AU625692B2 - Microcrystalline matrix for administration of beneficial agent - Google Patents

Description

OPI DATE 14/06/89 WORLI AOJP DATE 20/07/89 APPLN- ID 27137 88 PcT PCT NUMBER PCT/US88/03983 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4 (11) International Publication Number: WO 89/ 04687 A61M 31/00 Al (43) International Publication Date: 1 June 1989 (01.06.89) (21) International Application Number: PCT/US88/03983 (8 esi nated SteAT pe atent), AU, BE (Eu- 6ro ean liatnt),-l (Wropean patent), DE (Euro- (22) International Filing Date: 8 November 1988 (08.11.88) pean patent), FR (European patent), GB (European patent), IT (European patent), JP, LU (European patent), NL (European patent), SE (European patent).

(31) Priority Application Number: 121,316 (32) Priority Date: 16 November 1987 (16.11.87) Published With international search report.

(33) Priority Country: US Before the expiration of the time limit for amending the claims and to be republished in the event of the receipt of amendments.

(71) Applicant: BAXTER INTERNATIONAL INC. [US/ US]; One Baxter Parkway, Deerfield, IL 60015 (US).

(72) Inventors: WEINLESS, Naomi, L. 964 Deerfield Road, Highland Park, IL 60035 POKROPINS- KI, Sharon 4225 East Avenue, Berwyn, IL 60402

(US).

(74) Agents: MATTENSON, Charles, R. et al.; One Baxter Parkway, Deerfield, IL 60015 (US).

(54) Title: MICROCRYSTALLINE MATRIX FOR ADMINISTRATION OF BENEFICIAL AGENT (57) Abstract Medical solution is passed in a conduit (10) across a. solid, microcrystalline mass (18) of beneficial agent to cause the beneficial agent (18) to dissolve in the medical solution. The beneficial agent (18) comprises a mass of citrate or mannitol ,'a in a substantially anhydrous form, the mass (18) being shaped and proportioned so that a controlled amount of the beneficial I agent (18) dissolves into passing medical solution in a manner that is substantially predetermined. For example, the benefi- cial agent (18) can dissolve in substantially uniform manner, whereby no substantial portion of the medical solution, such as blood or another parenteral solution, is exposed at a relatively constant flow to a significantly higher concentration of the beneficial agent than other flowing portions of the medical solution. The citrate or mannitol mass of the beneficial agent (18) may include at least one added effective agent for dissolving in the medical solution as the citrate or mannitol dissolve therein.

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-1- In Australian Patent Application 29,155/89 the use of dry materials containing beneficial agents is disclosed as a vehicle for conveying such beneficial agents to a medical solution such as blood, or simpler parenteral solutions such as saline solution, glucose solution, or the like.

Preferably, a solid mass, and typically a tablet, of beneficial agent is positioned typically in an enlarged chamber in an administration, blood collection, or processing set, so that as the medical solution passes through the administration set, a controlled amount of the beneficial agent dissolves into the passing medical solution in a manner that is substantially uniform or otherwise predetermined.

Generally, the beneficial agent comprises a sugar or sugar alcohol in a substantially anhydrous glass form, typically with other beneficial agents admixed with the sugar. Such beneficial agents may be citrate in the form of citric acid and sodium citrate, and possibly including a sodium phosphate salt, to provide an anticoagulant for blood which may be uniformly administered to various aliquots of blood passing 0 20 through the system, particularly the early aliquots of the flow which in the present technology may be exposed to an S excessive concentration of anticoagulant, with undesirable effects on the living cells in those early flow portions of blood. The beneficial agent in substantially anhydrous, S5 glass form is capable of assuming the glassy form (of the S i

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1:: I ii -2order of hard candy), because a significant percentage of the formulation is a sugar or sugar alcohol.

According to one aspect of the invention there is provided a method of passing medical solution through a conduit, the improvement comprising: passing said medical solution across a solid mass of microcrystalline beneficial agent positioned within said conduit, said microcrystalline beneficial agent comprising a material selected from the group consisting of citrate and mannitol in a substantially anhydrous form, wherein said mass of microcrystalline I

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beneficial agent is shaped and proportioned whereby a controlled amount of said microcrystalline beneficial agent dissolves into passing solution at a substantially uniform rate of dissolution.

