions and, more particularly, to an improved technique for formulating and packaging the components of a tissue irrigating solution containing glutathione, bicarbonate, and Ringer solution.
During the surgical procedures, it has been found extremely important to minimize disturbance of the environment of tissue and cells as much as possible. A
traumatic change in the environment surrounding inter-nal cells may lead to the destruction of such cells or the destruction of the function of such cells. The destruction of cell function may even lead to destruc-tion of other cells which are dependent upon a proper functioning of the destroyed cells. Therefore, during surgical procedures such as, for example, intraocular ~ -surgery, it is very important that the exposed tissue be continuously irrigated with solutions which approxi-mate natural body fluids. Such solutions are called "tissue irrigating solutions". One of the earliest ~ tissue irrigating solutions for ophthalmic procedures `~' was an isotonic saline. However, it was quickly ~ - recognized that the isotonic saline was not adequate as `~ 25 an ophthalmic irrigating solution because it resulted in endothelial cell swelling, cell damage, and con-sequent corneal clouding.
Alternatively, various electrolyte solutions have i been proposed as tissue irrigating solutions, par-ticularly in ophthalmic procedures, because such solu-tions more closely resemble the aqueous humor of the eye. The earliest electrolyte solution was known as ~ Ringer's solution, which was a combination of sodium, i calcium and potassium ions along with sodium lactate.
Another solution intended for tissue irrigation is known as a balanced salt solution which contains the essential sodium, potassium, calcium, and magnesium ~ salt ions along with an acetate-citrate buffer system.
-' 5 It has been somewhat successful and was used extensively until several years ago Within the last 10-15 years, there has developed a tissue irrigating solution which is a combination of the Ringer solution along with glutathione and sodium bicarbonate. This is sometimes referred to G~R, and in recent years has become a recognized tissue irrigating solution, espe-cially for ophthalmic procedures. When dextrose, sodium hydrogen phosphate (Na2HPO4), and sometimes ade-nosine are added to GBR, there results a fortified or enhanced balanced salt solution (sometimes referrea to - as "BSS Plus), which has proven to be the most effec-tive for intraocular surgery.
The problem with all GBR solutions and particularly the fortified or enhanced balanced salt solution is that they are not stable. Because they must be mixed essentially at the operative site, it is difficult to ~`1 control and maintain sterility. There are various reasons why GBR type solutions are not stable. First, bicarbonate and phosphate tend to precipitate in the presence of the magnesium and calcium ions. Therefore, once mixed, the sodium bicarbonate quickly loses its ability to act as a pumping agent for causing the endothelium to perform its fluid transport function of maintaining an outward fluid transport to the stromal layer, which results in damage to the cornea. Stated otherwise, the purpose of the bicarbonate is to act as a pump and, when mixed with the magnesium or calcium ions, i~ quickly loses its propensity for pumping. A
; second reason why the GBR solutions are not stable is ~ '.
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-' 5 It has been somewhat successful and was used extensively until several years ago Within the last 10-15 years, there has developed a tissue irrigating solution which is a combination of the Ringer solution along with glutathione and sodium bicarbonate. This is sometimes referred to G~R, and in recent years has become a recognized tissue irrigating solution, espe-cially for ophthalmic procedures. When dextrose, sodium hydrogen phosphate (Na2HPO4), and sometimes ade-nosine are added to GBR, there results a fortified or enhanced balanced salt solution (sometimes referrea to - as "BSS Plus), which has proven to be the most effec-tive for intraocular surgery.
The problem with all GBR solutions and particularly the fortified or enhanced balanced salt solution is that they are not stable. Because they must be mixed essentially at the operative site, it is difficult to ~`1 control and maintain sterility. There are various reasons why GBR type solutions are not stable. First, bicarbonate and phosphate tend to precipitate in the presence of the magnesium and calcium ions. Therefore, once mixed, the sodium bicarbonate quickly loses its ability to act as a pumping agent for causing the endothelium to perform its fluid transport function of maintaining an outward fluid transport to the stromal layer, which results in damage to the cornea. Stated otherwise, the purpose of the bicarbonate is to act as a pump and, when mixed with the magnesium or calcium ions, i~ quickly loses its propensity for pumping. A
; second reason why the GBR solutions are not stable is ~ '.
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that bicarbonate decomposes at a pH of less than 8 and be-comes carbon dioxide which ag~in causes the bicar-bonate to fail to act as a chemical pump during the surgical procedure. Finally, the glutathione is unstable at a pH greater than 5. Therefore, the glu-tathione cannot exist in a basic solution and the bicarbonate cannot exist for extended periods in an - acid solution.
A solution to this problem has been offered in United States Patents Nos. 4,443,432 and 4,550,022, both issued to Garabedian et al. According to these two patents, initially two solutions are prepared, one a basic solution providing the bicarbonate and sodium phosphate, and the second an acidic solution which pro-vides the calcium and magnesium ions, as well as the dextrose and glutathione. The solutions are packaged ~ and stored separately for extended periods of time and u mixed within 24 hours of use. While the resulting ~i irrigating product as described the Garabedian et al ~i 20 technique has achieved some degree of acceptance and -~ success, there are some limitations as a res~lt thereof. The long-term stability and maintenance of acceptable pH values is difficult in accordance with - the method and technique described in the Garabedian et al patents. In order to steam sterilize the large solution, it is necessary to place the glutathione in the smaller package, because glutathione cannot stand steam sterilizing. Therefore, since the sodium bicar-bonate is in the larger package, the large package must be glass, because it is difficult to maintain the sta-bility of sodium bicarbonate in solution in a polymeric container. This occurs because sodium bicarbonate will not remain stable as a result of the transmission of ;; vapors through the wall of the polypropylene bottle.
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1 33030~
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Summary of the Present Invention In order to overcome the problems described herein-` above and offer an improved formulating and packaging - technique, the present invention contemplates a two-part intraocular or tissue irrigating system. A first part includes a stable, sterile pre-packaged acidic solution containing at least the calcium ions and magnesium ions. The second part includes a lyophilized powder containing at least the sodium bicarbonate and glutathione. The sodium hydrogen phosphate is pre-ferrably included with the second part (powder). The potassium ions and dextrose may be provided in either the first or second part. When the first and second - parts are mixed together, there is formed an extremely satisfactory irrigating solution. Preferrably, the ~-` powder and solution should be aseptically mixed to maintain the sterility thereof.
- More specifically, in the proposed irrigating pro-duct, a larger solution (on the order of 500mls) con-tains all the chlorides, i.e., sodium, potassium, ~-calcium and magnesium, in a polypropylene bottle that is terminally steam-sterilized according to conventional processes. The second or smaller part is a lyophilized - powder which includes sodium bicarbonate, disodium hydrogen phosphate, dextrose and glutathione disulphide. The second part is sterile-filtered before being aseptically filled into either a glass vial or a small polypropylene bottle for lyophil-ization. It has been found preferrable to include the sodium hydrogen phosphate with the sodium bicarbonate. Thus the calcium and magnesium ions are placed in the large . .
bottle. Both the bicarbonate and the glutathione are stabilized by the lyophilizing (freeze-drying) process.
A special technique has been developed to eliminate any : .
