CN101124003A - Novel methods for administration of drugs and devices useful thereof - Google Patents

Abstract

The present invention relates to methods for administration of insulin into the intradermal compartment of subject's skin, preferably to the dermal vasculature of the intradermal compartment. The methods of the present invention enhance the pharmacokinetic and pharmacodynamic parameters of insulin delivery and effectively result in a superior clinical efficacy in the treatment and/or prevention of diabetes mellitus. The methods of the instant invention provide an improved glycemic control of both non-fasting (i.e., post-prandial) and fasting blood glucose levels and thus have an enhanced therapeutic efficacy in treatment, prevention and/or management of diabetes relative to traditional methods of insulin delivery, including subcutaneous insulin delivery.

Description

The new method of drug administration and the device that is used for this method

1. invention field

The present invention relates to be used for material is administered to the knitting layer of patient skin, i.e. the method for the transition tissue between the corium of the corium reticular layer of skin and hypodermic layer.The invention provides improving one's methods of parenteral, wherein, the advantage that it provided comprises and reduces undesirable immunoreation and by using the unexpected immunotoxicity effect that described material causes.In addition, the pharmacokinetic characteristic that the application of the invention method can be improved.Also disclosed the device that is used for the inventive method.

2. background of invention

The importance of using effectively and safely such as the medical substance of diagnostic preparation and medicine has just had realized that for a long time.The use of tradition aciculiform thing provides a kind of for a long time and by dermal administration medical substance has been transported to human body and the intravital method of animal via traditional aciculiform thing.In order to realize percutaneous reproducible and effective conveying, improve the convenience of injection simultaneously and alleviate the patient worry and/or with the relevant pain of conventional aciculiform thing, made considerable effort already.In addition, some induction system has fully phased out the aciculiform thing, and depends on chemical mediator or external motivating force, as iontophoretic current or electroporation, or hot piercing or ultrasound wave importing, so that destroy horny layer, be the outermost layer of skin, by the skin surface transportation of substances.But, described induction system can not always reproducibly be broken skin barrier or described drug substance is transported to certain depth below the skin surface, and therefore, clinical effectiveness may be beaten.Therefore, to cuticular mechanical damage,, be considered to provide the highest method of reproducibility, and provide localized control of the material of being used and reliability by the skin surface application of substances as using the aciculiform thing.

The method of mass transport below skin surface almost can only be passed through applied dermally, promptly by skin with the position of mass transport below skin.Percutaneous dosing comprises subcutaneous, intramuscular or intravenous route of administration, and wherein, intramuscular and subcutaneous injection are the most frequently used.

On anatomy, the outer surface of health is made up of two kinds of main organized layers, the epidermis of outside and following corium, and they have constituted skin jointly, and (relevant summary is referring to Physiology, Biochemistry, and Molecular Biology of the Skin, Second Edition, L.A.Goldsmith, Ed., Oxford University Press, New York, 1991).Epidermis is subdivided into five layers, and gross thickness is 75-150 μ m.Corium is in the below the epidermis, and it comprises two-layer, and outmost part is known as papillary layer of corium, is known as the corium reticular layer than deep layer.Papillary layer of corium comprises a large amount of microcirculatory vasculars and lymphatic plexus.On the contrary, the corium reticular layer is acellular relatively and avascular, and is made up of the collagen and the elastic [connective of densification.Be subcutaneous tissue below epidermis and corium, be known as down corium again, it is made up of connective tissue and fatty tissue.Muscular tissue is positioned at below the subcutaneous tissue.Corium reticular layer and subcutaneous tissue are to separate by the interface that is known as knitting layer.

Knitting layer is the border with some collagen bundles, and it has constituted the corium reticular layer that is close to above the knitting layer.These collagen bundles are to arrange in the mode that is parallel to skin surface, fixing dermopapillary elastic fiber.In knitting layer, constitute slickly, the fibrous connective tissue of elastic and dispersive collagen fiber is with respect to the corium reticular layer and vertical orientated.This connective tissue combines with glycosaminoglycans and Dan Baijutang, and supports to fibrocyte, a spot of adipose cell and from the infiltration cell of blood vessel.Another feature of described knitting layer is the fine and close network that has the blood vessel of the capillary tube loop that forms corium.Importantly, concentrate the dark venous plexus of postcapillary venule to be arranged in knitting layer.Below the skin engagement layer, be fatty tissue, it has constituted hypodermic layer.The thickness estimation of knitting layer is 1.9-3mm.These data are based on the clinical research to healthy premenopausal volunteers, have adopted X-light CT scan and high frequency (20MHz) ultrasound imaging techniques.

As indicated above, subcutaneous tissue and muscular tissue all are used as the position of using medical substance usually.But, one of the most serious problem that is run into when medical substance is administered to these parts is to cause undesirable immunoreactive potential danger in subject.In some cases, this undesirable immunoreation may cause experimenter's death.Therefore, although also there is the illeffects that has caused by medication having weakened simultaneously in the method for the application of substances of the pharmacokinetics that has needed to cause improving always, need as the feature of the method for undesirable immunoreactive application of substances.

3. summary of the invention

The invention provides by optionally deciding the new parenteral administration method of the knitting layer of patient skin, so that the material that causes being carried has higher treatment effectiveness with specificity ground target.The additive method that comprises intradermal and subcutaneous administration method relatively, the material of carrying according to the inventive method have the clinical application and the treatment that have improved and render a service.The invention provides the advantage that is better than conventional medication, the pharmacokinetics that has included, but are not limited to improve, the alleviating of undesirable and deleterious side effect, the experimenter alleviates or eliminates pain perception, not to the restriction of volume injected.

The present invention is based on inventor's accident to a certain extent and finds, be about to the knitting layer of mass transport to patient skin, and the carrying method that has improved is provided.In this article, knitting layer is represented the deep layer of the corium of skin, that is, and and the transition tissue district between the corium of corium reticular layer and hypodermic layer.

In this article, be applied to and be intended in the knitting layer comprise as follows material is administered to knitting layer, make described electrodeposition substance in knitting layer, so that it can arrive the venous plexus of knitting layer and the thick network of postcapillary venule easily, and by fast Absorption and systematically distribution.According to the inventive method, the deposition of material in knitting layer mainly is on the degree of depth of about at least 1.5mm, preferably about at least 2mm, be no more than about 3mm at most, preferably be no more than about 2.5mm, caused the fast Absorption of described material thus, and weakened immunoreation.Therefore, the material of carrying according to the inventive method can be than comprising that other route of administration of ID and IM produce their advantageous effects quickly.

Preferably, the material of carrying according to the inventive method can enter the knitting layer of patient skin, and don't passes it.Described material is put into hypodermic layer (for example, surpassing the degree of depth of 2.5mm) may not only can cause the slow absorption of described material, and may be relevant with undesirable immunoreation, and be that the inventive method is undesirable therefore.

The invention provides the method that is used for material is imported and is deposited on the skin engagement layer.According to the inventive method with mass transport in experimenter's knitting layer, the pharmacokinetics that caused improving, for example, the pharmacokinetic characteristic that has improved.Although do not wish to be subjected to the constraint of particular theory, it is believed that, owing to infiltrate the venous plexus of knitting layer and the dense network of postcapillary venule, directly described material is used for knitting layer, can cause described material than the subcutaneous or more effective absorption of intramuscular administration, conversely, the pharmacokinetics that can cause again improving.In addition, by specificity ground and optionally target be used for the knitting layer of administration surely, the pharmacokinetics that is showed by described material is reproducible all the time, has caused the weakening of interindividual variation of relative other carrying methods PK parameter.

