CN103209691B - Alpha adrenergic receptor agonists is used for the purposes preventing or treating in the medicine of cutaneous tumor in preparation - Google Patents
Alpha adrenergic receptor agonists is used for the purposes preventing or treating in the medicine of cutaneous tumor in preparation Download PDFInfo
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- CN103209691B CN103209691B CN201180042175.3A CN201180042175A CN103209691B CN 103209691 B CN103209691 B CN 103209691B CN 201180042175 A CN201180042175 A CN 201180042175A CN 103209691 B CN103209691 B CN 103209691B
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Abstract
The present invention relates to for preventing cutaneous tumor in experimenter to be formed or method, compositions and the product of cutaneous tumor development present in suppression experimenter.Described method relates to using the compositions containing alpha 2-adrenoceptor agonist such as brimonidine to experimenter.
Description
Background technology
UV radiation has proved to be a series of skin injury (from premature aging to the U.S. most common skin in all cancers
Cancer) reason.Skin carcinoma is a kind of pernicious epidermis/corium tumor, say, that it has uncontrolled growth, invades
Enter tissue around, and if treat not in time, whole health may be spread to, transfer also finally kills host.Substrate is thin
Born of the same parents and squamous cell carcinoma account for the great majority of skin cancer cases.The first cause dead because of skin carcinoma is malignant melanoma.According to estimating
Meter, the U.S. population of 20% will develop into skin carcinoma in its life cycle.
In addition to skin carcinoma, there is also benign skin tumour and front pernicious (pre-malignant) cutaneous tumor.Optimum
Cutaneous tumor will not change into skin carcinoma.The example of benign skin tumour includes, but not limited to nevus, seborrheic keratosis, skin
Labelling (acrochordons) (also referred to as skin tag), epidermoid cyst or sebaceous cyst and dermatofibroma.Front pernicious skin
Tumor is an airtight agglomerate, and it does not invade surrounding tissue, is the most not yet defined as carcinous (cancerous).But,
As time goes on, they can dedifferente and become pernicious.A kind of common form of front malignant cancer is cancer in situ, wherein
Described cell is tumor (neoplastic) and continues breeding, but without departing from its airtight space.
Cutaneous tumor can be treated by various Therapeutic Method, as surgical resection or via excision, cold therapy,
Electric cautery, chemical burns and radiation or the destruction of external cytotoxic drug.If Malignant skin tumor is sent out in early days
Existing, treatment is typically effective.But, described treatment still has invasive.
Alpha-2-adrenergic agonist components is a kind of medicine optionally stimulating alpha-2 adrenoceptor.Described α-adrenal gland
Element can have two subclass α 1 and α 2 by receptor.Complete selectivity between receptor stimulating agent seldom can realize, and some medicines have portion
Component selections.
Alpha adrenergic receptor agonists has been used for treating some symptoms, including hypertension, congestive heart failure,
Angina pectoris, muscle spasm, glaucoma, diarrhoea, and be used for suppressing Opiate withdrawal symptoms (J.P.Heible and
R.R.Ruffolo,Therapeutic Applications of Agents Interacting with a-
Adrenoceptors,p.180-206in Progress in Basic and Clinical Pharmacology Vol.8,
P.Lomax and E.S.Vesell Ed.,Karger,1991)。
It is reported, use alpha adrenergic receptor agonists (such as, clonidine, oxymetazoline, MPV-1440
Deng) activation and human tumor epithelium breast cancer cell line or the increasing of mouse mammary tumor cells system of alpha-adrenergic receptor
Strong propagation is relevant.See, e.g., V á zquez et al., Cancer Chemother Pharmacol.2006Jul;58(l):
50-61.Epub2005Nov15;With Bruzzone et al., Br J Pharmacol.2008Oct;155(4):494-
504.Epub2008Jul7.According to another report, α 2-adrenoceptor antagonists Yohimbine suppresses the propagation of pancreatic cancer cell and lures
Leading its apoptosis, this shows that Yohimbine can act as the cancer therapy drug for cancer of pancreas.Shen et al., World J
Gastroenterol.2008Apr21;14(15): 2358-63.According to another report, the stimulation suppression of α 2-adrenoreceptor
Cancer of biliary duct, the cancer of bile duct.Kanno et al., Hepatology, 2002, Volume35, Issue6 (p1329-1340).At present
Document, so rather than widely, really show that alpha-adrenergic receptor can play a role in tumor is formed, and this
The stimulation of a little receptors or antagonism can result in growth or the suppression of the enhancing of tumor tissues, and this depends on that bottom cell is sub-
Type (underlying cellular sub-type).
Needing the method and composition of the Noninvasive of improvement, it will prevent formation or the minimizing of cutaneous tumor effectively
The development of cutaneous tumor, particularly by the cutaneous tumor that UV is radiation-induced.The present invention relates to method and the combination of such improvement
Thing.
Invention summary
It has surprisingly been found that use the treatment of alpha 2-adrenoceptor agonist to already lead to be exposed in UV radiation
Subject inner skin swell the notable decline of neoplastic notable delay and cutaneous tumor growth.
In a general aspect, embodiment of the present invention relate to a kind of subject inner skin tumour progression of preventing
Method.The method comprises uses a kind of compositions to experimenter, and its alpha 2-adrenoceptor comprising therapeutically effective amount is exciting
Agent and pharmaceutically acceptable carrier.
In another general aspect, embodiment of the present invention relate to a kind of skin suppressing the interior existence of subject and swell
The method of tumor progress, it comprises uses a kind of compositions to experimenter, and described compositions comprises α 2 adrenal gland of therapeutically effective amount
Element can receptor stimulating agent and pharmaceutically acceptable carrier.
In another general aspect, embodiment of the present invention relate to a kind of induced skin death of neoplastic cells or suppression
The method of Skin Tumor Cells growth, it comprises makes a kind of compositions of Skin Tumor Cells contact, and described compositions comprises respectively
Be enough to the alpha 2-adrenoceptor agonist of inducing death of neoplastic cells or the amount that suppresses it to grow.
In another general aspect, embodiment of the present invention relate to a kind of for protecting the skin of experimenter, lip
Or scalp is with the method for the damage effect of antagonism UV-radiation.Described method comprises uses a kind of compositions to experimenter, and it comprises
The alpha 2-adrenoceptor agonist of safe and effective amount.
In another general aspect, embodiment of the present invention relate to a kind of for making the tanned side of subjects skin
Method, wherein said method comprises uses a kind of compositions to experimenter, and α 2 adrenergic that it comprises safe and effective amount is subject to
Body agonist.
