United States Patent [19J
`Pfirrmann
`
`[54] PHARMACEUTICAL COMPOSmONS
`Inventor: Rolf W. Pfirrmann, Lucerne,
`[75]
`Switzerland
`[73] Assignee: Ed. Geistlich Sohne A.G. fur
`Chemische lndustrie, Lucerne,
`Switzerland
`[21] Appl. No.: 672,010
`Mar. 19, 1991
`
`[22] Filed:
`
`Related U.S. Application Data
`[63) Continuation of Ser. No. 552,359, Jul. 12, 1990, aban(cid:173)
`doned, which is a continuation of Ser. No. 408,425,
`Sep. 14, 1989, abandoned, which is a continuation of
`Ser. No. 298,857, Jan. 19, 1989, abandoned, which is a
`continuation of Ser. No. 74,875, Jul. 17, 1987, aban(cid:173)
`doned.
`Foreign Application Priority Data
`[30]
`Jul. 17, 1986 [GB] United Kingdom ................. 8617482
`Int. Cl.5 •••••••••••••••••••••••••••••••••••••••••••••• A61K 31/54
`
`[51]
`
`I 111111111111111111111111111111111111 IIIII 111111111111111111111111111111111
`US005210083A
`5,210,083
`[I I] Patent Number:
`[45] Date of Patent: May 11, 1993
`
`[52] U.S. Cl . .................................................. 514/222.5
`[58] Field of Search ...................................... 514/222.5
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`4,587,268 5/1986 Pfirrmann ........................... 514/222
`4,626,536 12/1986 Pfirrmann ........................... 514/222
`
`FOREIGN PATENT DOCUMENTS
`0162705 5/1985 European Pat. Off ..
`7612644 11/1976 France .
`Primary Examiner-Jerome D. Goldberg
`Attorney, Agent, or Firm-Rothwell, Figg, Ernst & Kurz
`ABSTRACT
`[57]
`An aqueous solution containing a bacterially effective
`concentration of taurolidine and/or taurultam together
`with a parenterally acceptable polyol. The aqueous
`solution is particularly suitable for parenteral adminis(cid:173)
`tration.
`
`10 Claims, No Drawings
`
`APOTEX EXHIBIT 1061
`Apotex v. Alkermes
`IPR2025-00514
`
`

`

`PHARMACEUTICAL COMPOSITIONS
`
`This is a continuation of application Ser. No.
`07/552,359, filed Jul. 12, 1990, which is a continuation
`of application Ser. No. 07/408,425 filed on Sep. 14,
`1989, which is a continuation of application Ser. No.
`07/298,857 filed on Jan. 19, 1989, which is a continua(cid:173)
`tion of application Ser. No. 07/074,875 filed Jul. 17,
`1987 all abandoned.
`This invention relates to formulations of taurolidine
`and/or taurultam, primarily for parenteral administra(cid:173)
`tion.
`The antibacterial compounds taurolidine and taurul(cid:173)
`tam have the following formulae:
`
`TAUROLIDINE
`
`TAURULTAM
`
`These compounds are condensation products of
`formaldehyde with taurinamide and are active not only 25
`against both gram-positive and gram-negative bacteria
`but also against exotoxins and endotoxins produced by
`these organisms.
`The mode of action of taurolidine has been shown to
`include the transfer of methylol groups to hydroxyl or 30
`amino groups present on the above toxins or on the
`mureine of the bacterial cell walls. In solution, tauroli(cid:173)
`dine exists in equilibrium with taurultam and N(cid:173)
`methylol taurultam, taurolidine being greatly predomi(cid:173)
`nant. Taurultam is itself in equilibrium with methylol 35
`taurinamide, the equilibrium being greatly in favour of
`taurultam. When the above methylol derivatives, meth(cid:173)
`ylol taurultam and methylol taurinamide, contact the
`toxins or bacteria, methylol groups are transferred.
`Methylol taurultam is thereby converted to taurultam, 40
`while methylol taurinamide is converted to taurine, a
`naturally occurring aminosulphonic acid which is ex(cid:173)
`tremely well tolerated in the human body. It will thus
`be appreciated that taurolidine and taurultam act in
`essentially the same way and produce the same final 45
`products.
