CN100339066C - Stable injecta composition and method - Google Patents
Stable injecta composition and method Download PDFInfo
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- CN100339066C CN100339066C CNB008199655A CN00819965A CN100339066C CN 100339066 C CN100339066 C CN 100339066C CN B008199655 A CNB008199655 A CN B008199655A CN 00819965 A CN00819965 A CN 00819965A CN 100339066 C CN100339066 C CN 100339066C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
Abstract
The present invention relates to a composition for transferring stable bioactive compounds to individuals. The composition comprises a first component and a second component, wherein the first component comprises a fine particle of sugar glass or phosphate glass containing a bioactive substance; the sugar glass or the phosphate glass can contain or not contain a glass formation accelerating agent compound, and the second component is composed of at least one kind of biocompatible liquid perfluorocarbon; the first component does not dissolve in the liquid perfluorocarbon and disperses in the liquid perfluorocarbon. Besides, the liquid perfluorocarbon can contain or not contain a surface active agent.
Description
Background technology of the present invention
Vaccine or the drug solution of preparing injection are original just unstable, need cold preservation.Traditional pharmaceuticals industry overcomes this problem of unstable by medicine is carried out lyophilization.Do very waste, inconvenience like this and have certain danger inherently, this is maybe may cause solution to pollute because the wrong reconstruct of dry drug may cause dosage to make a mistake.A century in the past, carried out many effort develop dense, stable, be equipped with injection liquid preparations, but it's a pity not success.Only born firm small-molecule drug may reside in the aqueous solution and has the useful storage life.
This problem is especially sharp-pointed in vaccine industry.During by 2005, estimate that the employed vaccine dose in the whole world can reach 3,600,000,000.The World Health Organization (WHO) has stated and can not use standard vaccine preparation (" change of immunization " (the Revolutionizing Immunizations) that all needs cold preservation in all, Jodar L., Aguado T., Lloyd J. and LambertP-H.Genetic Engineering News on February 15th, 1998).That use at present is " cold-chain (the cold chain) " of cold storage, and it can be transported to it in cities and towns of developing world from vaccine factory.For the health tissues of vaccine enterprise and non-government property, it is huge utilizing cold-chain to carry out immune active cost.WHO estimates that maintenance cost every year of this cold-chain is more than 200,000,000 dollars.In addition, the immunity activity only can be arrived near the people of these last links of living in this cold-chain.
The people that vaccine motion need be carried out medical training is to guarantee the correct sign of dosage being injected and occurred degraded.Some vaccines such as measles, yellow fever and BCG vaccine need be reconstructed, and this also is the problem that need pay close attention in the art.Must accurately operate with the correctness of guaranteeing dosage and in the process of operation and also may introduce potential polluter, this usually can cause calamity clinically.In addition, because owing to the chemical incompatibility of some component makes it to obtain particular mixtures or " multivalence " vaccine, so the vaccine more than usually needing to give once in a period, this may need to carry out multiple injection.WHO by positive encouragement study with obtain not need cold preservation and do not need the stabilization of vaccines of future generation of reconstruct emphasized these problems (" pre-single dose injection device of filling: a kind of safety standards of novel vaccine; or change that immune material transmits? " (Pre-Filled Monodose Injection Devices:A safety standard for new vaccines, ora revolution in the delivery of immunizations?), Lloyd J. and Aguado M.T., WHO publishes, in May, 1998." general policy problem: injectable solid vaccine: the role in following immunization? " (General Policy issues:injectable solidvaccines:a role in future immunization?), Aguado M.T., J ó dar L., Lloyd J., Lambert P.H., WHO publication No.A59781).
A kind of ideal solution of this problem provides the preparation that a kind of completely stable remarks are penetrated.Such stable vaccine may be packaged in becomes independently dosage in the injection device itself, perhaps, for a large amount of immunity is movable, can be transported with the form of larger capacity, does not have the jet injector of syringe needle to carry out administration by a kind of then.Relevant for do description (Sarphie DF, Burkoth TL, the method for use compact substance particulate composition in the percutaneous granule transmits that solid percutaneous transmits by the gas jet injection.PCT publication number WO9748485 (1996)); the percutaneous of dried dna vaccination inoculation obviously very effective (" the hepatitis B dna vaccination of PowderJect is the protection immunoreation that has caused the people of success for the first time " (PowderJect ' s Hepatitis B DNA Vaccine First To Successfully ElicitProtective Immune Response In Humans), http://www.powderject.com/pressreleases.htm (1998)).
The helium supersonic speed that can be used to drive these powder syringes is impacted and is had limited strength, so fine grain dosage can not be carried out the intramuscular transmission.This is because low-quality granule can not obtain the required enough momentum of deep infiltration.Be enough to obtain good immunogenicity though be coated on the percutaneous transmission of the dna vaccination on the aurosol granule, carry out auxiliary common vaccine with insoluble aluminum or calcium salt and can induce unacceptable skin irritation.They must be by intramuscular administration.Required is a kind of can from intradermal to the flexiblesystem that gos deep into transmitting in the intramuscular transmission depth bounds, its degree of depth that can transmit is similar to the degree of depth that can reach with existing pin and injector technology.For a large amount of immunity were movable, this a kind ofly can impel narrow flow of liquid (liquid jet syringe of diameter～0.15mm) enter into " liquid fingernail " has obtained solution, and it uses about 3, the pressure of 000psi by developing.This device can be by on epidermis, passing small hole painless with its dosage by skin-communication in deep subcutaneous or muscular tissue.Provide high momentum the degree of depth to infiltrate for this flow of liquid to guarantee it.Up to now, the medicine of injection and vaccine always are based on water, but because problem of unstable discussed above, and the scope of stabilized aqueous product that can be used for this technology is very limited.
Have realized that now many bioactive molecules by sugar on glass carry out drying and can be stabilized (Roser B. " protections of protein etc. " the UK patent No. is 2,187,191.Roser B and Colaco C. " the biology macromolecular substances and the stabilisation of other organic compound " PCT publication number WO 91/18091.Roser B. and Sen S. " glass of new stabilisation " PCT number of patent application is: 9805699.7,1998 years).These exsiccant stable active substances are not subjected to the influence of hostile environment such as high temperature and ionizing radiation.
