CN1909911A - Treatment of a condition in a mammal with adminisration of aminosugar and uses thereof - Google Patents

Abstract

The present invention relates to treating joint related conditions in mammals by administering an aminosugar, and wherein said treatment specifically prevents, lessens or reverses pathologies associated with the joint condition, said pathologies being selected from the group consisting of synovitis, subchondral bone edema, and cartilage degradation.

Description

The morbid state and application thereof for treating mammal by giving amino sugar

Government authorization

[0001] present invention part obtains the support of U.S. government, and the grant number for authorizing National Institutes of Health (National Institutes of Health) is NIH AG 07996 and AT 00052.U.S. government can have certain rights to this invention.

Related application

[0002] this application claims the Provisional Patent Application No. 60/507 that on October one, 2003 submits, 716 priority, entitled Treatment Of A Condition In A MammalWith Administration Of Aminosugar And Uses Thereof.

Invention field

[0003] the present invention relates to the severity that mammal joint associatcd disease state is treated by application amino sugar, wherein the treatment particularly prevents, mitigates or reverses many neuropathological hallmarks relevant to the joint condition, and the neuropathological hallmarks are selected from synovitis, subchondral bone edema (subchondral bone edema) and cartilage degradation (cartilage degradation).

Background of invention

[0004] a variety of neuropathological hallmarks are all related to the morbid state and disease for being related to joint.The morbid state (condition) or disease (disease) for being related to joint may include, but be not limited to the physical hazard in joint, osteoarthritis (OA) and rheumatoid arthritis.Specifically, these relevant neuropathological hallmarks may include synovitis, subchondral bone edema and progressive cartilage degradation (progressive cartilage degradation), although there is also many other marks really.(Ayral etc., Rheumatology, Vol 35,14-17；McAlindon, Best Pract Res ClinRheumatol 1999；13 (2): 329-44；Ayral etc., Annals of the RheumaticDiseases 2002 vol.61 suppl.1, #OP0014；Kerin etc., Cell Mol Life Sci2002；59:27-35；Hedbom etc., Cell Mol Life Sci 2002；59:45-53；Silver etc., Crit Rev Biomed Eng 2001；29:373-91；Elsaid etc., Osteoarthritis Cartilage.2003；11:673-80；Altman etc., Am J Med.1983 Oct 31；75 (4B): 50-5).

[0005] unfortunately, the therapy of current joint condition (joint conditions) is typically limited to the intra-articular corticosteroid of paracetamol, non-steroidal anti-inflammatory drugs, injectable (injectableintra-articular corticosteroid) and hyaluronic acid, can only treat the analgesic activity of general inflammation and offer to a certain degree.(Geletka etc., Best Pract Res Clin Rheumatol.2003 Oct；17:791-809；Altman etc., Am J Med.1983 Oct 31；75 (4B): 50-5)

[0006] recently, aminoglucose (GlcN) is used to treatment joint condition osteoarthritis, and anti-inflammatory effect has been universally accepted as its mechanism of action.Just propose that GlcN can make progressive articular cavity narrow (progressive joint space narrowing) stopping improving the kneed biomethanics for suffering from osteoarthritis recently.(Reginster etc., Lancet 2001；357:251-6；Hughes etc., Rheumatology (Oxford) 2002；41:279-84).Unfortunately, observe that concentration range when the external optimum activity of GlcN is difficult or can not even be reached by the oral sugar given, in addition, GlcN just has cytotoxicity to cartilage cell under the concentration of low mmoles, this to be not suitable for being treated using high concentration GlcN.(Sandy etc., Arch Biochem Biophys1999；367:258-64；Shikhman etc., J Immunol 2001；166:5155-60；Setnikar etc., Arzneimittelforschung 2001；51:699-725；Adebowale etc., BiopharmDrug Dispos 2002；23:217-25；Aghazadeh-Habashi etc., J Pharm Pharm Sci2002；5 (2): 181-4；De Mattei etc., Osteoarthritis Cartilage 2002；10:816-25.).

[0007] N-acetyl-glucosamine (GlcNAc) is also used to treatment OA and RA.Studies have shown that GlcNAc is non-toxic to human articular chondrocytes and even will not cause cartilage cell dead under the concentration higher than 50mM compared with GlcN.(de Mattei etc., OsteoarthritisCartilage 2002；10:816-25.).

[0008] many patents are related to using GlcN and GlcNAc treatment OA and/or RA.U.S. Patent number 3,683,076 (Rovati), which is disclosed using the salt of GlcN, treats OA and RA；U.S. Patent number 4,870,061 (Speck), which is disclosed, treats degenerative joint disease (degenerative joint disease) using GlcNAc by buccal administration；U.S. Patent number 5,840,715 and U.S. Patent number 6,136,795 (being Florio) disclose and use GlcNAc as the nutritional supplement of diet to alleviate arthritis.

[0009] however, up to now, still treating without effective means, the severity of synovitis, subchondral bone edema and cartilage degradation is prevented or mitigated.Therefore, still it is highly desirable to the severity for the treatment of, these symptom for preventing and mitigating related joint condition.

Summary of the invention

[0010] it has been found that amino sugar mitigates, prevent and reverse the symptom in relation to joint condition.To which this discovery is provided to there are the specific therapies of any joint condition of these one or more symptom.It is a targeted approach that this newfound treatment, which has the method for the joint condition of one or more neuropathological hallmarks, wherein the influence of newfound amino sugar allows to treat joint condition, and wherein otherwise joint condition never receives amino sugar treatment.

[0011] the present invention relates to be related to the joint associatcd disease state of mammal by giving amino sugar treatment, wherein the treatment particularly prevents, mitigate or reverse symptom related with joint condition, the symptom is selected from synovitis, subchondral bone edema and cartilage degradation.

[0012] preferred embodiment of the invention is related to the amino sugar by applying therapeutically effective amount to mammal to prevent, the method for mitigating or reversing serious symptom related with joint condition, wherein amino sugar includes but is not limited to N-acetyl-glucosamine, aminoglucose, galactosamine, N- acetylgalactosamine, acceptable salt in imino group cyclitol (iminocyclitol) and their pharmacy.In the one aspect of this preferred embodiment, the specific neuropathological hallmarks of joint condition are evaluated, if the mark exists, apply the amino sugar of therapeutically effective amount.In another optional aspect of the present embodiment, is treated with the amino sugar of effective therapeutic dose and known in the art be related to the joint condition of these neuropathological hallmarks.Preferably, the amino sugar of therapeutically effective amount is applied to mammal by intra-articular.It is also preferable that the amino sugar is GlcNAc, it is highly preferred that it includes GlcNAc in matrix that the amino sugar, which is, it is controlled release preparation.

[0013] in the other preferred embodiments of the present invention, GlcNAc gives the mammal with joint condition by intra-articular, to treat cartilage degradation, subchondral bone edema and synovitis.Preferably, therapeutic effect can be observed in macroscopic level or electronmicroscopic level.It is also preferable that therapeutic effect in particular cartilage degradation delays, cell crosses the reduction of mucosal inflammation in the reduction and synovitis of Sheng in subchondral bone edema marrow.

[0014] presently preferred embodiment is the method to mammal application composition, the composition includes the amino sugar of therapeutically effective amount, preferably GlcNAc, GlcNAc are used alone or combine with existing anti-inflammatory agent or hexosaminidase (hexoaminidase) inhibitor.Preferably, the method for giving preparation of the invention is including but not limited to intra-articular, part and intramuscular administration method.It is highly preferred that controlled release preparation is applied in the mammal joint for needing this treatment.