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: ~ 33030~
, -5-breakdown that could occur before the solution con-taining bicarbonate and glutathione are frozen.
-; According to the improved technique, the sodium bicar-bonate is first frozen, then the glutathione is frozen ; 5 onto the surface of the sodium bicarbonate, ~hen both ~` frozen components are lyophilized (freeze-dried).
The large solution is preferrably placed in a 500ml polypropylene bottle and the small solution con-taining the lyophilized powders are placed in a small 50ml glass or polypropylene vial. The two components are ~ixed aseptically through a transfer spike. One end of the spike is inserted through the stopper in the ~' small vial. With the bottle containing the larger ; amount of solution in the upright positionJ the small vial is then inverted and the other end of ~he spike is ~-, inserted through the stopper into the large bottle.
The large bottle, being polypropylene, is then squeezed ~ ~i which forces a small amount of fluid into the vial ;~ which promptly dissolves the lyophilized powder. When " 20 the polypropylene bottle is released, the fluid and powder dissolved therein will return to the large bottle. This process is repeated several times to ~` flush all the contents of the vial into the bottle and ~ to thoroughly mix the contents of the two containers.
It is, therefore, an object of the present inven-tion to provide an improved formulating and packaging technique for the manufacture of glutathione/bicarbonate/
Ringer solution type products.
Another object of the present invention is to pro-~ 30 vide an enhanced balanced salt solution of the type -, described in which ~he sodiu~ bicarbonate, sodiu~
:! hydrogen phosphate, and glutathione are packaged -~ together in a powderous for~.
- Other objects and a fuller understanding of the , .
1 33030~
invention will become apparent upon reading the following detailed description along with the accom-panying drawings in which:
Figures 1 and lA illustrate a two-part packaging system in which the components of the irrigating solu-~; tion of the present invention are prepackaged and stored; and Figure 2 is a schematic block diagram illustrative of the procedural steps involved in for-mulating the irrigating solution of present invention.
10Detailed Description of a Preferred Embodiment The present invention is directed generally to an improved technique for pacXaging a tissue irrigating solution of the type which includes glutathione/bicarbonate/ i~
Ringer solution, whereby the components are initially ~ ~`
~` lS packaged in a two-component system. The composition and concentration of the two components of the system are such that they remain stable, even when stored for long periods of time. The two components are separa~
tely sterili~ed, then aseptically mixed so that the ultimate solution is completely sterile and available for use in surgery during the ensuing 24 hours. The mixed solution has been found to be extremely useful r . for maintaining the appropriate environment and pre-venting cell damage during surgical procedures, par-ticularly procedures such as intraocular surgery~
- The desired irrigatin~ solution, when mixed, pre-ferrably contains the following components in the amount indicated:
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` ' , .
.: ~ .
.. ' ; 1 330304 : -7-, Ingredients for Enhanced Balanced Salt Solution - mgm/ml ~ Sodium chloride (NaCl) 7.14 '.J Potassium chloride (KCl) 0.378 .~ 5 Calcium chloride (CaC12 2H2o) 0.154 Magnesium chloride (MgC12 6H20) 0.20 Dextrose ~.916 ~ Sodium carbonate (NaHCO3) 2.096 .. Sodium hydrogen phosphate (Na2HPO4) 0.415 ` 10 Glutathione disulphide 0.184 , ~
~,-b, As has been described above, the irrigating solu-~ tion identified hereinabove is supplied in two parts ¦ that will be mixed by the end user immediately prior to usage and will `have usable life, when mixed, of 6-24 ;~`
hours. One part is a mixed salt solution shown below in Formula 1 and the second part will be a powder con-taining the components shown in Formula 2. Formula 2 dissolves readily in Formula 1 and forms a clear solu- ,-.
tion consisting of the components in the amounts shown above. When packaged and before mixing the Formula 1 and Formula 2 powder contain the following ingredients ; in the indicated amounts.
. ~ .
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' ' , .
~' .
,~
`t ~` .
',` '. " ' ' Foxmula 1 (Solution) : .
Ingredients mgm/ml Sodium chloride (~aCl) 7.14 Potassium chloride (KCl) 0.378 Calcium chloride (CaC12 2H20) 0.154 Magnesium chloride (MgC12 6H20) 0.20 Formula 2 (Powder) ~ .
In~redients Percentage by Weight Dextrose 25.3 NaHC03 58.04 Na2Hpo4 11. 49 Glutathione disulphide 5.10 :
Looking now at the drawing, Formula 1 is placed in the large polypropylene container (SOOml) 10 and Formula 2 is placed in the small container (50ml) 12.
A mixing spike 14 is provided and utiliæed in the following manner The mixed salt solution is carried in container 10 and the lyophilized in container 12. One end of the spike 14 i5 placed through the rubber stopper 13 in vial 12. The vial 12 and spike 14 are then inverted and the other end of the spike is placed through the rubber stopper 11 in the cap o~ bottle 10.
The bottle 10 is preferrably formed of a resilient polypropylene material, so that when it is squeezed, a portion of the fluid is forced up into the small vial, where it mixes with and dissolves the powder therein.
i When the bottle 10 is released, the fluid then flows ' back down through spike 14 into the large container.
`~, When this process is repeated several times, the powder is fully mixed, dissolved, and transferred into the -large container 10. The small vial and spike are then . ~ , . . ~ , ;, ...... ,, ~ : ~
- ' .. g ^~ disposed of, and the large container is ready for use in the operative procedure.
In the ensuing examples, there are explained several experiments which were conducted in order to determine the preferred manner for formulating the '~ irrigating solution of the present invention. In prep-aration for experiments 1-6, the following solutions A
and B were prepared.
Solution A
Ingredients Amounts Distilled water 10 liters NaCl 71.4 gms KCl 3.79 gms CaC12 1.54 gms MgC12 2.00 gms , Divide Solution A into four equal lots, each lot equaling approximately 2.5 liters, and adjust the pH of each lot with lN.HCl as follows:
~:
., Target Actual Lot lApH 3.0pH 2.9 Lot 2ApH 4.0pH 4.1 Lot 3ApH 5.0pH 5.5 Lot 4ApH 6.0pH 6.9 ~ill nine 250ml plastic bottles from each pH lot, cap and sterilize. Retain the remainding 25ml of each lot of Solution A for further observation.
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Solution B
Ingredients Quantities Distilled water 1 liter NaHCO3 42 gms .
Na2HPo4 8.32 gms Dextrose 18.4 gms Glutathione 3.68 gms Dissolve the Na2HPO4 and the dextrose in the one - - liter of distilled water. Check the pH (8.8). Add glu-tathione and check the pH again (7.38). Adjust the pH
to 7.9-8.0 using 1 N.NaOH solution. Add NaHCO3 Check pH (7.86). Divide the solution into three equal lots and ajdust the pH as follows:
Lot lB pH 7.9-8.0 Lot 2B pH 7,7 Lot 3B pH 7.4 Each of the above lots should be filled into 30ml glass vials there being 13.25ml in each of 18 vials of each pH. Freeze dry each vial as soon as possible ~' 20 after mixing.
, .
