CN1223340C - Electrospun pharmaceutical compositions - Google Patents

Electrospun pharmaceutical compositions Download PDF

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Publication number
CN1223340C
CN1223340C CNB018042422A CN01804242A CN1223340C CN 1223340 C CN1223340 C CN 1223340C CN B018042422 A CNB018042422 A CN B018042422A CN 01804242 A CN01804242 A CN 01804242A CN 1223340 C CN1223340 C CN 1223340C
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poly
activating agent
cellulose
agent
water
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Chinese (zh)
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CN1396823A (en
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弗朗西斯·伊格内修斯
约翰·M·鲍多尼
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
    • D01D—MECHANICAL METHODS OR APPARATUS IN THE MANUFACTURE OF ARTIFICIAL FILAMENTS, THREADS, FIBRES, BRISTLES OR RIBBONS
    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/0007—Electro-spinning
    • D01D5/0015—Electro-spinning characterised by the initial state of the material
    • D01D5/003—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion
    • D01D5/0038—Electro-spinning characterised by the initial state of the material the material being a polymer solution or dispersion the fibre formed by solvent evaporation, i.e. dry electro-spinning
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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    • D01D5/00—Formation of filaments, threads, or the like
    • D01D5/0007—Electro-spinning
    • D01D5/0015—Electro-spinning characterised by the initial state of the material
    • D01D5/0023—Electro-spinning characterised by the initial state of the material the material being a polymer melt
    • D—TEXTILES; PAPER
    • D01—NATURAL OR MAN-MADE THREADS OR FIBRES; SPINNING
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    • D01F1/00—General methods for the manufacture of artificial filaments or the like
    • D01F1/02—Addition of substances to the spinning solution or to the melt
    • D01F1/10—Other agents for modifying properties

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Abstract

The present invention is directed to an electrospun pharmaceutical composition comprising a pharmaceutically acceptable actibe agent, and a pharmaceutically acceptable polymeric carrier for use in therapy.

Description

The pharmaceutical composition of electrospinning silk
Invention field
The present invention relates to nanofiber, its preparation method of drug particles and contain the pharmaceutical composition of these nanofibers.The invention further relates to this class nanofiber and obtain purposes in the different dosage form of the highest bioavailability at the design drug moiety.
Background technology
The dissolution rate of known granule medicament can be with the increase of surface area, promptly reduces granularity and increases.Therefore, after deliberation the particulate medicine preparation method and be devoted to control pharmaceutical composition Chinese medicine granularity and particle size range.For example, dry milling technique is used to reduce granularity and has influenced drug absorption therefrom.Yet, in the dry grinding method of routine, as Lachman etc. described in the 45th page of the 2nd chapter " grinding " (" Milling ") (1986) of " theory and practice in the industrialization pharmacy " (The Theory and Practice of Industrial Pharmacy), when material lumps on grinding chamber granularity reach about 100 microns (100, limit 000nm).Lachman etc. notice that wet grinding helps further reducing granularity, but flocculation with less particle size restrictions to about 10 microns (10,000nm).Yet, because of the problem that relates to aspect the pollution there is a kind of prejudice in wet grinding at pharmaceutical field.Commercial airjet milling technique provide mean particle size range be low to moderate about 1-50 micron (1,000-50, granule 000nm).
Other technology that is used for pharmaceutical compositions for example comprises inserts liposome or polymer at emulsion polymerization process with medicine.Yet, this class technology existing problems and limitation.For example, in preparing suitable liposome process, need fat-soluble medicine usually.A large amount of liposomees that in addition, need be difficult to accept usually or polymer manufacture unit's drug dose.Again in addition, some technology that prepare this class pharmaceutical composition are all tended to complexity.The major technique difficulty of using emulsion polymerisation to run into is on the thing that decontaminates when preparation technology finishes, as may deleterious unreacted monomer or initiator.
U.S. Pat 4,540,602 (Motoyama etc.) disclose a kind of solid drugs that uses wet milk to pulverize in the water-soluble high-molecular substance aqueous solution.Yet people such as Motoyama point out, the result of wet grinding like this, with medicine make diameter range≤0.5.mu.m (500nm) to 0.5.mu.m (5, particulate 000nm).
U.S. Pat 5,145,684 (Liversidge etc.) disclose the high dispersible drug crystallization material of bioavailability that is lower than the 400nm granularity that has by wet grinding production.
The production method that contains less than the colloidal dispersion system of the form of spherical particles material of 500nm has been described among the EPO 275,796.Yet this method relates to and is subjected to compounding substances and does not precipitate with the effect of the miscible solvent of this material, and the result forms the amorphous nano granule.In addition, prepare particulate sedimentation and easily produce the granule that is subjected to solvent contamination.This kind solvent is normally deleterious, promptly enables to use, and also is difficult to fully remove to the acceptable practical extent of pharmacy.
U.S. Pat 4,107, described in 288 contain biology or pharmacokinetics active substance granularity at 10-1, the granule of 000nm scope.Yet this granule contains crosslinked macromole substrate, and wherein active substance is loaded on the substrate or sneaks in the substrate.
Studying the solid dispersion of medicine in polymer so that solve the little problem of bioavailability of medicament that the utmost point is insoluble in water.Nearest commentary is referring to Serajuddin, " pharmaceutical science magazine " (Journalof Pharmaceutical sciences), 1999,88 (10), 1058.
Expidet is the aspect that the utmost point is paid close attention to, and its purpose is to satisfy the specific demand of department of pediatrics, old people and dysphagia patients.
U.S. Pat 4,855, a kind of like this technical scheme has been described in 326: but will convert it into fibers form with the equipment melt-spun of manufacturing " cotton candy " then such as the sugar support agent and the medicament mixed of melt-spun like this.This textile product is just changed into the single dosage unit that compresses.For some drugs, in this support agent, to add binding agent.Example is useful on oral administration, part and is coated with usefulness, system and non-systemic intravenous and intramuscular infusion by multi cavity container.All application all are can form solution very apace when contacting with solvent.
U.S. Pat 4,946,684, US 5,298,261, US 5,466,464, US 5,501, and 861, US 5,762,961, US 5,866, disclose the covered Expidet of taste in 163, has the acceptable characteristic of organ sensation, fast disintegrate and need not chew or use a spot of water in patient's mouth.
U.S. Pat 5,948 discloses a kind of composition of polymeric film in 430, and it can produce constant wettability, takes back dissolving/disintegrate rapidly in the oral cavity.This situation is only applicable to soluble agents.
The present dosage form of studying energetically is the dosage form that the gentle slow release of release at once of pulmonary's transmission is put.
U.S. Pat 5,747 discloses the advantage of aerosolization nano-particle in pulmonary transmits in 001.
The purposes that has greater than the drug of 1.6 ratio of elongation for improve to suck transmitting has been described among the WO 99/48476.This class granule is produced by the SCF technology or by the depositing technology of complexity.Electrospinning silk (Electrospinning) provides a kind of direct measurable method for the nano-particle that production has big ratio of elongation.
US 5,985, described in 309 to be used for the biodegradable macroporous microsphere body that contains protein and peptide class that pulmonary transmits.
Need the so a kind of simple pharmaceutical composition of design, be that the high bioavailability of nano-particle and the physicochemical characteristic of nanofiber are combined in the polymer support substrate, for above-mentioned dosage form provides all reliable characteristics, the nano-particle that wherein comprises medicine equably, make can needn't change by selecting suitable polymers simply production method produce a kind of convenient use instant, at once, the dosage form that postpones, slowly discharge.
Summary of the invention
An object of the present invention is to propose a kind of method of in the presence of the heavy polymer carrier that forms agent as viscosifier and fiber, pharmaceutically acceptable a kind of activating agent or multiple actives being carried out the electrospinning silk.The pharmaceutical composition of this electrospinning silk can be from solution or molten mass preparation.
The invention still further relates to a kind of pharmaceutical composition, it contains a kind of electricity spinning fibre that pharmaceutically acceptable activating agent and pharmaceutically acceptable polymer support are combined into one.
The invention still further relates to the purposes of the electrospinning silk pharmaceutical composition that contains pharmaceutically acceptable activating agent and pharmaceutically acceptable polymer support, be directly used in oral, pulmonary administration or be dissolved in medicinal fluid medium such as suspension or solution or by non-intestinal/intramuscular or intracavity (intracavernosum) injection.
The invention still further relates to a kind of method for preparing the pharmaceutical composition of electrospinning silk, said composition comprises pharmaceutically acceptable activating agent and pharmaceutically acceptable polymer support, wherein this activating agent is that be slightly soluble in or water-fast, and described polymer support is selected from poly(ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, hyaluronic acid, alginate, carrageenin, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, Hydroxypropyl Methylcellulose Phathalate, the cellulose acetate phthalate ester, starch, hetastarch, sodium starch glycollate, chitosan and derivant thereof, albumin, gelatin or collagen protein, polyvinyl acetate, methylcellulose, ethyl cellulose, noncrystalline cellulose, polyacrylate and derivant thereof; Poly-('alpha '-hydroxy acids) and copolymer thereof, such as polycaprolactone, poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester), poly-(a-amino acid) and copolymer, poe, group of polyphosphazenes, poly phosphate or polyanhydrides, this method comprises the following steps:
A) with acceptable solvent pharmaceutically activating agent and pharmaceutically acceptable polymer support are made solution; With
B) solution in the step (a) is electrospun to fiber, wherein activating agent is the granule of nano-scale particle size.
Preferably, described solvent is can be miscible or not miscible with water with water.
More preferably, described solution is the mixture of one or more solvents, and described solvent be water and can with the mixture of the miscible solvent of water.
The invention still further relates to the product of producing by said method.
The invention further relates to a kind of preparation of drug combination method that contains the electrospinning silk of pharmaceutically acceptable activating agent and pharmaceutically acceptable polymer support, wherein this activating agent is that be slightly soluble in water or water-fast, and described polymer support is selected from poly(ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, hyaluronic acid, alginate, carrageenin, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, Hydroxypropyl Methylcellulose Phathalate, the cellulose acetate phthalate ester, starch, hetastarch, sodium starch glycollate, chitosan and derivant thereof, albumin, gelatin, collagen protein, polyvinyl acetate, methylcellulose, ethyl cellulose, noncrystalline cellulose, polyacrylate and derivant thereof; Poly-('alpha '-hydroxy acids) and copolymer thereof, polycaprolactone, poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester), poly-(a-amino acid) and copolymer, poe, group of polyphosphazenes, poly phosphate or polyanhydrides, this method comprises the following steps:
A) make described activating agent and polymer support fusion; With
B) molten mass in the step (a) is electrospun to fiber, wherein activating agent is the granule of nano-scale particle size.
Preferably, this activating agent is water-insoluble or is slightly soluble in water.
More preferably, activating agent is homodisperse by the carrier in the fiber.
The invention further relates to the product of producing by said method.
The accompanying drawing summary
Accompanying drawing 1 expression makes the viscous medicaments/polymer composition of solution or molten mass form carry out the electrospinning silk and produces the process of nanofiber.
Accompanying drawing 2 expressions contain the dissolution rate of the gauged nabumetone nanofiber of useful nabumetone nano-particle.