Another aspect of the present invention relates to a kind of cosmetics, and it comprises:
(1) topical composition of the alpha 2-adrenoceptor agonist of safe and effective amount is comprised;With
(2) about described topical composition being applied on the skin of experimenter, lip or scalp with antagonism UV-radiation
The explanation of damage effect.
Other another aspect of the present invention relates to a kind of for making the tanned topical composition of subjects skin, its bag
Contain:
(1) the alpha 2-adrenoceptor agonist of safe and effective amount and;
(2) suntan of safe dose.
(detailed description of the present invention and preferred embodiment thereof and claims are included in following disclosure
Book) in, other aspects, features and advantages of the present invention will be apparent from.
Accompanying drawing is sketched
Fig. 1. the group of tumor incidence compares
Detailed Description Of The Invention
Background technology and entire description are quoted or describes various publication, article and patent;By quoting it
Each piece in these lists of references is expressly incorporated herein by the mode of full content.For having included literary composition in this manual
The purpose of the discussion of shelves, behavior, material, equipment, article etc. is to provide the context for the present invention.Such discussion is not
It is to recognize that for arbitrarily disclosed or claimed invention, arbitrarily or all of these factors taken together constitutes prior art
A part.
Unless otherwise defined, all technology used herein and scientific terminology have institute usual with those skilled in the art
The identical implication of implication understood.Otherwise, some term used herein has the implication specified in the description.By drawing
It is incorporated in literary composition with by all patents cited herein, disclosed patent application and publication, as the most fully illustrated
Typically.It must be noted that as herein and used in appended claims, singulative " (a) ", " one (an) " and
" described (the) " includes plural number object of reference, unless otherwise expressly specified in context.
As used herein, " alpha 2-adrenoceptor agonist " or " α 2 adrenoreceptor agonists " refers to oneization
Compound, it is bound to and stimulates alpha-2 adrenoceptor subclass α2。
As used herein, the title of compound is intended to the isomeric forms (example all that may be present of compound
As, optical isomer, enantiomer, diastereomer, racemic modification or raceme mixture), ester, prodrug, metabolism
Thing form or pharmaceutically acceptable salt.Such as, " brimonidine " can be compound (the bromo-quinoxalin-6-yl of 5-)-(4,5-
Dihydro-1H-imidazoles-2-base)-amine, and any pharmaceutically acceptable salt of compound, such as brimonidine tartrate.
As used herein, phrase " pharmaceutically acceptable salt " refers to the salt of those compounds interested, its for
It is safe and efficient for the external of mammal and there is required biological activity.Pharmaceutically acceptable salt includes depositing
The acidity being in specific compound or the salt of basic group.Pharmaceutically acceptable acid-addition salts includes, but not limited to hydrochloric acid
Salt, hydrobromate, hydriodate, nitrate, sulfate, disulfate, phosphate, acid phosphate .gamma.-pyridinecarboxylic acid salt, acetic acid
Salt, lactate, salicylate, citrate, tartrate, pantothenate, biatrate, Ascorbate, succinate, horse
Come hydrochlorate, gentisinate(without middle translation), fumarate, gluconate, glucaronate(is without middle translation), sucrose acid
Salt, formates, benzoate, glutamate, Glu, mesylate, esilate, benzene sulfonate, tosilate and pamoic acid
Salt (that is, 1,1'-methylene-bis--(2-hydroxyl-3-naphthoic acid)).Some compound used in the present invention can be with various
Aminoacid forms pharmaceutically acceptable salt.The suitably salt of alkali includes, but not limited to aluminium salt, calcium salt, lithium salts, magnesium salt, potassium
Salt, sodium salt, zinc salt and diethanolamine salt.Summary about pharmaceutically acceptable salt sees BERGE et al.,
66J.PHARM.SCI.1-19 (1977), is incorporated into herein by quoting
As used herein, term " hydrate " refers to compound (or its pharmaceutically acceptable salt) interested, its
Farther include to be bound to its stoichiometry or the water of non-stoichiometry amount by non-covalent intermolecular forces.
In one embodiment of the invention, described alpha 2-adrenoceptor agonist include, but not limited to 5
The alpha 2-adrenoceptor agonist disclosed in U.S. Patent application US20050276830 announced is complete by quoting it
Portion's content is incorporated into herein.
The representative alpha 2-adrenoceptor agonist that can use in the present invention includes, but not limited in Table 1
Those listed.
Table 1: representative alpha 2-adrenoceptor agonist
Most preferably alpha 2-adrenoceptor agonist is brimonidine, (the bromo-quinoxalin-6-yl of 5-)-(4,5-bis-
Hydrogen-1H-imidazoles-2-base)-amine and pharmaceutically acceptable salt thereof, such as brimonidine tartrate.
Other example of the alpha 2-adrenoceptor agonist that can use in the present invention includes, but not limited to the right side
Rotation medetomidine, medetomidine, romifidine, clonidine, detomidine, lofexidine, xylazine, tizanidine, guanidine method
Pungent and Amitraz.
According to the present invention, alpha 2-adrenoceptor agonist can pass through external, epidermis (epicutaneous), warp
Skin, the approach subcutaneously or intramuscularly delivered are applied to experimenter.In a preferred embodiment, by subcutaneous delivery or skin
On applications, alpha 2-adrenoceptor agonist is delivered to tumor sites or the skin area damaged by UV.
As used herein, " applications (topical application) " and " applications (topically
Applying) " refer to directly smear or spread on the skin needing treatment, such as, by using hands or administrator
(applicator).
As used herein, " subcutaneous delivery " refers to Direct precipitation in skin or below skin, or at subcutaneous fat
In Ceng, it can subcutaneous be passed by using such as one pin of administrator, pin matrix tube more than a group (multi-needle array), one
The delivery system based on energy that send, a kind of can subcutaneous delivery delivery system based on pressure, one can subcutaneous delivery
Needleless (needleless) delivery system, or similar medical apparatus and instruments.
As used herein, " cutaneous tumor " includes skin carcinoma, benign skin tumour and front Malignant skin tumor.Skin carcinoma
Include, but not limited to basal cell carcinoma and squamous cell carcinoma and malignant melanoma.The example of benign skin tumour includes,
But being not limited to, nevus, seborrheic keratosis, skin labelling (also referred to as skin tag), epidermoid cyst or sebaceous cyst and skin are fine
Dimension tumor.Front Malignant skin tumor includes, but are not limited to cancer in situ.
