Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
  • A61K47/40—Cyclodextrins; Derivatives thereof
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions

Definitions

• Carbapenems are a class of ⁇ -lactam antibiotics which includes, for example imipenem, meropenem, ertapenem and doripenem.
• the compound of formula 1 is relatively unstable at ambient conditions and remains unstable above approximately -20°C.
• a current approach to increase the stability of carbapenem compounds is to form a reversible carbon dioxide-carbapenem adduct during manufacture .
• a carbon dioxide-ertapenem adduct can be formed by use of a carbon dioxide source, such as a carbonate buffer (e.g. sodium carbonate or sodium bicarbonate) in the course of manufacture of the drug product. This process is
• Carbapenem compositions according to the present invention allow a greater holding time of the bulk carbapenem solution (Bulk solution) prior to lyophilisation, provide a final
• the invention provides a composition comprising a carbapenem, a buffer, and a stabiliser, wherein the stabiliser is a cyclic oligosaccharide or a
• the buffer comprises a carbonate source, for example a carbonate and/or a
• bicarbonate buffer In one such embodiment, the buffer is sodium bicarbonate.
• the buffer does not comprise a carbonate source.
• the buffer is a citrate buffer, for example sodium citrate.
• the composition further comprises sodium chloride, preferably in a ratio of between about 90
• the stabiliser is a polysaccharide.
• the polysaccharide is preferably a dextran or, egually preferably, a hydroxyethyl starch.
• the stabiliser is present in a ratio of between about 0.5 grams to about 5 grams of stabiliser per gram of carbapenem, preferably between about 1 gram to about 3 grams of
• the carbapenem is ertapenem.
• the bulk solution composition comprises less than about 8%, preferably less than about 5% total degradation products after being stored at 0-2°C for 24 hours .
• the composition is lyophilised.
• the lyophilised composition comprises less than about 5% total degradation products, preferably less than about 4% total degradation products.
• the lyophilised composition has an in-use shelf life of more than 6 hours at 25°C.
• the composition is a pharmaceutical composition.
• the invention provides a method of producing a stabilised carbapenem composition, the method comprising combining in a buffered solution:
• a stabiliser wherein the stabiliser is a cyclic oligosaccharide or a polysaccharide
• the stabilised carbapenem composition comprises less than about 8%, optionally less than about 5% total
• the invention provides a method of producing a stabilised carbapenem composition, the method comprising combining in a buffered solution:
• a stabiliser wherein the stabiliser is a cyclic oligosaccharide or a polysaccharide
• the stabilised carbapenem composition is lyophilised; wherein, when lyophilised, the stabilised carbapenem composition comprises less than about 5% total degradation products, optionally less than about 4% total degradation products.
• the buffer comprises a carbonate source, for example a carbonate and/or a bicarbonate buffer.
• the buffer is sodium bicarbonate.
• the buffer does not comprise a carbonate source.
• the buffer is a citrate buffer, for example sodium citrate.
• the composition further comprises sodium chloride, preferably in a ratio of between about 90
• the stabiliser is a cyclic oligosaccharide, preferably a cyclodextrin, more preferably sulfobutylether-p-cyclodextrin (SBECD).
• the stabiliser is a polysaccharide.
• the polysaccharide is preferably a dextran or, egually preferably, a hydroxyethyl starch.
• the stabiliser is present in a ratio of between about 0.5 grams to about 5 grams of stabiliser per gram of carbapenem, preferably between about 1 gram to about 3 grams of stabiliser per gram of carbapenem.
• the carbapenem is ertapenem. All embodiments relate to each and all of the above aspects and embodiments, alone or in combination with any one or more other embodiments, unless otherwise specified.
• Stabiliser as used herein is any substance which, when included in a composition comprising a carbapenem, the carbapenem in that composition is more stable than in the same carbapenem composition without the stabiliser.
• the stability of a carbapenem in a carbapenem composition is determined by the rate at which degradation products or impurities are accumulated m the carbapenem composition.
• the respective degradation products/impurities for a particular carbapenem are known to the skilled person.
• the major degradation products are Dimer I, Dimer II, Dimer III, Dimer-H 2 Oa, Dimer-H 2 Ob, Dimer V and the open-ring degradation product, as detailed in Sajonz et al . J. Lig. Chrom. & Rel. Technol., 24(19), 2999- 3015 (2001) .
• These impurities form the majority of the degradation products for ertapenem, although small amounts of other impurities can also be formed.
• the total amount of degradation products/impurities in a carbapenem composition can be determined by methods known in the art, for example reverse-phase high-performance liguid chromatography (HPLC) .