Accompanying drawing 3 expressions are schemed with the scanning electron microscope (SEM) of (spun) 60%w/w nabumetone of POLYOX  fibre spinning.
Detailed Description Of The Invention
The present invention relates to a kind of novel composition of electricity spinning fibre, this fiber is to be produced by the heavy polymer carrier as tackifier and fiberizing agent, and this carrier is obtained by pharmaceutically acceptable activating agent or medicine spinning.
Term used herein " is combined into one " and refers to that medicine is combined with carrier, mixing, hybridization or be blended together. Be not with on its coated fiber at Electrospun (spin or nonwoven) surface. Specifically, this fiber preferably is included in activating agent and carrier together in even mode. Although think that incomplete stirring to the pure composition of solution or melting may make the gained fiber produce to a certain degree inhomogeneities, prerequisite is that medicine and carrier are together spinning rather than after the spinning it are being coated on the fiber.
The diameter that the fiber of estimating Electrospun of the present invention has nanometer range can produce great surface area thus. Its importance of fiber that this method is produced is the surface to volume ratio that it is high. This great surface area has very large effect to the bioavilability of the medicine that is insoluble in water, and this is can cause dissolution rate to improve because people know the surface area increase.
Physicochemical characteristic by reasonably considering polymer support and the state of adjustment thereof can be designed a kind of suitable formulation and be used for oral or parenterai administration, comprise pulmonary administration. Can comprise other pharmaceutically acceptable excipient in order to improve the stable or depolymerization of medicament nano particle. Described drug excipient can also have other characteristic, such as sorbefacient characteristic.
That the pharmaceutical composition of Electrospun can be designed to have is instant, at once, postpone or the slow characteristic of dissolving, such as slowly-releasing and/or pulsation release characteristics.
Can also be by using with promoting the polymer with the interactional functional group of drug moiety specificity to hide the taste of activating agent. The formulation of Electrospun can be pressed into tablet, sachet or film. As described in this area, can by suitable selective polymer carrier, drug regimen design conventional formulation as at once, postpone the formulation such as gentle On The Drug Release.
An object of the present invention is to provide the pharmaceutically acceptable medicament nano particle that evenly is embedded in the polymer nanofiber, in order to the bioavilability of this medicine and method of administration are had nothing to do.
Electrospun is commonly referred to as electrostatic spinning, and it is the production method of the fiber of a kind of diameter about 100nm. The method is comprised of the step that applies high voltage to polymer solution or molten mass and produce polymeric spray stream. When this injection stream through in the air time, produce nanofiber at the effect downward-extension of electrostatic repulsion forces. The method begins just existing bibliographical information since nineteen thirty. Under optimum conditions natural the and synthetic various polymer with optkmal characteristics have been carried out Electrospun and produced nanofiber (referring to " nanometer technologies " such as Reneker (Nanotechnology), 1996,7,216). Nanofiber to these Electrospuns has proposed different application, such as air cleaner, molecular composite material, blood vessel graft and wound dressing.
US Patent No. 4,043,331 have proposed the purposes as wound dressing, and US Patent No. 4,044,404 and US Patent No. 4,878,908 relate to the blood compatibility wadding of producing for prosthetic appliance. All disclosed insoluble polymers all are not as herein described pharmaceutically acceptable, still, think that disclosed water-soluble polymer is pharmaceutically acceptable. In these patents, there is not a kind of preparation method to disclose the example of the electricity spinning fibre that contains activating agent. The claimed enzyme of these patents, medicine and/or active carbon are in the lip-deep purposes of nanofiber, and the preparation of this nanofiber is they to be worked and " not infiltration in whole body " active part in site of administration.
EP 542514, US 5,311,884 and US 5,522,879 relate to the purposes of spinning fibre in piezoelectric biomedical device. Be not considered to the used pharmaceutically acceptable polymer of the present invention such as those fluorinated polymers with piezoelectric property that derive from vinylidene fluoride and TFE copolymer.
US Patent No. 5,024,671 are used for the electrospinning porous fibre directly to transmit medicine to the suture site as the vascular graft of having filled medicine. This porous graft materials is soaked with (not carrying out electrospinning) medicine and adds biodegradable polymer so that the release of regulating drug. This blood vessel graft also can be by making such as polytetrafluoroethylene (PTFE) or the so non-pharmaceutically acceptable polymer of its blend.
US Patent No. 5,376,116, US Patent No. 5,575, and 818, US Patent No. 5,632,772, US Patent No. 5,639, and 278 and US Patent No. 5, describe various forms in 724,004 and had the non-pharmaceutically acceptable polymer coated material of Electrospun and various prosthetic device of wadding. Use such as a kind of medicine of disclosed usefulness in ' 116 patents skin of Electrospun is carried out post processing (being used for breast prosthesis). Other patent has been described constructed and polymer, but this technology is used for other application, such as intracavity implant or endovascular stent.
Therefore, first production of the present invention goes out the pharmaceutical composition that is comprised of as electrospinning fibre a kind of activating agent (or multiple actives) and a kind of pharmaceutically acceptable polymer. This method can produce a large amount of fully decentralized fibers of the nano particle that makes medicine equably. The size of particle and the quality of dispersion make medicine have large surface area. People utilize the long-pending increase of medical surfaces to improve the bioavilability of the medicine that is insoluble in water. Other application is for reducing effect or enzyme interacting between the drug-drug.
The present invention relate to thus separately or with the purposes of nanofiber medicine in the bioavilability of the medicine that preferably is insoluble in water that improves medicine of the arbitrary form of pharmaceutically acceptable polymer (or its combination) coupling.
The invention still further relates to a kind of water-soluble polymer of Electrospun and Expidet of activating agent of containing, this Expidet is rapidly disintegration in oral cavity or other suitable body cavity at short notice. So just in the scope of cavity, produce the finely ground particle substance that does not need water just can be ingested.
Quick-dissolving dosage form can comprise water solublity or water-insoluble drug.Having an effect rapidly is not the prerequisite of Expidet.With regard to the medicine that bitterness is arranged, preferably utilize the dissolubility of himself or make it to become insoluble form by polymer coating.Therefore, the key property of Expidet is excipient fast disintegrate in the oral cavity, thereby drug particles is exposed and easy-to-swallow.In this case, can be in spinning process polymer (water solublity) nanofiber of electrospinning silk be mixed with the suitable premix of medicine or at preparation Expidet process middle and late stage.
This method can be used for local transmit be mixed with pharmaceutically acceptable medicine, but that main purpose is used for is oral, intravenous, intramuscular or suction.
Pharmaceutically acceptable activating agent used herein, active component or medicine are meant and comprise and be used for mammal, the preferred intravital activating agent with pharmacologically active of people.This pharmacologically active may be preventative or disease treatment.This purposes is not meant that the agricultural that comprises plant or soil uses or use as insecticide.It is not purpose of the present invention that dressing that the fiber of electricity consumption spinning is directly handled as local wound as yarn fabric or adhesive-bonded fabric or covering carry out Local treatment.But in pharmaceutical formulation for topical administration, use this fiber to be considered to belong to scope of the present invention.
Term used herein " activating agent ", " drug moiety " or " medicine " can exchange use.
The water solublity of activating agent is by USP definition.Therefore, the present invention includes the activating agent that meets this standard is exactly very easily molten, Yi Rong as herein described, solvable and sl. sol. activating agent.The pharmaceutical composition that it is believed that the most effective electrospinning silk polymer is insoluble or sl. sol..
Suitable drug substance can be selected from the medicine of various known types, for example comprises: analgesic, the antibiotic medicine, anthelmintic, anti-arrhythmic, antibiotic (comprising penicillins), anticoagulant, antidepressants, antidiabetic drug, antuepileptic, antihistaminic, antihypertensive, anti-gill fungus alkali medicine, antimycobacterial drug, antineoplastic agent, immunosuppressant, antithyroid drug, antiviral agents, antianxiety drug (sleeping pill and Antipsychotic drug), astringent, the B-adrenergic receptor blocker, contrast agent, blood products and succedaneum, the heart contraction medicine, corticosteroid, anti-tussive agents (expectorant and mucolytic), diagnostic reagent, diuretic, dopaminergic (antiparkinsonism drug), the homeostasis agent, immunizing agent, the fat regulator, muscle relaxant, parasympathomimetic agent, the parathyroid gland medicine, calcitonin and bisphosphonates, prostaglandin, radiopharmaceutical, gonadal hormone (comprising steroid), antiallergic agent, stimulant and anoretics, sympathomimetic, thyroid, PDE IV inhibitor, the NK3 inhibitor, the CSBP/RK/p38 inhibitor, Antipsychotic drug, vasodilation and xanthine.
Preferred drug substance comprises that those are used for the medicine of oral administration and intravenous administration.About the description of these types of drug and the kind enumerated can be at " pharmacopeia is augmented " the 29th edition, the The Pharmaceutical Press of Martindale, London finds in 1989, and the full content of the document is incorporated herein by reference.These drug substances be purchased and/or can prepare by techniques well known in the art.
As mentioned above, the compositions of electrospinning silk can also hide medicine many hardships or that taste is difficult to be subjected to, and these and its dissolubility has nothing to do.The suitable active component of sneaking in the fiber of the present invention comprises medicine many bitterness or that taste bad, includes but not limited to: histamine H 2-antagonist is such as cimetidine, ranitidine, famotidine, nizatidine, etintidine; Lupitidine, nifenidine, niperotidine, roxatidine, sulfotidine, tuvatidine and zaltidine; Antibiotic is such as penicillin, ampicillin, amoxicillin and erythromycin; Acetaminophen; Aspirin; Caffeine, dextromethorphan, diphenhydramine, bromine pheniramine (bromopheniramne), chlorine pheniramine (chloropheniramine), theophylline, spironolactone; NSAIDS ' s is such as ibuprofen, ketoprofen, naproxen and nabumetone; 5HT 3Inhibitor is such as granisetron (Kytril ) or ondansetron (Zofran ); 5-hydroxy tryptamine (seratonin) cell reabsorption inhibitor is such as paroxetine, fluoxetine, fluvoxamine and Sertraline; Vitamin is such as ascorbic acid, vitamin A and vitamin D; Edible mineral and nutrient are such as calcium carbonate, calcium lactate etc.; Or the combination of said medicine.
If suitable, could also be with above-mentioned activating agent, particularly antibiotic medicine and such as various types of sterin, Decongestant, other such therapeutic activity agent associating of antihistaminic.
This activating agent preferably has: nabumetone, cis-4-cyano group-4-[3-cyclopentyloxy)-the 4-methoxyphenyl]-cyclohexane-carboxylic acid, ASA, paroxetine (Seroxat ), Ariflo, ropinirole (ropirinole) (Requip ), rosiglitazone (rosiglitazone) (Avandia ) or hydrochlorothyazie and traimeterene (Dyazide ).