[0015] to which the present invention provides the method for particularly treating joint condition, the neuropathological hallmarks that wherein there are the joint condition one or more pairs of amino sugar therapies to have sound response.Present invention provides new application of the amino sugar in the targeted therapies of joint condition, joint condition therein has one or more neuropathological hallmarks.In addition, joint condition therein has one or more neuropathological hallmarks the present invention provides compound and its pharmaceutical preparation for targeted therapy joint condition.

Brief description

[0016] Figure 1A shows the general form histological grading of the femur ankle of rabbit, and wherein rabbit is handled by the cross-section art of bilateral anterior cruciate ligament (ACLT) and using intramuscular GlcNAc or physiological saline.

[0017] Figure 1B shows the general form histological grading of the tibial plateau of rabbit, and wherein rabbit is handled by bilateral anterior cruciate ligament (ACL) cross-section art and using intramuscular GlcNAc or physiological saline.

[0018] Fig. 2 shows the general form histological grading of the femur ankle of rabbit, and wherein rabbit by the cross-section art of unilateral side ACL and uses intra-articular GlcNAc, Sodium Hyaluronate or saline treatment.

[0019] Fig. 3 shows the general form histological grading of the tibial plateau of rabbit, and wherein rabbit by the cross-section art of unilateral side ACL and uses intra-articular GlcNAc, Sodium Hyaluronate or saline treatment.

[0020] Fig. 4 illustrates the general form evaluation of the arthroncus of rabbit, and wherein rabbit by the cross-section art of unilateral side ACL and uses intra-articular GlcNAc, Sodium Hyaluronate or saline treatment.

[0021] Fig. 5 illustrates the DNA content in the synovial tissue derived from rabbit, and wherein rabbit by the cross-section art of unilateral side ACL and uses intra-articular GlcNAc, Sodium Hyaluronate or saline treatment.

[0022] Fig. 6 shows the digital image analysis derived from the femur ankle (Fig. 6 A) of rabbit and the damaged area of tibial plateau (Fig. 6 B), and wherein rabbit is handled by the cross-section art of unilateral side ACL and using intra-articular GlcNAc or Sodium Hyaluronate.

[0023] Fig. 7 shows the time dependence of the release in vitro of GlcNAc, and wherein a GlcNAc embodiment according to the present invention is embedded in the polymer formulations of injectable.

Detailed description of the invention

Abbreviation and term

[0024] according to the present invention and as used herein, unless otherwise expressly stated, the meaning that term and abbreviation below is defined as.These intentions explained are only exemplary.Throughout the specification, when these terms are described or are mentioned, it is not intended to be limited.In contrast, these explain that being intended to includes any additional aspect and/or example as described herein with term that is requiring.

Following abbreviation is used herein

ACL=anterior cruciate ligament (anterior cruciate ligament)；

The cross-section art of ACLT=anterior cruciate ligament (anterior cruciate ligament transection)；

GlcN=aminoglucose (glucosamine)；

GAG=glucosaminoglycan (glycosaminoglycan)；

GlcNAc=N- acetylglucosamine (N-acetylglucosamine)；

HA=hyaluronic acid (hyaluronic acid)；

IL-1 β=Interleukin -1β (interleukin-1 β)；

IL-6=interleukin-6 (interleukin-6)；

NSAID=non-steroidal anti-inflammatory drugs (nonsteroidal anti-inflammatory drug)；

OA=osteoarthritis (osteoarthritis)；

PBS=phosphate buffer (phosphate-buffered saline)；

PEG=polyethylene glycol (polyethylene glycol)；

PMSF=phenylmethylsulfonyl fluoride (phenylmethylsulfonyl fluoride)；And

RA=rheumatoid arthritis (rheumatoid arthritis)；

[0025] " effective component (active ingredient) refers to the drug and its preparation of therapeutically effective amount to term.Preferably, effective component of the invention is amino sugar, more preferably amino sugar GlcNAc and GlcN；And most preferably amino sugar GlcNAc.

[0026] term " therapeutically effective amount (therapeutically effective amount) " refer to generate present invention contemplates that one or more pharmacological effects required for effective component amount.The effect of according to concrete activity substance；Age, weight and the reaction of individual；And the property and severity of individual symptom, this amount can be very different.Therefore, to the amount of active material, there is no the stringent upper limits or lower limit.The therapeutically effective amount that the present invention uses can be easy to be determined by one skilled in the art.

[0027] term " alginate jelly (alginate gel) " refers to natural polysaccharide polymers, in varing proportions includes Isosorbide-5-Nitrae-connection beta-D-mannuronic acid and α-L- guluronic acid residues.Alginates are capable of forming stable gel, when being especially in the presence of certain bivalent cations, such as calcium, barium and strontium.

[0028] term " amino sugar (aminosugar) " refers to any synthesis or naturally occurring sugar, wherein one or more carbon atoms are by amino (- NH₂) replace.This substitution is not related to the orientation of any asymmetric carbon atom or configuration present in sugar and exists.Unless otherwise stated, term " amino sugar " refers to any anomer (α or β) of cyclic amino sugar.Amino sugar can perhaps acyl group N- replaces a hydrogen atom of wherein side amino by alkyl or acyl moiety (- COR, wherein R=low alkyl group) replacement by alkyl.According to a preferred embodiment of the invention, R=the methyl (- CH in-COR₃)。

[0029] term " arthritis " refers to any disease specific characterized by arthritis, although the cause of disease of inflammation in varied situations can be different.Relatively common arthritis disease includes rheumatoid arthritis, juvenile arthritis (juvenile arthritis), ankylosing spondylitis (ankylosingspondylitis), psoriatic arthritis (psoriatic arthritis) and osteoarthritis.

[0030] term " articular cartilage (articular cartilage) " or " cartilage " (cartilage) are referred to overlaying on bone end and are formed the substance of articular surface.Cartilage can resist compressing force and generate the surface of low friction, and joint can be slided on a surface.Articular cartilage include cartilage cell and further comprise albumen and glucosaminoglycan (glycosaminoglycan) polysaccharide substance.

[0031] term " cartilage degradation (cartilage degradation) " refers to including the degeneration in the tissue of cartilage.

[0032] term " chitin " refers to (poly-) GlcNAc connected in the form of β-Isosorbide-5-Nitrae.Chitin is seen everywhere in nature, such as in the ectoskeleton of insect and shellfish. 

[0033] term " chitosan " refers to the deacylation chitin or (poly-) N- aminoglucose connected in the form of β-Isosorbide-5-Nitrae.

[0034] term " cartilage cell " (chondrocyte) refers to cell present in articular cartilage.Cartilage cell generates collagen, colloidal carrier matter and proteoglycan, for the glucosaminoglycan (glucosamine glycan) (being also mucopolysaccharide) connected with albumen.

[0035] term " morbid state in joint " (condition of the joint) or " joint condition " (joint condition) indicate one of to influence mammal joint and show following pathological condition or a variety of any pathological states: synovitis, subchondral bone edema and cartilage degradation.

[0036] term " cladding effect (encapsulation efficiency) " refers to the amount of compound that is including, incorporation, loading, united, combining or being otherwise embedded in Injectable polymer gel, liposome, microballoon, nanoparticle (nanoparticle) or homologue or effective component.

Generally, " yield " is expressed as the percentage of active constituent cladding.

