PCI‘
`
`International Bureau
`WORLD INTELLECTUAL PROPER-Ff ORGANIZATION
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 5 :
`
`AfilK 3lll95, 37/02, A23L 1:305
`
`(11} International Publication Number:
`
`W0 92to92't7
`
`11 June 1992 {11.06.92}
`
`(43) International Publication Date:
`
`
`
`(21) International Application Number:
`
`PCT/SE91/00810
`
`(22) International Filing Date:
`
`28 November 1991 (28.12.91)
`
`(74) Agents: TANNERFELDT, Agneta; Kabi Pharmacia AB,
`8-112 87 Stockholm {SE} et a1.
`
`(30) Priority data:
`9003844—9
`
`3 December 1990 (03.12.90)
`
`SE
`
`(71)Applicant for all designated States except US}: KARI
`PHARMACIA AB [SE/SE]; 5-751 82 Uppsala (SE).
`
`(72) Inventors: and
`(75] [mentors/Applicants (fin- US only) : KIHLBERG, Reinhold
`[SE/SE]; Riddarvagen 373, 8.184 5] éstemkar (SE).
`NORRLIND, Bjorn [SE/SE}; Birkagatan 35. S«113 39
`Stockholm (SE).
`
`{81)Designated States: AT (European patent), AU, BE [Euro-
`pean patent), CA, CH (European patent}, DE (Euro-
`pean patent), DK (European patent), ES (European pa-
`tent), FI, FR (European patent), GB {European patent),
`GR [European patent}, IT (European patent}, JP, LU
`(European patent), NL (European patent), NO, SE (Eu-
`topean patent), US.
`
`Published
`With internatiouttirearch report.
`
`
`
`(54}1‘itle: NUTRIENT SUPPLY
`
`(57) Abstract
`
`The invention relates to a composition for oral or parenteral use, characterized in that the composition contains free L-glut-
`amine and also at least one derivative of Lglutamine and optionally at least one precursor to L-glutamine, the composition being
`prepared aseptically and freeze-dried in powder form and radiation-sterilized, or in the form of a solution which is stored at low
`temperature, preferably in deep-frozen form. The derivative preferably consists of peptides, such as glycyl-L—glutarnine and/or L-
`alanyl-L-glutarnine, and the precursor may consist of alpha-keto-glutaric acid or the salt/derivative thereof. The derivative may
`also consist of N-acetyl-L-glutamine. The composition may also contain other nutrient components, or technical auxiliary sub- '
`stances, such as carbohydrates, sugar alcohols, vitamins and/or amino acids, preferably in freeze-dried form. The invention also
`relates to the production of the composition and to a method of preparing a nutrient solution.
`
`
`
`USPIabs EXHIBIT 1004
`
`USPlabs EXHIBIT 1004
`
`

`

`l
`
`FOR ME PURPOSES 0F INFOM'HON ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT-
`
`any such designation has effect in other States of the former Soviet Union.
`
`Spain
`Finland
`Franc:
`Gabon
`United Kingdom
`Guinea
`01cm:
`Hungary
`Italy
`Japan
`Democtatic People's Republic
`of Korea
`Republic ol’ Korea
`Lioch'iunflcln
`Sri lanka
`Luxembourg
`Montana
`
`NT
`All
`38
`BE
`BF
`80
`31
`BR
`CA
`CF
`(1:
`CH
`CI
`
`4.
`
`Austria
`Australia
`Ramadan
`Bcigiutn
`Bufkina Fan
`Bulgaria
`Benin
`Branil
`Canada
`Ceolral African Republic
`Congo
`Swine-{land
`one d'lucire
`Cam-moon
`mnwovakiu
`Germany
`Denmark
`
`ES
`Fl
`FR
`GA
`GB
`BN
`GR
`HIJ
`it
`J?
`KP
`
`KR
`Ll
`LK
`LII
`MC
`
`Madagascar
`Mali
`Mongolia
`Mauritania
`Malawi
`Netherlands
`Norway
`Poland
`Romania
`Sudan
`Smalcn
`Emegal
`Soviet Union
`Chad
`Togo
`United States of America
`
`Any designation of “SU” has effect in the Russian Federation. It is not yet known whether
`
`