`Taurolidine and taurultam have previously been pro(cid:173)
`posed primarily for use in maintaining sterility in surgi(cid:173)
`cal operations where gross infection with bacteria and
`bacterial toxins was likely, for example in cases of peri- 50
`tonitis. More recently, however, it has been found that
`bacterial toxaemia can advantageously be treated paren(cid:173)
`terally. Bacterial endotoxins and exotoxins are primarily
`responsible for many of the most serious pathological
`effects of bacterial infections. When such toxins are 55
`present at above certain concentrations, the patient can
`suffer septic shock. It is often found that use of antibiot(cid:173)
`ics is contra-indicated in the case of some gram-negative
`bacterial infections due to the release of large quantities
`of endotoxins when the cell walls of gram-negative 60
`bacteria are attacked by the antibiotic. It is thus particu(cid:173)
`larly useful in such cases to be able to administer tauroli(cid:173)
`dine and taurultam parenterally, for example intrave(cid:173)
`nously both to combat infections and to deal with septic
`shock.
`However, the water-solubility of both compounds is
`relatively low, namely 1 g/liter in the case of tauroli(cid:173)
`dine and 8 g/liter in the case of taurultam. Relatively
`
`65
`
`1
`
`5,210,083
`
`2
`large quantities of the compounds are required where
`toxaemia is well established and even where the com(cid:173)
`pounds are administered in large volumes by intrave(cid:173)
`nous infusion, low solubility can limit their use. In par-
`s ticular, during treatment of patients suffering from sep(cid:173)
`tic shock and consequent renal insufficiency, adminis(cid:173)
`tration of significant quantities of liquid (after an initial
`period of volume compensation) is contra-indicated and
`the intravenous infusion solution should be as concen-
`10 trated as possible. Where glucose is present, this is also
`beneficial in such cases in order to support the brain
`cells.
`Taurolidine has previously been formulated in aque(cid:173)
`ous solution at concentrations up to 2% by weight by
`15 incorporating polyvinyl pyrrolidone as a crystallisation
`inhibitor. At higher concentrations of taurolidine, how(cid:173)
`ever, crystallisation can occur, so rendering the solu(cid:173)
`tions unuseable.
`In view of the mode of action of taurolidine men-
`20 tioned above, it was not initially thought suitable to use
`compounds containing hydroxyl groups to increase the
`solubility or inhibit the crystallisation of the compound.
`In the case of bacteria and their endo- and exotoxins, it
`has been found that after the methylol transfer as set out
`above, there is a further irreversible step involving
`dehydration. Thus, in the case of bacterial endotoxins,
`which are lypopolysaccharides, it is found that an irre(cid:173)
`versible cross-linking reaction takes place which pre(cid:173)
`vents the endotoxin from exerting its lethal effect. Simi(cid:173)
`larly, in the case of bacterial exotoxins, which are prote(cid:173)
`ins or polypeptides and do not contain lypopolysaccha-
`ride material of the kind found in the endotoxins, the
`detoxification reaction is found to be irreversible. How(cid:173)
`ever, our investigations have shown that the transfer of
`methylol groups by the mechanism set out above is
`reversible in the case of many hydroxyl or amino com-
`pounds, so that an equilibrium is established which does
`not significantly interfere with the availability of
`taurolidine.
`We have now found that surprisingly polyols such as
`sugars and sugar alcohols can be used to maintain rela(cid:173)
`tively high concentrations of taurolidine and/or taurul(cid:173)
`tam in aqueous solution without significantly effecting
`the antibacterial and antitoxin activity.
`When 2% aqueous taurolidine (containing polyvinyl(cid:173)
`pyrrolidone to aid solubility) is administered intrave(cid:173)
`nously it has sometimes been observed that at high rates
`of infusion, short duration vagotonic side effects occur,
`such as meiosis, lachrymation, salivation, bradycardia
`and excitation. We have found that when taurolidine is
`administered in glucose solution rather than polyvinyl(cid:173)
`pyrrolidone, such vagotonic effects are not observed.
