CN101189009A - Dermatological compositions and salts for the treatment of dermatological diseases - Google Patents
Dermatological compositions and salts for the treatment of dermatological diseases Download PDFInfo
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- CN101189009A CN101189009A CNA2006800109385A CN200680010938A CN101189009A CN 101189009 A CN101189009 A CN 101189009A CN A2006800109385 A CNA2006800109385 A CN A2006800109385A CN 200680010938 A CN200680010938 A CN 200680010938A CN 101189009 A CN101189009 A CN 101189009A
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Abstract
The invention relates to dermatological compositions of Oxaprozin or a closely related compound suitable adapted for the treatment of a dermatological disease, where at least two of the enzymes selected from protein tyrosine kinase Syk, protein tyrosine kinase ZAP-70 and phosphodiesterase IV play a role in mediating the dermatological disease. The invention also encompasses dermatological compositions for the treatment of pruritus.
Description
Technical field
The present invention relates to be adapted to treat the particularly pharmacology and the pharmaceutical preparation of the dermatosis compositions of local application promazine or its chemical compound that is closely related in the eczema of dermatosis.
Background technology
Have now found that, effectively inhibitory enzyme protein tyrosine kinase Syk, protein tyrosine kinase ZAP-70 and phosphodiesterase IN (PDE-IV) of the dosage of being correlated with the pharmacology as the promazine of nonsteroid anti-inflammatory drugs (NSAID) by approval so far, and reduce the symptom and the inflammation of the animal model of contact dermatitis effectively.
It is generally accepted ground, term " nonsteroidal antiinflammatory drug " is used to describe the chemical compound that has based on the molecular formula of phenol that replaces or phenyl ring, and pharmacological action relates generally to inhibition cyclooxygenase-1 (Cox-1), the inhibition that also relates to COX-2 (Cox-2) to a certain extent is (referring to Greaves MW, pharmacology and the meaning (Pharmacology and significance ofnonsteroidal anti-inflammatory drugs in the treatment of skin diseases) thereof of nonsteroid anti-inflammatory drugs aspect the treatment dermatosis, J Am AcadDermatol, 1987, April, 16 (4): 751-64).Can not produce the prostaglandin of Cox-1 derivatization in skin, and the cox-2 enzyme produces prostaglandin at inflammation part, therefore pharmacology's anti-inflammatory treatment purpose is to suppress the prostaglandin of Cox-2 derivatization always in the past.
But as what the inventor found, comparing ， Evil promazine with other known NSAID has very different pharmacodynamicss and safety.
Every kind enzymatic activity in pheron tyrosine kinase Syk, protein tyrosine kinase ZAP-70 and the phosphodiesterase IN (PDE-IV) is the committed step of antiinflammatory process, compares with the cyclooxygenase approach, carries out on the level of higher level.Therefore, the promazine disturbs many critical paths in the consecutive process of inflammation, make this medicine at the anti-inflammatory agent candidate, particularly about than what expect previously prospect being arranged more in the treatment of inflammation dermatosis such as eczema.Protein tyrosine kinase Syk and ZAP-70 are the enzymes that a class catalysis phosphate group shifts to the tyrosine residue that is positioned at protein substrate from ATP.Their regulation and control cause the inflammatory process detectable signal response the earliest of reacting before the multiple cascade inflammation to the activation of mastocyte, T cell and B cell.Protein tyrosine kinase Syk relate to cell in the inflammatory cell take off particle response, the lipid intermediate is synthetic and cytokine production, can expect that protein tyrosine kinase Syk participates in allergy or inflammatory reaction by the function of control mastocyte, basophil and eosinophilic granulocyte.Protein tyrosine kinase ZAP-70 needs T cell development and T cell original receptor function.
The PDE-IV enzyme belongs to phosphodiesterase (PDE) family of the hydrolysis response of pair cell internal ring adenosine monophosphate and cyclic guanosine list phosphoric acid (being respectively cAMP and cGMP).IV type phosphodiesterase is the cAMP-enzyme-specific that is positioned at airway smooth muscle and immunity and inflammatory cell.IV type enzyme is the key enzyme of the cAMP hydrolysis in mastocyte, basophil, eosinophilic granulocyte, mononuclear cell and the lymphocyte.
In addition, except the enzyme system of being recognized by the inventor, the promazine suppresses arachidonic acid ethanolamine (anandamide) hydrolytic enzyme (fatty amide hydrolase) and the activation of the NF-kappaB in the inflammatory cell in the neuron.The Evil promazine is also induced apoptosis (Dallegri, the Franco of activated monocyte in dose-dependent mode, anti-inflammatory Yao Evil promazine new situation summary (A review of the emerging profileof the anti-inflammatory drug oxprozin) (Expert Opin Pharmacother, 2005, May; 6 (5): 777-85).
Obviously, the inventor has recognized that pharmacology's potentiality that the promazine is very huge, at least aspect the treatment dermatosis, because this unification compound just can be regulated and control the key of immune response in several Living Organisms and main approach, this need take several chemical compounds usually could obtain same effect.
It is existing for a long time as the treatment of osteoarthrosis and scorching rheumatoid arthritis that Sui Ran Evil promazine and NSAID are used for the whole body inflammatory diseases, and for example the purposes in the eczema treatment is former did not emphasize or confirm but the promazine is at inflammatory dermatosis.
Proposed and set up the NSAID that some are used for the specific skin disease.What mention is to be used for the treatment of dermatosis aspirin, indomethacin, parfenac (with Bufexamac listing) for a long time.Aspirin has been used for the treatment of pruritus in atopic eczema; Indomethacin be used to the to tan severely treatment of skin; Parfenac has been used for eczema, dermatitis and anus treatment (the Greaves MW of pruritus on every side, pharmacology and the meaning (Pharmacology and significance of nonsteroidal anti-inflammatory drugs in thetreatment of skin diseases) of nonsteroidal antiinflammatory drug in treating skin disease, J Am Acad Dermatol, 1987, April; 16 (4): 751-64).
Salicylic acid has been used to treat psoriasis (Going SM, Guyer BM, Jarvie DR, HunterJA, the salicylic acid gel (Salicylic acid gel for scalp psoriasis) that is used for scalp itch, Clin ExpDermatol, 1986, May; 11 (3): 260-2) and be used for pruritus (Jhomsen JS, SimonsenL, Benfeldt E, Jensen SB, Serup J, the topical application salicylic acid compound is induced 5-hydroxy tryptamine does not have the scratch therapeutic effect (The effect of topically applied salicylic compoundson serotonin-induced scratching behaviour in hairless rats) of behavior of hair rat, Exp Dermatol, 2002, August; 11 (4): 370-5).
Demonstrated reaction (Lowe NJ, Virgadamo F, the Stoughton RB of topical application indomethacin at the contact dermatitis animal model, prostaglandin antibody, corticosteroid and indomethacin are at antiinflammatory property (the Anti-inflammatory properties of a prostaglandin antagonist of tentative contact dermatitis, a corticosteroid and indomethacin in experimental contact dermatitis), Br JDermatol, 1977, April; 96 (4): 433-8) reduce human body skin inflammation (Black AK, Hensby CN, Greaves MW with the flurbiprofen topical application, the topical application of flurbiprofen is to the effect [procceedings] of human body skin inflammation (The effect of topical flurbiprofen on human skin infammation[proceedings]), Br J Clin Pharmacol, 1980, February; 9 (1): 125P).
But some NSAID fail to demonstrate any clear and definite ability of the definite dermopathic inflammation of treatment.For example, one studies confirm that the topical application indomethacin is very poor to the erythema and the edema effect of hyperphlogosis to eliminating cryotherapy treatment back moderate.Comparatively speaking, topical application steroid, Clobesol confirm to have effect (Humphreys F, Spiro J, topical application indomethacin and Clobesol to cryotherapy after the effect (The effects of topical indomethacin and clobetasol propionate onpost-cryotherapy inflammation) of inflammation, Br J Dermatol, nineteen ninety-five, May; 132 (5): 762-5).Green and Shuster confirm that topical application 1% indomethacin does not have effect (Green CA, Shuster S to human trial chronic stable plaque psoriasis, the topical application indomethacin does not have effect (Lack of effectof topical indomethacin on psoriasis) to psoriasis, Br J Clin Pharmacol, 1987, JIUYUE; 24 (3): 381-4).
Unfortunately, the part of various NSAID is used and is accompanied by significant skin side reaction.For example, the parfenac listing is used for the treatment of pruritus and contact allergy, but it is reported that chemical compound itself can cause contact allergy.Moreover, it is reported that aspirin and indomethacin can induce urticaria reaction, and piroxicam can cause phototoxicity or photoallergic dermatitis.Ketoprofen and parfenac are approved (Gebhardt M and Wollina U as main contact allergen, the skin side-effects of on-steroidal hormone anti-inflammatory agent (NSAID) thing (Cutaneous side-effects of nonsteroidalanti-inflammatory drugs (NSAID)), Z Rheumatol, nineteen ninety-five, November; 54 (6): 405-12).Diclofenac is that another topical application causes NSAID (Rivers JK and the McLean DI that follows the generation skin side-effects in the contact dermatitis at stimulus object, 2.5% hyaluronic acid derivatives of topical application 3% diclofenac is used for the effectiveness of actinic keratosis treatment and the open trial (An open studyto assess the efficacy and safety of topical 3% diclofenac in a 2.5%hyaluronic acidgel for the treatment of actinic keratoses) of safety evaluatio, Arch Dermatol, 1997, November; 133 (10): 1239-42).
Therefore, the inventor's discovery is very surprising, because do not resemble the NSAIDs of other uses, Fa Xian Evil promazine is very effective and safety in the treatment dermatosis.Consider the present invention and in the treatment of chafing tissue, the promazine no longer is considered as typical NSAID, because its main pharmacodynamics character relevant with inflammation skin does not comprise the inhibitory action to cyclooxygenase (Cox-1/Cox-2).In fact, the promazine is one optionally NSAIDs (Kawai S of relatively poor Cox-2 inhibition activity and Cox-2 inhibitory action, the gastrointestinal complication of cyclooxygenase selectivity and various nonsteroid anti-inflammatory drugses (Cyclooxygenase selectivityand the risk of gastrointestinal complications of various non-steroidalanti-inflammatory drugs), A clinical consideration.In Inflamma.Res.Supplement2 (1998) S102-S106).Therefore, the inventor believes that the promazine does not belong to Cox-2 inhibitor class.
According to new discovery, have the safety of promazine in handling dermatosis and the needs of effective topical application.But this has relatively poor dissolubility the promazine in water.Therefore, still need to provide to present the fully dermatosis compositions of the chemosmotic of containing promazine at the outermost layer (epidermis) of skin, so that realize that the abundant release of promazine in skin is to reach dermopathic best topical therapeutic.
Many patents that relate to NSAIDs dermatosis compositions are used, but these are quoted the problem of not recognizing the Ying Yong Evil of Ju portion promazine or provide any solution to problem.
US2005014729A1 and WO05009342A2 (Pharmacia Corporation) have described the general item of COX2 inhibitor topical compositions.According to US2005014729 A1 and WO05009342A2, can randomly provide Cox-2 inhibitor with pharmaceutical acceptable salt.Relate to the example of promazine although use, use and clearly disclose and instruct the dermatosis compositions that contains the promazine as the Cox-2 inhibitor.And then the inventor's opinion Shi Evil promazine in fact is not the Cox-2 inhibitor.
The main purpose of WO05027977A2 (AGIS INDUSTRIES (1983) LTD) relates to the skin gel preparation, and it is substantially free of molecular weight 150,000～750, the hyaluronic acid between 000 dalton, and purpose is the treatment actinic keratosis.Suggestion can be used other NSAID that comprise the promazine in gel combination.
Severally relate to other NSAID dermatosis compositions quoted passages, but they all do not emphasize to use the NSAID with salt form.
JP7316075A2 (POLA CHEM IND INC) relates to expection and grants NSAID by the part, the dermatosis compositions (cream preparation) of the waterproofing agent treatment dry skin of preferred Bufexamac, indomethacin, ibuprofen or tenoxicam and 10-20%.
WO0059475A1 (Lipocine) relates to and contains the dermatosis compositions that can dissociate NSAID and the carrier, surfactant and the triglyceride that contain the NSAID that can dissociate (suggestion 2-ethylaminoethanol) chemical compound.
WO02074290 (AGIS INDUSTRIES (1983) LTD) relates to the part of NSAID and uses for example prescription of antibiotic, antibiotics, antiviral agents, anesthetis, analgesic, antiallergic drugs, corticosteroid, biostearin, antihistaminic, immunosuppressant and antiproliferative agents and composition thereof of compositions (particularly piroxicam, tenoxicam, Tolmetin, diclofenac and ketorolac) and less important therapeutic component.
US2005232957A1 (Katz K) relates to by granting specificity or non-specific cox inhibitor and is used for the dermatosis compositions that dry skin is treated.
Proposition ophthalmic preparation (WO9531968 and WO0205815) is also arranged.
Moreover, many patent applications relate to the dermatosis compositions that promazine and other treatment active component share, anesthetis (WO9709973) for example, salicylic acid (US5804572), farnesol (WO0062743), antiviral agent (WO0069255 and WO04056349), xanthine (WO0069406), ferulic acid, caffeic acid or tannic acid (WO02069963), selectivity cox-2 inhibitor such as celecoxib (WO02096435), antiviral agent (WO03059347), antibiotic (WO03061704), retinol (WO03105806), indole (EP1424325), EP-3 antibody (EP1426059), capsaicin (WO04056305) and lactams (WO04093796).
The sick compositions of anhydrous skin of promazine has been proposed among the WO9810742, and invention US20030157138 relates to coagulant by adding 1-25% in the dermatosis compositions and the water-repelling agent of 75-99%, the dermatosis compositions that designs in the mode of guaranteeing compositions liquefaction when being applied to skin.
The inventor also finds the special salt that is called cholamine salt of promazine, and excellent performance is provided in the time of in being applied in skin-use preparation.Notably be in the dermatosis compositions, to emphasize to use this salt without any one in above-mentioned patent or the patent application.The salt of promazine early has description in the general term of (Pharmacia Corporation) in US2005014729A1 and WO05009342A2.Potassium, sodium or Tris salt that patent application WO 9744022 relates to the promazine are used for Orally administered composition, and US 4,465, and 838 calcium salts that relate to the promazine are used for oral.
Cholamine is the biogenic amine of the 2-ethylaminoethanol (ethanolamine) that chemically refers in particular to.Amine is the trona of some phospholipid that exists in the mammalian cell membrane, and it can be used for various industrial purposes.
Therefore, the inventor provides dermatosis compositions effective and safe in treating skin disease.This is quite surprising, once does many effort because use NSAID to be used for the treatment of the dermatosis aspect for a long time, but success is still very limited so far, because effect is too low and significant skin irritation arranged.
Summary of the invention
Surprisingly, the inventor Fa Xian Evil promazine unlike other NSAID, it is having very strong treatment potentiality aspect treatment dermatosis, and its inhibitory action at least a enzyme of the protein tyrosine kinase Syk in the skin, protein tyrosine kinase ZAP-70 and phosphodiesterase IN (PDE-IV) will make dermopathic inflammatory symptom alleviate, suppress or remove.These dermatosiss especially think and comprise various forms of eczemas, for example contact dermatitis, atoipc dermatitis and hand eczema.Moreover the cardinal symptom that these diseases also will be removed, alleviate or be reduced to this inhibitory action is that scabies is overworked, and other symptoms of erythema and edema for example.
Test data shown here has confirmed to follow significantly and fully the alleviating (referring to embodiment 2 (irritant contact dermatitis and atoipc dermatitis), 3 (insect bite inflammation), 4 (psoriasiss) and 5 (contact dermatitis in the inductive mice of oxazolone) of characteristic symptom of the inflammation of various eczemas.Somatic data shown here has clearly confirmed to suffer contact dermatitis, atoipc dermatitis and psoriasic patient to alleviate significantly rapidly, completely.In addition, the erythema of skin and fish scaleization be also the improving of treatment in 1-2 week, shown that it causes effect aspect the psoriasis in indefinite disease.The promazine has shown the dosage with clinical meaning, and very strong inhibitory action is comparable to strong steroid hormone betamethasone-17 valerate at least.
The inventor proposes hypothesis, the compellent effect of observed promazine is the pharmacological property that is accompanied by promazine excellence, promptly with protein tyrosine kinase Syk, the protein tyrosine kinase ZAP-70 of micro-molar concentration and one or more enzymes in the PDE-IV enzyme inhibitory action is arranged.The promazine of this micro-molar concentration can be desirably in the Skin Cell after local the use and exist, but has pharmacologically active dosage after also being expected at the whole body administration.
Be used for the treatment of inflammatory dermatosis for example the composition of eczema is opposite with existing, according to treatment of the present invention the advantage that can not follow any serious side reaction is arranged, the promazine has shown that the dosage with the pharmacology meaning uses biological tissue's safety and is easy to tolerance.For example, promazine (with the form of ethanolamine salt) can not produce any skin side-effects of the form of sensitization, phototoxic reaction or acute skin irritation effect.In addition, skin-use preparation of the present invention even when granting 28 days continuously, still show the advantages of good skin toleration with 5% concentration.