`

`WO 92109277
`
`PCUSE91 {00810
`
`1
`
`NUTRIENT SUPPLY
`
`The present invention relates to a preparation which
`
`makes possible the parenteral or oral administration of
`
`a balanced nutrient solution containing a high concen-
`
`tration of glutamine and glutamine derivative or glutaw
`
`mine precursors.
`
`10
`
`15
`
`20
`
`More specifically, but not exclusively,
`
`the invention
`
`relates to a preparation which contains L-glutamine and
`
`also at least one glutamine derivative, preferably
`
`glycyl—L—glutamine and/or L-alanyl-L—glutamine or a
`
`precursor of L—glutamine, preferably alpha—keto-glutaric
`
`acid and salts/derivatives thereof. N—acetyl-Lrglutaw
`
`mine can also be used.
`
`The invention also relates to a nutrient solution and to
`
`a method of preparing the same, said solution optionally
`
`containing such nutrients as amino acids, fats, particu-
`
`larly emulsified fats, energy substrates, such as glu-
`
`cose, sugar alcohols and keto—acids, electrolytes,
`vitamins and trace elements.
`
`25
`
`name
`
`Intravenous nutrient therapy has become progressively
`
`more complete and better balanced as the significance of
`
`new substances, or the significance of substances which
`
`have earlier been overlooked, has become more apparent.
`
`Observations made in recent years have shown that gluta-
`
`mine is highly significant when used as a component of
`
`nutrient support compositions.
`
`In the metabolic circu-
`
`lation of nitrogen, glutamine is the most significant
`
`transporter by means of which nitrogen is transported
`
`30
`
`35
`
`

`

`\WIJ92/09277
`
`FKIT/SEQIIOBSIO
`
`2
`
`from muscle to intestines and liver. According to
`
`certain theories, glutamine has a stimulating effect on
`
`the synthesis of proteins in muscle tissue.
`
`The store
`
`of free glutamine in skeletal muscle diminishes drasti-
`
`cally in patients who have suffered Serious trauma,
`
`surgical operations, sepsis, etc.
`
`(Vinnars E., Berg-
`
`strdm, and Furst, P.:
`
`Influence of the Postoperative
`
`State on the Intracellular Free Amino Acids in Human
`
`Muscle Tissue; Annals of Surgery 182:665—671 (1975) and
`
`Askanazi, J., et a1: Muscle and Plasma Amino Acids
`
`Follow Injury.
`
`Influence of Intercurrent Infection.
`
`Ann Surg.
`
`192:78-85 (1980;.
`
`Glutamine also constitutes an essential energy source
`
`for the intestinal mucus membrane (Windmueller, H.G.,
`
`Spaeth, A.E.:
`
`Identification of Ketone Bodies and
`
`Glutamine as the Major Respiratory Fuels in Vivo for
`
`Postabsorptive Rat Small Intestine, J. Biol. Chem.
`
`253:69-76 (1978}. Total intravenous nutrition results
`
`in some degree of atrophication or wasting of the intes—
`
`tine mucus membrane. Animal experimentation has shown
`
`that glutamine is able to counteract this negative
`
`effect, when administered intravenously.
`
`The atrophica~
`
`tion of intestine mucus membrane observed in conjunction
`
`with intravenous nutrition, and also in conjunction with
`
`serious trauma, can contribute to the passage of bac-
`
`teria from the wall of the intestine into the blood,
`
`which can have a decisive influence 0n the ability of
`
`the patient to survive.
`
`The administration of glutamine
`
`to animals suffering from experimentally induced bowel
`
`damage has been found to result in a lower mortality
`
`rate (Huang, T.L., et al: Preservation of Small Bowel
`
`Hucosa Using Glutamine-Enriched Parenteral Nutrition.
`
`10
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`35
`
`Surg. Forum 37:56-58 {1986).
`
`