Sugar is gamma transition to the remarkable stabilizing mechanism of molecule.When the sugar juice that will comprise bioactive molecule carried out drying, it can crystallize out when reaching the solubility limit of sugar, maybe can become oversaturated syrup.The crystalline ability of sugar opposing is a kind of critical nature of good stabilizing agent.Trehalose has good properties (Green JL.﹠amp in this respect; Angel CA. " phase relationship in the sucrose solution and vitrification and trehalose unusual " .J.Phys.Chem.932880-2882 (1989)) but be not unique.Progressively drying makes this sugar constantly solidify further, becomes a kind of glass under low residual moisture content.This active component liquid solution from water unawares becomes solid solution in the sugared glass of doing.Chemical diffusion in glass is negligible, has therefore in fact stopped chemical reaction.Because Denaturation is a kind of chemical change, it can not take place in glass, so can be with the molecule stabilisation.If can satisfy a kind of other condition, the molecule that exists with this form does not still change.This is a kind of second critical nature of good stabilizing agent, promptly is chemically inert and does not have active.Many glass can not be with reacting with product between the storage life because of them exactly.Tangible problem can take place in reducing sugar, its can form good physics glass but then in typical Maillard reaction their aldehyde group can attack the amino group of product.This is the main cause that many cryodesiccated medicines need cold preservation.Do not have active sugar can provide stable product, do not need to carry out cold preservation.
The biomolecule that is fixed in the sugared glass also is stable in nonaqueous industrial solvent, these molecules itself and sugar all are that insoluble (Cleland JL. and Jones AJS. " the excipient stabilisation of the polypeptide of handling with the organic solvent " patent No. is 5 in the industrial solvent of this non-water, 589,167 United States Patent (USP) (1994)).Because sugared glass can be used as the barrier of impermeability in the liquid of non-solvent,, the biomolecule in the solid solution of glass do not carry out chemical reaction with solvent and environment so can being protected.If this liquid itself is stable, then the responsive product in the glass particle of suspendible has just been formed a kind of stable biphase liquid preparation.The industrial solvent of the described classification of Cleland and Jones (1994) pines for having limited practicality adding.Substitute with the non-aqueous liquid of bio-compatible and can guarantee even least stable medicine, vaccine and diagnostic reagent can be prepared to stable liquid preparation.
Having designed the stable non-aqueous liquid of the first generation is used for medicine or vaccine transmission (B.J.Roser and S.D.Sen " at the stable granule of liquid preparation " is numbered the PCT patent application of GB98/00817, it has described the powder formulation of the stabilisation glass that comprises active component, and it is suspended in injectable oil such as Oleum sesami, Oleum Arachidis hypogaeae semen or the Oleum Glycines or is suspended in simple ester such as the ethyl oleate.By the hydrophilic of the sugared glass particle of suspendible very strong and oily be hydrophobic.Because aqueous favoring and hydrophobic mutually intensive separation trend, so should tend to assembling together by sugar glass.In order to stablize such " Water-In-Oil " type suspension, usually need to use the oil soluble surfactant that is dissolved in the oil-continuous phase.
The surfactant of these low HLB values (hydrophilic value) gathers on the interface between hydrophilic granule and the oil, and with a kind of amphiphilic layer they is coated, and this amphiphilic layer is more compatible with successive oil phase.Because separated by drying oil between the various sugared glass particles, so the interaction of chemistry can not take place between granule.Therefore, some different particle swarms can be arranged in identical Oily preparation, each particle swarm can comprise different may interactional molecule, they can not interact in this oil formulation.Can produce compound polyvalent vaccine in this way.
But, find that subsequently this method has some shortcomings, make it can not form a kind of general solution.Shortcoming comprises the deposition that mix suspension grain inevitably can take place, and it generally has about 1.5g/cm in the lower oiliness excipient of density
3Density.This patent has admitted this problem and has wished to solve this problem below particulate diameter is reduced to 1 μ m, and reducing particulate diameter is in order to make these granules keep the state of suspendible by thermodynamic force such as Brownian movement.Requiring all particulate diameters is a shortcoming for the preparation of being advised less than 1 μ m all.Obtain so little granule easy task anything but.The spray drying scheme of improvement may can accomplish this point but small grain size will make and can not use the cyclone-type catcher and need a kind of filtration system that product reclaims that be used for.
The size that granule is reduced to submicron in theory also is feasible, can reach this target with high pressure trace homogenizer such as micro-fluidisation device (Constant SystemsInc.) after being suspended in this granule in the oil.So just need carry out extra step, and we find spray-dired sugared glass microsphere pulverized and be not very effective, this is because these granules have spheric shape, so have very high mechanical strength.This just need make it repeatedly by this device.Even so, it is uninfluenced also may to have a lot of bigger granules, therefore need subsequently to filter or settling step to remove these bigger granules.The high viscosity of suspension also makes and is difficult to it is drawn in the syringe in common oiliness excipient, and can only inject slowly when injection.Can not resembling in liquid jet injecting systems, it passes through thin nozzle fast.
Also have been found that, be suspended in the granule in the oil, especially when it comprises a kind of surfactant of low HBL value, it is difficult to be extracted in a kind of aqueous environments subsequently, even after the use buffer washs, they are still astonishing tightly to combine, and this is to cause because be looped around the repellency coating of circumgranular oil.Therefore, need carry out ferocious jolting and mixing or need add more water soluble detergent (having high HBL value specifically) again and enter water so that granule leaves oil phase.When particulate granularity diminished, it is more outstanding that this problem becomes.Last result usually is the blended Emulsion of a kind of confusion rather than a kind of obviously isolating biphase.The release that this problem mainly can cause the slow of active substance and be difficult to expect, rather than required rapid and predictable transmission.External, can make oil float when extracting in the aqueous environments above the water that comprises lysed active substance.This is unacceptable in some situation of external application, as in diagnostic kit or automatic measuring system.At last, but the great majority in the natural oil of the clinical practice that FDA ratified all are easy to suffer the infringement of light degradation, oxidation or other form, need be by careful being stored in the dark environment under relatively low temperature.In addition, they are not chemical inertnesses completely, to such an extent as to they can react slowly with the granule of institute suspendible.
