Classifications

• • 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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents

Definitions

• the present invention relates to the field of intraocular surgery. More particularly, the invention relates to a solution which performs the dual functions of: (1) maintaining mydriasis, and (2) maintaining the integrity, stability, and function of ocular tissues, during invasive intraocular surgical procedures.
• cataract surgery which is a very delicate operation involving replacement of the natural crystallin lens of the human eye with an artificial lens
• cataract surgery which is a very delicate operation involving replacement of the natural crystallin lens of the human eye with an artificial lens
• cataract surgery was previously considered to be a major surgical procedure requiring hospitalization of the patient and a significant recovery period, but today this procedure is routinely performed on an out-patient basis and enables vision to be restored almost immediately.
• Similar advancements have been achieved in other areas of ophthalmic surgery.
• the present invention is directed to a further improvement in one such pharmaceutical product, a solution for irrigating ocular tissue during intraocular surgery.
• a solution for irrigating ocular tissue during intraocular surgery are discussed in United States Patent No. 4,550,022; the entire contents of that patent are hereby incorporated in the present specification by reference. The importance of such solutions to ophthalmic medicine is explained in the '022 patent. The relevant portions of that explanation are repeated below.
• the need to keep cell loss to a minimum is particularly crucial during any surgical procedure performed on delicate and irreplaceable tissues, such as the tissues of the eye, nerves, etc.
• the cornea of the eye is comprised of five layers: epithelium, Bowman's membrane, stroma, Decemet's membrane, and endothelium.
• the endothelium layer is particularly vulnerable to trauma as the endothelial cells are infrequently, if ever, replaced as a normal process in the adult life.
• the endothelium is principally responsible for the maintenance of the proper state of hydration of the stromal layer.
• the stromal layer has a tendency to imbibe fluid, a tendency which is counter-balanced by outward fluid transport via the endothelium. If the proper fluid balance is not maintained in the stromal layer, the cornea thickens and the characteristic transparency of the cornea is lost. Accordingly, cell loss or damage in the endothelial layer will result in decreased vision. Failure of the endothelium to perform its fluid transport function for short periods of time will result in corneal thickening and visual clouding. Because of the importance of, and the vulnerability of, the endothelial layer, it is necessary during eye surgery, such as cataract and retinal surgery or corneal transplants, to make provisions for the protection of the endothelial cells.
• a significant factor causing cell loss during tissue scission is the traumatic change in environment experienced by the internal cells. Exposure to the atmosphere presents a far different environment for the cells than is provided by the natural fluids in which they are bathed. To simulate the natural cellular environment and thereby prevent cell damage, exposed tissue during surgery is frequently irrigated in solutions which attempt to approximate natural body fluids. The value of bathing eye tissue during surgery to prevent cell damage has long been recognized.
• the aqueous humor is the natural bathing fluid and, hence, an ophthalmic irrigating solution intended to protect the endothelium should as closely as possible resemble the aqueous humor.
• osmolality of the solution be generally isotonic with cellular fluids so as to maintain equal osmotic pressure within and without the cell membranes.
• isotonic 0.8% saline.
• isotonic saline is quite inadequate as an ophthalmic irrigating solution and has been shown to result in endothelial cell swelling, cell damage, and consequent corneal clouding.
• Balanced salt solution contains the essential ions, calcium, sodium, potassium, magnesium and chloride in generally optimal concentrations for ocular tissue, and has an acetate-citrate buffer system which is compatible with divalent calcium and magnesium ions.
• Mg** is an important cofactor for adenosine triphosphatase, an enzyme which plays an important role in mediating the fluid transport pump in the eye.
• Ca** is necessary to maintain the endothelial junction.
• K + is an important factor in many biochemical processes, and the fluid transport pump of the endothelium requires a proper
• an irrigating solution in addition to electrolytic balance must provide metabolic support and must particularly provide factors needed for the enzyme-mediated Na + /K + pump system through which excess fluid is removed from the stroma.