According to a further aspect of the invention there is provided a method of passing medical solution through a conduit, the improvement comprising: passing said medical solution across a solid mass of microcrystalline beneficial agent positioned within said conduit, said microcrystalline beneficial agent containing at least 30 weight percent of citrate or mannitol, said mass of microcrystalline beneficial agent being shaped and proportioned whereby a controlled amount of said microcrystalline beneficial agent dissolves into passing solution at a substantially uniform rate of dissolution.

According to a still further aspect of the invention there is provided a method of passing medical solution through a conduit, the improvement comprising: passing said b 1:

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i OjFICl 1. 'L II j -2amedical solution across a solid mass of microcrystalline beneficial agent positioned within said conduit, said microcrystalline beneficial agent comprising a material selected from the group consisting of citrate and mannitol in a substantially anhydrous form, along with an added beneficial ingredient other than said citrate and mannitol, wherein said mass of beneficial agent is shaped and proportioned whereby a controlled amount of said beneficial agent dissolves into passing solution in a manner that is substantially uniform.

According to yet another aspect of the invention there is provided a microcrystalline tablet shaped and proportioned whereby a controlled amount of a microcrystalline beneficial agent dissolves into passing solution at a substantially uniform rate of dissolution, which may be postioned in a flow conduit for dissolving in a stream of medical solution passing through said flow conduit, said tablet comprising a mixture of sodium citrate and citric acid.

According to yet another aspect of the invention there is provided a microcrystalline tablet shaped and proportioned whereby a controlled amount of a microcrystalline beneficial agent dissolves into passing solution at a substantially uniform rate of dissolution, which may be postioned in a flow conduit for dissolving in a stream of medical solution i 25 passing through said flow conduit, said tablet comprising Smannitol.

F WO 89/04687 PCT/US88/03983 Preferably, at least 70 weight percent of the mass of beneficial agent is citrate citrate salts and/or citric acid) or mannitol, there being preferably no more than 20 weight percent of sugar present. The mass of beneficial agent is shaped and proportioned whereby a controlled amount of the beneficial agent dissolves into passing medical solution in a manner that is substantially uniform or otherwise predetermined. Alternatively, nonuniform administration rates may be predetermined, depending on the shape and condition of the citrate mass.

In one typical use of the invention of this application, the medical solution may be blood, for example blood which is in the process of being collected from a donor and passed into the donor bag of a single or multiple blood bag system which may be of conventional design and use, but for the modifications provided by this invention. In this circumstance, the beneficial agent may comprise an anticoagulant including the citrate itself present, typically in substantially pure form. However, any known anticoagulant or other blood cell preservative, such as platelet preservatives, may be so incorporated into such a dry citrate mass. Additionally, a water soluble, non-toxic source of phosphate may be present in a concentration effective to promote blood storage in known manner. Adenine may be present, if desired, as well as any other ingredient which is desired for the storage of blood or components thereof.

By the term "blood", it is intended to include not only whole blood, but components of blood as may be desired, for example blood plasma (either platelet rich or platelet poor) or suspensions of packed red cells, white cells, or platelets in saline solution, any other appropriate suspension of blood cells, or L I .I i i i -1 WO 89/04687 PCT/US88/03983 -4the like.

Alternatively, the beneficial agent may comprise mannitol which is, in itself, a drug administered by parenteral administration. In this instance, a dried mass of mannitol may be positioned in the path of flow of parenteral solution or blood being administered to the patient. As the solution of blood passes by the mannitol, there is a selectively controlled dosage administration of mannitol provided by dissolution from the tablet or mass of mannitol into the solution or the blood.

With respect to either the citrate or the mannitol dried masses, other ingredients may be present. While either the citrate or the mannitol may be the active ingredient as described above, either of them, or both of them admixed together, may serve as a carrier for a different beneficial agent active ingredient.

Other ingredients may also be present in the citrate or mannitol mass as well. For example, typical sugars or sugar alcohols may be present in minor proportions. They should be soluble, non-toxic sugars or sugar alcohols which may or may not be metabolizable as a nutrient according to the desires of the formulator and the use to which the mass of beneficial agent is to be put.

Examples of usable citrates which may be used in the manner described above include sodium citrate, and citric acid. The proportions of sodium citrate and citric acid may, for example, be adjusted to obtain the pH desired.

