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CN1440298A - Medical aerosol formulation - Google Patents

Medical aerosol formulation Download PDF

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Publication number
CN1440298A
CN1440298A CN01807195A CN01807195A CN1440298A CN 1440298 A CN1440298 A CN 1440298A CN 01807195 A CN01807195 A CN 01807195A CN 01807195 A CN01807195 A CN 01807195A CN 1440298 A CN1440298 A CN 1440298A
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China
Prior art keywords
preparation
medicine
mixture
aerosol
insulin
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CN01807195A
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Chinese (zh)
Inventor
A·L·阿德杰
Y·朱
J·Z·孙
S·斯特发诺斯
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Aeropharm Technology LLC
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Aeropharm Technology LLC
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Priority claimed from US09/702,195 external-priority patent/US6585957B1/en
Application filed by Aeropharm Technology LLC filed Critical Aeropharm Technology LLC
Publication of CN1440298A publication Critical patent/CN1440298A/en
Pending 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Otolaryngology (AREA)
  • Pulmonology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

A medicinal formulation is disclosed. The formulation comprises: a therapeutic amount of a protein or peptide medicament, a fluid for containing said medicament having a molecular size ranging from 1 K Dalton to about 150 K Daltons, a fluid carrier for containing the medicament, and a stabilizer selected from an amino acid, a derivative thereof or a mixture of the foregoing.

Description

Medicinal aerosol
The application requires the 60/177th, No. 987 U.S. Provisional Application No. in submission on January 25th, 2000, and this application is incorporated herein with for referencial use.
Background of invention
Invention field
The present invention relates to medicinal aerosol, relate more specifically to comprise protective colloid-stabilised dose medicinal aerosol.
Description of related art
Delivering drugs in the lung by suction is the important means of treatment various disease conditions, such disease comprises that for example Cystic fibrosis, pneumonia, bronchial asthma and chronic obstruction pneumonopathy and some systemic disorders comprise pain control, immunodeficiency, hormone therapy, erythropoiesis, diabetes etc. to common local disease.Steroid, β2Ji Dongji, anticholinergic, albumen and polypeptide are the medicines that is administered to for such purpose in the lung.Such medicine is administered in the lung to have the particulate aerosol form that can breathe particle diameter (diameter is less than about 10 μ m) usually.In order to ensure the suitable particle diameter in the aerosol, can prepare to have and to suck size particles, then it is incorporated in the aqueous colloidal dispersion that contains propellant (for example using the metered dose inhaler (MDI) of pressurization) or air (for example using Diskus (DPI)).Perhaps, can prepare the preparation of solution or emulsion form to avoid worrying the problem of suitable particle diameter aspect in the preparation.Yet pharmaceutical solutions must have the granule that can suck size or the mode of droplet is provided and delivered with generation.
For the MDI preparation,, be about to aerosol and be filled in the aerosol container that is equipped with metered dose valve in case make.The patient with hand channel by with provide the driver that dosage adapts to and dosage provided and delivered to the patient from valve.
Aerosol is stable very important, and the dosage delivered of emitting from the dosing valve is reproducible like this.In suspension formulation, quick creaming, precipitation or the flocculation after the stirring is the common cause that dosage can not reproduce.Only contain medicine and propellant for example 1,1,1 when using, during the binary aerosol of 2-tetrafluoroethane or when such preparation also contains low quantity of surfactant, to understand especially true.The valve adhesion can cause that also dosage can not reproduce.In order to overcome these problems, the MDI aerosol often contains surfactant, and surfactant plays suspension aids so that effect suspension stabilization is enough to reproduce time of administration.Some surfactants also the work of super fatting agent in order to lubricated valve, thereby guarantee slick operation.Known and disclose a variety of materials that in aerosol, are used as dispersing aid.Yet certain drug and propellant or used propellant grade in the preparation are depended in the fitness of material.
Sometimes be difficult to the capacity conventional surfactants is dissolved in fluorohydrocarbon (HFC) propellant for example among HFC-134a and the HFC-227.Of U.S. patent 5,225,183, used cosolvent for example ethanol overcome this problem.Avoid using the other method of cosolvent to comprise that use can dissolve or be dispersed in the fluorohydrocarbon propellant and it is said active surface activating agent in the aerosol or the material of dispersing aid.Such material is some fluorinated surfactants and some polyethoxy surfactants.
In the aerosol characteristic aspect, have more predictability than macromole than the medicine of micromolecule.Forming stable and providing in the aerosol that can reproduce dosage, molecular size be about 1K dalton-daltonian macromole of Yue 150K for example peptide or albumen be very unpredictable, and the problem of existence uniqueness.
Most of peptides and protein drug for example hormone as insulin, amylopectin etc., enzyme, anti-infective its aminoacid form with three dimensional structure aspect be very different.Therefore its surface activity is highly different, and importantly, also not obtaining at present can for example molecular weight, absorbability, dissolubility, partition coefficient and isoelectric level pH explains any model of protein surface activity difference according to its most basic and architectural feature.For example, hemoglobin to the affinity of the surface of solids far above albumin, though these two kinds of proteic molecular weight are very similar.The active multiformity of peptide and protein surface is the linear aminoacid sequence that comes from as the unique property of every albuminoid basically.Amino acid side chain often has very big change, because some side chain does not carry any electric charge at any pH, still also shows significant polarity (serine, threonine).Other aminoacid is ionizable, from having suitable acidity (aspartic acid and glutamic acid 7.4 physiological pH band negative charge) completely to having for example imidazole radicals (carrying the part positive charge at pH7.4) the histidine of basic functionality, carrying in the lysine of complete positive charge and the arginine at pH7.4 has more alkalescence amino.As if how many another similar in a measure group aminoacid of character and hydrocarbon show the water solublity (tryptophan, phenylalanine, isoleucine etc.) more much lower than many other aminoacid of finding in biosystem.Noteworthy is that the amino acid whose hydrophobicity of these hydrophobicities is along with its ad hoc structure in albumen has a great difference.For example, for the free energy of transferring to organic facies from water, the single methyl chains in the alanine has only been contributed 0.5 kcal/mol, and the dicyclo indyl in the tryptophan has been contributed 3.4 kilocalories.Should expect, the variation of amino acid side chain has appreciable impact to aerosol stability and these peptides and the transhipment of protein biology therapeutic agent by biomembrane with the number of different types chemical interaction that causes in solution and on the surface.