• GRR glutathione-bicarbonate-Ringers solution
• GBR has been shown effective in maintaining corneal thickness and endothelial cell integrity for up to three hours. While the effectiveness of a GBR ocular irrigating solution has been known for many years, prior to the early 1980's its use in surgery was quite limited due to stability and sterility problems. It is to be appreciated that sterility of an ophthalmic irrigating solution is absolutely essential. To insure sterility, it is desirable that an irrigating solution be prepackaged so that the quality and sterility may be closely monitored and tested as contrasted with an extemporaneously mixed solution as might be prepared in a hospital pharmacy.
• the solution will perfuse the eye in essentially a closed system where even a small number of organisms, such as pseudomonas aeruginosa, can produce an overwhelming endophthalmitis.
• GBR may not be prepackaged due to the long term incompatibility and/or instability of its various moieties.
• bicarbonate is perhaps the most important.
• the bicarbonate as well as the phosphate in a bicarbonate-phosphate buffer system may form insoluble precipitates with Mg "1"1" and Ca**. While at the ionic concentrations useful in ophthalmic irrigation, precipitation is not a problem in freshly prepared solution, long-term storage is proscribed. As insoluble crystals introduced into the eye will cloud vision, the importance of keeping a tissue irrigating solution free of insoluble precipitates may be readily appreciated.
• Complicating the maintenance of GBR's stability is the fact that the pH of GBR will gradually increase due to the inadequacy of the bicarbonate-phosphate buffer. To provide proper pH, i.e., about 7.4, the pH of the original GBR solutions prepared in the hospital pharmacy had to be monitored and adjusted with CO 2 immediately prior to use and even during use. The chances for contamination during pH adjustment was great.
• a further factor which proscribes long-term storage of GBR is the unavailability of a proper pH at which all of the moieties are stable.
• Several moieties of GBR are unstable at the physiological pH of about 7.4. Below a pH of about 8, bicarbonate generally decomposes to CO 2 , resulting both in a loss of bicarbonate concentration and increased pH.
• glucose stability requires a pH of less than about 6.
• Glutathione while biologically effective either in reduced or oxidized form, is preferred in the oxidized form because the reduced form quickly oxidizes in aqueous solutions, preventing proper labeling of the irrigating solution.
• Oxidized glutathione (glutathione disulfide) is unstable over extended periods of time at a pH of above about 5. The concentration of glutathione may also decrease to an unacceptable concentration when stored over long periods of time in admixture with all other components. Because of the demonstrated efficacy of GBR as an ocular irrigating solution, it was highly desirable to provide a formulation which contains the essential factors found in GBR and which could be stored in a sterilized form for use in eye surgery. The invention described in U.S. Patent No. 4,550,022 provided such a product
• adjunctive drugs directly in the irrigating solution at the time of manufacture, if possible.
• these solutions tend to be complex in terms of chemical incompatibilities, required pH conditions, and so forth. This is also true of many of the adjunctive drugs which ophthalmic surgeons may desire to add to the solution.
• One such drug is epinephrine.
• Epinephrine is frequently used in the field of ophthalmology to effect dilation of the pupil (i.e., mydriasis).
• the use of this drug is particularly prevalent in ophthalmic surgical procedures, since dilation of the pupil is frequently necessary in order to increase surgeons' ability to see inside the eye with the aid of a microscope. More specifically, dilation of the pupil during intraocular surgery is necessary to allow visualization and manipulation of tissues which lie behind the plane of the iris, including the lens, retina, and all ocular structures in the posterior segment.
• Pupillary dilation is accomplished by the use of sympathomimetic agents which stimulate the iris dilator muscle.
• Intraocular injections of epinephrine are frequently used during ophthalmic surgical procedures to produce and maintain mydriasis during surgery.
• the epinephrine may be injected directly in the eye and/or may be administered as an added component of a surgical irrigating solution.
• the epinephrine added to intraocular irrigating solutions for constant infusion into the eye during the surgical procedure commonly consists of commercial products intended for parenteral administration.
• Parenteral preparations may contain undesirable additives such as sodium bisulfite, an antioxidant, and chlorobutanol, a preservative.
• the pH, osmolality, and buffer capacity of parenteral epinephrine preparations may also be inappropriate for intraocular use.
• a sympathomimetic agent administered during intraocular surgical procedures can have serious consequences.