For example, a mixture of 5.6 molar parts of sodium citrate to one molar part of citric acid, intimately mixed and formed into a microcrystalline tablet will dissolve to yield in distilled water a

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WO 89/04687 PCT/US88/03983 solution having a pH of 5. A mixture of 133.3 molar parts of sodium citrate per one molar part of citric acid will dissolve to yield in distilled water a pH of 7.4. Thus, it can be seen that a desired pH can be obtained from the dry material used in this invention by control of the citrate to citric acid ratio. This ratio may typically range from 2 to 200/1, and is more preferably 5 to 150/1, expressed in molar parts.

The dry, typically microcrystalline, mass of beneficial agent is preferably provided in the form of one or more dry tablets, with means provided in the conduit for carrying the solid mass of beneficial agents and permitting blood or other medical solution flowing through the conduit to enter into contact with the solid mass. As solution passes through the solid mass, it picks up a substantially predetermined amount of beneficial agent and carries it away. The geometry of the preferred tablet may be specifically shaped to provide a desired, controlled, relatively constant release of the beneficial agent as the solution passes across it. Specifically, a single tablet may be provided which is relatively long and wide relative to y its thickness. With such a configuration, as the tablet erodes, there is little change in the surface area of the tablet, so that the amount of beneficial agent which dissolves into passing medical solution remains substantially uniform, at least until the tablet begins to disintegrate. It may be desirable to have the tablet or tablets of a desired size and thickness so that the last of the medical solution has passed through the conduit before the tablet or tablets erode away so much that they begin to break up, at which point a significant difference in the i transfer rate of beneficial agent into the solution can take place. Otherwise, the complete tablet or 1 J 1 1 15 1 1 WO 89/04687 PCT/US88/03983 -6tablets may be dissolved in the process, giving visual indication that the complete, desired dose has been administered.

The dryv beneficial agent may be a molded, exrtruded, or pressed structure, which may be flat and thin as described above, or the tablet may be a pressed, solid structure having multiple flow channels through it for flow of medical solution therethrough, or of a cylinder shape so that medical solution flows through its bore, or any other shape or structure as desired. By this invention, since the geometry and size of the mass of beneficial agent can be controlled, improvements in control of transfer of the beneficial agent to the medical solution are obtained.

For example, an increased amount of beneficial agent may be initially provided by a tablet having a porous outer portion and a denser, less porous inner portion.

Thus, the use of the substantially dry mass of beneficial agent, typically positioned in a conduit, provides significant advantages. The empty bag or the receptacle which thus may be used for blood or other I medical solution is sterilized with much greater ease than current blood bags which contain liquid anticoagulant. Additionally, transportation and handling advantages are achieved, when compared particularly with containers of frozen drug solution, which must be transported in frozen condition. In many cases, the drug is simply incorporated into the citrate or mannitol mass. If desired, a parenteral solution such as saline may be passed over the mass and directly into the patient, carrying the dissolved citrate and a controlled amount of drug with it.

Thus, critical drugs may be administered to a patienti without a special step of reformulation of the dry drug into a parenteral solution.

I i i WO 89/04687 PCT/US88/03983 -7- Therefore, significant advantages of manufacturing, transportation, storage, and handling are provided in accordance with this invention.

Additionally, citrate and mannitol microcrystalline masses having a low water content (for example 2 to 5 percent by weight) may be good oxygen barriers. Thus, oxygen-sensitive drugs may be protected while incorporated in the mass of beneficial agent used in this invention.

Also, the system of this invention may be well suited for gamma irradiation sterilization, and moisture sensitive drugs are also protected by storage in the mass of beneficial agent in accordance with this invention. It is believed that the citrate or mannitol present can exert a protective action on drugs or other effective agents which are mixed in the mass of citrate prior to contact with the medical solution for use, providing protection against moisture, oxygen, and even gamma radiation, to reduce loss of effective agent during gamma irradiation sterilization, for example.

Without wishing to be limited to any theory of operation of the invention, it is believed that the hydroxyl groups of particularly mannitol present can i act as free-radical scavengers to protect sensitive, effective agents present from degradation during or following gamma irradiation for sterilization.

Additionally, the citrate or mannitol masses used in this invention are resistant to bacterial attack due to thuir low water content. It is generally preferred for the water content of such dry masses to be about 1 to 2 percent, and typically no more than about 5 percent by weight.