Alliance drugmaker after deliberation the application of powder in noticeable new non-aqueous perfluorocarbon liquids of water-soluble substances (Kirkland WD is used to transmit the compositions and the method for active substance, the patent No. is 5,770,181 United States Patent (USP) (1995)).This piece patent major concern be the function of PFC as the oral contrast reinforcing agent of intestinal diagnosing image.Wherein adding cited water-soluble powder is in order to improve the enhancing of palatability or the PFC contrast effect in gastrointestinal tract.Though do not provide embodiment,, Kirkland perceives these liquid also can be used for drug delivery.In this patent, only enumerated especially stable storing at commercially available powder.We find now, and the active substance of stabilized fragility can be used to produce and very stable can be used for oral and biphase PFC liquid preparation parenterai administration in sugared glass microsphere.This has greatly expanded the Kirkland practical applicability, with its extended to be used for transmitting non-intestinal medicine and vaccine do not need to carry out the preparation that the remarks of any form cold preservation are penetrated.Valuable especially is that low viscosity, high density and the low surface tension of having found PFC makes these stable suspensions to transmit by automaton such as liquid jet syringe.This has opened up two important fields for this technology again, promptly a large amount of immune activity and self-injection.
Perfluocarbon (PFC) is novel, the very stable liquid that is obtained by fluoridizing fully of some organic compound.In fact can not be classified as hydrophilic it or lipophilic, because they substantially all can not mix (Krafft MP ﹠amp mutually with oil except that other PFC and water or other any polarity or nonpolar solvent; The summary of Riess JG. " high fluorizated amphiphile and colloidal dispersion, and their application in biomedical sector.Some contribution.”Biochimie?80?489-5141998)。In addition, they had not both had to participate in and oily hydrophobic interaction, did not have the hydrophilic of participation and water or hydroaropic substance to interact again.As a kind of total result who is separated, the hydrophilic granules piece of being seen being combined in strongly among the PFC in oil generally can not taken place.It can not need surfactant just can make stable suspension, but can use fluorohydrocarbon (FHC) surfactant (Krafft ﹠amp; Riess 1998) and its in PFC liquid, under very low concentration, just have activity.Under these low-down concentration, the FHC surfactant can guarantee that some granule can form perfect monodisperse system, and wherein said granule shows accumulative tendency when not having the FHC surfactant.This PFC liquid itself is not have chemically reactively fully, and this volatile liquid of low-molecular-weight type can not accumulate in body, only is at last to be breathed out along with breathing.
Because be the splendid solvent of gas, so the very special clinical practice that PFC is used in a large number always.They are better than the ability of hemoglobin with the ability of carbon dioxide exchange dissolved oxygen.This has obtained confirmation (GeyerRP, Monroe RG ﹠amp at first at R.P.Geyer in nineteen sixty-eight " depletion of blood rat "; Taylor K. " uses the survival condition of the dabbling rat of perfluocarbon-detergent formulations " fully, Organ Perfusion and Preservation, J.V Norman, J Folkman, L.E.Hardison, L.E Ridolf and F.J.Veith edit .Appleton-Century-Crofts, New York, 85-95 (1968)).At present in some operation process as the commodity Oxygent by name of the water bag PFC type Emulsion form of the alternate selection of confession of human blood blood transfusion
TMThe perfluoro-octyl bromide of (AlliancePharmaceutical Corp.) is assessed.The PFC of liquid form is inhaled into the respiratory distress syndrome that is used for the treatment of premature infant in the lung by suction.
High density and the chemical inertness of also finding them are very valuable.With commodity Vitreon by name
TMThe Decafluorophenanthrene of (Vitrophage Inc.) prevents the withering of intra-operative eye capsule, and it also can make the reattachment of retina that breaks away from.PFC also has been used as the contrast agent of nuclear magnetic resonance (MRI), and for this purpose, has also reported hydrophilic powders to be suspended in wherein to improve its imaging or to make it more agreeable to the taste.(Kirkland W.D. " transmits the compositions and the method for active substance ", and the patent No. is 5,770,181 United States Patent (USP), 1998).This piece patent has also hinted the application of PFC as the continuous phase of transmitting microgranular water soluble drug.Because the number of the at room temperature stable non-intestinal medicine that exists with the dry powder state is limited, so this piece patent is inapplicable for most of injectable medicines.But the stabilisation in the microsphere powder of medicine at sugared glass of describing in Roser and Garcia de Castro (1998) combines with injectable PFCs, makes this technology be applicable to all basically non-intestinal medicine and vaccine.
General introduction of the present invention
The present invention uses a kind of two-phase system as the drug delivery preparation, uses PFC as continuous phase in suspension, and it comprises a kind of discontinuous glassy phase.To obtain density range be about 1.5 to 2.5g/cm thereby be different PFC to be mixed based on the major advantage of the preparation of perfluocarbon
3Final mixture.This make microgranule can be prepared to density matching suspendible liquid so that these microgranules can be from the teeth outwards not floating or deposit to the bottom of container and still can keep the form of stable suspersion.Therefore, different with the preparation based on oil, this preparation does not need the microgranule submicronization is prevented deposition that the microgranule in this preparation can alter a great deal in size.Only be just final particulate diameter to be controlled for the purpose of preparation.The preparation of wanting to be used for pin injection or jet injection can comprise 0.1 to 100 micron granule, or preferred 1 to 10 micron.Do like this and can simplify particulate manufacture method greatly and avoided making very tiny particulate necessity by grinding.Carry out simple dry method after spray drying that can be by routine or the lyophilization or wet grinding prepares granule.When in suspension, needing when highly filled, wish that coating of particles is spherical.Granule in irregular shape " combination " thus can suppress free-flow to together trend is stronger, and spheric granule has inherent " lubricity ", thereby guarantees that solids content can reach more than 20%.Such granule can solidify by spray drying, atomizing freeze drying or Emulsion easily and is prepared.