[0037] method that term " embedding " (entrapped) or " (encapsulated) of cladding " refer to any manufacture effective component, it limits, isolation or effective component in matrix is otherwise inhibited freely to dissolve, mesostroma such as solution or solid phase.The preferred example of the effective component of embedding and cladding includes but is not limited to the preparation being embedded in matrix, wherein the matrix is selected from particle, implantation material or gel.

[0038] term " matrix (matrix) " refers to solid, gel or liquid component, can embed one or more amino sugars and optional other raw materials, such as anti-inflammatory agent wherein.

[0039] term " glucosaminoglycan (glycosaminoglycan) " refers to long heteroglycan molecule, contains duplicate disaccharide unit.Disaccharide unit may include the amino sugar of modification: D-, N- acetylgalactosamine or D-GlcNAc and uronic acid, such as D-Glucose aldehydic acid or L- iduronic acid.In other function, GAGs works as the lubricating fluid in joint.It is hyaluronic acid, dermatan sulfate, chondroitin sulfate, heparin (heprin), Heparan sulfate and keratan sulfate in the specific GAGs physiologically with importance.

[0040] term " hyaluronic acid (hyaluronic acid) " refers to naturally occurring mucopolysaccharide, and it includes alternate D- glucuronic acids and D-N- acetylglucosamine subunit.Hyaluronic acid is the linear polysaccharide (long-chain biological polymer) formed by duplicate disaccharide unit, and disaccharide unit is made of D- glucuronic acid β (1-3) N- acetyl group-d-glucosamine of β (1-4) glucosides key connection.Hyaluronic acid can be obtained by commercial sources with several molecular weight ranges, and molecular weight ranges span can be from about 50,000 dalton to about 8 × 10⁶Dalton.Hyaluronic acid can also be obtained with sodium-salt form, be dry, highly purified substance.Sodium Hyaluronate can be saved with Determination of Preservatives known in the art comprising but it is not limited to alkyl-substituted benzoic ether, alcohols and its conjugate, blend and mixture.

[0041] term " hyaluronan (hyaluronan) " refers to the polymer of the repetition molecule of N-acetyl-glucosamine and glucuronic acid.

[0042] term " IL-1 β " refers to that Interleukin -1β, a kind of immunomodulator can mediate extensive immune and inflammatory reaction, including activation B- and T- cell.

[0043] term " injectable formulation " (injectable formulation) refers to sterile, injectable the composition that liquid solution or suspension is made.The solid form for being suitble to be dissolved in or be suspended in front of the injection liquid-carrier can also be prepared.It is that the prepared product is also possible to emulsification or embedded effective component.Injectable formulation also may include a variety of preservatives known in the art, including but not limited to alkyl-substituted benzoic ether, alcohols and its conjugate, blend and mixture.

[0044] term " Injectable polymer gel " refers to the polymer base carrier for embedding or coating inventive compound.Injectable formulation based on polymer allows to be customized drug dose and duration by selecting and preparing the combination of plurality of active ingredients/polymer.The accumulated dose of drug and the dynamics of release are diversified and can be adjusted.For example, the delivery parameter of drug can be optimized by changing quantity of solvent, the polarity of copolymer ratio and molecular weight and polymer solvent.System based on polymer can increase the service life of effective component.It uses in the formulation and provides certain advantages, such as biocompatibility and biodegradability comprising polylactide and the polymeric system of lactide-glycolide copolymer.Injectable polymer gel can be prepared according to method known in the art, such as processing, mixing, filtering, heating or sterilizing.

[0045] term " microballoon (microsphere) " refers to the polymer base carrier for embedding or coating effective component of the invention.Allow to be customized drug dose and duration by selecting and preparing the combination of plurality of active ingredients/polymer based on the preparation of microballoon.Drug total amount and release dynamics can be changed and can be adjusted.For example, drug delivery parameter can be optimized by the molecular weight for changing copolymer ratio and copolymer.System based on microballoon can also increase the service life of effective component.Certain advantages, such as biocompatibility and biodegradability are provided using the microballoon for including lactide-glycolide copolymer in the formulation.Can be according to method known in the art, such as process, be machined, mill, grind or squeeze to prepare microballoon.

[0046] term " intra-articular " refers to the method directly to endoprosthesis delivery drugs.Traditional drug delivery route such as, such as takes orally, intravenous injection or intramuscular administration, the vascular perfusion of dependence synovial membrane reach joint to carry drug.Such efficiency is very low, because across synovial membrane transhipment of the small molecule from synovial membrane capillary to articular cavity is occurred by Passive diffusion, efficiency declines with the increase of target molecule size.Therefore, indication molecule (directing molecules) such as GlcN enters articular cavity and is substantially restricted.The intra-articular injection or perfusion of drug overcome these limitations.

[0047] term " polymer " " (polymeric) refers to hyaluronic acid, polyethylene glycol, the copolymer of polyethylene glycol and poly- (lactic acid/glycolic acid), lactic acid polymer and poly- (ethylene glycol-y- (DL-LACTIC ACID -co- glycolic acid) (acceptable salt in poly (ethylene glycol-y- (DL-lactic acid-co-glycolic acid)) copolymer, alginate jelly, chitosan or their pharmacy.

[0048] term " sustained release (sustained release) " refers to the period, and drug is released to be utilized during this period of time, or otherwise becomes to be absorbed and utilizing by physiology.There can be an induction period before the period of sustained release, in induction period, drug is seldom discharged or do not discharged, or can be two-phase, including initial time period, it is released in this period some drugs, and second period, it is released in this period other drug.It is different from, term " continuous release (continuous release) " is only used to describe to show single-phase release figure, the release time figure with smooth curved.It will be appreciated by persons skilled in the art that release figure actually may conform to index or logarithm one release figure of time.

[0049] term " synovitis " refers to the inflammation of joint internal layer (synovial membrane).Synovitis appears in a variety of morbid states for being related to joint, including but not limited to osteoarthritis, physical or traumatic lesion, rheumatoid arthritis and other autoimmune diseases (autoimmunedisorder).

[0050] it has been found that amino sugar mitigates, prevents and reverse symptom related with joint condition.To which this discovery is provided for there are the specific therapies of any joint condition of these one or more symptom.This newfound method is a targeted approach of the joint condition that treatment has one or more neuropathological hallmarks, wherein the effect of this newfound amino sugar allows to treat joint condition, and wherein otherwise joint condition does not receive amino sugar treatment.However, it should be noted that, term " symptom " (pathology), " a variety of symptom " (pathologies) and " neuropathological hallmarks " (pathological markers) is used interchangeably herein, they refer to synovitis, subchondral bone edema and cartilage degradation.

[0051] the present invention relates to the joint associatcd disease states that mammal is treated by application amino sugar, wherein the treatment particularly prevents, mitigates and reverses symptom relevant with joint condition, and the symptom is selected from synovitis, subchondral bone edema and cartilage degradation.

[0052] the preferred embodiments of the invention are related to the amino sugar by applying therapeutically effective amount to mammal to prevent, mitigate or reverse serious symptom related with joint condition, and wherein amino sugar includes but is not limited to N-acetyl-glucosamine, aminoglucose, galactosamine, N- acetylgalactosamine, acceptable salt in imino group cyclitol and its pharmacy.In the one side of this preferred embodiment, the specific neuropathological hallmarks of joint condition are evaluated, if the mark exists, apply the amino sugar of therapeutically effective amount.In another optional aspect of this preferred embodiment, joint condition known in the art is treated using the amino sugar of therapeutically effective amount, wherein joint condition has these relative neuropathological hallmarks.Preferably, to the amino sugar for applying therapeutically effective amount in mammal joint.It is also preferable that the amino sugar is GlcNAc, and it is highly preferred that the amino sugar is included in GlcNAc of the matrix as control delivery formulations.