Additionally, the dry citrate mass of this invention can be effectively molded during manufacture i i S- -8to form a tablet or tablets of desired dimensions to obtain the exact, desired dissolution rate as medical solution passes in contact therewith.

Typically at least 30 weight percent of mannitol or citrate salt and citric acid are present in the formulation as a vehicle for delivery of a beneficial agent.

Examples of drugs that may be included in the citrate or mannitol formulation of this invention include drugs that are desirably released on a controlled release basis, for example, aspirin, antibiotics, thyroid hormones, cancer chemotherapy agents, or insulin. Accordingly, the uniformity of release which is available through one or more tablets .15 of the citrate or mannitol mass of this invention may facilitate the controlled administration of such drugs through I.V. infusion.

Additionally, the citrate or mannitol tablets described above may be taken orally for in situ release of drugs such as ampicillin or other antibiotics, or the like.

As another use, the citrate or mannitol mass of this invention may be reconstituted with peritoneal dialysis solution, for example CAPD solution, to place medicaments and nutrients such as ketoacids into the CAPD solution. Likewise, collected blood may be brought into contact with microcrystalline citrate masses for short term anti-coagulation of blood, for example, for use in a plasmapheresis or other procedure involving the short term extracorporeal storage of blood. For example, this technique may prove advantageous for use with diabetics rather than using an anticoagulant having larger quantities of sugar.

cc_ C I. WO 89/04687 PCT/US88/03983 DESCRIPTION OF DRAWINGS Fig. 1 is a plan view of a blood collecting set made in accordance with this invention, shown to be integrally connected to a medical solution storage bag; and Fig. 2 is a sectional view taken along line 2-2 of Fig. 1.

DESCRIPTION OF SPECIFIC EMBODIMENTS Referring to the drawings, there is shown a set 10 for collecting blood from a patient and conveying it to blood storage container 12, which may be made in substantially conventional manner. Set carries at one end a conventional blood connection needle 14 for collecting blood from the venous system of the patient, which blood then passes through set into blood bag 12.

In accordance with this invention, the conduit of set 10 defines an enlarged portion 16 which includes a microcrystalline, solid mass 18 of dry blood storage anticoagulant preparation, typically having a water content on the order of no more than about 2-5 percent by weight. Anticoagulant tablet 18 is shown to be made in the form of thin, rectangular member positioned within enlarged portion 16. The inner walls of both sides of enlarged portion 16 define an array of small projections 20 which project inwardly to define flow passages between the inner wall of enlarged portion 16 and the surface of anticoagulant preparation tablet 18. Alternatively, separate flow screening may replace the projections as flow passage defining means.

Specifically, anticoagulant preparation tablet 18 I^ i WO 89/04687 PCT/US88/03983 may comprise, for example, a dried mixture of: Sodium Citrate 50 gin.

Citric Acid 10 gm.

The above ingredients are dissolved as a near saturated solution in water by heating to boiling at about 239 degrees Then about 1 per cent by weight of dry sodium citrate powder is mixed into the solution, in order to promote crystal growth. The mixture is then spooned into molds and placed in a heated oven at 30" of vacuum for about 12 hours, until the desired water cottent of about 2-5 per cent or less by weight is reached (the water content being as defined by its temperature at the air pressure obtained by the vacuum system). The viscous mass is then cooled to obtain a microcrystalline mass. The term "microcrystalline" means that the crystals present are predominantly less than 50 microns in size.

Other ingredients, when present, may be added when the temperature of the molten citrate falls to about 200 degrees F. or below, with vigorous stirring or alternatively in a twin screw extruder, tc form a homogeneous mass. This material is molded into the desired shape and allowed to solidify, to form the microcrystalline mass in the shape of tablet 18, which may be then placed in portion 16.

Blood bag 12 may be initially free of any anticoagulant. The entire system, including tablet 18, is typically radiation sterilizable, since it is substantially free of moisture. Additionally, no overpouch or other outer package is required to prevent the loss of water from a liquid anticoagulant present, which constitutes a significant advantage -11over the conventional, present blood collection equipment.