The complexity of different aminoacids that the amino acid side chain multiformity exists in every kind of specific protein combination means, proteic physico-chemical property, it is intermolecular with inner molecular reaction, with and should be highly different with the ability of surface interaction.Because its big size, and correspondingly owing to a large amount of charged amino acid side chains, albumen has a lot of distributions electric charge on its outer surface.This can cause the lung picked-up of aerosol stability and these chemical compounds that very large variation is arranged.Peptide and protein drug also have a plurality of ionizings site usually, so they often show the dissolubility property that depends on pH.Importantly, the hydrophilic of these chemical compounds provides good condition to highly-water-soluble.
Therefore, most of peptides and protein drug show low-down fat-soluble, and this may be that the dispersibility of why these medicines in the fluorohydrocarbon propellant is a physics and a chemically stable reason under the condition of storage of wide region.Need in carrier or preparation medium (medicine is insoluble to wherein basically), comprise hydrolysis and chemical deactivation that the medicinal aerosol of peptide and protein drug has usually to alleviate aqueous solution.
When sending by the lung approach, the combination of big surface area, thin absorption carrier and extensive vasculature brings good absorbing environmental for albumen and peptide.Studies show that interior (i.t.) administration for peptides of trachea is rapidly and can be quantitative; Yet the frequent concentration of local of the distribution that is caused is at the maincenter air flue.Can be used for providing by the aerosol drug delivery that for example depends on the distribution particle diameter and have the uniform distribution that stronger alveolar penetrates.Depend on that from the drug absorption of air flue deposition position, medication, solute are presented type and preparation is formed.Therefore, preparation and device characteristic will have a significant impact speed and the degree that absorbs peptide from lung.Studies show that about 2 times after its i.t. sends of the infiltration rate after the aerosol of small molecular weight compounds is sent.Wish that peptide and albumen are that hydrophobic dispersion is sent via multiple dose suction apparatus (" pMDI ") so that drug particles can be penetrated on every side in the lung better, the absorption in the lung will significantly be better than central authorities' deposition of using the medicine that the aqueous solution instillation caused around.
Insulin can absorb the fact that enters in the blood flow from lung and be confirmed by several scientists.The review article of one piece of nineteen ninety [Lung, supplement 677-684 page or leaf] goes out from multinomial research summary, and the half-life that is delivered to the insulin generation of the aerosolization in the lung is 15-25 minute, but the result is very different.Comprehensive study has confirmed that also it is more than 50.7% that periphery is delivered to the bioavailability that the insulin of the aerosolization in the rabbit lung produces, and the bioavailability that is instilled into the liquid insulin in the central airway is 5.6%.Therefore, such argument has been supported in these researchs, i.e. the insulin of aerosolization must periphery be delivered in the lung, and with the generation maximal efficiency, and the central once in a while deposition of the insulin of the aerosolization that sucks will produce the effect than low 10 times of desirable effect.If the insulin of aerosolization will become to treat the effective means of diabetes, 10 times of such in administration obvious differences are unacceptable.Therefore, need effective high-precision aerosol agent device to give human patients required tolerance to realize the insulin atomizing.The islets of langerhans that uses aerosolization usually this idea of control of diabetes should also be applicable to amylopectin and glucagon, the hormone that uses with insulin combination in blood sugar concentration control, such hormone must be used by subcutaneous injection (s.c.) so far.
The dry powder form of peptide and protein drug has unique chance in preparation, they can not appear at liquid form for example in pMDIs and the aerosol solution.Owing to have the solid-state stability of improvement, thus be attractive from the dry powder aerosol of preparation viewpoint peptide and protein drug, because avoided many unfavorable solution and liquid the interaction.Can be about this with reference to people's such as people's such as Rubsamen US patent 5,672,581 and Patton US patent 5,775,320.
The method of Rubsamen and Patton is feasible in treatment, but is controlling for example suitability aspect the diabetes of chronic disease because intrinsic cost complicated and that infer has limited it.Therefore, it is debatable using expensive for example portable, the electronic portable spray device of complex appts that the hypoglycemic drug routine is delivered to the patient who needs.Use dry powder aerosol device that is big, heavy, that be difficult to clean for example the Patton device hypoglycemic drug is delivered to via lung also is debatable in the body.Therefore, the main target that peptide or protein drug is mixed with dry powder inhalation aerosol (DPI) is to make medicine and the excipient that is added in some cases can be formed in chemistry and physically stable and can remain in the suspension until drug particles and arrive alveolar or other absorbs the aerosol colloid of position.Absorb the position in case arrive, drug particles should be captured on the deposition position effectively, is dissolved in rapidly in the endo-endothelial layer liquid, and promptly absorbs via biomembrane, has limited the inactivation that may be caused by the metabolic enzyme in the air flue thus.
Spray drying is the method that is used for the drug particles of useful in preparing drug formulations.Spray drying comprises the single-step operation that solution or suspension is changed into fine powder.Spray drying generally produces spheroidal particle, and spheroidal particle is normally empty, causes thus comparing with initial material, and powder has low bulk density.The powder characteristics of spray-dried materials (being particle size distribution, bulk density, porosity, moisture, dispersibility etc.) is good in many aspects generally, but the particle performance that makes by this method goes out not good flowability.In addition, need heating during forming granule by this method, this makes that spray drying is more worthless for heat sensitization compound for example peptide and protein drug.Therefore, problem is that adhesion and not good flowability that most of dry powder aerosol show through the device device time make dosage send the difficult problem that precision becomes the patient.