One embodiment of the invention relates to a kind of prevention subject inner skin and swells neoplastic method, its comprise to
Experimenter uses a kind of compositions, alpha 2-adrenoceptor agonist that described compositions comprises effective dose and pharmaceutically can connecing
The carrier being subject to.
As used herein, " effective dose of alpha 2-adrenoceptor agonist " refers to be enough to prevent or delay (suckling
Animals or humans) consumption of the alpha 2-adrenoceptor agonist that cutaneous tumor is formed in tissue system.
As used herein, term " experimenter " refers to quilt or has been applied the chemical combination according to embodiment of the present invention
Thing or any mammal of external preparation, preferably people.
As used herein, term " compositions " is intended to the product of the special component comprising specified quantitative, and directly
Or indirectly it is derived from any product of the combination of the special component of specified quantitative.
As used herein, " prevention (prevention) " or " prevention (preventing) " refers to obtain cutaneous tumor
The reduction of risk.In the preference pattern of an embodiment, the specific compound as preventive measure is applied to tool
There is the experimenter of cutaneous tumor susceptibility, even if the symptom of this disease does not exists or minimizes.
As it is used herein, " pharmaceutically acceptable carrier " refers to be suitable for present invention application and the most inappropriate
Toxicity, incompatibility, unstability, zest, the carrier of allergy etc..It is described that this term is not intended to limit it
Composition.
Another embodiment of the invention relates to a kind of method suppressing the interior cutaneous tumor progress existed of subject,
It comprises uses a kind of compositions to experimenter, and described compositions comprises the alpha 2-adrenoceptor agonist of therapeutically effective amount
With pharmaceutically acceptable carrier.
As used herein, " therapeutically effective amount of alpha 2-adrenoceptor agonist " refers to be enough to prevent or delay
The consumption of the alpha 2-adrenoceptor agonist of cutaneous tumor progress in (mammal or the mankind) tissue system.
It would be recognized by those skilled in the art that the alpha 2-adrenoceptor of the therapeutically effective amount used in the present invention swashs
Dynamic agent can change along with factor, such as special experimenter's (such as, age, diet, health status etc.), is exposed to UV radiation
Degree, seek treatment or the order of severity of cutaneous tumor prevented and complication, the preparation etc. used.Based on the disclosure,
The program that can be standardized is carried out evaluation group compound and is applied to the effect of experimenter, uses so that those skilled in the art determine
Alpha 2-adrenoceptor agonist in the therapeutically effective amount of experimenter.Such as, alpha 2-adrenoceptor agonist is in advance
Anti-cutaneous tumor is formed or the beneficial effect that arrives of clinical observation in terms of prevention or delaying skin tumour progression.
Described clinical observation to beneficial effect can be a kind of situation, when be able to observe that relevant with cutaneous tumor
When the compositions of the present invention being applied to experimenter after sign and/or symptom, described sign and/or symptom can be prevented into one
Step develops or increases the weight of, or with less than the degree development not using the particular composition according to embodiment of the present invention.Described
Clinical observation to beneficial effect can be equally, when be able to observe that the sign relevant with cutaneous tumor and/or symptom it
Front time the compositions of the present invention is applied to experimenter, described sign and/or symptom can be prevented generation or subsequently to be less than
The degree not using the particular composition according to embodiment of the present invention occurs.
In another embodiment, the alpha 2-adrenoceptor agonist of therapeutically effective amount will reduce and cutaneous tumor
Or the discomfort of the relevant experimenter of the sign relevant to cutaneous tumor and/or symptom.
The method of the present invention can be used for preventing cutaneous tumor formed or suppress it to be in progress with one or more, or treatment
The cutaneous tumor existed or other treatment or Drug combination of relative sign and/or symptom.
Such as, the alpha 2-adrenoceptor agonist of therapeutically effective amount can with for treating the therapy of cutaneous tumor,
Such as surgery-scalpel (surgery-scalpel), cryosurgery (cryosurgery), electricity-surgical operation (electro-
Surgery), chemistry-surgical operation (chemo-surgery), or radiation and cytotoxic agent, such as alkylating agent, such as, nitrogen
Mustard, aziridine, fluorouracil, cyclophosphamide;Antimetabolite, such as, guanozola, Ismipur, aminopterin-induced syndrome,
Methotrexate;Antibiotic, such as, anything superfluous or useless mycin, D actinomycin D, carcinophyrin(are without middle translation), Mitomycin-C, color
Mycin, bleomycin, vinblastine;Hormone, such as, gonadal hormone, adrenocortical hormone, glucocorticoid;Radiosiotope-
P32、I131、Co60、Au190;Or botanical derivative, such as podophyllin, Colchicine, silkweed or Semen Abri Precatorii (Abrus
Precatorius).
Other medicines or treatment can with α 2 adrenoceptor agonists simultaneously, or one after the other and in a period of time
Be applied to experimenter in interval, to such an extent as to active component or medicine can play a role jointly with treatment or prevention cutaneous tumor and
Relative sign and/or symptom.Such as, other medicines or treatment can be identical with alpha 2-adrenoceptor agonist
Or individually preparation was used in the same or different time.
Any suitable route of administration can be used in delivering extra treatment or medicine includes, but are not limited to, oral, oral cavity
In, rectum, parenteral, external, epidermis, percutaneous, subcutaneous, intramuscular, intranasal, Sublingual, buccal, in dura mater, in ophthalmic, respiratory tract or
Nose sucks.
Another embodiment of the invention relates to a kind of induced skin death of neoplastic cells or the method suppressing it to grow,
It comprises makes Skin Tumor Cells a kind of compositions of contact, and described compositions comprises respectively and be enough to inducing death of neoplastic cells or press down
Make the alpha 2-adrenoceptor agonist of the amount of its growth.Connecing subject cell can be thin in culture in vitro
Cell in born of the same parents, or mammal body.
The invention still further relates to a kind of for protecting the skin of experimenter, lip or scalp with the damage effect of antagonism UV-radiation
The method answered, wherein said method comprises uses a kind of compositions to experimenter, and it comprises α 2 adrenal gland of safe and effective amount
Element can receptor stimulating agent.
As it is used herein, the safe and effective amount of alpha 2-adrenoceptor agonist refers to be enough to protect skin
The damage effect (cutaneous tumor of particularly UV-induction) of antagonism UV-radiation, but of a sufficiently low to avoid serious side effect
The consumption of alpha 2-adrenoceptor agonist.The safe and effective amount of alpha 2-adrenoceptor agonist by along be subject to
Uv light exposure, the persistent period for the treatment of and character in the age of examination person, health status and environment, special component, or made
Compositions, the factor such as special pharmaceutically acceptable carrier utilized and change.