Unfortunately, the physicochemical properties of promazine make this molecule be difficult to be made for satisfactorily the dermatosis compositions of local skin therapeutic purposes.Must realize that high concentration is to obtain the relevant layers that competent amount penetrates the skin that comprises epidermis and corium at skin surface.The main cause of difficulty is the water and the middle mutually dissolubility inequality of fat that comes from the assorted dermatosis compositions of promazine.The relatively poor problem of dissolubility can be by adding various solubilizing agents, and for example ethanol, isopropyl alcohol or diethylene glycol monoethyl ether improve promazine dissolubility to the dermatosis compositions.Unfortunately, these solubilizing agents are the skin irritants that possible worsen the patient's condition, increase tedious character often for compositions itself, for example, and the toleration that compositions reduces.Moreover chemical compound itself can cause the problem of resistance of skin because of its low pH value.
The problem that the inventor finds the promazine and the chemical compound that is closely related uncannily is resolved by the mode of carrying for the water soluble salt of Evil promazine or its chemical compound that is closely related, solves to small part.These compositionss provide the promazine of q.s for the skin of morbid state, because compositions can comprise even high concentration De Evil promazine, do not need the saturated solution of Zhi Bei Evil promazine and introduce the danger of promazine crystal growth.In addition, with regard to the pH character of skin, obtain the compatible salt of physiology, because salt has the pH value corresponding to the basic group of promazine.In addition, although find uncannily to dissociate shape promazine for pass upper layers of skin, horny layer has relatively poor affinity because it is a dissociative type, the dissociative type of finding the promazine will return to non-dissociative type original shape when having the skin of low pH value under being used for normal condition.Original shape will have better affinity with horny layer.Therefore, promazine even when topical application is separated release Evil promazine, also can realize enough skin absorbs.
Correspondingly, a first aspect of the present invention relates to the dermatosis compositions of the water soluble salt form that comprises the promazine or the chemical compound that is closely related, dissolubility 5mg/ml at least in 25 ℃ of water for example, 10mg/ml at least for example, for example at least 20,25,30,50mg/ml, and excipient (vehicle) comprises acceptable composition of one or more skins or carrier (carrier).
The advantage of this compositions is physics and chemically stable, and they can not cause the problem of resistance of skin, for example erythema and skin breach, and they can treat inflammatory dermatosis, particularly eczema effectively.
The inventor recognizes that also the 2-ethylaminoethanol is the very interesting counter ion of promazine, because its balance hydrophilic and hydrophobic characteristic, this makes that keratodermatitis is had affinity, means that this specific compound is easy to remove from upper layers of skin by the horny layer diffusion.On the contrary, more hydrophilic counter ion tends to be gathered in skin surface, because they are not easy to pass horny layer, this will cause at its counter ion is that the diffusion of promazine is relatively poor under the situation of water-wet behavior.It is generally acknowledged that these counter ions comprise K
+, Na
+, Ca
2+And TRIS (Tris salt), these are the compositionss that are elected to be oral rapid release.Therefore, the inventor provides has good physico-chemical property and salt that have good cutaneous permeability.
Therefore, the inventor finds the ethanolamine salt of the promazine or the derivant that is closely related, and has excellent performance at least with regard to Evil promazine topical application and toleration.
Therefore, a second aspect of the present invention relates to the 2-ethylaminoethanol salt of the promazine or the chemical compound that is closely related, and wherein 2-ethylaminoethanol cation combines with promazine anion.
In addition on the one hand, the present invention relates to the purposes of the dermatologic compositions among the present invention, it can be used for preparing the medicine for the treatment of inflammatory dermatosis, particularly eczema.
Therefore invention also relates to and treats the particularly method of eczema of inflammatory dermatosis, comprises the dermatosis compositions of granting invention to its patient (subject) of needs.
In the various aspects of invention, the treatment or the prevention of inflammatory dermatosis comprise:
The treatment of eczema;
The treatment of the hypersensitivity reaction in the skin;
IV type treatment hypersensitive in the skin;
The treatment hypersensitive of skin I type;
The treatment of contact dermatitis or prevention;
The treatment of allergic contact dermatitis or prevention;
The treatment of irritant contact dermatitis or prevention;
The treatment of atoipc dermatitis;
The treatment of hand eczema; Or
The alleviation of one or more the following skin symptoms in the inflammatory dermatosis patient, elimination or prevention, described and attached symptom is selected from the group of following composition: scabies is overworked, edema, erythema and fish scale skin (scaling).
Others relate to dermatosis compositions of the present invention and are used to prepare skin general pruritus or owing to or the pruritus that cause relevant with the dermatosis of mentioning herein or or the pruritus that cause relevant with systemic administration, contact the pruritus of being correlated with or causing with water or be correlated with systemic disease or the purposes of the medicine of the pruritus that causes.
Therefore, the invention still further relates to the overworked method of skin scabies that treatment needs its patient.
The specific embodiment
The inventor has recognized that the needs that are suitable for the promazine or are closely related the local dermatological formulation that uses of chemical compound, is preferred for disease skin, and eczema patient's skin is particularly for example arranged.Importantly, that such compositions should be sent is sufficiently high, the local concentration of dissolving promazine is to corium, and need not to add solubilizing agent to the dermatosis compositions.
Importantly, dermatosis compositions of the present invention should be fit to put on suffers from dermopathic skin, for example follows or because anaphylactic reaction the dermatosis such as the eczema of I type and the anaphylactic reaction of IV type.
The inventor is unlike promazine or the dermatosis compositions of other NSAIDs, and inventor's Special attention will be given to provides the needs of the water soluble salt form of promazine in the past.In addition, the inventor need to emphasize the dermatosis compositions of application of water substrate, helps to obtain required effect.For example, its dermatosis compositions (being excipient) scalable horny layer itself is so that obtain the skin that is delivered to normal or morbid state of promazine or required transmission rate of the chemical compound that is closely related or capacity.Therefore, excipient can change the Evil promazine of Ben Faming or be closely related dissolubility and/or the diffusibility of chemical compound in horny layer.Sending of the ， Evil promazine or the chemical compound that is closely related will cause promazine or the related compound high local concentrations in Skin Cell Zhong optimal formulation.
Therefore, on the one hand, the invention provides the dermatological formulation i that comprises following composition) with the promazine of water soluble salt form or the chemical compound that is closely related; The excipient that ii) comprises acceptable composition of one or more skins or carrier.
Dermatosis compositions purpose is to grant skin for the part, need to be used to the topical therapeutic of its patient's skin upper surface.Therefore, ophthalmic preparation and the agent of percutaneous Gypsum Fibrosum need not to be category of the present invention, may be considered to the eliminating embodiment of the dermatosis compositions that reaches mentioned herein in some embodiments.
Term " skin " means the skin that comprises whole body, specifically comprises scalp, forehead, head, arm, lower limb, breast, perianal area or the like.Term " skin " also refers to comprise the different layers of skin, for example horny layer, epidermis and corium.
Term " water-soluble " meaning is to Ding Yi Evil promazine or the chemical compound that is closely related obtaining Bi the mode modification of the higher water solubility of Evil promazine, for example Bi high 5,10,20,25,40,50,75,100,200,250,400 and 500 times or higher Bi the water solubility of Evil promazine.The dissolubility of Evil promazine in 25 ℃ of water is about 1.7mg/ml.The water-soluble modified meaning of the Yin Ci ， Evil promazine or the chemical compound that is closely related is meant that obtaining modifying De Evil promazine dissolubility in 25 ℃ of water is 5,10,20 at least, 25,30 and 50mg/ml, for example preferably 75,100,150,200,250 or even the modification of 300mg/ml at least.
Term " excipient " is to be defined as liquid, solid or the semisolid matrix of being made up of skin acceptable auxiliary or carrier, Evil promazine or its be closely related chemical compound water-soluble form dissolving or be suspended in wherein, be preferably dissolved in wherein.
The meaning " can be accepted " in term used herein on the Dermatology be that composition, carrier or the excipient described like this are applicable to human keratinous tissue and contacts, can toxigenicity especially for eczema skin, incompatibility, unstability, anaphylaxis respond and similar situation.
Phrase " part of salt exists in skin " is the skin that is locally applied to that comprises salt, and the whole body absorption of supposing salt is limited or is zero.Local application is meant that weight is less than 50%, and for example 40%, 30%, 25%, 20%, 15% or 5% the weight of being less than of the salt of local application may intravasation or reclaim from urine and feces.The local therapeutic approaches at patient's scytitis or skin irritation position comprises that compositions is applied to patient's skin surface, preferably is in or contiguous inflammation and/or irritating position.And compositions is placed this position a period of time, to allow the topical therapeutic amount of its delivering active ingredients.
Term " disease skin " is meant in present specification suffers from dermopathic skin, for example eczema particularly.The inventor finds that the prerequisite Shi Evil promazine of dermatosis compositions of the present invention is used with water-soluble form, so that think also can realize well tolerable property and low skin irritability the time that when it realization high dose level becomes possibility in skin at least.
The be closely related water-soluble modification of chemical compound of promazine or its can obtain by several method, for example:
By promazine or its chemical compound micropowder that is closely related being changed into the particle of micrometer range, for example more than 80% particle diameter less than 30 μ m or even more I to be a kind of method;
By the molecular dispersoid that provides promazine or its to be closely related chemical compound, for example, it is dissolved in the appropriate solvent by Zhong Evil promazine, adds under the dry powder structure then in the silica gel of high surface;
The formation of complex, for example cyclodextrin clathrate, and the formation method of passing through water soluble salt.
The water soluble salt of Yi through finding ， Evil promazine or its chemical compound that is closely related can or have the simple reaction of R side chain of the chemical compound that is closely related of suitable base to form drug acceptable salt by promazine free acid group, for example adds the salt of alkali.The type of salt depends on the specified disease that will treat and the particular type of preparation.Therefore, can use excessive base addition salts.
The example of inorganic base addition salts comprises Na, K, Ca, Mg, Cu, Zn and Mn salt.Usually, the organic base that is used to prepare base addition salts is a primary amine, secondary amine or tertiary amine, it comprises alkyl benzene amine, ammonia, the 2-ethylaminoethanol, aminopyrimidine, aminopyridine, arginine, benethamine (benethamine), Benzathini Benzylpenicilinum (benzathine), betanin, caffeine, choline, deanol, diethanolamine, diethylaminoethanol, the 2-dimethylaminoethanol, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, aminoglucose, glycinol (glycinol), Compocillin (hydrabamine), imidazoles, 2-aminopropane., meglumine, methylglucosamine, morpholine, piperazine, piperidines, procaine, purine, pyrrolidine, theobromine, thiamine, triethanolamine, triethylamine, trimethylamine, tripropyl amine (TPA), trimethylol aminomethane, spermidine etc.In addition, base addition salts can be derived by the natural amino acid reaction and be obtained, for example, for example D-isomer or substituted amino acid of glycine, alanine, valine, leucine, isoleucine, nor-leucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, threonine and phenylalanine and alpha-non-natural amino acid; Guanidine and replacement guanidine, wherein substituent group is selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salt and aluminum salt.Below be the non-limitative example of associated salts:
Slaine, wherein cation usually is selected from Li
+, Na
+, K
+, Ca
2+, Mg
2+, Cu
2+, Zn
2+And Mn
2+
- promazine or its be closely related free acid and the primary amine of chemical compound, the amine salt that secondary amine or reactive tertiary amine form, described primary amine, secondary amine or tertiary amine comprise alkyl benzene amine, ammonia, the 2-ethylaminoethanol, aminopyrimidine, aminopyridine, arginine, benethamine, Benzathini Benzylpenicilinum, betanin, caffeine, choline, deanol, diethanolamine, diethylamine, 2-diethylaminoethanol, the 2-dimethylaminoethanol, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, aminoglucose, glycinol, Compocillin, imidazoles, 2-aminopropane., meglumine, methylglucosamine, morpholine, piperazine, piperidines, procaine, purine, pyrrolidine, theobromine, thiamine, triethanolamine, triethylamine, trimethylamine, tripropyl amine (TPA), trimethylol aminomethane, spermidine etc.;
-Tong crosses the free acid of Evil promazine or its chemical compound that is closely related and the formed amine salt of reaction of natural amino acid, for example for example D-isomer or substituted amino acid of glycine, alanine, valine, leucine, isoleucine, nor-leucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, threonine and phenylalanine and alpha-non-natural amino acid; The guanidine of guanidine and replacement, wherein substituent group is selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salt and aluminum salt.
Should be appreciated that any alkali can be used for the formation of water soluble salt, as long as its dissolubility in 25 ℃ water for example is preferably greater than 75,100,150 and 200mg/ml greater than 5,10,20,25,30,40 or 50mg/ml.
In addition, preferably use the pKa scope at 8-12 in order to obtain in water the pH scope at the water soluble salt of 6-8, the alkali of the scope of preferred 8.5-11.That is to say that water soluble salt can have organic amine preparation at the pKa of 8-12 scope by amino group, preferred range is 8.5-11, preferred 8.5-10.5, and for example scope is 8.5-10.
In the present important embodiment of the present invention, the be closely related salt of chemical compound of promazine or its mainly is that they will be easy to transdermal, move to the upper surface of skin with not too hydrophilic counter ion preparation, avoid stopping up Skin Cell whereby, otherwise more hydrophilic counter ion may occur.Not too hydrophilic counter ion like this is believed to comprise ethanolamine and other logP values and ethanolamine at same order or the molecular weight organic counter ion in same order.This counter ion is thought and is comprised organic amine or aminoacid, for example comprises ethylenediamine, diethanolamine, choline, lysine and glycosamine at least.Ethanolamine and 2-ethylaminoethanol are the term that is used interchangeably here.The counter ion of less stable comprises inorganic counter ions according to the present invention, as Li
+, Na
+, K
+, Ca
2+, Mg
2+, Cu
2+, Zn
2+, Mn
2+With some a little hydrophilic organic amine such as TRIS.
The logP value of ethanolamine is about 1-3, and molecular weight is about 61.1 dalton.Therefore, can use other counter ions to be selected from the logP value, preferably below-0.5 at the organic amine below 0.In fact, the logP value of these amine is between 0 to-10, preferably between 0 to-5, more preferably between 0 to-3, for example between 0 to-2.5.
The dermatosis compositions can be physics, chemistry and Biostatic, is delivered to horny layer to a great extent from excipient at least, and can not hinder is salt of the present invention.The content (electrolytical content) that the problem that the invention of this department of dermatologry aspect will run into is the salt in the different emulsifiers is responsive to the oil phase that causes emulsifying and Emulsion and the electrolytical content of aqueous phase separation.
In addition, the dermatosis compositions must the whole body absorption be limited, even after being applied on the skin of morbid state.Therefore, the dermatosis compositions must be made respective design.
There are many parameters when design dermatosis compositions, to consider; 1) concentration of water soluble salt; 2) if contain the lipophilic phase, then water and lipophilic ratio mutually; 3) viscosity; 4) content of penetration enhancer; 5) selection of oil-phase component, for example phospholipid, emulsifying agent, coemulsifier and surfactant and 6) pH.These parameters all will influence promazine salt and pass cuticular speed, or influence the amount of the water soluble salt that keeps in epidermis and/or upper epidermis.
The term aqueous favoring meaning is meant aqueous solution, and the material of water and picture water sample is promptly electropolarized usually and can form the material of valence link with hydrone, and it can make it in water than in oil or easier dissolving in other " nonpolar " solvents.Aqueous favoring usually comprises the water of 50%-100%.The water of 80%-100% particularly.The composition that aqueous favoring can further comprise other liquid hydrophilic compositions and dissolve or suspend at aqueous phase, for example antioxidant, polar solvent, surfactant, emulsifying agent, penetration enhancer, pH regulator agent, antiseptic, pigment and spice.
Lipophilic looks like mutually and is meant and contains one or more smectics as described below and oiliness composition oil/fat mutually, is randomly formed by emulsifying agent, surfactant, softening agent, antioxidant, antiseptic, pigment and combinations of perfumes.
In general, the dermatosis compositions can provide in several designs, for example comprises the Emulsion form of microemulsion and Liposomal formulation, gel, solution, liniment, ointment, foam, spray, aerosol, miniature sponginum, patch or powder.
Use on the skin of considering at morbid state the dermatosis compositions and by horny layer with water soluble salt satisfied be delivered to skin corium the time, compositions should adapt to such situation.The skin of morbid state, the dermatosis that is defined the here skin that infects of eczema particularly for example, there is breach on the surface usually, and horny layer is not too complete.Therefore, the dermatosis compositions is easy to coat the major part of the skin of morbid state, particularly skin, and the skin of this Dao Zhi Evil promazine salt by morbid state to be coated with unevenly be essential.These compositionss think and comprise Emulsion, gel, solution, spray, foam and aerosol, and are preferably soft and be easy to coat the Emulsion of the skin of morbid state.
Dermatosis compositions of the present invention is water-based preferably.Aqueous-favoring content may be crucial to suitable infiltration situation, enough reservations (if desired) in the cell of morbid state skin.The dermatosis compositions of the water-based used herein meaning is meant 40% the aqueous favoring that comprises more than excipient weight.Described excipient preferably comprise more than 45%, 47%, 50%, 55% or 60% until more than 75% such as 90%, 85% or 90% aqueous favoring.Therefore, such ointment tends to anhydrously because of it, needs not to be the working of an invention mode.Therefore, in some embodiments, ointment is not in category of the present invention.That is to say to comprise in the dermatosis compositions excipient of invention to be no less than 5wt%, for example be less than 10wt%, for example be less than the water of 15wt%.