`This is a surprising effect of considerable value in ensur(cid:173)
`ing that taurolidine can be given intravenously at a
`rapid rate of infusion, for example in cases of endotoxin
`shock. In general, the overall intravenous tolerance of
`taurolidine is increased by the presence of glucose. The
`same advantages apply also to taurultam.
`Furthermore, the beneficial effect observed with
`glucose can also be obtained using similar polyhydrox(cid:173)
`ylic compounds such as glycerol, other sugars and also
`sugar alcohols.
`Glycerol, sugars and sugar alcohols are commonly
`administered parenterally, e.g. intravenously, as compo(cid:173)
`nents of nutritional solutions, which may additionally
`contain amino acids and trace elements. However, such
`solutions are often pyrogenic due to bacterial infection
`
`

`

`5,210,083
`
`4
`3
`ise solutions containg a polyol (and optionally tauroli-
`during formulation, which is extremely difficult to
`dine or taurultam) it is preferable that this be done rap-
`avoid. The pyrogens are not, of course, removed when
`the solutions are finally sterilised. We have found that
`idly, in the substantial absence of oxygen. Thus, the
`vessel containing the solution can be evacuated and the
`taurolidine and taurultam are capable of detoxifying
`such pyrogens. Furthermore, although such nutritional 5 space above the liquid purged with an inert gas such as
`solutions are sterile when infusion is started, there is
`nitrogen prior to sealing, so as to provide a very low
`inevitably transmission of infection from the patient to
`partial pressure of oxygen. Furthermore, the presence
`the solution via the intubation. We have found that
`of heavy metals should be avoided.
`incorporation oftaurolidine and/or taurultam into such
`Although polyols and, indeed amino acid solutions,
`nutritional solutions at anti-bacterial concentrations has 10 are most stable at slightly acid pH, it is preferred that
`the added benefit of maintaining sterility during infu-
`the solutions for infusion should be at about neutral pH.
`sion.
`The principal adverse reaction is the conversion of
`Polyhydroxy compounds are difficult to sterilise by
`sugars such as glucose or fructose to aldehydes such as
`autoclaving due to side reactions which may occur. By
`hydroxymethylfurfural and ultimately to acids. This
`including taurolidine or taurultam in bacterial quantities 15 reaction has been shown to be catalysed by aspartic
`we have found it possible to sterilise the solutions by
`acid, which will sometimes be a component of nutri-
`filtration procedures only.
`tional solutions containing amino acids. However, if the
`Further, where amino acids are included in such
`above precautions are taken, there is no difficulty in
`nutritional solutions, the Maillard reaction can take
`preparing the solutions of the invention in sterile form
`place,. We have found that the presence of taurolidine 20 at an acceptable level of titratable acidity (e.g. 0.1 to
`or taurultam prevents or inhibits this reaction.
`0.5,. equiv./liter). As indicated above, it is also possible
`According to the present invention, therefore, we
`to sterilise the solutions by filtration.
`provide aqueous solutions containing a bacterially ef-
`The solution will normally be at physiological pH. If
`fective concentration of taurolidine and/or taurultam
`necessary, the pH can be adjusted by the addition of an
`together with a parenterally acceptable polyol, such as 25 acid or a base. While mineral acids such as hydochloric
`a glycerol or sugar or sugar alcohol.
`acid can be used, it is preferred to use a metabolisable
`Suitable polyols for inclusion in the solutions of the
`acid such as acetic, malic or lactic acid, which does not
`invention include carbohydrates, e.g. hexoses such as
`tend to cause acidosis. The pH can also be adjusted by
`glucose and fructose, (or mixtures of these such as in-
`electrolysis. The relatively high concentrations of sugar
`vert sugar), pentoses such as xylose or polysaccharides 30 or sugar alcohol render the solutions hypertonic but this
`such as dextran or hydrolysed starch; glycerol and
`is physiologically acceptable and, indeed, not uncom-
`sugar alcohols such as sorbitol, mannitol or xylitol.
`mon where glucose is used in intravenous alimentation.