Be that material is packaged in the device as aggregation as the peptide of dry powder aerosol another problem relevant with protein formulation, like this during aerosolization, aggregation fragmentation, and individual particles discharged before entering air flue.Preparation micron or the particulate firm aggregation of sub-micron are suitable shirtsleeve operations, can use or not use polymer-binder to granulate by routine and realize.Yet, should be broken into the requirement of primary particles for aggregation when entering air flue, may get rid of simple conventional method of granulating, because intergranular power may be too big and can not depolymerization easily, effectively and promptly.Total cohesiveness between total bonding force between two dissimilar granules or two the similar granules can be considered and constituted one or more captivation sums.Known many these power are to form the unitary reason of adhesion in the preparation between dry powder and excipient granule.Therefore, the target of power all will be that the generation diameter is the aggregation of 50-200 μ m between any operation granule, such aggregation enough firm and stand mobile, store and be filled in the delivery apparatus, but can be by the depolymerization fully rapidly of the shear stress in the air-flow that sucks.In peptide and albumen aerosol very common this problem therein medicine do not dissolve, send and space protection can be avoided fully to resist in self associating liquid preparation as colloidal dispersion.Therefore, wishing peptide and protein drug for example are mixed with in the fluorohydrocarbon at non-aqueous media can be rapidly when being sprayed in the air flue and easily be broken into discontinuous particulate unstable flocculated colloid.In addition, also wish have peptide and the random motion constantly of proteic preparation of Chinese medicine granule, eliminated the probability of each drug particles formation aggregation thus.
Proposed other non-injection diabetotherapy, some has confirmed can produce the Biotherapeutics reaction behind the nasal administration insulin when with detergent and the preparation of other membrane permeablizer, as people such as Moses, and Diabetes, 32 volumes, November 1983; With people such as Salzman, NewEngland Journal of Medicine, 312 volumes are proposed among the No.17.Observed significant interindividual variation and nasal mucosa zest in various degree.Because diabetes are to pass through the administration of insulin chronic disease of treatment continuously, and because along with being exposed to membrane permeation promoter repeatedly, the mucous membrane irritation effect is tending towards increasing, the effort of developing the insulin of Noninvasive nasal administration never has industrialization.Therefore, safe, reproducible, the effective Noninvasive delivery apparatus (PMDIS) of sending peptide and protein drug via lung is ideal and needs.
Summary of the invention
It has surprisingly been found that and not use for example ethanol or surfactant sorbitan trioleate and obtain medicinal aerosol new and stable macromolecular drug for example of the cosolvent that is added in the small-molecule drug binary aerosol.Stable medicinal aerosol can obtain by using protective colloid-stabilised dose.
Detailed Description Of The Invention
The application is referred to the 09/158th, No. 369 U.S. application that JIUYUE was submitted on the 22nd in 1998, and this application is introduced the present invention in full with for referencial use.
The present invention relates to be suitable for the steady suspension aerosol of pressurized delivery, wherein comprise (1) macromole medicament or drug particles, the propellant that (2) are suitable and (3) suitable stabilizers.
Suitable macromole medicament or medicine are to be suitable for the medicine used by suction, and wherein said suction is to be used for per os and per nasal sucks treatment.Medicine has been described at fluid air, appropriate hydrocarbon gas, chlorofluorocarbon (CFC) propellant or the non--CFC propellant stable colloidal dispersion in tetrafluoroethane (HFA-134a) and the heptafluoro-propane (HFA-227) for example for example.
For example aminoacid and small-molecular peptides are used as causing the nonactive formulation components that the adhesion bond strength between the drug particles descends to use the polyion stabilizing agent.The electret of selected medicine or the aerosol colloidal solid of stereoscopic stable have been formed thus.Electret is the static coordinate of permanent magnet, still for example is present in the presence of the airborne moisture or under the ambient humidity, light and temperature condition at respiratory tract at moisture to be easy to break.Therefore, the present invention is suitable for dry powder aerosol, portable spray device system and pressurised metered dose inhaler preparation.
Gained aerosol colloid is chemistry and physically stable, and can remain in the suspension until selected medicament or drug particles and arrive the patient that treated for example alveolar of people, animal or other absorption site in the air flue.Absorb the site in case arrive, because the effect of moisture on every side, drug particles should be captured on the deposition site effectively, are dissolved in rapidly in the endo-endothelial layer liquid, and, limited the inactivation that may cause thus by the metabolic enzyme in the air flue promptly via patient's biomembrane absorption.
The suitable medicine that the present invention relates to is can form to be suitable for being delivered to for example medicine of human or animal's stable hydrophobic dispersion of patient.Medicine generally comprises peptide, polypeptide or the protein biology medicine that molecular size is 0.5 kilodalton-150 kilodalton.Particularly, peptide, polypeptide or protein biology medicine comprise the diabetes auxiliary agent; Insulin and insulin analog; Amylopectin; Glucagon; Surfactant; Immunomodulatory peptides is for example paclitaxel, il-1, interleukin-2 and interferon of cytokine, chemotactic factor, lymphokine, interleukin for example; Erythropoietin; Thrombolytics and heparin; Protease inhibitor agent (antiproteases), antitrypsin agent (antitrypsins) and amiloride; RhDNase; Antibiotic and other anti-infectives; Hormone and somatomedin be parathyroid hormone, LH-RH and GnRH analog for example; Nucleic acid; DDAVP; Calcitonin; Cyclosporin A; Ribavirin; Enzyme; Heparin; Hemopoietic factor; Cyclosporin; Vaccine; Immunoglobulin; Vasoactive peptide; Antisense agent (antisense agent); Gene; Oligonucleotide; And nucleotide analog.
Term diabetes auxiliary agent comprises natural, synthetic, semi-synthetic and reconstituted drug for example nandrolone phenylpropionate, glucagon, insulin, somatostatin, proinsulin, amylopectin etc.