`

`W0 92/0921"?r
`
`PCT/SE91 {00810
`
`3
`
`An optimal treatment with the intention of maintaining
`
`normal bowel wall function would therefore seem to
`
`require the administration of considerable quantities of
`
`glutamine, for example in the case of serious trauma,
`
`sepsis and burns, for patients treated with cytostatic
`
`or radioactive radiation, and also in the case of in—
`
`flammatory diseases, such as morbus Chron or ulcerative
`
`colitis.
`
`A nutrient solution which contains glutamine together
`
`with other nutritious substances is highly desirable.
`
`The problem with such solutions, however, is that solu-
`
`tions which contain glutamine cannot be sterilized by
`
`autoclaving, since free glutamine in solution is not
`
`heat resistant. When a solution which contains gluta—
`
`mine is heated or stored for long periods of time at
`
`room temperature,
`
`the glutamine will decompose to ammo-
`
`nia and pyroglutamic acid.
`
`Such substances are unac-
`
`ceptable in nutrient solutions intended for intravenous
`
`administration. Consequently, present-day commercially
`
`available parenteral nutrient amino acid solutions con—
`
`tain no glutamine.
`
`Alpha-keto-glutarate (AKG) is active in various trans-
`
`amination reactions and thereby adopts a central roll in
`
`the amino acid metabolism.
`
`It has long been known that
`
`glutamine can be formed from AKG via glutamic acid.
`
`It
`
`has also been found that when administered intra-
`
`venously, AKG is able to counteract the depletion of the
`
`free content of glutamine intracellular in muscle after
`
`operative trauma {Wernerman, et al, The Lancet 335, No.
`
`8691, 701-703, 1990). This indicates that AKG could be
`
`used as a glutamine precursor in an intravenous nutrient
`
`supply or support.
`
`10
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`WO 92109277
`
`P(TTRSE9I!00810
`
`4
`
`Wilmore (W0 37/015873 discloses the use of glutamine in
`
`quantities of up to 0.2-3 gfkg of body weight and day in
`
`conjunction with trauma.
`
`Veech (WO 87/03806) utilizes glutamine, optionally in
`
`mixture with AKG—in small quantities, to influence the
`
`redox system.
`
`Vinnars (EP 0 318 446) discloses the composition of a
`
`posttraumatic solution treatment. Although based on a
`
`conventional amino acid mixture, this composition is
`
`characterized in that it also includes 5-30 9 glutamine
`
`and/or 5—25 g AKG per litre, and optional L-asparagine
`and acetoacetate.
`
`It has been found that peptide—bound glutamine, e.g.
`
`glycyl—L-glutamine and also L-alanyl—L-glutamine are
`
`acceptably stable when subjected to heat treatment in
`
`solution; it has also been found that these substances
`
`are biologically active as a glutamine source. This
`
`also applies to N-acetyl-L—glutamine.‘ Ffirst, et al
`
`(DE 3206 784] discloses an amino acid solution which is
`
`characterized in that it contains glutamine in the form
`
`of water‘soluble dipeptides or tripeptides.
`
`Adibi
`
`(BE-887941) discloses an aqueous solution which
`
`contains at least two dipeptides or tripeptides having a
`
`single glycine molecule as the N-terminal amino acid.
`
`Magnusson, et al (SE 8703567-1) discloses an amino acid
`
`solution which is characterized in that it contains
`
`2-30 g of N-acetyl-L-glutamine per litre of solution.
`
`10
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`35
`
`

`

`wo 92:09:77
`
`'
`
`PCT/SE91100810
`
`Emblems
`
`Nutrient solutions for parenteral administration (Large
`
`Volume Parenterals) are normally sterilized at about
`
`121'C for 15 minutes,
`
`in accordance with standardized
`
`techniques. When the solutions contain components that
`are able to react with one another or which become
`
`unstable when subjected to heat, it is not, however,
`
`possible to follow the standardized procedures. Thus,
`
`none of the commercially available amino acid solutions
`
`contains glutamine.
`
`Our earlier patent application, SE 8902544-9, discloses
`
`a method of solving the problem of the instability of
`
`glutamine, this solution involving the sterilization of
`
`powdered glutamine by ionizing radiation prior to mixing
`
`the glutamine with the remaining components in the
`
`nutrient solution.
`
`It is also conceivable to freeze-dry a sterile filtered
`
`glutamine solution and to dissolve the freeze-dried
`
`powder aseptically in conjunction with its use.
`
`How—
`
`ever, because glutamine is not readily dissolvable, the
`
`dissolution of glutamine requires the use of large
`
`volumes of liquid, which renders the freeze-drying
`
`process considerably expensive. Since it is necessary
`
`to dissolve the freeze-dried glutamine in corresponding
`
`volumes of liquid, this method would also necessitate
`
`administering large quantities of liquid to the patient,
`
`which is not possible or feasible in many instances.
`
`For example,
`
`the administration of 60 grams of L—gluta-
`
`mine would require a liquid volume in excess of 2
`
`litres.
`
`A third possibility is to supply the glutamine in the
`
`form of a precursor which can be converted at least
`
`10
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`