`Where the solutions are for use in intravenous infu-
`Where taurolidine is administered by intravenous
`sion, to combat bacterial infections and/or toxic shock
`infusion in order to treat septic shock, a suitable dose
`it is particularly useful if the polyol can be metabolised. 35 will be 20-30 g taurolidine over a 24 hour period in the
`For this reason, glucose and fructose are particularly
`case of a 70 kg adult human patient. This will be admin-
`useful and also sorbitol and xylitol. Glucose is advanta-
`istered conventionally by catheter. Where the solutions
`geous in that it is particularly readily inetabolised and,
`are intended for administration of taurolidine or taurul-
`indeed, can provide a valuable nutritional element. On
`tam as such, the polyol will conveniently be glucose and
`the other hand, fructose may be advantageous where a 40 in general, no other components will be present.
`patient cannot tolerate large quantities of glucose, for
`Where the solutions are intended for other forms of
`example in cases of diabetes.
`infusion therapy and taurolidin or taurultam are added
`The concentration of taurolidine in the solution is
`to maintain sterility, a wide range of other components
`preferably in the range 1 to 5%, advantageously 2 to
`are possible.
`3%, by weight. The concentration of taurultam is pref- 45
`For therapy of metabolic acidosis, such other compo-
`erably in the range 1 to 7.5%, advantageously 3 to 5%,
`nents will include buffer salts such as sodium acetate,
`by weight.
`sodium carbonate and/or hydrogen carbonate, sodium
`The concentration of the polyol can usefully be in the
`malate or trometamol. The polyol may, for example, be
`range 3-40% by weight, In the case of glucose, the
`sorbitol.
`concentration is preferably in the range 10-30% by SO
`For osmotherapy, for example, for treatment of cere-
`weight, preferably 20%.
`bral oedema, the polyol is advantageously a combina-
`Thus, particularly preferred formulations according
`tion of glycerol and glucose and an electrolyte such as
`to the invention are aqueous solutions oftaurolidine at a
`sodium chloride and/or acetate may be present. Manni-
`concentration in the range 2--4% by weight containing
`tol may also be used as polyol. Where an isotonic, iso-
`glucose at a concentration of 10-40% by weight. For- 55 ionic electrolyte solution is required, the electrolyes
`mulations containing 3--4% by weight of taurolidine
`may be such as to provide sodium, potassium, calcium,
`and 15-25% by weight of glucose are especially pre-
`magnesium ions in their physiological proportions to-
`ferred.
`gether with anions such as chloride, phosphate, glycer-
`Although the solutions according to the invention are
`ophosphate and/or acetate ions. The polyol may conve-
`surprisingly stable at room temperature, there is some 60 niently be glucose or fructose. Such solutions may alter-
`evidence that reaction can occur at elevated tempera-
`natively be enriched in one or more cations, e.g. potas-
`tures, for example those used in sterilisation by auto-
`sium and magnesium.
`claving. Consequently, as indicated above, it is pre-
`Where the solutions are intended for parenteral nutri-
`ferred that the formulations are prepared by dissolving
`tion, e.g. peripheral venous nutrition, amino acids will
`the taurolidine or taurultam in an aqueous solution of 65 be present as well as trace elements and vitamins. The
`the polyol, which may optionally previously be steri-
`amino acids will generally comprise L-isoleucine, L-
`lised, for example by autoclaving, and to complete
`leucine, L-lysine, L-methionine, L-phenylalanine, L-
`sterilisation by filtration. If autoclaving is used to steril-
`threonine, L-tryptphane, L-valine, L-arginine, L-histi-
`
`

`

`5,210,083
`
`6
`-continued
`
`I liter contains:
`
`in water for injection
`
`5
`dine, L-alanine, L-glutamic acid L-proline and glycine.
`The proportions of the amino acids will generally be•
`those conventional in parenteral nutrition. The vitamins
`which may be present may include pyridoxine (hydro(cid:173)
`chloride), inositol, riboflavin (5'-phosphate sodium salt) 5
`and nicotinamide. Electrolytes where present may in(cid:173)
`clude sources of sodium, potassium, calcium and/or
`magnesium with acetate, malate or chloride ions.