Interesting embodiment of the present invention comprises excipient, and described excipient further comprises lipid component or oils composition, and they may constitute the 20-70wt% up to this excipient, for example are preferably the 30-50wt% of this excipient weight.That is to say that only the gel combination of being made up of hydrophilic component is not in this embodiment.
promazine or its are closely related the water soluble salt concentration of chemical compound should be according to required infiltration rate adjustment.May need low concentration so that realize treatment response fully, least concentration should be about 0.005wt% of excipient weight at least, for example is 0.01,0.02,0.04,0.06,0.08,0.1,0.2,0.5,0.7 or 1wt% at least.Upper limit of concentration can be the saturated concentration that approximates water soluble salt in the excipient aqueous favoring.Usually, salinity can be up to the 25wt% of excipient weight.Usually, concentration range is at the 0.002wt%～20wt% of about excipient weight, more preferably 0.01wt%-10wt%, more preferably 0.1wt%-5wt%.
Usually, the dermatosis compositions should comprise promazine or the salt of its chemical compound that is closely related, the more preferably 1wt% of 0.5wt% at least, 1.5wt% at least more preferably, 2wt% at least more preferably, for example about 2.5wt%, about 3wt%, about 3.5wt%, about 4wt%, about 4.5wt%, about 5wt%, about 5.5wt%, about 6wt% or about 7wt%.
Chemical compound is easy to tolerance in skin although promazine or its are closely related, and can think the amount of bestowing the active component of guaranteeing safe treatment.Therefore, the salt amount that the dermatosis compositions should comprise promazine or its chemical compound that is closely related should be less than 7wt%, more preferably less than 6.5wt%, further preferably is less than 5wt%, for example less than 4.5wt%, for example less than 4wt%, for example less than 3.5wt%.
Correspondingly, the preferred embodiment of the present invention should comprise that promazine or its are closely related the amount of salt of chemical compound between 0.5-10wt%, for example between 0.5-8wt%, preferably between 0.5-7wt%, 0.5-6wt% for example, 0.5-5.5wt%, 0.5-5wt%, 0.5-4.5wt%, 0.5-4wt%, 0.5-3.5wt%, for example 0.5-3wt%.The embodiment that the present invention is more preferably comprises the be closely related salt of chemical compound of promazine or its, and the amount of this salt is in the 1-7wt% scope, preferably in the 1-6.5wt% scope, 1-6wt% for example, 1-5.5wt%, 1-5wt%, 1-4.5wt%, 1-4wt%, 1-3.5wt%.1-3wt% for example.The embodiment that the present invention is more preferably comprises the be closely related salt of chemical compound of promazine or its, the amount of this salt is at 1.5-7wt%, preferably between 1.5-6.5wt%, for example at 1.5-6wt%, 1.5-5.5wt%, 1.5-5wt%, 1.5-4.5wt%, 1.5-4wt%, 1.5-3.5wt% is for example between the 1.5-3wt%.
In the embodiment in the present Central Asia of the present invention, described dermatosis compositions comprises promazine or its chemical compound that is closely related, and its amount is about 1wt%, about 1.5wt%, about 2wt%, about 2.5wt%, about 3wt%, about 3.5wt%, about 4wt%, about 4.5wt%, about 5wt% or about 6wt% are preferably 2.5wt%, 3wt%, 3.5wt% or 4wt%.
The concentration of required salt is with the function representation of the saturation solubility of acceptable salts in aqueous favoring in the excipient.The saturation solubility meaning is meant that salt can dissolved Cmax in aqueous favoring.Therefore, the concentration of salt in aqueous favoring may be saturation solubility 0.01 until 100%, preferably 0.1 of saturation solubility to 20%.
It is if desired, aqueous-favoring that pH can for example diethanolamine, citric acid, lactic acid, triethanolamine, sodium hydroxide, hydrochloric acid and sodium phosphate be regulated by adding acceptable acid or alkali.The aqueous-favoring pH value of dermatosis compositions can be in the 3-8 scope, but preferred pH is in the 5-8 scope, more preferably in about 6.5-7.8 scope.
In the at present important embodiment of the present invention, aqueous-favoring pH value between 6.8-7.5, for example between the 7.0-7.5, for example about 7.2,7.3 or 7.4.Finding that such pH value has constituted improvement embodiment of the present invention, is undesired at low pH value, because promazine salt has sedimentary danger, and higher pH is because skin irritation also is undesired.
Usually, dermal compositions of the present invention can be a kind of in the following form:
Water in oil emulsion: the promazine can join in the Emulsion of the continuous phase that comprises hydrophobic phase and water, and described water comprises water and one or more optional polar hydrophilic carrier and salt.These Emulsions can comprise that the polymer of oil-soluble or oil swell and one or more can make the stable emulsifying agent of Emulsion. promazine salt preferably adds to aqueous phase.
Oil in water emulsion: the promazine can emulsified adding Emulsion in, described Emulsion comprises the discontinuous phase and the aqueous continuous phase of hydrophobic phase, and the described water continuous phase that contains comprises water and optional one or more polar hydrophilic carriers and salt, surfactant, emulsifying agent and other compositions.These Emulsions can comprise that water solublity or water swellable polymer and one or more help the stable emulsifying agent of Emulsion.
Hydrophobic ointment: promazine salt can be mixed with hydrophobic phase (in the water by the promazine being added vaseline, thickening or gelation, insoluble oil, triglyceride, the carbitol etc.), randomly with making the promazine keep dissolved small amounts of water soluble phase.
The hydrogel of thickening: promazine salt can be mixed with and contain water, this water by thickening to obtain high viscosity.Thickening can realize by adding suitable natural or artificial high polymer natural, that modify described below.In addition, the hydrogel of thickening can use the polyethoxylated alkyl chain surfactant of suitable effectively thickener composition and other nonionics, cation or anion emulsifier system to come thickening.Preferably, can select the nonionic emulsifier system, because ionic emulsifying agent tends to the content sensitivity to salt.The example of non-ionic emulsifier system is emulsifing wax Polawax, emulsifing wax Cosmowax and pentaerythritol stearate (Crothix) emulsifying systems.
Hydrophilic gel: promazine salt can be mixed with continuous phase, and this continuous phase comprises the water solublity hydrophilic component of at least a non-water.Said preparation can comprise and be up to about 70-99wt%, for example the water of 80-95wt%.Reduced levels may be suitable for some compositions.Suitable hydrophilic composition comprises polyalcohols for example glycerol, propylene glycol, butanediol etc., and random or block copolymer, the per molecule of Polyethylene Glycol (PEG), oxirane, expoxy propane and/or epoxy butane has poly-alkoxyl surfactant, silicone copolymer and the combination thereof etc. of one or more hydrophobic parts.
Foam: promazine salt can be mixed with foam, and it typically comprises excipient water, lipophilic solvent, surfactant, emulsifying agent and specificity gel component.When these carriers place aerosol container, and when being used in combination with the liquid gas propellant, their produce translucent, under prewired state stable o/w Emulsion.The liquid gas propellant adds in the carrier with the 3-18wt% of total approximately composition weight.When discharging from aerosol container, carrier forms can broken foam product, is suitable for topical.
The various compositions that can be used for the dermatosis compositions usually are:
-oils composition, be the hydrophobic phase constituent of various dermatosis composition forms, and form one or both or more kinds of mixture that following skin can be accepted composition: almond oil, Oleum Ricini, cocoa butter, Oleum Cocois, Semen Maydis oil, cotton seed oil, oleum lini, olive oil, Petiolus Trachycarpi oil, Oleum Arachidis hypogaeae semen, poppy seed oil, Oleum Brassicae campestris, Oleum sesami, soybean oil, Oleum Helianthi and Oleum Camelliae), mineral oil, fatty oil, liquid paraffin, mineral oil, isopropyl myristate, Cera Flava, cotton seed oil, cetostearyl alcohol (cetosteraryl alcohol), lanoline, paraffinum molle alba, yellow soft paraffin, canola oil (canola oil), hexadecanol, Oleum Arachidis hypogaeae semen, oleic acid, isopropyl palmitate, Oleum Ricini, stearyl alcohol, Jojoba oil, stearic acid and silicone oil.
-lipid component, it is the hydrophobic phase constituent of various dermatosis composition forms, can be used for being used in combination or replacing oil phase, comprise that usually one or more are selected from Cera Flava, paraffin, vaseline, triglyceride, cetyl palmitate, vegetable oil, sorbitan fatty esters (Span), Polyethylene Glycol (PEG) and the sorbitan ester of fatty acid and the condensation product of oxirane, for example polyoxyethylene sorbitan monoleate (Tween).The group of the typical optional self-contained vaseline of lipid component, paraffin, vegetable oil, Animal fat, synthetic glyceride, wax, lanoline and the poly-alkyl silane of liquid.Usually lipid component is but is not limited to solid polyethylene glycol (PEG).
-water is formed aqueous favoring and mainly is made up of water, hydrophilic solvent, surfactant, emulsifying agent, antiseptic, pH regulator agent, spice, pigment and other hydrophilic compositions.
-can add to the hydrophilic solvent of aqueous phase, for example polar solvent in the water form, propylene glycol, glycerol, sorbitol, ethanol, industrial methylated spirit, Polyethylene Glycol, propylene glycol, propylene carbonate and glyceryl triacetate
-can add to the lipophilic solvent of lipophilic in mutually, non-polar solven-the softening agent in isopropyl alcohol and medium chain triglycerides (MCT) form for example, fatty acid list, two or triglyceride and fatty acid ester, dodecane, squalane, cholesterol, isohesyl dodecane (isohexadecane), different nonyl ester in the different ninth of the ten Heavenly Stems, PPG ether, vaseline, safflower oil, Oleum Ricini, Oleum Cocois, Oleum Gossypii semen, palm-kernel oil, Oleum Arachidis hypogaeae semen, soybean oil, polyol carboxylate and derivant and its mixture for example.
-emulsifying agent can add to water or oil phase.Compositions of the present invention can comprise one or more emulsifying agents and be used for emulsification composition.Term used herein " emulsifying agent " meaning is meant can covalently bound polarity and nonpolar district and can reduce the amphipathic molecule of interfacial tension between water surface tension and water and the immiscible liquids.Term comprises soap class, detergent, emulsifying agent, surfactant etc.Emulsifying agent can be cationic, anionic, nonionic or amphotericity.This comprises the conventional emulsifier of wide region;
Nonionic emulsifier.The nonionic emulsifier that can make example includes but not limited to that polyol ester comprises glycols (for example ethylene glycol, diethylene glycol, ethylene glycol stearate and fatty acid propylene glycol monoester (1, the 2-propylene glycol monostearate, propylene glycol oleate or propylene glycol stearoyl glyceride)) and glyceride (for example, tristerin, glyceryl monooleate, glyceryl monolaurate, glycerol ricinoleate ester, Monooctamoin);
Dehydration Pyrusussuriensis ester derivant is sorbitol and fatty acid (C
12-C
18) the ester that forms of dehydration condensation.Dehydration Pyrusussuriensis ester derivant can be divided into two classes.I) sorbitol ester of fatty acid (for example, sorbitan monolaurate, sorbitol monooleate, sorbitol monostearate).(SPAN 60
TM), sorbitol palmitate, sorbitol sesquioleate, sorbitol olein or sorbitol tristearate) and ii) Polyoxyethylene sorbitol tristearate TWEEN 65
TM, octadecanoic acid ester of polyethylene glycol (TWEEN80
TM), macrogol ester (also being called the macrogol ester) is that the list of Polyethylene Glycol (PEG) or di fatty acid ester are (from C
1To C
18) ester, for example, the myristinate ester of the stearate of PEG (PEG-40, PEG-50 and PEG-55), laurate, oleate and PEG; Polyoxyethylene ether is the ether of Polyethylene Glycol and aliphatic alcohol, for example the ether of following alcohol: stearyl alcohol (steareth emulsifying agent), cetostearyl alcohol (ceteareth emulsifying agent) and oleyl alcohol (oleth emulsifying agent);
Poloxamer (for example, poloxamer-188) with polyoxyethylene-polyoxypropylene derivant of polyoxyethylene group; The nonylplenyl ether of the nonyl phenol of ethoxylation (nonokynol-9); Propylene glycol diacetate; Polyvinyl alcohol;
Alkanolamide is by fatty acid and ethanolamine or diethanolamine prepared in reaction; Aliphatic alcohol (for example, spermol and stearyl alcohol); The alkyl polyglucoside; The poly-hydroxy fatty acid amide; Sucrose ester; Fatty acid alkanol amides; Ethoxylated fatty acid, ethoxylated fatty acid; Ethoxylized fatty alcohol (for example, Octylphenoxy gathers (ethylene oxy) basic ethanol, and its trade mark is called NONIDET P-40, all comes from Sigma, St.Louis, MO); Ethoxylation and/or propoxylated fatty alcohol; The ethoxylated glycerol ester; Ethoxy-c oxygen group block copolymer for example comes from the PLURONIC and the TETRONIC surfactant of BASF AG.
Cationic emulsifier.The cationic emulsifier that can be used as example includes but not limited to: the salt that may optionally be polyoxyethylene primary amine, secondary amine or tertiary amine, tetra-allkylammonium for example, alkylamine alkyl trialkyl ammonium, the triakyl benzyl ammonium, trialkyl hydroxy alkyl ammonium, or alkyl pyridine halogenide (being preferably chlorine or bromine) and other anionic counter ions, such as but not limited to alkyl sulfate, such as but not limited to methoxy sulfate and ethoxy sulfate, imidazolidine derivatives; The amino oxide of cation attribute (for example, under acid pH).The example of amino oxygen emulsifying agent comprises lauryl dimethyl base amine oxide, Laurel aminopropyl dimethylamine oxide and cetyl amino oxide,
Anion emulsifier.The anion emulsifier that can be used as example includes but not limited to sarcosinate, glutamate, Glu, alkyl sulfate, alkylol ammonium sulfate, aureth-n-ammonium sulfate, isethionate, glycerol ether sulfonate, sulfosuccinate, alkyl glyceryl ether sulfonate, alkylphosphonic, aralkyl phosphate, alkylphosphonic.But these anion emulsifier second are by the counter ion of metal or organic amine.
The amphion emulsifying agent.The amphoteric ion type emulsifying agent comprises emulsifying agent can be protonated, that have tertiary amine group and the quaternary ammonium that contains the amphion emulsifying agent.The example of this amphoteric emulsifier includes but not limited to: some betaine is cocoa betanin and cocamido propyl betaine for example; Monoacetate is lauroyl both sexes guanidine-acetic acid sodium for example; Diacetin, for example, lauroyl both sexes base diethyl sodium; Amino and alkyl aminopropionic acid salt is laurylamino-propionic acid for example.The ichthyodin amphoteric surfactant.This class amphoteric emulsifier is meant " alkyl sulfobetaines (sultaines) " or " thetine (sulfobetaines) ", for example, and the cocamidopropyl propyl amide hydroxy sulfo lycine.
Preferred solvent is to have HLB (being hydrophile-lipophile balance value) to be at least 4 or preferably be at least those materials of 6.Further preferred solvent is that the scope of HLB is at 8～20 hydrophilic emulsifying agent, for example in 10～20 scope.Most preferred emulsifying agent has at least 12 HLB value, and for example at least 15.Compositions of the present invention can use one or more emulsifying agents to produce the result who wants under proper level.In preferred embodiment, based on the gross weight of the compositions of using immediately, one or more emulsifying agents are at least 0.1wt%, the preferred 0.5wt% that is at least, and the preferred 1.0wt% that is at least.The stimulation of the emulsifying agent in preferred embodiment, based on the gross weight of the compositions that will use, the amount of emulsifying agent is not more than total amount 10wt%, more preferably no more than 5wt% at once, further preferably be not more than 3wt%, even more preferably no more than 2wt%.
-can add to aqueous-favoring macromolecule thickener; For example, the glue class of arabic gum, alginate, antler glue, chitosan, collagen, tragakanta and xanthan gum; Cellulose, the sodium cellulosate of for example carboxymethyl, methylol, hydroxypropyl and hydroxypropyl methyl; Acrylic acid, for example, carbomer and polycarbophil; Colloidal solids is silica gel, clay and microcrystalline Cellulose for example; Hydrogel is polyvinyl alcohol and polyvinylpyrrolidone for example; The reversible high polymer of heat is poloxamer for example.
-can add to the pH regulator agent (buffer agent) in the aqueous favoring, for example diethanolamine, lactic acid, ethanolamine, triethanolamine, sodium hydroxide, sodium phosphate, citric acid, tartaric acid, hydrophosphate, phosphate and diethylamine.
-penetration enhancer can add to aqueous favoring or oleophylic phase, so that increase the infiltration of promazine in horny layer.
-antiseptic, for example anti-equal agent is as benzalkonium chloride, benzyl alcohol, chlorhexidine, imidazolidinyl urea, phenol, potassium sorbate, benzoic acid, bronopol, chlorocresol, p-hydroxybenzoic acid, phenyl phenol and sorbic acid
-wetting agent, for example, glycerol, glycerol, propylene glycol, sorbitol.
-chelating agen, for example citric acid and edetic acid.
-antioxidant, for example alpha-tocopherol, ascorbic acid, anti-bad blood base cetylate, BHA, butylated hydroxytoluene, sodium ascorbate, sodium pyrosulfite.
-can be selected from the suspending agent of cellulose and cellulose derivative, for example, carboxymethyl cellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, carrageenin, acacin, arabic gum, tragakanta and their mixture.