The inventive method not only provide conventional relatively medication improvement pharmacokinetics, but also other advantages are provided, comprise and having reduced by using the deleterious side effect that a kind of material causes, as at as described in the undesirable immunoreation and the unexpected immunotoxicity effect of active component of material.In this article, the experimenter's of material of the present invention natural immunity reaction is accepted in term " undesirable immunoreation " expression, wherein, when using, does not wish that described material causes such reaction.Can comprise with the undesirable immunoreactive example of the inventive method prevention, but be not limited to, the anaphylaxis of IgE-mediation, as disclosed, risk with part and/or system's anaphylactic reaction, for example, after parenteral injection insulin or heparin and a lot of other drug, described medicine is to have albumen or polysaccharide as active component; Antibody-mediated cytotoxicity anaphylaxis, and the anaphylaxis of immune complex mediation, it can cause systemic negative event, the kidney and/or liver and/or the microvascular change that cause as the deposition owing to circulating immune complex; Cell-mediated anaphylaxis exists in the injection site and induces the reaction of tardy type and the immune neutral risk of active component, or any systemic negative event, as the thrombocytopenia that is caused by heparin therapy.

Therefore, the inventive method is specially adapted to carry such therapeutic substance, promptly inductive immunoreation at it be disadvantageous for the therapeutic effect of the described material that will carry.Described examples of substances comprises low molecular weight heparin, pentasaccharides, α and interferon-, erythropoietin, antibody, polypeptide hormone, growth hormone, and interleukin.The risk of the less immunotoxicity effect of medication of the present invention is the ratio owing to lower immunologically competent cell in knitting layer to a certain extent.Therefore, the inventive method is better than the intradermal conveying when carrying described material.Under latter event, undesirable immunoreactive risk is bigger, because intradermal space is with the immunologically competent cell of high concentration, for example, and dendritic cell, mononuclear cell, lymphocyte, macrophage etc. are feature.In specific embodiments, the described material that use according to the inventive method is not a vaccine, may be disadvantageous because the immunoreation that produces with its weakens.

According to the inventive method transportation of substances, reduced or eliminated the pain that the experimenter experiences.Therefore, the inventive method is better than comprising other parenteral method of intradermal conveying.Although do not wish to be subjected to the restriction of particular mechanism of action, the corium internal layer is to be the sensory organ of feature with nerve ending and neural Wagner's corpuscles.On the contrary, knitting layer has less nerve ending and sensation corpusculum, therefore, and by material being administered to pain perception that knitting layer causes than by a little less than the pain perception that described mass transport is produced to the corium internal layer.

Another advantage according to the inventive method transportation of substances is, and organizes chamber to compare to other described mass transport, do not have the restriction to the volume injected of described material.Therefore, compare with the intradermal conveying, the inventive method is particularly advantageous, because the volume of intradermal delivery injection material is restricted to about 50-250 μ L, this is because the collagen bundle of skin corium and the height network and the dermal tissue deformability of elastin fiber are limit to a certain extent.Although do not wish to be subjected to because the constraint of the feature mechanism of the pliability of knitting layer connective tissue and alterable height shape property, mass transport in knitting layer the time, to volume injected without limits, is particularly being passed through bolus injection.The volume that can be used for the material of the inventive method can be identical with the volume injected that is used for subcutaneous administration.Therefore, use the inventive method, the volume of described material can for about 0.5mL or more than, more preferably approximately 1.0mL or more than.

The present invention relates to be used for accurately and any device of knitting layer that optionally target is decided patient's skin.The character of employed device is unimportant, if the target depth of the skin that it can penetrate the patient in the knitting layer district, and don't penetrate this district just.Described device preferably thrusts at least approximately degree of depth of 2mm of skin, is no more than about 3mm at the most, is most preferably not exceeding about 2.5mm.

In certain embodiments, the present invention relates to use comprise at least one aciculiform thing, the device of preferred miniature operation pin is with the knitting layer of mass transport to patient skin.Preferably, the length of described aciculiform thing is enough to thrust knitting layer, and the outlet degree of depth is in knitting layer, so that described material is transported to and is distributed in the knitting layer.In certain embodiments, the length of described aciculiform thing is the about 5mm of about 2mm-, preferably approximately the about 3mm of 2mm-.In other embodiments, when inserting described aciculiform thing, the outlet of described aciculiform thing is positioned at the degree of depth of the about 3mm of about 2mm-, preferably approximately the about 2.5mm of 2mm-.

The present invention relates to be used for the pharmaceutical formulation that comprises one or more materials of knitting layer place administration.In certain embodiments, the preparation that comprises material of the present invention comprises the described material of treatment or prevention effective dose.In other embodiments, preparation of the present invention comprises one or more other additives.The preparation that can use according to the inventive method can be any form that is fit to the administration of knitting layer place.

Use the inventive method, material can be used as bolus injection and uses, or uses by transfusion.In this article, term " bolus injection " is illustrated in the medication amount of carrying in the time that is less than 10 minutes." transfusion " expression is used and is surpassed 10 minutes time transportation of substances.Be understandable that, use or the bolus injection carried can be undertaken by speed control unit, pump for example, or do not have special speed control unit, and for example, user oneself injection.

4. brief description of drawings

Fig. 1 shows skin anatomy: schematically show each layer of skin and their corresponding border.

Fig. 2 injection device: the aciculiform thing length of doser depends on the compartment of wanting the fixed skin of target.Be used for intradermal, the best aciculiform thing length of knitting layer and the injection of shallow subcutaneous tissue is respectively 1.5mm, 2-3mm, and 4-5mm.

The geometric mean titer of Fig. 3 antibody: compared different injecting pathways at D0, D7, D14 is by the antibody titer that rabies vaccine produced of injection single dose.Rabies vaccine is by IM, and ID or knitting layer approach are used.

The geometric mean titer of Fig. 4 antibody: twice and three injections antibody titer afterwards in succession of monitoring in time.By IM, ID or knitting layer approach are used rabies vaccine.

5. detailed description of the invention

The present invention partly relates to for the method to the patient skin application of substances, comprises carrying described material, preferably optionally and in specific manner is transported to the knitting layer of patient skin. In one embodiment, described experimenter is the human or animal, preferred people. In this article, knitting layer represents the bottommost layer of corium, i.e. transition tissue space between the lower corium of corium reticular layer, and hypodermic layer. Knitting layer is delimited by some collagen bundles, and it has consisted of the corium reticular layer that just is positioned at the knitting layer top. In described knitting layer. by smooth, the soft fibrous connective tissue that forms with the collagenous fibres that disperse is perpendicular to corium reticular layer direction. Another feature of knitting layer is to have the dense network of the blood vessel of the capillary loops that is decomposed into corium. Importantly, concentrate the dark veniplex of rear capillary to be arranged in knitting layer.

The invention provides by target optionally and in specific manner and decide the new parenteral administration method of the knitting layer of patient skin, render a service so that the material that causes carrying has the treatment of enhancing. In certain embodiments, the described knitting layer of direct targeting. In this article, being administered in the knitting layer expression comprises as follows a kind of material is administered to knitting layer, make described electrodeposition substance in knitting layer, so that it can arrive the veniplex of knitting layer and the dense network of post capillary venules easily, and is absorbed rapidly and systematic distribution. According to the inventive method, the deposition of material in knitting layer mainly is on the degree of depth of at least about 1.5mm, preferred at least about 2mm, and the degree of depth are no more than about 3mm at most, preferably be no more than about 2.5mm, caused so quick absorption and the immune response of described material to weaken. Therefore, compare with other route of administration that comprise SC and IM according to the material that the inventive method is carried, can produce rapidly their advantageous effects.

The inventive method is compared with traditional medication, and its advantage is, for example, has improved the pharmacokinetics of institute's application of substances, has weakened undesirable and harmful side effect, weakens or has eliminated the pain impression, and do not have the volume restrictions to volume injected.

The dynamical phase that the pharmacokinetics that the material of using according to the inventive method produces and the same substance of using by conventional medication obtain is than better and better clinically. Although do not wish to be subjected to the constraint of particular theory, it is believed that owing to immerse the veniplex of knitting layer and the dense network of post capillary venules, described material is applied directly to knitting layer can cause described material than the subcutaneous or more effective absorption of intramuscular administration, the pharmacokinetics that conversely, can cause improving. In addition, decide knitting layer by target in specific manner and optionally, but reproduced by the pharmacokinetics uniformity ground that described material shows, the difference between other conventional medication individualities is less relatively to cause the PK parameter.

