Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/74—Synthetic polymeric materials
  • A61K31/765—Polymers containing oxygen
  • A61K31/77—Polymers containing oxygen of oxiranes

Definitions

• the present invention relates to a stable pharmaceutical formulation of a polyoxypropylene/polyoxyethylene block copolymer.
• Certain surface-active polyoxypropylene/polyoxyethylene block copolymers have been found to have beneficial effects in animal and human medicine.
• the copolymers may be used for treating circulatory disorders alone or in combination with other agents, such as fibrinolytic enzymes, anticoagulants, free radical scavengers, anti- inflammatory agents, antibiotics, membrane stabilisers and/or perfusion media. These uses are described in US Patent Nos.
• the surface-active copolymers are effective in circulatory disorders where there is a pathological hydrophobic interaction between cells and/or molecules. These interactions are believed to be caused by 1) a higher than normal concentration of fibrinogen, 2) generation of intravascular or local soluble fibrin, especially high molecular weight fibrin, 3) increased friction in the microvasculature, or 4) mechanical or chemical trauma to blood components. These disorders cause an increase in pathological hydrophobic interactions of blood components such as cells and molecules. It is believed that fibrin, especially soluble fibrin, increases adhesion of cells to one another, markedly increases friction in small blood vessels, and increases viscosity of the blood especially at low shear rates. The effects of the surface-active copolymers are believed to be essentially lubrication effects because they reduce the friction caused by the adhesion.
• antioxidants Commercially available surface-active polyoxypropylene/polyoxyethylene block copolymers generally contain antioxidants .
• poloxamer 188 that may be purchased from BASF (Parsippany, New Jersey, U.S.A.) contains BHT (butylated hydroxytoluene).
• BHT butylated hydroxytoluene
• This antioxidant is not standardised for pharmaceutical use.
• antioxidants tend to be hydrophobic and insoluble in aqueous medium, and some may also present toxicity problems. This is clearly undesirable in an injectable solution for use in medicine. It is therefore an object of the present invention to provide an aqueous solution of a block copolymer that is substantially free of such antioxidants.
• EP-A- 103290 describes aqueous pharmaceutical formulations of polyoxypropylene and polyoxyethylene adjusted to a physiologically acceptable pH. preferably from 6 to 8, by addition of electrolytes and buffers. It does not however describe a pharmaceutical formulation of a block copolymer of polyoxypropylene/polyoxyethylene and does not describe or allude to any of the above-mentioned disadvantages associated with such a polymer.
• US Patent No. 4,938,961 describes an aqueous solution of polypropylene glycol but makes no reference to solutions of a block copolymer of polyoxypropylene/polyoxyethylene.
• the present invention accordingly provides a sealed pharmaceutically acceptable container which contains in a vacuum or in an inert atmosphere a sterile aqueous injectable solution of a block copolymer of formula (I):
• a is an integer such that the hydrophobe represented by (C ⁇ H O) has a
• the solution being substantially free from an antioxidant and being buffered at a pH from 5.5 to 6.5.
• a preferred block copolymer of formula (I) is wherein the molecular weight of the hydrophobe (C H O) is approximately 1750 Daltons and the total molecular weight of
• the copolymer is approximately 8400 Daltons.
• a particular example of such a block copolymer is that which is referred to as poloxamer 188 (BASF, Parsippany, New Jersey,
• poloxamer 188 Commercially available sources of poloxamer 188 are stated to have a molecular weight of approximately 8400 Daltons. In reality, the block copolymer is composed of molecules having a molecular weight from less than 3000 Daltons to over 20,000 Daltons. The molecular diversity and distribution of molecules of commercial poloxamer 188 can be illustrated by broad primary and secondary peaks detected using gel permeation chromatography, as described in WO 92/16484.
• the high molecular weight components i.e. the components having a molecular weight greater than 15kDaltons, that are present in commercially available poloxamer 188 normally amount to 3%, by weight, of the block copolymer or even more. Such significant amounts may give rise to unwanted side-effects in the clinical application of the block copolymer. In particular, these components have a longer elimination phase half life than the bulk of the block copolymer and thus accumulate in the plasma and kidneys. In addition, these high molecular weight components may be responsible for activation of the complement system. It is thus preferred that the block copolymer of use with the present invention is free, at least to a substantial extent, i.e. less than 1%, preferably 0.5% or 0.2%, by weight, of any molecules having a molecular weight greater than 15kDaltons.
