CN107617107A - A kind of anti-scar preparation of compound Angiotensin-Converting class - Google Patents

Abstract

The present invention provides a kind of anti-scar preparation of compound Angiotensin-Converting class, is made up of the active component of one or more of ACE classes medicines and the active ingredient of other one or more of anti-scarring drugs, dosage form is pulvis or solution (suspension).Invention formulation under aseptic conditions, is imported in cicatricial tissue by the mode such as injection in laser assisted, scar, plays a part of suppressing cicatrix of skin.Invention formulation is introduced directly into scar and carries out multi-angle collaboration and complementary therapeutic action, and effect is comprehensive, better；Curative effect is improved so as to reduce side effect into after subassembly, each Ingredient Amount is reduced using multi-medicament.The present invention imports in cicatricial tissue, increase concentration of the active ingredient in cicatricial tissue, and unstable peptides can be imported, avoid the first pass effect of digestive system, suitable for different type or the scar of different patients, the target of individualized treatment can be achieved by the research and screening of the proportioning to solution component.

Description

A kind of anti-scar preparation of compound Angiotensin-Converting class

Technical field

The invention belongs to field of medicaments, and in particular to a kind of anti-scar preparation of compound Angiotensin-Converting class, it has It is compound ACE (Angiotensin Converting Enzyme, Angiotensin-Converting) class medicine, i.e., at least 1 to imitate composition The combination of other anti-scarring drugs of individual ACE classes medicine (ACE related activities peptide and its corresponding inhibitor/antagonist) and at least one, Formulation is solution (suspension) or pulvis, can be led under aseptic conditions by laser assisted or by the way of being injected in scar Enter in scar, play a part of suppressing cicatrix of skin formation.

Background technology

Scar (scar, scar, cicatrix) be caused normal skin tissue after various wounds mode of appearance and The general designation of the change of histopathology.After it is human body wound, one kind during wound or surface of a wound normal healing is normal, Inevitable physiological reaction, and the inevitable outcome of wound healing process.The essence of scar is that one kind does not possess normal skin tissue Structure and physiological function, losing normal structure vigor, abnormal, unsound tissue.

Cicatricial tissue hyperplasia is then likely to form hypertrophic scar, influences the outward appearance of patient, causes cacesthesia, influences The function of local skin.Wound healing of the skin after sustaining damage goes through several stages：Inflammatory phase, proliferative phase and remodeling phase. In proliferative phase, body by cytothesis, differentiation and ECM (extracellular matrix) formed supplement or repair due to skin injury and Cause the tissue for lacking or being damaged.Regulation and control to fibroblast regeneration, differentiation perhaps can provide a kind of suppression cicatrization Effective way.In proliferative phase, the cell of several approach repair tissues is referred to as repair cell more than, and fibroblast is to repair One kind of multiple cell, and formed in fibr tissue and played an important role with links such as contraction of wounds；After the completion of tissue repair, Fibroblast is mainly disappeared by the form of Apoptosis.When fibroblast is because of some specific reasons regeneration increase, apoptosis During reduction, fibr tissue is formed and increased, and collagen deposition increase, granulation tissue shrinks enhancing, thus pathologic scar produces.

Pathologic scar includes keloid (keloid) and hyperplastic scar (hypertrophic scar).Typically handle Only be higher by surface but be confined to injury scope, often can the scar of spontaneous regression be referred to as hyperplastic scar；And lesion Tissue is not only higher by surface, and is higher by surface part and exceeds its substrate continued propagation to the extension of hyperplasia around, seldom disappears naturally The scar moved back is referred to as keloid.Cicatrix of skin hyperplasia and the keloid occurred and hyperplastic scar can cause shouting pain, burn Sense and itch, and dysfunction can be caused.The preceding upper breast of the upper part of the body, shoulder back, upper limbs deltoid muscle, ear-lobe, chin portion are apt to occur in, It is more common in coloured race.

