US20020009789A1 - Powder containing physiologically active peptide - Google Patents

Powder containing physiologically active peptide Download PDF

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Publication number
US20020009789A1
US20020009789A1 US09/810,483 US81048301A US2002009789A1 US 20020009789 A1 US20020009789 A1 US 20020009789A1 US 81048301 A US81048301 A US 81048301A US 2002009789 A1 US2002009789 A1 US 2002009789A1
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Prior art keywords
physiologically active
active peptide
weight
powder
nonionic
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Inventor
Yoshinobu Hanyu
Mariko Okada
Chihiro Shindo
Satoshi Nishimuro
Tetsuo Yokoyama
Masato Horie
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JCR Pharmaceuticals Co Ltd
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JCR Pharmaceuticals Co Ltd
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Assigned to JCR PHARMACEUTICAL CO., LTD. reassignment JCR PHARMACEUTICAL CO., LTD. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: OKADA, MARIKO, NISHIMURO, SATOSHI, HANYU, YOSHINOBU, HORIE, MASATO, SHINDO, CHIHIRO, YOKOYAMA, TETSUO
Priority to US09/994,773 priority Critical patent/US7235253B2/en
Publication of US20020009789A1 publication Critical patent/US20020009789A1/en
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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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the present invention relates to a physiologically active peptide-containing powder, and in particular to a physiologically active peptide-containing powder in which contamination by denatured peptides has been suppressed by stabilizing the physiologically active peptide and thereby preventing its denaturation from taking place in the process of forming a powder by drying an aqueous liquid containing the physiologically active peptide.
  • the present invention further relates to a physiologically active peptide-containing powder suitable for transpulmonary and transnasal administration by inhalation.
  • compositions for systemic administration of a drug are under investigation that are intended either for transpulmonary absorption of a pharmacologically active ingredient by inhalation (referred to as an “inhalant composition” in the present specification) or for absorption of such an ingredient through the nasal mucous membrane by intranasal application, i.e. compositions for transnasal administration, as compositions utilizing other, new administration routes than those relied on by conventional pharmaceutical compositions such as injections, oral preparations, suppositories and the like.
  • Inhalant compositions and compositions for transnasal administration are not directly injected into the body, but they are applied onto the surface of mucous membranes which are exposed to the air such as membranes of the respiratory tract.
  • stabilization of a given active peptide in a production process should be achieved by means of approved pharmaceutical additives which are highly safe and have been used for years. This is because such an additive would allow to expect higher safety with regard to the final pharmaceutical product obtained. It is also required that the absorption and transferal to the blood of an physiologically active peptide is attained in sufficient efficiency.
  • the present invention has as its objectives to provide a method to improve stability of a physiologically active peptide in a process of producing a powder by drying an aqueous liquid containing the physiologically active peptide, as well as to provide a physiologically active peptide-containing powder produced by the method.
  • the present invention has as its further objectives to provide a physiologically active peptide-containing powder especially suited for absorption of the physiologically active peptide by inhalation, and to provide an inhalant composition.
  • the present inventors found that, in a process of preparing a powder containing a physiologically active peptide by drying an aqueous liquid containing the peptide, addition of certain compounds to the aqueous liquid remarkably increases the stability of the physiologically active peptides during the powder preparation.
  • the present inventors also found that physiologically active peptides contained in the powder thus prepared are efficiently absorbed into the blood when the powder is transpulmonarily administered. The present invention was made on the basis of these findings.
  • the present invention provides a method for stabilization of a physiologically active peptide in a process of preparing a powder containing the physiologically active peptide by drying an aqueous liquid containing the physiologically active peptide, wherein the method comprises adding to the aqueous liquid at least one compound selected from the group consisting of a nonionic surfactant, a water-soluble, nonionic, organic binder, hydrogenated lecithin, and mannitol.
  • a nonionic surfactant a water-soluble, nonionic, organic binder, hydrogenated lecithin and mannitol serve as stabilizers in preparing a powder containing a physiologically active peptide from an aqueous liquid containing it.
  • these compounds employed suppress denaturation such as dimer formation in the process of forming a powder from an aqueous liquid containing the peptide, thereby enabling to prepare a physiologically active peptide-containing powder which is substantially free of denatured peptides.
  • the present invention further provides a method for stabilization of a physiologically active peptide in a process of preparing a powder containing the physiologically active peptide by drying an aqueous liquid containing the physiologically active peptide, wherein the method comprises adding to the aqueous liquid mannitol and at least one compound selected from the group consisting of a nonionic surfactant, a water-soluble, nonionic, organic binder, and hydrogenated lecithin.