`\V()92/09277
`
`PCHYSE91/00810
`
`partially to glutamine in the body.
`
`6
`
`It is impossible, however,
`
`to administer large quanti—
`
`ties of AKG, in View of the resultant pH—values (very
`
`low), among other things. Neither is it possible to
`
`administer large quantities of AKG in the form of sodium
`
`or calcium salt,
`
`in View of the non-physiological load
`
`represented by these mineral substances. Corresponding-
`
`ly,
`
`the administration of large quantities of the neu-
`
`tral ornithine salt of the alpha—keto-glutarate would
`
`subject the body to an unreasonable quantity of
`
`ornithine.
`
`A fourth possibility is one of administering glutamine
`
`in the form of a derivative, preferably in the form of a
`
`dipeptide. However, when it is necessary to administer
`
`glutamine in large quantities,
`
`the other amino acid in
`
`the dipeptide, preferably glycine or alanine, will also
`
`be present in large quantities.
`
`(A daily dosage of 60 g
`
`glutamine corresponds, e.g., to 37 grams of alanine,
`
`alternatively 31 grams of glycine, depending on whether
`
`the supply is effected in the form of the alanyl-peptide
`
`or the glycyl-peptide).
`
`From the physiological aspect,
`
`this implies unfavourable quantities of glycine or
`
`alanine. When supplying the glutamine peptide to a
`
`commercial amino acid solution,
`
`the peptide—bound ala—
`
`nine or the peptide-bound glycine is also added to
`
`corresponding free amino acid in the solution, and the
`
`patient is thereby liable to obtain a negative imbalance
`
`10
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`15
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`20
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`25
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`30
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`in the amino acid conversion.
`
`Furthermore, a supply of 80-90 g of a dipeptide would be
`
`likely to exceed the ability of the organism to cleave
`
`(hydrolyze) the peptide in order to release l-glutamine.
`
`35
`
`This would result in a drastic increase in plasma levels
`
`of the peptide, pronounced secretion of the unconsumed
`
`

`

`\V(}92l09277
`
`P(TF/SE91I00810
`
`7
`
`peptide in the urine and therewith poor use of the
`
`peptide administered.
`
`Furthermore, when in solution the dipeptides in question
`
`are,
`
`in many cases, not completely stable during the
`
`sterilizing process or when stored for long periods of
`
`time at room temperature. Consequently, the dipeptide
`
`solution must be subjected to comprehensive analytical
`
`and biological processes in order to ensure the quality
`
`of the peptide solutions from a technical and toxicolog-
`
`ical aspect.
`
`Furthermore,
`
`the price per unit of glutamine based on a
`
`glutamine peptide is about 10-20 times higher than the
`
`price of a corresponding quantity of pure L-glutamine.
`
`The proposed invention enables large quantities of
`
`glutamine to be administered without interference from
`
`the aforediscussed problems concerning technical insta—
`
`bility, large volumes when dissolving and administering
`
`glutamine, and, particularly with respect to peptide
`
`supply, high costs. metabolic imbalances and physiologi-
`cal overloads.
`
`The invention relates to a preparation for oral or
`
`parenteral use, characterized in that the preparation
`
`includes free Lfiglutamine and also at least one L~
`
`glutamine derivative and optionally at least one L—
`
`glutamine precursor, said preparation being prepared
`
`aseptically and freeze-dried:
`
`in that the preparation is
`
`in powder form and is radiation sterilized, or is in the
`
`form of a solution which is stored at low temperature,
`
`preferably in a frozen state.
`
`By low temperature is
`
`meant a temperature lower than rOOm temperature, and
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`\NK)92109277
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`FWSIYSE9I/00810
`
`preferably a temperature within the range of 2-8°C.
`
`8
`
`The derivative preferably consists of peptides, such as
`
`glycyl-L—glutamine and/or L-alanyl-L-glutamine, and the
`
`precursor may consist of alpha-keto-glutario acid or the
`
`salt/derivative thereof.
`
`-The derivative may also con—
`
`sist of N-acetyl-L-glutamine.
`
`In addition to containing L—glutamine and at least one
`
`derivative of L—glutamine and/or a precursor to L—gluta-
`
`mine,
`
`the preparation may also contain other nutrient
`
`components, alternatively technical auxiliary sub—
`
`stances, such as carbohydrates, sugar alcohols, vitamins
`
`and/or amino acids, preferably in freeze-dried form.
`
`The present invention also relates to a nutrient solu-
`
`tion which contains the aforedescribed preparation and
`
`further amino acids, fat emulsion, energy substrate,
`
`such as glucose, sugar alcohols and keto—acids, vita-
`
`mins, electrolytes and/or trace elements.
`
`According to one method, the claimed preparation is
`
`produced by dissolving the preparation components,
`
`sterile filtering the solution and thereafter freeZe-
`
`drying the sterile solution.
`
`According to an alternative method, the components are
`
`mixed together in powder form and the resultant mixture
`
`is then sterilized by radiation.
`
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`
`According to another alternative, the preparation compo-
`
`nents are mixed in solution and the solution is sterile
`
`filtered and stored in'a cold or frozen state.
`
`It will
`
`be understood that the preparation is produced under
`
`35
`
`aseptic conditions.
`
`