EXPERIMEi~T
Samples of the freeze-dried Solution B were received and the following tests were performed. First 13.1mls of water was added to each of ~wo vials of each of the three different types of pH samples and the pH
checked immediately and after one hour.
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.Z 'i" `' . ' .` ' :' . . ' ' . ' ' " ' 1 33030~
Table 1 Ori~inal pH Sample No.Reconstituted pH
7.6 (1) 8.~4 `
(2) 8.23 ~```
5After 1 hour ~ (2) 8.26 ! 7.73 (1) 8~27 (2) 8.28 After 1 hour ~--- (2) B.30 7.86 (1) 8.28 (2) 8.28 After 1 hour ~ (2) 8.30 Preliminary tests excluded the pH 5 and pH 6 of Solution A as being too high initially. Thereafter, the pH 3 and pH 4 samples of Solution A were used to mix with the three pH levels of freeze-dried Solution , B.
'~ Table 2 Mix ImmediateThree Hour ~, 2.9/7.86 7.68 7.91 204.1/7.~6 8.10 8.26 2.9/7.73 7.58 7.84 4.1/7.73 8.04 8.23 2.9/7.6 7.47: 7.69 4.1/7.6 *8.26 8.32 : ' 25 *This is not a true result as a solution in water from Sample 1 had to be used.
In conclusion as to Experiment 1, it was determined i~
~ that the pH of Solu,tion B could not be reduced below `. about 7.9 before freeze-drying. The HCl used to reduce :~
the pH appears to liberate C~2 from the bicarbonate and 1 33030~
eventually all free C02 is lost on freeze-drying It would, therefore, probably be necessary to have a very low pH (2.0 or less) in Solution A to counteract the buffering effect of the phosphate and the bicarbonate.
.
A fresh batch of Solution A and Solution B were prepared, and the pH of Solution B was adjusted to 7~89 before the NaHC03 was added. After the addition of - NaHC03, the pH of Solution B was 7.98. The pH of Solution A was adjusted down to 2.5 by using 0.5 N HCl.
When Solutions A and B were mixed in the correct pro-portions (lOml to 0.5ml), the pH of the initial mixture was 7.3. After 24 hours, this had risen to pH 8.2 and, thus, did not meet the necessary criteria of pH 7.4.
The purpose of Experiments 3 and 4 are to determine S by comparison in Experiment 5 what is the best tech-nique for freeze-drying Solution B. In Experiment 3, 18.4 gms of dextrose was dissolved in 1 liter of distilled water. 900ml of the distilled watertdextrose solution had dissolved in it 8.3 gms of Na2HP04 and 42.0 gms of NaHC03 to form a Solution B-l having a p~l of 8.15.
Using 12mls of the remaining lOOmls of the dextrose solution, dissolve therein .442 gms of glutathione disulphide to form Solution B-2 having a pH of 2.63. ~-Pipette 11.9mls of Solution B-l into each of twelve -~ 30ml vials, cap and place in a freezer. Cool Solution B-2 to about the freezing point, and when Solution B-l is frozen and thoroughly chilled, add 1.3mls of Solution B-2 to each of nine vials of Solution B-l and return all twelve immediately to the freezer. The second layer of Solution B-2 froze al~ost immediately on contact with the first layer, which was expected and intended. Retain in the freezer one of the nine vials of the combination solution B-l and B-2 and one of the three vials of Solution B-1 only. Freeze-dry the remainder for further tests in Experiment 5.
Dissolve 18.4gms of dextrose in 1 liter of distilled water. Into 900mls of the dextrose solu-tion, dissolve therein 42gms of NaHC0 to form Solution B-l with a pH of 8.03. Fill ll.9mls of Solution B-l ; into each of twelve vials, stopper and freeze. To the remaining lOOmls of the dextrose solution, add 8.32gms of Na2HP0~. When completely dissolved (pH 3-9~5), transfer 12mls to another container and add .442gms glutathione and dissolve forming a Solution B-2 at pH
7.36. Cool Solution B-2 to about the freezing point and, when Solution B-l is frozen and thoroughly chilled, add 1.3mls of Solution B-2 to each of nine vials, and return all twelve immediately to the freezer. In the lab experiment, the second layer again froze almost immediately on contact with the first ;
layer as was intended. Retain in the freezer one of the nine vials of the combination solution B-l and B-2 and one of three vials of Solution B-l only. Freeze-dry the remainder for further tests in Experiment 5~ ~-The freeze-dried samples from Experiments 3 and 4 . . .
were received and the following tests were performed on them. First, the four retained frozen samples were thawed and four equivalent freeze-dried samples were reconstituted with distilled water. The pH of all eight samples was measured with the following results~
-~ ~ 330304 Table I
Sample Frozen(A)pH Freeze-dried(B)pH
Exp. 4, Solution 1 (1) 8.24 8.32 Exp. 4, Solution 1 5& Glutathione (2) 7.99 8.23 Exp. S, Solution 1 (3) 8.15 8.26 Exp. 5, Solution 1 (4) 8.10 8~33 ~-& Glutathione & Na2HPo4 It was observed that Sample 4-B did not dissolve as rapidly as the other samples, presumably because o~
"caking" of the phosphate in its anhydrous state.
Next, three samples each of the freeze-dried ,, complete solution (Samples 2 and 4) were reconstituted with exactly 12mls of distilled water and the final pH
checked.
~ Table II
: :. :, Sample ' 1 2 3 i - 20Exp. 4, Solution 1 (2) 8.26 8.21 8.27 & Glutathione .: ~ : ::.
Exp. 5, Solution 1 (4) 8.28 8.25 8.27 & Glutathione &
Na2HP0 ~..: :: :: ::
Mixt~re 2 went easily into solution whereas Mixture 4 took five minutes to completely dissolve.
In conclusion as to Experiment 5, in both Experiments 3 and 4" there was an increase in the final pH after freeze-drying which indicates some slight ~
30 loss of CO2 during the process. The fact that the ~ ;
; samples without glutathione showed a loss, although somewhat smaller, shows that the bicarbonate is inherently unstable - as is well known - and it will probably be necessary to match the Solution 1 to the freeze-dried component in each lot in a production environ~ent in order to produce a consistent pH in the final mixture. There was no marked difference in the apparant bicarbonate stability between the two experi-ments. In view of the solution difficulty with Experiment 4 material, it seems reasonable to con-centrate on the Experiment 3 approach, i.e., using the NaHC03 and Na2HP04 in Solution B-l with only the glu-tathione in Solution B-2. This should help with any possible instability of the glutathione in an alkaline pH.
~; The purpose of this experiment was to now determine j whether a Solution A could be formulated with a Solution B-l from Experiment 3 successfully. Again, -~ 20 it should be kept in mind the purpose of the line of experiments (Exp. 1-6) is to determine whether a solu-, tion having a final pH of approximately 7.4 when Solution B is dissolved into it can be attained and whether such pH will remain stable.