  • This method enables, in addition to the above-mentioned benefit, to prepare a powder effecting especially efficient transpulmonary absorption of a physiologically active peptide.
  • the concentration range where they exhibit a potent stabilizing effect is 0.01-0.5 % by weight for a nonionic surfactant and 0.01-1 % by weight for a water-soluble, nonionic, organic binder.
  • mannitol it exhibits a potent stabilizing effect when added in an amount of 1-50 parts by weight per one part by weight of a physiologically active peptide.
  • the nonionic surfactant is selected from the group consisting of polysorbate, polyoxyethylenehydrogenated castor oil, and a poloxamer (polyoxyethylene polyoxypropylene block copolymer: Pluronic).
  • the water-soluble, nonionic, organic binder is more preferably selected from the group consisting of polyvinylpyrrolidone, a water-soluble, nonionic, cellulose derivative and polyvinylalcohol.
  • the water-soluble, nonionic, cellulose derivative is more preferably selected from the group consisting of hydroxypropylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose.
  • a still more preferable concentration range for a nonionic surfactant is 0.05-0.3 % by weight, where a particularly potent stabilization effect is obtained.
  • a concentration range still more preferable than the above is 0.02-0.5 % by weight, where a particularly potent stabilization effect is obtained.
  • hydrogenated lecithin its stabilizing effect is particularly remarkable even at a concentration as low as 0.01% by weight. While its effect peaks at concentrations of 0.5-1 % by weight, the effect remains still remarkable outside this range, and even at 2% by weight.
  • the decline in its stabilizing effect is only limited even when its concentration goes up beyond the peak concentration.
  • An upper limit concentration therefore, is not clear over which hydrogenated lecithin would substantially lose its stabilizing effect.
  • concentration may be chosen as desired considering ease of handling in production of the pharmaceutical composition as there is no reason for using an unnecessarily large amount of hydrogenated lecithin insofar as it exhibits a sufficient effect as an additive.
  • the concentration of hydrogenated lecithin is preferably in the range of about 0.005-4% by weight, and more preferably in the range of 0.01-2% by weight.
  • the weight proportion of a physiologically active peptide to mannitol is more preferably 1:1 to 1:40, further more preferably 1:1 to 1:30, still more preferably 1:1 to 1:20, and most preferably 1:1 to 1:10.
  • any of the above stabilizers may be used alone, or two or more of them may be used in combination. When used in combination, they exhibit a still more remarkable stabilizing effect than when one of them is used alone, thus allowing to almost completely prevent the formation of denatured peptide such as a dimer.
  • the present invention is characterized in that its uses, in drying an aqueous liquid containing a physiologically active peptide, a certain group of compounds that were found to stabilize active peptides.
  • the compounds can be used in a wide variety of specific methods for drying.
  • example of methods for drying aqueous liquids include, but are not limited to, spray drying, lyophilization and spray-freeze drying, and, furthermore, a variety of methods which include a process of drying a solution by spraying it, such as drying performed in fluid-bed granulation, in a variety of coating method such as fluid-bed coating which allow to coat the surface of core particles, as well as drying performed in a granulation process in fluid-bed granulation involving coating of, or attachment of materials to, the surface of core particles.
  • Inhaled particles are more easily carried on the air flow deep into the respiratory system when their average size is 1-10 ⁇ m, and more preferably 2-5 ⁇ m.
  • the particles of the physiologically active peptide-containing powder obtained in a stable form by one of the above methods are easily carried deep into the respiratory system by inhalation, allowing efficient and relatively long-lasting transferal of the physiologically active peptide into the circulating blood.
  • the present invention further provides one of the above method in which the average size of the particles making up the powder is 1-10 ⁇ m, and more preferably 2-5 ⁇ m.
  • Examples of active peptides stabilized according to the present invention include calcitonins, insulins, growth hormones, erythropoietin, glucagon, somatostatin, somatostatin derivatives, interferons ( ⁇ , ⁇ or ⁇ ), interleukins (I, II, III, IV, V VI or VII), superoxide dismutase, urokinase, proteases, tumor necrosis factors, colony-stimulating factors, kallikrein, lysozyme, fibronectin, as well as a variety of factors regulating growth or differentiation of cells such as insulin-like growth factors, epidermal growth factor, fibroblast growth factors, platelet-derived growth factor, nerve growth factor, hepatocyte growth factor, vasculogenesis factors, and anti-vasculogenesis factors.