According to the present invention, the pharmacokinetics of having improved represents to compare with conventional application process (T time delay that has the bioavailability that improved, reduced_lag), the T that reduced_max, the C that shows effect faster and/or improved of the application of substances of infiltration rate, specified quantitative faster_max。

Described bioavailability represents to arrive the total amount of given dose of institute's application of substances of blood vessel chamber. It is normally weighed as the area below concentration and the time graph. " time delay " expression is used described material to measuring the delay that maybe can detect between blood or the plasma content. T_maxThe time value that expression obtains the maximum haemoconcentration of described material, and C_maxIt is the maximum haemoconcentration that reaches with given dose and application process. Duration of seizure is T_lag，T _max, and C_maxFunction because all these parameters all affect the time that reaches essential when realizing the necessary blood of biology effect (or destination organization) concentration, T_maxAnd C_maxCan measure by the visual inspection to graph results, and usually can provide enough information, be used for the relatively method of two kinds of application of substances. But, can use Mathematical Modeling known in those skilled in the art and/or additive method to measure more accurately numerical value by dynamic analysis.

The mensuration of pharmacokinetic parameter and MEC is carried out according to this area conventional method. Whether improved by compare the value that affirmation obtains with the standard route of administration, for example subcutaneous, in the corium or intramuscular administration. This relatively in, preferably, but optionally be, be administered to knitting layer and be administered to reference site, relate to identical dosage level such as subcutaneous administration, namely, the medicine of same amount and concentration, and identical carrier, with identical application rate, this speed represents with amount and the volume of unit interval. Therefore, for instance, with 5 minutes specific medical substance is administered to knitting layer such as the concentration of 100 μ g/mL and the speed of per minute 100 μ L, preferably used identical medical substance with the speed of 100 μ g/mL of same concentrations and per minute 100 μ L with 5 minutes and compare to subcutaneous space.

The inventive method not only provide the transportation of substances of comparing with traditional medication improvement pharmacokinetics, but also other advantages are provided, comprise alleviating the harmful side effect that causes by application of substances, as undesirable immune response and to as described in the unexpected immunotoxicity effect of active component of material. In this article, the experimenter's of material of the present invention innate immune reaction is accepted in term " undesirable immune response " expression, and wherein, described material does not wish to cause such reaction when using. Can comprise by the undesirable immunoreactive example of the inventive method prevention, but be not limited to, the anaphylaxis of IgE-mediation, the cytotoxicity anaphylaxis of antibody-mediation, the anaphylaxis of immune complex mediation, and cell-mediated anaphylaxis, antibody is to the immunity neutralization of active component, and for the final cross reactivity of described active component for the antibody of native compound formation, described native compound has identical antigen motif with the described material of using.

Therefore, the inventive method is specially adapted to therapeutic substance, and its immune response for it of inducing is disadvantageous for the result for the treatment of of the material of carrying. Be used for the example of the therapeutic substance of the inventive method, comprise low molecular weight heparin, pentasaccharides, α and IFN-β, hematopoietin, antibody, polypeptide hormone, growth hormone and interleukin. The therapeutic substance that is used for the inventive method comprises recombinant protein. Disclose other non-limiting examples of the material that can be used for the inventive method in following 5.1 parts of this paper.

Medication of the present invention is because the low ratio of immunocompetent cell in knitting layer in a way to being reduced in of immunotoxicity effect risk. Therefore, the inventive method is better than carrying in the corium of described material, and undesirable immunoreactive risk is higher in corium, because the corium internal clearance is take the immunocompetent cell of high concentration as feature, for example, dendritic cells, monocyte, lymphocyte, macrophage etc. In specific embodiments, the material that use according to the inventive method is not vaccine, may be disadvantageous because reduce its immune response.

In addition, optionally the fixed knitting layer for delivery of material of target can cause other clinical effectiveness, as the pain perception that has weakened. Although do not wish to be bound by theory, because knitting layer has less nerve ending and sensation corpusculum, may be lower than the pain that causes by being administered to its hetero-organization compartment by material being administered to the pain perception that knitting layer induces. According to the inventive method transportation of substances, alleviate or eliminated the pain of being experienced by the experimenter. Therefore, the inventive method comprises in the corium and carrying better than other medications.

Comparing with described material is transported in its hetero-organization compartment, is not have the restriction to described material volume injected according to another advantage of the inventive method transportation of substances. Therefore, the inventive method is better than carrying in the corium especially, and wherein, the volume of latter's injection mass is limited to about 50-250 μ L, and this part is owing to the height network of the collagen bundle of skin corium and EF and the reason of dermal tissue deformability. Although do not wish to be subjected to the constraint of specific mechanism, because elasticity and the alterable height shape property of knitting layer connective tissue, when target is decided knitting layer, to volume injected without limits, particularly bolus injection injection. The volume that can be used for the material of the inventive method can be the volume injected identical with subcutaneous administration. Therefore, use the inventive method, the volume injected of described material can for about 0.5mL or more than, more preferably approximately 1.0mL or more than.

Therefore, the inventive method provides and has been used for the treatment of, prevention or alleviation and disease, and the method for one or more symptoms that imbalance or infection are relevant comprises the knitting layer that one or more materials of the present invention is transported to patient skin. Compare with other carrying methods, the material carried according to the inventive method has the clinical efficacy and the treatment that have strengthened and renders a service.

5.1 the material that is used to use

The present invention includes the knitting layer of deciding the experimenter by target optionally and use multiple material.Can include, but are not limited to pharmacology or biological active agents with the examples of substances that the inventive method is used, comprise diagnostic preparation, medicine and other materials, these materials can provide treatment or health-care effect, for example, but are not limited to neutriceuticals.The present invention relates to use any albumen, particularly human cytokines, and all salt, polymorph, analog, derivant, fragment, analogies and other peptide, these materials can obtain by standard method known in those skilled in the art.

The material that is specially adapted to the inventive method is that those undesirable immunoreation and immunotoxicity effect risk reduce and have an advantageous effects, and the material that benefits because have the pharmacokinetic characteristic that has improved, described material includes, but are not limited to low molecular weight heparin, pentasaccharides, α and interferon-, erythropoietin, antibody, polypeptide hormone, growth hormone, and interleukin.

The inventive method is specially adapted to carry anti--thrombotic medicine, as low molecular weight heparin and synthetic pentasaccharides.These materials can have great advantages because of the inventive method reduces undesirable immunoreation.In the art, reported already and used low molecular weight heparin, as the negative immunoreation of Enoxaparin .For example, reported already that the anaphylactic reaction that produces (for example when SC uses Enoxaparin , referring to Pharmacotherapy, 2002,22 (11): 1511-5) and at the intravital delayed-type hypersensitivity of the patient who accepts the LMW heparin therapy (DTH) react (for example, referring to Dermatol.Surg.2001 27 (1): 47-52).In addition, reported already that it was to use the major side effects of heparin by heparin-induced thrombocytopenia (HIT); HIT is serious and life-threatening syndrome, and it is to cause at the antibody that platelet factor 4/heparin complex forms.According to estimates, HIT had occurred in all of 1-3% are accepted the patient of heparin therapy already that (referring to Perfusion, 2003,18 (1): 47-5 3; Eur.J.Pediatr.158 (Suppl.3): S130-133 (1999).Although synthetic pentasaccharides, it is relevant with lower (comparing with low molecular weight heparin) immunotoxin risk to be in the news already as Fondaparinux , but still has tangible potential threat (Clin.Ther.24 (11): 1757-1769 (2002).Therefore, the inventive method provides the alternate and more perfect method that is used for antithrombotic therapy, because carry the antithrombotic such as heparin, comprise low molecular weight heparin, can weaken or eliminate undesirable immunoreation, this reaction is relevant with existing antithrombotic therapy, as DTH and HIT.