-one-tenth gel (thickening agent).The composition (thickening agent) of suitable gel-type vehicle and increase viscosity can be selected from liquid paraffin, polyethylene, fatty oil, colloidal silica or aluminum, zinc soap, glycerol, Polyethylene Glycol, tragakanta, carboxy vinyl polymer, aluminium-magnesium silicate, Carbopol
, hydrophilic high polymers for example carboxymethyl cellulose, hydroxyethyl-cellulose and other cellulose derivatives of starch or cellulose derivative for example, for example water-soluble bloated hydrocolloid, carrageenin, hyaluronic acid (for example randomly the hyaluronic acid derivatives of Chinese sodium chloride) and the Sargassum acids that comprises the Polyethylene Glycol alginic acid.Also having other examples is high-molecular weight polysaccharide glue, for example xanthan gum.
In embodiments of the present invention, there is stability problem in the water soluble salt of promazine in rising, and for example because the lipophilic in the Emulsion separates with aqueous favoring mutually, importantly selects the emulsifying agent not too responsive to electrolyte.Therefore, some preferred embodiment in, nonionic emulsifier includes but not limited to that polyol ester comprises ethylene glycol and glyceride; Dehydrated sorbitol derivative comprises fatty acid sorbitol ester and polyoxyethylene sorbitan ester; Polyoxyethylene ester; Polyoxyethylene ether; Poloxamer; Nonylphenyl Ether.Preferably fatty acid sorbitol ester and polyoxyethylene sorbitan ester.
Physical stability can be by observing the tendency that is separated after the challenge of Emulsion reply physical strain.For example, Emulsion can be exposed to " freeze thawing " in a plurality of cycles, and is for example 6 times, then centrifugal again.Perhaps, after Emulsion is stored in 25 ℃, 40 ℃ or 60 ℃ following 1 month, 3 months, 6 months, 12 months prolongations storages, observe its situation that is separated, randomly can be after the dermatosis compositions be centrifugal.In some embodiments of the present invention, the dermatosis compositions is an o/w Emulsion, for example, provides with emulsifiable paste or ointment form.Adjust aqueous favoring and oleophylic ratio mutually, to adapt to the diffusion/dissolving of water soluble salt in horny layer.The scope that typical aqueous favoring is compared with oleophylic is between 5: 1 to 1: 1 (w), preferably between 4: 1 to 1: 4 (w).
Representative instance in the embodiment of dermatosis compositions is provided with the Emulsion form, and for example o/w type Emulsion comprises those that contain following material:
The promazine of-0.5wt%-7.5wt% or the salt of its chemical compound that is closely related are preferably 1-5wt%, and wherein said salt is present in the aqueous favoring, and excipient comprises acceptable composition on one or more Dermatologys;
-30wt%-80wt%, the aqueous favoring of preferred 50-70wt%, described aqueous favoring comprise water, optional hydrophilic solvent (for example, glycerol and/or propylene glycol) and thickening agent (for example, xanthan gum or Carbopol2020
TM); And
-20wt%～70wt%, the hydrophobic phase of preferred 30wt%～50wt%, the described hydrophobic mixture that comprises lipid component, emulsifying agent or emulsifying agent mutually, optional one or more oils compositions and one or more optional lipophilic solvent,
Condition is the amount of composition that all the components constitutes 100wt%.
In a certain embodiment of invention, described dermatosis compositions is an Emulsion, oil-in-water emulsion for example, and this Emulsion comprises:
-0.5wt%-7.5wt%, the promazine of preferred 1-5wt% or the salt of its chemical compound that is closely related, wherein said salt is present in the aqueous favoring; And excipient comprises one or more skins can accept composition;
-30wt%-80wt%, the aqueous favoring of preferred 50-70wt%, described aqueous favoring comprises the water of 80-95wt%, optional hydrophilic solvent (for example, glycerol and/or propylene glycol) and thickening agent (for example, xanthan gum or Carbopol 2020
TM); And
-20wt%-70wt%, the hydrophobic phase of preferred 30wt%-50wt%, is chosen any one kind of them or multiple oils composition and choosing any one kind of them or multiple lipophilic solvent at the described hydrophobic mixture that comprises lipid component, nonionic emulsifier or nonionic emulsifier mutually,
Condition is the amount of composition that all the components constitutes 100wt%.
More specifically, this compositions comprises:
-0.5wt%-7.5wt%, the promazine of preferred 1-5wt% or the salt of its chemical compound that is closely related, described salt is present in the aqueous favoring; Described excipient comprises acceptable composition on one or more Dermatologys;
-30wt%-80wt%, the aqueous favoring of preferred 50-70wt%, described aqueous favoring comprises the water of 80-95wt%, hydrophilic solvent (for example is selected from propylene glycol, glycerol, sorbitol, ethanol, industrial methanolizing ethanol, Polyethylene Glycol, propylene glycol, propylene carbonate and triglyceride) and thickening agent (for example, be selected from starch, cellulose derivative (carboxymethyl cellulose for example, hydroxyethyl-cellulose and other cellulose derivatives), water-soluble bloated aqueous colloidal, carrageenin, hyaluronic acid (for example hyaluronic acid of optional sodium chloride-containing), (for example Carbopol 2020 for alginic acid ester (comprising the Polyethylene Glycol alginic acid ester) and high-molecular weight polysaccharide glue (for example flavin glue) and cross-linking polylactic acid copolymer
TM); With
-20wt%-80wt%, the hydrophobic phase of preferred 30wt%-50wt%, it comprises lipid component and (for example is selected from Animal fat, synthetic glyceride.Wax, lanoline, vaseline, poly-alkyl silane and solid polyethylene glycol), the mixture (for example being selected from poloxamer, fatty acid sorbitol ester and Polyethylene Glycol sorbitol monostearate and composition thereof) of nonionic emulsifier or nonionic emulsifier, choose any one kind of them or multiple oils composition, with choose any one kind of them or multiple lipophilic solvent, prerequisite be all the components form composition weight 100%.
In current interesting embodiment, the dermatosis compositions is an Emulsion, o/w Emulsion for example, and it comprises;
The promazine of-1-5wt% or the salt of its chemical compound that is closely related, wherein said salt are present in aqueous favoring and one or more skins can be accepted in the excipient of composition;
The water of-50wt-70wt%, this water comprise 80-95wt% water, be selected from the hydrophilic solvent of glycerol and propylene glycol) and (for example Carbopol 2020 to be selected from high-molecular weight polysaccharide glue (for example flavin glue) and cross-linking polylactic acid copolymer
TM) thickening agent; And
-20wt%-50wt%, the hydrophobic phase of preferred 30wt%-50wt%, this is hydrophobic comprise mutually lipid component (for example being selected from Animal fat, synthetic glyceride, wax, lanoline, vaseline, poly-alkyl silane and solid polyethylene glycol), nonionic emulsifier or nonionic emulsifier mixture (for example being selected from poloxamer, fatty acid sorbitol ester and Polyethylene Glycol sorbitol monostearate and composition thereof), choose any one kind of them or multiple oils composition and choosing any one kind of them or multiple lipophilic solvent, prerequisite be all the components constitute composition weight 100%.
In yet another embodiment of the present invention, the dermatosis compositions comes down to anhydrous or contains the water that is less than 20wt%, preferably is less than 15, for example the water of 15-10wt% or 5wt%.Typically, this embodiment comprises 0.5wt%-7.5wt%, the promazine of preferred 1-5wt% or the salt of its chemical compound that is closely related, and comprise solubilizing agent such as carbitol and oils composition, optional lipid component, oils composition and hydrophilic solvent.
Further embodiment can be mixed with solution, spray, foam and aerosol according to the skilled person of medicament scientific domain.
Use salt of the present invention to rectum at needs, described dermatosis compositions can be the form of suppository, ointment, gel and enema.If desired salt of the present invention is applied to the vagina place, described dermatosis compositions can be vaginal suppository, molded vaginal suppository, vaginal capsule, vaginal tablet etc.
Further spendable dermatosis compositions comprises shampoo, gel, soap class, stick, 30 powder, membrane, pad agent, sponginum, dressing, medicinal liquid (drench), binder and plaster, and this can prepare according to medicament science skilled person's knowledge.The optional free alginic acid of suitable powder composition, collagen, collagen protein, lactose, powder, these can stably form the form (absorbing liquid/Wound exudate) of gel when imposing on the wound.
In the preferred embodiment of the present invention, can accept by the salt of anhydrous promazine or its chemical compound that is closely related and one or more skins in fact during the dermatosis compositions that composition or carrier form.Used herein " in fact by ... form " meaning is meant that the dermatosis compositions may comprise except that be closely related composition the water soluble salt of chemical compound of promazine or gas, but only works as the new characteristic of fundamental sum that other composition can not change promazine or its compounds for treating effect that is closely related in essence.Therefore, in some embodiments, promazine or its chemical compound that is closely related is a therapeutic activity composition unique in the dermatosis compositions.
Should be understood that in the preferred embodiment of the present invention, water soluble salt is made up of the non-derivative form of promazine.But, can use the compounds for treating dermatosis that is closely related of identical basic molecular structure, and the water soluble salt form is better.Therefore, invention comprises 4 of design, 5-diphenyl-2-oxazole-propanoic acid, and following chemical structural formula is arranged:
Several derivants that the of antiinflammatory action promazine is arranged have been described in patent documentation.General derivant and production method thereof are described in US3,578,671.Specific derivatives is described in US 5,380,738 (4-fluorophenyl and 4-methyl sulphonyl phenyl), US 4,659,728 (hydroxyl substitutive derivative), US 6,090,834 (sulfonyl-derivatives), US 3,506679 (4,5-diaryl thiazole).
Term used herein " chemical compound is closely related " comprises the chemical compound and the isostere thereof of general formula I.
These chemical compounds comprise the R chain of all lengths, and the meaning is that the propanoic acid of promazine molecule can be replaced by acetic acid or butanoic acid.
In addition, one or more hydrogen atoms of R chain and two phenyl ring substituent group that can be defined here replaces.At last, these chemical compounds also comprise that azoles ring is replaced the isostere of the thiazole ring that obtains by sulfur.Isostere also can be replaced hydroxy-acid group by thio-acid (COSH).
As used herein, radicals R mainly is defined as the straight or branched that contains 2 carbon atoms, saturated or unsaturated fatty acids carbochain.Therefore, can expect n Propanoic acid, isopropyl acid and n Propanoic acid.In the embodiment that is closely related, radicals R is defined as the straight chain that contains 1 or 3 carbon atom or straight chain, saturated or unsaturated fatty acids base.Therefore, acetic acid, acrylic acid and butanoic acid are also expected.
Therefore, R can be selected from C
1-3Alkyl, C
2-3Thiazolinyl, C
2-3Alkynyl.Radicals R can be derived, and comprises that a hydrogen atom is by cyano group (CN), halogen (Br, Cl, F, I), hydroxyl (OH), amino (NH
2) and nitro (NO
2) replace.
Term R
1, R
2, R
3And R
4Be meant the substituent group of the phenyl ring that is defined as formula I, unsubstituted to define, the single replacement or dibasic phenyl ring, wherein R
1, R
2, R
3And R
4Can be identical or different.Phrase " the single replacement and di-substituted-phenyl " is defined as on a phenyl ring and uses R
1And/or R
3Replace one or two hydrogen atom on each phenyl ring, and use R independently
2And/or R
4Replace one or two hydrogen atom on second phenyl ring.
R
1And R
2Be defined as independently and be selected from hydrogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl, carbonyl (CO), aldehyde radical (CHO), carboxylic acid and derivant (COR thereof
5), halogen (Br, Cl, F, I), hydroxyl (OH), hydroxy derivatives (OR
1), amino (NH
2), primary amine groups (NHR '), secondary amine (NR ' R "), nitro (NO
2), sulfonyl (HSO
2) and sulfonyl-derivatives (R
7-SO
2), R
7Be meant and be selected from C
1-6Alkyl, aryl, NH
2, NHR ', NR ' R " substituent group.
R
3And R
4Expression is selected from following group independently: hydrogen, C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, C
1-6Alkoxyl, CO, CHO, CO-Me, CO-Et, COR
5, CN, halogen, OH, OR
1, NH
2, NHR ', NR ' R " and NO
2In preferred embodiment, R
3And R
4Expression is selected from hydrogen, C independently
1-6Alkyl, C
2-6The group of thiazolinyl.In the embodiment that is more preferably, R
3And R
4All be hydrogen.
Just as defined here, R
5Expression is selected from following group: hydroxyl (OH), hydroxy derivatives (OR
6) NH
2, NHR ', NR ' R ", SH or SR
6
R
6Be expressed as and be selected from C
1-6Alkyl, C
2-6The group of alkenyl and aryl.
R ' and R " are expressed as and are selected from C
1-6Alkyl and C
2-6The identical or different substituent group of thiazolinyl.
R
7Be expressed as and be selected from C
1-6Alkyl, aryl, NH
2, NHR ', NR ' R " substituent group.
Term " aryl " meaning is phenyl, the single replacement or di-substituted-phenyl, and one of them or two hydrogen atoms are selected from C
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, C
1-6Alkoxyl, carbonyl (CO), carbonyl derivative (COR '), aldehyde radical (CHO), carboxyl (COOH), carboxy derivatives (COOR '), cyano group (CN), halogen (Br, Cl, F, I), hydroxyl (OH), amino (NH
2), primary amine groups (NHR '), secondary amine (NR ' R ") and nitro (NO
2) substituent group replace.Preferably, term " aryl " is meant that phenyl or one of them hydrogen atom are selected from C
1-6Alkyl, C
2-6Alkenyl, C
1-6Alkoxyl, CO, CHO, CN, halogen, OH, NH
2And NO
2The monosubstituted phenyl that replaces of substituent group.
In the context of this article, C
1-3Alkyl is defined as the straight or branched of 1 to 3 carbon atom, and wherein carbochain is positioned at azoles ring and COOR
5Between the group, for example-CH
2-,-CH
2CH
2-and-CH
2CH
2CH
2-comprise its isomer.Similarly, C
2-3Alkenyl and C
2-3Alkynyl means the unsubstituted aliphatic carbon chain that contains 2 or 3 carbon atoms, for example-and CHCH-,-CC-,-CHCHCH
2-,-CCCH
2-, comprise its isomer.
C
1-6Alkyl is defined as saturated, the straight or branched alkyl that contains the indication carbon number, and for example, " 1-6 " meaning is to comprise its isomer from methyl up to the group of hexyl.For example, isobutenyl.If can use, alkyl can be annular, for example cyclohexyl.
C
2-6Thiazolinyl is defined as that to comprise carbon number be specified unsaturated straight or branched alkenyl, for example, and 1-or 2-acrylic, 1-, 2-or 3-cyclobutenyl and analog and its isomer.
C
2-3Alkynyl is defined as and contains the unsaturated of represented carbon number or side chain alkynyl group, as acetenyl, 1-or 1-propyl group, 1-, 2-or 3-butynyl etc. and their isomer.
C
1-6Alkoxyl means and comprises carbon number and mostly be 6 and preferably mostly be most 4 alkoxyl most, for example, and methoxyl group, ethyoxyl, propoxyl group etc.
Group C
1-6Alkyl, C
1-9Alkyl, C
2-6Alkenyl, C
2-9Alkenyl, C
2-6Alkynyl and C
2-9Alkynyl can be randomly by CN, CO, CHO, COR
5, halogen, OHOR ' NH
2, " and the nitro list replaces, wherein R for NHR ', NR ' R
5, R
6, R ' and R " definition as above.
Term halogen is defined as bromine, chlorine, fluorine and iodine.
Term " hydrogen " is defined as single hydrogen atom (H).
Chemical compound of the present invention can comprise asymmetric carbon atom, and therefore, the present invention also can comprise single optical activity form and raceme, well known to a person skilled in the art method preparation or separation.
As mentioned, in the preferred embodiment of the present invention, prepared ethanolamine salt with the promazine.
In other interesting embodiments, the promazine is to provide with the form according to the derivant of formula I.In the embodiment of one group of appointment A, R is-CH
2-.Be appointed as in the embodiment of B in another group, R is selected from C
2-alkyl, C
2-alkenyl and C
2-alkynyl, for example-CH
2CH
2-,-CHCH-,-CC-.In another group embodiment (being appointed as C), R is selected from C
3-alkyl, C
3-alkenyl and C
3-alkynyl, for example-CH
2CH
2CH
2-,-CHCHCH-,-CCC-and its how much and stereoisomer.In all these embodiments (A, B and C), the hydrogen atom of R can be by CN, halogen, OH, NH
2, NO
2Replace, preferably replaced by OH.In addition, in these embodiments, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R ' and R " as defined above.
In the more interesting embodiment of A, B and C (being appointed as AA, BA, CA), R
2And R
4Be independently selected from hydrogen, C
1-6The group of alkyl, halogen, OH and OR ', and R
2, R
3, R
4, R
5, R
6, R
7, R ' and R " as defined above.
In A, B and other more interesting embodiments of C (being set at AB, BB, CB), R
2And R
4Be hydrogen, and R
2, R
3, R
4, R
5, R
6, R
7, R ' and R " as defined above.
In the more interesting embodiment of A, AA, AB, B, BA, BB, C, CA and CB, under each group embodiment, radicals R
1, R
2, R
3, R
4, R
5, R
6, R
7, " as defined above, but term " aryl " meaning is meant phenyl or monosubstituted phenyl, and one of them hydrogen atom is selected from C for R ' and R
1-6Alkyl, C
2-6Alkenyl, C
2-6Alkynyl, C
1-6Alkoxyl, CN, CO, CHO, COOH, halogen, OH, NH
2, NHR ', NR ' R " and NO
2Substituent group replace.