Other suitable activating agent is amprenavir (Agenerase ), lamivudine (Epivir ), epomediol (Flolan ), zanamivir (Relenza ), alosetron (Lotronex ), alclometasone (Aclovate ), beclometasone (Beclovent and Beconase ), malphalan (Aleran ), naratriptan (Amerge ), succinylcholine, cephalo husband suffering (cefuroxiime) (Ceftin ), ceftazidime (Ceptaz ), cephalo husband suffering (Zinacef ), zidovudine (Retrovir ), fluticasone (Flonase  or Cutivate ), ethamine miaow pyridine (Daraprim ), colfocsceril palmitate, sumatriptan (Imiitrex ), lamotrigine (Lamictal ), chlorambucil (Leukeran ), atovaquone (Malaron  or Mepron ), mivacurium (Mivacron ), busulfan (Myleran ), vinorelbine (Navelbine ), cisatracurium (Nimbex ), doxacurium (Nuromax ), atacurium (Tracrium ), oxiconazole (Oxistat ), mercaptopurine (Purinethol ) and thioguanine (Tabloid ), grepafloxacin (Raxar ), salmaterol (Serevent ), clobetasol (Temovate ), ranitidine, famotidine, omeprazole (R and S isomer), remifentanil (Ultiva ), valaciclovir (valacyclovir) (Valtrex ), acyclovir (Zovirax ), famciclovir (Famvir ), penciclovir (Denavir ), albuterol (Ventolin ), amfebutamone (Wellbutrin  or Zyban ); Or abacavir (Ziagen ), 4-(3,4-dihydro-1-methyl-2 (1H)-isoquinolyl)-N-(4-fluorophenyl)-5,6-dimethyl-2-pyrimidinamine, (N-(2,6-dichloro-benzoyl base)-4-(2, the 6-Dimethoxyphenyl)-L-phenylalanine); Telmisartan, lacidipine, eniluracil, amoxicillin (Amoxcil ), clavulanate potassium, mupirocin, ticarcillin, cerivastatin (Baycol ), carvedilol (Coreg ), the holder pool is for bearing (Hycamtin ), Factive , Locilex , Novastan , tranilast, Lotrifiban, 8-[(4-amino-1-methyl butyl) amino]-2,6-dimethoxy-4 '-methyl-5-(3-4-trifluoromethylphenopendant) quinoline succinate, (1S, 2R, 3S)-l-(1,3-benzo dioxole-5-yl)-2,3-dihydro-3-[2-(2-hydroxyl-oxethyl)-4-methoxyphenyl]-5-propoxyl group-1H-indenes-2-carboxylic acid, nelarabine, dutasteride, maribavir, 3-(3-{1-[(isopropyl-phenyl-carbamoyl)-methyl]-2,4-dioxy-5-phenyl-2,3,4,5-tetrahydrochysene-1H-benzo [b] [1,4] diazepine-3-yl }-urea groups)-benzoic acid; 6-amino-3-(2,3, the 5-trichlorophenyl) pyrazine-2-base amine; (2R, 3R, 4S, 5R)-2-[6-amino-2-(1S-methylol-2-phenyl-ethylamino)-purine-9-yl]-5-(2-ethyl-2H-tetrazolium-5-yl)-tetrahydrochysene-furan-3, the 4-glycol; (6 α, 11 β, 16 α, 17 α)-6,9-two fluoro-11-hydroxyls-16-methyl-3-oxygen-17-([(3S)-and 2-oxygen oxolane-3-yl] sulfur } carbonyl) androstane (androsta)-1,4-diene-17-base propionic ester; (3S)-oxolane-3-base (1S, 2R)-the 3-[[(4-aminophenyl) sulfonyl] (isobutyl group) amino]-1-phenyl-2-(phosphonato) propyl carbamate; (3R, SR)-3-butyl-3-ethyl-7,8-dimethoxy-5-phenyl-2,3,4,5-tetrahydrochysene-1,4-benzothiazepine (benzothiazepine) 1,1-dioxide; (1S, 3S, 4S, 8R)-3-(3, the 4-Dichlorobenzene base)-7-aza-tricycle [5.3.0.04,8] last of the ten Heavenly stems-5-alcohol; (2S, 3S, 5R)-and 2-(3, the 5-difluorophenyl)-3,5-dimethyl-2-morpholine alcohol; (S)-2-(2-benzoyl-phenyl amino)-3-{4-[2-(5-methyl-2-phenyl-4-yl)-ethyoxyl]-phenyl }-propanoic acid; 3 '-[(2-{[(2R)-and 2-(3-chlorphenyl)-2-ethoxy] amino } ethyl) amino] [1,1 '-diphenyl]-the 3-carboxylic acid; (2S)-2-{[(1Z)-and 1-methyl-3-oxygen-3-phenyl third-1-thiazolinyl] amino }-3-{4-[2-(5-methyl-2-phenyl-1,3-azoles-4-yl) ethyoxyl] phenyl } propanoic acid; Or all combination of compounds as herein described and composition thereof.
Briefly, in the purposes described herein, the medicine of indissoluble should have good dissolubility or indissoluble in organic solvent medicine must be available in the following melting method of mentioning in addition.
Nanofiber of the present invention contains the high molecular weight polymers carrier.These polymer form the viscosity solution that can produce nanofiber being subjected to electrostatic pressure to do the time spent owing to its high molecular.
The suitable polymers carrier preferably can be selected from some known drug excipient.The physicochemical characteristic of these polymer require the dosage form of design be instant, discharge at once, postpone to discharge, slowly release (as slow release), controlled release, pulsation release etc.
By what the electrospinning silk formed fiber dna fiber arranged, referring to (J.Macromol.Sci.-Phys.) B36 (2) such as Fang " macromolecular science-physics magazine ", 169-173 (1997).To mix with DNA, RNA or derivatives thereof such as the pharmaceutically acceptable like this activating agent of bioactivator, vaccine or peptide and also belong to scope of the present invention as spinning fibre.
In the process of preparation nanofiber, utilized polymer can form the characteristic of fiber.Therefore, the molecular weight of polymer is the unique most important parameter of selective polymer.As mentioned above, most polymers can be carried out the electrospinning silk, such as cellulose acetate, PVA, PEO, PVP, polyacrylamide, polyurethanes, Merlon, PTFE, PE, PP, polyacrylate, Kevlar, PHB, polyaniline, DNA, poly-(phenylene terephthalamide (phenylene terphthalamide)) and silk.
Yet for the object of the invention, other the representational example that is suitable for medicinal polymer includes but not limited to: poly(ethylene oxide); Polyvinyl alcohol; Polyvinyl acetate; Polyvinylpyrrolidone; Hyaluronic acid; Alginate; Carrageenin (carragenen); Cellulose derivative is such as sodium carboxymethyl cellulose, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, Hydroxypropyl Methylcellulose Phathalate, phthalic acid cellulose ethanoate, noncrystalline cellulose; Starch and derivant thereof are such as hetastarch, sodium starch glycollate, chitosan and derivant thereof; Albumen; Gelatin; Collagen protein; Polyacrylate and derivant thereof are such as the Eudragit adoption compound of Rohm Pharma production; Poly-('alpha '-hydroxy acids) and copolymer thereof are such as poly-(caprolactone), poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester), poly-(a-amino acid) and copolymer thereof; Poly-(ortho esters); Group of polyphosphazenes; Poly-(phosphate ester); And polyanhydrides; Or its mixture.
Major part in these pharmaceutically acceptable polymer specifically describes in " handbook of pharmaceutical excipients " (Handbook of Pharmaceuticalexcipients) that united states drug association (American Pharmaceutical association) and Britain medicine association (Pharmaceutical societyof Britain) co-publicate.
Preferably described polymer support is divided into three classes: (1) is used to make activating agent water-soluble polymer instant and that discharge at once; (2) be used to make the insoluble polymer of activating agent controlled release; (3) be used to make the pH sensitive polymer that the activating agent pulsation discharges or orientation discharges.The present invention can use the combination of two kinds of carriers.Think that also that its dissolubility of several polyacrylate is arranged is relevant with pH, they can be divided into two classes.
Water-soluble polymer includes but not limited to: poly(ethylene oxide); Polyvinyl alcohol; Polyvinylpyrrolidone; Hyaluronic acid; Alginate; Carragenen; Cellulose derivative is such as sodium carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, Hydroxypropyl Methylcellulose Phathalate, Cellacefate; Starch and derivant thereof are such as hetastarch, sodium starch glycollate, dextrin, chitosan and derivant thereof; Albumen, zein, gelatin and collagen protein.
Preferred water-soluble polymer used herein is the poly(ethylene oxide) such as trade mark POLYOX  by name.Think that the polymer that can use different molecular weight is that a kind of polymer is made up of such as being 100K, 200K, 300K, 400K, 900K and 2000K several molecular weight.Sentry POLYOX is a kind of water-soluble resin that is listed among the NF, has the molecular weight of about 100K-900K and 1000K-7000K.These polymer that are purchased can use 1%, 2% and 5% solution (depending on molecular weight).
NF level Sentry POLYOX is a kind of water-soluble resin with different molecular weight that obtains as mentioned above.The information that concerns between grade that the embodiment of the invention uses and the approximate molecular weight is provided in the following table.
Range of viscosities under 25 ℃, cP
The NF grade Approximate molecular weight 5% solution 2% solution 1% solution
WSRN-10 100,000 30-50
WSRN-80L 200,000 500
WSRN-80H 200,000 90-105
WSRN-750 300,000 500-1200
WSRN-3000 400,000 1,250-4,500
WSR-20S 600,000 4,500-8,800
WSR-1105 900,000 8,800-17,600
WSRN-12K 1,000,000 400-800
WSRN-60K 2,000,000 2,000-4,000
WSR-301 4,000,000 1,500-4,500
The WSR coagulant 5,000,000 4,500-7,500
WSR-303 7,000,000 7,500-10,000
Other preferred polymer comprises the polyvidone (poridone) with following K value and molecular weight ranges:
The K value Molecular weight
12 25
15 8000
17 10,000
25 30,000
30 50,000
60 400K
90 1000K
120 3000K
Insoluble polymer includes but not limited to: polyvinyl acetate; Methylcellulose; Ethyl cellulose; Noncrystalline cellulose; Polyacrylate and derivant thereof are such as the Eudragit adoption compound available from RohmPharma (Germany); Poly-('alpha '-hydroxy acids) and copolymer thereof are such as poly-(6-caprolactone), poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester), poly-(a-amino acid) and copolymer thereof; Poly-(ortho esters); Group of polyphosphazenes; Poly-(phosphate ester); And polyanhydrides.
These pharmaceutically acceptable polymer and derivant thereof be purchased and/or prepare by techniques well known in the art.So-called derivant refers to the polymer of different molecular weight, the polymer of modifying the functional group or copolymer or its mixture of these derivants.
In addition, can unite two or more polymer of use and form fiber of the present invention.This class associating can promote fiber to form or reach required drug release profile.
The selection of the polymer of reinstating with activating agent one will make it have the function of suitable covering activating agent taste.For example, use have opposite charges Ionomer for example with the compound cation type polymer of anionic activating agent or with the compound anionic polymer of cation active agent, can produce required effect.Can also add in the present invention such as second kind of such covering agent of suitable cyclodextrin or derivatives thereof.