Alpha 2-adrenoceptor agonist can be used together with the sunscreen of safe and effective amount, and described sunscreen is inhaled
Some UV radiation in receipts or reflected sunlight, thus contribute to protecting the skin against sunlight or UV damage.
As used herein, " safe and effective " refers to when set of applications compound, it is sufficient to provide light protection (photo
Protection) but be unlikely to cause the consumption of the sunscreen of any unacceptable side effect or dermoreaction.This consumption
Change along with selected sunscreen and required SPF (sun protection factor) (SPF).Commercially available sunscreen product have scope from 2 to 40 or
Higher spf value.According to embodiment of the present invention, a kind of topical composition comprises safety and effectively protects the α of UV-amount of damage
23 adrenergic receptor agonists, and about 1% to about 20%(weight) sunscreen.
Suitably sunscreen can be exciting with the alpha 2-adrenoceptor used in the present invention in such a way
Agent mixes, to such an extent as to the compositions for preventing and/or treat cutaneous tumor and light protection does not occur inherently to reduce
The interaction of effectiveness.Numerous sunscreen is suitable for using with alpha 2-adrenoceptor agonist combinations, including, but not
It is limited to: para-amino benzoic acid, its salt and derivant (ethyl, isobutyl group, glyceryl ester;P-dimethylaminobenzoic acid);Ammonia fennel
(that is, o-Aminobenzoate;Methyl, menthyl, phenyl, benzyl, phenethyl, berganol, terpinyl and cyclohexenyl group ester);
Salicylate (amyl group, phenyl, benzyl, menthyl, glyceryl and dipropylene glycol base ester);Cinnamic acid derivative (menthyl and benzyl
Base ester, α-phenylc nitrile;Butyl cinnamoyl pyruvate);Dihydroxycinnamic acid derivant (umbelliferone, methyl umbelliferone, first
Base acetyl group umbelliferone);Trihydroxy-trihydroxy cinnamic acid derivative (esculetin, methyl esculetin, daphnetin, and glucosides,
Esculin and daphnin);Hydrocarbon (diphenyl diethylene);Dibenzalacetone and benzylidene acetophenone;Naphthols sulphur
Hydrochlorate (beta naphthal-3,6-disulfonic acid and the sodium salt of 2-naphthol-6,8-disulfonic acid);Dihydroxy naphthlene formic acid and salt thereof;O-and p-
Hydroxy diphenyl disulfonate;Coumarin derivative (7-hydroxyl, 7-methyl, 3-phenyl);Diazole (2-acetyl group-3-bromo-indazole,
Phenyl benzothiazole, methyl naphtho-azoles, various aryl benzothiazoles);Quinine salt (disulfate, sulfate, chloride, oil
Hydrochlorate and tannate);Quinoline (oxinate, 2-phenylchinoline);Hydroxyl-or methoxyl group-substituted hexichol
Ketone;Uric acid and violuric acid;Tannic acid and derivant (such as, Hexaethyl ether) thereof;(butyl Ka Biji) (6-propyl group piperonyl) ether;
Hydroquinone;Benzophenone (oxybenzone, sulisobenzone, dioxybenzone, benzo resorcinol, 2,2', 4,4'-tetrahydroxybenzophenone, 2,
2'-dihydroxy-4,4'-dimethoxy-benzophenone, tower benzophenone difficult to understand;4-isopropyldibenzoylmethane methane;Butylmethoxy two
Benzoyl methane;Etocrilene;With 4-isopropyl-two-benzoyl methane.See, e.g., Segarin et al., at
Chapter VIII,pages189et seq.,of Cosmetics Science and Technology。
The preferred sunscreen used in the compositions of the present invention includes, such as, and 2-ethylhexyl p-methoxycinnamic acid
Ester, butylmethoxydibenzoylmethane, ESCALOL 567, octyldimethyl para-amino benzoic acid and
Its mixture.
Another aspect of the present invention relates to a kind of compositions and a kind of method by the skin tanning of experimenter, Qi Zhongsuo
The method of stating comprises the compositions using the alpha 2-adrenoceptor agonist comprising safe and effective amount to experimenter.
As used herein, the safe and effective amount of alpha 2-adrenoceptor agonist refers to be enough to protect skin to resist
The consumption of the alpha 2-adrenoceptor agonist of the damage effect (cutaneous tumor of particularly UV-induction) of UV radiation, but
Of a sufficiently low to avoid the consumption of serious side reaction.The safe and effective amount of described alpha 2-adrenoceptor agonist will be along with
Suntan and concentration used herein, experimenter be exposed to persistent period of UV and character, the persistent period for the treatment of and
Character, special component, or the compositions used, the factor such as special pharmaceutically acceptable carrier utilized and change.
Alpha 2-adrenoceptor agonist can be used together with the suntan of safe dose, and described suntan contributes to
Increase after being exposed to nature or alpine light and/or extend skin tanning.According to one embodiment of the invention, Yi Zhongyong
In the topical composition of the skin tanning of experimenter is comprised safe and effective amount alpha 2-adrenoceptor agonist and peace
The suntan of full dose.
Suitably suntan can be exciting with the alpha 2-adrenoceptor used in the present invention in such a way
Agent mixes, to such an extent as to does not occur from essentially decreased for cutaneous tumor prevention and/or treatment and for the group of skin tanning
The interaction of the effectiveness of compound.The example of the suntan that can use in the present invention include, but not limited to tyrosine,
Riboflavin, collagen hydrolysate and combinations thereof.
A kind of compositions according to embodiment of the present invention comprises effective dose, or therapeutically effective amount, or safety and
The alpha 2-adrenoceptor agonist of effective dose and pharmaceutically acceptable carrier.
Based on the disclosure, described compositions can be formulated for various route of delivery, such as external, table
Skin, percutaneous, subcutaneous or intramuscular delivery.In a preferred embodiment, described alpha 2-adrenoceptor agonist is joined
Make subcutaneous or external preparation.
One embodiment of the invention relates to a kind of topical composition, and it comprises pharmaceutically acceptable carrier and treatment
The alpha 2-adrenoceptor agonist of effective dose.The specific compound according to embodiment of the present invention is delivered for external
Carrier can be any of carrier in external used medicine field, includes, but not limited to pharmaceutically acceptable solvent, as many
Unit's alcohol or water;Emulsion (oil-in-water or water-in-oil emulsion), such as frost or dew;Microemulsion;Gel;Ointment;Liposome;Powder;And aqueous
Solution or suspension.Described pharmaceutically acceptable carrier includes required and inert drug excipient, including, but do not limit
In, binding agent, suspending agent, lubricant, flavoring agent, preservative, coloring agent and coating materials.
