CN1942171B - Liquids containing suspended glass particles - Google Patents

Liquids containing suspended glass particles Download PDF

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Publication number
CN1942171B
CN1942171B CN2005800110373A CN200580011037A CN1942171B CN 1942171 B CN1942171 B CN 1942171B CN 2005800110373 A CN2005800110373 A CN 2005800110373A CN 200580011037 A CN200580011037 A CN 200580011037A CN 1942171 B CN1942171 B CN 1942171B
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China
Prior art keywords
particle
liquid
glassy
density
preparation according
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Expired - Fee Related
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CN2005800110373A
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Chinese (zh)
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CN1942171A (en
Inventor
布鲁斯·约瑟夫·罗泽
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Cambridge Biostability Ltd
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Cambridge Biostability Ltd
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Priority claimed from PCT/GB2005/050050 external-priority patent/WO2005099669A1/en
Publication of CN1942171A publication Critical patent/CN1942171A/en
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Publication of CN1942171B publication Critical patent/CN1942171B/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0019Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Glass Compositions (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Physical Or Chemical Processes And Apparatus (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Present proposals to use perfluorocarbons as a medium to suspend glass particles presents the problem of aggregation of the particles within the suspending medium. Overcoming this problem requires careful particle sizing and density matching techniques. An additional disadvantage of the large scale use of perfluorocarbons is their contribution to global warming. The inventor has realised that by replacing perfluorocarbons with the more environmentally friendly fluorinated ethers such as hydrofluoroethers or hydrofluoropolyethers a long lasting suspension of glass particles can be achieved without the need for such rigorous particle sizing or density matching processes.