[0053] in another preferred embodiment of the invention, GlcNAc is applied to the mammal with joint condition by intra-articular, to treat cartilage degradation, subchondral bone edema and synovitis.Preferably, therapeutic effect can be observed in macroscopic level and electronmicroscopic level.It is also preferable that the therapeutic effect is specially the delaying of cartilage degradation, cell crosses the reduction of Sheng and the reduction of synovitis mucosal inflammation in the marrow of subchondral bone edema.

[0054] another preferred embodiment of the invention is the method for applying composition to mammal, and the composition includes the amino sugar of therapeutically effective amount, preferably GlcNAc, individually to give or being given in combination with existing anti-inflammatory agent or hexosaminidase inhibitor.Preferably, the method for applying invention formulation is including but not limited to intra-articular, local and intramuscular method.It is highly preferred that the control delivery formulations of the intra-articular application amino sugar to the mammal for needing this treatment.

[0055] therefore, the present invention provides the method for particularly treating joint condition, and wherein joint condition has one or more neuropathological hallmarks, has sound response to amino sugar therapy.The present invention also provides new application of the amino sugar in the targeted therapies of joint condition, and joint condition therein has one or more neuropathological hallmarks.In addition, useful in the targeted therapies of joint condition, wherein joint condition has one or more neuropathological hallmarks the present invention provides compound and its pharmaceutical preparation.

[0056] all patents being incorporated herein, open and patent application are all incorporated by reference with its complete form.Unless separately laying down a definition, all technical and scientific terms as used herein are all identical as the meaning that those skilled in the art in the invention are commonly understood by.Exemplary method and material is described below.It is also possible, however, to use to method and the similar or of equal value method and material of material those of is described herein to be changed to the present invention.These materials, method and embodiment are only illustrative, it is not intended to as limitation.

[0057] the following examples are provided by describing specific embodiment of the present invention, it is not intended to limit the scope of the invention in any way.

[0058] ACLT (the cross-section art of anterior cruciate ligament) model of post-traumatic degenerative joint is the most widely used model of a degeneration variation for being used to study articular cartilage.ACLT is in Setton etc., Osteoarthritis Cartilage 1999；It is described in 7:2-14.ACLT leads to abnormal knee biomethanics, increase including stretching with the preceding drawing (anterior drawer) when 90 ° of bucklings, and the similar increased interior rotation observed in the knee of the bitter man by joint condition, joint condition therein includes traumatic damage or arthritis.

[0059] osteoarthritis is one of a variety of joint conditions that one or more following symptom are presented, these symptom are synovitis, subchondral bone edema and cartilage degradation.Other joint conditions include but is not limited to physical or traumatic damage and rheumatoid arthritis.As used hereinafter, and in conjunction with the discussion to ACLT model, term " experimental OA " does not limit the invention to osteoarthritis.On the contrary, " experimental OA " is only the trivial nomenclature of this field.The present invention is useful to the joint condition of the full scope in relation to being previously mentioned symptom.

[0060] in order to study effect of the amino sugar to the relevant neuropathological hallmarks of joint condition, experimental OA is induced in the knee of rabbit by ACLT.The part that the most serious of cartilage degradation occurs for these rabbits is medial femoral ankle, followed by lateral femur ankle (Chang etc., OsteoarthritisCartilage 1997；Sep；5:357-72.).On tibial plateau, the ACL cross-section region in meniscus covering causes the slightly damage to moderate.

[0061] reagent.GlcNAc is commercially available from Sigma (St.Louis, MO).GlcNAc is dissolved in physiological saline and by 0.22 micron filter (Corning, Acton, MA) degerming.GlcNAc sterile solution is stored at 4 DEG C.Sodium Hyaluronate (Hyalgan^TM) bought from Sanofi-Synthelabo (New York, NY).

[0062] preparation of GlcNAc extended release preparation

[0063] polylactic acid library (Poly Lactic Acid Depot, PLAD).By GlcNAc (the Greenfield Inc of the cGMP grade of freeze-drying, Gumee, IL, USA) powder is dissolved or is suspended in polymer solution, the polymer solution includes the low molecular weight (L-102 of medical grade, BoehringerIngelheim (BI) Chemicals, Inc.Wallingford, CT, USA), low molecular weight is dissolved in USP/NF grades of solvent (benzyl alcohol (BA), Ergol (BB), ethyl alcohol (EtOH)).Obtained mixture is evaluated in vitro and in vivo.

[0064] polylactic acid -co- glycolic acid (PLGA) injectable gel.By the GlcNAc powder dissolution of freeze-drying or it is suspended in polymer solution, it includes medical grade low molecular weight PLGA (RG 502-H, Boehringer Ingelheim (BI) Chemicals, Inc.Wallingford, CT, USA), low molecular weight PLGA is dissolved in USP/NF grades of solvent (NMP, DMSO, benzyl alcohol, Ergol, ethyl alcohol).Obtained mixture is evaluated in vitro and in vivo.

Preparation	Composition	It measures (batch #)	Catalogue #
				PLAD 1	20%PLA 75%BB 5%BA	2.5g BI(200479)  3.75g Sigma(97H1569)  0.25g Sigma(11K3682)	R202H  B9550  B-1042
PLAD 2	20%PLA	2.5g BI(200479)	R202H

	79%BB 1%BA	3.95g Sigma(97H1569)  0.05g Sigma(11K3682)	B9550  B-1042
				PLAD 3	20%PLA 75%BB 5%NMP	2.5g BI(200479)  3.75g Sigma(97H1569)  0.25g Aldrich(01948CA)	R202H  B9550  270458
PLAD 4	20%PLA 79%BB 1%NMP	2.5g BI(200479)  3.95g Sigma(97H1569)  0.05g Aldrich(01948CA)	R202H  B9550  270458
				NMP 1	50%502H 50%NMP	1.0g BI(1005122)  1.0g Aldrich(01948CA)	RG502H  270458
NMP 2	50%503H 50%NMP	1.0g BI(1006370)  1.0g Aldrich(01948CA)	R503H
				NMP 3	50%503H 50%NMP	2.5g BI(1006370)  2.5g Aldrich(01948CA)	R503H  270458
NMP 4	55%PLA 45%NMP	2.75g BI(200479)  2.25g Aldrich(01948CA)	R202H  207458
				NMP 5	55%502H 45%NMP	2.75g BI(1005122)  2.25g Aldrich(01948CA)	RG502H  270458
NMP 6	55%503H 45%NMP	2.75g BI(1006370)  2.25g Aldrich(01948CA)	R503H  270458
				NMP 7	25%PLA 25%502H 50%NMP	1.25BI(200479)  1.25g BI(1005122)  2.5g Aldrich(01948CA)	R202H  RG502H  270458

[0065] production and quality control.Injectable gel preparation is passed through into 0.22 micron filter end filtration degerming as an aqueous solution, then carries out sterile drying.When in use, sterile polymer solution and sterile GlcNAc powder are mixed using asptic technique.Number (identity), purity, effect, sterility and the useful load of every kind of preparation are all remembered on production batch record.Number, purity, effect and useful load are measured with HPLC or FT-IR.Sterility is measured with the experiment of the USP sterility of modification.Briefly, sample is dissolved in suitable solvent (usually DMSO), then its Sterile dilution to existing any solvent is all no longer had to the level of biocidal property using sterile water.Standard USP aseptic experiment (USP monograph number<71>) are carried out to these diluted samples.