`

`wo 92109277
`
`'
`
`PCT/SE91/00810
`
`9
`
`The invention also relates to a method of preparing a
`
`nutrient solution, which comprises the steps of trans-
`
`ferring a solution of amino acids, fat emulsion and/or
`
`energy substrate to the glutamine preparation, said
`
`solution being enclosed in a container which is placed
`
`under a pressure that is higher than the pressure over
`the preparation.
`An alternative method of preparing
`
`I
`
`this nutrient solution is characterized by enclosing a
`
`solution of amino acids, fat emulsion and/or energy
`
`substrate in a container which is placed under a pres-
`
`sure that is lower than atmospheric pressure, and by
`
`reconstituting the glutamine preparation and transfer-
`
`ring said reconstituted preparation to said solution
`
`under the influence of a pressure which is greater than
`
`the pressure over the solution.
`
`A conceivable alternative to the aforedescribed embodi-
`
`ments of the preparation is to pour the sterile-filtered
`
`solution containing free glutamine and at least one
`
`glutamine derivative/glutamine precursor into an appro-
`
`priate container, freezing the container and its con-
`
`tents, delivering said container to the destination and
`
`storing the container in a frozen state (at about —20°C)
`
`until the time of its use. Alternatively,
`
`the solution
`
`can be stored in cold conditions (+2'C to +8°C) over a
`
`shorter period of time.
`
`The final parenteral nutrient solution can be prepared
`
`in accordance with any one of a number of different
`
`methods,
`
`the method chosen depending on the chosen-form
`
`of the inventive preparation and on which other compo-
`
`nents shall be present in the final nutrient solution.
`
`A number of examples of different methods of producing
`
`the inventive preparation are described below. These
`
`examples take their starting point from an inventive
`
`preparation of a freeze-dried powder, which is the
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`W0 9309277
`
`PCTI'SEQU00810
`
`10
`
`alternative of most interest from a commercial and
`
`handling aspect. When the third alternative method of
`
`preparing the preparation is chosen (solution/deep-
`frozen solution of free glutamine and at least one
`
`glutamine derivative), it is, of course, possible to use
`
`the solution directly, subsequent to bringing the solu—
`
`tion to a suitable temperature.
`
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`35
`
`In the case of partial nutrient therapy, it is often
`
`desired to administer a main component, this component
`
`normally being contained in a single package or dosage
`
`unit.
`
`For example, it is possible to administer a glu-
`
`cose solution, or to administer an amino acid solution
`
`in order to improve the patient's nitrogen balance.
`
`When wishing to also administer glutamine, the freeze-
`
`dried preparation can be dissolved in a part of the
`
`aforesaid solution.
`
`The transfer of liquid between the
`
`containers can be effected by creating a partial vacuum
`
`in the receiving container (see the following).
`
`An advantage can be gained in this case, when signifi-
`
`cant guantities of nutrient components are already”
`
`present in the freeze-dried preparation.
`
`It is often desired to administer the patient with a
`
`more complete nutrient mixture that contains glutamine.
`
`In this case,
`
`the technique of transferring solution
`
`from one container to another with the aid of a partial
`
`Vacuum can be beneficially applied.
`
`In this case, there is preferably transferred to the
`
`inventive preparation of freeze-dried glutamine a con-
`
`centrated glucose solution, alternatively an amino acid
`
`solution or a fat emulsion, with the inventive prepara-
`
`tion placed under a partial vacuum.
`
`Subsequent to
`
`dissolution of the freeze—dried substances and
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`

`

`WO 92109277
`
`PCTISE9] {00810
`
`11
`
`equalization of the pressure in the container, this
`
`solution can be transferred,
`
`in turn, to the glucose/
`
`amino acid/solution or to the fat emulsion present in an
`
`incompletely filled Container under vacuum.
`In this
`way,
`there is obtained a nutrient solution which con—
`
`tains several significant nutrient components that can
`
`be administered to the patient from one single package,
`
`which affords important advantages in practice.
`
`When it is desired to administer to a patient a solution
`
`that contains all the necessary nutrient components,
`
`these components can be supplied by simultaneous or
`
`consecutive intusion from different bottles or other
`
`container types.
`
`It is often preferred to administer a complete mixture
`
`of nutrient components from one single container (nor-
`
`mally a 3—litre plastic container). However, it is
`
`necessary to prepare such a mixture regularly frOm
`
`individual nutrient solutions at the time of use, or is
`
`obtained from the supplier in the form of a prepared
`
`mixture.
`
`An inventive glutamine preparation is also
`
`used in these cases to produCe a glutamine-containing
`
`nutrient solution, which is then transferred to the
`
`mixing container.
`
`The present invention involves the aforediscussed probw
`
`lens concerning large volumes, high costs, metabolic
`
`imbalances and the necessity of carrying out comprehen-
`
`sive analytical and biological processes, and provides a
`
`nutrient solution which fulfils all requirements with
`
`respect to variation, sterility, stability and nutri-
`
`tional balance.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Because the solution contains both free, natural L—
`
`glutamine and one or more glutanine-containing peptides
`
`

