Electro-powder

• US 6,696,090 B1
• Filed: 08/11/2000
• Issued: 02/24/2004
• Est. Priority Date: 08/04/2000
• Status: Expired due to Fees

• Current Assignee: Mederio AG
• Original Assignee: Microdrug AG
• Inventors: Nilsson, Lars-Gunnar, Nilsson, Thomas
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): TRAN, SUSAN T
• Application Number:
  US09/636,548
• Time in Patent Office: 1,292 Days
• Field of Search: 424/489, 424/490, 424/491, 424/497, 424/498, 264/4, 264/4.1, 264/4.32, 264/4.33, 436/149
• US Class Current: 424/489
• CPC Class Codes: A61K 9/0009 involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis microelectromechanical systems A61K9/0097
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61M 15/02 with activated or ionised fluids, e.g. electrohydrodynamic [EHD] or electrostatic devices; Ozone-inhalators with radioactive tagged particles
• CPC Class Codes: A61M 2202/064 Powder

Abstract

A method and a process are disclosed for preparation of medical electro-powders. The electro-powder results from preparations of chemical and biological substances to form electro-powders suitable for electrostatic charging and dosing for functionality in a dry powder inhaler device. The electro-powder resulting from the method and process forms an active powder substance or a dry powder medical formulation with a fine particle fraction representing of the order 50% or more of the content having a size ranging between 0.5-5 μm and provides electrostatic properties with an absolute specific charge per mass after charging of the order 0.1×10⁻⁶ to 25×10⁻⁶ C/g and presenting a charge decay rate constant Q₅₀>0.1 sec with a tap density of less than 0.8 g/ml and a water activity a_w of less than 0.5. In the processing the active substance is a generally pharmaceutical active chemical or biological substance, for instance a polyeptide or any other corresponding substance selected alone or mixed or blended together with one or more excipients being a compound to improve electrostatic properties of the medical dry powder substance or dry powder medical formulation. Further the electro-powder may even be formed as a micro-encapsulation by coating micronized powder with the excipient in such a way that the active substance is capsulated, whereby the powder electrostatic properties mainly comes from the excipient.

Claims

1. A method for preparing electro-powder constituting micronized medical powder to be electrostatically charged by corona, induction or triboelectric charging and suitable for administration into the deep or upper lung airways by oral inhalation from a dry powder inhaler device, comprising the steps of:

selecting an active chemical or biological substance for conversion into an electro-powder;

micronizing and electrostatically charging the active substance for determining at least its electrostatic charging capacity and for determining a preparation and manufacturing equipment;

preparing a candidate electro-powder preparation in accordance with said electrostatic charging capacity using a selected preparation and manufacturing equipment;

analyzing the thereafter prepared candidate electro-powder preparation to verify that the obtained electro-powder has an electrostatic charging capacity rendering it suitable for utilization with a dry powder inhaler;

whereby, if the electro-powder is found not to possess said electrostatic charging capacity, the process is repeated with another manufacturing process to prepare a further candidate electro-powder preparation from the active substance.

2. The method according to claim 1, comprising the further steps of controlling the manufacture of the candidate electro-powder preparation to be a powder substance or dry powder medical formulation having a fine particle fraction (FPE) with 50% or more of particles between 0.5-5 μ

m and providing electrostatic properties regarding absolute specific charge per mass after charging of the order 0.1-25 μ

C/g and presenting a charge decay rate constant Q₅₀ of more than 0.1 sec.

3. The method according to claim 1, comprising the further step of preparing the candidate electro-powder preparation by a Fluid Jet Milling or a Spray Drying, a Cryo-technique or microwave techniques using raised temperature in the supplied air to dry the milled powder and as a result obtaining a water activity a_w below 0.5.

4. The method according to claim 3, comprising the further step of analyzing the candidate electro-powder preparation by a Karl-Fisher method for a total analyzed water content to be below 4%.

5. The method according to claim 3, comprising the further step of transporting the candidate electro-powder preparation between a preparation process and a dosing unit with the electro-powder preparation being kept under vacuum.

6. The method according to claim 1, comprising the further step of selecting the active chemical or biological substance selected from the group consisting of vasopressin, a vasopressin analogue, desmopressin, glucagon, corticotropin, gonadotropin, calcitonin, C-peptide of insulin, parathyroid hormone, human growth hormone, growth hormone, growth hormone releasing hormone, oxytocin, corticotropin releasing hormone, a somatostatin analogue, a gonadotropin agonist analogue, atrial natriuretic peptide, thyroxine releasing hormone, follicle stimulating hormone, prolactin, an interleukin, a growth factor, a polypeptide vaccine, an enzyme, an endorphin, a glycoprotein, a lipoprotein, a kinase, intra-cellular receptors, transcription factors, gene transcription activators/repressors, neuro-transmitters, proteoglycans, a polypeptide involved in the blood coagulation cascade that exerts its pharmacological effect systemically, any other polypeptide having a molecular weight (Daltons) of up to 50 kDa, proteins, polysaccharides, lipids, nucleic acids and combinations thereof, leuprolide and albuterol, opiates, nicotine, nicotine derivates, scopolamin, morphine, apomorphine analoges, pharmaceutical active chemicals for asthma treatment and salts thereof.