Fibroblastic propagation is with differentiation mainly by the shadow of cell factor, mechanical stress and extracellular matrix microenvironment Ring.Wherein TGF-β 1 stimulates fibroblast proliferation by TGF-β signal path and migrated to wound；It can induce into fibre simultaneously Endochylema of the cell synthesis rich in collagen is tieed up, myofibroblast is divided into so as to induce fibroblast.Endothelium Local angiotensin system of myocardial (renin-angiotensin system, RAS) plays key player in TGF-β signal path.

In recent years RAS research is found：Local RAS can be a variety of by promoting the synthesis of cell propagation and extracellular matrix to participate in The formation of histoorgan fibrosis.From the proangiotensin of liver, angiotensin I is converted into the presence of feritin (angiotensin I, Ang I), Ang I are converted into Angiotensin II (angiotensin II, Ang in the presence of ACE II), Ang II are secreted into target tissue by blood circulation, are combined with I receptors, cause aldosterone release and vessel retraction etc. raw Effect is managed, blood pressure and the blood flow change of body is adjusted, maintains body blood volume and water-electrolyte balance.Constantly there is scholar both at home and abroad The expression for having RAS is found in local organizations such as heart, vascular wall, kidney, fat and brains；Local RAS is independent action, but Influenced each other again with circulation RAS, participate in a variety of pathophysiological processes jointly.

There is also complete RAS (McGinn R, Meade RD, Kenny GP.Angiotensin II in for skin histology human skin:an age-dependent role for core temperature regulationAm J Physiol Heart Circ Physiol.2015,308(10):H1192-3).After normal skin is impaired, RAS is activated, and participates in tissue Injury repair and later stage tissue reconstruction process.In hyperplastic scar forming process, ACE and Ang II expression increase, and ACE Activity is significantly higher than normal and trauma skin.The TGF-β signal path that Ang II are mediated by its I receptor induces human desmocyte The propagation of cell, and this propagation can be suppressed by the antagonist of this receptor (rather than II receptors).

It is the shearing enzyme (Fig. 1) of Several Active Peptides as the ACE of RAS system hinges.Its substrate is except above-mentioned Ang I, in addition to Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (Substance P, SP), N- acetyl group-seryl-aspartoyl-lysyl-proline (N- Acetyl-seryl-aspartyl-lysyl-proline, AcSDKP), angiotensins-(1-7) (hypertensin 1-7, Ang1-7), bradykinin (Bradykinin), enkephalins (Enkephalin), neurotensin (Neurotensin), Chemotactic Peptide (N- formyl-methionines-Ile-Phe, N-formyl-Met-Leu-Phe, fMLF), insulin B chain (Insulin b chain) and amyloid (Amyloid peptides) Ab1-40 and Ab1-42 etc. (Bernstein KE, Ong FS,Blackwell WL,Shah KH,Giani JF,Gonzalez-Villalobos RA,Shen XZ,Fuchs S, Touyz RM.A modern understanding of the traditional and nontraditional biological functions of Angiotensin-converting enzyme.Pharmacol Rev.2012,65 (1):1-46.)。

Exogenous SP can effectively facilitate fibroblast proliferation, so as to promote cicatrization.On the contrary, another dropped by ACE The substrate A cSDKP of solution can then alleviate fibrosis.In addition, though ACE and other enzymes participate in Ang 1-7 formation jointly, but it is also Degrade its main peptase.Ang 1-7 have the function that anti-tissue fibrosis, and its mechanism is relevant with suppressing TGF-β path.It is slow to swash The B2 receptor antagonists of peptide can weaken glomerulosclerosis and myocardial fibrosis, and its B1 acceptor gene knockout can mitigate kidney fibrous Change, B1 receptor antagonists can improve glomerulonephritis, but bradykinin is main related to vessel retraction.

Although detecting that enkephalins increases in hyperplastic scar, it acts on the mainly itch with cicatricial tissue, pain It is related etc. cacesthesia.Neurotensin is mainly distributed on brain and intestines and stomach, mainly to blood pressure control, stress, pain etc. it is related； The peptide and its activator are possibly as potential tranquilizer, antalgesic and depressor.Other 3 kinds of active peptides also temporarily have no document report Road is related to cicatrization, and wherein Chemotactic Peptide fMLF mainly plays the role of smooth muscle contraction, insulin B chain mainly with diabetes phase Close, Ab1-40 and Ab1-42 are mainly related to the pathogenesis of alzheimer disease.