Term " insulin " should be understood to comprise the insulin human of natural extract, insulin human that reorganization produces, the insulin that extracts from cattle and/or pig source, pig that reorganization makes and bovine insulin and the mixture of these insulin products arbitrarily, this term also comprises the polypeptide of the pure form basically that is usually used in treating diabetes, but comprises that also this term comprises the application of the commercial form of other excipient with it.Insulin is preferably recombinated and is made, and can dewater (bone dry) or in solution.
Term " insulin analog ", " monomer insulin " etc. are used alternatingly in this article, and comprise any form of " insulin " as defined above: wherein the intrachain one or more aminoacid of polypeptide are lacked by other aminoacid replacement and/or wherein one or more aminoacid, or wherein one or more other aminoacid being added to polypeptide chain or aminoacid sequence, they have been used as the insulin of blood sugar lowering horizontal force.The present invention's " insulin analog " generally comprises as in U.S. patent 5,547, in 929 (document is introduced the present invention with for referencial use) disclosed " insulin lispro analog ", insulin analog comprises LysPro insulin and humalog insulin, and other " super insulin analog ", energy force rate insulin regular and liver selectivity insulin analog (activity of the specific activity in liver in fatty tissue is strong) that wherein such insulin analog influences blood sugar level are strong a lot.Preferred analog is a monomeric insulin analog, and they are for example insulin lispro of the Insulin-Like chemical compound that uses in order to realize the general objects identical with insulin, promptly use the chemical compound with the blood sugar lowering level.
Term " amylopectin " comprises the natural human amylopectin, cattle, pig, rat, rabbit amylopectin, and synthetic, semi-synthetic or reorganization amylopectin, or the amylopectin analog, comprise Pramlintide and as in U.S. patent 5,686,411 and U.S. patent 5, disclosed other amylin agonists in 854,215, these two pieces of full patent texts are introduced the present invention with for referencial use.
Term " immune modulator " comprises cytokine, chemotactic factor, lymphokine complement component, immune system is auxiliary and adhesion molecule and people or the specific receptor of non-human animal.Spendable example comprises GM-CSF, IL-2, IL-12, OX40, OX40L (gp34), lymphotactin, CD40, CD40L.Spendable example comprises for example interleukin-11-15 of interleukin, alpha-interferon, interferon-or gamma interferon, tumor necrosis factor, granulocyte-macrophage colony stimutaing factor (GM-CSF), M-CSF (M-CSF), granulocyte colony-stimulating factor (G-CSF), chemotactic factor is neutrophilia activator protein (NAP) for example, macrophage chemistry attractant and activity factor (MCAF), RANTES, macrophage inflammatory peptide MIP-1a and MIP-1b, complement component and receptor thereof, or accessory molecule B7.1 for example, B7.2, ICAM-1,2 or 3 and cytokine receptor.OX40 and OX40-part (gp34) are other useful examples of immune modulator.For various objectives, immune modulator can be that people or non-human animal are specific, and for the object of the invention, as the case may be and for the purpose of convenient, can by extracellular domain or have native protein in conjunction with active other fragment, its mutain (muteins) and with other peptide sequence for example with the fusion rotein representative of heavy chain immunoglobulin constant domain.When coding inserted the nucleotide sequence of more than one immune modulators, they can for example comprise the combination of a kind of cytokine or cytokine and auxiliary/adhesion molecule.
Term used herein " interferon " or " IFN " are meant and suppress virus replication and cell proliferation and regulate immunoreactive height homology species specificity albumen section.Interferon is divided three classes according to its cell source and antigenicity: alpha-interferon (leukocyte), beta-interferon (fibroblast) and gamma interferon (immunologically competent cell).Developed every group recombinant forms and analog, and be commercially available.Hypotype in every group is divided according to antigen/architectural feature.At least 24 kinds of alpha-interferons (being divided into A hypotype-H hypotype) have been identified with different aminoacids sequence by the sequence of separating and measure the DNA of these peptides of coding.Also referring to Viscomi, 1996Biotherapy 10:59-86, the document is introduced the present invention in full with for referencial use.Term " alpha-interferon ", " interferon-alpha ", " interferon-ALPHA ", " human leukocyte interferon " and IFN are the member who is used for describing this group convertibly mutually in this article.Natural and recombinant alpha interferon comprises those that total interferon is for example described in U.S. patent 4,897,471 (document is introduced the present invention in full with for referencial use), and can be used for implementing the present invention.The human leukocyte interferon that makes in this mode comprises the mixture of the human leukocyte interferon with different aminoacids sequence.Natural human interferon-alpha that can be used for implementing purification of the present invention and composition thereof includes but not limited to originate from Sumitomo, the Sumiferon RTM interferon alfa-n1 of Japan; Originate from Glaxo-Wellcome Ltd., London, the Welfferong interferon alfa-n1 (Ins) of Great Britain; With originate from Purdue Frederick Co., Norwalk, the AlferonRTM Alferon N of Conn.
That term " erythropoietin " is meant is synthetic, semi-synthetic, reorganization, natural, people, monkey or other animal or the isolating polypeptide product of microorganism, primary structure conformation (being successive amino acid residue sequence) and one or more biological properties (for example immune property and body are interior and external biological activity) that it has some or all natural erythropoietin comprise its equipotential modification.These polypeptide also have such specific characteristic, and promptly they are prokaryote or the eukaryote host expresses products (for example passing through antibacterial, yeast and mammalian cell expression in culture) by genome or cDNA clone or the synthetic exogenous DNA sequence that obtains of gene.Another feature of microbial expression product in vertebrates (for example mammal and birds) cell can be not with people's albumen or with in its natural mammalian cell environment or relevant other pollutant of the erythropoietin in cell drain style such as blood plasma or urine combine.The product of products of typical yeast (for example Saccharomyces cerevisiae (Saccaromyces cerevisiae)) or prokaryote (for example escherichia coli (E.coli)) host cell does not combine with any mammalian proteins.According to used host, polypeptide of the present invention can by mammal or other eukaryote saccharide be glycosylated or can be not glycosylated.Polypeptide of the present invention can also comprise initial methionine amino acid residue (in the 1-position).The new glycoprotein product of the present invention comprises having that to be enough to be that the primary structure conformation of duplicate of natural (for example people) erythropoietin is to have one or more its biological properties and to have those that the average saccharide that is different from natural (for example people) erythropoietin forms.