In the more interesting embodiment of A, AA, AB, B, BA, BB, C, CA and CB, under each group embodiment, radicals R
1, R
2, R
3, R
4, R
5, R
6, R
7, " as defined above, but term " aryl " meaning is meant phenyl or monosubstituted phenyl, and one of them hydrogen atom is selected from C for R ' and R
1-6Alkyl, C
1-6Alkoxyl, CN, CHO, COOH, halogen, OH, NH
2, and NO
2Substituent group replace.
In the more interesting embodiment of A, AA, AB, B, BA, BB, C, CA and CB, radicals R 2 and R4 are defined as independently and are selected from hydrogen, C
1-6Alkyl, C
1-6Alkoxyl, CN, COOH, halogen, OH, NH
2, NHR ', NR ' R ", NO
2, HSO
2, R
7-SO
2Group, and R
1, R
2, R
3, R
4, R
5, R
6, R
7, R ' and R " defining as it under the embodiment separately.
In the more interesting embodiment of A, AA, AB, B, BA, BB, C, CA and CB, C
1-6Alkyl, C
1-9Alkyl, C
2-6Alkenyl, C
2-9Alkenyl, C
2-6Alkynyl and C
2-9Alkynyl can be randomly by CN, halogen, OH, OR ' NH
2, " and the nitro list replaces, and R for NHR ', NR ' R
1, R
2, R
3, R
4, R
5, R
6, R
7, R ' and R " defining as it under the embodiment separately.In these embodiments, term " aryl " meaning is meant phenyl or monosubstituted phenyl, and one of them hydrogen atom is selected from C
1-6Alkyl, C
1-6Alkoxyl, CN, CHO, COOH, halogen, OH, NH
2, and NO
2Substituent group replace.
Be to be understood that R is-CH in above all more interesting embodiments of mentioning
2-or C
2-alkyl or C
2-alkenyl.
The ethanolamine salt of promazine or its chemical compound that is closely related can pharmaceutically useful solvate forms provide as defined above, can be that hydrate (contains half mole of H in every molar salt
2O is until 10 moles of H
2O) or contain other recrystallisation solvents for example alcohol.
. the representative instance of Evil promazine related compound is:
4,5-diphenyl thiazol-2-yl-propanoic acid;
4,5-diphenyl azoles-2-base-acrylic acid;
4,5-diphenyl azoles-2-base-acetic acid;
4,5-two-(4 '-chlorphenyl)- azoles-2-base-propanoic acid;
4-(4 '-bromophenyl)-5-phenyl azoles-2-base-propanoic acid;
4-(4 '-hydroxy phenyl)-5-phenyl-2- azoles-propanoic acid;
4-(4 '-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-2- azoles propanoic acid;
4-(4 '-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-2- zole acetic acid;
4-(4-fluorophenyl)-5-[4-(methyl sulphonyl) phenyl]-2- azoles butanoic acid;
[4-(4-amino-sulfonyl phenyl)-5-[3,4-Dichlorobenzene base]]-2- zole acetic acid;
[4-(4-amino-sulfonyl phenyl)-5-[3-chloro-4-fluorophenyl]-2- zole acetic acid;
[4-(4-amino-sulfonyl phenyl)-5-[3-fluoro-4-methoxyphenyl]-2- zole acetic acid;
[4-(4-amino-sulfonyl phenyl)-5-(4-chlorphenyl)]-2- zole acetic acid;
[4-(4-amino-sulfonyl phenyl)-5-phenyl]-2- azoles butanoic acid;
[4-(4-amino-sulfonyl phenyl)-5-phenyl]-2- azoles propanoic acid;
[4-(4-amino-sulfonyl phenyl)-5-(3, the 4-difluorophenyl]-2- zole acetic acid;
[4-(4-methylamino sulfonyl phenyl)-5-phenyl]-2- zole acetic acid;
[4-(4-methylamino sulfonyl phenyl)-5-phenyl]-2- azoles butanoic acid;
[4-(4-methyl sulphonyl phenyl)-5-phenyl]-2- azoles lactic acid;
4-[(4-amino-sulfonyl phenyl)-5-(3-fluoro-4-methoxyphenyl)- azoles base]-alpha bromoisobutyric acid;
5-(4-nitrobenzophenone)-4-phenyl-2- azoles-2-base propanoic acid;
5-(4 '-fluorophenyl)-4-phenyl azoles-2-base-propanoic acid;
5-(4-hydroxy phenyl)-4-phenyl-2- azoles lactic acid;
5-(4-fluorophenyl)-4-[4-(methyl sulphonyl) phenyl]-2- azoles propanoic acid;
[5-(4-amino-sulfonyl phenyl)-4-(4-chlorphenyl)]-2- zole acetic acid;
[5-(4-amino-sulfonyl phenyl)-4-phenyl]-2- zole acetic acid;
[5-(4-amino-sulfonyl phenyl)-4-phenyl]-2- azoles butanoic acid;
[5-(4-amino-sulfonyl phenyl)-4-phenyl]-2- azoles propanoic acid;
[5-(4-amino-sulfonyl phenyl)-4-phenyl]-2- azoles propanoic acid.
Put it briefly, term " promazine or its are closely related chemical compound " meaning comprises the chemical compound according to formula I, and it comprises metabolite, its bioisostere thing and its derivant of promazine as defined above.The metabolite example of Evil promazine is the promazine that hydroxyl replaces, as describing among the US4659728, be called 5-(4-hydroxy phenyl)-4-phenyl-2- azoles propanoic acid, 4-(4-hydroxy phenyl)-5-phenyl-2- azoles propanoic acid and 4-(4-hydroxy phenyl)-5-(4-hydroxy phenyl)-2- azoles propanoic acid.
Should be understood that an interesting embodiment of the present invention comprises the dermatosis compositions, it comprises i) ethanolamine salt of promazine or its chemical compound that is closely related; The excipient that comprises acceptable batching of one or more skins or carrier ii) as mentioned above.
According to the advantage of ethanolamine salt, the further aspect of invention relates to the ethanolamine salt of the promazine or the chemical compound that is closely related.
promazine ethanolamine salt of the present invention can obtain by method known per se.
One aspect of the present invention relates to the favorable method of the salt of preparation invention, be included in both equal solubilized wherein solvent or mixed solvent in dissolving promazine and ethanolamine, mix each chemical compound solvent, then randomly by fling to solvent or randomly the method by cooling solution precipitate this salt.The yield that this method obtains is very high, and is easy to handle, and makes production cost low,
The suitable solvent that is used for production method of the present invention comprises: alcohols, and lower alcohol for example is as ethanol, ether is two lower alkyl ether for example, diethyl ether for example, cyclic ethers, for example dioxy alkane or oxolane, ketone is two lower alkyl ketone for example, for example, acetone, carboxylate is the low-grade alkyl carboxylate for example, ethyl acetate for example, amide is N for example, N-two lower alkyl amide, for example N, dinethylformamide, the sulfoxide class is two low alkyl group sulfoxide classes for example, for example, and dimethyl sulfoxide, or its mixture, or itself and the mixing of water.
Purposes and method
According to the present invention, dermatosis compositions of the present invention can be used in the treatment of inflammatory dermatosis, preferably at least a among protein tyrosine kinase SyK, protein tyrosine kinase ZAP-70 and the PDE-IV, and preferred at least two kinds of enzymes play the effect of regulating inflammatory skin.Usually this dermatosis of expection is because initial skin allergy causes, for example the I type allergy or the type iv allergic reaction of skin.
Correspondingly, another aspect of the present invention relates to dermatosis, is preferably the treatment of inflammatory dermatosis, and invention provides and be used for the treatment of the particularly method of eczema of inflammatory dermatosis, and dermatosis compositions of the present invention is granted in the part, skin place that is included in the patient.
The dermatosis compositions that relates to invention on the other hand is used for the purposes that the medication preparation of skin is coated in the part, for example is used for the treatment of dermopathic inflammation treatment, particularly eczema.
According to the present invention, the inflammatory dermatosis that treat comprises that at least a among protein tyrosine kinase SyK, protein tyrosine kinase ZAP-70 and the PDE-IV plays those of regulation and control inflammatory dermatosis effect.This inflammatory dermatosis of general expectation is because I type allergy or type iv allergic reaction.
Therefore, the inhibition method that relates in one aspect to one or more enzymes that are selected among protein tyrosine kinase SyK, protein tyrosine kinase ZAP-70 and/or the PDE-IV again of invention comprises that local application dermatosis compositions of the present invention is in described patient's skin.
The dermatosis compositions that the present invention relates to invention on the other hand is used for preparing that to be used for being locally applied to skin diagnosis be the purposes that the patient's of inflammatory dermatosis inflammatory Skin Cell is selected from the medication preparation that one or more enzymes among protein tyrosine kinase SyK, protein tyrosine kinase ZAP-70 and the PDE-IV suppress.
According to the following pharmacology principle of invention, the dermatosis compositions is applied to skin and alleviates effectively, removes or prevent patient's inflammation or special symptom that anaphylaxis causes or the anaphylaxis that is diagnosed as or suffers the patient of inflammatory dermatosis.For example, pruritus is the leading of most inflammatory diseasess and makes us least happy symptom.
Therefore, the importance of invention relate to scabies overworked and optional follow inflammatory dermatosis or by they other remarkable symptoms that cause, eczema particularly for example.
Correspondingly, the invention provides the patient who is used to alleviate, remove or prevent inflammatory dermatosis, for example particularly have eczema the patient be selected from one or more symptoms in pruritus, erythema and/or the fish scale skin.Method comprises that the dermatosis compositions of local application invention is in patient's skin.
The dermatosis compositions that the present invention relates to invention on the other hand is used to want to be locally applied to inflammatory dermatosis, for example particularly have eczema the patient be selected from that scabies is overworked, the purposes of the preparation of the medicine of alleviation, removal or the prevention of one or more symptoms of erythema and/or fish scale skin.
In the context of the present invention, term " inflammatory dermatosis " is meant that at least a or plurality of enzymes that wherein is selected from a group that is made up of protein tyrosine kinase SyK, protein tyrosine kinase ZAP-70 and/or PDE-IV enzyme plays the dermatosis of regulating and controlling effect in dermatosis.
Term " at least a enzyme that wherein is selected from a group that is made up of protein tyrosine kinase SyK, protein tyrosine kinase ZAP-70 and/or PDE-IV enzyme plays regulating and controlling effect in dermatosis " is the various dermatosiss that limit these enzyme overexpressions or the too much effect that measures.Following dermatosis is so dermopathic limiting examples: acne vulgaris, adult's eczema, alopecia, allergic contact dermatitis, allergic dermatitis, allergic dermatitis, the anaphylaxis contact eczema, dry eczema, atopic eczema, hand eczema, atoipc dermatitis, cancer, childhood eczema, the chronic dermatitis of hands or foot, contact dermatitis, contact eczema, dish type eczema, the sting inflammation, drug-induced property dermoreaction, dermatitis herpetiformis, discoid lupus erythematosus, eczema, epidermolysis bullosa, erythroderma, erythema nodosum, erythema multiforme, hand eczema, hands and foot skin inflammation, ichthyosis vulgaris, infantile eczema, keratoconus, keratosis pilaris, caterpillar dermatitis, lichen planus, nummular dermatitis, melanoma, over-treatment dermatitis, pemphigus, pemphigoid, photodermatosis, pityriasis rosea, PG, pompholyx, psoriasis, prurigo nodularis, acne erythematosa, scabies, seborrheic dermatitis, seborrhea, scleroderma, sjogren's disease, stasis dermatitis, SCLE, sunburn, the cutaneous manifestations of systemic lupus erythematosus, vitiligo and urticaria.
Term " treatment of inflammation in skin conditions " is will limit treatment described herein to reduce, remove or prevention is followed dermopathic or by it inflammation that causes.The character of inflammation as if edema, erythema and fish scale skin in the dermatosis, the present invention can reduce, removes or prevent.Term " is made and is used for the preparation that the part imposes on skin " and local application is the interchangeable term that will define, the preparation that comprises active component of the present invention ( promazine or its are closely related chemical compound) is made the dosage form that can be applied to patient's skin, and can cause active component to exist at local skin.Term " active component on skin part exist " is to comprise that active component is locally applied to skin, suppose that the whole body absorption of active component is very limited or does not have.Therefore, the active component of expection local application be less than 25% weight, for example be less than 20% weight, for example be less than 15% weight, for example be less than 10%, 8%, 5% and 3% weight, enter blood flow or in urine He in the feces, reclaim.The dosage form that is applied topically to skin usually comprises Emulsion (emulsifiable paste), ointment, gel, liniment, powder and solution.
Term " Skin Cell " is meant and comprises the cell that exists in horny layer, corium and the epidermis.When considering inflammatory dermatosis, these cells can comprise the cell of forming scytitis, for example T cell, macrophage, mastocyte, langerhans cell and neutrophilic granulocyte.
Term " skin " is meant and comprises and specifically comprise scalp, forehead, head, arm, lower limb, breast or the like by whole skin.Term " skin " also comprises each layer of skin, for example horny layer, epidermis and corium.
Term comprises any patient for " patient " of therapeutic purposes, but preferred, needs the patient of treatment inflammatory dermatosis.In order to prevent the patient of purpose, the patient is any patient, and preferably adventurous patient, or easily infected and develop into inflammatory dermatosis.The patient is typical animal, and more generally is mammal." mammal " used herein be meant and can be categorized as mammiferous any animal, comprises human body, domestic and farm-animals, zoo, sports ground or pet animals, for example Canis familiaris L., horse, cat, cattle or the like.Preferably, mammal is the people.Usually, the patient is diagnosed as or suffers various forms of eczemas, for example contact dermatitis, atoipc dermatitis and hand eczema.In preferred embodiment, the patient is people, Canis familiaris L., cat or horse.
Term used herein " treatment " (verb), " treatment " (gerund) and " treatment " (noun) are to comprise alleviating or elimination inflammatory dermatosis or its symptom of following, and alleviate or the removal cause of disease itself.Term used herein " prevention " (verb), " prevention " (gerund) and " prevention " (noun) are meant the generation that postpones or get rid of the inflammatory dermatosis symptom in advance, for example overworked recurrence of prevention of inflammation or scabies.
In the interesting embodiment of present invention, the treatment of inflammatory dermatosis or prevention comprise one or more in protein tyrosine kinase SyK in the inflammatory cell that suppresses described patient, protein tyrosine kinase ZAP-70 and/or the PDE-IV enzyme.Be familiar with as the inventor, the treatment of inflammatory dermatosis can be by suppressing a plurality of targets not just a target improve, reason for this reason, the improved embodiment of invention preferably relates to treating for skin disease, at least two kinds of the wherein above-mentioned enzymes that works, for example protein tyrosine kinase SyK and protein tyrosine kinase ZAP-70, protein tyrosine kinase SyK and PDE-IV enzyme, protein tyrosine kinase ZAP-70 and PDE-IV enzyme.
In order to be provided for dermatosis, the general treatment principle of eczema for example, all enzymes that can suppress above-mentioned enzyme are more favourable.
Interesting like this embodiment of the present invention relates to the treatment of inflammatory dermatosis, and its anaphylaxis is the part of its pathology, for example particularly IV type or type i allergic reaction.These dermopathic current interesting examples are eczema and dermatitis, for example contact dermatitis, atoipc dermatitis and hand eczema.
The meaning of speech " eczema " is some " the flowing over " that describes that above inflammatory changes.Use vocabulary eczema and dermatitis to be used interchangeably in some sense, because what take place on two kinds of patient's condition skin is similar inflammatory reaction.
Eczema is meant several situations of total skin surface changing pattern.Eczema occurs as scytitis, may occur that the skin scabies is overworked, fish scale skin and erythema.When it develops into long-term condition of illness (chronic eczema), it can cause pachyderma, fish scaleization, decortication, drying and change color.The eczema that is divided into many types according to the cause of disease, shape and the position of measles.Great majority relate to allergy or contact with the zest chemical substance.Some are followed or are caused by the following medical condition of shank fluid retention that causes.
Term " dermatitis " is the inflammation that definition influences the corium on epidermis and surface, and it is characterized in that the skin redness and the skin heating of feature.Some the time, dermatitis further is characterized as the edema that produces the Intradermal vesicles; Body fluid oozes out into surface, incrustation, fish scaleization and be full of cracks.
Eczema can be divided into endogenous eczema and exogenous eczema.Endogenous eczema comprises atoipc dermatitis at least, comprises its various forms (infantile eczema, childhood eczema, adult's eczema, keratosis pilaris, ichthyosis simplex), pompholyx, dish type eczema and nummular eczema.Exogenous eczema comprises allergic contact dermatitis, the basic dermatitis of zest, hand eczema at least.In addition, term " eczema " also can comprise stasis dermatitis, dry eczema, lichen simplex chronicus, psoriasis, seborrheic dermatitis and seborrhea.
Therefore, in the current interesting embodiment of the present invention, dermatosis is meant various types of eczemas, comprises following disease at least: atoipc dermatitis, hand eczema, infantile eczema, child's hand eczema, adult's eczema, keratosis pilaris, ichthyosis simplex, hands and foot's dermatitis, keratoconus, pompholyx, dish type eczema, nummular eczema, allergic contact dermatitis, irritant contact dermatitis, over-treatment dermatitis, dry eczema, stasis dermatitis, lichen simplex chronicus, prurigo nodularis, seborrheic dermatitis, seborrhea and psoriasis.
