EP2056796A2 - Gefriergetrocknete zubereitung - Google Patents

Gefriergetrocknete zubereitung

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Publication number
EP2056796A2
EP2056796A2 EP07806699A EP07806699A EP2056796A2 EP 2056796 A2 EP2056796 A2 EP 2056796A2 EP 07806699 A EP07806699 A EP 07806699A EP 07806699 A EP07806699 A EP 07806699A EP 2056796 A2 EP2056796 A2 EP 2056796A2
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EP
European Patent Office
Prior art keywords
lyophilized preparation
active ingredient
solution
sun
cyclodextrin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07806699A
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English (en)
French (fr)
Inventor
Tetsu Ono
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Asubio Pharma Co Ltd
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Asubio Pharma Co Ltd
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Filing date
Publication date
Application filed by Asubio Pharma Co Ltd filed Critical Asubio Pharma Co Ltd
Publication of EP2056796A2 publication Critical patent/EP2056796A2/de
Withdrawn legal-status Critical Current

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    • 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
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a lyophilized preparation containing as an active ingredient, (2S) -1- (4-amino-2,3,5- trimethylphenoxy) -3- ⁇ 4-[ 4- (4-fluorobenzyl) phenyl] -1-piperazinyl ⁇ -2- propanol or its pharmaceutically acceptable salt having remedial and therapeutic effect against symptoms based on ischemic disorder andneurodegenerative disease, symptoms from spasm, epilepsy and migraine, as well as various symptoms caused by diabetes, arteriosclerosis and inflammatory disease.
  • [ 0004] or its pharmaceutically acceptable salt is a compound having remedial and therapeutic effect against symptoms based on ischemic disorder and neurodegenerative disease, symptoms from spasm, epilepsy and migraine, as well as various symptoms caused by diabetes, arteriosclerosis and inflammatory disease because it has not only an ability to block Na + and T-type Ca 2+ channel of neuron, but also anti-oxidization activity.
  • a dimethane sulfonic acid salt thereof is a clinically interested compound (Patent document 1 and Non-patent document 1) .
  • This compound and its pharmaceutically acceptable salt have very poor solubility around neutrality, and do not have good stability in solution.
  • solubility 5 mg/mL or higher is required.
  • solubility around neutrality is very low, it is difficult to develop an injectable preparation by usual formulation technique. [ 0006] In developing an injectable preparation, it is necessary to secure stability of an active ingredient contained therein during production or storage, as well as to avoid stimulus of the preparation at the time of administration.
  • Patent document 1 International Patent Publication WO99/23072
  • Patent document 1 J. Med. Chem. , 2000, 43, 3372-3376
  • a lyophilized preparation which contains a specific antioxidant and a specific solubilizing agent comprising a ⁇ -cyclodextrin derivative, together with a compound represented by the formula (I) or its pharmaceutically acceptable salt is stable by itself, and provides a uniform liquid formulation exhibiting stable dissolved state when prepared before use, and thus accomplished the present invention.
  • a basic aspect of the present invention is: (1) A lyophilized preparation comprising, as an active ingredient, (2S)-l-(4-amino-2,3,5-trimethylphenoxy)-3- ⁇ 4-[ 4- (4-fluorobenzyl) - phenyl] -1-piperazinyl ⁇ -2-propanol represented by the formula (I) or its pharmaceutically acceptable salt, the lyophilized preparation further comprising:
  • At least one antioxidant selected from the group consisting of sulfite, bisulfite, pyrosulfite, ⁇ -thioglycerol and cysteine;
  • the present invention provides: (2) The lyophilized preparation according to the above (1) , comprising (a) at least one selected from the group consisting of sodium bisulfite, sodium pyrosulfite, ⁇ -thioglycerol, L-cysteine hydrochloride monohydrate and L-cysteine;
  • the present invention provides:
  • a lyophilized preparation comprising: (2S) -1- (4-amino-2, 3,5- trimethylphenoxy) -3- ⁇ 4-[ 4- (4-fluorobenzyl)phenyl] -1-piperazinyl ⁇ -2- propanol or its pharmaceutically acceptable salt as an active ingredient; sodium bisulfite in an amount of 0.1 to 1.0 times (weight ratio) that of the active ingredient; and ⁇ -cyclodextrin sulfobutyl ether sodium salt (representatively, 7 sodium salt) in such an amount relative to the active ingredient that satisfies 1:4 to 1:8 (molar ratio) by active ingredient: ⁇ -cyclodextrin derivative.