If preparation is appropriate, the powder of this suspendible does not need surfactant just can produce stable suspension, should the almost dissolving immediately of sugar glass particle when water carries out jolting.If regard a spot of gathering as a problem, then can mix preceding or to mix back useful adding in this PFC liquid a spot of as Krafft and the described FHC surfactant of Riess (1998) will stablizing powder.Similar to PFC, the original inertia of these FHC is just very strong and do not have a reactivity.Therefore, there is not particulate solvation and do not have chemical reaction between mutually at the granule of suspendible and PFC.Because should the sugar glass particle and PFC liquid all be stable in environment, so can be owing to light, high temperature, oxygen or the like are degraded.It has in vivo or the external toxicity that can ignore and the authoritative institution that managed deeply test and ratify can be used as a large amount of being infused in animal and human's body of succedaneum of blood.Though reported that high-molecular weight PFC can gather in liver, low-molecular-weight example used in the present invention uses is all discharged from body when exhaling at last.
Their low surface tension and low viscosity guaranteed they be highly susceptible to by in pin, automatic system or the liquid jet syringe of hypodermic syringe the narrow hole that can run into.PFC is an excellent electrical insulators, therefore is easy to obtain to have particulate single dispersive suspension of identical low surface electrostatic lotus.They are exsiccant, and are complete non-hygroscopic liquid.Their extremely low water content has kept the drying property of suspendible powder, has prevented to be entrained in the dissolving or the degraded of active substance wherein.The solvent properties of their uniquenesses lacks the desirable material that property makes it to become the hydrophilic or hydrophobic granule of suspendible, promptly final suspension in fact can with used any substances compatible in container or the transfer device.This is opposite with preparation based on oil, can cause the serious obstruction of syringe based on the preparation of oil, is for example sealed by the rubber on the piston and expands and cause obstruction.Can obtain various density, vapour pressure and volatile PFC, (Table I).Their high density makes them sink in the buffer that great majority are used always, and this product particle that makes it to be easy to being dissolved in the aqueous phase that swims in the top separates.Therefore, this has promoted it in external application such as diagnostics's application.
The present invention describes in detail
The character of some PFC of Table I
| Perfluor- | MW | Density (Kg/L) | Viscosity (mPas) | Surface tension (mN/m) | Vapour pressure (mbar) |
| Hexane just-octane decahydronaphthalene phenanthrene | 338 438 462 624 | 1.682 1.75 1.917 2.03 | 0.656 1.27 5.10 28.4 | 11.1 16.98 17.6 19 | 294 52 8.8 ＜1 |
In Kirkland (1995), hinted the application of PFC as the excipient that transmits pharmacological agents or bioactive substance.This piece patent only enumerated born stable can the commercial seasoning that obtains or effervescent powder or the like.It does not comprise the bioactive substance of any stabilisation such as the example of vaccine or medicine.In addition, it is not considered by prepare the probability of a kind of injectable (non-intestinal) preparation as the suspendible excipient of active particle with PFC.For obtain a kind of have long pot life with PFC as the stabilization formulations of the fragile biomolecule of this lifes of non-aqueous excipient, preferably this preparation of granules one-tenth is comprised can stablize the form of forming of glass agent of adulterated active substance.Can use various sugar, be included in trehalose described in the PCT application that is numbered WO 91/18091, lactose, hydroxyl isomaltulose (palatinit) or the like or be other more effective monosaccharide sugar alcohol or forming of glass agent described in 9820689.9 the UK patent application more preferably at application number.
For prevent granule swim in compact substance PFC mutually above, useful in this granule, add a kind of density adjuster.It can be salt such as sodium chloride or potassium chloride or the sodium sulfate or the potassium sulfate of solubility, or more preferably is a kind of insoluble material such as barium sulfate, calcium phosphate, titanium dioxide or aluminium hydroxide.Preferred insoluble innocuous substance, this is because the release of a large amount of ion salt can cause sizable local pain and stimulation in body.In some cases, as in bacterin preparation, a part such as adjuvant that this insoluble material can be this active ingredient.This density adjuster can exist with the solid solution form in sugared glass particle or can exist with a kind of form that is suspended in the insoluble granule material in the sugared glass.When carrying out appropriate preparation, the density of this sugar glass particle can be approximately and the PFC density of liquid match, buoyancy is moderate, and neither floating not sedimentation again but still non-caking stable suspendible body.
Because PFC liquid is good electrical insulator, resistivity generally is higher than 10
13Ohm.cm is so the small surface charge on mix suspension grain has significant effects for the stability of suspension.For the gathering that prevents that mix suspension grain from taking place owing to weak short distance power, it preferably is prepared to and comprises and can provide the excipient of weak remaining electrostatic charge such as the form of lysine or aspartic acid for this dried granule.Do like this and can prevent aggregation by guaranteeing particulate electrical charge rejection power, this is to viewed similar in stable colloid.Perhaps, can valuably a spot of FHC surfactant such as perfluoro decanoate be dissolved in the dispersive suspension of formation among the PFC, preferably form monodispersed suspension.
These granules can be prepared in various manners, comprise air-dry, spray drying or lyophilization, and these granules do not need especially little, and can be that a kind of diameter is the particulate heterogeneous mixture of 0.1 μ m to 100 μ m.For some application, even can use millimeter-sized particles.
The application of the suspension that these are stable both had been not limited only to parenteral application listed above, was not limited only to again as cited oral application among the Kirkland (1995).Because the PFC liquid excipient is nontoxic and reactionless active, so it is a kind of ideal excipient that is applicable to mucosa, comprise can be used in the lung, intranasal, ophthalmic, internal rectum and intravaginal administration.This piece patent is provided can make stable, aseptic and non-irritating can be used for even the ability of the preparation of the mucosa transmission of very unsettled medicine or vaccine is quite advanced.Because microorganism can not be grown under the situation that lacks water, so during long term storage and batch applications, this very exsiccant and complete non-hygroscopic PFC liquid also very helps to keep the aseptic of these preparations.