`Solutions for plasma replacement (e.g. in treatment of
`hypovolumic shock, burns, thrombosis etc) may in- 10 - - - - - - - - - - - - - - - - - - - - -
`1 liter contains:
`elude, for example, dextran or hydroxymethyl starch as
`plasma extender together with an electolyte such as
`sodium chloride and/or a further polyol such as glu-
`cose.
`The following Examples are given by way ofillustra-
`tion only:
`
`EXAMPLE6
`Isotonic and isoionic electrolyte solution
`
`15
`
`Na+
`K+
`ea++
`Mg++
`ci-
`Acetate
`Glucose Monohydrate
`
`3.151 g
`0.156 g
`0.066 g
`0.030 g
`3.900 g
`2.173 g
`55.0 g
`
`EXAMPLE 1
`50.0 g Glucose were dissolved in 495 ml distilled
`water and the pH adjusted to 6.6 with N-sodium hy(cid:173)
`droxide. This solution was autoclaved and 10.0 g
`taurolidine were then added. After dissolution of the
`taurolidine, the volume was made up to 500 ml with
`sterile distilled water and sterile-filtered prior to sealing 25
`in a 500 ml flask.
`
`20
`
`EXAMPLE2
`100.0 g Glucose were dissolved in 495 ml distilled
`water and the pH adjusted to 6.6 with N-sodium hy- 30
`droxide. This solution was autoclaved and 10.0 g
`taurolidine were then added. After dissolution of the
`taurolidine, the volume was made up to 500 ml with
`sterile distilled water and sterile-filtered prior to sealing
`in a 500 ml flask.
`
`35
`
`EXAMPLE 3
`100.0 g Glucose were dissolved in 495 ml distilled
`water and the pH adjusted to 6.6 with N-sodium hy(cid:173)
`droxide. This solution was autoclaved and 20.0 g 40
`taurolidine were then added. After dissolution of the
`taurolidine, the volume was made up to 500 ml with
`sterile distilled water and sterile-filtered prior to sealing
`in a 500 ml flask.
`
`45
`
`EXAMPLE4
`Solution for therapy of metabolic acidosis
`
`for injection
`20.0 g
`Taurolidine
`____ m_· _w_a_te_r_fo_r_in..:.jec_ti_on _ _ _ _ _ _ _ _ _ _ _ _
`
`The taurolidine content may alternatively be 30.0 g The
`20.0 g taurolidine may also be replaced by 30.0 g taurul(cid:173)
`tam.
`
`EXAMPLE?
`Isotonic and isoionic electrolytic solution
`
`I liter contains:
`Na+
`K+
`ea+
`Mg++
`c1-
`Acetate
`Fructose
`Fructose
`Taurolidine
`in water for injection
`
`3.151 g
`0.156 g
`0.066 g
`0.030 g
`3.900 g
`2.173 g
`50.0 g
`100.0 g
`20.0 g
`
`The taurolidine content may alternatively be 30.0 g The
`20.0 g taurolidine may also be replaced by 30.0 g taurul(cid:173)
`tam.
`
`EXAMPLES
`Isotonic and isoionic electrolytic solution with
`increased potassium content
`
`1000 ml infusion solution contains:
`
`Sodium acetate
`Sodium hydrogen carbonate
`Sodium L-malate
`Trometamol (THAM)
`Sorbitol
`Taurolidine
`in water for injection
`
`8.2 g
`4.2 g
`6.2 g
`4.0 g
`50.0 g
`30.0 g
`
`50
`
`55
`
`I liter contains
`Na+
`K+
`ea++
`Mg++
`c1-
`Acetate
`Fructose
`Taurolidine
`in water for injection
`
`3.151 g
`0.156 g
`0.066 g
`0.030 g
`3.900 g
`2.820 g
`50.0 g
`20.0 g
`
`EXAMPLE 5
`Solution for osmotherapy
`
`60
`
`The taurolidine content may alternatively be 30.0 g
`The 20.0 g taurolidine may also be replaced by 30.0 g
`taurultam.