To sum up, this 5 ACE related activities peptides of Ang II, SP, AcSDKP, Ang 1-7 and bradykinin and its corresponding inhibitor (including the antagonist of Ang II, SP and bradykinin, and AcSDKP, Ang 1-7 and ACE inhibitor) and fibrosis and scar Formed related.According to literature query and our research, play facilitation is：Ang II, SP, AcSDKP inhibitor (used in us is (that used in us is AcSDKP prolyl endopeptidase inhibitor S-17092), Ang 1-7 inhibitor Ang 1-7 MAS acceptor inhibitor A779) and bradykinin；And play inhibitory action is ACEI (ACE Inhibitors, blood Angiotensin converting enzyme inhibitor), ARB (Angiotensin Receptor Blocker, angiotensin-ii-receptor retardance Agent), SP antagonist (that used in us is SP NK1 receptor antagonist L-733060), AcSDKP, Ang 1-7, bradykinin Antagonist (that used in us is B1 receptor antagonist DALBK and B2 the receptor antagonist HOE-140 of bradykinin).

Wherein, ACEI and ARB has clinically been widely used in the treatment of hypertension.In addition, ACEI is also applied to control Congestive heart failure, heart infarction, diabetic nephropathy and diabetes mellitus hypertension, high-risk-type angiocardiopathy etc. are treated, ARB can also be used for changing Mercy declined, treatment after heart infarction, diabetic nephropathy, left ventricular hypertrophy, atrial fibrillation, metabolic syndrome and the clinics such as ACEI is cough caused are asked Topic.Experimental study confirms that ACEI and ARB can be played in the pathologic processes such as Ventricular Remodeling, glomerulus fibrosis, pulmonary fibrosis Improved effect.

In theory, it is not preferred plan only with ACEI or ARB.ARB can only suppress II 1 scar proliferation factors of Ang, ACEI can not suppress hyperplasia factors all downstream.ACEI reduces Ang II, AcSDKP and Ang 1-7 increase, the above 3 Person is advantageous to suppress scar；But SP and bradykinin increase due to lacking ACE degraded, can cause scar proliferation in theory.

Glucocorticoid is that wide variety of suppression scar medicine, its mechanism of action are to suppress collagen α-peptide both at home and abroad at present The synthesis of chain and prolyl hydroxylase, reduces collage synthesis, while energy induced fibroblast produces clostridiopetidase A, drops collagen Solution increase；Make fibroblast mitochondria cavitation, change in quality, prevent fibroblastic hyperplasia, reduce collagenous fibres Synthesis；Make scar endothelial cell injury, scar blood supply can be reduced, contribute to collagen to rearrange, make thinning (Cai that softens of scar Scape dragon modern times scars, second edition .2008, Beijing:People's Health Publisher .438-39.).Conventional medicine has Triamcinolone acetonide (alias has Triamcinolone Acetonide, Pevisone, Kenacort-A, Triamcinolone Acetonide, Adcortyl A etc.), betamethasone (trade name " Diprospan ") and dexamethasone etc..5 FU 5 fluorouracil (5-FU) can suppress cell division, prevent cell growth, before suppressing collagen The secretion of body and the crosslinking of collagen.Bleomycin is by suppressing DNA, RNA and protein synthesis and the production of inhibitory activity oxygen It is raw, so as to arresting cell cycle；It is generally used for treating wart, hyperplastic scar and keloid.Bleomycin A5 is from China Zhejiang Isolated antitumor antibiotics in unwrapping wire bacteria culture fluid in the Pingyang County soil of river, through studying and external bleomycin (Bleomycin) composition is close.Both compare, and bleomycin is multi-component composite medicine, main component A2；Bleomycin A5 is then For single A5.Bleomycin A5 is close with the effect of bleomycin, and the main thymidine that suppresses participates in DNA, is combined with DNA It is allowed to destroy.It can also make DNA single-strand breaks in addition, and discharge the free core alkali in part, it might therefore destroy DNA masterplates, hinder Only DNA duplication, disturb carefully full division growth；It periodically acts on G2 the and M phases, can suppress fibroblastic hyper-proliferative And collage synthesis, so as to suppress cicatrization and hyperplasia；Vascular endothelial cell is killed, reduces scar blood supply.