This polymer composition can be from solvent substrate or straight polymer (molten mass) electrospinning silk.Choice of Solvent is preferably based on the dissolubility of activating agent.Water is water-soluble active agent and the optimum solvent that is similar to the such water-soluble polymer of POLYOX.Perhaps, also can make water and organic solvent that can be miscible with water.Yet, when medicine during water insoluble or slightly soluble, must be with an organic solvent so that the homogeneous solution of preparation medicine and polymer.
It is generally acknowledged that these straight polymer compositionss that spinning is used can also contain such as other such additive of plasticizer.These plasticizers are used to improve the melting behaviour of said composition.Can be used for typical plasticizer of the present invention is triethyl citrate, glyceryl triacetate, tributyl citrate, citric acid acetyl triethyl, citric acid acetyl tributyl, dibutyl phthalate, dibutyl sebacate, vinyl pyrrolidone, propylene glycol, triacetic acid glycol ester, Polyethylene Glycol or Tween-20 and combination or mixture.
Preferred selected solvent is the organic solvent that GRASS allows, but this solvent can need not to be " pharmaceutically acceptable " a kind of solvent, and the amount of formation may be outside detection range or is set in the limiting quantity of operable human consumption.Suggestion is pressed the ICH guide and is selected.The implication of GRASS is " being commonly considered as safe ".
The suitable solvent that the present invention uses includes but not limited to acetic acid, acetone, acetonitrile, methanol, ethanol, propanol, ethyl acetate, propyl acetate, butyl acetate, butanols, N, N-dimethyl acetylamide, N, dinethylformamide, 1-Methyl-2-Pyrrolidone, dimethyl sulfoxine, ether, diisopropyl ether, oxolane, pentane, hexane, 2-methyl cellosolve, Methanamide, formic acid, hexane, heptane, ethylene glycol, dioxane, cellosolvo, trifluoroacetic acid, methyl isopropyl Ketone, methyl ethyl ketone, dimethoxy propane, dichloromethane etc. or its mixture.
Preferred solvent is the mixture of water and acetonitrile or water and acetone.
The suitable ratio of components of solvent and polymer is measured by the finished product preparation with required viscosity.
The key parameter that pharmaceutical polymer composition carries out the electrospinning silk is viscosity, surface tension and the electrical conductance of solvent/polymer combinations thing.
Term used herein " nano-particle medicine " refers to the activating agent that electrospinning fibre includes nano particle size.
Polymer support can also play the surface modifier of nano-particle medicine.Yet, can also in electrospinning silk solution, add second kind of oligomer surface modifier.All these surface modifiers are adsorbed on the nano grain surface of medicine with physics mode, thereby have prevented their gatherings.
The representational example of these second kind of oligomer surface modifier or excipient includes but not limited to: Pluronics (block copolymer of oxirane and expoxy propane); Lecithin; AerosolOT TM(dioctyl sodium sulphosuccinate); Sodium lauryl sulphate; The polyoxyethylene sorbitan fatty acid ester class, i.e. polysorbate esters is such as Tween TM, such as Tween 20,60 and 80; The sorbitan fatty acid ester class, i.e. Span-20, sorbitan monooleate, anhydrosorbitol acid anhydride monopalmitate, sorbitan monostearate etc. are such as Span TMOr Arlacel TM, Emsorb TM, Capmul TMOr Sorbester TM, alevaire (Triton) X-200; Polyethylene glycols; Glyceryl monostearate; Vitamin E-TPGS TM(cetomacrogol 1000 succinic acid d-α-tocoretinate); The sucrose-fatty esters is such as stearic acid sucrose ester, oleic acid sucrose ester, Palmic acid sucrose ester, lauric acid sucrose ester, acetic acid butanoic acid sucrose ester etc.
Surfactant is added in the pharmaceutical composition in w/w.This surfactant is: oxirane and propylene oxide block copolymer; Lecithin; Dioctyl sodium sulphosuccinate; Sodium lauryl sulphate; Polyoxyethylene sorbitan fatty acid ester; Fatty acid esters of sorbitan; Triton X-100 sulfuric ester sodium salt; Polyethylene Glycol; Glyceryl monostearate; D-alpha-tocopherol cetomacrogol 1000 succinate; Sucrose fatty acid ester; Or the suitable addition of the blend surfactants of above-mentioned substance is about 10%, preferred below about 5% or 5%.Surfactant can reduce the viscosity and the surface tension of preparation, but higher amounts may have a negative impact to the quality of fiber of electrospinning silk.
The selection of surfactant can be according to the HLB value, but it might not be a kind of available standards.Already used HLB surfactant is such as Tween among the present invention TM80 (HLB=10), pluronic (Pluronic) F68 (HLB=28) and SDS (HLB＞40), but the surfactant that so hangs down the HLB value such as Pluronic F92 also can be used.
Can in electrospinning silk compositions, add another kind of pharmaceutically acceptable excipient.These excipient generally can be divided into absorption enhancer, additional surfactants, flavoring agent, dyestuff etc.
The used suitable flavoring agent of the present invention includes but not limited to Ilicis Purpureae, orange, grapefruit and Fructus Pruni pseudocerasi-Fructus Rubi.Although the w/w% of every kind of composition can change, the content of flavoring agent in total preparation should be the about 5%w/w of about 0.25-.
In preparation, can also comprise suitable coloring agent, pigment or dyestuff, such as FD﹠amp; C or D﹠amp; Color lake and dyestuff, ferrum oxide and the titanium dioxide of C permission.The content of pigment in compositions is about 2.0% (weight) of about 0.1%-.
In addition, described preparation can also contain such as the such sweetener of various natural saccharides, aspartame, sodium cyclamate and sodium saccharinate (sodium saccharinate) with such as aforesaid those flavoring agents.
If suitably select, polymer support or second kind of oligomerization surface modifier self can play absorption enhancer so, and this depends on used medicine.The used suitable absorption enhancer of the present invention includes but not limited to: chitosan; Lecithin; Agglutinin; Such as by stearic acid, oleic acid, Palmic acid, the deutero-sucrose-fatty esters of lauric acid; And vitamin E-TPGS.
Electrospinning silk compositions of the present invention can be with its conventional capsule or tablet.Perhaps, can suitably be used for tabletting or make capsule, or use with suction or parenterai administration mode with the low temperature method milled fibre.Can also make fiber dispersion become aqueous solution, directly suck then or oral this aqueous solution.Fibre cutting and processing can also be formed a kind of polymeric film with activating agent more in flakes and use, this film can dissolve fast.
Another aspect of the present invention is the alternative electrospinning process of preparation pharmaceutical composition of the present invention.Operation embodiment of the present invention makes solution static electrification lotus, at this moment pharmaceutical composition also from ejector, be ejected into the static electrification lotus and have on the acceptance surface of suitable distance with ejector.When ejecta reaches charged catcher from ejector process air, form fiber.Catcher can be the form of metallic screen or conveyer belt.Fiber can be deposited on the conveyer belt, can be taken out or leave conveyer belt continuously from conveyer belt then, carries out further required processed.
With embodiment preferred of the present invention of water-insoluble activating agent be the active nabumetone of electrospinning silk in the content range of w/w% at 0-82%, contain POLYOX and Tween 80, SDS, Pluronic F68 or the TPGS of 200K, 400K, 900K and 2000K.Preferred dicyandiamide solution is water/acetonitrile.
Embodiment
Describe the present invention referring now to the following examples, these embodiment only are used to explain the present invention and are not used for limiting scope of the present invention.Except as otherwise noted, all temperature are Celsius temperature, and all solvents are the solvent of obtainable highest purity.
Embodiment 1
The electrospinning silk of 25% (w/w) aspirin composition
2.5% POLYOX WSR N-60KTM (Union Carbide) stock solution is to use MilliQ TMWater slowly stirs in shaking bath and preparation.This POLYOX solution of 10 milliliters (hereinafter with " mL " or " ml " expressions) is joined in the 0.5mL acetone soln of 0.12 gram (hereinafter with " g " expression) aspirin (Sigma).The vigorous stirring content also adds 1mL acetone to obtain a kind of settled solution.Change this solution over to 0.03 millimeter (hereinafter with " mm " expression) capillary outlet (in the bottom) and have in the 25mL glass container of two imports, one in wherein said two imports is used to apply orthohelium Helium (He) pressure, and another is used to introduce electrode.The anode tap of this electrode and high voltage power supply (ModelD-ES30P/M692, Gamma High Voltage Research Inc.FL) connects.The earth terminal of high voltage power supply is connected with the rotary drum that is coated with aluminium foil.It is that 2.5psi and general+14.5KV voltage are added to this solution that the helium of import is pressed.On the drum that rotates with the speed of 50-60rpm, collect dried fibres.This fiber is peeled off from drum.
This electrical spinning method further describes in August, 1994 J.Doshi ' s Dissertation " application of the fiber of electrical spinning method and electrospinning silk " (" The ElectroSpinning Processand Applications of Electrospun Fibers ") at University ofAkron, and the full content of the document is incorporated herein by reference.
Embodiment 2
The electrospinning silk of 25% nabumetone compositions
(molecular weight 400K, stock solution Aldrich) is to use MilliQ to 30% polyoxyethylene TMWater preparation through slowly vibrating.This 30% solution of 5mL is joined in the 0.5g nabumetone (SB Corporation) that is dissolved in the 6ml acetonitrile.Slowly stir content and divide several fractions to add other 5mL acetonitrile, till obtaining settled solution.Of Tween with 0.1ml TM80 (Sigma) join in this solution.Use and this solution is carried out the electrospinning silk with condition identical described in the foregoing description 1.Collect fiber and from the drum taking-up.
Embodiment 3
The electrospinning silk of 30% nabumetone compositions
The MilliQ of 7.5% (w/v) POLYOX  WSR N-3000 (molecular weight is about 400K, Union Carbide) TMWater/acetonitrile stock solution prepares by sneak into 15g PEO in 50ml water and 150mL acetonitrile.
In this solution of 10mL, add 0.4g nabumetone and 1mL acetonitrile and 0.2mLTween TM80, obtain a kind of homogeneous solution.Under the condition identical, this solution is carried out the electrospinning silk, obtain the 1.3g fiber with the foregoing description 1.
Embodiment 4
The electrospinning silk of 50% nabumetone compositions
Add the 0.8g nabumetone to 10mL in from the 10mL water/acetonitrile stock solution of the foregoing description 3.By adding 1mL acetonitrile and 0.2mL Tween TM80 make this solution homogenize.Use and the foregoing description 1 similar condition, but this solution is carried out spinning, obtain the fiber of 1.2g with feed pressure and the 16KV of 2psi.
Embodiment 5
The electrospinning silk of 70% nabumetone compositions
Add the 0.86g nabumetone to 5mL in from the POLYOX  N-3000 solution of embodiment 3.By adding 1.6mL acetonitrile and 0.1mL Tween TM80 make this solution homogenize.Use with the foregoing description 1 similar condition but this solution is carried out spinning, obtain the fiber of 0.93g with feed pressure and the 16KV of 0.5psi.