  • active peptides share a common chemical structure that they consist of two or more amino acids linked by peptide bonds
  • the present invention is also applicable to a wide variety of other active peptides than those enumerated above. Moreover, it does not matter whether those peptides have been obtained by extraction from natural sauces or produced by application of genetic recombination technology, for such difference will not influence the basic physicochemical characters of the peptides.
  • human growth hormone and human insulin are particularly preferred peptides in the present invention, for they are such peptides that patients have had to continue administering themselves by subcutaneous injection for a long period of time
  • the present invention provides a method for preparation of a powder containing a physiologically active peptide.
  • the method for preparation comprises forming a powder by drying an aqueous liquid containing a physiologically active peptide and a nonionic surfactant, a water-soluble, nonionic, organic binder, hydrogenated lecithin, and/or mannitol.
  • a physiologically active peptide-containing powder is prepared which is substantially free of denatured peptides.
  • the present invention further provides a method for preparation of a powder containing a physiologically active peptide, wherein the method comprises forming a powder by drying an aqueous liquid containing the physiologically active peptide, mannitol, and at least one compound selected from the group consisting of a nonionic surfactant, a water-soluble, nonionic, organic binder, and hydrogenated lecithin.
  • This method for preparation in addition to the above-mentioned benefit, provides a powder that effects especially efficient transpulmonary absorption of a physiologically active peptide.
  • the nonionic surfactant is more preferably selected from the group consisting of polysorbate, polyoxyethylenehydrogenated castor oil, and a poloxamer (polyoxyethylene polyoxypropylene block copolymer: Pluronic).
  • the water-soluble, nonionic, organic binder is more preferably selected from the group consisting of polyvinylpyrrolidone, a water-soluble, nonionic, cellulose derivative and polyvinylalcohol.
  • the water-soluble, nonionic, cellulose derivative is more preferably selected from the group consisting of hydroxypropylcellulose, hydroxyethylcellulose, and hydroxypropylmethyl-cellulose.
  • preferable ranges of the amount of the enumerated stabilizers when employed are the same as those mentioned for them in the method for stabilization of physiologically active peptides above. Therefore, a still more preferable concentration range for a nonionic surfactant is 0.05-0.3% by weight, and, for a water-soluble, nonionic, organic binder, a still more preferable concentration range is 0.02-0.5% by weight.
  • a nonionic surfactant is 0.05-0.3% by weight
  • a still more preferable concentration range is 0.02-0.5% by weight.
  • hydrogenated lecithin an upper limit concentration is not clear over which hydrogenated lecithin would substantially lose its stabilizing effect.
  • the concentration of hydrogenated lecithin is preferably in the range of about 0.005-4% by weight, and more preferably in the range of 0.01-2% by weight.
  • the weight proportion of a physiologically active peptide to mannitol is more preferably 1:1 to 1:40, further more preferably 1:1 to 1:30, still more preferably 1:1 to 1:20, and most preferably 1:1 to 1:10.
  • example of methods for drying aqueous liquids include, but are not limited to, spray drying, lyophilization and spray-freeze drying, and fluid-bed granulation, as well as a variety of coating method, such as fluid-bed coating, which allow to coat the surface of core particles, and fluid-bed granulation involving coating of, or attachment of materials to, the surface of core particles.
  • the average size of the particles making up the powder is preferably 1-10 ⁇ m, and more preferably 2-5 ⁇ m, when considering transpulmonary administration of a physiologically active peptide.
  • the present invention further provides a powder containing a physiologically active peptide, wherein the powder is made up of particles comprising a physiologically active peptide and mannitol at a weight proportion of 1:1 to 1:50.
  • the particles making up the powder further comprise, per one part by weight of the physiologically active peptide, at least one component selected from the group consisting of a nonionic surfactant in an amount of 0.05-3 parts by weight, a water-soluble, nonionic, organic binder in an amount of 0.05-6 parts by weight, and hydrogenated lecithin.
  • a nonionic surfactant in an amount of 0.05-3 parts by weight
  • a water-soluble, nonionic, organic binder in an amount of 0.05-6 parts by weight
  • hydrogenated lecithin Such a powder effects an efficient absorption of a physiologically active peptide through a mucous membrane deep in the respiratory system.
  • the weight proportion of a physiologically active peptide to mannitol in the particles above is more preferably 1:1 to 1:40, further more preferably 1:1 to 1:30, still more preferably 1:1 to 1:20, and most preferably 1:1 to 1:10.