• a standard measure of the molecular weight distribution of a polymer is its polydispersity. This is referred to and described in WO92/16484, the contents of which are incorporated herein by reference. Briefly, a polydispersity of 1.0 is indicative of a polymer in which all molecules have the same molecular weight. A typical polymer may have a polydispersity of 2 to 5.
• the block copolymer of polyoxypropylene/ polyoxyethylene of use with the present invention preferably has a polydispersity less than 1.4, preferably 1.3 or 1.2 or even 1.1.
• the surface-active block copolymer may be formed by condensation of ethylene oxide and propylene oxide at elevated temperature and pressure in the presence of a basic catalyst.
• a basic catalyst there is statistical variation in the number of monomer units which combine to form a polymer chain in each copolymer.
• the molecular weights given are approximations of the average weight of copolymer molecule in each preparation. A more detailed discussion of the preparation of these copolymers is found in U.S. Patent No. 2,674,619, which is incorporated herein by reference.
• block copolymer that is the forms which are free from any significant amount of molecules having a molecular weight greater than 15kDaltons, or which have a polydispersity of less than 1.4, may be obtained by the process described in WO 92/16484.
• block copolymers such as poloxamer 188
• the antioxidant should be removed from the copolymer, for example, by filtration or by some other means known in the art.
• the block copolymer is obtained in a form that is already substantially free from an antioxidant.
• the amount of block copolymer contained within the aqueous injectable solution is preferably from 135 to 165 mg/mL, especially about 150 -mg mL (i.e. milligrams per millilitre).
• the pH of the aqueous injectable solution is preferably about 6.
• the aqueous injectable solution is buffered at the desired pH using a buffering agent.
• buffering agents include citrate (for example sodium citrate/citric acid).
• concentration of the buffering agent, in particular citrate buffering agent should preferably be from 0.005 to 0.05M, particularly about 0.01M.
• the medium for the aqueous injectable solution is wholly or substantially aqueous.
• the aqueous injectable solution is preferably of such tonicity with the blood serum of the patient so as to avoid undesirable side effects. If the tonicity of the aqueous injectable solution needs to be increased, then a substantially isotonic solution may be obtained by the inclusion of a pharmaceutically acceptable agent that is capable of raising the tonicity of the solution to the required level. Examples of such an agent are well known in the art and include dextrose and sodium chloride and mixtures thereof.
• the aqueous injectable solution may be provided in sterile form by filtration or by autoclaving.
• the formulation of the aqueous injectable solution and its filling into a pharmaceutically acceptable containers are preferably carried out in accordance with procedures known in the art in which conditions are designed to minimise the oxygen in the formulation solution or headspace.
• Examples of a pharmaceutically acceptable container include plastic and glass containers, such as vials, ampoules and bottles.
• the containers may optionally be coloured, such as amber, to reduce the exposure of the aqueous injectable solution to UN light and possible degradation.
• the containers may be colourless but packaged in opaque cartons.
• the aqueous injectable solution is contained in an inert atmosphere which is nitrogen.
• the surface-active copolymer may be used in the treatment of circulatory disorders which are caused by or which cause pathological hydrophobic interaction of blood components.
• diseases include myocardial infarction, stroke, bowel or other tissue infarctions, malignancies, adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), diabetes, unstable angina pectoris, hemolytic uremic syndrome, red cell fragmentation syndrome, heat stroke, retained fetus, eclampsia, malignant hypertension, sickle cell disease, burns, crush injuries, fractures, trauma producing shock, major surgery, sepsis, bacterial, parasitic, viral and rickettsial infections which promote activation of the coagulation system, central nervous system trauma, and during and immediately after any major surgery.