Embodiment 6
The electrospinning silk of 80% nabumetone compositions
To 2g nabumetone, 0.1g SDS (JT Baker) and 0.4g POLYOX Add 1.2mL MilliQ in the mixture of WSR-1105 (900K) Water and 10.5mL acetonitrile.Under 37 ℃, this mixture is retained in the shaking bath become viscosity solution to all solids substance dissolves till.Use with the foregoing description 1 similar condition but gained solution is carried out the electrospinning silk, obtain the fiber of 2.1g with feed pressure and the 18KV of 2psi.
Embodiment 7
The electrospinning silk of 80% nabumetone compositions
To 2g nabumetone, 0.05g Pluronic F68 (BASF) and 0.4g POLYOX Add 1mL MilliQ in the mixture of WSR-1105 (900K) Water and 12mL acetonitrile.Under 37 ℃, this mixture is retained in the shaking bath become viscosity solution to all solids substance dissolves till.Use with the foregoing description 1 similar condition but gained solution is carried out the electrospinning silk, obtain the fiber of 2.1g with feed pressure and the 18KV of 2psi.
Embodiment 8
The electrospinning silk of 80% nabumetone compositions
2 gram nabumetones are dissolved in the acetonitrile of 11mL.Vitamin E-the TPGS (Eastman) and the 0.4g POLYOX that in this solution, add 0.1g WSR-1105 (900K).Under 37 ℃, this mixture is retained in the shaking bath become viscosity solution to all solids substance dissolves till.Use with the foregoing description 1 similar condition but gained solution is carried out the electrospinning silk, obtain the fiber of 2g with feed pressure and the 16KV of 0.5psi.
Embodiment 9
Nabumetone Determination on content in the nanofiber compositions
With the accurate weighing of nanofiber of aforesaid 20-50mg (medicament contg that depends on expectation) go into to glimmer bottle and it is dissolved in 5mL acetonitrile/water (80/20) mixture.Use acetonitrile/water (80/20) quantitatively to change this solution over to the 50mL volumetric flask and use acetonitrile/water to be mixed with volume (50mL) as diluent.Preparation is taken from 3 parts of different samples of fibre plate different piece and is measured intrastitial macroheterogeneity.
The 20mg nabumetone sample of use accurate weighing in the 100mL volumetric flask prepares the standard solution of nabumetone.Use acetonitrile/water (80: 20) to prepare sample as diluent.This solution of 20uL is injected the Waters HPLC system that Waters 550 pumps, 717+ automatic sampler and Spectroflow 783 UV detectors are installed.Obtain data by PE Nelson Box and Turbochrom (PE) software.Mobile phase is made up of the acetonitrile/water/acetic acid of 44/55/1 volume ratio.Flow velocity is 1.4ml/min and detects under 254nm.
Nabumetone content (wt.%)
Sample #1 Sample #2 Sample #3
Sample 8 81.2 79.5 81.2
Sample 6 82.9 82.8 83.0
Sample 5 59 61.2 60.8
Sample 4 36 36.9 35
Sample 3 30 30.5 29.8
Embodiment 10
Residual solvent analysis in the nabumetone nanofiber
(Whitehouse carries out the residual solvent analysis under NJ) and is undertaken quantitatively by capillary gas chromatography the sample that use is dissolved in DMSO (dimethyl sulfoxine) at QTI.Result shown in the following table shows the acetonitrile that all contains in whole samples of being analyzed below the 100ppm.
Table
Ethane nitrile content
Embodiment 5 ＜100ppm
Embodiment 4 ＜100ppm
Embodiment 3 ＜100ppm
Embodiment 11
Extracorporeal dissoluting test
The equipment that is used for this method is improved USP4, and the main distinction is: 1) low volume cell; 2) teeter chamber; 3) keep enough fibers under the submicron material.Total testing time is 20 minutes, wherein uses 2.5mg medicine (weighing up more formulation in proportion).
Flow cell is described: (Millipore is MA) as the Swinnex fiber module of internal fiber available from the 0.2 micron nitrocellulose filter that has of Millipore.The internal volume of this chamber is about 2mL.Use customization to be fit to the little PTFE agitator (Radleys Lab EquipmentHalfround Spinvane F37136) of Swinnex assembly.Dissolve medium is that flow velocity is 5mL/ minute a water.The entire equipment of setting is placed on the calorstat under 37 ℃.Measure drug level by making eluent stream through the UV detector that has 10mm small-large flow chamber.Carrying out UV under 284nm detects.
The mensuration of drug solubility scope
This experiment is used to assess the medicine dissolution rate.Use the medicine of utmost point indissoluble like this and 100% medicine is dissolved in 20 minutes test time limit as the water of dissolve medium.In order to measure the solubility range of medicine in this time limit, collect whole 100ml solution of eluting from the dissolving chamber.Use UV spectrophotometer commonly used relatively this solution with contain 2.5mg for example the such activating agent of nabumetone be dissolved in the reference solution of 50/50 methanol.(with regard to nabumetone, the solution dilution that this solution can will contain the 25mg nabumetone by 50/50 methanol with 100mls prepares for 10 times).The appropriate wavelength that is used for comparison is 260nm.
Embodiment 12
The mensuration of hot property that contains the nanofiber of nabumetone
(Wilmington carries out the heat research of nabumetone nanofiber on DE) at MDSC TA.Under per 30 seconds ± 0.159 ℃ modulating frequency, sample is heated to 120 ℃ from 0 ℃ with 2 ℃/minute.The sodium rice fiber that contains nabumetone is being equivalent to 50 ℃ of the fusing of POLYOX and nabumetone and 75 ℃ two kinds of different heat absorption phenomenons of appearance down respectively, this moment, the content of nabumetone was higher than 30% (wt.), be lower than this content and only observe a kind of fusing heat absorption phenomenon, this is owing to forming eutectic or causing because heat absorption takes place simultaneously.
Nabumetone content (wt.%) The fusing point of POLYOX ℃ and Δ H The fusing point of nabumetone ℃ and Δ H
Embodiment 8 81.2 49.4(22.2J/g) 75(80J/g)
Embodiment 7 84.4 51.5(22.4J/g) 75.3(82.4J/g)
Embodiment 6 82.9 50.5(19.6J/g) 75.3(87.3J/g)
Embodiment 5 60.3 49.2(87.4J/g) 69(86.2J/g)
Embodiment 4 35.9 45.1(69.1J/g) 59(7.39J/g)
Embodiment 3 30.1 47(101J/)
Embodiment 2 29.3 48(94.5J/g)
Embodiment 13
40% cis-4-cyano group-4-[3-(cyclopentyloxy)-4-methoxyphenyl]
The electrospinning silk of-cyclohexane-carboxylic acid compositions
Add cis-4-cyano group-4-[3-(cyclopentyloxy)-4-methoxyphenyl of 0.5g in from the POLYOX WSRN-3000 solution of embodiment 3 to 10ml]-cyclohexane-carboxylic acid and 1mL acetonitrile and 0.1mLTween TM80 and obtain a kind of homogeneous solution.With the same terms described in the foregoing description 1 under gained solution carried out the electrospinning silk and obtain containing the nanofiber of title compound.
Embodiment 14
(S)-the electrospinning silk of 3-hydroxyl-2-phenyl-N-(1-phenyl propyl)-4-quinoline formyl amine composition
(S)-3-hydroxyl-2-phenyl-N-(1-phenyl propyl)-4-quinoline formyl amine of 400 milligrams are dissolved in the oxolane (G.T Baker) of 5mL.The POLYOX WSR-1105 (900K) and the 50mg vitamin E-TPGS (Eastman) that in this solution, add 450mg.Till under 37 ℃ this mixture being remained to entire solid matters in shaking bath and being dissolved into viscosity solution.Reduce the viscosity of this solution by the 5mL acetonitrile that adds.Similar condition is carried out the electrospinning silk to gained solution in use and the foregoing description 1, but uses feed pressure and the 16KV of 0.5psi, thereby obtains the fiber of 0.5g.
Embodiment 15
4-[2-(dipropyl amino) ethyl]-1, the electrospinning silk of 3-dihydro-2H-indol-2-one one hydrochlorate
200 milligrams ropiniroles (Ropirinole) are dissolved in the milliQ water of 15mL.The POLYOX that in this solution, adds 1g WSR N3000 NF and 50mg Tween 80.Under 37 ℃ with this mixture till persistent oscillation to entire solid matters is dissolved into clarifying viscosity solution in water-bath.Under the feed pressure of 1psi and 16KV, use with the foregoing description 1 in similarly condition this solution is carried out the electrospinning silk and obtains the described material of 0.8g.
Embodiment 16
4-[2-(dipropyl amino) ethyl]-1, the electrospinning silk of 3-dihydro-2H-indol-2-one one hydrochlorate
350 milligrams ropiniroles (Ropirinole) are dissolved in the milliQ water of 15mL.The POLYOX that in this solution, adds 650mg WSR N3000 NF and 50mg Tween 80.Under 37 ℃ with this mixture till persistent oscillation to entire solid matters is dissolved into clarifying viscosity solution in water-bath.Under the feed pressure of 1psi and 16KV, use with the foregoing description 1 in similarly condition this solution is carried out the electrospinning silk and obtains the material of 0.7g.
Embodiment 17
The electrospinning silk of paroxetine (Paroxefine)
100 milligrams paroxetines are dissolved in the milliQ water of 20mL.The POLYOX that in this solution, adds 800mg WSR N3000 NF and 50mg Tween 80.Under 37 ℃ with this mixture till persistent oscillation to entire solid matters is dissolved into clarifying viscosity solution in water-bath.Under the feed pressure of 1psi and 16KV, use with the foregoing description 1 in similarly condition this solution is carried out the electrospinning silk and obtains the material of 0.75g.
Embodiment 18
The electrospinning silk of granisetron (Kytril)
300 milligrams Kytril are dissolved in the milliQ water of 15mL.The POLYOX that in this solution, adds 650mg WSR N3000 NF and 50mg Tween 80.Under 37 ℃ with this mixture till persistent oscillation to entire solid matters is dissolved into clarifying viscosity solution in water-bath.Under the feed pressure of 1psi and 16KV, use with the foregoing description 1 in similarly condition this solution is carried out the electrospinning silk and obtains the material of 0.7g.
Embodiment 19
10%2,3-dihydro-5-methyl-N-[6-(2-pyridine radicals methoxyl group)-3-pyridine radicals]
The electrospinning silk of-6-(trifluoromethyl)-1H-indole-1-Methanamide compositions
By shaken overnight in 35 ℃ water-bath with 850 milligrams POLYOX WSR-1105 (900K) is dissolved in the 20ml acetonitrile.This system forms a kind of dense condensed viscosity solution.Vitamin E-the TPGS (Eastman) and the stirring that in this solution, add positive methyl pyrrolidone (NMP) and the 50mg of 5ml.The 100mg title compound that will be dissolved in 1ml NMP joins in this polymer solution.Under the condition identical, the settled solution that obtains carried out the electrospinning silk and obtain the product of 0.5g with embodiment 1.