The design feature of barrier action and cicatricial tissue densification because of skin, causes medicine to not easily penetrate into scar group Knit, effective drug concentration can not be partially formed.Cutaneous penetration technology is that one kind improves medicine by either physically or chemically The technology of thing infiltration, the depth of medicine local action can be effectively improved, avoids first pass effect of the digestive system to medicine, reduces medicine Thing usage amount and the adverse reaction for reducing medicine.Laser possesses height accuracy and controllability, laser assisted cutaneous penetration technology Permeability mainly is improved by destroying keratoderma, different size, the medicine of different stability can be imported efficiently, be One of prefered method of skin administration.The Impact cutaneous penetration technologies of Fei Dun laser companies of Israel exploitation, pass through CO₂Dot matrix swashs Light makes keratoderma form many microchannels, and the frequency mixing ultrasonic wave energy of particular design has in micro- strip off in passage to medicine There is " push-and-pull " effect, it is quick to promote medicine to be permeated downwards along microchannel.

Local injection therapy's treatment pathologic scar is a kind of simple and easy to do, small to systemic effects method, all the time It is widely used and studies, and therapeutic effect is definite.

The content of the invention

It is an object of the invention to provide a kind of anti-scar preparation of compound ACE classes, by one or more of ACE classes medicine (ACE phases Close active peptide and its corresponding inhibitor/antagonist) active component and other one or more of anti-scarring drugs active ingredient Composition, dosage form is pulvis or solution (suspension).How other anti-scarring drugs (are selected from Qu An from glucocorticoid Moral, betamethasone, dexamethasone), 5-FU, bleomycin or bleomycin A5.

The ACE classes medicine (ACE related activities peptide and its corresponding inhibitor/antagonist), refers specifically to vasotonia Plain ARBs (ARB), N- acetyl group-seryl-aspartoyl-lysyl-proline (AcSDKP), hypertensin 1- 7 (Ang 1-7), Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 (SP) antagonist L-733060, brad ykinin antagonists DALBK and HOE-140 and angiotensins turn Change enzyme inhibitor (ACEI).Wherein, ARB be mainly selected from Losartan (Losartan), Irbesartan (Irb, Irbesartan), Valsartan (Valsartan), Telmisartan (Telmisartan), Olmesartan (Olmesartan), candy Sha Tan (Candesartan) etc.；ACEI is mainly selected from lisinopril (Lisinopril), Ramipril (Ramipril), Kato Puli (Captopril), Cilazapril (Cilazapril), enalapril (Enalapril), benazepil (Benazepril) Deng.Other described anti-scarring drugs refer to suppressing scar proliferation glucocorticoid (Triamcinolone acetonide, betamethasone, fill in Rice pine etc.), 5 FU 5 fluorouracil, bleomycin and bleomycin A5 etc..