  • a stable lyophilized preparation comprising a compound represented by the formula (I) or its pharmaceutically acceptable salt as an active ingredient is provided.
  • the lyophilized preparation provided by the present invention stably contains a compound represented by the formula (I) or its pharmaceutically acceptable salt, which is an active ingredient, and forms a very stable and uniform solution when dissolved before use. Since the- compound represented by the formula (I) or its pharmaceutically acceptable salt has remedial and therapeutic effect against symptoms based on ischemic disorder and neurodegenerative disease, symptoms from spasm, epilepsy and migraine, as well as various symptoms caused by diabetes, arteriosclerosis and inflammatory disease, a before-use-preparative type preparation which is very effective for therapy of these diseases can be realized.
  • a basic form of the present invention is a lyophilized preparation comprising as an active ingredient, (2S)-I- (4-amino-2,3,5-trimethylphenoxy)-3- ⁇ 4-[ 4- (4-fluorobenzyl) phenyl] -1- piperazinyl ⁇ -2-propanol represented by the formula (1) or its pharmaceutically acceptable salt, further comprising: (a) at least one antioxidant selected from the group consisting of sulfite, bisulfite, pyrosulfite, ⁇ -thioglycerol and cysteine; and
  • organic acid examples include formic acid, acetic acid, lactic acid, oxalic acid, malonic acid, propionic acid, valeric acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-toluene sulfonic acid, methane sulfonic acid, ethane sulfonic acid, trifluoromethane sulfonic acid, benzene sulfonic acid and the like organic acids.
  • a salt comprising one to three acid molecules may be selectively produced by increasing/decreasing the use amount of inorganic or organic acid within the range of 1 to 3 equivalents, depending on the number of basic nitrogen atom in the compound of formula (I) .
  • dimethane sulfonic acid salt is particularly preferred as the pharmaceutically acceptable salt of formula (I).
  • This compound namely (2S) -1- (4-amino-2,3,5-trimethyl- phenoxy)-3- ⁇ 4-[ 4- (4 ⁇ -fluorobenzyl)phenyl] -1-piperazinyl ⁇ -2-propanol dimethane sulfonate is a compound for which clinical development is being examined under the development code number: SUN N8075.
  • a compound of the formula (I) represented by SUN N8075 or its pharmaceutically acceptable salt contained as an active ingredient has very low solubility at pH around neutrality, and an aqueous solution of the compound has properties such as stimulus property when administered as an injectable preparation, self- oxidation property, low stability against light and susceptibility to light decomposition.
  • the problems to be solved by the present lyophilized preparation is to ensure sufficient solubility as a before-use-dissolving type lyophilized preparation which is to be dissolved in a distilled water for injection; to ensure dilution stability; to reduce stimulus at the time of vessel administration in administration; to prevent oxidation and light decomposition of the active ingredient during storage; and to prevent generation of insoluble matters when dissolved.
  • Test example 1 Examination of solubilizing agent (Part 1)
  • the present inventors of the present application examined properties of the SUN N8075 itself, and found that this compound had very low solubility at pH around neutrality.
  • solubility of SUN N8075 was examined using compounds listed in Table 1 below which are conventionally used as a solubilizing agent.
  • an aqueous solution having approximately 0.4% of solubilizing agent was prepared for each solubilizing agent.
  • Mixture A 10 mli of SUN N8075 aqueous solution and 10 mL of solution of each solubilizing agent were mixed to give Mixture A, and Mixture A was filtered through a filter of 0.22 urn.
  • Mixture of each 2.5 mL of Mixture A and Mixture B was provided as a test solution (in each test solution, the concentration of SUN N8075 corresponds to 2 mg/mL, and the concentration of solubilizing agent corresponds to 0.1%).
  • test solution was shaken in a reciprocating shaker at 24 0 C for 30 minutes, filtered through a filter of 0.22 um, and the concentration of SUN N8075 in the filtrate was measured by HPLC method to determine its solubility.
  • Test example 2 Examination of solubilizing agent (Part 2)
  • An objective preparation of the present invention is a before- use-dissolving type lyophilized preparation which is to be dissolved in distilled water for injection, diluted as appropriate, and administered typically in the form of an injection preparation
  • a ⁇ -cyclodextrin derivative which may be used in the present invention has improved water solubility compared to ⁇ -cyclodextrin by introducing a substituent such as a sulfoalkyl group or hydroxyalkyl group into ⁇ -cyclodextrin, and hydroxypropyl ⁇ - cyclodextrin can be exemplified in addition to the aforementioned ⁇ - cyclodextrin sulfobutyl ether sodium salt.