  • the amount of a nonionic surfactant is more preferably 0.25-1.8 parts by weight per one part by weight of a physiologically active peptide, in which range efficient absorption of a physiologically active peptide is attained while suppressing the amount of a nonionic surfactant employed.
  • the amount of water-soluble, nonionic, organic binder is more preferably 0.1-3 parts by weight per one part by weight of a physiologically active peptide.
  • the average size of the particles making up the powder is preferably 1-10 ⁇ m, and more preferably 2-5 ⁇ m.
  • Method for preparation of the above powder containing a physiologically active peptide is not limited.
  • the powder may be prepared, for example, by spray drying, spray-freeze drying or lyophilization.
  • the present invention further provides an inhalant composition containing a physiologically active peptide, wherein the inhalant composition comprises above-mentioned particles containing a physiologically active peptide.
  • the inhalant composition may simply be such particles containing a physiologically active peptide, or they may be either clusters consisting of such particles loosely associated with one another or composites consisting of such particles plus larger, inert carrier particles (e.g. lactose) onto the surface of which the former particles are loosely attached.
  • Such loose clusters or composites are constructed in an extent of looseness that, at the time of inhaling the composition, they will be disintegrated upon release from an inhalation device by the flow of air and the each fine particle containing a physiologically active peptide will thereby be liberated from the clusters or carriers into a separate particle
  • Preparation of such loose clusters or loose and coarse composite particles can be prepared by any of a variety of methods well known to those skilled in the art for bringing particles of the size of one to several ⁇ m making up a powder into a loose association with one another or into a loose association onto larger, inert carrier particles.
  • Such loose clusters or loose and coarse composite particles are intended to increase flowability of the composition for improved ease of filling and accuracy of filling amount in a process in which a unit dose of the inhalant compositions is filled into each of predetermined containers like capsules employed in a inhalation device. Therefore, once put in a capsule, it is allowed that the whole or part of particles are liberated to separate particles by external agitation and thus forming a powder within the capsule.
  • FIG. 1 is a graph illustrating the effect of nonionic surfactants.
  • FIG. 2 is a graph illustrating the effect of water-soluble, nonionic, organic binders.
  • FIG. 3 is a graph illustrating the effect of hydrogenated lecithin.
  • FIG. 4 shows blood concentration profiles of human growth hormone in rat after transpulmonary administration of a human growth hormone-containing powder and subcutaneous injection of the same amount of the powder.
  • an “aqueous liquid containing a physiologically active peptide” includes not only a simple aqueous solution of a physiologically active peptide but also a solution of a physiologically active peptide further containing one or more other components that do not adversely affect the stability of the physiologically active peptide, e.g., buffering agents such as phosphates, pharmaceutically acceptable salts such as sodium chloride, and diluents such as sorbitol.
  • buffering agents such as phosphates, pharmaceutically acceptable salts such as sodium chloride, and diluents such as sorbitol.
  • the method for stabilization of the present invention stabilizes a physiologically active peptide dissolved in an aqueous liquid in a process of evaporating water from the aqueous liquid, its stabilization effect on a physiologically active peptide is not affected even by drying the physiologically active peptide coated on the surface of larger particles chemically inert to the active peptide, such as lactose and the like.
  • Such inert particles serve as cores which carry on their surface a coat of the physiologically active peptide mixed with one or more stabilizing agents
  • the powder of the present invention containing a physiologically active peptide is based on the discovery that a very efficient transpulmonary absorption is attained by employing particles comprising a physiologically active peptide and mannitol.
  • any method of preparation may be chosen as desired for preparing such powder containing a physiologically active peptide.
  • the method of the present invention for preparation of a powder containing a physiologically active peptide is based also on the discovery that mannitol has an effect of remarkably stabilizing a physiologically active peptide in the process of forming a powder by drying an aqueous liquid containing the peptide.
  • drying of an aqueous solution containing a physiologically active peptide and mannitol may be performed by any conventional method as desired.
  • an example of particularly preferred physiologically active peptides is human growth hormone.
  • the term “human growth hormone” means not only 22K hGH extractable from the pituitary of a human, which consists 191 amino acids and has a molecular weight of 22,125, but also 20K hGH, which lacks 15 amino acids corresponding amino acids 32 - 46 . 20K hGH has a growth stimulating effect comparable to 22 K hGH.
  • the term “human growth hormone” means not only these natural types of human growth hormones, but also proteins which are produced by application of genetic recombination technology and having a substantially comparable effect to the natural human growth hormones.