Term " heparin " and " thrombolytics " comprise anticoagulant factor for example heparin, low molecular weight heparin, tissue plasminogen activator (TPA), urokinase (Abbokinase) and be used to control other factor of blood clotting.
Term " protease inhibitor " and " protease inhibitor " commutative use, and be meant synthetic, semi-synthetic, reorganization, natural or non-natural exists, solubility or activating agent fixed and that receptor reacts or play antibody, enzyme or nucleic acid effect.The receptor (for example glutamate receptor, Glycine Receptors, γ-An Jidingsuan (GABA) receptor) that these comprise the receptor (for example T-cell receptors) of regulating the immunoreactive receptor of body fluid, regulating cell immune response and regulate nerves reaction.These comprise cytokine receptor (relating to arthritis, septic shock, transplant rejection, autoimmune disease and inflammatory diseases), with bonded main histocompatibility (MHC) I of antigen-presenting and II receptoroid, cytotoxic T-cell receptor/or T-accessory cell receptor (relating to autoimmune disease) and thrombin receptor (relating to blood clotting, cardiovascular disease).These comprise that also the antibody of discerning autoantigen for example relates to the antibody of autoimmune disease and the antibody of identification virus (for example HIV, herpes simplex virus) and/or microbial antigen.
Term " hormone " and " somatomedin " comprise hormone releasing hormone for example growth hormone, thyroxin, throtropin releasing hormone (TRH), gonadotropin releasing hormone (GnRH), lutropin, the luteinizing hormone releasing hormone (LHRH comprises super agonist and antagonist for example leuprorelin (leuprolide), deltirelix, goserelin, nafarelin, danazol etc.) that is derived from natural, people, pig, cattle, sheep, synthetic, semi-synthetic or recombinant sources.These also comprise for example octreotide (Sandostatin) of somatostatin analogs.Other medicament in such biopharmaceuticals comprises and is used for uterotonic medicine (for example oxytocin), is used for diuretic medicine (for example vassopressin), is used for neutropenic medicine (for example GCSF), respiratory disorder (for example superoxide dismutase), RDS (for example optional surfactant that comprises apoprotein) etc.
Term " enzyme " comprises that recombinant deoxyribonuclease for example derives from the DNAse of Corporation (Genentech), protease (for example serine protease such as trypsin and thrombin), polymerase (for example RNA polymerase, archaeal dna polymerase), reverse transcriptase and kinases relate to that arthritis, osteoporosis, inflammatory diseases, diabetes, anaphylaxis, organ-graft refection, oncogene activate that (for example dihydrofolate reductase), signal conduction, self-loopa are regulated and control, transcribed, the enzyme of dna replication dna and reparation.
Term " nucleic acid " comprises any DNA or the RNA segment that contains natural or non-natural nucleoside, perhaps can via complementary hydrogen bond combine with other nucleic acid or oligonucleotide specificity and can with bonded other proteinoid material of non-nucleic acid ligates.Can be about this with reference to Bock, L. waits the people, Nature 355:564-566 (1992), the document has been reported and has been used similar DNA to come anticoagulant enzymatic fibrinogen to change into fibrin.
Can be according to the present invention synthetic and select the example of the biomolecule of its guide's molecule to include but not limited to the agonist of cell-membrane receptor and the analog of antagonist, neurotransmitter, toxin and venom, virus epitopes, hormone, opiate, steroid, peptide, substrate and inhibitor, cofactor, medicine, agglutinin, sugar, oligonucleotide, nucleic acid, oligosaccharide, lipid, albumen and any above-mentioned molecule.
Term " analog " is meant such molecule, it with think that it is that the molecule of its analog has common function activity, and also have common architectural feature usually.
Term " reorganization " is meant the clone's biopharmaceuticals or the genetic engineering molecule of any kind of expressing in prokaryote; or can further be processed into the molecule of another state with the protecting group that forms the molecular combinations storehouse of another combinatorial libraries, especially contain the materialization, pharmacology and the clinical safety that improve biopharmaceuticals.
Term " vaccine " is meant the therapeutic combination that is used to stimulate body fluid and cell immune response, stimulation is carried out separately, or for example can activate via antigen-presenting cell that the T-cell carries out with the activated arborescent cell that produces anti-selected antigenic multivalence cell immune response.Potential antigen-presenting cell is by producing polypeptide complex with external cells contacting irriate.Polypeptide complex can comprise the conjugated protein and polypeptide antigen of arborescent cell, but polypeptide antigen preferably tissue specificity tumor antigen or oncogene product.Yet, should be appreciated that other antigen for example virus antigen can be used for such combination to produce the immunostimulation reaction.In another embodiment preferred, the arborescent cell of the part of formation immunostimulation polypeptide complex is conjugated protein to be GM-CSF.In another embodiment preferred, the polypeptide antigen that forms the part of this complex is the tumor specific antigen prostatic acid phosphatase.In another embodiment preferred, polypeptide antigen can be any oncogene product peptide antigen.Polypeptide complex can also be at arborescent cell comprises connection peptides between the conjugated protein and polypeptide antigen.It is conjugated protein that polypeptide complex can also comprise covalently bound arborescent cell on polypeptide antigen, and such polypeptide complex preferably forms from conjugated protein, the preferred GM-CSF of arborescent cell and polypeptide antigen.Polypeptide antigen is tissue specificity tumor antigen prostatic acid phosphatase (PAP) for example preferably, or oncogene product for example Her2, p21RAS and p53; Yet other embodiment for example virus antigen is also contained in the present invention.