  • Products having various average degrees of substitution are commercially available. Among others, those having degree of substitution by sulfobutyl group is about 7 are preferred, and Captisol (registered trademark) is exemplified as such a product.
  • a compound of the formula (I) represented by SUN N8075 or its pharmaceutically acceptable salt, which is an active ingredient is easy to be oxidized. Therefore, it is necessary to prevent a content of SUN N8075 in the lyophilized preparation from reducing due to oxidation, and further to prevent oxidation in various processes such as in the process of preparing the lyophilized preparation, in the process of lyophilizing SUN N8075 dissolved in an aqueous solution, or to prevent oxidization of SUN N8075 in a reconstituted solution.
  • hydrochloride of the compound of formula (I) was used instead of SUN N8075. Approximately 400 mg of the hydrochloride of compound of formula (I) were precisely weighed and water was added to make the volume precisely 200 mL, which was provided as an original drug aqueous solution.
  • sodium bisulfite, sodium pyrosulfite, L-cysteine hydrochloride monohydrate and ⁇ -thioglycerol provide desired anti-oxidation effect on the solution of SUN N8075.
  • sulfites such as sodium sulfite, potassium sulfite and calcium sulfite
  • bisulfites such as potassium bisulfite and ammonium bisulfite
  • pyrosulfites such as potassium pyrosulfite and the like may be used, and in addition to L-cysteine hydrochloride monohydrate, cysteine such as L-cysteine, DL-cysteine and hydrochlorides thereof may also be used.
  • sodium bisulfite is particularly preferably added as an antioxidant.
  • the added amount is 0.05 to 2 times, preferably 0.1 to 1.0 times (weight ratio) , that of SUN N8075 which is an active ingredient, and the concentration when reconstituted is desirably in a range of from 0.02 to 1.0% (w/v) , and preferably in a range of from 0.1 to 0.50% (w/v).
  • the preparation provided by the present invention is a lyophilized preparation comprising a compound represented by the formula (I) or its pharmaceutically acceptable salt, for example, SUN N8075, which is parenterally administered, for example, in the form of a before-use-dissolving type injection preparation.
  • the dose is not uniquely defined because it differs depending on various factors, including condition of the patient to be treated, degree of severity, age, presence/absence of complication and the like.
  • the lyophilized preparation provided by the present invention is preferably a preparation that is reconstituted in, for example, saline, and ensure the aforementioned dose.
  • a lyophilized preparation containing 50 mg of SUN N8075 as an active ingredient is reconstituted in 9 ⁇ iL of saline to prepare a before- use-prepared solution preparation containing 5 mg/mL of SUN N8075 having its pH value of 3 to 5.
  • a content of SUN N8075 in the lyophilized preparation provided by the present invention is not limited to the above, but a preparation that ensures objective dose may be provided as appropriate.
  • the lyophilized preparation provided by the present invention is produced by preparing a uniform solution stably containing SUN N8075 which is an active ingredient, and further containing an antioxidant and a solubilizing agent, and lyophilizing the solution.
  • a solution of distilled water or the like for injection for dissolving SUN N8075 is desirably used as a solution in which dissolved oxygen is removed as much as possible in order to prevent oxidation of the SUN N8075.
  • dissolved oxygen is removed by bubbling with inert gas (for example, nitrogen gas, argon gas and the like) .
  • inert gas for example, nitrogen gas, argon gas and the like
  • Test example 4 Examination of added ratio of Captisol relative to SUN N8075 [ Method]
  • Lyophilized preparations according to Formulations 1 to 3 in Table 4 below were prepared in the following manner.
  • each solution in which the original drug solution and each of the three additive solutions were mixed water was added to make the volume precisely 200 mL, which was provided as a formulation solution.
  • Each of the three kinds of formulation solutions was filtered through a filter of 0.22 ⁇ m (Commercial name: Stericup GV, available from Millipore) and dispensed by 10 mL into a 25 mL-volume vial (specification V-N25, available from FUJI GLASS CO., LTD.) and half plugged.
  • Each formulation solution thus dispensed was conveyed into a vacuum lyophilization dryer (Type FZ-6, available from Laboconco) and then lyophilized in the following conditions. [ 0048]
  • Each of these lyophilized preparations was reconstituted in 10 mL of saline, and appearance of the obtained solution was observed to evaluate generation of insoluble contaminants.
  • a preferred use amount of Captisol which is a solubilizing agent is 15 to 20 times by weight part, relative to the SUN N8075 which is an active ingredient.