In preferred embodiment of the present invention, dermatosis is meant atoipc dermatitis, hand eczema, infantile eczema, childhood eczema, adult's eczema, keratosis pilaris, ichthyosis simplex, hands and foot's dermatitis, keratoconus, pompholyx, dish type eczema, nummular eczema, allergic contact dermatitis, irritant contact dermatitis, over-treatment dermatitis and hand eczema.
Pharmacology's principle below according to the present invention, the method for invention and purposes comprise be diagnosed with or suffer or the dangerous patient's who occurs as inflammatory dermatosis inflammatory Skin Cell in be selected from one or more inhibition in one group of enzyme that protein tyrosine kinase SyK, protein tyrosine kinase ZAP-70 and PDE-IV enzyme form.
According to the present invention, also can use the dermatosis preparation of compositions to be used for the treatment of the medicine of skin scabies disease.That is to say that invention also is specially the method that is used for the treatment of skin pruritus, comprise to its patient's dermal administration dermatosis compositions of the present invention of needs.
Term " pruritus " (" pruritus ") and term " send out overworked " (" itch ") can exchange, and be defined as on record being accompanied by and want the state of feeling of grabbing.Different with the overworked state of feeling of following of scabies with pain, although pruritus and pain can be produced by various chemistry, machinery, heat or electricity irritation.It is overworked with different being (1) of pain to itch, and unlike pain, can only be caused by skin surface, mucosa and conjunctiva, and (2) is overworked can not take place simultaneously at identical skin area usually with pain.For example, histamine being coated skin produces overworked but not pain.As if in addition, overworked and pain use different pharmacology principles to treat, and is overworked insensitive to the treatment of opium and nonsteroid anti-inflammatory drugs (NSAID), but they are effective to pain therapy.At last, itching occurs over just skin, and pain is to be caused by DEEP STRUCTURE, and itches and can local betide the skin area of various good qualifications, for example ankle, wrist, lip portion, hand, skin of chest reach similarly, and perhaps extensive pruritus is not limited to indivedual positions of skin.
Pruritus is mentioned the cardinal symptom of eczema more than normally, and the inventor confirmed can eliminate fully this symptom of the patient that suffers above-mentioned various types of eczemas, particularly contact dermatitis and atoipc dermatitis.In addition, follow that the scabies of sting is overworked also can be alleviated fully after part coating dermatosis compositions.
No matter how are their attribute, inflammation and anaphylactoid degree, general said pruritus can be accompanied by a series of dermatosiss, is the part of pathology.These dermopathic limiting examples are: acne vulgaris, adult's eczema, alopecia, allergic contact dermatitis, allergic dermatitis, the anaphylaxis contact eczema, dry eczema, atopic eczema, hand eczema, atoipc dermatitis, cancer, childhood eczema, chronic hands or foot dermatitis, contact dermatitis, contact eczema, dish type eczema, the sting inflammation, drug-induced property dermoreaction, dermatitis herpetiformis, discoid lupus erythematosus, eczema, epidermolysis bullosa, erythroderma, erythema nodosum, erythema multiforme, hand eczema, hands and foot's eczema, ichthyosis vulgaris, infantile eczema, keratoconus, keratosis pilaris, lichen simplex chronicus, lichen planus, nummular dermatitis, melanoma, the over-treatment dermatitis, pemphigus, pemphigoid, photodermatosis, pityriasis rosea, PG, pompholyx, psoriasis, prurigo nodularis, acne erythematosa, scabies, seborrheic dermatitis, seborrhea, scleroderma, sjogren's disease, stasis dermatitis, SCLE, sunburn, the epidermis performance of systemic lupus erythematosus, vitiligo and urticaria.
The overworked Dermatology cause of disease of scabies is usually directed to skin allergy or atopic reaction, the I type of skin or IV type atopic reaction.Therefore, overworked atoipc dermatitis and all kinds (atoipc dermatitis, hand eczema, infantile eczema, childhood eczema, adult's eczema, keratosis pilaris, ichthyosis vulgaris, hands and foot dermatitis, keratoconus, pompholyx, dish type eczema, nummular eczema and the reaction of anaphylaxis contact, for example contact dermatitis and all kinds thereof (allergic contact dermatitis, irritant contact dermatitis and over-treatment dermatitis) of being accompanied by of scabies.
Usually, scabies is overworked is the unhappy symptom of sting, bullous pemphigoid, T-cell lymphoma,cutaneous, dermatitis herpetiformis, folliculitis, lichen planus, lichen simplex chronicus, pediculosis (lice infestation), prurigo nodularis, psoriasis, scabies, sunburn, urticaria and dry eczema.
Therefore, of the present invention one preferred embodiment in, the treatment of skin pruritus is followed or caused by following situation: insect bite (for example insect bite inflammation), insecticide sting, bullous pemphigoid, T-cell lymphoma,cutaneous, dermatitis herpetiformis, folliculitis, lichen planus, lichen simplex chronicus, pediculosis (lice infestation), prurigo nodularis, scabies, sunburn and urticaria.
Other embodiments refer to the treatment or the prevention of eczema and dermatitis, relate to anaphylaxis atypically, for example comprise dry eczema, stasis dermatitis, psoriasis, seborrheic dermatitis and the seborrhea of pruritus.
In another embodiment of the present invention, the symptom of eczema is as follows:
1) is exposed to heat, for example causes cholinergic urticaria (to the response of hot bath, fever and exercise) and summer rash (miliaria alba);
2) occupational exposes, for example cement in potassium dichromate, adhesive and the rubber in glass fibre, glycerol list mercaptoacetate, methyl methacrylate (for example, plexiglas), cement and the dyestuff and Colophonium or the epoxy resin in dyestuff, adhesive and the rubber.
3) systemic administration for example antimicrobial drug, aspirin, the vitamin B as fluconazol (Diflucan), itraconazole (Sporanox), ketoconazole (Nizoral) comprise nicotiamide.Drug anaphylaxis to rifampicin (Rifadin), vancomycin (Vancocin), nitrate (food preservative), quinidine and anesthetis (scabies that causes face, cervical region and breast top is overworked);
4) be exposed to water, for example cause aquagenic pruritus (follow polycythemia vera, contact pruritus in the 15min with any water), cholinergic urticaria (to the response of hot water), polycythemia vera, swimmer's pruritus (fresh water swim back 7 days eruptions).
Therefore, in other related embodiment of the present invention, pruritus supporter or by systemic administration be exposed to water and cause.
In addition, pruritus can be caused by following general disease.The undistinguishable laceration of skin of the general disease of wide region can cause generalized pruritus.
Therefore, the present invention treats specificly and follows or by being selected from diabetes, hyperthyroidism, hypothyroidism, disease of parathyroid glands, carcinoid syndrome, hepatopathy, conceived, intrahepatic cholestasis, obstructive jaundice (outside biliary tract or liver), primary biliary cirrhosis, drug-induced cholestasis, chronic renal failure, uremia, erythrocytosis, asiderosis, Hokdkin disease, mycosis fungoides, lymphosarcoma, chronic leukemia, myleomatosis,; paraprotein mass formed by blood stasis; mast cell disease; HIV; the assorted auspicious syndrome (t cell lymphoma) of match; leukemia; multiple myeloma; Walden is executed special Ai Mushi macroglobulinemia; mycosis fungoides; optimum gammopathy; systemic mastocytosis; hematology and lymphadenosis obstacle; the metastasis of cancer; the adenocarcinoma of various organs and squamous cell cancer; cerebroma; the overworked treatment of scabies that the treatment of multiple sclerosis and cerebroma general disease causes.
In addition, the invention provides the dermatosis compositions that comprises in order to the treating skin disease medicine of the Gai Jin Evil promazine or the compound effect that is closely related.
The representative instance for the treatment of skin disease medicine is hydryllin, antibacterial, antifungal, overworked dose of anti-scabies, antiviral agent, antiparasitic, steroid hormone anti-inflammatory agent, on-steroidal hormone anti-inflammatory agent, anesthetis, keratolytic agent, free radical resisting medicine, metal-chelator, antidandruff agent, anti-ordinary medicine for treating comedo, P material or Kallidin I or O-synthase inhibitor.
The present invention further describes by embodiment.
Embodiment 1 has described the exemplary formulations of dermatosis compositions of water soluble salt (ethanolamine salt) form of promazine and the forming process of promazine water soluble salt.Embodiment 2,3 and 4 has confirmed that topical application promazine (with the form of water soluble salt) follows beneficial effect in contact dermatitis, atoipc dermatitis, insect bite inflammation and the psoriasic pruritus respectively in treatment.
Embodiment 5 has confirmed the new pharmacological property of promazine, and the parfenac that only suppresses the PDE-IV enzyme then can not confirm these character.
Embodiment 6 has confirmed to give the remarkable effect of promazine in prevention and therapeutic test contact dermatitis in the relevant mode of dosage, and than observing the stronger of effect at betamethasone 17-valerate.
Embodiment 7 has confirmed that the edema of promazine in can the inhibition test model of contact dermatitis forms, but parfenac then do not observe this effect.
Embodiment 8 confirms that the promazine is safe when being applied topically to skin, and can not cause sensitized reaction, phototoxicity or acute skin irritation when using high dose.
Embodiment 9 confirms that the Emulsion (embodiment 1) of promazine even the concentration continuous application of working as with 5% still had the advantages of good skin toleration in 28 days.
Embodiment 10 and 11 relates to the clinical evaluation that the promazine acts in treating hand eczema and contact dermatitis respectively.
Embodiment
Embodiment 1
The ethanolamine salt of promazine prepares according to following method easily.
10.0g promazine is dissolved in the 230ml ethyl acetate under mild heat.2.3g ethanolamine be dissolved in the 30ml ethyl acetate, and under agitation add in the promazine solution.After several seconds, observe significant precipitation.Solution cooling 60min filters and collects salt and dry.
Medicinal composition for part use according to the present invention is that the aqueous phase that 2.5% or 5.0% Evil promazine ethanolamine salt is dissolved in by the topical creams of following composition the (w/w) is prepared from:
Hydrophobic phase
Tween 80
TM(polyoxyethylene sorbitan monoleate) 1%
Span 60
TM(sorbitan ester type emulsifying agent) 2%
The triglyceride of medium chain (MCT) 20%
White vaseline 10%
Lightweight paraffin oil 10%
Spermol 4%
Aqueous favoring
promazine ethanolamine salt 2.5%
Water 42.5%
Xanthan gum 0.5%
Glycerol 2%
Propylene glycol 2%
Benzyl alcohol 0.5%
At first lipophilic phase and part aqueous favoring (xanthan gum and water) are heated to 70 ℃ during preparation Emulsion, mix.The aqueous favoring of remainder is heated to 50 ℃ and adding, then cooling under agitation.
Embodiment 2
71 years old elderly men patient suffers the irritant contact dermatitis puzzlement more than 5 years always.Dermatitis is usually located at shank.The symptom of dermatitis is erythema, fish scale skin and significant pruritus.
In in the past 5 years, this patient with powerful local steroid hormone treatment, has good relatively therapeutic effect to erythema, but pruritus is not had shortterm effect always.During the dermatitis state of an illness aggravation of accompanied by intense pruritus, the patient begins the 1 described ethanolamine salt Emulsion treatment that contains 5.0% promazine with embodiment.Patient's pruritus behind the Emulsion 20min of Application Example 1 is just alleviated immediately and fully.In order to keep curative effect, the patient used Emulsion 3 times first day every day, after use 2 times every days in 2 weeks, erythema and fish scale skin gradually reduce.Behind 14 days of treatment, erythema does not occur yet again.This shows not only at pruritus, also to failing to understand that disease has amazing good efficacy.
Three and half women suffered from atoipc dermatitis at least 2 years.Facial and more than 30% health dermatitis is arranged, feature is erythema and extensive pruritus.The patient is closed with hydrocortisone ointment or pyrrole periodically and is not taken charge of the emulsifiable paste treatment, and these treatments have certain curative effect to erythema, but pruritus is not had short run effect.
During dermatitis was followed the overworked aggravation of extensive scabies, the patient treated with the embodiment 1 described 2.5% De Evil promazine ethanolamine salt Emulsion that contains.After using Emulsion 15min, patient's pruritus is promptly alleviated fully, continues 8h.In next all time, repetitive therapy when needs, is observed the overworked recovery fully of scabies at every day 1-3 time at every turn.Between the one-period of treatment, also observe erythema and significantly improve, showing not only also has amazing good efficacy to not clear disease to scratching where it itches.
Embodiment 3
37 years old women, the front once suffered the insect bite inflammation, and skin pruritus, edema are cardinal symptoms, treat with the embodiment 1 described Emulsion that contains 2.5% promazine ethanolamine salt behind mosquito bite.This treatment scabies after using Emulsion 20min is overworked to be alleviated fully, and edema overnight disappears.On the contrary, the overworked and edema of scabies can not be reduced satisfactorily with the hydrocortisone ointment treatment in the front behind mosquito bite.
Embodiment 4
32 years old male patient suffers plaque psoriasis more than 2 years.The state of an illness is obvious at ancon, and erythema, fish scale skin and remarkable pruritus are arranged.During patient's symptom aggravation, begun for the time one week treatment, application rights requires twice of 1 described Emulsion every day that contains 5.0% promazine ethanolamine salt.Patient's scabies after treatment for the first time is overworked to be obtained immediately and significant the alleviation.The effect of this level is all kept in the treatment of whole week.In addition, observing erythema and fish scale skin has significantly and alleviates.This show again not only overworked to scabies, also not clear disease is had amazing good efficacy.
Embodiment 5
The inhibitory action of phosphodiesterase PDEIV, protein tyrosine kinase SYK and protein tyrosine kinase ZA70 (ZAP-70) is measured the antiinflammatory potentiality of promazine by estimating the promazine.Enzymatic determination carries out at MSD Pharma Services.
Below for to the inhibitory action of following enzyme being the concentration (IC of 50% promazine (with the form of ethanolamine salt)
50):
Enzyme MSD Pharma Services service-number: IC
50
Phosphodiesterase PDEIV 154,000 22 μ M
Protein tyrosine kinase SYK 155,761 28 μ M
Protein tyrosine kinase ZA70 (ZAP-70 155,987 38 μ M
Comparatively speaking, parfenac only shows the inhibitory action to the PDE-IV enzyme.
Embodiment 6
The antiinflammatory action Screening test of oxazolone inducing mouse dropsy of ear
The anti-inflammatory activity of promazine induces the mice of ear's inflammation to estimate by the Shi Yong Evil of Ju portion promazine Yu Yong azolactone.Screening technique is normally used anti-inflammatory drug screening and the method, the particularly inflammation about seeing in the contact dermatitis estimated of being used for.Betamethasone-17 valerate is as positive control drug.
The promazine with the form of ethanolamine salt with the amount local application of acetone diluted to 250-1000 μ g/ ear.Betamethasone is with the consumption local application of 20 μ g/ ears.Betamethasone is to use with 0.1% commercially available celestone-V (Celeston valerate ).
Determination step
The 0th day
All groups all use the 1.6% concentration De azolactone ethanol of 20 μ l, and (96% (w/v) solution is on left ear and auris dextra.
The 7th day
Measure the ear thickness of all mices with ammeter on the 7th day time left side and right side.All groups all use the 1.6% concentration De azolactone ethanol of 20 μ l, and (96% (w/v) solution excites left ear and auris dextra.Use excipient (acetone) or tried thing solution before the Zai azolactone excites and behind the 20min.
The 8th day
24h after azolactone excites, it is thick to measure all mouse ear with ammeter.
Group, dosage and number of animals are as follows:
| Group | Medicine | Dosage | Number of animals |
| 1 | Excipient, acetone | - | 1-10 |
| 2 | promazine ethanolamine | 1000 μ g/ ears | 11-20 |
| 3 | promazine ethanolamine | 500 μ g/ ears | 21-30 |
| 4 | promazine ethanolamine | 250 μ g/ ears | 31-40 |
| 5 | Betamethasone 17-valerate | 20 μ g/ ears | 41-50 |
Calculate the average thickness and the standard deviation of ear.Calculated the 7th day and the 8th day ear thickness between difference to calculate the bulge of the ear situation.The inhibition percentage rate of bulge of the ear is to estimate with the difference of representing with percent between the 1st group average bulge of the ear and the 2nd group to the 5th group.
Statistics
Bulge of the ear difference between vehicle-treated group and other groups uses the analysis-Mann-Whitney U of nonparametric statistical method to check significance.The significance level that requires is p＜0.05.
The result
The inflammation of oxazolone provocative test causing ear, vehicle-treated group behind 24h significantly because bulge of the ear and be shiny red.Tried thing and prevented this reaction to a certain extent.Any thing that tried is not all observed side reaction.
Bulge of the ear
The various concentration of being tried thing have suppressed bulge of the ear, and are as shown in the table:
| Medicine | Dosage | Bulge of the ear suppression ratio (%) | Mann-Whitney U check |
| Excipient, acetone | - | - | - |
| promazine ethanolamine | 1000 μ g/ ears | 95 | P＜0.001 |
| promazine ethanolamine | 500 μ g/ ears | 77 | P＜0.001 |
| promazine ethanolamine | 250 μ g/ ears | 53 | P＜0.001 |
| Betamethasone 17-valerate | 20 μ g/ ears | 66 | P＜0.001 |
Conclusion
The promazine ethanolamine salt of invention has shown that dose-effect relationship reaches the ten minutes significant inhibitory effect to bulge of the ear.Be better than the inhibitory action that the betamethasone 17-valerate of clinical using dosage level obtains significantly in the observed inhibitory action of maximum dose level.