[0066] release of the GlcNAc from incubation in the preparation of phosphate buffer.Release in vitro research is carried out in phosphate buffer to evaluate the release dynamics under physiological condition.Every kind of extended release preparation (100 μ l) is placed in 1.0mL phosphate buffer, is then incubated at 37 DEG C.Point in different times removes phosphate buffer Incubating Solution by using pipette to separate pharmaceutical base.After forming GlcNAc derivative using preceding method (Reissig etc., J.Biol.Chem.1955 217:959-966), the solution analyzed using UV detector.Then said preparation matrix is suspended in 1.0mL phosphate buffer again and is incubated under above-mentioned the same terms.As a result as shown in following Fig. 7.

[0067] animal.What all experiments used is all 8-12 months big, weight 3.7-4.2kg and the New Zealand White Rabbit (New Zealand White rabbit) with closure epiphysis, in addition to alzet discussed below pump (alzet pump) research in exception, used in rabbit weight be 3.0-3.5kg.All research is all carried out according to AACL guide, and achieves Universityof California, the agreement of the animal commission for inspecting discipline (animal review committees) of San Diego and Scripps Research Institute.

[0068] the cross-section art of anterior cruciate ligament (ACLT).As noted, unilateral or bilateral ACLT is carried out to every group of experiment.Arthrotomy (medial arthrotomy technique) Lai Jinhang ACLT (Yoshioka etc., Osteoarthritis Cartilage 1996 on the inside of use；4:87-98).It dislocates, is then done on ACL using sharp blade crosscutting from outside by kneecap.Manual front drawer test (anterior drawer test) confirmation, crosscutting is complete.Knee joint wound is rinsed using Sterile Saline and with suture layer-by-layer suture.All animals are individually brought up, and do not limit its activity.Operation put to death animal after 8 weeks.It is disclosed above statistics indicate that, on this time point, all there is cartilage degradation (1997 Mar of Sah etc., JOrthop Res in most of rabbits with ACLT；15:197-203).

[0069] intramuscular injection of GlcNAc.Start intramuscular injection GlcNAc art the latter week, 3 times per week, continues 7 weeks.The GlcNAc dosage of per injection is 200mg/kg.The physiological saline intramuscular injection of identical quantity is carried out to control group.

[0070] intra-articular injection of GlcNAc.Art the latter week starts intra-articular injection GlcNAc, continues 7 weeks.Double injection is carried out to rabbit weekly, the volume of each knee injection GlcNAc is 0.3ml.The GlcNAc single dose of per injection is 80mg.To control animals intra-articular injection physiological saline (each joint 0.3ml) twice weekly.To the rabbit of third group, hyaluronan (each joint 0.3ml) continues 7 weeks since after ACL crosscutting one week twice for intra-articular injection weekly.The animal for naked eyes synovial fluid exudation (gross synovial effusion) occur to 3 has carried out synovial fluid analysis.(2 animals of control group, 1 animal of hyaluronan).The synovial fluid of all three animals is that culture is negative (culture negative).

[0071] kneed general form evaluation.The general form evaluation of knee includes the macroscopic articular cartilage form and evaluation meniscus of evaluation arthroncus, synovial fluid exudation, tibial plateau and femur ankle.

[0072] arthroncus is evaluated with following rating system: 0 grade-normal；1 grade (slightly inflammation and/or joint capsule are proliferated mild swelling-；2 grades of (moderate swelling)-joint capsules thicken and/or synovial membrane inflammation；3 grades of a large amount of inflammation of (severe swelling)-synovial membrane, meniscus or ligament (anterior cruciate ligament or posterior cruciate ligament of knee) swelling.

[0073] it evaluates synovial fluid with following rating system to ooze out: 0 grade-normal；1 grade (slight exudation)-diffusate is more than normal condition, but underfill knee joint；2 grades of (moderate exudation)-diffusates are filled with knee joint, but do not gush out when joint capsule opening；3 grades of (severe exudation)-diffusates expand knee joint, and diffusate is gushed out when joint capsule is opened.

[0074] the general form evaluation of articular cartilage.Distal femur and proximal tibia are acquired, the backbone of 3.5cm to 4cm is had.The articular cartilage surface of each sample is dissolved in PBS (ratio 1: 5) composition coated with solution, by india ink (India ink) (Eberhard Faber Lewisburg, TN).Using in advance with PBS soak blotting paper gently suck extra ink solution.Then, to all arthrographies and digital image is analyzed.

[0075] evaluated using following rating system to articular cartilage: 1 grade of (intact surface)-appearance is normal and does not retain india ink；2 grades of (micro fibrosis)-surfaces retain india ink, the spot to elongate or light grey sheet spot；Velvet shape is presented in 3 grades of (obvious fibrosis)-region appearances, and the india ink of reservation is in aterrimus sheet spot；4 grades (erosion)-lose cartilage, the sclerotin of exposure lower layer.

[0076] digital imagery.It gently blots the articular surface of femur ankle and tibial plateau and cleans up loose tissue.Each femoral shaft is clipped on optical bench.Image (the resolution ratio: every millimeter of 60 pixels of femur ankle is obtained using Canon EOS D30 digital camera；Enlargement ratio (onscreenmagnification): 20x on screen), wherein digital camera uses 100mm micro-lens, and distance is about 12cm.It include micron scale in photo to carry out measure of precision to image.It then will be on the 3D model of the image projection through measuring to femur ankle.By the 3D surface area for alternatively surveying and drawing the edge metering damage field of damage.The digital image on tibial prosthesis surface is obtained as described above.Without using 3D projection, because of femoral surface relatively flat, there is no marked differences with 3D measurement for 2D measurement.

[0077] kneed histological grade.The distal femur for deriving from rabbit knee and proximal tibia are mixed, the decalcification in TBD-2 decalcifier (ThermoShandon, Pittsburg, CA) with 10% formalin buffer, and is embedded in paraffin mass.The coronal-plane of the sagittal plane and tibial plateau of outside and medial femoral ankle is used as further histologic analysis.

[0078] after by tissue section with safranin O/fast green dyeing, mucoitin sulfate (SGAG) content is evaluated.

[0079] evaluate SGAG content using following rating system: the 1 grade-safranin O less than 25% dyes loss；2 grade -25% -50% of safranin O dyes loss；3 grades-the safranin O more than 50% dyes loss；

[0080] using the integrality of following hierarchy system evaluation cartilage: 1 grade-intact cartilage surface；2 grades-there are fibrosis；3 grades-full thickness cartilage loss.In addition, performing an analysis to determine whether that there are chondrocyte proliferation or clones to all tissue samples.

[0081] histological assessments of synovial membrane are to be occurred based on synovial membrane proliferation or synovial membrane new blood vessel, and separately carry out to the synovial membrane being attached on the outside of tibial plateau and on the femur ankle of inside.

[0082] the microscope evaluation of marrow is that the presence of Sheng and increased vascularization is crossed based on subchondral bone myelocyte, as shown in table 3.

[0083] measurement of synovial tissue's DNA content.Cell composition (Amiel etc., J the Orthop Res 1986 of synovial tissue is quantitatively evaluated by the concentrate of the DNA to tissue；4:162-172).Briefly, at 65 DEG C, it will incubate 2 hours and make it dissolve by the synovial tissue washed and be lyophilized in 1N NaOH.Aliquot is reacted with 0.04% indoles-HCl reagent and is mixed with chloroform to remove interfering substance.The aqueous portion containing DNA is harvested, and measures absorbance at 490nm.Make reference with bovine chest gland DNA.As a result it is indicated with mg DNA/mg stem organization.

[0084] statistical analysis is carried out to experimental data using the Excel Analysis ToolPak of Microsoft.

[0085] alzet pump (alzet pump) administration of GlcNAc.The New Zealand White Rabbit of 3.0-3.5kg is used in this experiment.5 groups are randomly divided into, every group there are 8 rabbits.A group uses saline treatment (negative control group)；B group is 1.5M GlcNAc processing group；C group is 0.5M GlcNAc processing group；D group is 0.15M GlcNAc processing group；E group is 0.05M GlcNAc processing group.All compounds are all continuously fed to joint using Alzet micropump.The delivery rate of the pump is 2.5 μ l/ hours.The right knee of all rabbits all receives ACLT and GlcNAc is transported to right knee.

[0086] after ACLT operation, by alzet pump, knee applies GlcNAc to the right at once, continues 8 weeks.Pump is replaced at the 4th week end.Pump and delivery pipe are checked weekly twice, to ensure that delivery pipe is stayed in the appropriate location in joint.Experiment finally, being taken a picture using digital camera to confirm polyethylene pipe (ID:0.58mm) still in joint.

[0087] general form of two knees is changed, including arthroncus and joint fluid are evaluated.The distal femur and proximal tibia of doing operation and contralateral control knee are collected.Whether determining the generation damaged in sample surface by established standard under an optical microscope, position and severity.The same femur ankle that india ink dye using digital camera and tibial plateau photograph.Quantitative and comparison among groups are carried out using area of the image analysis software to the injured surface dyed on digital image.

[0088] equally there is the effect of intramuscular GlcNAc of rabbit of bilateral ACLT by compared with 6 control rabbits for bilateral ACLT but only receiving intramuscular salt water injection, having evaluated 6.In treatment group and the degree of the cartilage damage of control population, the general form credit analysis of tibial plateau and femur ankle does not show significant statistical difference between the two.Figure 1A and 1B is the figure of the general form evaluation of these groups.Figure 1A illustrates the evaluation of femur ankle, and Figure 1B illustrates the evaluation of tibial plateau.

[0089] on the other hand, the intra-articular injection of GlcNAc shows the improvement of tibial plateau and femur ankle situation.The intra-articular injection that GlcNAc (processing group, n=7) or salt water (control group, n=7) are carried out to the rabbit with two sides ACLT, is injected weekly twice, is carried out 7 weeks in total.As shown in Fig. 2, the general form of femur ankle analysis shows, relative comparison group, processing group, which is more intended to cartilage situation, improves (damage improve).Furthermore; as shown in Figure 3; the morphological analysis of tibial plateau shows the significant cartilage protection effect of GlcNAc, is compared with having 6 cartilage damage occur inside 7 rabbits in control group, and this damage (p < 0.003) occur in 7 the insides of processing group only 1.Figure 4 and 5 show that the intra-articular GlcNAc that gives does not make significant difference to the DNA content in arthroncus, synovial fluid exudation or synovial tissue.

[0090] therefore, the intramuscular injection of GlcNAc does not show cartilage protective effect, but is showing the tendency of synovitis reduction.However, the intra-articular administration of GlcNAc shows substantially reducing for cartilage degradation in naked eyes and electronmicroscopic level really.

[0091] it has then carried out intra-articular giving GlcNAc and the intra-articular comparative study for giving hyaluronan.As described above, the prepared product of hyaluronan be normally used as treatment knee osteoarthritis viscosity replenishers come using.In our current research, femur ankle general form analysis shows that, have no significant difference between GlcNAc group and hyaluronan group (n=7).Fig. 2.However, as shown in figure 3, GlcNAc relative transparent matter alkane shows stronger cartilage protection effect (p < 0.01) significantly.In addition, the surface area of the cartilage damage of GlcNAc group is greatly reduced compared with hyaluronan group.Fig. 6 A and 6B.The synovial fluid of GlcNAc group and hyaluronan group is oozed out without significant difference (Fig. 4)；However, DNA content evaluation is shown, compared with hyaluronan group, GlcNAc group synovial hyperplasia and cell composition substantially reduce (p < 0.05) (Fig. 5).

[0092] histologic analysis has been carried out to the experimental rabbit for receiving GlcNAc treatment or salt water and has compared the result derived from each group.As shown in Table 1 below, the medial femoral ankle of processing colony and control population loses with similar SGAG.However, the SGAG of tibial plateau, which is analyzed and compared, shows that GlcNAc group is tended to improve, it was furthermore observed that the lateral femur ankle SGAG loss of GlcNAc group substantially reduces.The cartilage integrity inspection of these groups also indicates that, relative to control group, GlcNAc group acts on the significant cartilage protection of tibial plateau and lateral femur ankle.

[0093] histological assessments of synovitis show that GlcNAc restrains synovial membrane proliferation (table 2).The effect that synovial membrane new blood vessel occurs for GlcNAc shows regional differentiation；However, GlcNAc shows significant improvement in adjacent medial side femur ankle.Table 2.The inspection of subchondral bone marrow shows that GlcNAc treatment reduces cell and crosses Sheng and the capillary of subchondral bone edema is caused to dilute (capillarydilution).Table 3.

[0094] generally speaking, cartilage, synovial membrane and subchondral bone marrow/oedema histologic analysis show the cartilage protection and antiphlogistic effects of the intra-articular GlcNAc given.

The histological grade of 1 articular cartilage of table

Anatomical site	Salt water N=7	Intra-articular GlcNAc N=6	P value
				Mucoitin sulfate loss
Medial femoral ankle	1.57±0.53	1.66±.33	P≤0.4
				Lateral femur ankle	2.43±0.53	1.50±0.83	P≤0.03
Tibial plateau	1.71±0.76	1.16±0.40	P≤0.14
				The damage of cartilage surface integrality
Medial femoral ankle	1.66±0.41	1.66±0.81	P≤0.91
				Lateral femur ankle	2.00±1.00	1.33±0.51	P≤0.17

Tibial plateau

1.71±0.49

1.16±0.41

P≤0.05

The histological grade of 2 synovial membrane of table

Anatomical site	Salt water N=7	Intra-articular GlcNAc N=6	P value
				Synovial membrane is thickened/is proliferated
Medial femoral ankle	7/7	2/6	P≤0.006
				Lateral femur ankle	7/7	2/6	P≤0.006
Tibial plateau	7/7	1/6	P≤0.0002
				Synovial membrane new blood vessel occurs
Medial femoral ankle	5/7	1/6	P≤0.05
				Lateral femur ankle	4/7	l/6	P≤0.16
Tibial plateau	4/7	1/6	P≤0.16

The histological grade of 3 subchondral bone marrow of table

Anatomical site	Salt water N=7	Intra-articular GlcNAc N=6	P value
				Medial femoral ankle	3/7	0/6	P≤0.07
Lateral femur ankle	3/7	0/6	P≤0.07
				Tibial plateau	3/7	1/6	0.35

[0095] these the results show that as naked eyes standard and microscope standard measurement, the intra-articular administration of GlcNAc reduces significantly and unexpectedly cartilage degradation.In addition, observing maximum cartilage protection effect in tibial plateau, followed by lateral femur ankle and medial femoral ankle, this strongly suggests that the joint area with less serious cartilage destruction is more sensitive to GlcNAc therapeutic effect.Finally, the intra-articular administration of GlcNAc, which unexpectedly reduces the severity of synovitis and also improves the cell of subchondral bone marrow, crosses Sheng.In addition, GlcNAc can be continuously conveyed in the time more than three weeks to joint, as using determined by above-mentioned sustained release and alzet pumping method after single-dose (intra-articular).

[0096] based on the intra-articular administration of GlcNAc; maximum cartilage protection effect is observed in tibial plateau; followed by lateral femur ankle; it is finally medial femoral ankle; show that the joint area for tending to minimal degradation has better reaction to GlcNAc administration really, this is for the region with severe cartilage damage.Comparatively, not showing the benefit of cartilage protection to the GlcNAc intramuscular administration of the rabbit with experimental OA, but the reduction of significant synovitis is shown really；Anti-inflammatory effect.The intra-articular administration of GlcNAc is more more effective than intramuscular administration.Under naked eyes and electronmicroscopic level, show significantly to delay cartilage degradation with the rabbit that intra-articular GlcNAc is handled.Finally, considering its cartilage protection effect, intra-articular GlcNAc is better than the viscosity replacement therapy using hyaluronan.

[0097] in a word, the cartilage degradation for unexpectedly reducing mammal using the intra-articular processing that GlcNAc carries out the rabbit of experimental OA shows as the reduction of macroscopic damaged area, significant the bone marrow cell for inhibiting synovitis and reducing subchondral bone edema crosses Sheng.

Pharmaceutical preparation and administration

[0098] once separation, amino sugar, preferably GlcNAc can be placed in pharmacy in acceptable preparation as effective component, and such as those are in Remington ' s PharmaceuticalSciences, 18th ed., described in Mack Publishing Co., Easton, PA (1990), it is incorporated herein by reference, and has small effect when its specific treatment as disease and pathological state to health tissues or do not influence.Pharmaceutical composition, it includes the effective component for being dissolved in or being dispersed therein, preparation is not necessary to be confined to based on preparation.Such composition can be prepared as injectable liquid liquid solution or suspension.It is suitble to however, it is also possible to prepare using the preceding solid form dissolved or be suspended in liquid again.The prepared product can also be emulsification.

[0099] in preferred embodiments, the composition is contained in container, it includes label, which states FDA approval (or other of equal value labels of other country) of the composition by U.S. government for treating the effect of disease described herein or morbid state.This container is applied to the effective component of the therapeutically effective amount of medication main body by providing.

[0100] the specific amino sugar for influencing interested morbid state, can be applied to mammal, can be administered alone, can also apply in pharmaceutical composition, and wherein amino sugar is mixed with suitable one or more carriers or one or more excipient.In the treatment of mammal that interested morbid state is presented, one or more medicaments of therapeutically effective amount, such as GlcNAc are applied.Effective component can be mixed with excipient, and wherein the excipient is that acceptable and compatible with the effective component and its dosage is suitable for treatment method described herein in pharmacy.

[0101] standard technique can be used to prepare in acceptable salt in pharmacy.For example, the free alkali form of compound is dissolved in suitable solvent first, such as water or water-alcohol solution, the solvent includes suitable acid.Then salt is separated by evaporation solution.In other example, the preparation of salt is by organic solvent being reacted free alkali and acid.

[0102] it can be used carrier or excipient to promote the administration of compound, for example, increasing the dissolubility of compound.The example of carrier and excipient includes the solvent of calcium carbonate, calcium phosphate, a variety of sugar or a plurality of types of starch, cellulose derivative, gelatin, vegetable oil, polyethylene glycol, water, salt water, glucose, glycerol, ethyl alcohol and physical compatibility.

[0103] composition of the invention can wherein include the ingredient pharmacy on acceptable salt.Acceptable salt includes acid-addition salts (any free amino of amino sugar is formed) in pharmacy, is formed by inorganic acid, such as, such as, hydrochloric acid or phosphoric acid, sulfuric acid etc. or organic acid, such as acetic acid, tartaric acid, mandelic acid and homologue.The salt formed with the free carboxyl group of amino sugar can also be derived from inorganic base, such as, for example, sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide or iron hydroxide, and organic base, such as isopropylamine, trimethylamine, 2- ethylaminoethanol, histidine, procaine and homologue.

[0104] toxicity and therapeutic effect of these compounds can be measured by the standard pharmaceutical procedures to cell culture or experimental animal, for example, measurement LD50 (dosage for causing the death of group 50%) and ED50 (to 50% dosage with therapeutic effect of group) method.The dosage rate of toxic effect and therapeutic effect is therapeutic index (therapeutic index), is represented by ratio LD50/ED50.It is preferred for showing the compound of big therapeutic index.The data obtained from these cell culture analyticals and zooscopy can be used for preparing a series of dosage for the mankind.The dosage of these compounds is preferably in circulation composition (circulating concentration) range, and it includes ED50, has very little toxicity or nontoxicity.According to the dosage form used and the administration route utilized, which can change within this range.

[0105] to any amino sugar compounds used in method of the invention, its treatment effective dose can be initially estimated by cell culture analytical.Such as, dosage can be modulated in animal model, to reach circulating plasma concentration range, it includes the IC50 such as measured in cell culture (to test the concentration of compound, the half of the half and/or composite parts maximum activity of its half for reaching the rupture of albumen composition maximum or cellular level maximum suppression).These information can be used to more accurately determine the dosage useful to the mankind.The level in blood plasma can be measured, such as passes through HPLC.

[0106] another preferred embodiment of the invention is related to the improved preparation of effective component GlcNAc.When by intra-articular injection, cladding or embedding of the GlcNAc in liposome or other embedding mediums improve its pharmacodynamics figure.Preferably, GlcNAc is embedded in matrix.It is highly preferred that GlcNAc is embedded in selected from particle, in the matrix of implantation material or gel.

[0107] exact preparation, administration route and dosage can consider the state of mammal by a other doctor and select.(see, e.g. Fingl etc., in The Pharmacological Basis ofTherapeutics, 1975, Ch.1 p.1 in).It should be noted that attending physician should be appreciated that how and when terminate, interrupt or adjust administration due to toxicity or organ dysfunction.On the contrary, if clinical response deficiency (excluding toxicity in advance), attending physician, which also should be recognized that, is adjusted to higher level for treatment.In the processing to interested disease, the size of dosage will change with the severity and administration route of the morbid state to be treated.The severity of morbid state can be evaluated, such as prognostic evaluation (prognostic evaluation) method that part passes through standard.Further, dosage, be perhaps dose frequency (dose frequency), will according to the age of mammalian subject, weight and reaction and change.It also can be used in veterinary science and the method discussed above being equal.

[0108] according to the disease specific state for the treatment of, such medicament can be prepared and capapie or be locally administered.The technology of manufacture and administration can be found in Remington ' s Pharmaceutical Sciences, 18th ed., Mack Publishing Co., Easton, PA (1990), be incorporated herein by reference herein.

[0109] in order to inject, medicament of the invention can be formulated in aqueous solution, it is preferred that in the buffer of PHYSIOLOGICALLY COMPATIBLE, such as Hank's solution (Hanks ' s solution), Ringer's solution (Ringer ' ssolution) or normal saline buffer solution.

[0110] using carrier acceptable in pharmacy will be disclosed the dosage form for being used for the compound that the present invention practices and being configured to suitable Formulations for systemic administration, this belongs to the scope of the present invention.By proper choice of carrier and suitable manufacturing practice, composition of the invention can use parenteral administration, such as be injected intravenously specifically, those are configured to the composition of solution.

[0111] it is suitble to be used in pharmaceutical composition of the invention to include such composition, effective component wherein included is effective quantity to reach expected purpose.Those skilled in the art can determine the effective quantity, in particular according to being disclosed in detail provided herein.Other than effective component, these pharmaceutical compositions also may include acceptable carrier in suitable pharmacy comprising promote active constituent to be machined into the excipient and adminicle of preparation, the preparation can use in pharmacy.It itself is known mode to manufacture that pharmaceutical composition of the invention, which can be used, for example, by traditional mixing, dissolution, granulation, sugaring clothing agent, floating, emulsification, cladding, embedding or freeze-drying process.

[0112] pharmaceutical preparation of parenteral administration includes the aqueous solution of reactive compound, and wherein reactive compound is water-soluble form.Furthermore the suspension of reactive compound can be prepared into suitable oily injection suspension.Suitable lipophilic solvent or carrier include fat oil, such as sesame oil or Acrawax, such as ethyl oleate or triglycerides or liposome.Aqueous injection suspensions contain the substance for increasing suspension viscosity, such as sodium carboxymethylcellulose, D-sorbite or glucan.Optionally, suspension containing suitable stabilizer or increases the deliquescent reagent of compound to allow to prepare highly concentrated solution.

[0113] the sugar-coat agent piece heart is provided with suitable coating.For this purpose, the sugar juice of concentration can be used, it can optionally include Arabic gum, talcum powder, polyvinylpyrrolidone, card bohr glue (carbopol gel), polyethylene glycol and/or titanium dioxide, paint solution (lacquersolution), and suitable organic solvent or solvent mixture.Dyestuff or pigment can be added on tablet or dragee coatings to distinguish or characterize the various combination of active compound doses.

[0114] present invention is illustratively described herein, not specifically disclosed any one or more of element, one or more limitations can be implemented in the case where being not present here.To for example, term "comprising", " comprising ", " containing " etc. can be understood by extension ground, without stint.Furthermore, terms and expressions as used herein are as descriptive, rather than restrictive term and use, and it is not intended to exclude any display in future and description equivalent and its any part when using these terms and expressions, and should be aware that the present invention claims in the range of, a variety of different modifications are all possible.To, it should be understood that, although the present invention is disclosed particularly by preferred embodiment and optional feature, the modifications and changes of the present invention disclosed herein are can be used in those skilled in the art, and these modifications and changes are recognized as the range for belonging to the present invention disclosed herein.Widely and generally describe the present invention herein.It falls into the narrower type of each of general the open scope and subclass also forms component part of the invention.This includes the general description carried out using restrictive clause or negative sense limitation (negative limitation) to each invention, the clause and limitation eliminate any title substance inside the category, and no matter whether the material of the exclusion is particularly included therein.In addition, this field is trained to be will recognize when describing the feature and aspect of invention in a manner of Ma Kushi group (Markush group), therefore which also describes according to any individual member of Ma Kushi group or member's subset.

[0115] it should be understood that above description meant for illustration rather than limit.By looking back above description, those skilled in the art will be readily conceivable that multiple embodiments.To which the scope of the present invention should not determine as described above, and should be determined according to appended claims in conjunction with the full scope of the equivalent of these claims imparting.Disclosed all documents and reference, including patent disclosure, are introduced by reference herein.

Claims (33)

1. the method for treating mammal symptom, the symptom is selected from synovitis, subchondral bone edema and cartilage degradation, and the treatment includes the amino sugar to mammal application therapeutically effective amount.

2. the method for claim 1 wherein the amino sugars to be selected from N-acetyl-glucosamine, aminoglucose, galactosamine, N- acetylgalactosamine, acceptable salt in imino group cyclitol and their pharmacy.

3. the method for claim 1 wherein the amino sugars to be embedded in matrix.

4. method for claim 3, wherein the matrix is selected from particle, implantation material or gel.

5. method for claim 4, wherein the particle includes liposome, nanosphere, microballoon or suspension body.

6. method for claim 4, wherein the implantation material includes polymer, pump or equipment.

7. method for claim 4, wherein the gel includes that implant in situ forms gel, semisolid gel, hydrogel or thermosensitive in situ gel (thermo sensitive gel).

8. injectable formulation is used for intraarticular therapies symptom related with joint condition, it includes amino sugars, and wherein amino sugar is by matrix entrapment, wherein the matrix includes particle, implantation material or gel.

9. the method for treating symptom related with joint condition comprising apply the N-acetyl-glucosamine of the therapeutically effective amount as control delivery formulations.

10. method for claim 9, wherein N-acetyl-glucosamine is administered by intramuscular injection or intra-articular injection.

11. method for claim 9, wherein N-acetyl-glucosamine is by subcutaneous injection or administered by infusion.

12. method for claim 9, wherein symptom related with joint condition is selected from synovitis, subchondral bone edema and cartilage degradation.

13. the method for claim 12, wherein the symptom is synovitis.

14. the method for claim 12, wherein the symptom is subchondral bone edema.

15. the method for claim 12, wherein the symptom is cartilage degradation.

16. method for claim 9, wherein joint condition is not osteoarthritis.

17. method for claim 9, wherein joint condition is not rheumatoid arthritis.

18. the method for treating joint condition comprising following steps:

A. neuropathological hallmarks related with joint condition are diagnosed；And

B. the amino sugar treated in effective preparation is given.

19. the method for claim 18, wherein neuropathological hallmarks are selected from synovitis, subchondral bone edema and cartilage degradation.

20. the method for claim 19, wherein neuropathological hallmarks are synovitis.

21. the method for claim 19, wherein neuropathological hallmarks are subchondral bone edema.

22. the method for claim 19, wherein neuropathological hallmarks are cartilage degradation.

23. the method for claim 18, joint condition therein is not osteoarthritis.

24. the method for claim 18, joint condition therein is not rheumatoid arthritis.

25. the method for claim 18, wherein realize the step of giving amino sugar by administration route be selected from intra-articular, intramuscular, infusion pump (infusion pump) or subcutaneous.

26. the method for claim 25, administration route therein is intra-articular.

27. the method for claim 18, wherein amino sugar is selected from N-acetyl-glucosamine, aminoglucose, galactosamine, N- acetylgalactosamine, imino group cyclitol, their combination therapy, acceptable salt and their injectable formulation in their pharmacy.

28. the method for claim 27, wherein amino sugar is N-acetyl-glucosamine.

29. the method for claim 27, wherein its injectable formulation is selected from matrix granule (matrixparticle), matrix gel (matrix gel) and control delivery formulations.

30. the method for claim 27, wherein its combination therapy combines amino sugar with the compound selected from anti-inflammatory agent and hexosaminidase inhibitor.

31. the method for preventing cartilage degradation comprising be administered to the animal that the slight cartilage degradation occurs, the N-acetyl-glucosamine including the therapeutically effective amount as control delivery formulations.

32. the method for claim 31, wherein the N-acetyl-glucosamine is administered by intramuscular or intra-articular injection.

33. the method for claim 21, wherein the N-acetyl-glucosamine passes through subcutaneous injection or infusion pump administration.

Images