The present invention relates to carry and be used for the treatment of and/or any preparation of the disease that prevention is relevant with thrombosis.The Therapeutic Method of four kinds of main types is used to prevention or treatment thrombosis: anti-platelet agents, anticoagulant (heparin), vitamin K antagonist (coumarin derivative) and thrombolytic agent.The preparation of each type can disturb at the different parts that solidifies approach and solidify (referring to Goodman ﹠amp; Gilman, The Pharmacological Basis ofTherapeutics, 9th ed., McGraw-Hill, NY (1996)).Dipyridamole is to be used to prevention sometimes or to treat thrombotic another kind of preparation; It is a vasodilation, with Hua Faling (coumarin derivative) combination, can suppress the thromboembolism of artificial heart valve, and make up the thrombosis that can reduce the patient who suffers from thrombotic disease with aspirin.The invention still further relates to the inhibitor of cell surface glycoprotein GPIIb/IIIA, it belongs to anti--new family of thrombotic medicine, be used for coronary heart disease mostly, and coagulation inhibitor, these factors are accredited as has anti--thrombosis effect.

The inventive method can be used for treating and/or preventing the thrombosis with disease association, comprise, but be not limited to, venous thrombosis, pulmonary infarction, thrombophlebitis, the tremulous pulse impatency that causes by thrombosis or thromboembolism, during angioplasty or thromboembolism or the impatency again of tremulous pulse afterwards, the restenosis after arterial injury or invasive cardiac procedures, operation posterior vein thrombosis or thromboembolism, acute or CAS disease, apoplexy, myocardial infarction, cancer and neoplasm metastasis, and nerve degeneration disease.

The diagnostic substances that can be used for the inventive method includes, but are not limited to, insulin, ACTH (for example, the thyroliberin injection), lutropin-releasing hormone is (for example, the hydrochloric acid GnRF), growth hormone-releasing hormone (for example, the acetic acid Sermorelin), cholecystokinin (sincalide), parathyroid hormone and its fragment are (for example, teriparatide acetate), thyroid releasing hormone and its analog (for example, Protirelin) and secretin etc.

Can be used for therapeutic substance of the present invention and include, but are not limited to α-1 anti-trypsin; Anti--the angiogenesis medicine; Antisense agents; Butorphanol; Calcitonin and analog; Ceredase; The Cox-II inhibitor; Dermatology preparation; Dihydroergotamine; Dopamine stimulant and antagonist; Enkephalin and other morphine-like peptides; Epidermal growth factor; Erythropoietin and analog; Follicle stimulating hormone; G-CSF; Glucagon; GM-CSF; Granisetron; Growth hormone and analog (comprising growth hormone-releasing hormone); Growth hormone antagonist; Heparin; Hirudin and hirudin analog are as HIRULOG; The IgE inhibitor; Insulin; Insulinotropin and analog; Insulin-like growth factor; Interferon; Interleukin; Lutropin; Lutropin-releasing hormone and analog; Low molecular weight heparin and other natural modified or synthetic glycosaminoglycans; M-CSF; Metoclopramide; The Dormicum; Monoclonal antibody, the antibody of Pegylation (pegylated), the albumen of Pegylation or any albumen of crossing with hydrophilic or hydrophobic polymer or other modified with functional group, fusion rotein, single chain antibody fragments or they and any bonded proteic combination, macromole or its other functional groups, the anaesthetic analgesics; Nicotine; The on-steroidal anti-inflammatory preparation; Oligosaccharide; Ondansetron; Parathyroid hormone and analog; Pth antagonist, prostaglandin antagonists; Prostaglandin; The recombinant soluble receptor; Scopolamine; Serotonin stimulant and antagonist; Sldenafil; Terbutaline; Albuterol; Modafinil; Thrombolytic; Organize the dissolved preferment activator of fibrin egg; TNF and its antagonist; And vaccine.

In certain embodiments, the material that can use with the inventive method is such material, and their desired characteristics is to take effect fast, is the long cyclical level of described medicine subsequently.Described examples of substances is an insulin, need it fast with the startup level on peak, so that overcome by to sugar or the digestion of other non-complex carbohydrates and the high glucose level that absorption obtains, simultaneously, blood glucose need be reduced to normal level rapidly.The present invention relates to insulin, glucagon-like peptide, the salt that they are all, polymorph, analog, derivant, fragment, the purposes of analogies and peptide.Another example that can be used for the material of the inventive method is pain relief preparation (for example, Cox inhibitor, morphine, opioid and other anaesthetic analgesics and a Qu Putan class); The erection disturbance preparation, for example, sldenafil; Anti--thrombin (for example, heparin, low molecular weight heparin, the GPIIb/IIa antagonist, fondaparine); Resist acute-anxiety disorders, as panic attack (for example, Midazolam is stabilized three toroidal molecules); Acute daytime is drowsiness (for example, modafinil); Epilepsy (for example, stable).In addition, for by conventional carrying method, the material that slowly absorbs usually when for example SC uses, it may be favourable absorbing faster.It is slowly to absorb that tradition SC uses the high molecular medicine, is inversely proportional to because absorb with molecular weight.

Described examples of substances includes, but are not limited to high molecular or hydrophobic pharmaceutical compounds.

5.2 be used for the preparation of knitting layer administration

The present invention relates to comprise that one or more are used for the preparation of the material of knitting layer administration.In certain embodiments, the preparation that contains material of the present invention comprises the described material of treatment or prevention effective dose.In other embodiments, preparation of the present invention comprises one or more other additives.

In this article, except as otherwise noted, " treatment effective dose " expression is enough to provide therapeutic effect or postponement when treatment or control disease or weakens material of the present invention or other absorption of active ingredient with the symptom of described disease association.In addition, the treatment effective dose of material of the present invention represents that described its makes up separately or with other treatment, produces the amount of therapeutic effect aspect treatment of diseases or control.When being used to represent amount of substance of the present invention, this term can comprise can improve overall treatment, alleviate or avoid symptom or cause the reason of disease, strengthen that treatment is renderd a service or with the enhanced amount of the synergism of another kind of therapeutic agent.

In this article, except as otherwise noted, " prevention effective dose " expression is enough to produce material of the present invention or other absorption of active ingredient of prevent disease recurrence or diffusion.The prevention effective dose can represent to be enough to prevent initial disease, and the recurrence of disease or diffusion or individual interior disease take place, including, but not limited to the consumption of morbidity tendency is arranged.The prevention effective dose can also be illustrated in the consumption that the disease prevention aspect provides preventive effect.In addition, the prevention effective dose of material of the present invention represents that it makes up separately or with other preparations, in the amount that preventive effect is provided aspect the described disease of prevention.When being used to represent the consumption of material of the present invention, this term can comprise can improve overall prevention strengthen that prevention is renderd a service or with the synergistic consumption of other prevention preparations.

Can be used for comprising that the additive in the preparation of material of the present invention comprises, wetting agent for example, emulsifying agent, or pH buffer agent.The preparation that comprises material of the present invention can comprise one or more other excipient, as saccharide and polyhydric alcohol.Preferably, itself can not induce physiological responses carrier that can be medicinal, for example, and immunoreation.Most preferably, described carrier that can be medicinal can not cause any negative or undesirable side effect and/or can not cause over-drastic toxicity.Can be used for to include, but are not limited to saline by medicinal carrier, buffer saline, glucose, water, glycerol, sterile isotonic aqueous buffer solution, and their combination in the preparation of the present invention.Other examples of carrier, diluent and excipient that can be medicinal in following document, are provided: Remington ' s Pharmaceutical Sciences (Mack Pub.Co., N.J., current edition; Above document is all intactly received does this paper reference).

Preparation of the present invention can be a solid, as the cryodesiccated powder that is fit to rebuild, liquid solution, suspension, tablet, pill, capsule, slow releasing preparation, or powder.