  • human growth hormone produced by application of genetic recombination technology examples include a N-terminal methionine-type hormone consisting 192 amino acids and variants which have part of their amino acids deleted, substituted, added or inserted and having a comparable activity to the natural types of human growth hormone.
  • GH growth hormone
  • active peptides the molecule of growth hormone (GH)
  • gas-liquid interface As the gas-liquid interface is expanded in a drying process such as spray drying, it is necessary, particularly in the case of GH, to manage to minimize its denaturation induced by this expansion of the interface in the process of forming GH into a powder.
  • human growth hormone was chosen as a representative of active peptides.
  • the human growth hormone employed in the Examples and Control Examples below was a recombinant human growth hormone (in which N-terminal methionine had been selectively deleted enzymaticaly) which had the same amino acid sequence as the natural human growth hormone consisting of 191 amino acids (22K hGH).
  • the recombinant human growth hormone is identified as “Growject Injection 4 IU”, it indicates that a pharmaceutical product (Growject Injection 4 IU: JCR pharmaceuticals, Co., Ltd.) was employed there.
  • the composition of Growject Injection 4 IU is as follows. Where the recombinant human growth hormone is specifically noted as a “bulk material”, it indicates the pure recombinant human growth hormone (produced by BTG), which is free of any additives.
  • r-hGH Injection (Growject Injection 4 IU): (Formula) (Formula) r-hGH 4 IU (1.7 mg) Disodium hydrogenphosphate 2.2 mg Sodium dihydrogenphosphate 0.35 mg Sodium chloride 1.0 mg D-mannitol 20.0 mg
  • Tests will be described below which were performed by spray drying as a representative model of drying processes of an aqueous liquid containing a physiologically active peptide.
  • the apparatus employed for spray drying was Spray Dryer SD-1000 (EYELA).
  • recovery rate of the physiologically active peptide monomer was employed, for it is considered to be the best indicator of stabilization of the physiologically active peptide. Calculation of recovery rate was done according to the following equation, based on the concentration of the physiologically active peptide in the aqueous liquid before drying (before spray drying) and the content of recovered active peptide in the solution prepared by reconstituting the obtained powder (spray dried product) to the initial volume
  • a P area of monomer peak on HPLC for spray dried product
  • a I area of monomer peak on HPLC before spray drying.
  • Inlet temperature 80° C.
  • Atomizing pressure 150 kPa
  • Liquid feeder pump flow 2.6 mL/min
  • Mobile phase 50 mM sodium dihydrogenphosphate, 50 mM disodium hydrogenphosphate, 0.2 M sodium chloride.
  • Inlet temperature 90° C.
  • Atomizing pressure 100 kPa
  • Fluid feeder pump flow 2.6 mL/min
  • aqueous solutions containing Tween 20 at different concentrations were prepared. Fifteen vials of the r-hGH injection (Growject Injection 4IU) were provided for each of the aqueous solutions containing Tween 20 at the different concentrations. The aqueous solutions containing Tween 20 at different concentrations were added to corresponding 15 vials, 1.0 mL each, and the injection was completely dissolved.
  • r-hGH solutions containing Tween 20 at different concentrations (15.0 mL: 15 vials for each Tween 20 concentration) were spray-dried to obtain dry powders.
  • the conditions for spray drying and HPLC were the same as those in Control Example 1.
  • aqueous solutions containing HCO-60 polyoxyethylenehydrogenated castor oil
  • concentration: 0.01, 0.05, 0.1, 0.5, 1.0 and 2.0 w/w %) were prepared.
  • Fifteen vials of the r-hGH injection (Growject Injection 4IU) were provided for each of the aqueous solutions containing HCO-60 at different concentrations.
  • the aqueous solutions containing HCO-60 at different concentrations were added to corresponding 15 vials, 1.0 mL each, and the injection was completely dissolved.
  • r-hGH solutions containing HCO-60 at different concentrations (15.0 mL: 15 vials for each HCO-60 concentration) were spray-dried to obtain dry powders.
  • the conditions for spray drying and HPLC were the same as those in Control Example 1.
  • aqueous solutions containing Pluronic F68 polyoxyethylene(160)polyoxypropylene(30) glycol
  • concentration: 0.01, 0.05, 0.1, 0.5, 1.0 and 2.0 w/w %) were prepared.
  • Fifteen vials of the r-hGH injection (Growject Injection 4IU) were provided for each of the aqueous solutions containing Pluronic F68 at different concentrations.
  • the aqueous solutions containing Pluronic F68 at different concentrations were added to corresponding 15 vials, 1.0 mL each, and the injection was completely dissolved.