`

`VVIJ92l09277
`
`PCHYSE91100310
`
`12
`
`and/or metabolic precursors to glutamine, it is possible
`to obtain sufficiently high quantities of glutamine
`
`without supplying unfavourable quantities of either
`
`peptide or other amino acids in the peptide, for example
`
`glycine and alanine, and without the volumes supplied or
`
`the resulting costs being unrealistic.
`
`Because the preparation may also contain other nutrient
`
`components, such as amino acids, carbohydrates, vita-
`
`mins, etc., the costs represented by the freeze-drying
`
`process can be carried by/shared among the various
`
`components. When the solution is prepared under the
`
`aforedescribed conditions and stored in a freeze-dried
`
`state, all problems relating to instability when prepar-
`
`ing the preparation and during the storage thereof are
`
`avoided.
`
`Completely new possibilities for complete nutrient
`
`therapy capable of being adapted to the needs of each
`
`individual patient are achieved by combining the freeze*
`
`dried material with different nutrient solutions accord-
`
`ing to the disclosures set forth in the following
`
`Examples 1-11.
`
`Corresponding advantages are also achieved when the
`
`mixture of glutamine components is radiation sterilized
`
`or prepared aseptically and deep-freezed.
`
`Wales
`
`The following named products from KABI Nutrition AB,
`
`Stockholm, were used in the Examples.
`
`10
`
`15
`
`20
`
`25
`
`3D
`
`Vamin°l4 EF, Vaminala EF, and Vaminas Glucose are
`
`35
`
`concentrated amino acid solutions.
`
`

`

`W0 92/0927?
`
`PCT/SE91I00810
`
`13
`
`-
`
`-
`
`-
`
`-
`
`—
`
`—
`
`Intralipido is a 20% fat emulsion for intravenous
`
`nutrient supply.
`
`Addamela is an additive solution with electrolytes
`and trace elements.
`
`Addiphoso is an additive solution with phosphate.
`
`Soluvit° is a mixture of water-soluble vitamins.
`
`Vitalipid° is an additive solution in emulsion
`
`form, containing fat-soluble vitamins.
`
`KABI Bag0 is a 3—litre mixing bag by means of which
`
`a complete nutrient mixture can be administered to
`
`the patient.
`
`Example 1
`
`A solution was prepared by dissolving 7.5 g of L—gluta-
`
`mine, 14.0 g of glycyl-L—glutamine, and 5.0 g of alanyl—
`
`L-glutamine in a total volume of 250 ml of distilled,
`
`pyrogenwfree water.
`
`The solution was sterile~filtered and poured into a 1-
`
`litre bottle under aseptic conditions.
`
`The solution was
`
`then frozen and freeze-dried under aseptic conditions,
`
`whereafter the bottle was sealed in the freeze drier
`
`prior to interrupting the vacuum.
`
`10
`
`15
`
`20
`
`25
`
`Prior to use,
`
`the freeze-dried solution was reconstitu-
`
`ted, by adding 500 ml of Vamin 18 EF”. This transfer
`
`was effected by placing the freeze—dried glutamine under
`
`partial vacuum and drawing the Vamin to the glutamine by
`
`30
`
`suction with the aid of a transfer device constructed
`
`herefor.
`
`This example provides a complete amino acid solution
`
`containing glutamine, which satisfies basal amino acid
`
`35
`
`requirements.
`
`

`

`WO 92/8927?
`
`PCHVSE9IIOQSID
`
`Example 2
`
`14
`
`A solution was prepared by dissolving 7 g of Leglutamine
`
`10.0 g of glycyl—L-glutamine and 10.0 g of alpha- ketc-
`
`. glutarate (the monosodium salt) in a total volume of 250
`
`ml of distilled, pyrogen-free water.
`
`The solution was sterile filtered and poured into a 1-
`
`litre bottle under aseptic conditions.
`
`The solution Was
`
`then frozen and freeze-dried under aseptic conditions.
`
`The bottle was sealed in the freeze-drier, prior to
`
`interrupting the vacuum.
`
`Prior to use,
`
`the freeze-dried solution was reconstitu—
`
`ted by adding 500 ml of Vamin 13 EFQ.
`
`The transfer of
`
`Vamin to the freeze-dried solution was effected by
`
`placing the glutamine under a partial vacuum and drawing
`
`the Vamine to the glutamine by suction with the aid of a
`
`transfer device constructed herefor.
`
`Example 3
`
`A solution was prepared by mixing 4 g of L-glutamine,
`
`10.0 g of glycyl—L—glutamine, 8.0 g of alanyl—L-gluta-
`
`mine and 8.0 g of alpha-keto-glutarate (as the ornithine
`
`salt) in a total volume of 250 ml of distilled, pyrogen-
`free water.
`
`The solution was sterile-filtered and poured into a 1-
`
`litre bottle under aseptic conditions.
`
`The solution was then frozen and freeze—dried under
`
`aseptic conditions.
`
`The bottle was sealed in the freeze
`
`drier, prior to interrupting the vacuum. Prior to use,
`
`the freeze-dried solution was reconstituted by adding
`
`500 ml of a 20%-glucose solution.
`
`The transfer of the
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`