• HPLC reverse-phase high-performance liguid chromatography
• the "in-use" shelf life of a carbapenem composition is the length of time following reconstitution of a lyophilised carbapenem composition before total degradation products exceed acceptable levels, when the reconstituted composition is stored at approximately 25°C.
• An example of unacceptable levels of degradation products is when total degradation products exceed approximately 8.0% of the active carbapenem.
• the "bulk solution" of a carbapenem composition is the final formulated solution which is to be filled into vials prior to lyophilisation .
• a pharmaceutical composition as used herein includes the bulk solution prepared during the manufacture of the final pharmaceutical composition product. Detailed description
• Carbapenem antibiotics exhibit significant instability, especially in solution state, degrading into hydrolysed open-ring structures and forming dimerised impurities .
• the present invention relates to carbapenem compositions comprising a stabiliser, the effect of which is to reduce the rate at which the carbapenem degrades into such
• Carbapenems suitable for use in compositions and methods according to the invention include imipenem, meropenem, ertapenem and doripenem, preferably ertapenem .
• compositions according to the invention may have a
• composition may contain an excess of carbapenem of up to 6%, 5%, 4%, 3%, 2% or up to 1% w/v compared to the intended concentration of the final product.
• the stabiliser used in compositions according to the invention is a cyclic oligosaccharide, preferably a
• cyclodextrin for example sulfobutylether- -cyclodextrin, hydroxypropyl- -cyclodextrin, or gamma cyclodextrin.
• the stabiliser is a polysaccharide, for example a dextran, a hydroxyethyl starch, a dextrin or maltodextrin .
• compositions or methods of the invention may be between about 0.5g to about 5g of stabiliser per lg of carbapenem, preferably between about lg to about 3g of stabiliser per lg of carbapenem.
• the amount of stabiliser may be about 0.5g, about lg, about 2g, about 3g, about 4g, or about 5g of stabiliser per lg of carbapenem.
• Buffers suitable for use in the compositions and methods of the invention may be buffers that provide a carbon dioxide source when in solution.
• Such buffers may be carbonate buffers, for example sodium carbonate or sodium bicarbonate.
• compositions and methods of the invention may be buffers that do not provide a carbon dioxide source when in
• buffers may be citrate buffers, for example sodium citrate.
• suitable buffers would be familiar to the person skilled in the art and include phosphate buffers, or ammonium acetate.
• the amount of buffer used in the compositions or methods of the invention may be in the range of between about 0.1g-0.3g per gram of carbapenem, for example about O.lg, about 0.15g, about 0.175g, about 0.18g, about 0.2g, about 0.25g, or about 0.3g of buffer per lg of carbapenem.
• compositions according to the invention or produced by methods according to the invention may further comprise sodium chloride.
• compositions according to the invention wherein the buffer is a carbon dioxide source, for example sodium bicarbonate further comprise sodium chloride .
• compositions according to the invention wherein the buffer is not a carbon dioxide source in solution, for example sodium citrate may further comprise sodium chloride.
• the amount of sodium chloride used in compositions according to any of these embodiments may be about 90mg, about lOOmg, about 120mg, about 150mg, about 180mg, or about 200mg of sodium chloride per lg of carbapenem.
• an ertapenem composition according to the invention comprising 3g of SBECD per gram of ertapenem and a carbonate buffer can be manufactured as follows :
• Preparation of sodium hydroxide solution A 2N solution of sodium hydroxide was prepared by dissolving sodium hydroxide NF pellets in reguired amount of Water for Injection (WFI) (80 g sodium hydroxide in 1000 mL WFI yields a 2N sodium hydroxide solution) .
• WFI Water for Injection
• the sodium hydroxide solution was chilled to a temperature of about 5°C.
• an ertapenem composition according to the invention comprising 3g of SBECD per gram of ertapenem and a citrate buffer, optionally also including 180mg of sodium chloride per gram of ertapenem, can be manufactured as follows :
• WFI Water Injection
• WFI guantity eguivalent to 50% of the batch size is taken.
• 3g of SBECD per gram of ertapenem is added into WFI and stirred for about 15 minutes to obtain a clear solution and then sodium citrate is added and further mixed for 5 minutes to obtain a clear solution, optionally 180mg of sodium chloride per gram of ertapenem is added to the solution and stirred for 5 minutes. Then the solution is chilled to about 5°C. 3.
• the Ertapenem bulk drug is thawed from -20 °C for approximately 30 minutes was then divided into 5 egual portions. The 5 portions of bulk drug were added into the above step 2 solutions over a period of about 50 minutes, while adding the sodium hydroxide solution to keep the pH of the bulk drug solution at about 7.8.
• compositions according to the invention are used in therapy.
• compositions according to the invention are used in the treatment of bacterial infections.
• the compositions according to the invention are suitable to be administered parenterally, optionally intramuscularly, optionally intravenously .