  • aqueous solutions containing Kollidone 17PF (polyvinylpyrrolidone: BASF) at different concentrations (concentration: 0.01, 0.05, 0.1, 0.5, 1.0 and 2.0 w/w %) were prepared. Fifteen vials of the r-hGH injection (Growject Injection 4IU) were provided for each of the aqueous solutions containing Kollidone 17PF at different concentrations. The aqueous solutions containing Kollidone 17PF at different concentrations were added to corresponding 15 vials, 1.0 mL each, and the injection was completely dissolved.
  • Kollidone 17PF polyvinylpyrrolidone: BASF
  • r-hGH solutions containing Kollidone 17PF at different concentrations (15.0 mL: 15 vials for each Kollidone 17PF concentration) were spray dried to obtain dry powders.
  • the conditions for spray drying and HPLC were the same as those in Control Example 1.
  • aqueous solutions containing Kollidone 12PF (polyvinylpyrrolidone: BASF) at different concentrations (concentration: 0.01, 0.05, 0.1, 0.5, 1.0 and 2.0 w/w %) were prepared. Fifteen vials of the r-hGH injection (Growject Injection 4IU) were provided for each of the aqueous solutions containing Kollidone 12PF at different concentrations. The aqueous solutions containing Kollidone 12PF at different concentrations were added to corresponding 15 vials, 1.0 mL each, and the injection was completely dissolved.
  • Kollidone 12PF polyvinylpyrrolidone: BASF
  • r-hGH solutions containing Kollidone 12PF at different concentrations (15.0 mL: 15 vials for each Kollidone 12PF concentration) were spray-dried to obtain dry powders.
  • the conditions for spray drying and HPLC were the same as those in Control Example 1.
  • aqueous solutions containing HPC-SSL hydroxypropylcellulose: TOSOH
  • concentration: 0.01, 0.05, 0.1, 0.5 and 1.0 w/w %) were prepared.
  • Fifteen vials of the r-hGH injection (Growject Injection 4IU) were provided for each of the aqueous solutions containing HPC-SSL at different concentrations.
  • the aqueous solutions containing HPC-SSL at different concentrations were added to corresponding 15 vials, 1.0 mL each, and the injection was completely dissolved.
  • aqueous solutions containing Lecinol S-10E hydrogenated lecithin: NIKKO CHEMICALS
  • concentration: 0.01, 0.05, 0.1, 0.5, 1.0 and 2.0 w/w %) were prepared.
  • Fifteen vials of the r-hGH injection (Growject Injection 4IU) were provided for each of the aqueous solutions containing hydrogenated lecithin at different concentrations.
  • the aqueous solutions containing hydrogenated lecithin at different concentrations were added to corresponding 15 vials, 1.0 mL each, and the injection was completely dissolved.
  • r-hGH solutions containing hydrogenated lecithin at different concentrations (15.0 mL: 15 vials for each hydrogenated lecithin concentration) were spray-dried to obtain dry powders.
  • the conditions for spray drying and HPLC were the same as those in Control Example 1.
  • Aqueous solutions were prepared which contained HPC-SSL (hydroxypropylcellulose) and a nonionic surfactant in combination as indicated in the following table.
  • HPC-SSL hydroxypropylcellulose
  • a nonionic surfactant in combination as indicated in the following table.
  • FIG. 1 shows the results of HPLC analysis performed in Control Example 1 and Examples 1-3.
  • FIG. 2 shows the results of HPLC analysis performed in Control Example 1 and Examples 4-6.
  • the water-soluble, nonionic, organic binders markedly increased the recovery rate of the monomer of physiologically active peptide r-hGH in the process of powder preparation from its aqueous solutions.
  • Example 4 Kerdone 17PF
  • 5 Kerdone 12PF
  • Their stabilizing effect was particularly potent up to a concentration of 1 w/w % and peaked at a concentration of 0.1 w/w %.
  • Example 6 hydroxypropylcellulose
  • stabilizing effect was still more remarkable than where the other binders were employed, showing a r-hGH recovery rate of about 95% at a concentration of 0.1 w/w %, where its effect peaked.
  • Example 6 hydroxypropylcellulose was tested only up to the concentration of 1 w/w %. However, it is largely evident that hydroxypropylcellulose would show a stabilizing effect even at 2 w/w %. This is because its effect at 1 w/w % was much higher than the effects of the other organic binders employed in Example 4 and 5 at the same concentration, and the decline in its effect by increasing its concentration beyond the peak is substantially not greater than the decline seen in the graphs for Examples 4 or 5.