The preparation that contains material of the present invention can prepare with any acceptable preparation method known in the art.Concrete preparation method depends on the concrete material that will use, and these variations belong to those of ordinary skills' the ken.

The present invention relates to use the method for solution and the particle form and their mixture of material of the present invention, comprise snap action, middling speed effect and long duration of action preparation, these preparations can be with any material acquisition.The preparation and the preparation of the present invention that are used for described method can be the mixture that comprises one or more preparations of material of the present invention.

Material in the described preparation can be in different physical bond states, for example, and single aggressiveness or dimer state.The chemical state of described material can be modified by the standard recombinant dna technology, so that produce the material of the different chemical structures formula that is in different bonding states.In addition, can change solution parameter, as pH, so that cause the preparation of described material to be in different bonding states.The invention still further relates to other chemical modifications of material of the present invention.

Use the inventive method, need the material of smaller dose just can obtain similarly to treat effectiveness with conventional application process.Compare with carry identical material by conventional method, the material carried according to the inventive method has the treatment that has improved and renders a service.

Using under the situation of biological molecule, described molecule can be from different animal species, including, but not limited to pig, and cattle, sheep, horse etc.

The present invention relates to material of the present invention is particle form, that is, be not the preparation that is dissolved in fully in the solution.In certain embodiments, at least 30%, at least 50%, at least 75% described material is a particle form.Although do not wish to be subjected to the restriction of specific function pattern, described material preparation of the present invention of a granular form has a kind of preparation that can promote described species precipitate at least.The precipitation preparation that can be used in the preparation of the present invention can be a protein matter, for example, protamine, cationic polymer, or non-protein matter, for example, zinc or other metals or polymer.

The form of the material of carrying or using comprise be present in can be medicinal diluent or its solution, emulsion, suspension, gel, suspension or the dispersive granule in the solvent such as minitype particle and nano-particle, and the vehicle that forms of their original position.The preparation that comprises material of the present invention can be any form that is fit to the knitting layer administration.In one embodiment, knitting layer preparation of the present invention is flowable, injectable form of medium, that is, the low-viscosity preparation, it can use injector to inject.The injectable medium of described flowability can be a liquid.In addition, the injectable medium of described flowability is the liquid of granular material of having suspended, and described like this medium has kept its flowability, so that can inject, for example, can use by syringe.

Preparation of the present invention can prepare with unit dosage form.Unit dose in each bottle can comprise the preparation of 0.1-1mL.In certain embodiments, the unit dosage form of knitting layer preparation of the present invention can comprise about 50 μ L-100 μ L, 50 μ L-200 μ L, the preparation of 50 μ L-500 μ L or 50 μ L-1mL.If necessary, can in each bottle, add sterile diluent and described preparation be adjusted to the concentration that needs.

The volume of the preparation of using according to the inventive method is not the volume that possible make the knitting layer overload, and this narrow meeting causes preparation to be assigned in one or more other compartments, as subcutaneous compartment.But, the volume of described preparation is compared not too important with using other conventional application processes when using by knitting layer application process of the present invention.Be not subjected under the prerequisite of particular theory constraint, it is believed that the knitting layer injection more can accept for the bolus injection of larger volume, this is because the elasticity of knitting layer connective tissue and high deformability.Therefore, use the inventive method, approximately 0.5mL or more than, more particularly approximately 1.0mL or above volume injected can be applied to described knitting layer.

5.3 knitting layer carrying method

In certain embodiments, the present invention relates to the method for the knitting layer administration of the disclosed material of this paper, for example, be transported to the knitting layer of patient skin, preferably pass through optionally to decide knitting layer, and don't penetrate it with specificity ground target.In the most preferred embodiment, directly target is decided described knitting layer.In case prepared the preparation that comprises the material that will carry, typically, described preparation is transferred to the injection device of knitting layer administration, for example in the syringe.The present invention is based on inventor's discovery to a certain extent, be about to mass transport and can weaken or eliminate undesirable immunoreation and immunotoxicity effect to knitting layer, comprise, but be not limited to the anaphylaxis of IgE-mediation, antibody-mediated cytotoxicity anaphylaxis, the anaphylaxis of immune complex mediation and cell-mediated anaphylaxis, the dangerous and/or cell-mediated immunity of the immunity neutralization of active component and/or the immune cross-reactivity of antibody to natural materials.According to the inventive method carry preparation of the present invention provide described material improvement treatment and clinical efficacy.The preparation that comprises material of the present invention has the pharmacokinetics of having improved, as the improvement in knitting layer the absorption picked-up.

In this article, be administered into and represent in the knitting layer to be transported to material in the knitting layer in such a way, make described material can arrive the venous plexus of knitting layer and the dense network of postcapillary venule easily, and absorbed rapidly that becoming can systematicness ground biological utilisation.It is believed that main distribution with about at least 1.5mm, preferably about at least 2mm is no more than about 3mm at most, and the sedimentary material of the degree of depth that preferably is no more than about 2.5mm can cause the fast Absorption of described material and immunoreation to weaken.Preferably, the material of carrying according to the inventive method can enter the knitting layer of patient skin, rather than penetrates it.Place hypodermic layer (for example, surpassing the degree of depth of 2.5mm) not only can cause described material absorbing slow described material, but also relevant with undesirable immunoreation, therefore, be that the inventive method is undesirable.

The practical methods that described preparation is imported knitting layer is unimportant, reaches ideal target depth in the knitting layer as long as it can thrust experimenter's skin, and don't passes it just.In most of the cases, described device can thrust skin, and reaches the degree of depth of about 2-3mm, the degree of depth of preferred 2.5mm.In certain embodiments, described device will thrust skin and reach the degree of depth that is no more than 2.5mm.Is that the thickness of knitting layer do not depend on the position of injection or specific experimenter with mass transport to one of advantage of knitting layer according to the inventive method.Any injection site that is used for the knitting layer administration that can be used for the inventive method includes, but are not limited to, thigh, abdominal part, chest muscle or chest triangular muscle, forearm and preceding post-brachial knitting layer.

The knitting layer method of using comprise miniature operation pin-type injection and transfusion system or accurately target decide any other device of knitting layer.The knitting layer method of using not only comprises micro device type injection member, but also comprise other carrying methods, as liquid or powder are delivered to knitting layer through the needleless ballistic injection, ionotherapy by the micro device reinforcement, and liquid, solid, or other dosage forms directly deposit in the skin.The present invention includes conventional injection aciculiform thing, conduit or miniature operation pin independent or all known types that spininess shape thing array uses.

In preferred embodiments, when using in knitting layer when relating to the aciculiform thing, the front end of aciculiform thing is apart from the preferred 2.5mm of skin surface, and the plagiocephaly heel is apart from skin surface 2mm.Preferably, decide knitting layer, described aciculiform thing is vertically inserted skin surface for target accurately and optionally.Size from aciculiform thing top to the sloping portion of the heel of described inclination must be in the 0.55-0.60mm scope, so that mass transport is arrived knitting layer.

Knitting layer application process of the present invention caused a kind of material improvement pharmacokinetics (PK) and pharmacodynamics (PD)." improve pharmacokinetics ", expression for example, by the standard drug kinetic parameter, as time and maximal plasma concentration (T _Max), the size (C of maximal plasma concentration _Max) or the minimum time (T that detects blood or plasma concentration occurs _Lag) enhancing of the pharmacokinetic characteristic measured." strengthen absorption feature " expression is weighed by described pharmacokinetic parameter, and described absorption has strengthened or be stronger.Pharmacokinetic parameter is measured and the mensuration of minimal effective concentration is to carry out according to the conventional method of this area.By with the standard route of administration, for example subcutaneous administration or intramuscular administration relatively determine that the value that is obtained has improved.In described comparison, although not necessarily, be administered in the knitting layer and be administered to reference site, as subcutaneous administration, preferably relate to identical dosage level, i.e. the medicine of same amount and concentration, and identical carrier intermediate, with identical application rate, represent with amount and the bulk form of unit interval.Therefore, for example, specific medical substance is administered to knitting layer with the concentration of 100 μ g/ml and the speed of per minute 100 μ l with 5 fens clock times, preferably with 5 fens clock times identical medical substance is administered to subcutaneous space and compares with speed with 100 identical μ g/ml and per minute 100 μ l.