`
`I liter contains:
`
`Glycerol
`Glucose monohydrate
`for injection
`Sodium chloride
`Taurolidine
`
`65
`
`100.0 g
`27.5 g
`
`25.0 g
`30.0 g
`
`EXAMPLE9
`Electrolyte solution
`
`I liter contains:
`
`Na+
`
`1,129 g
`
`

`

`7
`-continued
`
`I liter contains:
`K+
`Mg++
`c1-
`H2P04-
`Lactose
`Glucose Monohydrate
`for injection
`Taurolidine
`in water for injection
`
`0.973 g
`0.061 g
`1.741 g
`0.960 _g
`1.781 g
`55.0 g
`
`20.0 g
`
`The taurolidine content may alternatively be 30.0 g.
`The 20.0 g taurolidine may also be replaced by 30.0 g
`taurultam.
`The potassium content may be varied between 0.05
`and 24.9 millimol.
`
`EXAMPLE 10
`Isotonic sodium chloride solution containing
`hydroxyethyl-starch
`
`I liter contains
`
`0-(2-Hydroxy~thyl)-amylopectin
`hydrolysate
`(Hydroxyethyl starch)
`(Substitution grade 0.40--0.50)
`(Average molecular weight: 200,000)
`Sodium chloride
`(Na+: 154 mmol, c1-, 154 mmol)
`Glucose monohydrate for injection
`Taurolidine
`in water for injection
`
`100.00 g
`
`or 60.00 g
`
`9.00 g
`
`55.0 g
`20.0 g
`
`5,210,083
`
`8
`The 20.0 g taurolidine may also be replaced by 30.0 g
`taurultam.
`
`5
`
`EXAMPLE 13
`Solution for osmotherapy
`
`I Liter contains:
`
`Mannitol
`Taurolidine
`in water for injection
`
`200.0 g
`20.0 g
`
`The taurolidine content may· alternatively be 30.0 g
`The 20.0 g taurolidine may also be replaced by 30.0 g
`15 taurultam.
`
`EXAMPLE 14
`Solution with invert sugar
`
`20 - - - - - - - - - - - - - - - - - - - -
`I Liter contains:
`Sodium chloride
`Sodium acetate 3H2O
`Potassium chloride
`Calcium chloride
`Glucose Monohydrate
`for injection
`Fructose
`Taurolidine
`in water for injection
`
`2.483 g
`3.742 g
`o.373 g
`0.153 g
`14.90 g
`
`13.13 g
`20.0 g
`
`25
`
`30
`
`The taurolidine content may alternatively be 30.0 g
`The 20.0 g taurolidine may also be replaced by 30.0 g
`taurultam.
`
`The taurolidine content may alternatively be 30.0 g 35
`The 20.0 g taurolidine may also be replaced by 30.0 g
`taurultam.
`
`EXAMPLE 15
`Electrolyte solution with 10 mmol potassium
`
`EXAMPLE 11
`Ringer solution
`
`40
`
`I Liter contains:
`Na+
`K+
`ca++
`c1-
`Glucose monohydrate
`for injection
`20.0 g
`Taurolidine
`_____________________
`in water for injection
`50
`
`1.129 g
`0.052 g
`0.030 g
`1.840 g
`36.6 g
`
`45
`
`The taurolidine content may alternatively be 30.0 g
`The 20.0 g taurolidine may also be replaced by 30.0 g
`taurultam.
`
`EXAMPLE 12
`Solution for osmotherapy
`
`55
`
`I Liter contains:
`
`Sodium chloride
`Sodium acetate
`Potassium chloride
`Calcium chloride
`Magnesium chloride
`Taurolidine
`Glucose
`in water for injection
`
`4.968 g
`7.485 g
`0.746 g
`0.368 g
`0.305 g
`20.0 g
`55.0 g
`
`The taurolidine content may alternatively be 30.0 g
`The 20.0 g taurolidine may also be replaced by 30.0 g
`uru
`.
`ta
`ltam
`
`EXAMPLE 16
`Potassium-magnesium rich infusion solution
`
`----------------------60
`
`I Liter contains:
`Na+
`c1-
`Acetate
`Ethoxy-azorutoside
`Sorbitol
`Taurolidine
`in water for injection
`
`1.379 g
`1.595 g
`0.886 g
`0.200 g
`400.0 g
`20.0 g
`
`The taurolidine content may alternatively be 30.0 g
`
`65
`
`The taurolidine content may alternatively be 30.0 g
`The 20.0 g taurolidine may also be replaced by 30.0 g
`taurultam.