  • FIG. 3 shows the results of HPLC analysis performed in Control Example 1 and Example 7.
  • Example 8 A 0.05 HCO-60 0.05 99.20 ⁇ 1.16
  • Example 8 B 0.05 Pluronic F68 0.05 98.42 ⁇ 0.61
  • Example 8 C 0.05 Pluronic F68 0.10 97.96 ⁇ 1.34
  • Example 8 D 0.10 HCO-60 0.05 104.76 ⁇ 0.68
  • Example 8 E 0.10 HCO-60 0.10 104.81 ⁇ 0.17
  • GH a recombinant human growth hormone (r-hGH) bulk material was used.
  • r-hGH human growth hormone
  • stabilizers D-mannitol, HPC-SSL and Pluronic F68 were used.
  • r-hGH and additives were weighed and dissolved in 15.0 mL of purified water to prepare spray solutions.
  • r-hGH alone was dissolved in 15.0 mL of purified water to prepare a spray solution (Control Formula).
  • “% by weight” in parentheses indicates the ratio of the weight of respective solid component to the weight of the solid components as a whole.
  • EYELA SD- 1000 Spray Dryer were used as a spray dryer. Dry powders were prepared by spray-drying the above r-hGH solutions. The conditions for spray drying was as follows.
  • Inlet temperature 90° C.
  • Atomizing pressure 100 kPa
  • Fluid feeder pump flow 2.6 mL/min
  • Sample amount about 0.02 g/0.5 mL purified water
  • Mobile phase 0.1 M sodium dihydrogenphosphate, 0.1 M disodium hydrogenphosphate, 0.2 M sodium chloride.
  • Sample amount about 0.02 g/0.5 mL purified water
  • Solutions of about 0.04 mg/mL was prepared as samples. To each 10 ⁇ L of the solutions was added 10 ⁇ L of water and 20 ⁇ L of the sample buffer. As a standard sample, a solution of about 1.6 mg r-hGH bulk material/mL was prepared, to 10 ⁇ L of which was added 10 ⁇ L of water and 20 ⁇ L of the sample buffer.
  • An electrophoresis buffer for SDS-PAGE was prepared by adding 900 mL of water to 100 mL of the electrophoresis buffer for 10 ⁇ SDS-PAGE.
  • (C) A 0.25 M Tris-HCl buffer (pH 6.8) was prepared by adding water to 30.25 g of Tris to make into volume of 800 mL, then adjusting the pH of the solution to 6.8 with 6 N hydrochloric acid, and making into volume of 1000 mL with water (preserved by freezing).
  • a sample buffer for SDS-PAGE was prepared by adding water to 25 mL of 0.25 M Tris-HCl buffer (pH 6.8), 2 g of SDS, 5 g of sucrose and 2 mg of bromphenol blue (BPB) to make 50 mL.
  • r-hGH, HPC-SSL and D-mannitol were weighed and dissolved in 90 mL of purified water to obtain a spray solution.
  • “% by weight” in parentheses indicates the ratio of the weight of respective solid component to the weight of the solid components as a whole.
  • the concentration of r-hGH, HPC-SSL and D-mannitol is 0.27% by weight, 0.14% by weight and 2.92% by weight, respectively.
  • Spray drying and analyses were performed under the same conditions as in Example 9.
  • the areas of the main peak (%) and the peak (%) for deamidation products were as follows. TABLE 4 Area of Monomer Area of Deamidation Products Peak (%) Peak (%) Spray-dried 95.5 4.5 Product Standard 96.6 3.4
  • the GH powder was administered to rats for pharmacokinetic evaluation.
  • the same amount of the GH powder as transpulmonarily administered was dissolved in water and subcutaneously administered to rats to compare its pharmacokinetics with that of transpulmonarily administered GH.
  • the rats of the transpulmonary administration group were anesthetized with urethane.
  • Two mg/kg rat body weight of the r-hGH powder was placed in a transpulmonary administration device for rats (PennCentury).
  • the powder was discharged into the lungs of the rats through the device's delivery tube inserted in the trachea by thrusting out 3 mL of air from a syringe connected to the device.
  • the rats of the subcutaneous administration group were also fasted for a full day and night and then subcutaneously injected with the r-hGH powder suspended in purified water in an amount equivalent to 2 mg/kg rat body weight.