A 250ml bottle of Solution A from Experiment 1 at a pH of 2.9 was used. A vial of freeze-dried Solution B
(actually Solution B-l from Experiment 3) was added and the pH checked at 7.65. A small amount (0.2mls) o~ 0.5 -~
N HCl was added resulting in a pH of 7.54. A further 30 small amount (0.2ml) of 0.5 N HCl was added providing a pH of 7.4. ~hereafter, 0.4mls of .5 N HCl was added to a bottle (265mls) of pH 2.9 Solution A giving a pH of 2.58. When a vial of Solution B (actually Solution B-l from Experiment 3) was added to this solution, there ~ A~
. - ~ . . ' " .!,, ~
- ~ 3303~4 resulted a final mixture having a pH of 7.41. Four additional bottles of Solution A initially having a pH
of 4.1 (Lot 2A) were similarly adjusted to pH values around 2.6 with the following results when mixed with vials of Solution B from either Experime~t 3 or Experiment 4.
Table I
Final pH of Solution 1 ~ vial pH After 5 min. 1 hr. 3 hr. 24 hr~
2.53 + Solution B (Exp. 3) 7.2 7.22 7.32 7.4 2.60 + Solution B (Exp. 3) 7.36 7.33 7.36 7.42 2.65 + Solution B (Exp. 4) 7.45 7.4 7.4 7.51 2.80 + Solution B (Exp. 4) 7.65 7.59 7.67 7.73 After 48 hours, there were obvious signs of degra~
dation with deposits forming and in the case of the two higher pH values a strong smell of H2S presumably ~ ~;
from glutathione degradation. The two lower pH solu~
tions appeared more stable, with less deposit and no odor.
In conclusion~
1. The bicarbonate and phosphate in the first solution with glutathione only in the smaller - second portion is the choice because it affords a better chance of stability for the glutathione with the lower pH and there is no proble~ of phosphate solubility when it is -~
reconstituted.
2. A final pH of about 7.3 can be achie~ed by adjusting the chloride solution (Solutiorl A) to about pH 2.6. The higher pH of the final solution appears to be less stable and it appears preferable to hold the final pH to or below 7.4 t, t ~'` ` " " " "' :`
; ~ 33030 A pilot batch of the enhanced balanced salt solu-tion in accordance with the above invention was pro-duced to confirm the conclusion set rorth in the experiments above. A 15 liter batch of Solution A was prepared as follows:
14 liters of WFI (distilled water which has been tested and qualified for injection) were measured into a graduated container and 107.1gms of NaCl was dissolved therein.
1 liter of WFI had dissolved therein 22.7gms KCl; -~
9.24gms CaC12; and 12.00gms of MgC12. -~
250mls of the potassium/calcium/magnesium solution was added to the 14 liters of the ~aCl solution and the volume was made up to 15 liters by the addition of further WFI. The initial pH of Solution A was 6.03 and was lowered by the addition of 1 N HCl as follows: ~ -9mls ~Cl pH 3.02 +4mls HCl pH 2.80 +6mls HCl pH 2.67 ~ `
+6mls HCl pH 2.57 At this point, and after thorough mixing, the solu-tion was filled into 250ml plastic bottles, stoppered, capped and sterilized with Dispersa Balansalt.
Solution B was prepared for freeze drying in such a way that lOmls of the B-l solution was frozen and then lml of the B-2 solution was added on top of of the surface of the B-l solution. Solution B-l was preparea . "
by dissolving 22.0gms of dextrose in 1 liter WFI.
-30 Approximately 800mls of this solution was transferred and had dissolved in it 50gms of NaHC03 and 9.9gms of Na2HPO~. Additional amount of the dextrose WFI was added to make up 900mls and equally distributed throughout 30ml vials at lOml per vial and frozen.
` -18-This made 90 samples.
;~ 90mls of the remaining dextrose solution was trans-~- ferred to a flask and in it was dissolved 4.4gms of glutathione disulphide. This glutathione disulphide solution was chilled to near freezing and lml thereof ; was added to each of the 90 frozen lOml aliquots of the bicarbonate solution. The vials were immediately `; returned to the freezer and they were subsequently freeze-dried without allowing the material to thaw.
Five frozen samples were retained as control samples : and 85 were sent for freeze-drying.
After freeze-drying, five vials were taken and the ; contents mixed with each of the five bottles of Solution A at the pH of the mixtures were measured ' 15 immediately and after one hour, six hours, and 24 . ~ .
hours, all at room temperature. The following results were obtained~
Sample pH Value ~; 2mm 1 Hr. 5 Hrs. ~4 Hrs. 48 Hrs. 72 Hrs.
. _ _ ~;l 20 1 7.35 7.40 7.50 7.50 7.40 7.60 ~` 2 7.4~ 7.40 7.45 7.50 7.40 7.60 3 7 35 7-40 7.45 7,45 7.40 7.60 4 7.40 7.40 7.40 7.45 7.50 7.60 ;~
' 5 7.40 7.40 7.50 7.50 7.55 7.65 From the preliminary pH measurements, it appears that the process used gives reproducible results and that the mixed product is at least as stable as any other glutathione/bicarbonate/Ringer solution product on the market.
While preferred embodiments of the present inven-^~3: tion have been described in detail here and above, it -~ is apparent that various changes and modifications might be made without departing from the scope of the invention which is set forth in the accompanying claims.
' :
A solution to this problem has been offered in United States Patents Nos. 4,443,432 and 4,550,022, both issued to Garabedian et al. According to these two patents, initially two solutions are prepared, one a basic solution providing the bicarbonate and sodium phosphate, and the second an acidic solution which pro-vides the calcium and magnesium ions, as well as the dextrose and glutathione. The solutions are packaged ~ and stored separately for extended periods of time and u mixed within 24 hours of use. While the resulting ~i irrigating product as described the Garabedian et al ~i 20 technique has achieved some degree of acceptance and -~ success, there are some limitations as a res~lt thereof. The long-term stability and maintenance of acceptable pH values is difficult in accordance with - the method and technique described in the Garabedian et al patents. In order to steam sterilize the large solution, it is necessary to place the glutathione in the smaller package, because glutathione cannot stand steam sterilizing. Therefore, since the sodium bicar-bonate is in the larger package, the large package must be glass, because it is difficult to maintain the sta-bility of sodium bicarbonate in solution in a polymeric container. This occurs because sodium bicarbonate will not remain stable as a result of the transmission of ;; vapors through the wall of the polypropylene bottle.
.~
.......
1 33030~
.
Summary of the Present Invention In order to overcome the problems described herein-` above and offer an improved formulating and packaging - technique, the present invention contemplates a two-part intraocular or tissue irrigating system. A first part includes a stable, sterile pre-packaged acidic solution containing at least the calcium ions and magnesium ions. The second part includes a lyophilized powder containing at least the sodium bicarbonate and glutathione. The sodium hydrogen phosphate is pre-ferrably included with the second part (powder). The potassium ions and dextrose may be provided in either the first or second part. When the first and second - parts are mixed together, there is formed an extremely satisfactory irrigating solution. Preferrably, the ~-` powder and solution should be aseptically mixed to maintain the sterility thereof.
- More specifically, in the proposed irrigating pro-duct, a larger solution (on the order of 500mls) con-tains all the chlorides, i.e., sodium, potassium, ~-calcium and magnesium, in a polypropylene bottle that is terminally steam-sterilized according to conventional processes. The second or smaller part is a lyophilized - powder which includes sodium bicarbonate, disodium hydrogen phosphate, dextrose and glutathione disulphide. The second part is sterile-filtered before being aseptically filled into either a glass vial or a small polypropylene bottle for lyophil-ization. It has been found preferrable to include the sodium hydrogen phosphate with the sodium bicarbonate. Thus the calcium and magnesium ions are placed in the large . .
bottle. Both the bicarbonate and the glutathione are stabilized by the lyophilizing (freeze-drying) process.