`

`WO 92109277
`
`PCUSE9U00810
`
`15
`
`glucose solution to the freeze—dried solution was ef—
`
`fected by placing the glutamine under a partial vacuum
`
`and drawing the solution to the glutamine by suction
`
`with the aid of a transfer device constructed herefor.
`
`Example 4
`
`A solution was prepared by dissolving 6 g of L—gluta—
`
`mine, 10 g of glycyl-L-glutamine and 10 g of alpha-ketc—
`
`10
`
`glutarate (as the arginine salt) in a total volume of
`
`300 ml of distilled, pyrogen-free water.
`
`The remainder
`
`of the preparation process was effected in accordance
`
`with Example 3 above.
`
`15
`
`Example 5
`
`A solution was prepared by dissolving 9.0 g of L-gluta-
`mine, 14.0 g of glycyl—L—glutamine, 9.0 g of alanyl-L-
`
`glutamine and 50 g of glucose in a total volume of 250
`
`ml of distilled, pyrogen-free water.
`
`The solution was sterile—filtered and poured into a 1-
`
`litre bottle under aseptic conditions.
`
`The solution was frozen and freeze-dried under aseptic
`
`conditions.
`
`The bottle was sealed in the freeze-drier,
`
`prior to interrupting the vacuum.
`
`Prior to use, the freeze-dried solution was reconstitu-
`
`ted by adding 500 ml of Vamin 14 BF“.
`
`The transfer of
`
`Vamin to the freeze-dried solution was effected by
`
`placing the glutamine under a partial vacuum and drawing
`
`the Vamine to the glutamine by suction with the aid of a
`
`transfer device censtructad herefor.
`
`An ampull contain-
`
`ing Addamel Na
`tained.
`
`(10 ml) was added to the solution ob-
`
`20
`
`25
`
`30
`
`35
`
`

`

`\¥1)92l09277
`
`PC175E91I00810
`
`16
`
`This example provided a complete amino acid solution,
`
`containing glutamine, which covers low requirements of
`
`amino acids, glucose and trace substances.
`
`Example 6
`
`A solution was prepared by dissolving 7.0 g of L—gluta—
`
`mine, 18.0 g of glycyl-L-glutamine, 15.0 g of alanyl-L-
`
`glutamine and 100 g of glucose in a total volume of 300
`
`ml distilled, pyrogen-free water.
`
`The solution was sterile-filtered and poured into a 1-
`
`iitre bottle under aseptic conditions.
`
`The solution was
`
`frozen and freeze-dried under aseptic conditions.
`
`The
`
`bottle was sealed in the freeze drier, prior to inter"
`
`rupting the vacuum.
`
`10
`
`15
`
`Prior to use,
`
`the freeze—dried solution was reconstitue
`
`ted by adding at least 500 ml of Vamin 9 Glucosee taken
`
`20
`
`from a 1000 ml-bottle.
`
`The transfer of Vamin to the
`
`freeze—dried solution was effected by placing the glutae
`
`mine under a partial vacuum and drawing the Vamine to
`
`the glutamine by suction with the aid of a transfer
`
`device constructed herefor.
`
`The reconstituted solution
`
`and any residue of the Vamin 9 solution was transferred
`
`to a 3—litre mixing bag of the KABI Bag type.
`
`500 m1 Intralipida 20% were then added to the mixing
`
`bag. Appropriate trace elements, electrolytes, water—
`
`soluble and fat—soluble vitamins,
`
`in the form of pr2pa—
`
`rations Addamel, Addiphos, Soluvit and Vitalipid, were
`
`added to the amino acid solution or to the fat emulsion
`
`prior to mixing in the KABI Bag.
`
`The procedure described in this example enables a com-
`
`plete nutrient solution containing glutamine to be
`
`25
`
`30
`
`35
`
`