Because being used as propellant in inhalant always, volatile for a long time perfluoro-hydrocarbon and chlorofluorocarbon be used to make medicine can be delivered to the depths of lung, so this stable PFC preparation as described herein is the desirable material that is used to prepare transmit fluid STASIS fine mist of small droplets in the lung.For this application, form in the PFC droplet that discontinuous particulate size by the suspendible phase is very important should not to surpass 1 to 5 μ m, the diameter of preferred 0.1 to 1 μ m.For other mucomembranous surface in being passed to nose and eye, the importance of granule size is weaker a little, and can be as high as the diameter of 100 μ m, even can reach the diameter of several mm.
Description of drawings
Fig. 1
Alkaline phosphatase (Sigma Aldrich Ltd.) is by gelatin 33.3% (the Byco C with mannitol 33.3%, calcium lactate 33.3% and degraded, Croda Colloids Ltd.) is the glass institute stabilisation on basis, be spray dried to microsphere, and be stored in 55 ℃ with the form of dry powder or the stable suspension in perfluorodecalin.This activity still is about 100% mark value (20 days be 103%, 30 day be 94%).Be not suspended in dry powder among the PFC and do not have bigger loss (still have an appointment 80% activity)
Fig. 2
A kind of commercial tetanus toxoid vaccine (#T022 that is provided by Evans Medeva plc friendship) is prepared into the powder of density matching by in 20% aqueous trehalose, adding calcium phosphate.With two fluid nozzles it is sprayed onto and comes lyophilization in the liquid nitrogen, then, should carry out lyophilization by freeze dried microsphere powder in the Labconco exsiccator, initial shelf temperature is-40 ℃ between initial dry period.Having injected with saline buffer agent reconstruct or after during 4,8 and 12 weeks of same dose as the ASSIST stabilisation tetanus toxoid vaccine of the anhydrous formulation among oil or the PFC, measure the antibody response of six groups of Cavia porcelluss, every group has 10 Cavia porcelluss.
Be lower than the reaction (not showing) of fresh vaccine control for the reaction of all drying agents, this shows that spray-dired preparation significantly lost immunogenicity.As with catch ELISA measured, dry run does not change the antigenicity of this toxoid.This shows when drying need do the preservation that more work is improved aluminum hydroxide adjuvant.
Basically the vaccine that is reconstructed with in contrast use buffer agent for the reaction of having carried out the STASIS vaccine of density matching with calcium phosphate (group 3) and in oil bag powder-type vaccine (group 2) reacting phase with, and the control animal of only injecting with non-aqueous excipient (organizing 4 and 5) does not show reaction.
The description of preferred embodiment
Embodiment 1:
Spray-dired granule in PFC
Granule is with Labplant SD 1 type spray dryer, and with sugar and other excipient, spray drying is prepared by aqueous solution is carried out.Typical formulation is:
A. mannitol 15%w/v
Calcium lactate 15%w/v
In water
B. trehalose 15%w/v
Calcium phosphate 15%w/v
In water
Two fluid nozzles with the liquid pores with 0.5mm internal diameter prepare this granule.Half that find the maximum nozzle throughput is best, and under the condition of the outlet temperature of 135 ℃ inlet temperature and 70-75 ℃ hothouse operated.Come collecting granules with the glass eddy flow, and by in 4 hours, temperature being risen to gradually 80 ℃ and in a vacuum it to be carried out the second time dry.In case cooling is suspended in it among PFC with ultrasonic.Discovery in MSE MK 2 ultrasound rooms, under about 75% power, operate with ultrasonic energy that 30 seconds bursts is provided with the titanium probe or be immersed in carry out in the Decon FS200 Frequency cleaning ultra sonic bath high just enough to 10 minutes operation.
The suspension of gained is monodispersed and by microscopic examination, its spherical glass granule by about 0.5 to 30 μ m particle size range is formed, and its particle mean size is about 10 μ m.Mannitol/granular calcium lactate just rises to the top of this PFC layer in a few minutes, but it just can be disperseed easily again by jolting lightly.Basic and the PFC of the density of trehalose/calcium phosphate granules matches and has formed stable suspension.
With 1,10,20 and the concentration of 40%w/v the spray-dired powder of sugared glass particle is suspended in perflexane, perfluorodecalin and the Decafluorophenanthrene.Find that they can both obtain the monodispersed suspension of the situation of can assembling hardly.In this PFC, add any slight aggregation tendency that 0.1% perfluoro decanoate can suppress from the teeth outwards to be taken place.Find that these suspensions can be easy to the pin by 25g by sucking or spraying.
Embodiment 2:
The stability of the suspension of the enzyme of stabilizationization in PFC
Come spray drying alkaline phosphatase (SigmaAldrich Ltd.) with the Labplant machine as described above.Said preparation comprises the gelatin (Byco C, Croda colloids Ltd.) 33.3% of mannitol 33.3%w/w, calcium phosphate 33.3%w/w and degraded.The form of this exsiccant enzyme with the form of dry powder or the suspension in perfluorodecalin is stored under 55 ℃.When 55 ℃ of times of placing down were higher than 30 days, the enzymatic activity that the enzyme in these prepared microspheres shows was still near 100%, and wherein said microsphere is formed (Fig. 1) by the glass based on mannitol that is suspended in the perfluorodecalin.
Embodiment 3:
Render a service in the body
Carried out the preclinical test of similar formulations with national biological standard product and reference substance association (having passed through accredited laboratory of World Health Organization (WHO)), clinical tetanus toxoid vaccine (being provided by Medeva plc friendship) is provided wherein said similar formulations.The result of this test shows that ability that this stable STASIS preparation makes Cavia porcellus immunity form the serum antibody response of protectiveness is equal to the aqueous vaccine (Fig. 2) based on water.This confirms that suspension in PFC can form and a kind ofly has in vivo and the conventional preparation of penetrating for the remarks of the identical bioavailability of basic liquid preparation with water.