  • Captisol which is preferred as a use amount of the solubilizing agent relative to the active ingredient, and additionally corresponds to 7.5 to 13.5% (w/v) of Captisol at the time of before-use dissolution.
  • a lyophilized preparation of the present invention which will not generate insoluble contaminates at the time of reconstitution while offering a before-use preparative solution is provided.
  • the solution after reconstitution may be diluted appropriately in saline and administered intravenously or by drip.
  • Test example 5 Examination of stability of diluted solution of reconstituted solution [ Method]
  • a lyophilized preparation according to Formulation 3 of Test example 4 was dissolved in 10 mL of saline. The solution was diluted in saline so that concentration of the main drug, SUN N8075 was 30 ⁇ g/mL, to give a blend solution.
  • the present preparation is usually stored for a long term in the form of lyophilized product until it is reconstituted before use, We examined long-term stability of the lyophilized product.
  • Test example 6 Examination of stability in long-term storage of lyophilized product [ Method]
  • a lyophilized preparation according to Formulation 3 of Test example 4 was stored at 25°C/60%RH, or 40°C/75%RH. Each of the preparation stored in each storage condition was sampled in time- series, and observation of appearance (under room diffused light) , measurement of content remaining rate/related substance mass by HPLC method and water content measurement were conducted for evaluating stability. [ 0060] [ Result]
  • a lyophilized preparation comprising a compound of the formula (I) represented by SUN N8075 or its pharmaceutically acceptable salt, provided by the present invention has a basic mode which contains:
  • the present invention is a lyophilized preparation which comprises, as an active ingredient, a compound of the formula (I) represented by SUN N8075 or its pharmaceutically acceptable salt, sodium bisulfite in an amount of 0.1 to 1.0 times (weight ratio) that of the active ingredient, and ⁇ -cyclodextrin sulfobutyl ether sodium salt in such an amount that satisfies 1:4 to 1:8 (molar ratio) by active ingredient: ⁇ -cyclodextrin derivative.
  • a compound of the formula (I) represented by SUN N8075 or its pharmaceutically acceptable salt sodium bisulfite in an amount of 0.1 to 1.0 times (weight ratio) that of the active ingredient
  • ⁇ -cyclodextrin sulfobutyl ether sodium salt in such an amount that satisfies 1:4 to 1:8 (molar ratio) by active ingredient: ⁇ -cyclodextrin derivative.
  • the lyophilized preparation provided by the present invention may contain a variety of excipients such as maltose, sucrose, mannitol, trehalose and lactose. A plurality of kinds of these excipients may be blended. [ 0066]
  • the lyophilized preparation provided by the present invention may be produced by a process of producing lyophilized preparation which is commonly used in pharmacy. Examinations made by the present inventors revealed that the lyophilized preparation may be desirably prepared in the following steps.
  • a method of producing a lyophilized preparation which comprises the steps of: (a) dissolving a compound of the formula (I) represented by SUN N8075 or its pharmaceutically acceptable salt in an injection solvent in which dissolved oxygen has been reduced by inert gas replacement, to prepare an original drug solution;
  • the vial filled with the resultant lyophilized preparation was plugged and windingly fastened, for example, with a butyl rubber plug (available from Daikyo Seiko Co., Ltd.) laminated with Teflon (registered trademark) and an aluminum cap (Flip cap 20; available from Hisa Kinzoku Kogyo Co., Ltd.) for provision as an actual product.
  • a butyl rubber plug available from Daikyo Seiko Co., Ltd.
  • Teflon registered trademark
  • an aluminum cap Flip cap 20; available from Hisa Kinzoku Kogyo Co., Ltd.
  • the lyophilized preparation of the present invention thus provided is dissolved in saline before use, diluted as necessary for appropriately adjusting the dose, and administered by injection or administered by drip, whereby it can be used in therapy of a target disease.
  • a stable lyophilized preparation containing a compound represented by the formula (I) and its pharmaceutically acceptable salt which has poor solubility around neutrality as an active ingredient.
  • the lyophilized preparation provided by the present invention stably contains a compound represented by the formula (I) and its pharmaceutically acceptable salt as an active ingredient, and since such compound and its pharmaceutically acceptable salt have excellent remedial and therapeutic ability against symptoms based on ischemic disorder and neurodegenerative disease, symptoms from spasm, epilepsy and migraine, as well as various symptoms caused by diabetes, arteriosclerosis and inflammatory disease, the lyophilized preparation is highly effective for therapy of these diseases, and thus provides great industrial applicability.

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