Description

The liquid that contains suspended glass particles
The present invention relates to a kind of preparation, it comprises the active component that is deposited in the particle that is suspended in the glassy or unbodied material in the liquid.
Well-known is that saccharifying glass (sugar glass) has some ability organic, biological, phytological and protein material of preservation, and there is lot of documents to be devoted to propose to use this specific character of saccharifying glass to remove preservation medicine, particularly vaccine in theory.Other glassy mass have demonstrated similar preservation effect.
Because the most frequently used acceptable vaccine administration method is the drug administration by injection that passes through that has proposed, for example having been proposed in patent specification WO 02/32402 (Roser) suspends in a kind of liquid (perfluocarbon is perfluorodecalin for example) contains the water-soluble glass shape particle of vaccine to produce a kind of injectable preparation.It is highly stable and be considered to be used for medicine and medical usage is safe because of them to propose perfluocarbon.In patent specification PCT WO02/32402, also propose by in saccharifying glass (density about 1.5), adding the density that calcium phosphate (density about 2.7 to 2.8) increases this glassy mass, so that the Particle Density value that produces is matched with this density of liquid value 1.97, it is suspended in the liquid; Thereby keep them to be in suspended state.
Above-mentioned technology has shown huge hope, but the stability completely of perfluocarbon means that they will be stored in the troposphere lastingly, and if a large amount of the use, may in fact cause global warming.In addition, hydrophilic glassy microsphere particles has shown slight accumulative tendency in perfluocarbon, and perfluocarbon is strong hydrophobic.
According to the present invention, a kind of preparation is provided, it comprises the active component that is deposited in the glassy or unbodied particle, this particle suspension is in liquid, and wherein at least a component comprises the material of hydrogen fluorine ether, perfluor ether, hydrogen fluorine amine, perfluamine, hydrogen fluorine thioether, perfluor thioether, hydrogen perfluoroalkyl polyether, PFPE or following general formula:
R1-X-R2 or
R1-X-(CF2Y) n (CF2CF2Z) m-R2 or
R1-[(X-CF-R2)n-(X-CF2)m]OR3
Wherein X, Y and Z are defined as O (oxygen), ether, NR3 (N=nitrogen), amine or S (sulfur); And each R1, R2 and R3 are defined as nonfluorinated, partially fluorinated or fluorinated alkyl, cycloalkyl, aryl or aralkyl or organo-functional group, halogen group or cyano group fully.
Preferably, hydrogen fluorine ether or hydrogen perfluoroalkyl polyether are considered to ideal, therefore, provide a kind of preparation, and it is included in the active component in the glassy or unbodied particle, and this particle suspension is in the liquid that contains hydrogen fluorine ether or hydrogen perfluoroalkyl polyether.
The inventor finds, when blended glassy particle is added in hydrogen fluorine ether or the hydrogen perfluoroalkyl polyether, their shockingly disperse easily to form cream, even after this suspension has been placed some times, and glassy particle all seldom or not have a sign of luming.
The inventor has been developed now should theory: glassy particle has water-wetted surface, and the previous perfluocarbon that uses was strong hydrophobic.Because this reason is thought now and used in the early stage in the test of perfluocarbon, it is the result that they are ostracised by the hydrophobic property of perfluocarbon that glassy particle has the tendency of together luming.The fluorinated ether performance a bit more resembles the detergent of this particle, promotes this dispersion of nano-particles.
Many fluorinated ether classes at present during operation technique as anesthetis via inhalation.The use of a large amount of relatively during operation technique (going up to 200 grams) has shown the hypotoxicity of this group.
In addition, their density also is complementary with the density of the glassy mass that uses in above-mentioned preparation ideally.For example, with reference to the regulation that is limited in 3M:
HFE 7500 has 1.61 density,
HFE 7200 has 1.43 density, and
HFE 7100 has 1.52 density.
These values as one man are similar to the density of saccharifying glass: about 1.5.
Use another benefit of the present invention to be, when fluorinated ether is exposed to strong ultraviolet radiation and for example is present in stratosphere, be unsettled, and under normal condition, be high stability.This has been avoided relevant to perfluocarbon the known problem that causes damaging " greenhouse " effect when being released into atmosphere after use.
Yet to be fluorinated ether inexpensive relatively and be easy to obtain being higher than 98% high-purity for another advantage of the present invention.This is than the PFC class, and the latter's a exemplary can obtain only about 55% purity.
Because fluorinated ether and glassy mass have so good coupling, it has become and may take the method for new density matching.Past is by using additive formulate glass shape thing to mate its density to liquid PFC.Yet the suitable density that needn't reach as required of becoming is now forced the selection of glassy mass.The invention enables might go to select ideal glassy/the active component compositions; And then fluorinated ether may mix with a small amount of PFC class or other liquid phases that add, so that density of liquid and Particle Density are complementary.Even practicable employing is deposited in the ready-made compositions of the active component in the glassy mass; It is ground into particle also then is suspended in it in a kind of liquid that is complementary with Particle Density.
Particle and density of liquid are not to equate.Yet they should be very approaching, makes the influence of Brownian movement or other thermodynamics keep particle to be in suspended state.
With reference to above, disperse so effectively in fluorinated ether and other liquid because found particle, it is so eager that the as far as possible little needs that suspend with maintenance of particle have not been resembled over.The expert improves dry spray technique, and its past is thought for obtaining small particle diameter required by the inventor, be unwanted now, although the drying process with atomizing of normal business remains a kind of possible technology of preparation particle.Yet, for example lyophilization or grinding of alternative approach also applicatory now.It only needs the particle should be enough little of to allow to pass through hypodermic syringe.
Prospect the present invention, it will be applied to the preparation that the protein of vaccine, treatment or other pass the medication that patient skin injects usually.Yet other purposes of the present invention also are possible, for example: be used for medicinal liquid, its after efflorescence by oral or inhalation.Also possible is, has non-medical usage of the present invention, and it generally is applicable to any situation of the compositions that is desirably in preservation bioactive substance in the glass solid and need exists with liquid form.
Now describe into a kind of method of the present invention.
Obtain aseptic, big quantity of fluid Hepatitis B virus vaccine and aluminium hydroxide adjuvant from Panacea Biotech of Delhi.Itself and aseptic colloid calcium phosphate suspension and Raffinose solution obtain 10 microgram vaccines of the single adult's dosage in 50 milligrams of total solids with suitable mixed.The ratio of calculating calcium phosphate and Raffinose is the solid glass shape particle of hydrogen fluorine ether HFE 7,500 density matching of 1.61 kg/liter to provide with density.With the magnetic stirring apparatus continuous stirring time, this suspension by two flow nozzles with the nozzle air current injection of the speed of 2 milliliters of per minutes with 2.5 kilograms/hour.The droplet that obtains is used per hour 30 kilograms heated air stream drying in the chamber of GEANiro SD Micro aerosol apparatus.Keep feed flow rates constant by regulating inlet temperature, remain on 90 ℃ to regulate outlet temperature.Product is collected in the aseptic bottle, and is transferred in the laminar flow fume hood with 100 classification air-flows.Aseptic HFE7,500 by the speed adding with 1 milliliter in per 100 milligrams of powder, and stirs 10 minutes with this microsphere of abundant dispersion in the frequency sweep ultra sonic bath.In this laminar flow fume hood, liquid is disperseed to enter in the 2 milliliters aseptic serum phial by the volume with 0.6 milliliter, seals with the neoprene stopper jam-pack and with aluminium lid.This vaccine phial is used to be based upon the vitro stability research of this vaccine under the different storage temperatures.