• the administration of a low concentration is generally not a problem, since the surgeon will recognize that mydriasis is not being maintained and will therefore supplement the initial administration of the sympathomimetic agent.
• the administration of a high concentration is potentially dangerous.
• Sympathomimetic agents such as epinephrine constrict blood vessels and thereby restrict blood flow. This restricted blood flow may conceal the need to cauterize a blood vessel during a surgical procedure.
• intraocular bleeding will occur. This condition, known as hyphemia, will cause the eye to look very bloodshot, and may require surgical intervention in order to stop the bleeding.
• Epinephrine is known to be chemically unstable because it is very susceptible to oxidation when in solution. Since intraocular irrigating solutions, particularly GBR solutions such as BSS Plus ® Intraocular Irrigating Solution are already complex in terms of the number of components, the chemical incompatibility of certain components, and particular pH conditions needed to maintain the stability of some components, the addition of an another component known to be relatively unstable in solution presents a significant problem.
• a principal objective of the present invention is the provision of a standardized ophthalmic pharmaceutical composition for maintaining mydriasis and irrigating intraocular tissues during intraocular surgical procedures.
• standardized denotes a composition which has certain specified characteristics and properties, and which is substantially ready for use by ophthalmic surgeons at the time of surgery, without requiring any further, concentration calculations, dilutions, pH adjustments, or other activities generally associated with the preparation of pharmaceutical compositions.
• the present invention eliminates these risks by providing an ophthalmic pharmaceutical composition containing epinephrine or a similar mydriatic agent which is specifically formulated and adapted for use as an intraocular irrigant.
• Specific advantages of the compositions of the present invention therefore include: (1) delivery of a specified, controlled dose of a mydriatic agent to the patient, (2) assurance that the composition is sterile at the time of use, (3) elimination of chemical preservatives, such as sulfites, and other ingredients of parenteral preparations which are potentially damaging to intraocular tissues, and (4) adaptation of the pH, osmolality and buffering capacity of the composition so that it is ideally suited for intraocular use.
• the intraocular irrigating compositions of the present invention includes a first part containing a mydriatic agent.
• the first part is formulated as an acidic solution. This solution may be lyophilized to form a powder which is then resolubilized prior to administration to the eye.
• the low pH of the solution improves the stability of the epinephrine.
• the first part preferably also includes glutathione.
• the intraocular irrigating compositions of the present invention also include a second part containing a buffer to provide an ophthalmically acceptable pH when the first and second parts are combined.
• the first part preferably also includes one or more electrolytes to facilitate the maintenance of normal cellular function during intraocular surgical procedures. Combining the first part and the second part provides a physiologically balanced, standardized solution for maintaining mydriasis while maintaining the function and integrity of intraocular tissues.
• the irrigating compositions of the present invention contain one or more agents to produce and maintain mydriasis during an intraocular surgical procedure. Such agents are referred to herein as "mydriatic agents".
• mydriatic agents are catecholamines having sympathomimetic activity. As utilized herein, the term catecholamine denotes compounds which include a catechol group (O-dihydroxybenzene) and an amino group on the side chain.
• the preferred compounds include epinephrine; phenylephrine; dipivalyl epinephrine; norepinephrine; isoproterenol; and the pivaloyloxy and phenylacetyloxy ester derivatives of epinephrine and norepinephrine described in U.S. Patents Nos. 3,809,714; 3,839,584; and 4,085,270. The entire contents of those patents are hereby incorporated in the present specification by reference. Epinephrine and dipavalyl epinephrine (“DPE”) are particularly preferred.
• the 1-isomer of epinephrine is approximately 20 times more active than the d-isomer; use of the 1-isomer is therefore preferred.
• the irrigating solutions of the present invention will typically contain one or more mydriatic agents in an amount of about 0.0005 to 0.11 mM 1.
• the irrigating solutions of the present invention are formed by combining two or more parts immediately prior to an ophthalmic surgical procedure.
• the above-described mydriatic agents are contained in a first part which is formulated as an acidic composition.
• the acidic compositions containing one or more mydriatic agents preferably also contain glutathione to assist in the maintenance of corneal endothelial cells.