• the invention provides a method of treating a subject, optionally a mammalian subject, for example a human, comprising administering to the subject a therapeutic amount of a composition according to the invention .
• Example 1 The stability of the bulk solution of ertapenem manufactured according to the technigues known in the art was assessed to establish a baseline reference.
• hydroxide solution is used to maintain the pH of the bulk solution between 7.0 and 8.0 during the bulk solution compounding process.
• the detailed manufacturing process is set out below:
• the solution was mixed for an additional 15 minutes, and 2N NaOH titrations were preformed to maintain the pH at about 7.5.
• Water for injection at a temperature of about 5°C was added to bring the solution to about 97% of the batch size, based on 100% batch size.
• the pH thereof was adjusted to 7.5 by addition of 2N NaOH solution, ensuring that the mole ration of NaOH to bulk drug is about 0.85.
• the volume of the solution was adjusted to 100 percent of the final batch volume by addition of WFI at a temperature about 5°C, and then mixed for another 10 minutes.
• the compounder was then sealed and pressurized to NMT 2 bar to initiate filtration, and the solution was filtered through a Durapore 0.22 micron sterilizing filter into a sterile receiving vessel.
• the filtered solution exhibited a density of about 1.12 g/ml at 5°C.
• the stability of this bulk solution was evaluated by holding at 0°C and is provided in below Table 2.
• composition of bulk solution formulations made according to this process is set out in Table 1: Table 1.
• Control formulation composition is set out in Table 1: Table 1.
• control formulation was held at about 0°C and sampled every 6 hours up to 18 hours, with the levels of impurities in each sample measured by HPLC .
• the results are set out in Table 2. (For HPLC conditions please see Example 5)
• Dimer IV is a combination of Dimer-H 2 Oa and Dimer-H 2 Ob defined in Sajonz et al. J. Liq. Chrom. & Rel. Technol., 24(19), 2999-3015 (2001) .
• SBECD sulfobutylether- ⁇ - cyclodextrin
• the pH was adjusted to the target pH of 7.5 by addition of 2N NaOH solution.
• Formulation 1 Formulation 2: Formulation 3: Composition with 1 g Composition with 2 g Composition with 3 g SBECD SBECD and 175 mg SBECD and 175 mg and 175 mg Sodium Sodium Bicarbonate per Sodium Bicarbonate Bicarbonate per gram of gram of Ertapenem per gram of Ertapenem Ertapenem
• WFI Water Injection
• WFI guantity eguivalent to 50% of the batch size is taken.
• SBECD is added into WFI and stirred for about 5-15 minutes to obtain a clear solution and then sodium citrate is added and further mixed for 5 minutes to obtain a clear solution and then the solution is chilled to about 5°C.
• the Ertapenem bulk drug was thawed from -20°C for approximately 30 minutes was then divided into 5 egual portions.
• the 5 portions of bulk drug were added into the above step 2 solutions over a period of about 50 minutes, while adding the sodium hydroxide solution to keep the pH of the bulk drug solution at about 7.5.
• Formulation 6 improved the stability of the formulation, without any carbonate source .
• Formulations including sodium chloride were manufactured according to the following method. Their final composition is shown in Table 7 and the stability of the bulk solutions with sodium chloride is shown in Table 8.
• WFI Water Injection
• WFI guantity eguivalent to 50% of the batch size is taken.
• SBECD is added into WFI and stirred for about 15 minutes to obtain a clear solution and then sodium citrate is added and further mixed for 5 minutes to obtain a clear solution and then finally sodium chloride was added to the solution and stirred for 5 minutes. Then the solution is chilled to about 5°C.
• the Ertapenem bulk drug (as anhydrous free acid) was thawed from -20°C for approximately 30 minutes was then divided into 5 egual portions .
• the 5 portions of bulk drug were added into the above step 2 solutions over a period of about 50 minutes, while adding the sodium hydroxide solution to keep the pH of the bulk drug solution at about 7.8.
• compositions with SBECD had significantly lower impurity levels than the commercial product (Invanz®) and the control formulation.
• compositions with SBECD had significantly lower impurity levels than the commercial product (Invanz®) and the control formulation.
• the Formulation 7 that did not contain the sodium bicarbonate had significantly lower level of oxazinone impurity.
• the "in-use" stability after reconstitution of the lyophilised product was also tested for Invanz® and formulations 3 and 7. Stability of the reconstituted vials at a ertapenem concentration of 20 mg/mL was tested over a period of up to 24 hours. For the commercial product Invanz®, storage of the reconstituted solution is recommended to be no more than 6 hours at controlled room temperature, as after this point too much degradation has occurred and the level of impurities has increased.
• the stability data for the reconstituted formulations are provided in Table 10.

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