According to methods known in the art, such as, Standard reference works such as REMINGTON:THE SCIENCE AND
PRACTICE OF PHARMACY1577-1591,1672-1673,866-885(Alfonso R.Gennaro ed.19th
ed.1995);Ghosh,T.K.;Et al. TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS (1997)
The method that (being incorporated into herein by quoting) is provided, by α 2 kidney by pharmaceutically acceptable carrier Yu therapeutically effective amount
The topical composition according to embodiment of the present invention is prepared in the mixing of upper parathyrine energy receptor stimulating agent.
In one embodiment, the topical composition of the present invention exists with Emulsion form.Emulsion (such as cream and lotion)
It it is the suitable external preparation for the present invention.Emulsion is a kind of dispersion comprising the immiscible phase of at least two, wherein
One as droplet distribution in the other phase, and the diameter of described drop is in the range of 0.1 μm to 100 μm.Typically, including
Emulsifying agent increases stability.When water is dispersion phase, and oil is disperse medium, this Emulsion is referred to as water in oil emulsion.When oil is made
For droplet distribution the aqueous phase as drop everywhere time, this Emulsion is referred to as oil in water emulsion.Can act as the breast of topical carrier
Liquid (such as frost and dew) and preparation thereof are disclosed in REMINGTON:THE SCIENCE AND PRACTICE OF PHARMACY282-
291 (Alfonso R.Gennaro ed.19th ed.1995), are incorporated into herein by quoting.
In another embodiment, the topical composition of the present invention exists with gel form, such as, and biphasic gels
Or single-phase gels agent.Gel is partly consolidated by what the suspension of fluid communication formed by little inorganic particle or big organic molecule
Body system.When gel lump comprises the net of little discrete particle, it is classified as biphasic gels.Single-phase gels agent by
It is uniformly distributed in liquid organic macromolecule composition everywhere, to such an extent as to does not exist between scattered macromole and liquid significantly
Boundary.Suitable gel for the present invention is disclosed in REMINGTON:THE SCIENCE AND PRACTICE OF
PHARMACY1517-1518 (Alfonso R.Gennaro ed.19th ed.1995), is incorporated into herein by quoting.With
Other suitable gel in the present invention is disclosed in No. 6,387,383 United States Patent (USP)s (announcement on May 14th, 2002);6,517,
No. 847 United States Patent (USP)s (announcement on February 11st, 2003);With 6,468, No. 989 United States Patent (USP)s (announcement on October 22nd, 2002), logical
Cross to quote and each patent is expressly incorporated herein.
In one embodiment, described topical composition comprises aqueous gel further, and described aqueous gel comprises water
The pharmaceutically acceptable gellant of amount (water-gelling amount) solidifying with glue, described gellant selected from carbomer,
Glycerine polyacrylate and mixture thereof, and described topical composition has physiologically acceptable pH.
As used herein, " carbomer " is various dispersibling in water but the USP title of insoluble polymeric acid.Work as acidity
Dispersion by alkali and time, then form clarification, stable gel.Carbomer940 is that physiology is inert, and is not former
Send out sexual stimulus thing or sensitizer.Other carbomer includes 910,940,941 and 1342.Can be according to embodiment of the present invention
Compositions in the polymer viscosifier (gellant) that uses include well known by persons skilled in the art those, as at cosmetics and
The gellant of the hydrophilic and water alcohol frequently used in pharmaceutical industries.Preferably, described hydrophilic or water alcohol gellant comprise "" (B.F.Goodrich, Cleveland, Ohio), "" (Kingston Technologies,
Dayton, N.J.), "" (Aqualon, Wilmington, Del), "" (Aqualon,
Wilmington, Del) or "" (ISP Technologies, Wayne, N.J.).Preferably, described gelling
Agent comprises the weight in terms of composition weight between about 0.2% to about 4%.More particularly, "In "
Preferably composition weight percentage ranges between about 0.5% to about 2%, and "" and "In ", preferred weight percentage ranges is between about 0.5% to about 4%.“" and "In ", preferably composition weight percentage ranges is all between 0.5% to about 4%.
“" it is one of numerous crosslinked acrylic acid polymer being endowed common name carbomer.These polymerizations
Thing is dissolved in water and once use caustic such as sodium hydroxide, potassium hydroxide, triethanolamine or other amine alkali to neutralize, shape
Become clarify or the gel of slight haze.“" it is cellulosic polymer, it is dispersed in water and the most complete
Hydration then forms uniform gel.Other preferred gel polymer includes hydroxyethyl cellulose, cellulose gum, MVE/MA last of the ten Heavenly stems two
Alkene cross linked polymer, Gantrez AN-119 or a combination thereof.
In another preferred embodiment, the topical composition of the present invention exists with ointment form.Ointment is
Even if the oil having the water being also very few is semi-solid.Preferably, ointment is alkyl, such as wax, vaseline or gelling
Mineral oil.Suitable ointment for the present invention is known in the art and is disclosed in REMINGTON:THE
SCIENCE AND PRACTICE OF PHARMACY1585-1591 (Alfonso R.Gennaro ed.19th ed.1995),
It is incorporated into herein by quoting.
In one embodiment of the invention, the topical composition of the present invention contains at least one in frost and ointment,
Each of which all comprises the reagent selected from stearic acid, stearyl alcohol, spermol, glycerol, water and mixture thereof, and described external group
Compound has physiologically acceptable pH.
In another embodiment, the topical composition of the present invention exists with aqueous solution agent or suspended form, excellent
Select aqueous solution agent.Suitable aqueous external preparation for the present invention includes being disclosed in REMINGTON:THE SCIENCE
Those in AND PRACTICE OF PHARMACY1563-1576 (Alfonso R.Gennaro ed.19th ed.1995),
It is incorporated into herein by quoting.Other suitable aqueous topical carrier system includes being disclosed in No. 5,424,078 United States Patent (USP)s
(June 13 nineteen ninety-five is open), No. 5,736,165 United States Patent (USP)s (on April 7th, 1998 is open), No. 6,194,415 United States Patent (USP)s
(February 27 calendar year 2001 open), No. 6,248,741 United States Patent (USP)s (June 19 calendar year 2001 is open), No. 6,465,464 U.S. are special
Those in profit (on October 15th, 2002 is open), are fully incorporated herein by quoting.