• glutathione encompasses both the reduced (i.e., sulfhydryl) and oxidized (i.e., disulfide) forms of this compound; however, use of the oxidized form of glutathione is preferred.
• Glutathione is available from various commercial sources.
• the invention may be embodied in various types of irrigating solutions.
• the most preferred embodiment is a two-part product similar to BSS Plus ® Intraocular Irrigating Solution (Alcon Laboratories, Inc., Fort Worth, Texas USA).
• the first part is an acidic solution containing one or more mydriatic agents, and preferably also glutathione.
• the second part is a buffered, neutral solution containing one or more electrolytes.
• the compositions of the two parts are such that each is individually stable and may be separately stored for long periods.
• the resulting solution is useful for ocular surgery as it contains the necessary factors to maintain mydriasis, as well as maintain endothelial cell integrity and corneal thickness, during an intraocular surgical procedure. More specifically, when the first and second parts are combined, the resulting irrigating solution contains: one or more mydriatic agents to maintain mydriasis during the procedure; electrolytes necessary for tissue stability, Ca “1"1” , Mg * " , Na + , + and Cl " , in a bicarbonate-phosphate buffer; glutathione; and dextrose. The electrolytes are provided in proportions conducive to maintaining the physical integrity and metabolism of corneal endothelial cells and other ocular tissues.
• the irrigating solution formed by combining the above-described first and second parts will typically contain from about 50 to about 500 millimoles per liter ("mM/1") Na + , from about 1 to about 10 mM/1 K + , from about 0.1 to about 5 mM/1 Ca “ “ “ “ , from about 0.1 to about 10 mM/1 Mg ++ and from about 50 to about 500 mM/1 Cl " .
• the osmolality is between about 260 and about 330 mOsm and preferably about 290-310 mOsm.
• the pH of the final irrigating solution is between about 6.8 and about 8.0 and preferably about 7.2-7.8.
• the bicarbonate concentration in the combined irrigating solution is between about 10 and about 50 mM/1.
• an additional buffering agent is provided.
• the buffering agent is phosphate which is provided in sufficient quantity so that final phosphate concentration of the irrigating solution is between about 0.1 and about 5 mM/1.
• the final irrigating solution contains between about 1 and about 25 mM/1 glucose and between 0.01 and about 3 mM/1 of glutathione.
• the neutral, buffered solution provides the phosphate and bicarbonate buffering moieties, preferably in the form of dibasic sodium phosphate and sodium bicarbonate.
• the pH of the solution is adjusted to about the physiological pH, of 7.4, preferably to between about 7.2 and about 7.8.
• the pH of a bicarbonate-containing solution is preferably above about 8.0 to prevent decomposition of the bicarbonate.
• the bicarbonate may be stabilized if it is added to a solution with a pH of above about 8 and thereafter adjusted to a pH between 7 and 8. Accordingly, when the neutral, buffered solution is prepared, Na j HPO., is added prior to the addition of NaHCO 3 so that NaHCO 3 is dissolved in a solution with a pH of between about 8 and 9. The solution is thereafter adjusted with dilute acid, such as H 2 SO 4 , H 3 PO 4 or HC1, to the desired final pH of the neutral, buffered solution. Alternatively, carbon dioxide may be added to adjust the pH.
• dilute acid such as H 2 SO 4 , H 3 PO 4 or HC1
• carbon dioxide may be added to adjust the pH.
• Potassium and additional sodium are provided in the neutral, buffered solution in the form of sodium and potassium salts, such as sodium or potassium chlorides, sulfates, acetates, citrates, lactates, and gluconates.
• sodium and potassium salts such as sodium or potassium chlorides, sulfates, acetates, citrates, lactates, and gluconates.
• the sodium and potassium are compatible with all of the moieties present in the finished tissue irrigating solution, and sodium chloride and potassium chloride may be added to either solution or divided between the solutions.
• the pH of the final irrigation solution may be more accurately determined if all compatible salts are included in that solution.
• the acidic solution preferably also includes Ca** in the form of calcium chloride, Mg* in the form of magnesium chloride, glutathione and dextrose.
• the pH is adjusted to below about 5 to provide long-term stability to the mydriatic agent, glutathione and dextrose.