For use, a conventional phlebotomy is made into a vein of a blood donor with needle 14, and the blood flows through conduit 10. As it flows, it enters enlarged portion 16, where it flows in a pair of opposed flow halves 22 between the walls 24 of enlarged portion 16 and the flat surfaces of tablet 18. As the blood so flows, the substance of tablet 18 is dissolved away into the flowing blood at typically a relatively uniform rate of dissolution, so that each individual portion of the flowing blood passing through conduit 10 picks up a substantially similar amount of the •dissolved substance of tablet 18 as it flows across it. From there, the flowing blood, carrying the dissolved anticoagulant, passes into bag 12 for storage, without encountering an excessive concentration of anticoagulant or other agent.

I Any design of blood bag or other container may also be utilized in accordance with this invention. If desired, the tablet 18 or an equivalent mixture of materials may be encapsulated and released via diffusion through a semipermeable membrane.

Additionally, the invention of this application may be used in conjunction with various apheresis procedures, for example bag apheresis hardware collection, apheresis, or continuous apheresis procedures. For example, medications may be administered to blood in accordance with this i invention by an apheresis procedure or the like.

d Alternatively, an antibiotic or other drug C Cf kk32 WO 89/04687 PCT/US88/03983 may be mixed into the molten citrate when it is at a temperature of about 200 degrees F. as described above. After intimate mixing, the molten mixture is molded into tablet fcrm, or any other desired shape, and allowed to solidify to a solid form. The resulting tablets may be placed into a chamber similar to enlarged portion 16 of set 10 which may be adapted for connection, or integrally connected with, a bag of parenteral solution. Fig. 1 in this circumstance can represent such a system, in which bag 12 contains, for example, sterile normal saline solution, or even pure water, although such a system might not be fail safe since intravenously administered water is very damaging to blood cells.

In this instance, connection with the venous system of a patient is made by needle 14, and the parenteral solution in bag 12 is allowed to pass from bag 12 through set 10 into the patient's venous system. As it passes through enlarged portion 16, the citrate and admixed drug of tablet 18 dissolves into.

the passing parenteral solution at a predetermined rate, so that the desired amount of drug may be administered simply by administering a desired quantity of parenteral solution from bag 12 at a predetermined rate of flow.

Thus, the invention of this application may not only be used for the handling of blood, but it may be used for the administration of drugs or other beneficial agents directly to the patient, or to another container, in which solution from a bag is passed through a chamber which contains the desired beneficial agent. Such a system is very flexible as to the amount of beneficial agent which is delivered, contrary to many present systems. If one wishes to deliver only one third of the available beneficial 6TR

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0i WO89/04687 PCT/US88/03983 -:13agent in tablet 18, one can simply administer a predetermined amount of solution from bag 12 through set 10 to the patient, and then terminating such administration when the desired amount of beneficial agent has been delivered. Additionally, the enlarged chamber 16 may be manufactured in a form of a cartridge for connection to parenteral solution sets, with the various cartridges carrying different types of drugs as may be desired in the mass of citrate or mannitol. The doctor then needs to only select a cartridge which carries the drug of the desired type and concentration, and administer it to the patient without a special drug reconstitution step previous to the administration.

Examples of drugs which may be inserted into the citrate or mannitol mass of this invention include anticlotting agents such as heparin, antibiotics of any type such as Gentamycin, penicillin, or erythromycin, strongly biologically active drugs that require controlled administration to the patient such as thyroid hormones or insulin, and the like.

Not only can the citrate or mannitol mass of this invention be stored in a tubular set, but the citrate or mannitol mass may be placed within an empty storage container, to dissolve into an aliquot of solution that passes into the container, should that alternative technique be deemed desirable.

The following is a specific example of how a tablet 18 made of mannitol may be utilized for delivery of the mannitol, and any beneficial agent that it contains, to a patient.

Seventy-five grams of nannitol are dissolved in 125 ml. of sterile water which is boiling at 100 degrees C. After the mannitol has been mixed into the water, it is heated to 115 degrees as permitted by OKi -gi J L b 1 1 1 1 1l l T C i i 1 1-14 I i WO 89/04687 -4 PCT/US88/03983 the boiling point elevation provided by the mannitol.

The solution is then removed from heat, and 2 grams of powdered mannitol are added to promote microcrystallization. After the crystallization process is completed in a matter of five minutes or so, one spoons the viscous mass into tablet molds to form desired tablets, for example of the design of tablet 18.

The filled tablet molds are evacuated at 23 inches of mercury for one hour while cooling proceeds.

Following this, the evacuated chamber is heated to degrees C. for one hour to facilitate further water removal. The tablet molds are allowed to remain under evacuated conditions overnight.