  • Blood sampling was performed just before the administration of r-hGH and then 0, 15, 30, 60, 120, 240, 480 and 1440 minutes thereafter. Blood was sampled from the cervical vein of restrained rats. Blood sampling volume was 300 ⁇ L at one time. Following each blood sampling, the same amount (300 ⁇ L) of physiological saline was injected into the cervical vein. Blood samples were let stand for one hour at room temperature and then overnight at 4° C., and centrifuged (15,000 rpm, 10 minutes, 4° C.) to separate the sera.
  • An anti-hGH rabbit polyclonal antibody raised by a conventional method was diluted and adjusted to the absorbance OD280 of 0.02 with a 0.05 M Tris buffer. The solution was placed, 100 ⁇ L each, in the wells of 96-well plates and incubated for two hours at 37° C. The plates were washed five times with a 0.01 M phosphate buffer (washing buffer). The wells of the plates were filled with a block solution (Block Ace: Dainippon Pharmaceutical Co., Ltd.) and let stand overnight at 4° C.
  • HRP horseradish peroxidase
  • Table 5 and FIG. 4 show r-hGH concentrations in the blood after transpulmonary administration of the r-hGH powder or subcutaneous injection of the r-hGH suspension. TABLE 5 Time after Blood r-hGH Concentration (ng/ml) Administration Transpulmonary Subcutaneous (min) Administration Injection 0 22.6 41.5 15 584.4 423.1 30 451.4 446.1 60 315.1 491.8 120 254.9 423.9 240 101.6 347.9 480 61.5 175.5 1440 34.7 51.3
  • the blood concentration of r-hGH following transpulmonary administration was lower than that following its subcutaneous injection, except for a period immediately after pulmonary administration.
  • the above results show that r-hGH absorption after transpulmonary administration of the composition was very high.
  • the blood r-hGH concentration after the transpulmonary administration of the very composition was far higher than either of the blood r-hGH concentration after the transpulmonary administration or subcutaneous administration of the same amount of r-hGH suspension carried out in Control Example 3 below.
  • r-hGH and lactose were weighed and dissolved in 120 mL of purified water to obtain a spray solution.
  • concentration of r-hGH and lactose in the spray solution is 0.20 w/w % and 2.30 w/w %, respectively.
  • Lactose (monohydrate) 2.760 g (92.0% by weight)
  • Inlet temperature 120° C.
  • Fluid feeder pump flow 2.6 mL/min
  • r-hGH was transpulmonarily administered or subcutaneously injected to male 9-week-old Wistar rats, six animals per group, following the same dose and procedures as indicated in “Pharmacokinetic Evaluation of GH Powder after Transpulmonary Administration to Rats”, and the pharmacokinetics for r-hGH was determined. The results are shown in the table below. TABLE 7 Time after Blood r-hGH Concentration (ng/ml) Administration Transpulmonary Subcutaneous (min) Administration Injection 0 5 6 15 147 46 30 129 52 60 85 62 120 70 75 240 58 71 480 48 21 1440 37 5
  • Natural human growth hormone, 22K hGH, is composed of 191 amino acids, with two S-S bonds within the molecule, whereas human insulin is composed of 51 amino acids and has two S-S bonds within the molecule. It is reasonably expected that transpulmonary absorption demonstrated above with the powders containing human growth hormone will occur also with human insulin, considering that the far smaller molecule of human insulin compared with human growth hormone will render the former more suitable for absorption through mucous membranes and that it shares a structural similarity with human growth hormone in light that they have two S-S bonds within their molecule. Likewise, successful transpulmonary absorption is expected to take place also with calcitonin (32 amino acids) and somatostatin (28 amino acids), which are roughly of half the size of human insulin, by forming them into the powder of the present invention.
  • the present invention enables to remarkably stabilize a physiologically active peptide in forming a powder by drying an aqueous solution containing the physiologically active peptide, thereby minimizing loss of the peptide in the process of powder formation.
  • the present invention also enables to produce a powder stably retaining a physiologically active peptide, without evoking unnecessary concerns on the safety of such a product due to employed additives.
  • the present invention alto enables to provide physiologically active peptide-containing powder in which content of dimers or other denatured peptide is minimized, thereby making it easy to produce such types of pharmaceutical compositions that are adapted to be applied to mucous membranes in a powder form in order to introduce a drug into the circulating blood, e.g. pharmaceutical compositions for transnasal or transpulmonary administration.
  • the present invention further enables to provide inhalant compositions which allow efficient transferal of growth hormone or insulin into the blood by transpulmonary administration.

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EP1136068A2 (fr) 2001-09-26
EP1136068A3 (fr) 2003-04-02
US20020058624A1 (en) 2002-05-16
US7235253B2 (en) 2007-06-26

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