A special technique has been developed to eliminate any : .
.
.
: ~ 33030~
, -5-breakdown that could occur before the solution con-taining bicarbonate and glutathione are frozen.
-; According to the improved technique, the sodium bicar-bonate is first frozen, then the glutathione is frozen ; 5 onto the surface of the sodium bicarbonate, ~hen both ~` frozen components are lyophilized (freeze-dried).
The large solution is preferrably placed in a 500ml polypropylene bottle and the small solution con-taining the lyophilized powders are placed in a small 50ml glass or polypropylene vial. The two components are ~ixed aseptically through a transfer spike. One end of the spike is inserted through the stopper in the ~' small vial. With the bottle containing the larger ; amount of solution in the upright positionJ the small vial is then inverted and the other end of ~he spike is ~-, inserted through the stopper into the large bottle.
The large bottle, being polypropylene, is then squeezed ~ ~i which forces a small amount of fluid into the vial ;~ which promptly dissolves the lyophilized powder. When " 20 the polypropylene bottle is released, the fluid and powder dissolved therein will return to the large bottle. This process is repeated several times to ~` flush all the contents of the vial into the bottle and ~ to thoroughly mix the contents of the two containers.
It is, therefore, an object of the present inven-tion to provide an improved formulating and packaging technique for the manufacture of glutathione/bicarbonate/
Ringer solution type products.
Another object of the present invention is to pro-~ 30 vide an enhanced balanced salt solution of the type -, described in which ~he sodiu~ bicarbonate, sodiu~
:! hydrogen phosphate, and glutathione are packaged -~ together in a powderous for~.
- Other objects and a fuller understanding of the , .
1 33030~
invention will become apparent upon reading the following detailed description along with the accom-panying drawings in which:
Figures 1 and lA illustrate a two-part packaging system in which the components of the irrigating solu-~; tion of the present invention are prepackaged and stored; and Figure 2 is a schematic block diagram illustrative of the procedural steps involved in for-mulating the irrigating solution of present invention.
10Detailed Description of a Preferred Embodiment The present invention is directed generally to an improved technique for pacXaging a tissue irrigating solution of the type which includes glutathione/bicarbonate/ i~
Ringer solution, whereby the components are initially ~ ~`
~` lS packaged in a two-component system. The composition and concentration of the two components of the system are such that they remain stable, even when stored for long periods of time. The two components are separa~
tely sterili~ed, then aseptically mixed so that the ultimate solution is completely sterile and available for use in surgery during the ensuing 24 hours. The mixed solution has been found to be extremely useful r . for maintaining the appropriate environment and pre-venting cell damage during surgical procedures, par-ticularly procedures such as intraocular surgery~
- The desired irrigatin~ solution, when mixed, pre-ferrably contains the following components in the amount indicated:
..
` ' , .
.: ~ .
.. ' ; 1 330304 : -7-, Ingredients for Enhanced Balanced Salt Solution - mgm/ml ~ Sodium chloride (NaCl) 7.14 '.J Potassium chloride (KCl) 0.378 .~ 5 Calcium chloride (CaC12 2H2o) 0.154 Magnesium chloride (MgC12 6H20) 0.20 Dextrose ~.916 ~ Sodium carbonate (NaHCO3) 2.096 .. Sodium hydrogen phosphate (Na2HPO4) 0.415 ` 10 Glutathione disulphide 0.184 , ~
~,-b, As has been described above, the irrigating solu-~ tion identified hereinabove is supplied in two parts ¦ that will be mixed by the end user immediately prior to usage and will `have usable life, when mixed, of 6-24 ;~`
hours. One part is a mixed salt solution shown below in Formula 1 and the second part will be a powder con-taining the components shown in Formula 2. Formula 2 dissolves readily in Formula 1 and forms a clear solu- ,-.
tion consisting of the components in the amounts shown above. When packaged and before mixing the Formula 1 and Formula 2 powder contain the following ingredients ; in the indicated amounts.
. ~ .
.
' ' , .
~' .
,~
`t ~` .
',` '. " ' ' Foxmula 1 (Solution) : .
Ingredients mgm/ml Sodium chloride (~aCl) 7.14 Potassium chloride (KCl) 0.378 Calcium chloride (CaC12 2H20) 0.154 Magnesium chloride (MgC12 6H20) 0.20 Formula 2 (Powder) ~ .
In~redients Percentage by Weight Dextrose 25.3 NaHC03 58.04 Na2Hpo4 11. 49 Glutathione disulphide 5.10 :
Looking now at the drawing, Formula 1 is placed in the large polypropylene container (SOOml) 10 and Formula 2 is placed in the small container (50ml) 12.
A mixing spike 14 is provided and utiliæed in the following manner The mixed salt solution is carried in container 10 and the lyophilized in container 12. One end of the spike 14 i5 placed through the rubber stopper 13 in vial 12. The vial 12 and spike 14 are then inverted and the other end of the spike is placed through the rubber stopper 11 in the cap o~ bottle 10.
The bottle 10 is preferrably formed of a resilient polypropylene material, so that when it is squeezed, a portion of the fluid is forced up into the small vial, where it mixes with and dissolves the powder therein.
i When the bottle 10 is released, the fluid then flows ' back down through spike 14 into the large container.
`~, When this process is repeated several times, the powder is fully mixed, dissolved, and transferred into the -large container 10. The small vial and spike are then . ~ , . . ~ , ;, ...... ,, ~ : ~
- ' .. g ^~ disposed of, and the large container is ready for use in the operative procedure.
In the ensuing examples, there are explained several experiments which were conducted in order to determine the preferred manner for formulating the '~ irrigating solution of the present invention. In prep-aration for experiments 1-6, the following solutions A
and B were prepared.
Solution A
Ingredients Amounts Distilled water 10 liters NaCl 71.4 gms KCl 3.79 gms CaC12 1.54 gms MgC12 2.00 gms , Divide Solution A into four equal lots, each lot equaling approximately 2.5 liters, and adjust the pH of each lot with lN.HCl as follows:
~:
., Target Actual Lot lApH 3.0pH 2.9 Lot 2ApH 4.0pH 4.1 Lot 3ApH 5.0pH 5.5 Lot 4ApH 6.0pH 6.9 ~ill nine 250ml plastic bottles from each pH lot, cap and sterilize. Retain the remainding 25ml of each lot of Solution A for further observation.
,` ` ` ~.. , `J : ~ .
~ 33030~
Solution B
Ingredients Quantities Distilled water 1 liter NaHCO3 42 gms .