`
`I Liter contains:
`Xylitol
`Glucose Monohydrate
`for injection
`Malic acid
`Potassium chloride
`Magnesium chloride
`Magnesium acetate
`Tripotassium phosphate
`Taurolidine
`in water for injection
`
`70.0 g
`33.0 g
`
`2.5 g
`3.75 g
`1.015 g
`3.22 g
`2.123 g
`20.0 g
`
`

`

`5,210,083
`
`I Liter contains:
`
`10
`-continued
`
`9
`EXAMPLE 17
`Electrolyte solution
`
`I Liter contains
`Sodium chloride
`Potassium chloride
`Calcium chloride
`Magnesium chloride
`Fructose
`Taurolidine
`in water for injection
`
`8.182 g
`0.373 g
`0.368 g
`0.305 g
`100.0 g
`20.0 g
`
`Glycine
`5 L-Alanine
`L-( + )Glutamic acid
`L-Proline
`L-Serine
`N-Acetyl-L-tyrosine
`Sodium L-hydrogen glutamate H2O
`10 Sodium chloride
`Potassium chloride
`Magnesium acetate 4 H2O
`Calcium chloride 2 H2O
`Glycerol-1(2)-dihydrogenphosphate mixed with its
`disodium salt (30/70% W /W)5 H2O
`Sorbitol
`Xylitol
`Taurolidine
`in water for injection
`
`3.64 g
`6.06 g
`2.01 g
`3.26 g
`3.26 g
`0.23 g
`3.98 g
`1.169 g
`2.237 g
`1.072 g
`0.368 g
`3.061 g
`
`30.0 g
`30.0 g
`20.0 g
`
`The taurolidine content may alternatively be 30.0 g
`The 20.0 g taurolidine may also be replaced by 30.0 g 15
`t.aurultam.
`
`EXAMPLE 18
`Fully balanced L-amino acid solutions
`
`I Liter contains:
`Amino acid content
`Amino acids
`L-Isoleucine
`L-leucine
`L-Lysine monohydrochloride
`L-Methionine
`L-Phenylalanine
`L-Threonine
`L-Tryptophane
`L-Valine
`L-Alanine
`L-Arginine
`L-Glutamic acid
`Glycine
`L-Histidine
`L-Proline
`Polyois:
`Sorbitol
`Xylitol
`Ethanol
`Vitamins:
`Ascorbic acid
`Inositol
`Nicotinamide
`Pyrodoxine hydrochloride(B)
`Riboflavin-5'-phosphate sodium
`Electrolytes:
`Potassium hydroxide
`Magnesium acetate
`Sodium hydroxide
`L-Malic acid
`Taurolidine
`
`5%
`
`10%
`
`1.55 g
`2.20 g
`2.50 g
`2.10 g
`2.20
`1.00 g
`0.45 g
`1.50 g
`6.00 g
`4.00 g
`9.00 g
`10.00 g
`1.00 g
`7.00 g
`
`50.00 g
`50.00 g
`50.00 g
`
`0.40 g
`0.50 g
`0.06 g
`0.04 g
`
`1.68 g
`1.07 g
`1.60 g
`2.01 g
`20.00 g
`
`3.10 g
`4.40 g
`5.00 g
`4.20 g
`4.40 g
`2.00 g
`0.90 g
`3.00 g
`12.00 g
`8.00 g
`18.00 g
`20.00 g
`2.00 g
`14.00 g
`
`50.00 g
`50.00 g
`
`0.40 g
`0.50 g
`0.06 g
`0.04 g
`
`1.68 g
`1.07 g
`1.60 g
`0.67 g
`20.00 g
`
`The taurolidine content may alternatively be 30.0 g
`The 20.0 g taurolidine may also be replaced by 30.0 g
`t.aurultam.