• ARDS adult respiratory distress syndrome
• DIC disseminated intravascular coagulation
• diabetes unstable angina pectoris
• hemolytic uremic syndrome red cell fragmentation syndrome
• heat stroke retained fetus
• the surface-active copolymer is also effective in increasing the collateral circulation to undamaged tissues with compromised blood supply. Such tissues are frequently adjacent to areas of vascular occlusion. The mechanism appears to be reducing pathological hydrophobic interactions in small blood vessels. Circulatory disorders in which the surface-active copolymers are effective include cerebral thrombosis, cerebral embolus, myocardial infarction, unstable angina pectoris, transient cerebral ischemic attacks, intermittent claudication of the legs, plastic and reconstructive surgery, balloon angioplasty, peripheral vascular surgery, and orthopedic surgery, especially when using a tourniquet.
• the copolymer may also be used for the preservation of organs for transplantation.
• the aqueous injectable solution of the block copolymer may be administered to the patient by bolus injection or preferably by infusion.
• a convenient site for administration will normally be a peripheral vein.
• a bolus injection usually comprises administration over a two minute period.
• Infusions are normally carried out with the solution contained within an infusion bag or bottle or within an electrically operated infusion pump. The solution may be delivered from the infusion bag or bottle to the patient by gravity feed or by the use of the infusion pump.
• an effective amount of the block copolymer to treat a patient with a circulatory disorder will of course depend on a number of factors including, for example, the age and weight of the patient, the precise condition requiring treatment, the route of administration, and will ultimately be at the discretion of the attendant physician. It is likely however that an effective amount will generally be in the range of from 0.2 to 3.0 g kg, preferably 1.5 to 2.5 g/kg bodyweight, administered to a patient over a period from 1 to 48 hours.
• aqueous injectable solution provided in this way is a clear, colourless solution, free of particulate matter, haze or swirl and is stable, as evidenced by the following data:
• Fluor Fluoroscent met: methanol l.s.: labelled strength form: formaldehyde
• Example 1 The procedure of Example 1 was repeated for a 200 litre batch size using the following formulation and collecting 160 litres in vessel No.1 and 40 litres in vessel No.2 : Poloxamer 188, NF 1 30.00 kg
• the resulting aqueous injectable solution was similar in physical appearance as that provided by Example 1.
• the following stability data were obtained.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
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• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
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• Compositions Of Macromolecular Compounds (AREA)
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• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

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• 1992
  • 1992-10-19 GB GB929221883A patent/GB9221883D0/en active Pending
• 1993
  • 1993-10-18 WO PCT/GB1993/002141 patent/WO1994008596A1/en not_active Application Discontinuation
  • 1993-10-18 SK SK447-95A patent/SK44795A3/sk unknown
  • 1993-10-18 CA CA002147889A patent/CA2147889A1/en not_active Abandoned
  • 1993-10-18 SI SI9300545A patent/SI9300545A/sl unknown
  • 1993-10-18 AU AU52842/93A patent/AU674895B2/en not_active Expired - Fee Related
  • 1993-10-18 PL PL93308459A patent/PL308459A1/xx unknown
  • 1993-10-18 NZ NZ256890A patent/NZ256890A/en unknown
  • 1993-10-18 HU HU9501104A patent/HUT75701A/hu unknown
  • 1993-10-18 MX MX9306467A patent/MX9306467A/es unknown
  • 1993-10-18 KR KR1019950701458A patent/KR950703345A/ko not_active Application Discontinuation
  • 1993-10-18 EP EP93923008A patent/EP0671919A1/en not_active Withdrawn
  • 1993-10-18 ZA ZA937714A patent/ZA937714B/xx unknown
  • 1993-10-18 IL IL107313A patent/IL107313A0/xx unknown
  • 1993-10-18 CZ CZ95633A patent/CZ63395A3/cs unknown
  • 1993-10-18 BR BR9307268A patent/BR9307268A/pt not_active Application Discontinuation
  • 1993-10-18 TW TW082108706A patent/TW276183B/zh active
  • 1993-10-18 JP JP6509782A patent/JPH08502284A/ja active Pending
• 1995
  • 1995-04-18 NO NO951462A patent/NO951462L/no unknown

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