These data show that promazine ethanolamine salt of the present invention has strong inhibitory action to contact dermatitis.
Embodiment 7
The comparison of the inductive mouse ear edema test of promazine and parfenac Dui azolactone.
The anti-inflammatory activity of promazine and parfenac contrast are used and are estimated with test method identical described in the embodiment 6.Two kinds are tried thing all with the dosage of 500 μ g/ ears and be dissolved in 96% the ethanol and use.Betamethasone is usually used with the consumption of 20 μ g/ ears as positive control.
The result:
The promazine has shown the statistics significant inhibitory effect to the formation of dropsy of ear, but parfenac not to the formation of dropsy of ear without any inhibitory action.
Embodiment 8
Acute skin irritation
Water Jiang Evil promazine sample with the dilution of the form of ethanolamine salt make two concentration (2.5% and 5%, by weight), and test its acute skin irritation.
Method:
The promazine is applied to the unmarred skin area of right abdomen of every animal with the dosage of 0.5ml.For guaranteeing patch in position, snarl with the operation adhesive tape.
With untreated left abdomen zone in contrast.
According to following grading scale, estimate behind the 1h and remove patch after the dermoreaction of 24,48 and 72h.Grading scale:
Erythema (0: no erythema, 1: slight erythema (almost just can discern), 2: clear and definite erythema, 3: moderate is to the severe erythema, 4: have eschar to form the severe erythema (purple) of (degree of depth damage), erythema can not classification).
Edema (0: no edema, 1: very slight (almost just can discern) edema, 2: Mild edema (profile can clearly define), 3: intermediate edema (thickness), 4: serious edema (thickness is greater than 1mm, and surface area surpasses uses the zone)
The result:
promazine (2.5% weight) is not observed dermoreaction (erythema and edema) in each observing time. promazine (5% weight) is only observed slight edema at processing region when 1h.Be reflected between second day and the 3rd day of test and all reverse.
Phototoxicity:
Having carried out Phototoxicity experiment estimates Cavia porcellus and is exposed to dermoreaction under the ultra-vioket radiation.
Method:
promazine (providing with ethanolamine salt) dilute with water is prepared into the solution that contains promazine salt 2.5% or 5% weight.Solution is applied to the right pawl side of every Cavia porcellus with the dosage of 0.5ml.After handling 30min, animal is carried out ultra-vioket radiation (UV-B at first, ultraviolet-A) then.
Animal is used non-Erythema Dose (M.N.E.D) the UV-A 7000J/cm of irradiation source VLX 3W (Biotronic, Vilbert Lourmat) with maximum
2And UV-B150mJ/cm
2Shine.
The result:
Dermoreaction (erythema and edema) carries out macroscopic evaluation at postradiation 24h and 48h.With the reacting phase ratio that reference position (8-methoxy Psoralen: positive control, the negative contrast of product itself) observed, do not observe because of phototoxic macroscopical dermoreaction.Yin Ci ， Evil promazine is not phototoxic.
The sensitization of skin effect
According to Magnusson and Kligman method (J.Invest.Dermatol.1969.52,268-276) and abide by O.E.C.D. guideline on the 17th N July in 1992
0B.6 test method during 406 and 96/54 E.E.C instructs is carried out sensitization of skin effect test.
Method:
promazine (providing with ethanolamine salt) dilute with water is prepared into the solution of Han Evil promazine salt 2.5% weight.
The albefaction Cavia porcellus of Dunkin-Hartley kind system is exposed at least 5 days environmental adaptation after date is tried thing.
2.5%, 1.25%, 0.625%, 0.3125%, 0.1562% and 0.078% measure the not downright bad concentration of maximum (M.N.N.C.) by intradermal injection with what normal saline dilution formed:
Use the thing that tried of 2.5%, 1.25%, 0.625%, 0.3125% series concentration that normal saline dilution forms measures in advance-maximum non-irritating concentration (pre-M.N.N.C.) by 24h under impermeable plastic wound dressing.
Maximum non-irritating concentration (M.N.N.C.) is the induction period by the intradermal injection normal saline of initial foundation, and the local application distilled water is measured after 18 days convalescent period.In the stimulating phase that is tried thing 24h under impermeable plastic wound dressing, tried thing and be applied on the skin of albefaction Cavia porcellus with 2.5%, 1.25%, 0.625%, 0.3125% series concentration with the normal saline dilution.
The result:
Remove the viewing duration of impermeable plastic wound dressing (challenge phase) the animal of treatment group, do not record because of macroscopical dermoreaction hypersensitive.The negative control treated animal does not record not tolerance response of skin.Therefore, Wei Jian Evil promazine ethanolamine salt causes sensitivity response.
Embodiment 9
Continuous 28 days of not damage field every animal application dosage every day 2ml of rabbit, measure respectively and contain 2.5% and 5% skin-tolerant of heavily measuring the Emulsion (embodiment 1) of Evil promazine (form of ethanolamine salt).
During 28 days, just used every day and checked macroscopical skin conditions behind the Emulsion.Evaluating skin erythema, edema, drying, elasticity and skin fold thickness.
The result who obtains has slight erythema and edema after being presented at some days of processing, but all reverses the 19th day and the 10th day respectively.When handling beginning, be also noted that xerosis cutis, and also observe slight skin fold and thicken.Researcher is reached a conclusion, and after Emulsion was used with 2.5% and 5% concentration in 28 days repeatedly, presents the advantages of good skin toleration.
Embodiment 10
In 2 treatment groups that chronic hand eczema arranged with blind method with being subjected to test preparation or excipient every day to carry out the test in 4 weeks twice, measure promazine or its related compound effect at treatment and prevention hand eczema.The half patient will with the promazine of 2.5% concentration for example the cream preparation of promazine ethanolamine salt handle, and second half is handled with emulsifiable paste matrix.After handling for the first time preceding 1 day (baseline) and processing, the 1st, 2,3 and 4 weeks carried out clinical evaluation.The patient comprehensively estimates the patient answering the problem of relevant department of dermatologry quality of life index in addition.The dosage of using is about 25mg every day, and accumulated dose is about 700mg.
Carry out clinical evaluation according to HECSI marking system objective and that accurately estimate hand eczema seriousness.Consider the scope and the intensity of disease simultaneously.Every hands is divided into 5 zones (finger tip, finger (except that the tip), palm, the back of the hand portion and wrist).Every part in these zones is given a mark to clinical signs such as erythema, infiltration/formation pimple, vesicle, be full of cracks, fish scale skin and edema with 4 fens systems.0=does not have skin to be changed, and 1=is slight, 2=moderate, 3=severe
The scope that each position (two handss are overall) provides clinical sign promptly infects the percent of area: 0=0%, 1=1-25%, 2=26-50%, 3=51-75%, 4=76-100%
The mark of each position range that finally provides and the intensity of each Clinical symptoms multiply each other, (erythema (E), infiltration/formation pimple (I), vesicle (V), be full of cracks (F), fish scale skin (S) and edema (O).
Embodiment 11
promazine or its related compound are used for the treatment of and prevent the effect of contact dermatitis, can be at random, use the experimenter group with famous nickel anaphylaxis and healthy skin to carry out clinical evaluation in the contrast double-blind method test.According to standard step, each experimenter person specifies at least 3 zones of the healthy skin that is positioned at the back, and using nickel sulfate II vaseline stimulates and cause the allergy in this zone, and uses and be subjected to the reagent test effect.Being subjected to reagent can be that concentration is for example emulsifiable paste of promazine ethanolamine of 2.5% or 5% promazine, and use 15mg and 40mg respectively at pilot region every day respectively.Positive control can use 0.1% betamethasone 17-valerate emulsifiable paste, and using daily dose is about 0.6mg betamethasone/sky.In addition, also use the matrix treatments of non-activity composition.At the 1st day, be subjected to reagent, positive control and substrate all to use the about 200 μ l of each test preparation, for example by using special test chamber ((Finn Chambers , Epitest Ltd.Oy, Finland, internal diameter 18mm in respectively being subjected to examination zone (=pretreatment).
In the date subsequently, handle the experimental pretreatment zone with the nickel sulfate II vaseline of 2 kinds of concentration and come the induced hypersensitivity reaction or handle 1h with vaseline.Use for example Finn Chambers (R) of less test chamber, Epitest Ltd.Oy, Finland, the 12mm internal diameter is handled at the nickel sulfate II vaseline that variable concentrations is carried out than the zonule in the middle part in the experimental pretreatment zone that limits.Use about 30 μ l nickel sulfate II vaseline or vaseline.After this induces, will be to estimating with the effect that is subjected to test preparation to carry out Prevention Processing.The 4th day and the 7th day of test, pilot region will be with the method for describing in the 1st day with being handled 1 time every day by test preparation, with the therapeutic effect of evaluation to contact dermatitis.With the degree of TEWL measurement epidermis barrier injury, measure the redness of skin with determination of colority, and measure the clinical skin that marking is estimated.The file of taking a picture in addition.Carry out clinical evaluation according to following marking.
0=is reactionless, and discontinuous pimple is hardened, had to 1=erythema but do not have scleroma,, 3=erythema, scleroma, pimple, vesicle, the blister of 4=erythema, scleroma, fusion at the 2=erythema.
Transepidermal water loss (evaporimetry) is the non-damage method of widely used evaluating skin damage.The epidermis of healthy intact skin is to make the minimized barrier layer of outside loss of moist.Any damage of this barrier layer can cause the increase of water permeability, causes the increase of corresponding TEWL.And sour nickel II vaseline is handled and inductive anaphylaxis patient's damage test zone, can expect its TEWL value increase.
Claims (58)
1. dermatosis compositions, it comprises:
With the promazine that form was provided or the closely-related chemical compound of water soluble salt and ii) contain acceptable composition on one or more dermatological or the excipient of carrier, wherein, described closely-related chemical compound is defined by general formula I:
In the formula, R is selected from C
1-3Alkyl, C
2-3Thiazolinyl and C
2-3Alkynyl, R are randomly by using CN, halogen, OH, NH
2, and NO
2Replace a hydrogen atom and derived;
R
1And R
2Expression is selected from following group independently: hydrogen, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Alkoxyl, CO, CHO, CO-Me, CO-Et, CN, halogen, OH, OR ', NH
2, NHR ', NR ' R ", NO
2, HSO
2And R
7-SO
2
R
3And R
4Expression is selected from hydrogen, C independently
1-6Alkyl and C
2-6The group of thiazolinyl;
R
5Expression is selected from OH, OR
6, NH
2, NHR ', NR ' R ", SH and SR
6Group;
R
6Expression is selected from C
1-6Alkyl, C
2-6The group of thiazolinyl and aryl;
R
7Expression is selected from C
1-6Alkyl, aryl, NH
2, NHR ' and NR ' R " group;
" expression is selected from C for R ' and R
1-6Alkyl, C
2-6The identical or different group of thiazolinyl; And
" aryl " is meant that phenyl or one of them hydrogen atom are selected from the monosubstituted phenyl that following substituent group replaces: C
1-6Alkyl, C
2-6Thiazolinyl, C
1-6Alkoxyl, CO, CHO, CN, halogen, OH, NH
2And NO
2
And wherein the oxygen in the azoles ring is randomly replaced so that thiazole ring to be provided by sulfur (S).
2. compositions according to claim 1, wherein, described salt is to be selected from following base addition salts: Li
+, Na
+, K
+, Ca
++, Mg
++, Cu
+, Zn
+, Mn
+Alkyl benzene amine, ammonia, the 2-ethylaminoethanol, aminopyrimidine, aminopyridine, arginine, benethamine, Benzathini Benzylpenicilinum, betanin, caffeine, choline, deanol, diethanolamine, diethylamine, 2-diethylaminoethanol, the 2-dimethylaminoethanol, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glycosamine, aminoglucose, glycinol, Compocillin, imidazoles, 2-aminopropane., meglumine, methyl Portugal glycosamine, morpholine, piperazine, piperidines, procaine, purine, pyrrolidine, theobromine, thiamine, triethanolamine, triethylamine, trimethylamine, tripropyl amine (TPA), trimethylol aminomethane, spermidine, glycine, alanine, the figured silk fabrics amino acid, leucine, isoleucine, nor-leucine, tyrosine, cystine, cysteine, methionine, proline, hydroxyproline, histidine, ornithine, lysine, arginine, serine, threonine, phenylalanine and guanidinesalt.
3. compositions according to claim 1, wherein, described salt is the base addition salts that forms, wherein said alkali is pK
aOrganic amine in 8～12 scopes.
4. compositions according to claim 1, wherein, described salt is the 2-ethylaminoethanol salt of promazine or the chemical compound that is closely related.
5. according to each described compositions in the aforementioned claim, wherein, the amount of the described water soluble salt of promazine or the chemical compound that is closely related is in the 0.5wt%～10wt% scope of said composition weight.
6. according to each described compositions in the claim 1～4, wherein, the amount of the described water soluble salt of promazine or the chemical compound that is closely related is about 2.5wt%.
7. according to each described compositions of claim 1～4, wherein, the amount of the described water soluble salt of promazine or the chemical compound that is closely related is about 5wt%.
8. according to each described compositions in the aforementioned claim, wherein, pH value is in 6.5～7.8 scope.
9. according to each described compositions in the claim 1～7, wherein, aqueous-favoring pH value is in 6.5～7.8 scopes.
10. according to each described compositions in the aforementioned claim, wherein, described excipient further comprises the hydrophobic phase that contains lipid component and/or oils composition of 30wt% at least.
11. compositions according to claim 10, wherein, described lipid component is selected from the group of following composition: the sorbitan ester of the sorbitan ester of Cera Flava, paraffin, vaseline, triglyceride, fatty acid, solid polyethylene glycol and fatty acid and the condensation product of oxirane.
12. compositions according to claim 10, wherein, the oils composition is selected from the group of following composition: almond oil, Oleum Ricini, cocoa butter, Oleum Cocois, Semen Maydis oil, Oleum Gossypii semen, Semen Lini oil, olive oil, Petiolus Trachycarpi oil, Oleum Arachidis hypogaeae semen, opium poppy seed oil, Oleum Brassicae campestris, Oleum sesami, soybean oil, sunflower oil and Oleum Camelliae, mineral oil, fatty oil, liquid paraffin, mineral oil, isopropyl myristate, Cera Flava, Oleum Gossypii semen, cetostearyl alcohol, lanoline, paraffinum molle alba, yellow soft paraffin, canola oil, spermol (hexadecanol), Oleum Arachidis hypogaeae semen, oleic acid, isopropyl palmitate, Oleum Ricini, stearyl alcohol, Jojoba oil, stearic acid and silicone oil.
13. according to each described compositions in the aforementioned claim, wherein, described compositions is made into Emulsion, gel, solution, liniment, ointment, spray, aerosol or powder.
14. according to each described compositions in the claim 1～12, wherein, described excipient is an Emulsion.
15. compositions according to claim 14, wherein, described Emulsion comprises nonionic emulsifier.
16. compositions according to claim 15, wherein, described nonionic emulsifier is selected from the group of following composition: polyol ester comprises the ester of ethylene glycol and glycerol; The derivant of sorbitan comprises the sorbitan ester and the polyoxyethylene sorbitan ester of fatty acid; Polyoxyethylene ester; Polyoxyethylene ether, poloxamer, nonylplenyl ether.
17. compositions according to claim 15, wherein, described nonionic emulsifier is selected from the sorbitan ester of fatty acid and the group that the polyoxyethylene sorbitan ester is formed.
18. compositions according to claim 15, wherein, described excipient comprises the mutually hydrophobic of the aqueous favoring of 30wt%-80wt% and 20wt%-70wt%, and described aqueous favoring comprises water, thickening agent and the optional hydrophilic solvent of 80～95wt%; The described hydrophobic mixture of lipid component, nonionic emulsifier or nonionic emulsifier, optional one or more oils compositions and one or more optional lipophilic solvents of comprising mutually.