Na2HPo4 8.32 gms Dextrose 18.4 gms Glutathione 3.68 gms Dissolve the Na2HPO4 and the dextrose in the one - - liter of distilled water. Check the pH (8.8). Add glu-tathione and check the pH again (7.38). Adjust the pH
to 7.9-8.0 using 1 N.NaOH solution. Add NaHCO3 Check pH (7.86). Divide the solution into three equal lots and ajdust the pH as follows:
Lot lB pH 7.9-8.0 Lot 2B pH 7,7 Lot 3B pH 7.4 Each of the above lots should be filled into 30ml glass vials there being 13.25ml in each of 18 vials of each pH. Freeze dry each vial as soon as possible ~' 20 after mixing.
, .
EXPERIMEi~T
Samples of the freeze-dried Solution B were received and the following tests were performed. First 13.1mls of water was added to each of ~wo vials of each of the three different types of pH samples and the pH
checked immediately and after one hour.
`Z
.Z 'i" `' . ' .` ' :' . . ' ' . ' ' " ' 1 33030~
Table 1 Ori~inal pH Sample No.Reconstituted pH
7.6 (1) 8.~4 `
(2) 8.23 ~```
5After 1 hour ~ (2) 8.26 ! 7.73 (1) 8~27 (2) 8.28 After 1 hour ~--- (2) B.30 7.86 (1) 8.28 (2) 8.28 After 1 hour ~ (2) 8.30 Preliminary tests excluded the pH 5 and pH 6 of Solution A as being too high initially. Thereafter, the pH 3 and pH 4 samples of Solution A were used to mix with the three pH levels of freeze-dried Solution , B.
'~ Table 2 Mix ImmediateThree Hour ~, 2.9/7.86 7.68 7.91 204.1/7.~6 8.10 8.26 2.9/7.73 7.58 7.84 4.1/7.73 8.04 8.23 2.9/7.6 7.47: 7.69 4.1/7.6 *8.26 8.32 : ' 25 *This is not a true result as a solution in water from Sample 1 had to be used.
In conclusion as to Experiment 1, it was determined i~
~ that the pH of Solu,tion B could not be reduced below `. about 7.9 before freeze-drying. The HCl used to reduce :~
the pH appears to liberate C~2 from the bicarbonate and 1 33030~
eventually all free C02 is lost on freeze-drying It would, therefore, probably be necessary to have a very low pH (2.0 or less) in Solution A to counteract the buffering effect of the phosphate and the bicarbonate.
.
A fresh batch of Solution A and Solution B were prepared, and the pH of Solution B was adjusted to 7~89 before the NaHC03 was added. After the addition of - NaHC03, the pH of Solution B was 7.98. The pH of Solution A was adjusted down to 2.5 by using 0.5 N HCl.
When Solutions A and B were mixed in the correct pro-portions (lOml to 0.5ml), the pH of the initial mixture was 7.3. After 24 hours, this had risen to pH 8.2 and, thus, did not meet the necessary criteria of pH 7.4.
The purpose of Experiments 3 and 4 are to determine S by comparison in Experiment 5 what is the best tech-nique for freeze-drying Solution B. In Experiment 3, 18.4 gms of dextrose was dissolved in 1 liter of distilled water. 900ml of the distilled watertdextrose solution had dissolved in it 8.3 gms of Na2HP04 and 42.0 gms of NaHC03 to form a Solution B-l having a p~l of 8.15.
Using 12mls of the remaining lOOmls of the dextrose solution, dissolve therein .442 gms of glutathione disulphide to form Solution B-2 having a pH of 2.63. ~-Pipette 11.9mls of Solution B-l into each of twelve -~ 30ml vials, cap and place in a freezer. Cool Solution B-2 to about the freezing point, and when Solution B-l is frozen and thoroughly chilled, add 1.3mls of Solution B-2 to each of nine vials of Solution B-l and return all twelve immediately to the freezer. The second layer of Solution B-2 froze al~ost immediately on contact with the first layer, which was expected and intended. Retain in the freezer one of the nine vials of the combination solution B-l and B-2 and one of the three vials of Solution B-1 only. Freeze-dry the remainder for further tests in Experiment 5.
Dissolve 18.4gms of dextrose in 1 liter of distilled water. Into 900mls of the dextrose solu-tion, dissolve therein 42gms of NaHC0 to form Solution B-l with a pH of 8.03. Fill ll.9mls of Solution B-l ; into each of twelve vials, stopper and freeze. To the remaining lOOmls of the dextrose solution, add 8.32gms of Na2HP0~. When completely dissolved (pH 3-9~5), transfer 12mls to another container and add .442gms glutathione and dissolve forming a Solution B-2 at pH
7.36. Cool Solution B-2 to about the freezing point and, when Solution B-l is frozen and thoroughly chilled, add 1.3mls of Solution B-2 to each of nine vials, and return all twelve immediately to the freezer. In the lab experiment, the second layer again froze almost immediately on contact with the first ;
layer as was intended. Retain in the freezer one of the nine vials of the combination solution B-l and B-2 and one of three vials of Solution B-l only. Freeze-dry the remainder for further tests in Experiment 5~ ~-The freeze-dried samples from Experiments 3 and 4 . . .
were received and the following tests were performed on them. First, the four retained frozen samples were thawed and four equivalent freeze-dried samples were reconstituted with distilled water. The pH of all eight samples was measured with the following results~
-~ ~ 330304 Table I
Sample Frozen(A)pH Freeze-dried(B)pH
Exp. 4, Solution 1 (1) 8.24 8.32 Exp. 4, Solution 1 5& Glutathione (2) 7.99 8.23 Exp. S, Solution 1 (3) 8.15 8.26 Exp. 5, Solution 1 (4) 8.10 8~33 ~-& Glutathione & Na2HPo4 It was observed that Sample 4-B did not dissolve as rapidly as the other samples, presumably because o~
"caking" of the phosphate in its anhydrous state.
Next, three samples each of the freeze-dried ,, complete solution (Samples 2 and 4) were reconstituted with exactly 12mls of distilled water and the final pH
checked.
~ Table II
: :. :, Sample ' 1 2 3 i - 20Exp. 4, Solution 1 (2) 8.26 8.21 8.27 & Glutathione .: ~ : ::.
Exp. 5, Solution 1 (4) 8.28 8.25 8.27 & Glutathione &
Na2HP0 ~..: :: :: ::
Mixt~re 2 went easily into solution whereas Mixture 4 took five minutes to completely dissolve.
In conclusion as to Experiment 5, in both Experiments 3 and 4" there was an increase in the final pH after freeze-drying which indicates some slight ~
30 loss of CO2 during the process. The fact that the ~ ;
; samples without glutathione showed a loss, although somewhat smaller, shows that the bicarbonate is inherently unstable - as is well known - and it will probably be necessary to match the Solution 1 to the freeze-dried component in each lot in a production environ~ent in order to produce a consistent pH in the final mixture. There was no marked difference in the apparant bicarbonate stability between the two experi-ments. In view of the solution difficulty with Experiment 4 material, it seems reasonable to con-centrate on the Experiment 3 approach, i.e., using the NaHC03 and Na2HP04 in Solution B-l with only the glu-tathione in Solution B-2. This should help with any possible instability of the glutathione in an alkaline pH.
~; The purpose of this experiment was to now determine j whether a Solution A could be formulated with a Solution B-l from Experiment 3 successfully. Again, -~ 20 it should be kept in mind the purpose of the line of experiments (Exp. 1-6) is to determine whether a solu-, tion having a final pH of approximately 7.4 when Solution B is dissolved into it can be attained and whether such pH will remain stable.