Term " immunoglobulin " comprise relate to host defense mechanism for example by one or more genophores encode, at the different bound fractions of host defense cell infix synkaryon acid or coupling expression vector to help the polypeptide oligonucleotide of treatment human or animal individuality.The medicine that is included in this class polypeptide comprises separately or IgG, IgE, IgM, the IgD of combination with one another.
For the preparation of preparing to be drawn in the lung of the present invention, preferably with medicament or drug microparticlesization, the medicine of therefore treating effective dose or part (for example 90% or more) is a microgranule.Particulate diameter is generally less than about 10 microns, preferably less than about 5 microns, granule can be drawn in respiratory tract and/or the lung like this.
Selected medicament or medicine are present in the preparation of the present invention with the treatment effective dose, and promptly this amount makes medicine can be used as dispersion, aerosol per os or per nasal to suck and use, and produces required curative effect, preferably uses as single dose or via several dosage.Medicine generally as aerosol from valve commonly used for example the dosing valve also use via known as the aerosol jointer of driver.
Term used herein " amount " is meant amount or the concentration that depends on the circumstances for context.Constitute the treatment effective dose medicine amount along with factor for example effectiveness, the preparation of certain drug route of administration and be used for the mechanical system of administered formulation and become.Those skilled in the art can consider that these factors select the treatment effective dose of one or more certain drug.By selected fluid or propellant is 100 weight portions, and the treatment effective dose is generally about 0.001 weight portion-Yue 5 weight portions.
Suitable fluid comprises air, and hydrocarbon is normal butane, propane, isopentane etc. or propellant for example.Suitable propellant is any fluorocarbon fluorocarbon of for example containing 1-6 hydrogen (CHF for example 2CHF 2, CF 3CH 2F, CH 2F 2CH 3And CF 3CHFCF 3), perfluoroparaffin for example has the perfluoroparaffin (CF for example of 1-4 carbon atom 3CF 3, CF 3CF 2CF 3); Or any mixture of above-mentioned propellant, described propellant has enough vapour pressures so that they can be used as propellant effectively.Some typical suitably propellant comprises for example propellant 11,12 or 114 or their mixture of conventional chlorofluorocarbon (CFC) propellant.Non-CFC propellant for example 1,1,1,2-tetrafluoroethane (propellant 134a), 1,1,1,2,3,3,3-heptafluoro-propane (propellant 227) or its mixture are preferred.When used as such, fluid or propellant preferably exist with the amount that the medicine that is enough to advance a plurality of selected dosage discharges from aerosol container.
Select suitable stabilizers.Suitable stabilizers comprises that (1) is selected from following aminoacid (a) formula H 2N-R-COOH (I) amino carboxylic acid, (b) formula H 2N-R (COOH) 2(II) monoamino-dicarboxylic acid and (c) formula (H 2N) 2-RCOOH (III) diaminomonocarboxylic acid, wherein R is the straight or branched alkyl with 1-22 carbon atom, described alkyl can be by following structure division sulfide (S-), oxide (O-), hydroxyl (OH), amide (NH), sulfate radical (SO for example 4) single replacement or polysubstituted; Aryl shown in the following formula
Figure A0180719500161
Wherein X is hydrogen, halogen (F, Cl, Br, I), the alkyl with 1-6 carbon atom, the alkoxyl with 1-6 carbon atom, hydroxyl and nitro; And heterocyclic radical, for example thienyl, furyl, pyranose, imidazole radicals, pyrrole radicals, thiazolyl, oxazolyl, pyridine radicals and pyrimidyl compounds; (2) be selected from the acid-addition salts that following amino acid derivativges (a) derives from mineral acid and organic acid amino, described mineral acid is for example hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid and perchloric acid, and organic acid for example tartaric acid, citric acid, acetic acid, succinic acid, maleic acid, fumaric acid, oxalic acid; (b) carboxylic acid group's amide, glutamine for example, dipeptides is oxidation and unoxidized L-cysteinyl glycine for example, γ-L-glutamyl-L-cysteine, the salt and the ester of N-acetyl group-L-cysteine-glycine, put together, do not put together or the L-Gly-L-Glu and the L-Val-L-Thr of polymerized form, L-aspartyl-L-phenylalanine, Romurtide, nutrient be L-tyrosyl--L-tyrosine for example, L-alanyl-L-tyrosine, L-arginyl--L-tyrosine, L-tyrosyl--L-arginine, N-Cbz-L-Leu-L-Leu-OCH and salt thereof or ester, glycyl-glycine, N-acetyl group-L-aspartic acid-L-glutamic acid (NAAG) etc.; And tripeptides, for example oxidation and unoxidized γ-L-glutamyl-L-cysteinyl-glycine; Muramyl tripeptides etc. (c) derive from the carboxylic acid group's of aliphatic straight chain with 1-6 carbon atom or branched-chain alcoho ester, L-aspartyl-L-phenyalanine methyl ester (Aspartame ) for example, the ether of (3) any above-claimed cpd; (4) mixture of the hydrate of any above-claimed cpd or semihydrate and (5) aminoacid and amino acid derivativges.
Suitable formula I aminoacid comprise glycine, alanine, valine, leucine, isoleucine, leucyl alanine, methionine, threonine, 2-amino-3-methylpentanoic acid, phenylalanine, tyrosine, serine, cysteine, N-acetyl group-L-cysteine, histidine, tryptophan, proline and hydroxyproline for example trans-the 4-hydroxyproline.Formula II chemical compound comprises aspartic acid and glutamic acid, and formula (III) chemical compound comprises arginine, glutamine, lysine, oxylysine, ornithine, agedoite and citrulline.