• epinephrine is utilized as the mydriatic agent, a pH of 3 is most preferred for the acidic solution, since this pH has been found to be optimal for enhancing the stability of epinephrine.
• the compositions of the present invention are standardized.
• the volumes of the neutral, buffered solution and the acid composition are selected so that adding the entire acid composition to the entire neutral, buffered solution results in a solution which contains an amount of one or more mydriatic agents effective to maintain mydriasis during an intraocular surgical procedure, and has a pH, osmolality and buffering capacity adapted for irrigation of intraocular tissue.
• the volume of the neutral, buffered solution greatly exceed the volume of the acidic solution and that the acidic solution contain no buffering agents.
• the acidic solution may be adjusted below a pH of about 5 with a relatively small amount of HCl. Because the acidic solution is unbuffered, its pH is a reflection of the acid concentration and less acid is needed to adjust the pH of a small volume.
• the large volume of neutral, buffered solution may be adjusted very close to the final pH of the irrigating solution and will be relatively unaffected by the addition of the small volume of the acidic solution.
• the ratio of the volume of the neutral, buffered solution volume to the acidic solution volume is about 10 to 1 to about 50 to 1. A ratio of 25 to 1 is particularly preferred. If the acidic composition is provided in the form of a solution, rather than a lyophilized powder, the use of a relatively concentrated, small volume solution is preferred.
• epinephrine mydriatic agents such as epinephrine when those agents are in solution.
• epinephrine breaks down through two primary mechanisms: racemization and oxidation. Racemization leads to d-epinephrine which is twenty times less active than 1- epinephrine. There is less driving force for these decomposition reactions when the same quantity of epinephrine is dissolved in a smaller volume of solution. In other words, more concentrated epinephrine solutions are less prone to decomposition due to the kinetics of low volume solutions, relative to higher volume solutions.
• the stability of the epinephrine solutions is also enhanced by bubbling nitrogen through the solution to remove oxygen. However, it may not be possible to remove all of the oxygen by means of this technique. Utilizing a smaller volume solution results in less water and therefore less oxygen being present. Thus, the use of a smaller volume solution inherently reduces the amount of oxygen present.
• the use of volumes on the order of 10 to 20 milliliters or less for the acid solution are preferred.
• the neutral, buffered solution and the acidic composition are sterilized and separately bottled or contained under sterile conditions by standard techniques, such as autoclaving, or use of sterilizing filters, but preferably by heat sterilization.
• the neutral, buffered solution which primarily contains inorganic moieties, is autoclaved
• the acidic solution which preferably contains the organic components, is microfiltered.
• compositions may be packaged in various types of pharmaceutical containers.
• the compositions may be packaged in a container having a first chamber for the neutral, buffered solution, an. isolated second chamber for the acidic solution, and means to communicate the chambers without opening the container.
• the use of containers formed from Type I or Type-I SO 2 -treated glass are preferred.
• the two-part compositions of the present invention may also be packaged by means of a combination of a bottle for the neutral, buffered solution and a syringe for the acidic composition containing one or more mydriatic agents.
• the acidic composition may be contained in the syringe as either a sterile solution or a sterile, lyophilized power. If it is in the form of a lyophilized powder, the powder may be reconstituted by drawing an amount of the neutral, buffered solution sufficient to dissolve all of the powder into the syringe.
• a sterile diluent other than the neutral, buffered solution can also be utilized to dissolve the lyophilized powder.
• a two-compartment syringe can also be utilized, with the lyophilized powder in one compartment and a diluent for the powder in a second compartment.
• the compartments are separated by a movable stopper or membrane which can be displaced by depressing the plunger of the syringe, thereby allowing the diluent to be combined with the powder.
• the resulting solution is then added to a bottle containing the neutral, buffered solution by inserting a cannula attached to the front of the syringe through a stopper in the top of the bottle.
• the first and second parts can also be packaged in separate bottles.
• a sterile double- ended needle can be used to transfer the acidic solution to the neutral, buffered solution by aseptically inserting one end of the needle into a vial containing the acidic solution and then aseptically inserting the other end of the needle into the neutral, buffered solution package, whereby the vacuum that is maintained therein transfers the acidic solution to the neutral, buffered solution and is mixed.