Embodiment 20
20%2,3-dihydro-5-methyl-N-[6-(2-pyridine radicals methoxyl group)-3-pyridine radicals]
The electrospinning silk of-6-(trifluoromethyl)-1H-indole-1-Methanamide compositions
By shaken overnight in 35 ℃ water-bath with 750 milligrams POLYOX WSR-1105 (900K) is dissolved in the 20ml acetonitrile.This system forms a kind of dense condensed viscosity solution.Vitamin E-the TPGS (Eastman) and the stirring that in this solution, add positive methyl pyrrolidone (NMP) and the 50mg of 5ml.The 200mg title compound that will be dissolved in 1ml NMP joins in this polymer solution.Under the condition identical, the settled solution that obtains carried out the electrospinning silk and obtain the product of 0.7g with embodiment 1.
Embodiment 21
The electrospinning silk of 68% nabumetone compositions
The nabumetone of 3 grams is dissolved in the 20ml acetonitrile.In this solution, add 0.25g vitamin E-TPGS (Eastman), 0.8g POLYOX WSR-1105 (900K) and 0.25g Tween 80.Under 37 ℃ with this mixture till persistent oscillation to entire solid matters is dissolved into a kind of viscosity solution in water-bath.Similar condition is carried out the electrospinning silk to gained solution in use and the foregoing description 1, but uses feed pressure and the 16KV of 0.5psi, thereby obtains the fiber of 3.5g.
The include but not limited to patent and the patent application of quoting in this description are incorporated herein by reference at interior whole open source literatures, just introduce the present invention as a reference as each piece open source literature is refered in particular to single piece of full text.
Above-mentioned description discloses the present invention fully, comprises its preferred embodiment.To the modification of the concrete disclosed embodiment of the present invention with improve the scope that all belongs to claims.Although do not describe in further detail, think that those skilled in the art can use the content fullest ground of above-mentioned description to use the present invention.Therefore, embodiments of the invention only are for the purpose explained rather than will limit scope of the present invention by any way.The present invention will be defined as follows with the claim of exclusive right and exclusive right protection.

Claims (49)

1. the pharmaceutical composition of an electrospinning silk, the fiber that contains the electrospinning silk that pharmaceutically acceptable polymer support and pharmaceutically acceptable activating agent be combined into one, this activating agent is that be slightly soluble in water or water-fast, and described polymer support is selected from poly(ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, hyaluronic acid, alginate, carrageenin, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, Hydroxypropyl Methylcellulose Phathalate, the cellulose acetate phthalate ester, starch, hetastarch, sodium starch glycollate, chitosan and derivant thereof, albumin, gelatin, collagen protein, polyvinyl acetate, methylcellulose, ethyl cellulose, noncrystalline cellulose, polyacrylate and derivant thereof, poly-('alpha '-hydroxy acids) and copolymer thereof, polycaprolactone, poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester), poly-(a-amino acid) and copolymer thereof, poe, group of polyphosphazenes, poly phosphate or polyanhydrides; Wherein the spinning fibre of gained contains the active agent particle of nano-scale particle size.
2. the compositions of claim 1, wherein said activating agent is dispersed in the described fiber with carrier.
3. claim 1 or 2 compositions, wherein said activating agent is water-insoluble.
4. claim 1 or 2 described compositionss, wherein said activating agent is slightly soluble in water.
5. claim 1 or 2 compositions, wherein said polymer support is water miscible.
6. claim 1 or 2 compositions, wherein said polymer support is water-insoluble.
7. the described compositions of claim 1, wherein said composition further contains surfactant, and this surfactant is: oxirane and propylene oxide block copolymer; Lecithin; Dioctyl sodium sulphosuccinate; Sodium lauryl sulphate; Polyoxyethylene sorbitan fatty acid ester; Fatty acid esters of sorbitan; Triton X-100 sulfuric ester sodium salt; Polyethylene Glycol; Glyceryl monostearate; D-alpha-tocopherol cetomacrogol 1000 succinate; Sucrose fatty acid ester; Or the mixture of above-mentioned substance.
8. the described compositions of claim 7, wherein sucrose fatty acid ester is stearic acid sucrose ester, oleic acid sucrose ester, Palmic acid sucrose ester, lauric acid sucrose ester or acetic acid butanoic acid sucrose ester.
9. claim 1,7 or 8 described compositionss, wherein said composition further comprises absorption enhancer.
10. the described compositions of claim 1, said composition provide the effect that hides the activating agent taste.
11. the described compositions of claim 5, wherein said polymer support are poly(ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, hyaluronic acid, alginate, carrageenin, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, Hydroxypropyl Methylcellulose Phathalate, cellulose acetate phthalate ester, starch, hetastarch, sodium starch glycollate, chitosan and derivant, albumin, gelatin or collagen protein.
12. the described compositions of claim 1, wherein said polymer support is: polyvinyl acetate, methylcellulose, ethyl cellulose, noncrystalline cellulose, polyacrylate and derivant thereof; Poly-('alpha '-hydroxy acids) and copolymer thereof, polycaprolactone, poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester), poly-(a-amino acid) and copolymer, poe, group of polyphosphazenes, poly phosphate or polyanhydrides.
13. the described compositions of claim 1, wherein said activating agent is an analgesic, the antibiotic medicine, anthelmintic, anti-arrhythmic, antibiotic, anticoagulant, antidepressants, antidiabetic drug, antuepileptic, antihistaminic, antihypertensive, anti-gill fungus alkali medicine, antimycobacterial drug, antineoplastic agent, immunosuppressant, antithyroid drug, antiviral agents, antianxiety drug, astringent, the B-adrenergic receptor blocker, contrast agent, corticosteroid, anti-tussive agents, diuretic, dopaminergic, the homeostasis agent, immunizing agent, the fat regulator, muscle relaxant, intend the parasympathetic functions medicine, the parathyroid gland medicine, calcitonin, prostaglandin, radiopharmaceutical, gonadal hormone, antiallergic agent, antihistaminic, stimulant, sympathomimetic, thyroid, vasodilation, PDE IV inhibitor; Or the mixture of said medicine.
14. the described compositions of claim 13, wherein gonadal hormone is a steroid.
15. the described compositions of claim 13, wherein said activating agent are antibiotic medicine or PDE IV inhibitor.
16. the described compositions of claim 15, wherein said activating agent are nabumetone, aspirin, cis-4-cyano group-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-cyclohexane-carboxylic acid or (S)-3-hydroxyl-2-phenyl-N-(1-phenyl propyl)-4-quinoline formyl amine.
17. the described compositions of claim 13, wherein said activating agent are ropinirole, paroxetine or granisetron.
18. the described compositions of claim 1, wherein said compositions is the form of oral drugs.
19. the described compositions of claim 1, the activating agent in the non-electrospinning silk compositions wherein, the activating agent in the electricity spinning fibre has shown the bioavailability of improving.
20. the described compositions of claim 1, electricity spinning fibre are wherein made capsule or are pressed into tablet.
21. the described compositions of claim 1, wherein electricity spinning fibre further grinds to form littler granularity.
22. the described compositions of claim 1, wherein said composition is Expidet.
23. the described compositions of claim 1, wherein compositions is the form of oral drugs, and described activating agent is the form that controlled release, slow release or pulsation discharge from electricity spinning fibre.
24. the described compositions of claim 1, wherein said activating agent are the form that discharges at once from electricity spinning fibre.
25. method for preparing the pharmaceutical composition of electrospinning silk, said composition comprises pharmaceutically acceptable activating agent and pharmaceutically acceptable polymer support, wherein this activating agent is that be slightly soluble in water or water-fast, described polymer support is selected from poly(ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, hyaluronic acid, alginate, carrageenin, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, Hydroxypropyl Methylcellulose Phathalate, the cellulose acetate phthalate ester, starch, hetastarch, sodium starch glycollate, chitosan and derivant thereof, albumin, gelatin, collagen protein, polyvinyl acetate, methylcellulose, ethyl cellulose, noncrystalline cellulose, polyacrylate and derivant thereof, poly-('alpha '-hydroxy acids) and copolymer thereof, polycaprolactone, poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester), poly-(a-amino acid) and copolymer thereof, poe, group of polyphosphazenes, poly phosphate or polyanhydrides, this method comprises the following steps:
A) with acceptable solvent pharmaceutically activating agent and pharmaceutically acceptable polymer support are made solution; With
B) solution in the step (a) is electrospun to fiber, wherein activating agent is the granule of nano-scale particle size.
26. the described method of claim 25, wherein said solvent can be miscible with water.
27. the described method of claim 25, wherein said solvent are not miscible with water.
28. claim 26 or 27 described methods, wherein said solution is the mixture of one or more solvents.
29. the described method of claim 28, wherein said solvent be water and can with the mixture of the miscible solvent of water.
30. the described method of claim 25, wherein said polymer support are poly(ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, hyaluronic acid, alginate, carrageenin, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, Hydroxypropyl Methylcellulose Phathalate, cellulose acetate phthalate ester, starch, hetastarch, sodium starch glycollate, chitosan and derivant, albumin, gelatin or collagen protein.
31. the described method of claim 25, wherein said polymer support is: polyvinyl acetate; Methylcellulose; Ethyl cellulose; Noncrystalline cellulose; Polyacrylate and derivant thereof; Poly-('alpha '-hydroxy acids) and copolymer thereof, poly-(caproic acid lactone), poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester), poly-(a-amino acid) and copolymer thereof; Poly-(ortho esters); Group of polyphosphazenes; Poly-(phosphate ester); Or polyanhydrides.
32. the described method of claim 25, wherein said activating agent is an analgesic, the antibiotic medicine, anthelmintic, anti-arrhythmic, antibiotic, anticoagulant, antidepressants, antidiabetic drug, antuepileptic, antihistaminic, antihypertensive, anti-gill fungus alkali medicine, antimycobacterial drug, antineoplastic agent, immunosuppressant, antithyroid drug, antiviral agents, antianxiety drug, astringent, the B-adrenergic receptor blocker, contrast agent, corticosteroid, anti-tussive agents, diuretic, dopaminergic, the homeostasis agent, immunizing agent, the fat regulator, muscle relaxant, parasympathomimetic agent, the parathyroid gland medicine, calcitonin, prostaglandin, radiopharmaceutical, gonadal hormone, antiallergic agent, antihistaminic, stimulant, sympathomimetic, thyroid, vasodilation, PDE IV inhibitor; Or the mixture of said medicine.
33. the described method of claim 32, wherein gonadal hormone is a steroid.
34. the described method of claim 25, wherein said activating agent are antibiotic medicine, PDE IV inhibitor, nabumetone, aspirin, cis-4-cyano group-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-cyclohexane-carboxylic acid or (S)-3-hydroxyl-2-phenyl-N-(1-phenyl propyl)-4-quinoline formyl amine, granisetron, ondansetron, paroxetine, Ariflo or ropinirole.
35. the described method of claim 25, wherein this activating agent is water-insoluble.
36. the described method of claim 26, wherein this activating agent is slightly soluble in water.
37. product according to each described method production among the claim 25-36.