Among the most acceptable pH of pH of the external preparation of the present invention, such as, about 5 to about 8
In the range of, in the range of more preferably at about 5.5 to about 6.5.For stable pH, preferably include the buffer agent effectively measured.
In one embodiment, the amount that described buffer agent is of about 0.05 to about 1 with the percentage by weight relative to preparation exists
In aqueous external preparation.Bronsted lowry acids and bases bronsted lowry can be used as required to regulate pH.
Tension regulator (tonicity-adjusting agents) can be included in the aqueous external preparation of the present invention
In.The suitably example of tension regulator includes, but not limited to sodium chloride, potassium chloride, mannitol, dextrose, glycerol and the third two
Alcohol.The consumption of tension regulator significantly can change according to the character needed for preparation.In one embodiment, described tension force
The amount that regulator is of about 0.5 to about 0.9 with the percentage by weight relative to preparation is present in aqueous external preparation.
Preferably, the aqueous external preparation of the present invention has scope from about 15cps to the viscosity of about 25cps.Pass through
Add viscosity modifier and can regulate the viscosity of aqueous solution agent of the present invention, described viscous regulator, such as, but not limited to,
Polyvinyl alcohol, polyvidone, hydroxypropyl methyl cellulose, poloxamer, carboxymethyl cellulose or hydroxyethyl cellulose.
In a preferred embodiment, the aqueous external preparation of the present invention be comprise preservative, viscosity modifier and
The isotonic normal saline of buffer system, described preservative such as benzalkonium chloride or chlorine dioxide;Described viscosity modifier such as polyethylene
Alcohol;And described buffer system such as sodium citrate and citric acid.
Topical composition according to embodiment of the present invention can comprise pharmaceutically acceptable excipient, as being listed in
REMINGTON:THE SCIENCE AND PRACTICE OF PHARMACY866-885(Alfonso R.Gennaro
ed.19th ed.1995;Ghosh,T.K.;Et al. TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS
(1997) those in, are incorporated into herein by quoting, and described excipient includes, but not limited to protective agent, adsorbent, delays
Mediating recipe, emollient, preservative, antioxidant, wetting agent, buffer agent, solubilizing agent, skin penetrant and surfactant.
In one embodiment, the topical composition of the present invention comprises one or more further selected from preservative, office
Anesthetic and the reagent of skin moisturizer.
Suitably preservative includes, but not limited to quaternary ammonium compound, as benzalkonium chloride, benzethonium chloride, cetrimonium bromide,
Quinoline oronain and cetylpyridinium chloride;Mercury reagent, such as phenylmercuric nitrate, phenylmercuric acetate and thimerosal;Alcohol reagent, as methaform, phenethanol and
Benzylalcohol;Antibacterial ester, such as the ester of P-hydroxybenzoic acid;With other antimicrobial reagent, as chlorhexidine, chlorocresol, benzoic acid and
Polymyxin.
Topical composition according to embodiment of the present invention can include medicine or its pharmaceutically acceptable salt, such as α 2
3 adrenergic receptor agonists, and optionally one or more other pharmacy activity component, include, but not limited to sugar skin
Matter hormone and other antiinflammatory, such as betamethasone, diflorasone, amcinonide, fluocinolone acetonide, mometasone, hydrocortisone, strong
Pine and triamcinolone;Local anesthetic and analgesics, such as Camphora, menthol, lignocaine and cincaine and Pu Moka
Cause;Antifungal, such as ciclopirox, chloroxylenol, glyceryl triacetate, sulconazole, nystatin, 9-undecylenic acid, tolnaftate, miaow health
Azoles, clotrimazole, oxiconazole, griseofulvin, econazole, ketoconazole and amphotericin B;Antibiotic and anti-infective, as not
Luo Xing, erythromycin, clindamycin, gentamycin, polymyxin, bacitracin and silver sulfadiazine;And preservative, such as iodine,
Polyvidone-iodine, benzalkonium chloride, benzoic acid, chlorhexidine, nitrofural, benzoyl peroxide, hydrogen peroxide, hexachlorophene, phenol,
Resorcinol and cetylpyridinium chloride.
In a preferred embodiment, dioxy is contained further according to the topical composition of embodiment of the present invention
Change titanium (TiO2), preferably in an amount of from being enough to cover brimonidine or the color of other colored component in preparation, but will not
Skin is caused stimulation.TiO2Eyes can be caused the stimulation and rubescent of gentleness, therefore should avoid eyes with containing TiO2's
The contact of external application compositions.
Dosage and administration frequency will be determined by trained medical profession, and this depends on used compound
The character of the dermatological conditions that the characteristic of external preparation active, special and institute treat or prevent and the order of severity.
In one embodiment of the invention, described topical composition comprises on α 2 kidney of by weight 0.01% to 5%
Adrenergic receptor agonist.Such as, described compositions can comprise by weight 0.01%, 0.05%, 0.1%, 0.2%, 0.3%,
0.4%, the alpha 2-adrenoceptor agonist of 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4% or 5%.
In order to treat or prevent according to cutaneous tumor disclosed by the invention, such as, by the topical composition of the present invention to appoint
What direct applications of usual manner well known in the art to being exposed to region or other affected region of daylight, described
Usual manner known to field such as, by dropper or administrator, as the mist via aerosol drug delivery device, via Intradermal
Or transdermal skin patches or by use finger the preparation of the present invention is interspersed among affected region simply.Generally, it is applied to
The amount ranges of the external preparation of the present invention of affected skin is from about 0.1g/cm2Skin surface amasss to about 5g/
cm2, preferably from 0.2g/cm2To about 0.5g/cm2Skin surface amasss.Typically, it is recommended that during treating, every day applies one to four
Secondary.
Another embodiment of the invention relates to a kind of cosmetics, and it comprises:
(1) topical composition of the alpha 2-adrenoceptor agonist of safe and effective amount is comprised;With
(2) about described topical composition being applied on the skin of experimenter, lip or scalp with antagonism UV-radiation
The explanation of damage effect.
As used herein, when using in test kit, term " illustrates " to include can be used in earmarking for it
Pass on the publication of test kit serviceability, record, illustrate or other expression medium any.Such as, explanation can be adhered to
Or be included in the container of test kit.
Described cosmetics can comprise the second topical composition further, and described the second topical composition comprises safety
The sunscreen of effective dose.
Described alpha 2-adrenoceptor agonist and sunscreen can be formulated in identical or single topical compositions
In thing, described identical or individually topical composition be contained in one or two single container, described container is as by appointing
What dropper that the most suitably material is made, tank (jar) or there is the pipe of suitable little nozzle diameter (orifice size),
As stretched canalis pterygoideus (extended tip tube).