7. The method according to claim 1, comprising the further step of, in order to convert the active substance into a dry electro-powder, selecting and adding an excipient from a group consisting of polyvinyl alcohol, methalose, methyl cellulose, ethyl cellulose, propyl cellulose, hydroxy ethyl cellulose, carboxy methyl cellulose, polyoxyethylene cetyl ether, polyoxyethylene lauryl ether, polyoxyethylene octyl ether, polyoxyethylene octylphenyl ether, polyoxyethylene oleyl ether, polyoxyethylene sorbitan monolaurate, polyoxyethylene stearyl ether, polyoxyethylene nonylphenyl ether, and dialkylphenoxy poly(ethyleneoxy)ethanol sodium dodecyl sulfate, sodium dodecylbenzene sulfate and sodium dodecylnaphthalene sulfate glucolipids, phosphoglucolipids, a cationic surfactant dimethyl-β

-cyclodextrin, dioctanoylphosphatidylcholine, lysophos-phatidylcholine, a salt of caprate, laurate, oleate, myristate an anionic surfactant, a cationic surfactant, a phospholipid, an alkyl glycoside, a cyclodextrin, a salt of capric acid, a sodium, potassium or organic amine salt of a fatty acid, a bile salt, homo- and copolymers based on hydroxycarboxylic acids, polymers based on trioxanone, dioxanone (1,3 and 1,4), substituted dioxanone, trimethylene carbonate, ethylene carbonate, propylene carbonate, lactic acid, glycolic acid, pentaerythritol, sorbitol, adonitol, xylitol, fructose, epichlorohydrin, isopropyl-morpholine, isopropylmethyl-morpholinedione, β

-propionic acid, tetramethylglycolide, β

-butyrolactone, butyrolactone, pivalolactone, α

-hydroxybutyric acid, α

-hydroxyisobutyric acid, α

-hydroxyvaleric acid, α

-hydroxyisovaleric acid, α

-hydroxycaproic acid, α

-hydroxyisocaproic acid, α

-hydroxy-α

-ethylbutyric acid, α

-hydroxy-α

-methylvaleric acid, α

-hydroxyheptanoic acid, α

-hydroxyoctanoic acid, α

-hydroxydecanoic acid, α

-hydroxytetradecanoic acid, α

-hydroxystearic acid, a bio-degradable synthetic polymer, block copolymers poly(ethylene glycolaspartate, also named polymeric micelles a liposome forming substance, a natural or synthetic wax, sugar alcohols, monosaccarides, disaccarides, trisaccarides, polysaccarides, oligosaccarides, and buffering salts.

8. A method for preparing electro-powder constituting micronized medical powder to be electrostatically charged by corona, induction or triboelectric charging and suitable for administration into the deep or upper lung airways by oral inhalation from a dry powder inhaler device, comprising the steps of:

selecting a first active chemical or biological substance and a second active chemical or biological substance;

micronizing and electrostatically charging the first active substance for determining at least its electrostatic charging capacity with or without the second active substance for determining a preparation and manufacturing equipment;

preparing a candidate electro-powder preparation in accordance with said electrostatic charging capacity using a selected preparation and manufacturing equipment;

analyzing the thereafter prepared candidate electro-powder preparation to verify that the obtained electro-powder has an electrostatic charging capacity rendering it suitable for utilization with a dry powder inhaler;

whereby, if the electro-powder is found not to possess said electrostatic charging capacity, the process is repeated with another manufacturing process to prepare a further candidate electro-powder preparation from the active substance.

9. A method for preparing electro-powder constituting micronized medical powder to be electrostatically charged by corona, induction or tribo-electric charging and suitable for administration into the deep or upper lung airways by oral inhalation from a dry powder inhaler device, comprising the steps of:

inserting into a process of at least one active chemical or biological substance in combination with an excipient in order to convert the active substance into an electro-powder;

micronizing and electrostatically charging the active substance for determining at least its electrostatic charging capacity for determining a preparation and manufacturing equipment;

preparing a candidate electro-powder preparation in accordance with said electrostatic charging capacity by means of a selected preparation and manufacturing equipment;

analyzing the thereafter prepared candidate electro-powder preparation to verify that the obtained electro-powder has an electrostatic charging capacity rendering it suitable for utilization with a dry powder inhaler;

whereby, if the electro-powder is found not to possess said electrostatic charging capacity, the process is repeated for finding another manufacturing process for an operating preparation of the active substance.