Embodiment 4:
The granule of atomizing freeze drying
This granule is also by being injected to liquid droplets in the liquid nitrogen, then should refrigerated powder carries out drying in a vacuum and is prepared.These granules are lower than spray-dired particulate density, and form pastel when concentration is higher than 20%w/v in PFC.Under lower concentration, they can form monodispersed suspension after ultrasonic.
Used exemplary formulations is:
Material final concentration w/w
A. trehalose 100%
B. trehalose 50%
Calcium phosphate 49.5%
Aluminium hydroxide 0.5%
Embodiment 5:
The hydrophobic granule that grinds
When from the molten state quenching or from the solution of chloroform or dichloromethane during by rapid draing, hydrophobic sugar derivatives sucrose octaacetate and trehalose eight acetates are easy to form glass.They are described (people such as Roser " the solid transmission system of the controlled release of the molecule that is used for wherein being added with and preparation method thereof " publication number is the PCT application of WO 96/03978,1994) as the application of the controlled release matrix of drug delivery.
Trehalose eight acetate powder can be prepared this melt quenching on corrosion resistant plate by melting in Muffle furnace then.Grind with pestle and mortar sheet glass, with the high-speed homogenization machine it is handled it is prepared into a kind of fine powder then gained.With 1 and the concentration of 10%w/v this powder is suspended in perflexane, perfluorodecalin and the Decafluorophenanthrene.Find that they can provide finely disseminated suspension.Find that these suspensions can pass through the 23g pin easily.
Embodiment 6:
Reconstruct in aqueous environments
Because the person's character of soluble sugar glass particle and the character of PFC, the active component that can predict in these suspensions will discharge rapidly in body.The release fully of the active component that comprises in order to prove becomes to comprise with preparation of granules:
Trehalose 20%w/v
Lysine 0.5%w/v
Mordant Blue 9 dyestuff 1%w/v
With method as above said preparation is carried out spray drying, then it is joined the opaque suspension of the navy blue of making 20%w/v in Decafluorophenanthrene and the perfluorodecalin.After adding the water that equates with suspension volume and carrying out jolting, find that in fact all blue dyess all have been released to aqueous phase, form a kind of clarifying cyan coloring layer that swims on the almost colourless PFC, had obvious interface fully aware of between the two.
Embodiment 7:
Do not have reactivity between the granule in suspension
Because each microsphere in the PFC suspension is that other granule is isolated mutually with all physically,, the material that may react do not have any interactional danger so can coexisting as in the variable grain of identical suspension.When this sugar glass was dissolved, these molecules can be met, and react.
In order to prove this point, prepare a kind of two types of particulate suspensions that comprise, a kind of (a) is enzyme---alkaline phosphatase, another kind of (b) is its colourless substrate, the phosphoric acid p-nitrophenyl.
Preparation is:
A) trehalose 10%w/v
Alkaline phosphatase 20U/ml
In 5mM Tris/HCl buffer agent (pH 7.6)
B) trehalose 10%w/v
Phosphoric acid p-nitrophenyl 0.44%w/v
In the 100mM glycine buffer that comprises 1mM zinc chloride and 1mM magnesium chloride (pH 10.2)
Discovery comprises that the powder suspension does not form any color reaction in the perfluorodecalin of powder " b " of the powder " a " of 10%w/v and 10%w/v when placing for 3 weeks down for 37 ℃, and remains the suspension of white.
After adding entry and carrying out jolting, then this powder dissolution is in top aqueous phase.Enzyme reaction taking place in a few minutes, the true yellow of right-nitrophenol occurs, all this situation can occur in the sample in 3 weeks of placement in freshly prepd sample and under 37 ℃.
Embodiment 8:
Product in " organization space " model discharges
The behavior that the PFC suspension may take place in order to explain in being expelled to body prepares a kind of model---and transparent hydration organization space, this model are to be prepared by the agarose gel that moves heap 0.2% in the polystyrene ampoule.The perfluorodecalin suspension of 0.1ml embodiment 5 is expelled in this agarose gel with the 25g pin.So just formed the ball of the white of a flat suspension.At ensuing 5-10 minute, surplus afterwards next clarifying PFC ball was upwards carried out in the clarification that begins to become from the bottom of ball of this white.Because enzyme and substrate are owing to the dissolving of this glass particle is released, so they react each other and have produced xanchromatic paranitrophenol, it spreads in whole agarose in ensuing 1 hour then.
Embodiment 9:
Density matching
Generally has about 1.5g/cm by the sugared glass particle that any method obtained (being trehalose) in the seasoning of two kinds of routines
3Density.The density of the perfluocarbon that we tested is generally 1.68 to 2.03g/cm
3(Table I).For this reason, when being prepared to suspension, sugared glass particle tend to float to the PFC layer above, will produce a kind of active component like this can not equally distributed preparation.But, in order to prepare a kind of stable suspension in PFC, can carry out modification to powder, these powder have moderate buoyancy in this suspension, and it is non-rising again neither to sink.It can be realized to wherein adding highdensity material before forming at granule.These highdensity materials can be water miscible or water-insoluble.
Non-water soluble substance
Density is 3.14g/cm
3Orthophosphate tricalcique go through as the adjuvant of vaccine and in fact water insoluble.The prepared powder that comprises about 50% calcium phosphate shows density to be increased, and its density is about 2g/cm
3, and in Decafluorophenanthrene, form stable suspension with 20% solid-state amount.
In PFC, the example that forms the powder of stable suspension when 20% amount of solid comprises:
1 in perfluorodecalin
Material final concentration w/w
A. trehalose 50%
Calcium phosphate 50%
B. trehalose 47.5%
Calcium lactate 10.0%
Calcium phosphate 42.5%
2 in Decafluorophenanthrene:
Material final concentration w/w
Mannitol 18.2%
Inositol 18.2%
Calcium lactate 18.2%
Calcium phosphate 45.4%
Other the non-water soluble substance that always is used to increase density comprises barium sulfate and titanium dioxide.Can use any nontoxic and insoluble material with Suitable Density.