38. preparation of drug combination method that contains the electrospinning silk of pharmaceutically acceptable activating agent and pharmaceutically acceptable polymer support, wherein this activating agent is that be slightly soluble in water or water-fast, described polymer support is selected from poly(ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, hyaluronic acid, alginate, carrageenin, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, Hydroxypropyl Methylcellulose Phathalate, the cellulose acetate phthalate ester, starch, hetastarch, sodium starch glycollate, chitosan and derivant thereof, albumin, gelatin, collagen protein, polyvinyl acetate, methylcellulose, ethyl cellulose, noncrystalline cellulose, polyacrylate and derivant thereof, poly-('alpha '-hydroxy acids) and copolymer thereof, polycaprolactone, poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester), poly-(a-amino acid) and copolymer thereof, poe, group of polyphosphazenes, poly phosphate or polyanhydrides, this method comprises the following steps:
A) make described activating agent and polymer support fusion; With
B) molten mass in the step (a) is electrospun to fiber, wherein activating agent is the granule of nano-scale particle size.
39. the described method of claim 38, wherein said polymer support are poly(ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, hyaluronic acid, alginate, carrageenin, sodium carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, Hydroxypropyl Methylcellulose Phathalate, cellulose acetate phthalate ester, starch, hetastarch, sodium starch glycollate, chitosan and derivant, albumin, gelatin or collagen protein.
40. the described method of claim 38, wherein said polymer support is: polyvinyl acetate; Methylcellulose; Ethyl cellulose; Noncrystalline cellulose; Polyacrylate and derivant thereof; Poly-('alpha '-hydroxy acids) and copolymer thereof, poly-(caproic acid lactone), poly-(lactide-Acetic acid, hydroxy-, bimol. cyclic ester), poly-(a-amino acid) and copolymer thereof; Poly-(ortho esters); Group of polyphosphazenes; Poly-(phosphate ester); Or polyanhydrides.
41. the described method of claim 38, wherein said activating agent is an analgesic, the antibiotic medicine, anthelmintic, anti-arrhythmic, antibiotic, anticoagulant, antidepressants, antidiabetic drug, antuepileptic, antihistaminic, antihypertensive, anti-gill fungus alkali medicine, antimycobacterial drug, antineoplastic agent, immunosuppressant, antithyroid drug, antiviral agents, antianxiety drug, astringent, the B-adrenergic receptor blocker, contrast agent, corticosteroid, anti-tussive agents, diuretic, dopaminergic, the homeostasis agent, immunizing agent, the fat regulator, muscle relaxant, parasympathomimetic agent, the parathyroid gland medicine, calcitonin, prostaglandin, radiopharmaceutical, gonadal hormone, antiallergic agent, antihistaminic, stimulant, sympathomimetic, thyroid, vasodilation, PDE IV inhibitor; Or the mixture of said medicine.
42. the described method of claim 41, wherein gonadal hormone is a steroid.
43. the described method of claim 38, wherein said activating agent are antibiotic medicine, PDE IV inhibitor, nabumetone, aspirin, cis-4-cyano group-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-cyclohexane-carboxylic acid or (S)-3-hydroxyl-2-phenyl-N-(1-phenyl propyl)-4-quinoline formyl amine, granisetron, ondansetron, paroxetine, Ariflo or ropinirole.
44. the method for claim 38, wherein this activating agent is water-insoluble.
45. the method for claim 38, wherein this activating agent is slightly soluble in water.
46. the described method of claim 38, wherein activating agent is homodisperse by the carrier in the fiber.
47. the product that each described method is produced among the claim 38-46.
48. the application of the compositions of claim 1 in anapnotherapy.
49. the application of the compositions of claim 1 in water dispersion solution.
CNB018042422A 2000-01-28 2001-01-25 Electrospun pharmaceutical compositions Expired - Fee Related CN1223340C (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107072937A (en) * 2014-06-10 2017-08-18 德姆特里特有限公司 The active material of given dose is applied to the composition of skin or mucous membrane by being used for comprising the fiber obtained by Hydroelectric power

Families Citing this family (115)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9910505D0 (en) 1999-05-06 1999-07-07 Electrosols Ltd A method and apparatus for manufacturing consumable tablets
CA2464092C (en) * 2000-10-18 2013-03-12 Virginia Commonwealth University Intellectual Property Foundation Electroprocessing in drug delivery and cell encapsulation
AU2002225700A1 (en) * 2000-11-17 2002-05-27 Virginia Commonwealth University Intellectual Property Foundation Electroprocessed collagen
JP2010163435A (en) * 2000-11-17 2010-07-29 Virginia Commonwealth Univ Intellectual Property Foundation Electroprocessed collagen
WO2002074191A2 (en) * 2001-03-20 2002-09-26 Nicast Ltd. Portable electrospinning device
US6685956B2 (en) * 2001-05-16 2004-02-03 The Research Foundation At State University Of New York Biodegradable and/or bioabsorbable fibrous articles and methods for using the articles for medical applications
GB0123951D0 (en) * 2001-10-05 2001-11-28 Glaxo Group Ltd Therapies for treating respiratory diseases
EP1469832B2 (en) 2002-02-01 2016-10-26 Bend Research, Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials
KR100549140B1 (en) * 2002-03-26 2006-02-03 이 아이 듀폰 디 네모아 앤드 캄파니 A electro-blown spinning process of preparing for the nanofiber web
JP4969768B2 (en) 2002-04-04 2012-07-04 ザ ユニバーシティ オブ アクロン Nonwoven fiber assembly
US8367570B2 (en) 2002-04-04 2013-02-05 The University Of Akron Mechanically strong absorbent non-woven fibrous mats
WO2003087443A1 (en) * 2002-04-11 2003-10-23 Secant Medical, Inc. Covering process using electrospinning of very small fibers
TW200410714A (en) * 2002-08-07 2004-07-01 Smithkline Beecham Corp Electrospun amorphous pharmaceutical compositions
US20060083784A1 (en) * 2002-08-07 2006-04-20 Smithkline Beecham Corporation Amorphous pharmaceutical compositions
WO2004062697A2 (en) 2003-01-07 2004-07-29 Tufts University Silk fibroin materials and use thereof
CA2532931A1 (en) 2003-08-04 2005-02-10 Pfizer Products Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
US8974823B2 (en) 2003-12-31 2015-03-10 Bend Research, Inc. Solid compositions of low-solubility drugs and poloxamers
JP4526851B2 (en) * 2004-03-31 2010-08-18 明彦 谷岡 Polysaccharide nanoscale fibers and compacts
WO2006006746A1 (en) * 2004-07-09 2006-01-19 Hak-Yong Kim Polymer particles, and a method for manufacturing the same
CN100577720C (en) * 2005-03-21 2010-01-06 中国科学院化学研究所 Biodegradable and absorb polymer nano fibrous membrane materials and method for making and purposes
JP2006299459A (en) * 2005-04-20 2006-11-02 National Institute For Materials Science Method for producing biodegradable polymer nonwoven fabric tube
CN1300393C (en) * 2005-07-01 2007-02-14 中国科学院长春应用化学研究所 Preparation method of ultrafine fiber medical agent type emulsion electro spinning fiber
WO2007011030A1 (en) * 2005-07-21 2007-01-25 National Institute For Materials Science Device for inhalation of medicine
JP4787585B2 (en) * 2005-09-29 2011-10-05 帝人株式会社 Manufacturing method of fiber structure by electrostatic spinning method
CN100556399C (en) * 2005-12-23 2009-11-04 中国科学院广州化学研究所 A kind of intestine target medicinal controlled release fiber and preparation method thereof
US8367112B2 (en) 2006-02-28 2013-02-05 Alkermes Pharma Ireland Limited Nanoparticulate carverdilol formulations
KR100824719B1 (en) * 2006-09-04 2008-04-24 주식회사 아모메디 Bio-degradable food-packing materials consisting of starch-contained nonwoven-nanofabrics and preparation methods therefor
WO2009120365A2 (en) * 2008-03-27 2009-10-01 Agigma, Inc. Methods and compositions for the delivery of agents
EP2262470B1 (en) 2008-04-16 2017-07-05 The Procter & Gamble Company Non-lathering personal care composition in the form of an article
EP2328567A2 (en) 2008-08-08 2011-06-08 Basf Se Continuous fiber layer comprising an active substance on the basis of bio-polymers, the use thereof, and method for the production thereof
JP2011530661A (en) 2008-08-08 2011-12-22 ビーエーエスエフ ソシエタス・ヨーロピア Active ingredient-containing fiber surface structure with controlled release of active ingredient, its use and method for its production
CN101721751B (en) * 2008-10-10 2013-01-02 张阳德 Human tissue engineering support loaded with controlled-release cell growth factor and provided with hollow silicon dioxide ball with kernel and preparation method and applications thereof
US20100291182A1 (en) * 2009-01-21 2010-11-18 Arsenal Medical, Inc. Drug-Loaded Fibers
KR101065255B1 (en) * 2009-02-13 2011-09-16 김근형 New drug delivery system using electrospinning of biodegradable polymers
CN101559242B (en) * 2009-05-22 2015-07-29 广州迈普再生医学科技有限公司 A kind of can simultaneously as the nano artificial cerebral dura mater and preparation method thereof of drug controlled release system
WO2011029777A1 (en) 2009-09-11 2011-03-17 Basf Se Methods for producing coated polymer fibers
MX339322B (en) 2009-12-08 2016-05-20 Procter & Gamble A porous, dissolvable solid substrate and surface resident coating comprising matrix microspheres.
EP2536386A1 (en) 2010-02-16 2012-12-26 The Procter & Gamble Company A porous, dissolvable solid substrate and surface resident coating comprising a zync pyrithione
CN101816627B (en) * 2010-04-16 2012-03-07 浙江大学 Synergistic treatment type multi-material sustained-release eye drop and preparation method
WO2012003365A1 (en) * 2010-07-02 2012-01-05 The Procter & Gamble Company Filaments comprising an ingestible active agent nonwoven webs and methods for making same
WO2012003360A2 (en) 2010-07-02 2012-01-05 The Procter & Gamble Company Detergent product and method for making same
MX2012015169A (en) * 2010-07-02 2013-05-09 Procter & Gamble Filaments comprising a non-perfume active agent nonwoven webs and methods for making same.
CA2803629C (en) 2010-07-02 2015-04-28 The Procter & Gamble Company Filaments comprising an active agent nonwoven webs and methods for making same
RU2607747C1 (en) 2010-07-02 2017-01-10 Дзе Проктер Энд Гэмбл Компани Method for producing films from non-woven fabrics
CN103025930B (en) 2010-07-02 2014-11-12 宝洁公司 Method for delivering an active agent
CN102970987A (en) 2010-07-02 2013-03-13 宝洁公司 Methods of delivering a health care active by administering personal health care articles comprising a filament
MX360481B (en) * 2010-07-02 2018-11-05 Procter & Gamble Dissolvable fibrous web structure article comprising active agents.