Can realize above-mentioned PK and PD effect best now by accurate guiding knitting layer.For example, this purpose is by using external diameter to be no more than about 250 microns and have less than 5mm, preferably realizes less than the miniature operation needle system of the length of exposure of 3mm.The preferred conveyer device that is used for the inventive method is 30G, 2mm aciculiform thing length, is assembled into the syringe as medicament reservoir.Described system can comprise iron and steel with known method by various materials, silicon, and pottery and other metals, plastics, polymer, sugar, biology and/or biodegradable material, and/or their combination is made.

Have found that some feature of knitting layer application process provides useful clinically PK/PD and dose accuracy.For example, have found that the position of aciculiform thing outlet in skin can obviously influence the PK/PD parameter.

Another advantage of the present invention is that ID carries relatively, mass transport has been reduced the danger of back-pressure to knitting layer.Although do not wish to be subjected to the restriction of particular mechanism of action, this may be owing to lack due to the elastin fiber in the knitting layer to a certain extent.

Usually, the inject time of carrying 100-120 μ L with the bolus injection form by the ID approach, this was because the inherent elasticity of corium compartment to a certain extent in 8-15 scope second.Be expelled to maximum injection volume in the corium compartment in 50 μ L-250 μ L scopes, this depends on region.Opposite with the ID conveying, the inject time of knitting layer administration is faster, promptly is less than for 10 seconds, and the maximum injection volume is irrelevant with the injection site above 250 μ L.

Be used to implement application process of the present invention comprise with material of the present invention by bolus injection and infusion delivery in human body or animal subjects body.Bolus injection dosage is to use the short time with single volume unit form, is less than the single dose of conveying in about 10 minutes usually.Transfusion is used and is comprised with the selected velocity application of fluid, and this speed can be that constant or variable, used time is longer relatively, usually above about 10 minutes.For transportation of substances, the knitting layer access to plant is placed near experimenter's skin, provide direct orientation to enter the passage of knitting layer, and with described mass transport or be administered to knitting layer, here, described material can work the part, perhaps by blood absorption and systemic the distribution.Described knitting layer access to plant can want the container of transportation of substances to be connected with accommodating.

Being transported to knitting layer from container can carry out passively, promptly the material that will carry is not applied external pressure or other type of drive, and/or exerts pressure on one's own initiative or other type of drive.The example of preferred pressure generating means comprises pump, syringe, elastomer film, gas pressure, piezo-electric device, electric device, electromagnetism pumping, or disc spring or packing ring or their combination.If necessary, the transporting velocity of described material can be controlled changeably by pressure-generating device.As a result, described material enters knitting layer, and to be enough to produce the amount and the speed absorption of clinical effectiveness.

In this article, the biologically that term " clinical effectiveness " expression is useful clinically comprises the useful reaction of diagnosing on going up and treating, and this reaction produces by using material of the present invention.For example, diagnostic assay or prevention, the control of disease or symptom and treatment are clinical effectiveness.

5.4 be used for the device of knitting layer administration

The present invention relates to be used for accurately and any device that optionally target is decided the knitting layer of patient skin.The character of employed device is unimportant, arrives the target depth in the knitting layer and don't passes it as long as it can thrust experimenter's skin.Preferably, the degree of depth that described device thrusts skin is about at least 2mm, and depth capacity is no more than about 3mm, is most preferably not exceeding about 2.5mm.The present invention includes the delivery device and the aciculiform thing assembly that are disclosed in the following document: United States Patent (USP) 6,494,865 and Application No. 10/357,502 and 10/337,413 (applying date is respectively on February 4th, 2003 and on January 7th, 2003), all documents are all received with their integral form and are done this paper reference.In a single day those skilled in the art have grasped knowledge the application and boundary-related knitting layer, just can improve at the device disclosed in above-mentioned patent and the patent application, so that be suitable for the knitting layer administration by normal experiment.

The present invention relates to conventional injection aciculiform thing, the independent use of conduit or all known types or be used in miniature operation pin on the spininess shape thing array.In addition, the present invention relates to not have aciculiform thing device, comprise the ballistic injection device.In this article, term " aciculiform thing " is intended to the aciculiform thing spline structure that comprises that all are such.Its example includes, but are not limited to conventional injection aciculiform thing, sleeve pipe, the miniature operation pin of conduit or all known types.In this article, term " miniature operation pin " is intended to comprise No. 30 and littler, common approximately 31-50 number structure, and this structure is a cylinder character.Therefore, the non-tubular structure that the miniature operation pin of term is comprised should have suitable diameter, and comprises cone, rectangle, octagon, wedge shape and other geometries.

The present invention relates to use comprise at least one aciculiform thing, the device of preferred miniature operation pin with mass transport in knitting layer.Preferably, the length of described aciculiform thing is enough to thrust knitting layer, and the outlet degree of depth be arranged in knitting layer so that described material is transferred and is distributed in the knitting layer.In certain embodiments, the length of aciculiform thing is the about 5mm of about 2mm-, preferably approximately the about 3mm of 2mm-.In other embodiments, when inserting the aciculiform thing, the outlet of described aciculiform thing is placed on the about 3mm of about 2mm-, the preferably approximately degree of depth of the about 2.5mm of 2mm-.But, preferably described device has and is used for controlling the constructional device of skin penetration to the depth desired of knitting layer.Modally be,, limited by aciculiform thing interface up to of the puncture of aciculiform thing to skin by miniature operation pin being inserted with angle perpendicular to skin surface, or by preventing that the more deep penetrating parts of aciculiform thing from limiting.Described parts can be the parts of miniature operation needle cannula, or assembled components.The length that is used for the miniature operation pin of knitting layer administration can change in process of production easily, and usually with the produced in lengths less than 3mm.Described miniature operation pin can be disposable spicule, and it is assembled into medicament reservoir, as syringe, perhaps can be and the syringe top aciculiform thing of knitting layer in advance.The miniature operation pin that is used for the inventive method can also be very sharp-pointed, and has very little model, as 30 or 34G, so that further reduce pain and other impressions during injection or transfusion.They can be used as the miniature operation pin in independent single chamber and use, and perhaps can assemble a plurality of miniature operation pins or with linear array or two-dimensional array form production, so that improve transporting velocity or improve the amount of transportation of substances in the special time.Miniature operation pin can knitting layer on multiple device, as holder and shell, they can be used for restriction equally and thrust the degree of depth.The container that holds described material before knitting layer doser of the present invention can also be included in and carry, or pump or other are used for carrying the device of medicine or other materials under pressurized conditions.Perhaps, described knitting layer doser can from outside be connected with these optional features.

In one embodiment, the device that the present invention is used for the knitting layer administration comprises with the lower part: the aciculiform thing, and its length is enough to thrust knitting layer, and its outlet degree of depth is in knitting layer, so that described material is transferred and is assigned in the knitting layer; Be used for loading the structure that stores and distribute described material; Be used for controlling the structure of skin penetration to the depth desired of knitting layer.In one embodiment, described being used for loads, and storing and distributing the structure of described material is syringe.In another embodiment, described structure is the automatic injection device, for example, but is not limited to pen type, rifle formula or automatic injector.The structure that is used to control the skin penetration degree of depth can play a part permission the aciculiform thing is vertically inserted experimenter's skin.

In one embodiment, device of the present invention has and is used for loading, and stores and/or distribute the constructional device of the preparation that contains material of the present invention, i.e. container.Sending from described container to knitting layer can passively be carried out, and promptly the material that will carry do not used external pressure or other type of drive, and/or is applying pressure or other type of drive on one's own initiative.The example of preferred pressure generating means comprises pump, syringe, elastomer film, gas pressure, piezo-electric device, electric device, electromagnetism pumping, or disk-like means or packing ring or their combination.Specifically, syringe or automatic injection device for example, but are not limited to pen type, and rifle formula or automatic injector can be advantageously used among the present invention.