`
`EXAMPLE 19
`Complete solution for peripheralvenous nutrition
`
`I Liter contains:
`L-lsoleucine
`L-leucine
`L-Lysine monohydrochloride
`L-Methionine
`L-Phenylalanine
`L-Threonine
`L-Tryptophane
`L-Valine
`Arginine
`L-Histidine monohydrochloride
`Acetylcysteine
`
`0.98 g
`2.33 g
`2.21 g
`1.26 g
`1.16 g
`1.26 g
`0.49 g
`1.08 g
`3.26 g
`1.09 g
`0.26 g
`
`20
`
`The taurolidine content may alternatively be 30.0 g
`The 20.0 g taurolidine may also be replaced by 30.0 g
`taurultam.
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`EXAMPLE 20
`Electrolyte-free peripheral nutrition solution
`
`I Liter contains:
`
`L-Isoleucine
`L-leucine
`L-Lysine
`L-Methionine
`L-Phenylalanine
`L-Threonine
`L-Tryptophane
`L-Valine
`L-Histidine
`Sorbitol
`Xylitol
`Taurolidine
`in water for injection
`
`7.52 g
`11.38 g
`
`6.59 g
`7.76 g
`6.78 g
`2.91 g
`9.53 g
`4.90 g
`25.00 g
`25.00 g
`20.00 g
`
`The taurolidine content may alternatively be 30.0 g
`The 20.0 g taurolidine may also be replaced by 30.0 g
`taurultam.
`
`EXAMPLE21
`Dextran plasma replacement solutions
`
`I Liter contains:
`(a) Dextran(MW 40,000)
`NaCl
`Taurolidine
`in water for injection
`(b) Dextran(MW 40,000)
`Glucose
`Taurolidine
`in water for injection
`(c) Dextran (MW 40,000)
`NaCl
`Taurolidine
`in water for injection
`(d) Dextran(MW 70,000)
`Glucose
`Taurolidine
`in water for injection
`(e) Dextran(MW 70,000)
`Taurolidine
`in Ringer-lactate
`(Na+
`K+
`ea++
`Mg++
`
`100 g
`9 g
`20 g
`
`100 g
`50 g
`20 g
`
`60 g
`9 g
`20 g
`
`60 g
`50 g
`20 g
`
`30 g
`20 g
`
`130 m/mol
`5.4 m/mol
`0.9 m/mol
`1.0 m/mol
`
`

`

`5,210,083
`
`11
`-continued
`
`I Liter contains:
`
`27 m/mol)
`
`12
`4. A pharmaceutical composition as claimed in claim
`l wherein the polyol is glucose.
`S. A pharmaceutical composition as claimed in claim
`4 comprising taurolidine at a concentration in the range
`5 3 to 4% by weight and glucose at a concentration in the
`range 15 to 25% by weight.
`6. A pharmaceutical composition as claimed in claim
`l wherein the polyol is fructose.
`7. A pharmaceutical composition as claimed in claim
`10 l wherein the concentration of taurolidinc is in the
`range 2 to 3% by weight or the concentration oftaurul(cid:173)
`tam is in the range of 3 to 5% by weight.
`8. A pharmaceutical composition as claimed in claim
`l further comprising an additive selected from the
`group consisting of an electrolyte, one or more amino
`acids, trace clements and vitamins.
`9. A pharmaceutical composition as claimed in claim
`l wherein the concentration of taurolidine is in the
`range of 2 to 3% by weight.
`10. A pharmaceutical composition as claimed in claim
`l wherein the concentration of taurultam is in the range
`
`3 to 5% by weight. • • • • •
`
`The taurolidine content may alternatively be 30.0 g
`The 20.0 g taurolidine may also be replaced by 30.0
`taurultam.
`I claim:
`1. A liquid pharmaceutical composition for parenteral
`infusion or injection into a patient comprising a liquid
`aqueous solution containing a bactericide selected from
`the group consisting of 1-5 weight% oftaurolidine and 15
`1-7 .5 weight % of taurultam, together with 3--40 weight
`% of a parcnterally acceptable polyol.
`l. A pharmaceutical composition as claimed in claim
`l wherein the polyol is glycerol, a sugar or a sugar 20
`alcohol.
`3. A pharmaceutical composition as claimed in claim
`l wherein the sugar alcohol is sorbitol or xylitol.
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`