The external preparation of the present invention can be packed into or be packaged in squeeze bottle or pipe.For packing outside the present invention
Be be obtained commercially with the suitable container closure system of preparation, such as, from Wheaton Plastic Products,
1101Wheaton Avenue, buys at Millville, N.J.08332.
Preferably, illustrate that (such as, pamphlet or packaging label) is packed together with the preparation of the present invention.Label interpretation
As how be enough to treat or prevent cutaneous tumor and relative sign and/or symptom amount and the time cycle use
The external preparation of the present invention.Preferably, label includes dosage and uses explanation, the composition of external preparation, clinical pharmacology, drug resistance
Property, pharmacokinetics, absorption, bioavailability and contraindication.
It is better understood with the present invention by quoting the example of following indefiniteness, but those skilled in the art will be easily
Understand these examples to be only used for illustrating the present invention as being described more fully in claim.
Embodiment 1
Aqueous external preparation
This embodiment illustrates the aqueous external preparation that can use in the present invention.
The first aqueous solution external preparation comprises: brimonidine tartrate (0.01% to 5%w/w);As preservative
Puriteg(0.005%w/w) (chlorine dioxide of stabilisation);And non-active ingredient: boric acid;Calcium chloride;Magnesium chloride;Potassium chloride;
Pure water;Sodium borate;Sodium carboxymethyl cellulose;Sodium chloride;Use hydrochloric acid and/or sodium hydroxide by pH regulator to 5.6 to 6.6.
Osmotic pressure is in the range of 250-350mOsmol/kg.
The second aqueous solution external preparation comprises brimonidine tartrate (0.2% to 2%w/w);Benzene as preservative is pricked
Oronain (0.005%w/w);And non-active ingredient: boric acid;Calcium chloride;Magnesium chloride;Potassium chloride;Pure water;Sodium borate;Carboxymethyl
Sodium cellulosate;Sodium chloride;Use hydrochloric acid and/or sodium hydroxide by pH regulator to 5.6 to 6.6.Osmotic pressure is at 250-
In the range of 350mOsmol/kg.
Embodiment 2
Frost or ointment external preparation
This embodiment illustrates the frost that can use in the present invention or ointment external preparation.
Describe the first frost external preparation (hydrophilic ointment agent) in the following Table 2.
Table 2
In order to prepare said preparation, stearyl alcohol and white vaseline are melted on steam bath, and is heated approximately at 75 DEG C.Then
Add other composition being dissolved in water and being heated to 75 DEG C in advance, and stir this mixture, until it condenses.Then in stirring
Lower this mixture is cooled down, be subsequently adding the brimonidine tartrate as concentrated solution.
Describe a kind of ointment external preparation (hydrophilic ointment agent) in the following Table 3.
Table 3
In order to prepare said preparation, stearyl alcohol and white beeswax are mixed on steam bath.It is subsequently adding cholesterol, and
Stirring is until it is completely dissolved.It is subsequently adding white vaseline and stirs.This mixture is removed from bath, and stirs until it coagulates
Knot.With continuous stirring, add as the brimonidine tartrate concentrating slurry.
Embodiment 3
Gel external preparation
This embodiment illustrates the gel external preparation that can use in the present invention.
Describe the first gel preparation in the following Table 4.
Table 4
Describe the second gel preparation in the following Table 5.
Table 5
Each composition is mixed, and sodium hydrate aqueous solution is added slowly in mixture until pH reaches about
7, and form gel.
Describe the third gel preparation in the following Table 6.
Table 6
Composition | Percentage by weight |
Brimonidine tartrate | 0.1-2% |
Carbomer940 | 1.25% |
Methyl hydroxybenzoate | 0.3% |
Phenoxyethanol | 0.4% |
Glycerol | 5.5% |
10% titanium dioxide | 0.625% |
Propylene glycol | 5.5% |
10%NaOH solution | 6.5% |
Deionized water | QS |
Add up to | 100% |
Describe the 4th kind of gel preparation in the following Table 7.
Table 7
Component is mixed and stirs.Add triethanolamine until pH is of about 7.
Embodiment 4
Foam external preparation
This embodiment illustrates the foam external preparation that can use in the present invention.
Describe the first foam formulations in the following Table 8.
Table 8
Heat water to 80-85 DEG C, add stearic acid afterwards.Once stearic acid fusing, i.e. adds laureth-23,
Fusing, and be sufficiently mixed.Then, add triethanolamine, and the compositions of gained is sufficiently mixed about 30 minutes to form soap.
Then, the soap of gained is cooled to about 65 DEG C, adds sodium lauryl sulphate afterwards.Then, it is sufficiently mixed said composition.Connect
, add BHT and brimonidine tartrate, mix subsequently.Then, the compositions of gained is cooled to room temperature, and adds
Spice.Use conventional technique, use Ai Long A-31 propellant to be packaged in aerosol can by this product, and mechanical oscillation 5 points
Clock.This product disperses as spray cone, and this spraying is deposited on skin as one layer of abundant foam, and this foam covers rapidly
Relief of symptoms in large-area skin, and the most about 2 minutes.
Describe the second foam formulations in the following Table 9.
Table 9
Aqueous phase is prepared as follows.Heat the water to 80 DEG C, add Palmic acid afterwards.Once Palmic acid fusing, i.e. adds
Enter laureth-23, fusing, and be sufficiently mixed.Then, add triethanolamine, and the compositions of gained is sufficiently mixed about
15 minutes to form soap.
By stearyl alcohol, mineral oil, lauramide DEA, Cetyl Dimethicone copolyol, the acid of PEG-150 distearyl
Ester and BHT mix and are incorporated in 55 DEG C of heating to form oil phase.Oil phase is merged with aqueous phase in 80 DEG C, and is sufficiently mixed about 15 minutes.
Then, the mixture of gained is cooled to room temperature, and adds imidazolidinyl urea, methyl hydroxybenzoate and propylparaben, then fill
Divide mixing.It is subsequently adding brimonidine tartrate, and is sufficiently mixed.Then, spice is added, carry out gentle mixing subsequently.So
After Aloe is dissolved in astringent, and stir slowly to form product formulation, then this product formulation be packaged in spraying
In tank, as described in the first foam formulations.
This product disperses as spray cone, and this spraying deposits on skin as one layer of abundant foam, and this foam is fast
Speed covers relief of symptoms in large-area skin, and the most about 2 minutes.