Water-soluble substances
Water soluble salt is as having 2.7g/cm
3The sodium sulfate of density also can be used as density enhancing.Following powder can form stable suspension in perfluorodecalin:
Material final concentration w/w
Trehalose 50%
Sodium sulfate 50%
Can also use other nontoxic highdensity water-soluble substances.Have been found that these preparations can cause discomfort after Cavia porcellus is carried out subcutaneous injection, this may be because the rapid dissolving of the ion salt of high concentration causes.
Embodiment 10:
Density matching is to the effect of the active substance in the suspension
Some vaccine is prepared to and is adsorbed onto as the insoluble gel of adjuvant or the form on the granule.Aluminium hydroxide and calcium phosphate are widely used in this purpose.Their particulate density that just can be used to increase of these insoluble adjuvants own by suspendible.In this case, highdensity material is not inert fully, but in fact can be from solution the adsorption activity macromolecule.Must prove that this absorption is not enough to change this activity.For this point is tested, with the active substance/vaccine of alkaline phosphatase as model.
The solution that is prepared as follows:
The calcium phosphate 10%w/v of adjuvant grade (Superphos Kemi a/s)
Trehalose 10%w/v
ZnCl
2 1mM
MgCl
2 1mM
Alkaline phosphatase 20U/ml
In 5mM Tris HCl buffer (pH 7.6)
Then this solution is fully mixed 10 minutes down so that this alkaline phosphatase is adsorbed on the calcium phosphate at 37 ℃.Centrifugal by calcium phosphate is carried out, supernatant is taken a sample, under the wavelength of 405nm, use substrate---the phosphoric acid p-nitrophenyl is measured the trap change value that its enzyme kinetics is measured per minute.This solution is carried out spray drying, obtain a kind of fine powder.Use said method, in supernatant, any desorption of this enzyme after this powder rehydration is measured.Concentration with 20%w/v is suspended in this powder in the Decafluorophenanthrene, and discovery can form a kind of stable suspension.
Test specimen d trap/minute (405nm)
Initial soln (25 μ l) 0.409
The as above supernatant of gained (25 μ l) 0.034
The powder of rehydration (25 μ l, 20%w/v is in water) 0.425
The as above supernatant of gained (25 μ l) 0.004
The powder in perfluorodecalin of 20%w/v (25 μ l) 0.430
This experimental results show that:
By comprising auxiliary calcium phosphate, particulate density can be complementary with the density of PFC carrier.
Significant desorbing or loss of enzyme activity do not take place in the preparation process.
Embodiment 11:
The STASIS preparation of the mannitol based glass of embodiment 1 is suspended in the perfluorodecalin, filling it into a kind of the operation then goes up in polypropylene aerosol apparatus cleaning, pumping action, this aerosol apparatus is used to transmit oxymetazoline nose Decongestant (Sudafed, Warner Lambert) clinically usually.Two bursts of sprayings of this suspension are delivered to respectively in two nostrils of human volunteer, have required these volunteers that the degree of sense of discomfort is assessed.The volunteer reports does not have discomfort at all.Do not observe side effect after the administration.
Claims (12)
1. one kind is used for stable bioactive compound is passed to individual compositions, it comprises the glass particle that contains described bioactive compound, it is characterized in that described particulate diameter range is 0.1 to 100 micron, and described particle suspending is in the liquid that comprises at least a biocompatibility perfluocarbon, and described granule is insoluble to described liquid.
2. compositions as claimed in claim 1 is characterized in that by the described granule of spray drying method for preparation.
3. compositions as claimed in claim 1 or 2 is characterized in that described granule comprises the mixture that contains sugar and metal phosphate.
4. compositions as claimed in claim 1 or 2, wherein said glass is selected from sugared glass, metal carboxylate glass, phosphate glass and composition thereof.
5. compositions as claimed in claim 1 or 2 is characterized in that described granule contains forming of glass promoter.
6. compositions as claimed in claim 1 or 2 is characterized in that described liquid contains surfactant.
7. compositions as claimed in claim 1 or 2, it is characterized in that described granule comprises by being selected from following sugared formed sugared glass: trehalose, sucrose, silk floss sugar, stachyose, glucopyranosyl sorbitol, glucopyranosyl mannitol, hydroxyl isomaltulose, lactose, monosaccharide alcohol or by introducing the glycan molecule that hydrophobic side chain is modified, the glycan molecule of wherein said modification is selected from sucrose octaacetate or trehalose eight acetates.
8. compositions as claimed in claim 1 or 2 is characterized in that described granule comprises divalent metal phosphate or metal carboxylate.
9. compositions as claimed in claim 5 is characterized in that described forming of glass promoter is selected from peptide, protein, glucosan, polyvinylpyrrolidone, borate ion, calcium lactate, sodium polyphosphate and silicate or acetate.
10. compositions as claimed in claim 1 or 2 is characterized in that particulate density and density of liquid are complementary.
11. compositions as claimed in claim 1 or 2 is characterized in that making described microgranule have weak remaining electrostatic charge so that described microgranule repels each other by excipient.