US20180163325A1 (en) 2016-12-09 2018-06-14 Robert Wayne Glenn, Jr. Dissolvable fibrous web structure article comprising active agents
CN101915797B (en) * 2010-07-27 2011-09-28 北京师范大学 Method for preparing electrostatic spinning immobilized laccase electrode
US9808418B2 (en) 2010-11-26 2017-11-07 University Of The Witwatersrand, Johannesburg Pharmaceutical dosage form
WO2012084427A1 (en) 2010-12-22 2012-06-28 Unilever Nv Compositions comprising structured non-aqueous liquid phase
WO2012084441A1 (en) 2010-12-22 2012-06-28 Unilever Nv Compositions in the form of fibres
CZ303244B6 (en) 2011-01-17 2012-06-13 Elmarco S.R.O. Carrier for oromucosal, especially sublingual application of physiologically active compounds
CN102251317B (en) * 2011-05-18 2013-01-16 东华大学 Preparation method of electrospun fibers with controllable drug release
WO2013124869A2 (en) * 2012-02-21 2013-08-29 Amrita Vishwa Vidyapeetham University The art, method,manner process and system of fibrous bio-degradable polymeric wafers for the local delivery of therapeutic agents in combinations
CN102631715A (en) * 2012-05-04 2012-08-15 江南大学 Preparation method of anti-coagulation nano fiber membrane
CN102670483B (en) * 2012-05-09 2014-04-02 上海交通大学 Electrostatic spinning fiber membrane preparation for treating hyperlipidemia and preparation method thereof
CN102697727B (en) * 2012-06-12 2014-01-08 东华大学 Method for preparing self-assembly ketoprofen liposome by electrostatic spinning technology
KR101454360B1 (en) 2012-08-31 2014-10-24 서울대학교산학협력단 A gelatin nanofibrous web containing Phaeodactylum triconutum extracts and wound dressing using the same
US11896693B2 (en) 2019-12-01 2024-02-13 The Procter & Gamble Company Hair conditioner compositions with a preservative system containing sodium benzoate and glycols and/or glyceryl esters
MX370280B (en) 2012-10-12 2019-12-09 Procter & Gamble Personal care composition in the form of a dissolvable article.
CZ308409B6 (en) * 2013-02-26 2020-08-05 Elmarco S.R.O. Preparation for the administration of at least one biologically and / or pharmaceutically active substance
WO2014142675A1 (en) 2013-03-12 2014-09-18 Active Fibres Limited Nanofibre and bioactive compositions and related methods
EP2813212A1 (en) 2013-06-10 2014-12-17 Zentiva, a.s. Drug formulation using API in nanofibers
US10202636B2 (en) 2013-12-24 2019-02-12 General Electric Company Electrospun fibers for protein stabilization and storage
WO2015164227A2 (en) 2014-04-22 2015-10-29 The Procter & Gamble Company Compositions in the form of dissolvable solid structures
US9867762B2 (en) 2014-05-05 2018-01-16 The Procter & Gamble Company Consumer product comprising a porous dissolvable solid structure and silicone conditioning agent coating
US9861559B2 (en) 2014-05-05 2018-01-09 The Procter & Gamble Company Consumer product comprising a porous, dissolvable, fibrous web solid structure with a silicone coating
US9877899B2 (en) 2014-05-05 2018-01-30 The Procter & Gamble Company Consumer product comprising a fibrous web structure with a silicone conditioning agent coating
US9827173B2 (en) 2014-05-05 2017-11-28 The Procter & Gamble Company Porous dissolvable solid structure with two benefit agents and methods of forming an aqueous treatment liquor therefrom
US9861558B2 (en) 2014-05-05 2018-01-09 The Procter & Gamble Company Methods of forming an aqueous treatment liquor by dissolving a porous solid with a benefit agent coating
US9937111B2 (en) 2014-05-05 2018-04-10 The Procter & Gamble Company Consumer product comprising a fibrous web solid structure with a silicone conditioning agent coating
CN105362269A (en) * 2014-09-01 2016-03-02 天津药物研究院 Saccharose containing roflumilast tablets and preparation method thereof
BR112017020836A2 (en) * 2015-03-31 2018-07-03 Orthorebirth Co., Ltd. A manufacturing method of the biodegradable fibrin material containing a medicine using electrospinning
EP3319779A4 (en) * 2015-07-07 2019-02-27 Singapore Health Services Pte Ltd A polymer product and preparation thereof
CN105327357B (en) * 2015-10-14 2019-01-11 北京科技大学 A kind of drug-loading system of hyaluronic acid and preparation method thereof of catechol modification
WO2017085264A1 (en) * 2015-11-19 2017-05-26 Dermtreat Aps A pharmaceutical composition comprising electrohydrodynamically obtained fibres, the composition having improved residence time on the application site
WO2017130141A1 (en) * 2016-01-27 2017-08-03 Instar Technologies A.S. Oromucosal nanofiber carriers for therapeutic treatment
CN105727358B (en) * 2016-02-23 2019-01-22 广西易得佳医疗器械有限公司 Drug-loaded biological high-molecular composite nanometer tunica fibrosa and preparation method thereof
CN105663025A (en) * 2016-02-29 2016-06-15 浙江工业大学 Drug-containing microfilament and preparation method thereof
EP3570821B1 (en) 2017-01-23 2021-07-21 AFYX Therapeutics A/S Method for fabrication of a two-layered product based on electrospun fibres
KR102595001B1 (en) 2017-01-23 2023-10-26 에이에프와이엑스 테라퓨틱스 에스에이 Method for producing electrospun fibers with high content of bioadhesive substances
JP6882519B2 (en) 2017-01-27 2021-06-02 ザ プロクター アンド ギャンブル カンパニーＴｈｅ Ｐｒｏｃｔｅｒ ＆ Ｇａｍｂｌｅ Ｃｏｍｐａｎｙ Composition in the form of a soluble solid structure comprising effervescent agglomerated particles
MX2019008762A (en) 2017-01-27 2019-09-18 Procter & Gamble Compositions in the form of dissolvable solid structures.
MX2019013048A (en) 2017-05-16 2019-12-11 Procter & Gamble Conditioning hair care compositions in the form of dissolvable solid structures.
CN107447366A (en) * 2017-08-03 2017-12-08 东华大学 A kind of sensitive medicament-carried sustained release nano fiber films of pH and its preparation method and application
CA3087284C (en) 2018-01-26 2023-05-02 The Procter & Gamble Company Water-soluble unit dose articles comprising enzyme
WO2019147532A1 (en) 2018-01-26 2019-08-01 The Procter & Gamble Company Water-soluble unit dose articles comprising perfume
EP3743503A1 (en) 2018-01-26 2020-12-02 The Procter & Gamble Company Water-soluble articles and related processes
US20190233785A1 (en) 2018-01-26 2019-08-01 The Procter & Gamble Company Water-soluble unit dose articles comprising perfume
WO2019168829A1 (en) 2018-02-27 2019-09-06 The Procter & Gamble Company A consumer product comprising a flat package containing unit dose articles
JP7121944B2 (en) * 2018-05-07 2022-08-19 国立大学法人信州大学 Nanofiber and its manufacturing method
JP1629688S (en) 2018-07-16 2019-04-15
US10982176B2 (en) 2018-07-27 2021-04-20 The Procter & Gamble Company Process of laundering fabrics using a water-soluble unit dose article
US11666514B2 (en) 2018-09-21 2023-06-06 The Procter & Gamble Company Fibrous structures containing polymer matrix particles with perfume ingredients
US11859338B2 (en) 2019-01-28 2024-01-02 The Procter & Gamble Company Recyclable, renewable, or biodegradable package
EP3712237A1 (en) 2019-03-19 2020-09-23 The Procter & Gamble Company Fibrous water-soluble unit dose articles comprising water-soluble fibrous structures
MX2021013141A (en) 2019-06-28 2021-12-10 Procter & Gamble Dissolvable solid fibrous articles containing anionic surfactants.
CN114025738A (en) 2019-07-03 2022-02-08 宝洁公司 Fibrous structures comprising cationic surfactants and soluble acids
USD939359S1 (en) 2019-10-01 2021-12-28 The Procter And Gamble Plaza Packaging for a single dose personal care product
EP4045425B1 (en) 2019-10-14 2024-03-06 The Procter & Gamble Company Biodegradable and/or home compostable sachet containing a solid article
WO2021097691A1 (en) 2019-11-20 2021-05-27 The Procter & Gamble Company Porous dissolvable solid structure
USD941051S1 (en) 2020-03-20 2022-01-18 The Procter And Gamble Company Shower hanger
USD962050S1 (en) 2020-03-20 2022-08-30 The Procter And Gamble Company Primary package for a solid, single dose beauty care composition
USD965440S1 (en) 2020-06-29 2022-10-04 The Procter And Gamble Company Package
CN115867357A (en) 2020-07-31 2023-03-28 宝洁公司 Water-soluble fiber pouch containing spherulites for hair care
WO2022036352A1 (en) 2020-08-11 2022-02-17 The Procter & Gamble Company Clean rinse hair conditioner compositions containing brassicyl valinate esylate
WO2022036354A1 (en) 2020-08-11 2022-02-17 The Procter & Gamble Company Low viscosity hair conditioner compositions containing brassicyl valinate esylate
EP4196233A1 (en) 2020-08-11 2023-06-21 The Procter & Gamble Company Moisturizing hair conditioner compositions containing brassicyl valinate esylate
JP2023553395A (en) 2020-12-01 2023-12-21 ザ プロクター アンド ギャンブル カンパニー Aqueous hair conditioner compositions containing solubilized anti-dandruff actives
CN113041230B (en) * 2021-03-23 2022-06-24 浙江尖峰健康科技有限公司 Capsule shell of soft capsule and soft capsule prepared from capsule shell
KR102653460B1 (en) * 2021-09-01 2024-03-29 한남대학교 산학협력단 A method for manufacturing starch nanofiber comprising collagen and lecithin with controlled degradability
WO2023145886A1 (en) * 2022-01-31 2023-08-03 三菱ケミカル株式会社 Nanofibers
CN114808184A (en) * 2022-03-11 2022-07-29 深圳市法鑫忠信新材料有限公司 Long-acting mosquito-repelling electrostatic spinning fiber and preparation method and application thereof
CN115887422B (en) * 2022-12-31 2024-06-07 兰州交通大学 Lappaconitine knee joint pain relieving sustained-release patch and preparation method thereof

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1527592A (en) * 1974-08-05 1978-10-04 Ici Ltd Wound dressing
US4855326A (en) * 1987-04-20 1989-08-08 Fuisz Pharmaceutical Ltd. Rapidly dissoluble medicinal dosage unit and method of manufacture
US5567439A (en) * 1994-06-14 1996-10-22 Fuisz Technologies Ltd. Delivery of controlled-release systems(s)
US5736152A (en) * 1995-10-27 1998-04-07 Atrix Laboratories, Inc. Non-polymeric sustained release delivery system
US5980941A (en) * 1997-08-20 1999-11-09 Fuisz Technologies Ltd. Self-binding shearform compositions
US5869098A (en) * 1997-08-20 1999-02-09 Fuisz Technologies Ltd. Fast-dissolving comestible units formed under high-speed/high-pressure conditions
US6753454B1 (en) * 1999-10-08 2004-06-22 The University Of Akron Electrospun fibers and an apparatus therefor

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107072937A (en) * 2014-06-10 2017-08-18 德姆特里特有限公司 The active material of given dose is applied to the composition of skin or mucous membrane by being used for comprising the fiber obtained by Hydroelectric power

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