19. according to each described compositions in the aforementioned claim, wherein, the described chemical compound that is closely related is selected from down group chemical compound and pharmaceutically acceptable salt thereof:
4,5-diphenyl thiazol-2-yl-propanoic acid;
4,5-diphenyl azoles-2-base-acrylic acid;
4,5-diphenyl azoles-2-base-acetic acid;
4,5-two-(4 '-chlorphenyl)- azoles-2-base-propanoic acid;
4-(4 '-bromophenyl)-5-phenyl azoles-2-base-propanoic acid;
4-(4-hydroxy phenyl)-5-phenyl-2- azoles propanoic acid;
4-(4-fluorophenyl)-5-[4-(mesyl) phenyl]-2- azoles propanoic acid;
4-(4-fluorophenyl)-5-[4-(mesyl) phenyl]-2- zole acetic acid;
4-(4-fluorophenyl)-5-[4-(mesyl) phenyl]-2- azoles butanoic acid;
[4-(4-amino-sulfonyl phenyl)-5-(3, the 4-Dichlorobenzene base)]-2- zole acetic acid;
[4-(4-amino-sulfonyl phenyl)-5-(3-chloro-4-fluorophenyl)]-2- zole acetic acid;
[4-(4-amino-sulfonyl phenyl)-5-(3-fluoro-4-methoxyphenyl)]-2- zole acetic acid;
[4-(4-amino-sulfonyl phenyl)-5-(4-chlorphenyl)]-2- zole acetic acid;
[4-(4-amino-sulfonyl phenyl)-5-phenyl]-2- azoles butanoic acid;
[4-(4-amino-sulfonyl phenyl)-5-phenyl]-2- azoles propanoic acid;
[4-(4-amino-sulfonyl phenyl)-5-(3, the 4-difluorophenyl)]-2- zole acetic acid;
[4-(4-amino-sulfonyl phenyl)-5-phenyl]-2- zole acetic acid;
[4-(4-methyl sulphonyl phenyl)-5-phenyl]-2- azoles butanoic acid;
[4-(4-methyl sulphonyl phenyl)-5-phenyl]-2- azoles propanoic acid;
[4-(4-amino-sulfonyl phenyl)-5-(3-fluoro-4-methoxyphenyl)-2- azoles base]-alpha bromoisobutyric acid;
5-(4-nitrobenzophenone)-4-phenyl-2- azoles-2-base propanoic acid;
5-(4 '-fluorophenyl)-4-phenyl azoles-2-base-propanoic acid;
5-(4-hydroxy phenyl)-4-phenyl-2- azoles propanoic acid;
5-(4-fluorophenyl)-4-[4-(methyl sulphonyl) phenyl]-2- azoles propanoic acid;
[5-(4-amino-sulfonyl phenyl)-4-(4-chlorphenyl)]-2- zole acetic acid;
[5-(4-amino-sulfonyl phenyl)-4-phenyl]-2- zole acetic acid;
[5-(4-amino-sulfonyl phenyl)-4-phenyl]-2- azoles butanoic acid;
[5-(4-amino-sulfonyl phenyl)-4-phenyl]-2- azoles propanoic acid;
[5-(4-amino-sulfonyl phenyl)-4-phenyl]-2- azoles propanoic acid.
20.2-ethylaminoethanol is with the salt of promazine or derivatives thereof, wherein, described its derivant is defined by the general formula I in the claim 1, wherein R, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R ', R ", " aryl " and bioisostere thing thereof be defined as claim 1.
21. be used for preparing the application of the medicine of the inflammatory dermatosis for the treatment of the patient as each defined dermatological composition in the claim 1～19.
22. application according to claim 21, wherein, described inflammatory dermatosis is relevant with anaphylaxis in the skin, is perhaps caused by the anaphylaxis in the skin.
23. application according to claim 21, wherein, described inflammatory dermatosis is relevant with I type allergy or type iv allergic reaction in the skin, is perhaps caused by I type allergy or type iv allergic reaction in the skin.
24. application according to claim 21, wherein, described inflammatory dermatosis is selected from the group of following composition: acne vulgaris, adult's eczema, alopecia, allergic contact dermatitis, allergic dermatitis, the anaphylaxis contact eczema, dry eczema, atopic eczema, hand eczema, atoipc dermatitis, cancer, childhood eczema, the chronic dermatitis of hands or foot, contact dermatitis, contact eczema, dish type eczema, the sting inflammation, drug-induced dermoreaction, dermatitis herpetiformis, discoid lupus erythematosus, eczema, epidermolysis bullosa, erythroderma, erythema nodosum, erythema multiforme, hand eczema, hands and foot's dermatitis, ichthyosis simplex, infantile eczema, keratoconus, keratosis pilaris, lichen simplex chronicus, lichen planus, nummular dermatitis, melanoma, the over-treatment dermatitis, pemphigus, pemphigoid, photodermatosis, pityriasis rosea, PG, pompholyx, psoriasis, prurigo nodularis, acne erythematosa, scabies, seborrheic dermatitis, seborrhea, scleroderma, sjogren's disease, stasis dermatitis, SCLE, sunburn, the cutaneous manifestations of systemic lupus erythematosus, vitiligo and urticaria.
25. application according to claim 21, wherein, described inflammatory dermatosis is an eczema.
26. application according to claim 25, wherein, eczema is selected from the group of following composition: atoipc dermatitis, hand eczema, infantile eczema, childhood eczema, adult's eczema, keratosis pilaris, ichthyosis simplex, hands and foot dermatitis, keratoconus, pompholyx, dish type eczema, nummular eczema, allergic contact dermatitis, irritant contact dermatitis, over-treatment dermatitis, hand eczema, dry eczema, stasis dermatitis, lichen simplex chronicus, seborrheic dermatitis, seborrhea and psoriasis.
27. be used for preparing the application of medicine of the pruritus of treatment patient skin as the dermatological composition that each limited among the claim 1-19.
28. application according to claim 27, wherein, pruritus is relevant with dermatosis, is perhaps caused by dermatosis.
29. application according to claim 27, wherein, pruritus is relevant with allergy in the skin, is perhaps caused by skin hypersensitivity.
30. application according to claim 27, wherein, pruritus is relevant with IV type or type i allergic reaction in the skin, is perhaps caused by IV type or type i allergic reaction in the skin.
31. application according to claim 27, wherein, scabies is overworked relevant with dermatosis or cause that by dermatosis described dermatosis is selected from the group of following composition: acne vulgaris, adult's eczema, alopecia, allergic contact dermatitis, allergic dermatitis, the anaphylaxis contact eczema, dry eczema, atopic eczema, hand eczema, atoipc dermatitis, cancer, childhood eczema, the chronic dermatitis of hands or foot, contact dermatitis, contact eczema, dish type eczema, the sting inflammation, drug-induced dermoreaction, dermatitis herpetiformis, discoid lupus erythematosus, eczema, epidermolysis bullosa, erythroderma, erythema nodosum, erythema multiforme, hand eczema, hands and foot's dermatitis, ichthyosis simplex, infantile eczema, keratoconus, keratosis pilaris, lichen simplex chronicus, lichen planus, nummular dermatitis, melanoma, the over-treatment dermatitis, pemphigus, pemphigoid, photodermatosis, pityriasis rosea, PG, pompholyx, psoriasis, prurigo nodularis, acne erythematosa, scabies, seborrheic dermatitis, seborrhea, scleroderma, sjogren's disease, stasis dermatitis, SCLE, sunburn, the cutaneous manifestations of systemic lupus erythematosus, vitiligo and urticaria.
32. application according to claim 27, wherein, pruritus is relevant with eczema, is perhaps caused by eczema.
33. application according to claim 32, wherein, eczema is selected from the group of following composition: atoipc dermatitis, hand eczema, infantile eczema, childhood eczema, adult's eczema, keratosis pilaris, ichthyosis simplex, hands and foot dermatitis, keratoconus, pompholyx, dish type eczema, nummular eczema, allergic contact dermatitis, zest allergic dermatitis, over-treatment dermatitis.
34. application according to claim 27, wherein, pruritus is relevant with dry eczema, pruritus senilis, stasis dermatitis, psoriasis, seborrheic dermatitis and seborrhea or caused by them.
35. application according to claim 27, wherein, pruritus is relevant with dermatosis or cause that by dermatosis described dermatosis is selected from the group of following composition: sting inflammation, bullous pemphigoid, T-cell lymphoma,cutaneous, dermatitis herpetiformis, folliculitis, lichen planus, lichen simplex chronicus, pediculosis, prurigo nodularis, scabies, sunburn and urticaria.
36. application according to claim 27, wherein, the overworked and systemic medication of scabies is relevant, is perhaps caused by systemic medication.
37. application according to claim 27, wherein, scabies overworked be exposed to that water closes or cause by being exposed to water.
38. application according to claim 27, wherein, scabies is overworked relevant with systemic disease or cause that by systemic disease described systemic disease is selected from the group of following composition: diabetes, hyperthyroidism, hypothyroidism, the parathyroid gland imbalance, the carcinoid tumor syndrome, hepatopathy, gestation, intrahepatic cholestasis, obstructive jaundice (in biliary tract or outside the liver), primary biliary cirrhosis, drug-induced cholestasis, chronic renal failure, uremia, erythrocytosis, asiderosis, Hokdkin disease, mycosis fungoides, lymphosarcoma, chronic leukemia, myleomatosis; paraprotein mass formed by blood stasis; mast cell disease; HIV; the assorted auspicious syndrome (t cell lymphoma) of match; leukemia; multiple myeloma; Walden is executed special Ai Mushi macroglobulinemia; mycosis fungoides; optimum gammopathy; systemic mastocytosis; blood and lymphadenosis obstacle; the metastasis of cancer; the adenocarcinoma of various organs and squamous cell cancer; brain tumor; multiple sclerosis and cerebroma.
39. according to each described application in the claim 21～38, wherein, described patient is people, Canis familiaris L., cat or horse.
40. be used for the treatment of the method for inflammatory dermatosis, wherein, this method comprises and will deliver medicine to the patient's who needs said composition skin as the dermatosis compositions that each limited in the claim 1～19.
41. according to the described method of claim 40, wherein, described inflammatory dermatosis reacts relevant with the hypersensitivity in the skin, is perhaps caused by the reaction of the hypersensitivity in the skin.
42. according to the described method of claim 40, wherein, described inflammatory dermatosis is relevant with I type or type iv allergic reaction in the skin, is perhaps caused by I type or type iv allergic reaction in the skin.
43. according to the described method of claim 40, wherein, described inflammatory dermatosis is selected from the group of following composition: acne vulgaris, adult's eczema, alopecia, allergic contact dermatitis, allergic dermatitis, the anaphylaxis contact eczema, dry eczema, atopic eczema, hand eczema, atoipc dermatitis, cancer, childhood eczema, the chronic dermatitis of hands or foot, contact dermatitis, contact eczema, dish type eczema, the sting inflammation, drug-induced dermoreaction, dermatitis herpetiformis, discoid lupus erythematosus, eczema, epidermolysis bullosa, erythroderma, erythema nodosum, erythema multiforme, hand eczema, hands and foot's dermatitis, ichthyosis simplex, infantile eczema, keratoconus, keratosis pilaris, lichen simplex chronicus, lichen planus, nummular dermatitis, melanoma, the over-treatment dermatitis, pemphigus, pemphigoid, photodermatosis, pityriasis rosea, Pyoderma gangrenosum, pompholyx, psoriasis, prurigo nodularis, acne erythematosa, scabies, seborrheic dermatitis, seborrhea, scleroderma, sjogren's disease, stasis dermatitis, SCLE, sunburn, the cutaneous manifestations of systemic lupus erythematosus, vitiligo and urticaria.
44. according to the described method of claim 40, wherein, described inflammatory dermatosis is an eczema.
45. according to the described method of claim 44, wherein, eczema is selected from the following resistance of forming: atoipc dermatitis, hand eczema, infantile eczema, childhood eczema, adult's eczema, keratosis pilaris, ichthyosis simplex, hands and foot dermatitis, keratoconus, pompholyx, dish type eczema, nummular eczema, allergic contact dermatitis, irritant contact dermatitis, over-treatment dermatitis, hand eczema, dry eczema, stasis dermatitis, lichen simplex chronicus, seborrheic dermatitis, seborrhea and psoriasis.
46. be used for the treatment of the overworked method of scabies in the skin, wherein, this method comprises and will deliver medicine to the patient's who needs said composition skin as the dermatological composition that each limited in the claim 1～19.
47. according to the described method of claim 46, wherein, pruritus is relevant with dermatosis or caused by dermatosis.
48. according to the described method of claim 46, wherein, pruritus is relevant with skin allergy or caused by skin allergy.
49. according to the described method of claim 46, wherein, pruritus companion is relevant with I type or type iv allergic reaction in the skin, is perhaps caused by I type or type iv allergic reaction in the skin.
50. according to the described method of claim 46, wherein, pruritus is relevant with dermatosis or cause that by dermatosis described dermatosis is selected from the resistance of following composition: acne vulgaris, adult's eczema, alopecia, allergic contact dermatitis, allergic dermatitis, the anaphylaxis contact eczema, dry eczema, atopic eczema, hand eczema, atoipc dermatitis, cancer, childhood eczema, the chronic dermatitis of hands or foot, contact dermatitis, contact eczema, dish type eczema, the sting inflammation, drug-induced dermoreaction, dermatitis herpetiformis, discoid lupus erythematosus, eczema, epidermolysis bullosa, erythroderma, erythema nodosum, erythema multiforme, hand eczema, hands and foot's dermatitis, ichthyosis simplex, infantile eczema, keratoconus, keratosis pilaris, lichen simplex chronicus, lichen planus, nummular dermatitis, melanoma, the over-treatment dermatitis, pemphigus, pemphigoid, photodermatosis, pityriasis rosea, Pyoderma gangrenosum, pompholyx, psoriasis, prurigo nodularis, acne erythematosa, scabies, seborrheic dermatitis, seborrhea, scleroderma, sjogren's disease, stasis dermatitis, SCLE, sunburn, the cutaneous manifestations of systemic lupus erythematosus, vitiligo and urticaria.
51. according to the described method of claim 46, wherein, pruritus is relevant with eczema or caused by eczema.
52. according to the described method of claim 51, wherein, eczema is selected from the group of following composition: atoipc dermatitis, hand eczema, infantile eczema, childhood eczema, adult's eczema, keratosis pilaris, ichthyosis simplex, hands and foot dermatitis, keratoconus, pompholyx, dish type eczema, nummular eczema, allergic contact dermatitis, irritant contact dermatitis, over-treatment dermatitis.
53. according to the described method of claim 46, wherein, scabies is overworked relevant with seborrhea with dry eczema, senile pruritus, stasis dermatitis, psoriasis, seborrheic dermatitis, is perhaps caused by them.
54. according to the described method of claim 46, wherein, scabies is overworked relevant with dermatosis or cause that by dermatosis described dermatosis is selected from the group of following composition: sting inflammation, bullous pemphigoid, cutaneous T cell lymphoma, dermatitis herpetiformis, folliculitis, lichen planus, lichen simplex chronicus, pediculosis, prurigo nodularis, scabies, sunburn and urticaria.
55. according to the described method of claim 46, wherein, pruritus is relevant with systemic medication or caused by systemic medication.
56. according to the described method of claim 46, wherein, pruritus be exposed to that water closes or cause by being exposed to water.
57. according to the described method of claim 46, wherein, scabies is overworked relevant with systemic disease, and described systemic disease is selected from the group of following composition: diabetes, hyperthyroidism, hypothyroidism, the parathyroid gland imbalance, carcinoid syndrome, hepatopathy, gestation, intrahepatic cholestasis, obstructive jaundice (outside biliary tract or liver), primary biliary cirrhosis, drug-induced cholestasis, chronic renal failure, uremia, erythrocytosis, asiderosis, Hokdkin disease, mycosis fungoides, lymphosarcoma, chronic leukemia, myleomatosis; paraprotein mass formed by blood stasis; mast cell disease; HIV; the assorted auspicious syndrome (t cell lymphoma) of match; leukemia; multiple myeloma; Walden is executed special Ai Mushi macroglobulinemia; mycosis fungoides; optimum gammopathy; systemic mastocytosis; hematology and lymphadenosis obstacle; the metastasis of cancer; the adenocarcinoma of various organs and squamous cell cancer; brain tumor; multiple sclerosis and cerebroma.
58. according to claim 40 or 46 described methods, wherein, described patient is people, Canis familiaris L., cat or horse.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DKPA200500438 | 2005-03-30 | ||
| DKPA200500437 | 2005-03-30 | ||
| DKPA200500437 | 2005-03-30 | ||
| US60/694,774 | 2005-06-27 | ||
| DKPA200500948 | 2005-06-27 | ||
| DKPA200500949 | 2005-06-27 | ||
| US60/695,040 | 2005-06-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101189009A true CN101189009A (en) | 2008-05-28 |
Family
ID=39481044
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800109440A Pending CN101203222A (en) | 2005-03-30 | 2006-03-30 | Dermatological compositions and salts for the treatment of dermatological diseases |
| CNA2006800109385A Pending CN101189009A (en) | 2005-03-30 | 2006-03-30 | Dermatological compositions and salts for the treatment of dermatological diseases |
| CNA2006800108236A Pending CN101189008A (en) | 2005-03-30 | 2006-03-30 | Oxaprozin or closely related compound for the treatment and prevention of diseases |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800109440A Pending CN101203222A (en) | 2005-03-30 | 2006-03-30 | Dermatological compositions and salts for the treatment of dermatological diseases |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800108236A Pending CN101189008A (en) | 2005-03-30 | 2006-03-30 | Oxaprozin or closely related compound for the treatment and prevention of diseases |
Country Status (2)
| Country | Link |
|---|---|
| CN (3) | CN101203222A (en) |
| ZA (3) | ZA200708065B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109477102A (en) * | 2015-02-13 | 2019-03-15 | 菲克特生物科学股份有限公司 | Nucleic acid product and its method of administration |
-
2006
- 2006-03-30 CN CNA2006800109440A patent/CN101203222A/en active Pending
- 2006-03-30 CN CNA2006800109385A patent/CN101189009A/en active Pending
- 2006-03-30 CN CNA2006800108236A patent/CN101189008A/en active Pending
-
2007
- 2007-09-19 ZA ZA200708065A patent/ZA200708065B/en unknown
- 2007-09-27 ZA ZA200708279A patent/ZA200708279B/en unknown
- 2007-09-27 ZA ZA200708278A patent/ZA200708278B/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109477102A (en) * | 2015-02-13 | 2019-03-15 | 菲克特生物科学股份有限公司 | Nucleic acid product and its method of administration |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101203222A (en) | 2008-06-18 |
| ZA200708278B (en) | 2008-11-26 |
| ZA200708065B (en) | 2008-10-29 |
| ZA200708279B (en) | 2009-09-30 |
| CN101189008A (en) | 2008-05-28 |
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