12. compositions as claimed in claim 11, wherein said excipient is an aminoacid.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2000/028244 WO2002032402A1 (en) | 2000-10-13 | 2000-10-13 | Composition and method for stable injectable liquids |
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| CN200510067324A Division CN100594937C (en) | 2000-10-13 | 2000-10-13 | Stable injection composition and method therefor |
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| CN1527699A CN1527699A (en) | 2004-09-08 |
| CN100339066C true CN100339066C (en) | 2007-09-26 |
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| EP (1) | EP1328255A1 (en) |
| JP (1) | JP2004513093A (en) |
| KR (1) | KR20030096224A (en) |
| CN (1) | CN100339066C (en) |
| AU (2) | AU2001211986B2 (en) |
| CA (2) | CA2424656C (en) |
| ES (1) | ES2337252T3 (en) |
| MX (1) | MXPA03003236A (en) |
| NO (1) | NO20031706L (en) |
| PL (1) | PL360052A1 (en) |
| PT (1) | PT1452171E (en) |
| WO (1) | WO2002032402A1 (en) |
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| JPWO2004037293A1 (en) * | 2002-10-22 | 2006-02-23 | 大日本住友製薬株式会社 | Stabilizing composition |
| JP2007001865A (en) * | 2003-09-16 | 2007-01-11 | Ltt Bio-Pharma Co Ltd | Fine particle enclosing fat-soluble medicine, method for producing the same and preparation containing the same |
| AU2005232441B2 (en) | 2004-04-13 | 2010-11-11 | Cambridge Biostability Limited | Liquids containing suspended glass particles |
| GB0408199D0 (en) * | 2004-04-13 | 2004-05-19 | Cambridge Biostability Ltd | Liquids containing suspended sugar glass particles |
| GB2430880A (en) * | 2005-10-04 | 2007-04-11 | Cambridge Biostability Ltd | Pharmaceutical compositions stabilized in glassy particles |
| GB0523638D0 (en) | 2005-11-21 | 2005-12-28 | Cambridge Biostability Ltd | Pharmaceutical device for the administration of substances to patients |
| US8946200B2 (en) | 2006-11-02 | 2015-02-03 | Southwest Research Institute | Pharmaceutically active nanosuspensions |
| US9006225B2 (en) * | 2008-01-18 | 2015-04-14 | Asahi Kasei Pharma Corporation | Stable pharmaceutical composition |
| US8404850B2 (en) | 2008-03-13 | 2013-03-26 | Southwest Research Institute | Bis-quaternary pyridinium-aldoxime salts and treatment of exposure to cholinesterase inhibitors |
| US8722706B2 (en) | 2008-08-15 | 2014-05-13 | Southwest Research Institute | Two phase bioactive formulations of bis-quaternary pyridinium oxime sulfonate salts |
| US8309134B2 (en) | 2008-10-03 | 2012-11-13 | Southwest Research Institute | Modified calcium phosphate nanoparticle formation |
| WO2010146536A1 (en) | 2009-06-18 | 2010-12-23 | Koninklijke Philips Electronics N.V. | Suspension of particles with drug |
| WO2011007327A2 (en) | 2009-07-16 | 2011-01-20 | Koninklijke Philips Electronics N.V. | Suspension for therapeutic use and device for delivering said suspension |
| ES2362525B8 (en) | 2009-10-08 | 2013-01-03 | Azurebio, S.L. | Medication formulation in the form of penetrating percutaneous needles. |
| US9028873B2 (en) | 2010-02-08 | 2015-05-12 | Southwest Research Institute | Nanoparticles for drug delivery to the central nervous system |
| CN109094212B (en) | 2014-03-24 | 2021-03-19 | 精工爱普生株式会社 | Tape printing apparatus |
| WO2015145353A1 (en) * | 2014-03-27 | 2015-10-01 | Novartis Ag | Spray-dried solid-in-oil-in-water dispersions for inhalation of active pharmaceutical ingredients |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0091313A2 (en) * | 1982-04-05 | 1983-10-12 | Alcon Laboratories, Inc. | Perfluorohydrocarbons as vehicles for administering drugs |
| US5620699A (en) * | 1990-09-27 | 1997-04-15 | Allergan, Inc. | Method for delivering nonaqueous fluorinated drug delivery vehicle suspensions |
| CN1256626A (en) * | 1997-03-18 | 2000-06-14 | 扇形支撑剑桥有限公司 | Stable particle in liquid formulations |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1993018748A1 (en) * | 1992-03-19 | 1993-09-30 | Allergan, Inc. | Compositions comprising a drug delivery vehicle suspended in a nonaqueous fluorinated liquid |
| US6190701B1 (en) * | 1999-03-17 | 2001-02-20 | Peter M. Ronai | Composition and method for stable injectable liquids |
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2000
- 2000-10-13 JP JP2002535640A patent/JP2004513093A/en not_active Withdrawn
- 2000-10-13 ES ES04013422T patent/ES2337252T3/en not_active Expired - Lifetime
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- 2000-10-13 PT PT04013422T patent/PT1452171E/en unknown
- 2000-10-13 MX MXPA03003236A patent/MXPA03003236A/en active IP Right Grant
- 2000-10-13 KR KR10-2003-7004941A patent/KR20030096224A/en active Search and Examination
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0091313A2 (en) * | 1982-04-05 | 1983-10-12 | Alcon Laboratories, Inc. | Perfluorohydrocarbons as vehicles for administering drugs |
| US5620699A (en) * | 1990-09-27 | 1997-04-15 | Allergan, Inc. | Method for delivering nonaqueous fluorinated drug delivery vehicle suspensions |
| CN1256626A (en) * | 1997-03-18 | 2000-06-14 | 扇形支撑剑桥有限公司 | Stable particle in liquid formulations |
Also Published As
| Publication number | Publication date |
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| MXPA03003236A (en) | 2004-12-03 |
| WO2002032402A1 (en) | 2002-04-25 |
| CA2424656A1 (en) | 2002-04-25 |
| KR20030096224A (en) | 2003-12-24 |
| NO20031706D0 (en) | 2003-04-11 |
| NO20031706L (en) | 2003-04-11 |
| PL360052A1 (en) | 2004-09-06 |
| JP2004513093A (en) | 2004-04-30 |
| CA2689856A1 (en) | 2002-04-25 |
| AU1198601A (en) | 2002-04-29 |
| CN1527699A (en) | 2004-09-08 |
| EP1328255A1 (en) | 2003-07-23 |
| ES2337252T3 (en) | 2010-04-22 |
| PT1452171E (en) | 2010-03-08 |
| CA2689856C (en) | 2013-09-24 |
| AU2001211986B2 (en) | 2007-04-26 |
| CA2424656C (en) | 2010-03-23 |
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