Claims (10)

1. preparation, it comprises the active component that is deposited in glassy or the amorphous particle, and described particle is suspended in the liquid, and wherein said liquid contains at least a in hydrogen fluorine ether or the hydrogen perfluoroalkyl polyether.
2. preparation according to claim 1, wherein said particle contains saccharifying glass or glassy mass, and described saccharifying glass or glassy mass are the combination in any of sugar, metal carboxylate, aminoacid and/or calcium phosphate.
3. preparation according to claim 1, the density that wherein said particle has itself and described density of liquid are complementary, and make that described particle keeps suspending under normal condition.
4. preparation according to claim 1, wherein said liquid also contains perfluocarbon.
5. preparation according to claim 1, wherein said active component are vaccine.
6. preparation according to claim 1, wherein said particle makes by spray drying.
7. preparation according to claim 1, wherein said particle makes by lyophilization.
8. preparation according to claim 1, wherein said particle makes by grinding.
9. method for preparing according to the described preparation of claim 3, it comprises active component is deposited in the glassy or unbodied particle, suspend this particle in liquid, described liquid contains a kind of fluorinated ether, and select the density of perfluocarbon with the matching properties that obtains described needs, then with liquid and described mix particles.
10. preparation, it comprises the active component that is deposited in the glassy or unbodied particle, described particle is suspended in the liquid that contains hydrogen fluorine ether.
CN2005800110373A 2004-04-13 2005-04-13 Liquids containing suspended glass particles Expired - Fee Related CN1942171B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GB0408199.8 2004-04-13
GBGB0408199.8A GB0408199D0 (en) 2004-04-13 2004-04-13 Liquids containing suspended sugar glass particles
GB0504501A GB2413075B (en) 2004-04-13 2005-03-07 Liquids containing suspended glass particles
GB0504501.8 2005-03-07
PCT/GB2005/050050 WO2005099669A1 (en) 2004-04-13 2005-04-13 Liquids containing suspended glass particles

Publications (2)

Publication Number Publication Date
CN1942171A CN1942171A (en) 2007-04-04
CN1942171B true CN1942171B (en) 2011-04-06

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CN (1) CN1942171B (en)
AT (1) ATE457717T1 (en)
DE (1) DE602005019398D1 (en)
DK (1) DK1750668T3 (en)
ES (1) ES2339783T3 (en)
GB (2) GB0408199D0 (en)
MX (1) MXPA06011895A (en)
PT (1) PT1750668E (en)
RU (1) RU2363447C2 (en)
ZA (1) ZA200609158B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0517688D0 (en) * 2005-08-31 2005-10-05 Cambridge Biostability Ltd Improvements in the stabilisation of biological materials
GB0523638D0 (en) 2005-11-21 2005-12-28 Cambridge Biostability Ltd Pharmaceutical device for the administration of substances to patients
US9243626B2 (en) 2012-11-19 2016-01-26 Nordson Corporation Adhesive dispensing system and method including a pump with integrated diagnostics

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6190701B1 (en) * 1999-03-17 2001-02-20 Peter M. Ronai Composition and method for stable injectable liquids
WO2001037804A2 (en) * 1999-11-22 2001-05-31 Universal Preservation Technologies, Inc. Preservation and formulation of bioactive materials
US20020188281A1 (en) * 1997-09-29 2002-12-12 Dellamary Luis A. Stabilized bioactive preparations and method of use

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07258027A (en) * 1994-03-16 1995-10-09 Shiseido Co Ltd Makeup cosmetic
CN100339066C (en) * 2000-10-13 2007-09-26 剑桥生物稳定性有限公司 Stable injecta composition and method

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020188281A1 (en) * 1997-09-29 2002-12-12 Dellamary Luis A. Stabilized bioactive preparations and method of use
US6190701B1 (en) * 1999-03-17 2001-02-20 Peter M. Ronai Composition and method for stable injectable liquids
WO2001037804A2 (en) * 1999-11-22 2001-05-31 Universal Preservation Technologies, Inc. Preservation and formulation of bioactive materials

Also Published As

Publication number Publication date
RU2006137275A (en) 2008-05-20
ES2339783T3 (en) 2010-05-25
GB2413075B (en) 2009-01-21
GB0408199D0 (en) 2004-05-19
MXPA06011895A (en) 2007-11-20
CN1942171A (en) 2007-04-04
PT1750668E (en) 2010-04-07
GB0504501D0 (en) 2005-04-13
DK1750668T3 (en) 2010-05-10
RU2363447C2 (en) 2009-08-10
ZA200609158B (en) 2008-06-25
DE602005019398D1 (en) 2010-04-01
GB2413075A (en) 2005-10-19
ATE457717T1 (en) 2010-03-15

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