If necessary, the transporting velocity of described material can be carried out variable control by pressure-generating device.As a result, described material enters knitting layer, and to be enough to produce the amount and the speed absorption of clinical effectiveness.In certain embodiments, the speed of described conveying and volume can adopt the automatic programming control with logic element.The example of described program includes, but are not limited to physiological mode, based on the specification or the motion averaging method of model, and medicine kinetic model, monitor signal handling procedure, predictive control model and their combination.

In one embodiment, described device has and is used for controlling the constructional device of skin penetrating to the depth desired of knitting layer.This purpose is modal to be to realize that by the part that broadens or the interface that link to each other with the axle of knitting layer access to plant described knitting layer access to plant can adopt the form of supporting construction or platform, and the aciculiform thing is connected above it.In process of production, can change length easily as the aciculiform thing of knitting layer access to plant, and usually its length less than 5mm, preferably less than 3mm.The aciculiform thing still very sharp-pointed and have a very little model so that further reduce pain or other sensations during injection or transfusion.They can be used as single aciculiform thing in the present invention and use, perhaps with a plurality of aciculiform things assemblings or be processed into linear array or two-dimensional array, so that improve transporting velocity or the amount of transportation of substances in special time.Can be on multiple device with aciculiform thing knitting layer, as holder and shell, they can be used for restriction and thrust the degree of depth.The device that holds described knitting layer access to plant can externally be connected with miscellaneous part, as container and the control device that is used to control applied volume and speed.

The inventive method also comprises the trajectory fluid injector, powderject conveyer device, piezoelectricity, electronic, the auxiliary conveyer device of electromagnetism, the auxiliary conveyer device of gas, it can directly thrust skin, carries or directly with the passage of the target site of mass transport in the knitting layer so that provide.

5.5 the mensuration that treatment is renderd a service

The treatment effectiveness that contains the preparation of material of the present invention can use any standard method conventionally known to one of skill in the art or that this paper is disclosed to measure.Be used to measure the assay method that the treatment of preparation of the present invention renders a service and be based in the body or external assay method, comprise mensuration based on animal.Preferably, the treatment of preparation of the present invention is renderd a service and is measured in clinical facility.

In certain embodiments, preferably use the pharmacokinetics and the pharmacodynamic parameter of the conveying of standard method quantitative assay known in those skilled in the art material of the present invention.In preferred embodiments, the pharmacodynamics of the material of the present invention that will carry with the inventive method and pharmacokinetic properties and by other conventional mode of administration, for example subcutaneous or intramuscular carries the characteristic of the material of being carried to compare, and renders a service so that determine the treatment of the material used according to the inventive method.Can include, but are not limited to T according to the pharmacokinetic parameter that the inventive method is measured _Max, C _Max, T _Lag, AUC etc.Can comprise according to the other drug kinetic parameter that the inventive method is measured, for example, half-life (t _1/2), removing speed constant and part A UC value.Can use canonical statistics known in those skilled in the art to learn test pharmacokinetics and the pharmacodynamic parameter that is obtained carried out statistical analysis.

In specific embodiments, the treatment that the present invention relates to measure the material of using according to the inventive method is renderd a service, comprise with its pharmacokinetic characteristic with for example, subcutaneous or intramuscular carries the feature that obtains to compare.Being used to measure the typical assay method that the treatment of material renders a service can may further comprise the steps: use 30G, and the aciculiform thing of 1.5mm, or use 34G, the aciculiform thing of 2mm is used 34G, and the aciculiform thing of 3mm is used material of the present invention, or subcutaneous or intramuscular injection is in human body.Preferably 5/8 in2 5G aciculiform thing is used for intramuscular injection.The volume injected of 0.2mL is used for knitting layer and subcutaneous delivery, and the volume of 0.5mL is used for the intramuscular conveying.For vaccine, strengthened injection at the 0th, 7 and 21 day.Blood sample collection, and preferred after sample collecting in 1 hour under 2-8 ℃ with the speed of 3000rpm centrifugal at least 15 minutes.Transfer is used for the serum levels analysis from the serum of blood taking tube.

Can further specify the present invention by following indefiniteness embodiment.

6. embodiment

6.1 the knitting layer of Enoxaparin  is carried

With 2000 or the Enoxaparin  preparation of 4000aXa IU be expelled to experimenter's knitting layer.The knitting layer injection of Enoxaparin  has obtained 1.5-2.3 hour T _Max, the hypodermic speed of this time ratio is faster, has shown that Enoxaparin  works when knitting layer is carried quickly.C _MaxValue (0.2-0.6 aXa IU/mL) is identical with total AUC (2-4.5 aXa IU/mL/ hour) for knitting layer and subcutaneous injection.

6.2 the knitting layer administration of FONDAPARINUX 

Fondaparinux  is expelled to experimenter's knitting layer.The knitting layer injection of Fondaparinux  has obtained 1.5-2.3 hour T _Max, shown with subcutaneous injection and compared that Enoxaparin  can work sooner when knitting layer is injected.For knitting layer and subcutaneous injection, C _MaxValue (0.3-0.45mg/mL) is identical substantially with total AUC.

6.3 in the human volunteer body of health, carry out the open randomised study of rabies virus vaccine

The main purpose of this research is the immunoreactive influence of research delivery depth to rabies vaccine, comprises that assessment is to the antigenic antibody response of rabies.Rabies vaccine is transported in the seronegativity human volunteer body, and uses the aciculiform thing of different length to change delivery depth.Experimental design is open, parallel group of randomized research.

The experimenter: recruit 10 experimenters for every group, comprise masculinity and femininity, the age is between 18-40 year.Selected and non-selected index are provided in the table 1 below and 2.

Table 1: experimenter's inclusion criteria

Healthy male and women white people experimenter, the age is at 18-40 between year,

Experimenter's major organs function must be in acceptable medical science limit range, and this limit is definite by clinical medical history and physical examination,

When primary dcreening operation is made a house call, under standard conditions, measure: lying on the back had a rest at least 5 minutes after, the experimenter must have normal blood pressure and heart rates: SBP in the 90-140mmHg scope, DBP is in the 40-85mmHg scope, and HR is 40-85bpm,

When primary dcreening operation is made a house call, must be normally in the experimenter 12-lead electrocardiogram of the record after at least 5 minutes of having a rest: PR in the 120-200ms scope, QRS≤120ms, and QTc≤440ms.Incomplete right bundle branch block is an acceptable

The experimenter must have the experimental result in normal range, and perhaps be not studied the person and think uncorrelated clinically,

The experimenter must be seronegative at rabies vaccine antigen,

The experimenter must agree not use any medicine, and these medicines may influence the rabies antibody that produces in vivo after immunity,

Female subjects must take suitable birth control method (HORMONE TREATMENT or intrauterine device) avoiding before the immunity of this research and pregnancy at least 3 months afterwards, and urine pregnancy test must be negative when examination.

Table 2: experimenter's non-selected index

The experimenter has the irritated or super quick known medical history of any composition (albumin, neomycin) to rabies vaccine,

The experimenter has known immunodeficiency, systemic cancer, or used immunosuppressant therapy, comprise cancer chemotherapy and systemic steroid,

The experimenter has the activeness dermatosis,

The experimenter has type i diabetes or other severe disease,

The experimenter has slight upper respiratory tract and lower respiratory illness, the ENT local infection, gastroenteropathy or other incident of generating heat, these diseases be predict and record and will solve, such experimenter is temporarily foreclosed,

The experimenter who when examination, has Symptomatic or asymptomatic orthostatic hypotension, with lie on the back and standing state between SDP or DDP reduce and surpass 20mmHg and define,

The experimenter who when the urine medication examination, is positive (cannabinoid, benzene phenodiazine  class),

The experimenter of pregnancy or suckling,

During examination, in the blood at the experimenter of the antigenic antibody horizontal of rabies more than 0.5UI/mL,

Have the experimenter of hepatitis B or hepatitis C medical history and/or from the serological positive findings of hepatitis, it has shown and has existed acute or chronic type b or hepatitis C,

Have the serological experimenter of positive HIV,

The experimenter who surpasses 400mL blood is provided in nearest 3 months,

The experimenter who has participated in another clinical research within 30 days during participating in this research,

The experimenter who has too much chaeta at upper limb.