A 250ml bottle of Solution A from Experiment 1 at a pH of 2.9 was used. A vial of freeze-dried Solution B
(actually Solution B-l from Experiment 3) was added and the pH checked at 7.65. A small amount (0.2mls) o~ 0.5 -~
N HCl was added resulting in a pH of 7.54. A further 30 small amount (0.2ml) of 0.5 N HCl was added providing a pH of 7.4. ~hereafter, 0.4mls of .5 N HCl was added to a bottle (265mls) of pH 2.9 Solution A giving a pH of 2.58. When a vial of Solution B (actually Solution B-l from Experiment 3) was added to this solution, there ~ A~
. - ~ . . ' " .!,, ~
- ~ 3303~4 resulted a final mixture having a pH of 7.41. Four additional bottles of Solution A initially having a pH
of 4.1 (Lot 2A) were similarly adjusted to pH values around 2.6 with the following results when mixed with vials of Solution B from either Experime~t 3 or Experiment 4.
Table I
Final pH of Solution 1 ~ vial pH After 5 min. 1 hr. 3 hr. 24 hr~
2.53 + Solution B (Exp. 3) 7.2 7.22 7.32 7.4 2.60 + Solution B (Exp. 3) 7.36 7.33 7.36 7.42 2.65 + Solution B (Exp. 4) 7.45 7.4 7.4 7.51 2.80 + Solution B (Exp. 4) 7.65 7.59 7.67 7.73 After 48 hours, there were obvious signs of degra~
dation with deposits forming and in the case of the two higher pH values a strong smell of H2S presumably ~ ~;
from glutathione degradation. The two lower pH solu~
tions appeared more stable, with less deposit and no odor.
In conclusion~
1. The bicarbonate and phosphate in the first solution with glutathione only in the smaller - second portion is the choice because it affords a better chance of stability for the glutathione with the lower pH and there is no proble~ of phosphate solubility when it is -~
reconstituted.
2. A final pH of about 7.3 can be achie~ed by adjusting the chloride solution (Solutiorl A) to about pH 2.6. The higher pH of the final solution appears to be less stable and it appears preferable to hold the final pH to or below 7.4 t, t ~'` ` " " " "' :`
; ~ 33030 A pilot batch of the enhanced balanced salt solu-tion in accordance with the above invention was pro-duced to confirm the conclusion set rorth in the experiments above. A 15 liter batch of Solution A was prepared as follows:
14 liters of WFI (distilled water which has been tested and qualified for injection) were measured into a graduated container and 107.1gms of NaCl was dissolved therein.
1 liter of WFI had dissolved therein 22.7gms KCl; -~
9.24gms CaC12; and 12.00gms of MgC12. -~
250mls of the potassium/calcium/magnesium solution was added to the 14 liters of the ~aCl solution and the volume was made up to 15 liters by the addition of further WFI. The initial pH of Solution A was 6.03 and was lowered by the addition of 1 N HCl as follows: ~ -9mls ~Cl pH 3.02 +4mls HCl pH 2.80 +6mls HCl pH 2.67 ~ `
+6mls HCl pH 2.57 At this point, and after thorough mixing, the solu-tion was filled into 250ml plastic bottles, stoppered, capped and sterilized with Dispersa Balansalt.
Solution B was prepared for freeze drying in such a way that lOmls of the B-l solution was frozen and then lml of the B-2 solution was added on top of of the surface of the B-l solution. Solution B-l was preparea . "
by dissolving 22.0gms of dextrose in 1 liter WFI.
-30 Approximately 800mls of this solution was transferred and had dissolved in it 50gms of NaHC03 and 9.9gms of Na2HPO~. Additional amount of the dextrose WFI was added to make up 900mls and equally distributed throughout 30ml vials at lOml per vial and frozen.
` -18-This made 90 samples.
;~ 90mls of the remaining dextrose solution was trans-~- ferred to a flask and in it was dissolved 4.4gms of glutathione disulphide. This glutathione disulphide solution was chilled to near freezing and lml thereof ; was added to each of the 90 frozen lOml aliquots of the bicarbonate solution. The vials were immediately `; returned to the freezer and they were subsequently freeze-dried without allowing the material to thaw.
Five frozen samples were retained as control samples : and 85 were sent for freeze-drying.
After freeze-drying, five vials were taken and the ; contents mixed with each of the five bottles of Solution A at the pH of the mixtures were measured ' 15 immediately and after one hour, six hours, and 24 . ~ .
hours, all at room temperature. The following results were obtained~
Sample pH Value ~; 2mm 1 Hr. 5 Hrs. ~4 Hrs. 48 Hrs. 72 Hrs.
. _ _ ~;l 20 1 7.35 7.40 7.50 7.50 7.40 7.60 ~` 2 7.4~ 7.40 7.45 7.50 7.40 7.60 3 7 35 7-40 7.45 7,45 7.40 7.60 4 7.40 7.40 7.40 7.45 7.50 7.60 ;~
' 5 7.40 7.40 7.50 7.50 7.55 7.65 From the preliminary pH measurements, it appears that the process used gives reproducible results and that the mixed product is at least as stable as any other glutathione/bicarbonate/Ringer solution product on the market.
While preferred embodiments of the present inven-^~3: tion have been described in detail here and above, it -~ is apparent that various changes and modifications might be made without departing from the scope of the invention which is set forth in the accompanying claims.
' :
Claims (22)
1. A tissue irrigating solution comprising:
a) a first part including an acidic solution containing calcium ions magnesium ions;
b) a second part including a lyophi-lized powder containing sodium bicarbonate and glutathione;
c) sodium ions, potassium ions, and dextrose, each being included in one of said first and second parts;
d) said first and second parts when mixed together form a solution for irrigating body tissues during surgery.
a) a first part including an acidic solution containing calcium ions magnesium ions;
b) a second part including a lyophi-lized powder containing sodium bicarbonate and glutathione;
c) sodium ions, potassium ions, and dextrose, each being included in one of said first and second parts;
d) said first and second parts when mixed together form a solution for irrigating body tissues during surgery.
2. The irrigating solution according to Claim 1 wherein said first part includes said sodium ions and said potassium ions, and said second part includes said dextrose.
3. The irrigating solution according to Claim 2 wherein said second part further includes sodium hydro-gen phosphate.
4. The irrigating solution according to Claim 1 wherein said first part is steam-sterilized.
5. The irrigating solution according to Claim 1 wherein said first part and said second part are packaged in propylene bottles.
6. The irrigating solution according to Claim 3 wherein said solution includes ingredients in the following relation:
7. The irrigating solution according to Claim 3 wherein said first part of said solution includes ingredients in the following relation:
and wherein said second part includes ingredients in the following relation:
and wherein said second part includes ingredients in the following relation:
8. The irrigating solution according to Claim 7 wherein the pH of the the first part is no greater than 2.8 and the pH of the final solution, when mixed, is no greater than 7.6.