`

`“K)92/092??
`
`PCHYSE9lf00810
`
`obtained in a simple fashion.
`
`17
`
`Example 7
`
`A solution was prepared by dissolving 2.7 g of L-gluta-
`
`mine, 20.0 g of glycyl-L—glutamine and 11.8 g of alanyl-
`
`L-glutamine in 100 ml of sterile, pyrogen-free water.
`
`The solution was sterile-filtered and poured aseptically
`
`into a sterile 100 m1 glass bottle.
`
`The solution was
`
`10
`
`cooled and stored at a temperature of +2°C to +8°C up to
`
`its time of use, within 7 days.
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Example 8
`
`A solution was prepared by dissolving 2.7 g of L-gluta—
`
`mine, 20.0 g of glycyl-L—glutamine and 11.8 g of alanyl—
`
`L-glutamine in 100 ml of sterile, pyrogen-free water.
`
`The solution was sterile—filtered and poured aseptically
`
`into a sterile 100 ml plastic container.
`
`The solution
`
`was frozen and stored at a temperature of about ~18°C.
`
`Prior to use,
`
`the solution was thawed at a temperature
`
`of at most +40°C, prior to being administered as an
`
`infusion, or prior to being included in a mixture of
`nutrient solutions.
`
`Example 9
`
`A powder mixture was introduced into a 3—1itre plastic
`
`container of the KABI Bago type.
`
`The mixture contained
`
`40 g of L-glutamine and 10 g of alpha-keto-glutarate.
`
`The plastic container was then sealed and radiation-
`
`sterilized with a radiation dosage of 25 kiloGray.
`
`Prior to use, nutrient solutions were introduced to the
`
`container in accordance with the following program, such
`
`as to obtain a fully balanced nutrient solution for
`
`

`

`W0 9210921"?
`
`PCT/51391100810
`
`18
`
`patient administration.
`
`750 ml of Intralipido 20%, 1000
`
`ml of Vamin 14 EF, 1000 ml of glucose solution (30%) and
`
`appropriate trace elements, electrolytes, water—soluble
`
`and fat—soluble vitamins in the form of the preparations
`
`Addamel, Addiphos, Soluvit and Vitalipid, were added
`
`introduced into the mixing bag.
`
`(Were added to the
`
`amino acid solution or the fat emulsion prior to mixing
`
`in the KABI Bag).
`
`10
`
`Example 10
`
`A powder mixture was introduced into a 200 m1 plastic
`
`container which included suitable ports for aseptic
`
`solution supply and solution tapping purposes.
`
`The
`
`15
`
`mixture contained 5 g of L—glutamine and 20 g of glycyl—
`
`L—glutamine.
`
`The plastic container was sealed and then
`
`radiation sterilized with a radiation dosage of 25
`
`kiloGray.
`
`20
`
`25
`
`3D
`
`35
`
`Prior to use, 200 m1 of sterile water were introduced
`
`into the container.
`
`This example provides a concentrated additive solution
`
`of glutamine.
`
`Example 11
`
`A solution was prepared by dissolving 7.0 g of L—gluta—
`
`mine, 20.0 g of glycyl-L-glutamine, 12.8 g of alanyl-L—
`
`glutamine, 1.05 g of L—isoleucine, 1.50 g of L—leucine,
`
`1.70 g of Lwlysine, 1.05 g of L-methionine, 0.10 g of L-
`
`cysteine, 1.50 g of L—phenyl alanine, 0.04 g of L-
`
`thryosine, 1.05 g of L—threonine, 0.35 g of L—trypto—
`
`phan, 1.38 g of L—valine, 3.00 g of L-alanine, 2.10 g of
`
`L—arginine, 0.63 g of L-asparaginic acid, 1.05 g of L-
`
`u
`
`glutamic acid, 1.30 g of L-histidine, 1.30 g of
`
`

`

`WO 92109277
`
`PCT/SE91 (00810
`
`19
`
`L-proline, 0.85 g of L~serine, 1.50 g of glycine, and 50
`
`g of glucose in a total volume of 350 ml of distilled,
`
`pyrogen-free water.
`
`The solution was sterile-filtered and poured into a 1-
`
`litre bottle under aseptic conditions.
`
`10
`
`15
`
`The solution was frozen and freeze—dried under aseptic
`
`conditions.
`
`The bottle was sealed in the freeze drier
`
`prior to interrupting the vacuum. Prior to use,
`
`the
`
`freeze-dried solution was reconstituted by adding 500 ml
`
`of a 10%—glucose solution. The transfer of the glucose
`
`solu