The medicine of research: the Vero cell rabies (PVRV) of in this research, having used purification.This vaccine is used the Vero cells produce by Aventis Pasteur (France), and has confirmed already that being used for human rabies prophylaxis and treatment be safety and effective.The safety of relevant intramuscular conveying TVRV and the multinomial research of effectiveness had been reported already.In addition, also on human body, carry rabies vaccine to carry out comprehensive research, carried out expert's grouping and appraised through discussion intradermal.The intradermal transport way of rabies vaccine is considered to expose with early stage and later stage the same effective and safety of intramuscular approach of immunity.The major advantage of intradermal approach is that antigen dose is saved, and for example, 1/10 intramuscular dosage this means for rabies remain the developing country of public health problem and can save a large amount of costs.

Because the antigenic high antigen effect of PVRV rabies, all young healthy volunteers are the effect persons of this vaccine, in clinical experiment immunity after in the data of record without any the seriously danger of negative event.Therefore, the PVRV rabies vaccine to be considered in clinical research be safe and reliable immunopharmacology model.Except the security features of this vaccine, also exist to select PVRV rabies vaccine other advantages as volunteer's clinical research model, comprise it in the intravital strong antigen effect of adult, described vaccine is had about 100% reply.In addition, because rabies immune is not the compulsory immunization inoculation in France, most of French common people are seronegative to PVRV antigen.

Research device: in this research, used four kinds of different research devices:

As positive control, used length to carry out intramuscular injection (IM) as the aciculiform thing of 16mm.In this case, the dosage of the vaccine delivery of per injection is 0.5mL.For intradermal injection (ID), used 30G, the aciculiform thing of 1.5mm, wherein, the vaccine dose of per injection is 0.2mL.For knitting layer injection (JI), used the aciculiform thing of 34G length as 2mm and 3mm, and the delivered dose of per injection with use the identical of ID conveying.

Research design: each processed group comprises the volunteer of 10 adult healthy, comprises women and male in processed group; I group: use the aciculiform thing of 1.5mm to carry out the intradermal injection; II group: use the aciculiform thing of 2mm to carry out the knitting layer injection; III group: use the aciculiform thing of 3mm to carry out the knitting layer injection; IV group: use the aciculiform thing of 16mm to carry out the IM injection.

The purpose of this research is the difference between the research immunoreation, and this species diversity is to weigh by tiring in the circulating antigen of immunoreation induction period.Therefore, compared the antibody titer that rabies vaccine produced from D0 to D14 days that uses single dose.Described anti-rabies immune scheme is included in D0, three successive injections that D14 and D21 carry out.The mensuration of antibody titer is D0 after immunity, D7, and D14 carried out in D21 and D49 days.

The result:

Fig. 3 and table 3 are illustrated in the single injection rabies vaccine geometric mean titer (GMT) of antibody afterwards.Carrying out the knitting layer injection with the long aciculiform thing of 2mm compares with other transport way and has obtained lower GMT.Being injected at the lower GMT that produced in D7 days by knitting layer might be owing to antigen is being transported to the immunoreation of having postponed when the degree of depth is the knitting layer of 2mm.

Consider that rabies vaccine is unusual effective antigens, carry out the knitting layer administration in the 2mm degree of depth and shown that at D7 and D14 days lower GMT knitting layer compares with muscle with corium, knitting layer induce to the reactivity aspect the immunoreation of rabies virus vaccine a little less than.But, carry identical aspect the immunoreation intensity that is produced with the degree of depth of 3mm with the intradermal conveying.

After carrying out 2-3 injection subsequently, immunoreation is not subjected to the appreciable impact (Fig. 4) of transport way.

Table 3:The geometric mean titer (GMT) of antibody after the single injection rabies vaccine

IM	?0	?3.27	?20.8	?55.8	?69.74
						ID	?0	?2.12	?19.27	?37.45	?41.44
Knitting layer 3	?0	?2.22	?20.79	?31.99	?43.19
						Knitting layer 2	?0	?1.03	?16.73	?40.53	?51.82

Although described the present invention in conjunction with specific embodiments already, for a person skilled in the art, it is evident that, under the prerequisite of design of the present invention that does not exceed the appended claims qualification and scope, can make various changes and improvements.

Claims (19)

1. be selected from low molecular weight heparin, pentasaccharides, interferon-, erythropoietin, antibody, albumen, polypeptide hormone, growth hormone, the material of anti--thrombotic medicine and interleukin is used for producing and is used for the purposes of mass transport to the used medicine of the intravital method of human experimenter, described method comprises small size aciculiform thing by inserting knitting layer with the knitting layer of described mass transport to human patients skin, and the length of described aciculiform thing and the outlet degree of depth are enough to penetrate knitting layer.

2. be selected from low molecular weight heparin, pentasaccharides, interferon-, erythropoietin, antibody, albumen, polypeptide hormone, growth hormone, the material production of anti--thrombotic medicine and interleukin is used for the purposes of mass transport to the used medicine of the intravital method of human experimenter, and described method comprises the knitting layer that described mass transport is arrived human patients skin by the small size aciculiform thing that inserts knitting layer, described aciculiform thing has length and the outlet of the degree of depth in knitting layer that is enough to penetrate knitting layer, so that described electrodeposition substance is in knitting layer.

3. as the purposes of claim 1 or 2, wherein, described aciculiform thing is the knitting layer that vertically inserts patient skin.

4. as the purposes of claim 1 or 2, wherein, described material can arrive the venous plexus of knitting layer and the dense network of postcapillary venule easily, and can fast Absorption and systemic the distribution.

5. as the purposes of claim 1 or 2, wherein, described material can not cause undesirable immunoreation.

6. as the purposes of claim 1 or 2, wherein, the length of described aciculiform thing is 2mm-5mm.

7. as the purposes of claim 1 or 2, wherein, the length of described aciculiform thing is 2mm-3mm.

8. as the purposes of claim 1 or 2, wherein, described aciculiform thing is 30-34G.

9. as the purposes of claim 1 or 2, wherein use an aciculiform thing.

10. as the purposes of claim 1 or 2, wherein, described aciculiform thing is selected from following one group: miniature operation pin, conduit aciculiform thing and injection aciculiform thing.

11. as the purposes of claim 1 or 2, wherein, the described outlet degree of depth is about 2mm-2.5mm when inserting described aciculiform thing.

12. as the purposes of claim 1 or 2, wherein, described material is to carry with 0.5mL or above volume.

13. as the purposes of claim 1 or 2, wherein, described material is to carry with 1.0mL or above volume.

14. as the purposes of claim 1 or 2, wherein, described material is low molecular weight heparin or pentasaccharides.

15. as the purposes of claim 1 or 2, wherein, described material is an Enoxaparin.

16. as the purposes of claim 1 or 2, wherein, described material is Fondaparinux.

17. as the purposes of claim 1 or 2, wherein, described material is an insulin.

18. aciculiform thing that is used for patient skin is carried out the knitting layer administration of material, comprise and be used to limit the device that the aciculiform thing thrusts the degree of depth of skin, and has the described relatively localized outlet of restraint device that penetrates, so that described aciculiform thing is being inserted skin to the time by the described degree of depth that penetrates the restraint device decision, the degree of depth of described outlet makes described electrodeposition substance in knitting layer in described knitting layer.

19. a device that is used for patient skin is carried out the knitting layer administration of material comprises as the aciculiform thing of claim 18 and is used for loading, and preserves and distribute the device of described material.

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