Fluid preparation or aerosol preferably comprise protective colloid-stabilised dose of following amount: with respect to the same preparation that does not contain stabilizing agent; the stabilizing agent of this amount can be stablized said preparation effectively, stirs the not sedimentation too quickly of back medicine like this, creaming or flocculation take place and hinders the reproduced administration of medicine.In about 15 seconds-Yue 5 minutes time, keep basically drug level uniformly if stir the back preparation, can realize the administration of repeatability.
In order to make the aerosol as dry powder or aerosol suspension reach best-of-breed functionality and curative properties, stabilizing agent exists as coarse carrier (for example 20-90 μ m) or as the trickle atomizing powder of diameter≤10 μ m.Under any situation, can both obtain reproducible drug dosimetry, and need not to train patient's suction operation.Therefore, obtained good dosage concordance to be up to 2 liters damp formula air-flow or to be low to moderate 15 liters/minute-Yue 90 liters/minute inspiratory flow rate.
The specified quantitative that constitutes effective amount of stabilizer depends on used certain drug in specific stabilizing agent, specific propellant and the preparation.Therefore it is unpractiaca listing the used concrete effective dose of particular formulations of the present invention, but such amount can be considered above-mentioned factor and easily determined by those skilled in the art.Yet the amount that stabilizing agent exists in preparation is generally about 0.001 part/1,000,000 parts-Yue 200,000 parts/1,000,000 parts, more preferably from about 1 part/1,000,000 parts-Yue 10,000 parts/1,000,000 parts, and most preferably from about 10 parts/1,000,000 parts-Yue 5,000 parts/1,000,000 parts total preparations.
It has surprisingly been found that and need not to use cosolvent by preparation of the present invention for example ethanol or surfactant promptly are stable.Yet other component for example traditional lubrication agent or surfactant, cosolvent, ethanol etc. also can be present in the aerosol of the present invention by the amount that those skilled in the art determine being easy to.In this, can be with reference to U.S. patent 5,225,183, this full patent texts is introduced the present invention with for referencial use.
Preparation of the present invention can make like this, following component is merged: (i) present in an amount at least sufficient to provide a plurality of treatment effective dose of medicine things; (ii) its amount stabilizing agent of stabilization formulations each component effectively; (iii) present in an amount at least sufficient to from aerosol container for example, advance the fluid or the propellant of a plurality of dosage; (iv) any other optional components for example is used as the ethanol of cosolvent; With these components are disperseed.These components can use conventional mixer or homogenizer to disperse by jolting or by ultrasonic energy.These components can also use sand mill or Micro Fluid instrument to disperse.Can be by using valve that valve transfer method, pressure type are filled or using conventional cold completion method that preparation in enormous quantities is transferred in the small individuals aerosol bottle.The stabilizing agent that uses in the suspension aerosol need not to be dissolved in the propellant.Can with can not abundant dissolved stabilizing agent with the appropriate amount coating on drug particles, coated granules can be incorporated in the above-mentioned preparation then.
Can use the aerosol container that is equipped with conventional valve, preferred dosing valve to send preparation of the present invention.Yet, have been found that specific stabilizing agent and other used adjuvant (if any), propellant and used certain drug are depended in the selection of the suitable valve member that uses with aerosol.Conventional neoprene that uses in sending the dosing valve of conventional CFC preparation and Buna valve rubber often have relatively poor valve and send feature, and are not easy to operation when using with the preparation that contains HFC-134a or HFC-227.Therefore, some preparations of the present invention are preferably via the dispensing of such valve member, and barrier film wherein is with acrylonitrile-butadiene rubber DB-218 (American Gasket and Rubber, Schiller Park, 111.) or EPDM rubber Vistalon for example for example TM(Exxon), Royalene TM(UniRoyal), bunaEP (Bayer) makes.Also suitable is by extrusion molding, injection molding or compression moulding by thermoplastic elastomer FLEXOMER for example TMThe barrier film that GERS 1085 NT polyolefin (Union Carbide) form.
Can use bag by or do not wrap quilt, anodic oxidation or not anodised conventional aerosol container for example aluminum, glass, rustless steel, polyethylene terephthalate aerosol container and with bag quilts such as epon, epoxy jar or tin comprise preparation of the present invention.
Conventional nebulizer systems can be used with preparation of the present invention and powder aerosol.
Can suck formulation delivered of the present invention in respiratory tract and/or lung by per os, to realize disease that bronchiectasis or treatment be subject to suck the treatment influence for example asthma, chronic obstruction pneumonopathy.Can also suck by per nasal and send preparation of the present invention, perhaps can use and send preparation of the present invention to treat for example angina pectoris or local infection by local (for example oral cavity) to treat for example allergic rhinitis, rhinitis, (part) or (general) diabetes.

Claims (18)

1. pharmaceutical preparation wherein comprises:
(a) molecular size of treatment effective dose is the albumen or the peptide medicine of about 1 kilodalton-Yue 150 kilodaltons;
(b) comprise the fluid carrier of described medicine; With
(c) be selected from the stabilizing agent of aminoacid, amino acid derivativges or its mixture.
2. the preparation of claim 1, wherein said medicine is selected from the mixture of insulin, insulin analog, amylopectin, immune modulator, interleukin, interferon, erythropoietin, heparin, thrombolytics, antitrypsin agent, protease inhibitor agent, hormone, somatomedin, enzyme, nucleic acid, immunoglobulin, antibiotic, anti-infectives, calcitonin, Hemopoietic factor, vaccine, vasoactive peptide, antisense agent, oligonucleotide, DNase, cyclosporin, ribavirin or any said medicine.