Following this, the molds are opened to obtain the mannitol tablets. These tablets may be used in the manner of tablet 18 in the apparatus described above to provide a predetermined dose of mannitol to parenteral solution flowing across tablet 18, for reconstitution of the dry mannitol mass into a parenteral solution being administered to a patient.

Accordingly, by the invention of this application, a system is provided in which a solid drug or other beneficial agent can be reconstituted into its beneficial form at the site of use without intermediate diluent, if desired. The beneficial agent of this invention can be directly reconstituted into blood, where its beneficial action takes place directly on the blood without the need for an intermediate diluent. On the other hand, the citrate or mannitol tablet of this invention may also be reconstituted into a diluent for purposes of drug delivery jr the like, if desired.

The above has been offered for illustrative purposes only, and is not intended to limit the scope ~"di~U 'Y 3I L. p WO 89/04687 of the invention of this application, which is as defined in the claims below.

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Claims (12)

1. A method of passing medical solution through a conduit, the improvement comprising: passing said medical solution across a solid mass of microcrystalline beneficial agent positioned within said conduit, said micvocrystalline beneficial agent comprising a material selected from the group consisting of citrate and mannitol in a substantially anhydrous form, wherein said mass of microcrystalline beneficial agent is shaped and proportioned whereby a controlled amount of said microcrystalline beneficial agent dissolves into passing solution at a substantially uniform rate of dissolution.

2. The method of claim 1 in which said microcrystalline 6 beneficial agent contains no more than 20 weight percent of sugar.

3. The method of claim 1 in which said microcrystalline beneficial agent is selected from the group consisting of substantially pure citrate and substantially pure mannitol.

4. The method of passing medical solution through a conduit, the improvement comprising: passing said medical solution across a solid mass of microcrystalline beneficial agent positioned within said conduit, said microcrystalline beneficial agent containing at least 30 weight percent of citrate or mannitol, said mass of microcrystalline beneficial agent being shaped and proportioned whereby a controlled amount of said microcrystalline beneficial agent dissolves into passing solution at a substantially uniform rate of dissolution. r- i- V. 1 1 1 1 1 1 i 1 -17- A A A A A A -T m A The method of claim 4 in which said microcrystalline beneficial agent is substantially free of sugar.

6. The method of claim 4 in which said microcrystalline beneficial agent contains a further added beneficial ingredient other than citrate and mannitol.

7. The method of claim 4 in which said microcrystalline beneficial agent is selected from the group consisting of substantially pure citrate and substantially pure mannitol.

8. The method of claim 7 in which said microcrystalline beneficial agent is citrate in the form of a mixture of an alkali metal citrate and citric acid.

9. The method of claim 4 in which said microcrystalline beneficial agent is citrate in the form of a mixture of an alkali metal citrate and citric acid.

10. The method of passing medical solution through a conduit, the improvement comprising: passing said medical solution across a solid mass of microcrystalline beneficial agent positioned within said conduit, said microcrystalline beneficial agent comprising a material selected from the group consisting of citrate and mannitol in a substantially anhydrous form, along with an added beneficial ingredient other than said citrate and mannitol, wherein said mass of beneficial agent is shaped and proportioned whereby a controlled amount of said beneficial agent dissolves into passing solution at a substantially uniform rate of dissolution.

11. The method of claim 13 in which said beneficial agent is citrate in the form of a mixture of sodium citrate plus citric acid. Y- Ir Z i -18-

12. A microcrystalline tablet shaped and proportioned whereby a controlled amount of a microcrystalline beneficial agent dissolves into passing solution at a substantially uniform rate of dissolution, which may be postioned in a flow conduit for dissolving in a stream of medical solution passing through said flow conduit, said tablet comprising a mixture of sodium citrate and citric acid.

13. A microcrystalline tablet shaped and proportioned whereby a controlled amount of a microcrystalline beneficial agent dissolves into passing solution at a substantially uniform rate of dissolution, which may be postioned in a flow conduit for dissolving in a stream of medical solution passing through said flow conduit, said tablet comprising Smannitol. DATED this 27th day of April, 1992. o A* o•p g .BAXTER INTERNATIONAL INC. Patent Attorneys for the Applicant: PETER MAXWELL ASSOCIATES. i, z C B E R A t t'