Describe the third non-saponified foam formulations in the following Table 10.
Table 10
Alcohol phase is prepared as follows: dissolved in ethanol by the ethyl ester of Gantrez AN-119, adds dimethyl afterwards and gather
Siloxanes is also sufficiently mixed.Aqueous phase is prepared as follows: heat water to 65 DEG C, adds PVP/VA copolymer afterwards the most fully
Mixing.Oil phase be prepared as follows: by oleth-20, coconut oleoyl amine MEA, and stereth-16 60 DEG C of mixing with
Form blend.Then, at 65 DEG C, oil phase is joined in aqueous phase, and be sufficiently mixed.Then, methyl hydroxybenzoate is added to mixing
In thing, mix subsequently, add aminomethyl propanol afterwards, take charge of and draw oronain and pantothenylol and mix to uniformly.By the combination of gained
Thing is cooled to room temperature, adds alcohol phase afterwards and is sufficiently mixed.It is subsequently adding spice, and is gently mixed to form this product.Then
This product is packaged in aerosol can.
This product disperses as spray cone, and this spraying deposits on skin as one layer of abundant foam, and this foam is fast
Speed covers relief of symptoms in large-area skin, and the most about 2 minutes.
Embodiment 5
Use the light carcinogenecity research of brimonidine
According to the design in table 11, use ultraviolet radiation and brimonidine gel or blank process albefaction without hair
SKH1-hr mice (36/ sex/group) 40 weeks.Unprocessed, further look at mice 12 weeks.In Monday weekly, Wednesday and Friday
Ultraviolet radiation before and the ultraviolet radiation of Tuesday and Thursday weekly after carry out the external curing of about a hour.See
Table 11.
Relate to all programs of animal and carry out in the animal facility of fully accreditation and according to the scheme ratified in advance.
Table 11
N/A: inapplicable
RBU: the Luo Baisen-Bai Jie unit (tolerance of ultraviolet radiation effectiveness;400 RBU are about the most untanned
Application on human skin on a minimal erythema dose)
Monday, Wednesday and Friday the most weekly: be exposed to ultraviolet radiation in about 1 hour after pilot project is applied.Often
Tuesday in week and Thursday: before pilot project is applied, within about 1 hour, be exposed to ultraviolet radiation.
Result as shown in table 12, subtracts astoundingly with the concentration external application brimonidine of 0.18%, 1% and 2%
Delay the development of cutaneous tumor damage.Brimonidine causes the dose-dependent delay forming the cutaneous tumor of UV-induction.
Table 12
Group for the tumor invasion of the tumor of >=1mm compares
aTime, within this time, the group member of 1/2nd has obtained one or more qualified tumor.
The average tumor number of each survivor of b
Delay is observed in the average all numbers to tumor (>=1mm).It is true that the brimonidine of 1% and 2% is to have very much
Effect, to such an extent as to the group member less than 1/2nd during the research of 52 weeks in obtain one or more qualified swell
Tumor.Also delay is observed in tumor yield (>=1mm).Compared to blank group, the brimonidine of 0.18% is by tumor yield
Reducing 1.7 times, tumor yield is reduced 4.7 times by the brimonidine of 1%, and tumor yield is reduced by the brimonidine of 2%
8.1 times.These results represent the notable delay to swollen neoplastic morbidity.
Additionally, the group that Fig. 1 shows Tumor incidence compares.Note that the numeral on every line side represents at table 11
Number with the treatment group shown in table 12.As shown in fig. 1, along with brimonidine concentration increases, the size of tumor also reduces
?.This shows, external brimonidine promotes tumor regression equally.
It will be understood by those of skill in the art that and the embodiment above can be changed, without departing from the present invention
Concept widely.It is therefore to be understood that the present invention is not limited to disclosed particular, but it is intended to cover by appended
Amendment in the spirit and scope of the present invention that claims are limited.
Claims (10)
1. compositions in preparation needing in its subject in the medicine of the formation of the cutaneous tumor that pre-uv blocking is radiation-induced
Purposes, described compositions comprise by weight from 0.01% to 5% brimonidine and pharmaceutically acceptable carrier.
Purposes the most according to claim 1, wherein said cutaneous tumor is thin selected from papillary tumor, actinic keratosis, substrate
Born of the same parents' cancer, squamous cell carcinoma, keratoacanthoma, melanoma, sarcoma and lymphoma.
Purposes the most according to claim 1, wherein said compositions comprises another kind of for preventing or treating skin further
The treatment of general edema with abdominal distension tumor or active component.
Purposes the most according to claim 2, wherein said cutaneous tumor is actinic keratosis.
5. compositions needs its skin of experimenter, lip or the scalp damage effect with antagonism UV-radiation in preparation protection
Medicine in purposes, described compositions comprise by weight from 0.01% to 5% brimonidine.
6. according to the purposes according to any one of claim 1 and 5, wherein said compositions comprise by weight from 0.1% to
The brimonidine of 2%.
7., according to the purposes according to any one of claim 1 and 5, wherein said compositions is passed through outside, is subcutaneously or intramuscularly passed
The approach sent is applied to experimenter.
Purposes the most according to claim 7, wherein said compositions passes through subcutaneous delivery to needing this skin used
Region is applied to experimenter.
Purposes the most according to claim 7, wherein said compositions passes through applications in needing this skin used
Region is applied to experimenter.
10. according to the purposes according to any one of claim 1 and 5, the wherein said compositions approach quilt by dermal delivery
It is applied to experimenter.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US34433310P | 2010-06-30 | 2010-06-30 | |
US61/344,333 | 2010-06-30 | ||
PCT/EP2011/060939 WO2012001065A2 (en) | 2010-06-30 | 2011-06-29 | Method for preventing or treating skin tumor |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CN201410431044.XA Division CN104288768A (en) | 2010-06-30 | 2011-06-29 | Use of alpha-adrenergic receptor agonist |
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CN103209691A CN103209691A (en) | 2013-07-17 |
CN103209691B true CN103209691B (en) | 2016-12-14 |
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070082070A1 (en) * | 2005-10-11 | 2007-04-12 | Stookey Evangeline L | Treating skin disorders |
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070082070A1 (en) * | 2005-10-11 | 2007-04-12 | Stookey Evangeline L | Treating skin disorders |
Non-Patent Citations (1)
Title |
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《Catecholamine effects on human melanoma cells evoked by alpha 1-adrenoceptors》;SCARPARO ANA CRISTINA ET AL;《Archives of Dermatological Research》;20040831;第296卷(第3期);112-119 * |
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