3. the preparation of claim 1, wherein said medicine is selected from insulin, insulin analog, amylopectin, glucagon, LH-RH, deltirex, leuprorelin, goserelin, nafarelin, octreotide, somatostatin, calcitonin, parathyroid hormone, TRH, pig GRH, G-CSF, G-SF, cytokine, rhDNAse, heparin, antibiotic, albumin, ovalbumin, aminloride, DDAVP, VIP, cyclosporin, erythropoietin, interferon, IgG, IgE, IgM, IgA, IgD, interleukin, IRAP, papain, peroxidase, the serratio peptidase, catalase, α-1-antitrypsin, gene, carrier, amiloride, rhDNAse, oligonucleotide, ribavirin, or the mixture of any said medicine.
4. the preparation of claim 1, wherein said stabilizing agent is selected from 20 kinds of natural amino acids, its any mixture and any derivant thereof.
5. the preparation of claim 1, wherein said stabilizing agent is selected from (1) and is selected from following dipeptides: the salt and the ester of oxidation and unoxidized L-cysteinyl glycine, γ-L-glutamyl-L-cysteine, N-acetyl group-L-cysteine-glycine; (2) put together, do not put together or the L-Gly-L-Glu and the L-Val-L-Thr of polymerized form; (3) L-aspartyl-L-phenylalanine; (4) Romurtide; (5) be selected from following nutrient: L-tyrosyl--L-tyrosine, L-alanyl-L-tyrosine, L-arginyl--L-tyrosine, L-tyrosyl--L-arginine, N-Cbz-L-Leu-L-Leu-OCH and salt or ester; (6) glycyl-glycine; (7) N-acetyl group-L-aspartic acid-L-glutamic acid; (NAAG); (8) be selected from oxidation and the not tripeptides of the γ of oxidised form-L-glutamyl-L-cysteinyl-glycine or muramyl tripeptides etc.; (9) mixture of any aforementioned stable agent.
6. the preparation of claim 1, wherein said fluid carrier is to be selected from 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3, the propellant of 3-heptafluoro-propane or its mixture.
7. the preparation of claim 1, wherein said fluid carrier is the hydrocarbon propellants that is selected from normal butane, propane, isopentane or its mixture.
8. the preparation of claim 1, wherein said preparation also comprises cosolvent.
9. the preparation of claim 8, wherein said cosolvent comprises ethanol.
10. the preparation of claim 1, wherein said stabilizing agent exists so that can be able to reproduce the amount of administration after preparation is stirred can prevent the preparation sedimentation long enough time effectively, creaming or flocculation take place.
11. the preparation of claim 10, wherein said stabilizing agent exists with the amount of about 0.001 part/1,000,000 parts-Yue 200,000 parts/1,000,000 parts of total formulation weight amounts.
12. a method for preparing the stable medicinal aerosol of claim 1 comprises:
(a) following component is merged: (i) present in an amount at least sufficient to provide a plurality of treatment effective dose of medicine things; (ii) present in an amount at least sufficient to advance the described fluid carrier of a plurality of described treatment effective doses; (iii) its amount described stabilizing agent of stabilization formulations effectively; With
(b) with component (i), (ii) and (iii) disperse.
13. the method for claim 12, wherein said medicinal aerosol also be included in the step (a) merge with cosolvent and in step (b) with component (i), (ii), (iii) disperse with described cosolvent.
14. treat the method that can suck the disease for the treatment of among the human or animal for one kind, comprise and to suck the preparation of using claim 1 to described human or animal by per os or per nasal by per os or per nasal.
15. the preparation of the claim 1 in aerosol container with dosing valve.
16. stable method that comprises the suspension aerosol of propellant and albumen or peptide medicine, comprise: will be selected from suitable aminoacid, its derivant or its any mixture can prevent that the amount of preparation sedimentation, generation creaming or flocculation is incorporated in the preparation long enough time effectively, so that after preparation is stirred, can reproduce administration.
17. a metered dose inhaler that comprises medicinal aerosol, described preparation comprises
(a) albumen or the peptide medicine of treatment effective dose;
(b) propellant; With
(c) be selected from the suitable stabilizers of aminoacid, amino acid derivativges or its any mixture, described stabilizing agent is to present in an amount at least sufficient to stabilization formulations, can prevent its sedimentation the long enough time effectively, the amount existence of creaming or flocculation takes place, so that after preparation is stirred, can reproduce administration.
18. the metered dose inhaler of claim 17, wherein said stabilizing agent are selected from 20 kinds of natural amino acids, its any mixture and any derivant thereof.
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CN101563134A (en) * 2006-10-18 2009-10-21 派利尼斯有限公司 Method and pharmacological composition for the diagnosis and treatment of male sub-fertility
CN104162142A (en) * 2014-08-29 2014-11-26 宁波市微循环与莨菪类药研究所 Application of N-acetyl aspartoyl glutamic acid dipeptide preparation in treatment of heroin addiction
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CN100354000C (en) * 2004-09-24 2007-12-12 基立福有限公司 Use of alpha-1 antitrypsin for the preparation of medicaments for the treatment of fibromyalgia
CN101563134A (en) * 2006-10-18 2009-10-21 派利尼斯有限公司 Method and pharmacological composition for the diagnosis and treatment of male sub-fertility
US9149513B2 (en) 2006-10-18 2015-10-06 Periness Ltd. Method and pharmacological composition for the diagnosis and treatment of male sub-fertility
CN105664141A (en) * 2006-10-18 2016-06-15 派利尼斯有限公司 Method and pharmacological composition for the diagnosis and treatment of male sub-fertility
CN106132398A (en) * 2014-04-03 2016-11-16 瑞士杰特贝林生物制品有限公司 The atomization of immunoglobulin
TWI750108B (en) * 2014-04-03 2021-12-21 瑞士商Ｃｓｌ貝林股份有限公司 Nebulization of immunoglobulin
CN115177588A (en) * 2014-04-03 2022-10-14 瑞士杰特贝林生物制品有限公司 Nebulization of immunoglobulins
CN104162142A (en) * 2014-08-29 2014-11-26 宁波市微循环与莨菪类药研究所 Application of N-acetyl aspartoyl glutamic acid dipeptide preparation in treatment of heroin addiction

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