9. A tissue irrigating product comprising:
a) a first part including a stable sterile prepackaged acidic solution containing calcium ions and magne-sium ions;
b) a second part including a lyophi-lized powder containing sodium bicarbonate, c) sodium ions, potassium ions, and dextrose, each being included in one of said first and second parts;
d) means for aseptically mixing said acidic solution and said lyophilized powder;
e) said first and second parts, when mixed together, form a solution for irrigating body tissues during surgery.
a) a first part including a stable sterile prepackaged acidic solution containing calcium ions and magne-sium ions;
b) a second part including a lyophi-lized powder containing sodium bicarbonate, c) sodium ions, potassium ions, and dextrose, each being included in one of said first and second parts;
d) means for aseptically mixing said acidic solution and said lyophilized powder;
e) said first and second parts, when mixed together, form a solution for irrigating body tissues during surgery.
10. The irrigating product according to Claim 9 wherein said first part includes said sodium ions and said potassium ions and said second part includes said dextrose.
11. The irrigating product according to Claim 10 wherein said second part further includes sodium hydro-gen phosphate.
12. The irrigating product according to Claim 9 wherein said first part is steam-sterilized.
13. The irrigating product according to Claim 9 wherein said first part and said second part are packaged in polypropylene bottles and there is further included a double-ended mixing spike.
14. The irrigating product according to Claim 11 wherein said solution includes ingredients in the following relation:
15. The irrigating product according to Claim 11 wherein said first part includes ingredients in the following relation:
and wherein said second part includes ingredients in the following relation:
and wherein said second part includes ingredients in the following relation:
16. The irrigating product according to Claim 15 wherein the pH of said first part is no greater than 2.8 and the pH of the final solution is no greater than 7.6.
17. A method for preparing a prepackaged tissue irrigating solution comprising the steps of:
a) preparing an aqueous solution con-taining at least calcium ions and magnesium ions in distilled water;
b) preparing an aqueous dextrose solu-tion having dissolved therein at least sodium bicarbonate and glutathione;
c) lyophilizing the solution of step (b);
d) packaging the solution of step (a) and the lyophilized powder of step (c) separately.
a) preparing an aqueous solution con-taining at least calcium ions and magnesium ions in distilled water;
b) preparing an aqueous dextrose solu-tion having dissolved therein at least sodium bicarbonate and glutathione;
c) lyophilizing the solution of step (b);
d) packaging the solution of step (a) and the lyophilized powder of step (c) separately.
18. The method according to Claim 17 wherein sodium ions and potassium ions are also introduced into the aqueous solution of step (a).
19. The method according to Claim 17 wherein the aqueous solution of step (a) is steam-sterilized.
20. The method according to Claim 18 wherein step (b) includes forming a first dextrose solution of said sodium bicarbonate and sodium hydrogen phosphate and a second dextrose solution con-taining said glutathione.
21. The method according to Claim 20 wherein step (c) includes freezing said first dextrose solu-tion, then chilling said glutathione/dextrose solution to substantially the freezing point and introducing it onto the surface of the first dextrose solution immediately prior to the time the second dextrose/glutathione solution freezes, then freeze-drying the resulting combination of the frozen first solution and frozen second solution.
22. The method according to Claim 17 wherein the pH of the aqueous solution of step (a) is lowered to a point not exceeding 2.6 by adding hydrochloric acid thereto.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US243,085 | 1988-09-09 | ||
| US07/243,085 US4975419A (en) | 1988-09-09 | 1988-09-09 | Tissue irrigating solution |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1330304C true CA1330304C (en) | 1994-06-21 |
Family
ID=22917313
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000608460A Expired - Fee Related CA1330304C (en) | 1988-09-09 | 1989-08-16 | Tissue irrigating solution |
Country Status (5)
| Country | Link |
|---|---|
| US (2) | US4975419A (en) |
| EP (1) | EP0358369B1 (en) |
| JP (1) | JPH02115128A (en) |
| CA (1) | CA1330304C (en) |
| DE (1) | DE68902969T2 (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5304724A (en) * | 1988-09-09 | 1994-04-19 | Entravision, Inc. | Tissue irrigating solution |
| US4975419A (en) * | 1988-09-09 | 1990-12-04 | Entravision, Inc. | Tissue irrigating solution |
| US5328701A (en) * | 1992-09-10 | 1994-07-12 | Peregrine Surgical Ltd. | Tissue irrigation solution |
| US5523316A (en) * | 1994-06-23 | 1996-06-04 | Alcon Laboratories, Inc. | Intraocular irrigating solution containing agent for controlling IOP |
| US5686488A (en) * | 1995-08-25 | 1997-11-11 | Alcon Laboratories, Inc. | Polyethoxylated castor oil products as anti-inflammatory agents |
| US5750564A (en) * | 1995-09-12 | 1998-05-12 | Hellberg; Mark | Anti-oxidant esters of non-steroidal anti-inflammatory agents |
| JP3981784B2 (en) * | 1998-10-29 | 2007-09-26 | 千寿製薬株式会社 | Eye perfusion / cleaning solution bag |
| CN1196489C (en) * | 2000-01-11 | 2005-04-13 | 欧得士株式会社 | Perfusion liquid preparations for ophthalmic operations |
| ES2168226B1 (en) * | 2000-11-27 | 2003-09-16 | Recuperat Ion Electrolitos S L | COMPOSITION THAT INCLUDES SODIUM, POTASSIUM, CALCIUM AND MAGNESIUM. |
| WO2005099757A1 (en) * | 2004-04-16 | 2005-10-27 | Helbo Photodynamic Systems Gmbh & Co.Kg | Preparation for the photodynamic control of micro-organisms and use of said preparation |
| DK1737492T3 (en) * | 2004-04-16 | 2013-03-11 | Bredent Medical Gmbh & Co Kg | Preparation for photodynamic control of microorganisms and use of the preparation |
| CA159103S (en) * | 2014-04-29 | 2015-06-01 | Bayer Animal Health Gmbh | Transfer device |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4550022A (en) * | 1981-10-05 | 1985-10-29 | Alcon Laboratories, Inc. | Tissue irrigating solution |
| US4443432A (en) * | 1981-10-05 | 1984-04-17 | Alcon Laboratories, Inc. | Ophthmalic irrigating solution |
| US4975419A (en) * | 1988-09-09 | 1990-12-04 | Entravision, Inc. | Tissue irrigating solution |
-
1988
- 1988-09-09 US US07/243,085 patent/US4975419A/en not_active Expired - Fee Related
-
1989
- 1989-08-16 CA CA000608460A patent/CA1330304C/en not_active Expired - Fee Related
- 1989-08-21 DE DE8989308458T patent/DE68902969T2/en not_active Expired - Lifetime
- 1989-08-21 EP EP89308458A patent/EP0358369B1/en not_active Expired - Lifetime
- 1989-09-06 JP JP1231328A patent/JPH02115128A/en active Pending
-
1990
- 1990-09-04 US US07/577,306 patent/US5104663A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| DE68902969D1 (en) | 1992-10-29 |
| US5104663A (en) | 1992-04-14 |
| EP0358369A1 (en) | 1990-03-14 |
| US4975419A (en) | 1990-12-04 |
| JPH02115128A (en) | 1990-04-27 |
| DE68902969T2 (en) | 1993-04-01 |
| EP0358369B1 (en) | 1992-09-23 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |