CN107823214A - Treat the composition of Immunoinflammatory Disorders - Google Patents
Treat the composition of Immunoinflammatory Disorders Download PDFInfo
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- CN107823214A CN107823214A CN201710967930.8A CN201710967930A CN107823214A CN 107823214 A CN107823214 A CN 107823214A CN 201710967930 A CN201710967930 A CN 201710967930A CN 107823214 A CN107823214 A CN 107823214A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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Abstract
Present invention is disclosed a kind of tacrolimus that includes for treating Immunoinflammatory Disorders, present invention further teaches a kind of preparation or medicine box for including the composition with Beesia calthifolia saponin(e O compositions.
Description
【Technical field】
The present invention relates to the composition for the treatment of Immunoinflammatory Disorders.Specifically, the present invention relates to containing tacrolimus and Beesia calthifolia
The saponin(e O composition for being used to treat Immunoinflammatory Disorders.
【Background technology】
Immunoinflammatory disorders are characterized in the inappropriate activation of body immune defence.Immune response targets and damaged body itself
Tissue or the tissue of transplanting, rather than the infectious invader of targeting.Changed by the tissue that immune system targets with disease.
For example, in multiple sclerosis, immune response is directed to neuronal tissue, and what is be targeted in regional ileitis is then alimentary canal.
Immunoinflammatory Disorders affect millions of individuals, including illness such as asthma, allergic intraocular inflammatory disease, arthritis, spy
Answering property dermatitis, atopic eczema, diabetes, hemolytic anemia, inflammatory dermatosis, inflammatory bowel disease or gastrointestinal disease (such as segmental
Ileitis and ulcerative colitis), multiple sclerosis, myasthenia gravis, itch/inflammation, psoriasis, rheumatoid arthritis,
Cirrhosis and systemic loupus erythematosus.
Current Immunoinflammatory Disorders, transplant organ repel and the therapeutic scheme of graft versus host disease(GVH disease) usually relies on immune suppression
Preparation.The validity of these medicaments can change, often adjoint in its application adverse side effect occur.Therefore, it is necessary to improve
Therapeutic agent and method treat Immunoinflammatory Disorders.
Tacrolimus(Tacrolimus, FK-506)It is that the first granted non-cortical steroid external application in the whole world is immune to adjust
Agent is saved, its composition tacrolimus is initially from tsukubaensis streptomycetes by Japan(A kind of fungi bacterium of class, by
Tsukuba has found in soil sample)Fermentation medium in be isolated, belong to macrolides, have unique immune
Modulability.
Its chemical name is:
[3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,
26aR*]] ten hexahydro -5,19- dihydroxy -3- of -5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-
[2- (4- hydroxyl -3- methoxies cyclohexyl) the first and second alkenyls of -1-] -14,16- dimethoxy-4 's, 10,12,18- tetramethyls -8- (2- third
Alkenyl) -15,19- epoxy -3H- pyridos [2,1-c] [1,4] oxazepine ring tricosene -1,7,20,21 (4H, 23H) -
Tetrone, monohydrate.
Its structural formula is expressed as following formula:
It has been commonly used as medicine.Known tacrolimus has having including immunosuppressive action and anti-microbial effect
Beneficial pharmacological action, and therefore can be used for treating and preventing various autoimmune disease (such as organ or tissue's graft rejection or shifting
Graft versus host disease), infectious diseases etc..
Beesia calthifolia [Beesia calthaefolia (Maxim.) Ulbr.] is Ranunculaceae Beesia calthifolia category (Beesia) plant;
It is distributed widely in the Yunnan Province of China northwestward, Sichuan, Guizhou, In Northern Guangxi, Hunan, West of Hubei Province and Shaanxi, SOUTH OF GANSU, is the people
Between commonly use herbal medicine, and the distinctive medicinal plant in China.Its rhizome or herb are medicinal, have clearing heat and detoxicating, cool blood, promoting blood circulation, detumescence,
The effect of analgesia and dispersing wind and cold;It is among the people to be used for treating anemofrigid cold, rheumatic arthritis, red-white dysentery, swelling and sore throat, headache and tooth
Disease, external application for curing boil and the venomous snake bites such as pain.
Report that oneself produces isolated multiple Cyclolanstane triterpenic glycosides in Beesia calthifolia rhizome from Yunnan, i.e.,
Beesiosides A~F, G, H, J~N, O~P.Lymphproliferation response test result indicates that, Beesia calthifolia saponin(e O is small
It can suppress to be bred by the Q cells of ConA inductions during mouse vivo medicine-feeding, prompt have immunosuppressive activity.Experiment shows:Beesia calthifolia
Saponin(e O, which also has, suppresses Angiogenesis activity and suppression activity of osteoblast proliferation.
【The content of the invention】
The present invention provides the composition that can be used to treat Immunoinflammatory Disorders.
Therefore, in one aspect, the present invention discloses the composition with Beesia calthifolia saponin(e O comprising tacrolimus.The combination
Thing is used for Immunoinflammatory Disorders.The composition can also be used for reducing the proinflammatory secretion in the patient or production,
The amount wherein given is enough to reduce the proinflammatory secretion in the patient or production, and preferable cell factor is TNF
α, IL-1, IL-2 and INF- γ.The composition can be configured to for local administration or Formulations for systemic administration.
In one related fields, the present invention discloses the composition with Beesia calthifolia saponin(e O comprising tacrolimus.The combination
Thing can be configured to for local administration or Formulations for systemic administration (such as oral administration).One or both of both medicines in the composition may be used
To be each defined herein with low dosage or high dose presence, two kinds of dosage.
In its another related fields, the present invention discloses the tacrolimus and Beesia calthifolia saponin(e O for including unit dosage form
Composition.The unit dosage form of this composition is available for oral, local, parenteral, rectum, intracutaneous, intranasal, intravaginal, suction
Enter, skin (patch) or eye drops.
In another aspect, the present invention discloses medicine box, and the medicine box includes:(i) comprising tacrolimus and Beesia calthifolia saponin(e O
The composition of combination;(ii) give and make a definite diagnosis described in the patient with Immunoinflammatory Disorders or the risk for there are development Immunoinflammatory Disorders
The specification of composition.Wherein, the tacrolimus of Immunoinflammatory Disorders patient and Beesia calthifolia saponin(e O amount are given(With it is lasting when
Between)The patient can be treated.
In another aspect, make a definite diagnosis with Immunoinflammatory Disorders the invention discloses one kind treatment or have development immunoinflammatory
The preparation of the patient of the risk of disease, the preparation include tacrolimus with Beesia calthifolia saponin(e O and/or without pharmaceutically acceptable
Additive.
For the preparation of the present invention, its formulation is including but not limited to local, transdermal and Formulations for systemic administration is (such as intravenous, muscle
Interior, subcutaneous, suction, rectum is interior, intraoral, intravaginal, intraperitoneal, intra-articular, intraocular or oral administration) formulation.It is used herein
" Formulations for systemic administration " refer to all non-skin methods of administration, clearly exclude part and transdermal route.
Tacrolimus
The immunodepressant of tacrolimus (FK506) targeting T-cells intracellular signalling pathway.Tacrolimus is incorporated in structure
Intracellular protein FKBPL (FKBP-12) (Harding etc., Nature 341 incoherent with cyclophilin:758-
7601,1989;Siekienka etc., Nature341:755-757,1989;With Soltoff etc., J.Biol.Chem.267:
17472-17477,1992).FKBP/FK506 compound combination calcinerins simultaneously suppress the phosphatase of calcinerin
Activity.This inhibitory action prevents the dephosphorylation and nuclear translocation of the nuclear factor (NFAT) of activating T cell, and NFAT is that initiation is proinflammatory
Cell factor (such as IL-2, interferon) produces the nuclear composition with the genetic transcription needed for t cell activation.Therefore, Ta Kemo
Department suppresses t cell activation.
Tacrolimus is the macrolide as caused by building ripple mountain soil earth streptomycete (Streptomyces tsukubaensis)
Antibiotic.It suppresses immune system, extends the survival of transplant organ.Its oral formulations and injectable formulation can be obtained at present.
The gelatin softgel shell of tacrolimus capsules includes 0.5mg, 1mg or 5mg anhydrous tacrolimus.Injectable formulation contain 5mg without
Water tacrolimus (in castor oil and ethanol), diluted before the injection with 0.9% sodium chloride or 5% glucose.Although it is preferred that mouth
Clothes administration, but the patient that can not take oral capsule is subjected to the tacrolimus of injectable.It will pass through company after transplanting 6 hours
Continuous intravenous infusion gives initial dose.
Tacrolimus and tacrolimus analog by Tanaka etc., (J.Am.Chem.Soc., 109:5031,1987) and
Described in U.S. Patent No. 4,894,366, No. 4,929,611 and No. 4,956,352.FK506 related compounds, including
FR-900520, FR-900523 and FR-900525 are described in U.S. Patent No. 5,254,562;O- aryl, O- alkyl, O- alkene
Base and O- alkynyl-macrolides be described in U.S. Patent No. 5,250,678, No. 532,248, No. 5,693,648;Amino
O- aryl macrolides are described in U.S. Patent No. 5,262,533;Alkylidene macrolide is described in U.S. Patent No. 5,
No. 284,840;N- heteroaryls, N- miscellaneous alkyl aryls, N- alkenyl heteroaryls and N- alkynyl heteroaryl macrolides are described in the U.S.
Patent the 5,208,241st;Aminomacrolide and its derivative are described in U.S. Patent No. 5,208,228;The big ring of fluoro
Lactone is described in U.S. Patent No. 5,189,042;It is special that amino O- alkyl, O- alkenyls and O- alkynyl-macrolides are described in the U.S.
Profit the 5,162,334th;Halo macrolide is described in U.S. Patent No. 5,143,918.
Tacrolimus is mixed feature oxidase system particularly cytochrome P-450 system and is largely metabolized.Main generation
The mechanism of thanking is demethylation and hydroxylating.Although various tacrolimus metabolins may all show immunosuppressive biological activity,
13- demethy lations thing is it was reported that with active with tacrolimus identical.
Although it is recommended that dosage must be changed according to the situation of patient, standard recommended dosages presented below.Generally give
Make a definite diagnosis the oral tacrolimus of patient's 0.1-0.2mg/kg/ days with regional ileitis or ulcerative colitis.Have with it
The patient of transplant organ generally receives the oral tacrolimus dosage of 0.1-0.2mg/kg/ days.Rheumatoid arthritis is carried out to control
The patient for the treatment of generally receives 1-3mg/ days oral tacrolimus.For psoriasis treatment, patient 0.01-0.15mg/kg/ is given
The oral tacrolimus of day.Atopic dermatitis can by twice daily by the creme of the tacrolimus containing 0.03-0.1% be applied to by
Position is encroached on to treat.Receive the patients of oral tacrolimus capsules generally after transplanting 6 hours, or stop it is intravenous he
8-12 hours just receive first time dosage after Ke Mosi infusions.Others suggest that tacrolimus dosage includes 0.005-0.01mg/
Kg/ days, 0.01-0.03mg/kg/ days, 0.03-0.05mg/kg/ days, 0.05-0.07mg/kg/ days, 0.07-0.10mg/kg/
Day, 0.10-0.25mg/kg/ days or 0.25-0.5mg/kg/ days.
In one embodiment, tacrolimus dosage between 0.05 to 50 mg/kg/day (such as with 0.1 to
The amount of 12 mgs/kg/day is orally given).In another embodiment, tacrolimus dosage is in 0.0001 to 20 milli
Between g/kg/day (such as orally being given with 0.01 to 0.2 mg/kg/day of amount).
Beesia calthifolia saponin(e O
Beesia calthifolia saponin(e O (beesioside O), white amorphous powder, mp 196~200 DEG C (CHCl3-MeOH),
[α]D 20- 11.3○(c,0.12, CHCl3-MeOH, 1:1), there is immunosuppressive activity, suppress angiogenic activity and suppression
Cell-proliferation activity is made(Referring to patent CN01123448.2).
Beesia calthifolia saponin(e O its structural formula is (20S, 24S) -15 α-acetoxyl group -16 β, 24;20,24- bis-epoxies -9,19-
Cycloartane -3 β, 25- glycol -3-O- β-D- xylopyranoses glucosides [(20S, 24S) -15 α-acetoxy-16 β, 24;20,24-
diepoxy-9,19-cyclolanostane-3β,25-diol-3-0-β-D–xylopyranoside].Its structural formula is illustrated such as
Under:
In one embodiment, Beesia calthifolia saponin(e O dosages between 0.05 to 50 mg/kg/day (such as with 0.1 to
The amount of 20 mgs/kg/day is orally given).In another embodiment, Beesia calthifolia saponin(e O dosages are 0.0001 to 20
Between mg/kg/day (such as orally being given with 0.01 to 2 mg/kg/day of amount).
In one embodiment, tacrolimus is with Beesia calthifolia saponin(e O dosages ratio or in the composition or in medicine box
Amount ratio is 50:1 to 1:50, preferably 20:1 to 1:20, it is more preferably 10:1 to 1:10, it is most preferably 5:1 to 1:5.
The dosage and dosage of external preparation of the present invention can be easily according to illness to be treated, preparation, route of administration, objects
Age and body weight, sex or general health and matrix etc. determine.Preferably, tacrolimus is with 0.1 to 500mg/
My god, preferably 1 to 100mg/ days, apply within more preferably 5 to 10mg/ days, once or several times a day, such as daily 1 to 6 time;Beesia calthifolia
Saponin(e O was applied with 0.1 to 1000mg/ days, preferably 1 to 300mg/ days, more preferably 5 to 100mg/ days, once or several times a day, example
Such as daily 1 to 6 time.
The preparation of composition
The present invention combination give can by it is any cause target region suppress Pro-inflammatory cytokine levels appropriate method come
Carry out.Tacrolimus and Beesia calthifolia saponin(e O can be contained in any suitable amount in any suitable carrier mass, typically constituted from
The 0-95% of composition total weight.Composition can be to be suitable for oral, parenteral (such as intravenous, intramuscular), rectum
Interior, intracutaneous, intranasal, intravaginal, suction, the formulation of skin (patch) or eye drops approach provide.Therefore, composition can be
Such as tablet, capsule, pill, powder, granule, supensoid agent, emulsion, solution, gel (including hydrogel), paste,
Ointment, creme, emplastrum, heavy dose of decoction (drench), osmotic delivery device, suppository, enema, injectable agent, implantation
The form of thing, spray or aerosol.Composition can be prepared according to conventional pharmaceutical specification.
Tacrolimus and Beesia calthifolia saponin(e O in combination can be prepared by various methods well known in the art.For example, can one
Rise and prepare or individually prepare, for simultaneously or nearly giving the medicament simultaneously.This compositions formulated altogether can be formulated in together
Among pill, capsule, liquid agent etc..It should be appreciated that " during tacrolimus and Beesia calthifolia saponin(e O " preparation, adopted when mentioning
Preparation technique can also be used for preparing the independent medicament in the combination and other combinations of the present invention.By to different medicines
Agent uses different preparation strategies, can be properly matched the pharmacokinetic characteristic (profile) of every kind of medicament.
Tacrolimus or Beesia calthifolia saponin(e O indivedual or individually prepare are packaged into medicine box together.Non-limiting examples include
Contain the liquid agent in such as two kinds of pills, a kind of alkyl and a kind of powder, a kind of suppository and a kind of bottle, two kinds of part frosts
The medicine box of agent etc..Medicine box may include to contribute to the optional component that unit dose is given to patient, such as to the bottle of reconstitutable powders,
Injection syringe, the intravenous delivery system of customization, inhalator etc..In addition, unit dose kit can include relevant composition
Preparation and administration specification.Medicine box may be produced that the unit dose being intended for single use for a patient, multiple for particular patient
The dosage used (constant dosage or wherein each composition can change with therapeutic advance);Or medicine box can contain suitable administration
In the multiple dose (in bulk) of multiple patients.Medicine box composition can be mounted in carton box, blister package, bottle, pipe
Deng among.
The composition preferred dosage form of the present invention is the solid dosage forms of oral application.
The solid dosage forms and local topical formulation of oral application.
Include the tablet that the mixture of excipient is subjected to containing active component and nontoxic medicine for the preparation of oral application.
These excipient can be such as inert diluent or filler (such as sucrose and sorbierite), lubricant, glidant and anti-stick
Agent (such as magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil or talcum powder).
Two kinds of compounds can be mixed together in tablet, gelling agent or other carriers, or can separated.In an implementation
In example, the first compound is included in the inside of tablet, and second compound so has phase in outside before the release of the first compound
When the second compound of a part first discharges.
Chewable tablet can be also provided as the preparation of oral application, or is mixed for wherein active component with inert solid diluent
The hard-gelatin capsules being combined, or the Gelseal mixed for wherein active component with water or oil medium.
Therefore, for being suitable for the composition of oral application, oral carrier (such as capsule) contains 0.01%-25% (w/
Or more w) activating agent(Tacrolimus and/or Beesia calthifolia saponin(e O), preferably 0.01%-10% (w/w), more preferably 0.05%-
4% (w/w) activating agent(Tacrolimus and/or Beesia calthifolia saponin(e O).Capsule can be taken once a day to four times, or is pressed
It need to take.
To perform method described herein, preferably orally contain activating agent(Tacrolimus and/or Beesia calthifolia saponin(e O)Mouth
Take carrier.For example, the patient with Immunoinflammatory Disorders or immunoinflammatory relevant disease (such as platelet aggregation inhibitory activity) can be early
Evening respectively takes a capsule.
Topical preparation
Also it can use the activating agent containing 0.0001%-25% (w/w) or more(Tacrolimus and/or Beesia calthifolia saponin(e O)Office
Portion's carrier, makes composition be suitable for topical application.In this combination, preferred activating agent(Tacrolimus and/or Beesia calthifolia soap
Glycosides O)It is controlled by extension releasing mechanism.
In preferable combination, activating agent(Tacrolimus and/or Beesia calthifolia saponin(e O)Preferably 0.0001%-10% (w/
W), more preferably 0.0005%-4% (w/w) activating agent(Tacrolimus and/or Beesia calthifolia saponin(e O).Creme can apply one daily
It is secondary to four times, or apply on demand.
To perform method described herein, it will preferably contain activating agent(Tacrolimus and/or Beesia calthifolia saponin(e O)Part
With vector administration in the uncomfortable position on patient body.For example, creme can be applied to the scorching patient of articulations digitorum manus on hand, and
Part eye drops can be applied to the eyes of patient to treat Uveitis.
Term explanation
" low dosage " refers to than to treat particular compound that the specific administration approach of any human diseases or illness prepares
Low at least 5% (for example, at least 10%, 20%, 50%, 80%, 90% or even 95%) of minimum standard recommended dose.For example, to inhale
The corticosteroid low dosage for entering administration and preparing will be different from the corticosteroid low dosage prepared for oral administration.
" high dose " refers to the highest standard recommended dose than the particular compound for treating any human diseases or illness
High at least 5% (for example, at least 10%, 20%, 50%, 100%, 200% or even 300%).
" median dose " refers to the dosage between low dosage and high dose.
" treatment " refers to give for treatment or prevention Immunoinflammatory Disorders or the composition of prescription.
" patient " refers to any animal (such as mankind).Other of method of the invention, composition and medicine box treatment can be used
Animal includes horse, dog, cat, pig, goat, rabbit, hamster, monkey, cavy, rat, mouse, lizard, snake, sheep, ox, fish and bird
Class.
" sufficient amount " refers to treat or prevent needed for Immunoinflammatory Disorders in a manner of clinically relevant in the present invention combines
Chemical combination object amount.To implement the present invention, to treat the reactive compound for the illness for being caused by Immunoinflammatory Disorders or being facilitated, its is effective
Amount changes according to the age of administering mode and patient, body weight and general health.Finally by prescriber determine Sq and
Dosage.In addition, effective dose can be than by administrative authority (such as FDA Food and Drug Administration) determination and approval
Each independent medicament, the chemical combination object amount of the patient with Immunoinflammatory Disorders can be safely and effectively treated in the present invention combines.
" more effective " refers to some way, composition or medicine box compared with another method, composition or medicine box, and display is more
The effect of big, toxicity is smaller, safer, is more convenient, more preferable tolerance or more cheap, or provides more treatment satisfactions.Work(
Effect can be determined by skilled practitioner using any standard method for being suitable for specific adaptations disease.
Term " Immunoinflammatory Disorders " includes various disease conditions, including autoimmunity disease, hyperproliferative skin disease and inflammatory cutaneous
Disease.Immunoinflammatory Disorders cause health tissues by inflammatory process, the dysregulation of immune system and unnecessary cell propagation
Destruction.The example of Immunoinflammatory Disorders has acne vulgaris;ARDS;Addision's disease;Allergic rhinitis;Cross
Quick property intraocular inflammatory diseases;ANCA- correlation thin vessels vasculitis;Rhizomelic spondylitis;Arthritis;Asthma;Artery congee
Sample hardens;Atopic dermatitis;Autoimmune hemolytic anemia;Oneself immunity hepatitis;Shellfish Sai Teshi diseases;Bell's palsy;
Bullous pemphigoid;Cerebrum ischemia;Chronic obstructive pulmonary disease;Cirrhosis;Section's root Cotard;Contact dermatitis;COPD;Section
Section property ileitis;Cushing's syndrome;Dermatomyositis;Diabetes;Lupus erythematosus discoides;Eosinophilia fascitis;Knot
Section property erythema;Exfoliative dermatitis;Fibromyalgia;Stove glomerulosclerosis;Giant cell arteritis;Gout;Gouty is closed
Section is scorching;Graft versus host disease(GVH disease);Hand eczema;Purpura,Henoch-Schonlein;Herpes gestationis;Hirsutism;Idiopathic corneal-scleral is scorching;
Idiopathic pulmonary fibrosis;ITP;Inflammatory bowel disease or gastrointestinal disease;Inflammatory dermatosis;Lichen planus;Wolf
Sore ephritis;Struma lymphomatosa tracheobronchitis;Macula retinae portion oedema;Multiple sclerosis;Myasthenia gravis;Myositis;Bone
Arthritis;Pancreatitis;Pemphigoid gestationis (pemphigoid gestationis);Pemphigus vulgaris;Nodositas is more dynamic
Arteries and veins is scorching;Polymyalgia rheumatica;Pruritus scroti;Itch/inflammation;Psoriasis;Psoriatic arthritis;Rheumatoid arthritis;Recurrence
Property polychondritis;Brandy nose caused by sarcoidosis;Brandy nose caused by chorionitis;Schlempe caused by Sweet's syndrome
Nose;Brandy nose caused by systemic lupus erythematosus;Brandy nose caused by nettle rash;Schlempe caused by herpes zoster is ache related
Nose;Sarcoidosis;Chorionitis;Segmental glomerulosclerosis;Septic shock syndrome;Shoulder tendonitis or bursal synovitis;This Jaeger
Human relations Cotard;This ground Er Shi diseases;The brain cell that apoplexy induces is dead;Sweet diseases;Systemic lupus erythematosus;It is systemic hard
Skin disease;High iS-One arteritis;Temporal arteritis;Poisonous Epidermal necrosis it is molten from;Tuberculosis;Type i diabetes;Ulcerative colitis;Pigment
Layer is scorching;Vasculitis;Multiple granulomatosis.
" non-skin inflammatory disease " includes such as rheumatoid arthritis, inflammatory bowel disease, asthma and chronic obstructive pulmonary disease.
" inflammatory disease of the skin " or " inflammatory dermatosis " includes such as psoriasis, polarity febrile neutrophilic skin
Disease, eczema (such as dry eczema, dry sore, vesicular palmoplantareczema), thick liquid cell circumscripta plasmacellularis
(balanitis circumscripta plasmacellularis), balanoposthitis, Bei Saiteshi diseases, annulare centrifugum are red
Spot, erythema chromicum figuratum melanodermicum, erythema multiforme, granuloma annulare, lichen nitidus, lichen planus, lichen planus morphoeicus, lichen simplex
Running sore skin disease under liver moss, lichen spinulosus, coin shape dermatitis, pyoderma gangraenosum, sarcoidosis, cuticula, nettle rash and short
Temporary property spinous layer pine angle skin disease.
" hyperproliferative skin disease " refers to the benign or malignant disease characterized by cell division in epidermis or corium accelerates.Increase
Grow the example of dermatoses have psoriasis, atopic dermatitis, non-specific dermatitis, it is primary around here for contact dermatitis, anaphylaxis
Before contact dermatitis, the basal cell of skin and squamous cell carcinoma, flaggy shape fish scale moss, epidermolytic hyperkeratosis, canceration
Keratosis, acne and seborrhea.
It will be appreciated by those skilled in the art that disease specific, sufferer or illness can show as hyperproliferative skin disease and inflammation simultaneously
Dermatoses.One example of this disease is psoriasis.
【Embodiment】
Embodiment 1
Formula:
Material usage(g) | Embodiment 1-1 | Embodiment 1-2 | Embodiment 1-3 | Embodiment 1-4 |
Tacrolimus | 0.1 | - | - | - |
Elidel | - | 0.1 | - | - |
Rapamycin | - | - | 0.1 | - |
Cyclosporin A | - | - | - | 0.1 |
Beesia calthifolia saponin(e O | 0.1 | 0.1 | 0.1 | 0.1 |
Propene carbonate | 5.0 | 5.0 | 5.0 | 5.0 |
Beeswax | 3.2 | 3.2 | 3.2 | 3.2 |
Light liquid petrolatum | 18.2 | 18.2 | 18.2 | 18.2 |
Albolene | 73.5 | 73.5 | 73.5 | 73.5 |
Altogether | 100 | 100 | 100 | 100 |
Preparation method:
The beeswax and albolene for weighing recipe quantity are added in emulsion tank, and heating melting is standby after 65 ± 5 DEG C of insulations at 70 DEG C
With;
The propene carbonate for weighing recipe quantity is placed in liquid dispensing container, add the tacrolimus of recipe quantity or other drugs stir to
It is completely dissolved or disperses;
Material solution is added in emulsion tank, and liquid dispensing container is rinsed with part light liquid petrolatum, together with remaining lightweight liquid
Shape paraffin is added in emulsion tank in the lump, is stirred;
Dispersing emulsification machine is opened, the even 60~90min of breast, and slow cooling are carried out with 3500rpm rotating speed, temperature is persistently stirred to and is down to
30±2℃;
Filling sealing, filling 30 ± 5 DEG C of temperature control are carried out with composite soft tube.
Embodiment 2
Formula:
Material usage(g) | Embodiment 2 | Reference examples 2-1 | Reference examples 2-2 |
Tacrolimus | 0.1 | - | 0.1 |
Beesia calthifolia saponin(e O | 0.1 | 0.1 | - |
Glyceryl triacetate | 20 | 20 | 20 |
Sodium hydroxide | In right amount | In right amount | In right amount |
Carbopol 980 | 0.5 | 0.5 | 0.5 |
Citric acid | 0.5 | 0.5 | 0.5 |
Glycerine | 10 | 10 | 10 |
Propylparaben | 0.1 | 0.1 | 0.1 |
Methyl p-hydroxybenzoate | 0.15 | 0.15 | 0.15 |
Water | In right amount | In right amount | In right amount |
Altogether | 100 | 100 | 100 |
Preparation method:
0.15g methyl p-hydroxybenzoates and 0.1g propylparabens are dissolved in purified water under heating, cooled down
10g glycerine, 0.5g citric acids and carbopol 980 (0.5g) are dissolved after to 40 DEG C or lower.By 1.02g tacrolimus under heating
Hydrate dissolution is added in the solution in 20g glyceryl triacetates, is disperseed with agitator.It is added dropwise under agitation
Sodium hydrate aqueous solution, pH is adjusted to pH4 to 7 to form gel.Purified water is added so that total amount is adjusted to 100g, to provide
Hydrogel.Also, lotion can be prepared by using 0.1g to 0.2g carbopol 980.
Embodiment 3
Formula:
Material usage(g) | Embodiment 3 | Reference examples 3-1 | Reference examples 3-2 |
Tacrolimus | 5 | - | 5 |
Beesia calthifolia saponin(e O | 25 | 25 | - |
Ethanol | 32 | 32 | 32 |
Polyoxyethylene castor oil (Cremophor EL) | 5 | 5 | 5 |
PVP (Plasdone_K31/29) | 25 | 25 | 25 |
PVPP (Polplasdone_XL-10) | 176 | 176 | 176 |
Lauryl sodium sulfate | 10 | 10 | 10 |
Lactose | 150 | 150 | 150 |
Flavouring | 30 | 30 | 30 |
Thickener | 20 | 20 | 20 |
It is made altogether | 1000 bags | 1000 bags | 1000 bags |
Preparation method:
The surfactant that precision weighs recipe quantity tacrolimus addition recipe quantity makes its main ingredient complete wetting, adds a certain amount of
Ethanol it is dissolved to obtain clear solution,;The PVP for adding recipe quantity immediately stirs rapidly, obtains clear solution;Rapidly
The PVPP for adding recipe quantity is well mixed, and is pelletized.Put it into 50 DEG C of air dry ovens to dry, whole grain, with flavouring
It is well mixed with thickener, packs, seals, produce.
Embodiment 4
Formula:
Material usage(g) | Embodiment 4-1 | Embodiment 4-2 | Embodiment 4-3 | Embodiment 4-4 |
Tacrolimus | 2 | - | - | - |
Elidel | - | 2 | - | - |
Rapamycin | - | - | 2 | - |
Cyclosporin A | - | - | - | 2 |
Beesia calthifolia saponin(e O | 1 | 1 | 1 | 1 |
Lactose monohydrate | 42.2 | 42.2 | 42.2 | 42.2 |
PEG 6000 | 35.0 | 35.0 | 35.0 | 35.0 |
Poloxamer 18 | 14.8 | 14.8 | 14.8 | 14.8 |
Magnesium stearate | 0.5 | 0.5 | 0.5 | 0.5 |
Talcum powder | 4.5 | 4.5 | 4.5 | 4.5 |
Altogether(1000 are made altogether) | 100 | 100 | 100 | 100 |
Preparation method:
Direct tablet compressing after mixing, tablet hardness 41N.
Test case immunosupress test experiments
Test experiments 1
1.1. experiment material and instrument:
Mouse:Balb/c mouse, male, 18-20g body weight;
MTT:Tetrazole, it is purchased from Sigma companies;
Concanavalin A:It is purchased from Sigma companies;
C-RPMI-1640 cell culture fluids:In every 1000ml distilled waters, 10.4 grams of dry powder containing RPMI-1640, NaHCO32 grams, L-
0.3 gram, benzyl penicillin 100U/ml, streptomysin 100ug/ml of glutamine, 10% calf serum, it is sterile filtered;
Cell work liquid:0.01M pH7.2 Hank ' s liquid;
SRBC:De- fiber SRBC is taken, is washed till not haemolysis with physiological saline, the SRBC that last pressure product SRBC is made into 5%, 10% hangs
Liquid;
Sample liquid:Appropriate amount of sample accurately is weighed, dissolving (DMSO hydrotropies) with distilled water is made into tacrolimus 1mg/ml solution, then
With normal saline dilution into being sterile filtered after 10 μ g/ml.The decoction to be measured of various concentrations is configured to during experiment.
The ELIASAs of Model 550:Microplate Reader Instruction ManualCatalog Number
170-6750
CO2 incubators:NAPCO Model 5410
1.2. experimental method:
Sample liquid is taken to being injected intraperitoneally in Mice Body, while control group is set, successive administration is sterile respectively to take spleen, system after seven days
Standby splenocyte suspension, make mtt assay lymphocyte transformation experiment, record OD values.
The preparation of 2.1 mouse boosting cell suspensions:Draw neck to put to death mouse, 1-2 minutes are soaked with 75% ethanol, ultra-clean
It is sterile in platform to take spleen, put in the plate for filling Hank ' s liquid and be lightly ground with nook closing member in being shredded on steel mesh, single cell suspension.
Centrifuge 10 minutes (1000rpm), washed twice after abandoning supernatant, carry out cell count, cell precipitation c-RPMI1640 nutrient solutions
It is adjusted to 1 × 107/ ml concentration.
1.2.2 mtt assay lymphproliferation response is tested
1 × 107/ml mouse boosting cells suspension of fresh separated is added in 96 porocyte culture plates, and 100 μ l, then root are added per empty
Stimulant (ConA) 100 μ l/ holes are added according to experimental design, each sample sets three parallel holes and sets control wells (only plus c-
1640), per the μ l of hole cumulative volume 200, then culture plate is placed in 37 DEG C of 5%CO2 incubators and cultivated 48 hours.Take out culture
Plate, inhaled per hole and abandon the μ l of supernatant 100, each hole adds the μ l of 5mg/ml MTT 10, continues culture 4 hours.Culture plate is taken out, each hole adds
The μ l of 10% SDS lysates 100, put in incubator overnight, the ELIASA colorimetric estimation absorbance A at 570nm.
Then according to formula:Cell inhibitory rate (%)=% of (1-A experimental ports/A blank control wells) × 100 is counted
Calculate.
1.3. experimental result
It is shown in Table 1~4.
The mtt assay lymphocyte inhibiting rate experimental result of table 1
Cell inhibitory rate (%) | |
Embodiment 1-1 | 55.7 |
Embodiment 1-2 | 38.5 |
Embodiment 1-3 | 27.5 |
Embodiment 1-4 | 22.6 |
The mtt assay lymphocyte inhibiting rate experimental result of table 2
Cell inhibitory rate (%) | |
Embodiment 2 | 61.4 |
Reference examples 2-1 | 21.5 |
Reference examples 2-2 | 18.6 |
The mtt assay lymphocyte inhibiting rate experimental result of table 3
Cell inhibitory rate (%) | |
Embodiment 3 | 68.7 |
Reference examples 3-1 | 22.6 |
Reference examples 3-2 | 25.7 |
The mtt assay lymphocyte inhibiting rate experimental result of table 4
Cell inhibitory rate (%) | |
Embodiment 4-1 | 45.9 |
Embodiment 4-2 | 31.2 |
Embodiment 4-3 | 23.6 |
Embodiment 4-4 | 20.5 |
Test experiments 2
2.1.TNF α secretions experiment
The effect that testing experiment drug regimen is secreted to TNF α in the leucocyte from people's buffy coat as follows is described white thin
Born of the same parents are stimulated with LPS or phorbol 12-tetradecanoic acid 13- acetic acid esters and ionomycin.People from buffy coat is thin in vain
Born of the same parents 1: 50 are diluted in culture medium (RPMI;Gibco BRL, #11875-085), 10% hyclone (Gibco BRL, #25140-
097), 2% penicillin/streptomycin (Gibco BRL, #15140-122)) in, 50 μ L dilution leucocytes are added to breadboard
In each hole.Add drug solution(Sample liquid, compound method are same as above).Breadboard is 37 DEG C in humidified incubator, is incubated under 5%CO2
Centrifuged after educating 16-18 hours, supernatant, which is transferred to, is coated with the white impermeable of anti-TNF alpha antibodies (PharMingen, #551220)
The bright orifice plate of polystyrene 384 (NalgeNunc, Maxisorb).After the plate is incubated two hours, with containing 0.1%Tween's 20
PBS washs (Tecan Powerwasher 384), then anti-TNF alpha antibodies (PharMingen, the # with biotin labeling again
554511) one is incubated together with the HRP (horseradish peroxidase) (PharMingen, #13047E) for being coupled to Streptavidin
Hour.Then the plate is washed with 0.1%Tween20/PBS again.HRP- luminous substrates are added in each hole, with the luminous measurement of plate
Measure the luminous intensity in each hole.
2.2.IFN- γ secretions experiment
Effect of the testing experiment drug regimen to IFN-γ secretion in the leucocyte from people's buffy coat as follows, it is described white
Cell is stimulated with phorbol 12-tetradecanoic acid 13- acetic acid esters.Human leukocytes 1: 50 from buffy coat are diluted in culture
Base (RPMI;Gibco BRL, #11875-085), 10% hyclone (Gibco BRL, #25140-097), 2% penicillin/chain
Mycin (Gibco BRL, #15140-122)) in, 50 μ L dilution leucocytes are added to the above one and save the final experiment established
In each hole of plate.Breadboard is 37 DEG C in humidified incubator, is centrifuged under 5%CO2 after incubation 16-18 hours, and supernatant is transferred to
Be coated with anti-IFN-γ antibody (Endogen, M-700-AE) the orifice plate of White-opalescent polystyrene 384 (NalgeNunc,
Maxisorb).After the plate is incubated two hours, (TecanPowerwasher is washed with the PBS containing 0.1%Tween 20
384), then with the anti-IFN-γ antibody (Endogen, M-701-B) of biotin labeling and it is coupled to the HRP of Streptavidin again
(PharMingen, #13047E) is incubated one hour together.Then the plate is washed with 0.1%Tween 20/PBS again.HRP- is sent out
Light substrate is added in each hole, and the luminous intensity in each hole is measured with plate luminometer.
2.3.IL-1 secretion experiment
The effect that testing experiment drug regimen is secreted to IL-1 in the leucocyte from people's buffy coat as follows is described white thin
Born of the same parents are stimulated with LPS.Human leukocytes 1: 50 from buffy coat are diluted in culture medium (RPMI;Gibco BRL, #11875-
085), 10% hyclone (Gibco BRL, #25140-097), 2% penicillin/streptomycin (Gibco BRL, #15140-
122) in), 50 μ L dilution leucocytes are added in each hole that the above one saves the final breadboard established.Breadboard is humidifying
In incubator at 37 DEG C be incubated 16-18 hours after centrifuge, supernatant be transferred to be coated with anti-IL-1 antibody (R&D Systems,
MAB601 the orifice plate of White-opalescent polystyrene 384 (NalgeNunc, MAXISORB)).The plate be incubated two hours after, with containing
There are 0.1%Tween 20 PBS washings (Tecan Powerwasher 384), then the anti-IL-1 again with biotin labeling resists
Body (R&D Systems, BAF201) and the horseradish peroxidase (PharMingen, #554066) for being coupled to Streptavidin
It is incubated one hour together.Then the plate is washed with 0.1%Tween 20/PBS again, HRP- luminous substrates is added in each hole.
Then with plate luminometer measurement luminous intensity.
2.4.IL-2 secretion experiment
The effect that testing experiment drug regimen is secreted to IL-2 in the leucocyte from people's buffy coat as follows is described white thin
Born of the same parents are stimulated with phorbol 12-tetradecanoic acid 13- acetic acid esters.Human leukocytes 1: 50 from buffy coat are diluted in culture medium
(RPMI;Gibco BRL, #11875-085), 10% hyclone (Gibco BRL, #25140-097), 2% penicillin/strepto-
Plain (Gibco BRL, #15140-122)) in, 50 μ L dilution leucocytes are added to the above one and save the final breadboard established
Each hole in.Breadboard in humidified incubator at 37 DEG C be incubated 16-18 hours after centrifuge, supernatant be transferred to be coated with it is anti-
The orifice plate of White-opalescent polystyrene 384 (NalgeNunc, MAXISORB) of IL-2 antibody (PharMingen, #555051).
The plate be incubated two hours after, wash (TecanPowerwasher 384) with the PBS containing 0.1%Tween 20, then again with
The anti-IL-2 antibody (Endogen, M600B) of biotin labeling and the horseradish peroxidase for being coupled to Streptavidin
(PharMingen, #13047E) is incubated one hour together.Then the plate is washed with 0.1%Tween 20/PBS again, HRP- is sent out
Light substrate is added in each hole.Then with plate luminometer measurement luminous intensity.
Inhibiting rate
The inhibiting rate (%I) in each hole is calculated with below equation:
%I=[(average untreated well-processing hole)/(average untreated well)] × 100
Average untreated well value (" average untreated well " in formula) is only with 40 holes on the same breadboard of media processes
Arithmetic average.Compared to untreated hole, negative inhibiting value is caused by handling the localized variation in hole.
2.5. experimental result
It is shown in Table 5~8.
The TNF α of table 5 secretes inhibiting rate experimental result
Inhibiting rate (%) | |
Embodiment 1-1 | 58.5 |
Embodiment 1-2 | 35.8 |
Embodiment 1-3 | 26.7 |
Embodiment 1-4 | 21.8 |
The IFN-γ secretion inhibiting rate experimental result of table 6
Inhibiting rate (%) | |
Embodiment 2 | 64.6 |
Reference examples 2-1 | 23.7 |
Reference examples 2-2 | 19.2 |
The IL-1 of table 7 secretes inhibiting rate experimental result
Inhibiting rate (%) | |
Embodiment 3 | 61.5 |
Reference examples 3-1 | 21.3 |
Reference examples 3-2 | 25.2 |
The IL-2 of table 8 secretes inhibiting rate experimental result
Inhibiting rate (%) | |
Embodiment 4-1 | 47.4 |
Embodiment 4-2 | 33.8 |
Embodiment 4-3 | 26.2 |
Embodiment 4-4 | 21.7 |
Experiment conclusion:
Table 1,4,5,8 test result indicates that, the immunosuppressive action of tacrolimus and Beesia calthifolia saponin(e O combination is better than other groups
Close.
Table 2,3,6,7 test result indicates that, tacrolimus and Beesia calthifolia saponin(e O combination are immune with what is significantly cooperateed with
Inhibitory action.
Claims (12)
1. a kind of composition, the composition includes tacrolimus and Beesia calthifolia saponin(e O.
2. the composition of claim 1, wherein the composition is used to treat Immunoinflammatory Disorders.
3. the composition of claim 2, wherein the Immunoinflammatory Disorders are rheumatoid arthritis, regional ileitis, burst
Ulcer colitis, asthma, chronic obstructive pulmonary disease, rheumatic polymyopathy, giant cell arteritis, systemic lupus erythematosus, spy
Answering property dermatitis, multiple sclerosis, myasthenia gravis, psoriasis, rhizomelic spondylitis, cirrhosis or psoriatic arthritis.
4. the composition of claim 1, wherein the composition is configured to for local administration.
5. the composition of claim 1, wherein the composition is configured to supply Formulations for systemic administration.
6. the composition of claim 1, wherein tacrolimus are 50 with the amount ratios of Beesia calthifolia saponin(e O in the composition:
1 to 1:50.
7. the preparation of the patient with Immunoinflammatory Disorders or the risk for having development Immunoinflammatory Disorders is made a definite diagnosis in a kind for the treatment of, described
Preparation includes tacrolimus with Beesia calthifolia saponin(e O and/or without pharmaceutically acceptable additive.
8. the preparation of claim 7, wherein the Immunoinflammatory Disorders are rheumatoid arthritis, regional ileitis, ulcer
Property colitis, asthma, chronic obstructive pulmonary disease, rheumatic polymyopathy, giant cell arteritis, systemic lupus erythematosus, it is special should
Property dermatitis, multiple sclerosis, myasthenia gravis, psoriasis, rhizomelic spondylitis, cirrhosis or psoriatic arthritis.
9. the preparation of claim 7 or 8, wherein tacrolimus are 50 with Beesia calthifolia saponin(e O dosages ratio:1 to 1:50.
10. claim 7 or or 8 preparation, its formulation be oral application solid dosage forms or local topical formulation.
11. a kind of medicine box, the medicine box includes:(i) composition, the composition include tacrolimus and Beesia calthifolia saponin(e O;
(ii) explanation for making a definite diagnosis composition described in the patient with Immunoinflammatory Disorders or the risk for there are development Immunoinflammatory Disorders is given
Book.
12. the medicine box of claim 11, wherein the Immunoinflammatory Disorders are rheumatoid arthritis, regional ileitis, burst
Ulcer colitis, asthma, chronic obstructive pulmonary disease, rheumatic polymyopathy, giant cell arteritis, systemic lupus erythematosus, spy
Answering property dermatitis, multiple sclerosis, myasthenia gravis, psoriasis, rhizomelic spondylitis, cirrhosis or psoriatic arthritis.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3777865A4 (en) * | 2018-03-29 | 2022-01-19 | Morinaga Milk Industry Co., Ltd. | Anti-aging composition |
CN115154474A (en) * | 2021-04-01 | 2022-10-11 | 中国人民解放军总医院 | Application of cycloartane type triterpenoid saponin compound in preparation of T cell immunosuppressive agent |
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CN1342656A (en) * | 2001-07-25 | 2002-04-03 | 中国医学科学院药用植物研究所 | Cyclobornane triterpenoid saponin compound and its application in immunosuppresion and treating tumor |
CN101132768A (en) * | 2004-12-15 | 2008-02-27 | 伊兰制药国际有限公司 | Nanoparticulate tacrolimus formulations |
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2017
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CN1342656A (en) * | 2001-07-25 | 2002-04-03 | 中国医学科学院药用植物研究所 | Cyclobornane triterpenoid saponin compound and its application in immunosuppresion and treating tumor |
CN101132768A (en) * | 2004-12-15 | 2008-02-27 | 伊兰制药国际有限公司 | Nanoparticulate tacrolimus formulations |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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EP3777865A4 (en) * | 2018-03-29 | 2022-01-19 | Morinaga Milk Industry Co., Ltd. | Anti-aging composition |
CN115154474A (en) * | 2021-04-01 | 2022-10-11 | 中国人民解放军总医院 | Application of cycloartane type triterpenoid saponin compound in preparation of T cell immunosuppressive agent |
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