• the two-part composition of the present invention also provides an advantage as to safety if a technician should fail to properly mix the two solutions.
• the pH and osmolality of the larger volume neutral, buffered solution are at or near physiological levels, so that there is less chance of toxicity if the neutral, buffered solution were used without the acidic composition being mixed therewith.
• the present invention may be embodied in various types of formulations. Representative formulations are described in the following examples.
• Part I neutral, buffered solution
• Part II anhydrous dibasic sodium phosphate
• Additional water for injection is added to make the desired volume and IN HCl is added to adjust the pH to about 7.4.
• the solution is then passed through a 0.45 micron Millipore filter and placed in a bottle.
• the filled bottle is then stoppered, vacuumed and sealed.
• the sealed bottle is sterilized by autoclaving at 121" C for about 23 minutes.
• Part II (acidic solution) is made by dissolving calcium chloride dihydrate, magnesium chloride hexahydrate, dextrose, reduced glutathione and epinephrine in water for injection, The solution is then sterile filtered through a 0.22 micron membrane filter and aseptically filled into a presterilized bottle and sealed with a presterilized rubber stopper.
• This formulation may be prepared by means of the following procedure. First, all glassware is washed with hot water for injection (“WFI”) depyrogenated at 250° before use. Then each of the following ingredients is sequentially added to about 80% of the total volume of WFI to be utilized, allowing each ingredient to dissolve before the next is added:
• WFI hot water for injection
• the pH of the solution is then checked and, if necessary, adjusted with hydrochloric acid NF and/or sodium hydroxide, NF. WFI is then added in an amount sufficient to reach 100% of the intended batch volume, and the resulting solution is mixed by stirring.
• the solution is then passed through a 0.2 micron membrane filter into a pyrogen-free container.
• the container is then flushed with nitrogen gas (a nitrogen blanket is maintained over the solution to displace air and protect the solution from oxidation).
• nitrogen gas a nitrogen blanket is maintained over the solution to displace air and protect the solution from oxidation.
• a rubber stopper Immediately after flushing the filled container with nitrogen gas, it is sealed by means of a rubber stopper.
• the filled and sealed container is then placed in a cardboard box or sealed pouch to protect the contents, particularly epinephrine, from light during storage.
• the following formulation represents another embodiment of the present invention, wherein phenylephrine is utilized as the mydriatic agent in the acidic solution instead of epinephrine.
• This formulation can be prepared in accordance with the procedures described in Example 2 above.
• the invention may also be embodied in products formulated or configured differently from the two-part product described above.
• the acidic solution containing glutathione and epinephrine or another sympathomimetic compound can be lyophilized (i.e., freeze-dried) following preparation and then reconstituted as a solution prior to use.
• the low pH of the acid solution will have a stabilizing effect on epinephrine, both when the solution is initially formed, and after the lyophilized solution is reconstituted.
• the solution may be lyophilized in one basic step, or separate solutions may first be sequentially frozen in a single container, and then lyophilized, as described in United States Patent No. 4,975,419.
• the lyophilized powder must be stored in a sealed container, and that container should be placed in a sealed pouch constructed of a moisture impervious material, such as foil.
• the pouch should be opaque, in order to protect the epinephrine from light, and preferably also contains nitrogen gas, in order to protect the epinephrine from oxygen. If a bulking agent, such as mannitol, is utilized to form the lyophilized powder, this may increase the osmolality of the solution, and therefore necessitate an adjustment in the amount of sodium chloride contained in the second part of the composition.
• epinephrine In view of the instability of epinephrine, special precautions may need to be taken during the manufacturing of the compositions of the present invention, particularly the first part which comprises epinephrine or another mydriatic agent. If epinephrine is utilized as the mydriatic agent, it will need to be protected from light, heat, oxygen and metal surfaces during the manufacturing process. In view of the sensitivity of epinephrine to light, only covered tanks or vessels should be used, and lighting of the area around the tanks or vessels should be reduced to the lowest extent possible. Ultraviolet light should be totally eliminated, if possible. The epinephrine should also be protected from oxygen during the manufacturing process. This protection may include the following steps:

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