During the combination of active principles of described several ACE classes medicines, conventional combination is：ARB combines (matter with ACEI Amount proportioning is 0.33-3:0.33-3；Combine reason：ARB can suppress this very strong scar proliferation factor of Ang II, but can not be right Other active peptides act；Further suppress Ang II after adding ACEI, while AcSDKP and Ang 1-7 increase, the above It is more beneficial for suppressing scar；But after adding ACEI, SP and bradykinin increase due to lacking ACE degraded, have cause in theory The trend of scar proliferation)；ARB combines SP antagonist (quality proportioning 0.33-3:0.33-3；Combine reason：The combination suppresses Ang II and SP the two very strong scar proliferation factors, but other active peptides are not worked)；ACEI joints SP, bradykinin Antagonist (quality proportioning 0.33-3:0.33-3:0.33-3；Combine reason：ACEI reduces Ang II, AcSDKP and Ang 1-7 increases, and the above is advantageous to suppress scar；But SP and bradykinin increase due to lacking ACE degraded, can draw in theory Scar proliferation is played, therefore adds its antagonist and is suppressed；All scar proliferation factors related such then ACE are all inhibited)； ARB joints SP, antagonist (the quality proportioning 0.33-3 of bradykinin:0.33-3:0.33-3；Combine reason：The combination inhibits The two very strong scar proliferation factors of Ang II, SP, bradykinin this stronger scar proliferation factor is also inhibits, but to it He does not work at active peptide)；ARB joints SP, the antagonist of bradykinin, and AcSDKP, Ang 1-7 (quality proportioning 0.33- 3:0.33-3:0.33-3:0.33-3:0.33-3；Combine reason：The combination inhibits the two very strong scars of Ang II, SP to increase Raw factor, bradykinin this stronger scar proliferation factor is also inhibits, while increasing for AcSDKP and Ang 1-7 is also beneficial to Suppress scar, all scar proliferation factors related so then ACE are all inhibited)；Other combinations can suppress according to ACE The principle of fibrosis and scar (Fig. 1) come carry out derive and medicine selection.During multi-medicament active component, be usually etc. quality Mixing, if necessary the quality of any of which component can on 3 times of highest when the quality such as being transferred to or minimum when the quality such as being adjusted downward to 1/3。

When other described several anti-scarring drugs combine, conventional combination is：Glucocorticosteroidsin in combination 5- fluorine is urinated Pyrimidine (quality proportioning 0.33-3:0.33-3；Combine reason：Suppress inflammation, while suppress cell division)；Glucocorticoid joins Close bleomycin (quality proportioning 0.33-3:0.33-3；Combine reason：Suppress inflammation, while interference cell divides)；Sugared cortex Hormons bleomycin A5 (quality proportioning 0.33-3:0.33-3；Combine reason：Suppress inflammation, while interference cell divides)； 5 FU 5 fluorouracil joint bleomycin (quality proportioning 0.33-3:0.33-3；Combine reason：Suppress, interference cell division)；5- Fluorouracil Combined with Bleomycin for Oral (quality proportioning 0.33-3:0.33-3；Combine reason：Suppress, interference cell division)；Sugared skin Matter hormons 5 FU 5 fluorouracil and bleomycin (quality proportioning 0.33-3:0.33-3:0.33-3；Combine reason：Suppress scorching Disease, while suppress and interference cell division)；Glucocorticosteroidsin in combination 5 FU 5 fluorouracil and bleomycin A5 (quality proportioning 0.33- 3:0.33-3:0.33-3；Combine reason：Suppress inflammation, while suppress and interference cell division).When multi-medicament combines, generally To wait mass mixing, if necessary the quality of any of which component can on 3 times of highest when the quality such as being transferred to or the quality such as be adjusted downward to When minimum 1/3.

The anti-scar preparation is by the active component of one or more of ACE classes medicines and other one or more of anti-scar drugs The active ingredient combinations of thing, which are dissolved in physiological saline, is made into sterile solution or suspension, and the total mass concentration of medicine is 0.1%- 25%.Can also aseptic powdery form provide.

When being such as several drugses active ingredient combinations, the quality of mass mixing, if necessary any of which composition is usually waited Can on 3 times of highest when the quality such as being transferred to or minimum 1/3 when the quality such as being adjusted downward to.The solution of the anti-scar preparation of compound ACE classes (suspension) and pulvis are required for aseptic process, preferred sterile bulk drug, and keep sterile in process for preparation；If raw material Medicine is non-sterile, then first sterilizes bulk drug, or the filtration sterilization after solution (suspension) preparation using Co 60 irradiation etc. before preparation (at utmost to ensure the stability of medicine).The ACE classes sterile solution can be blended into liquor capacity 20%-100% 2% profit More cacaines, pain during mitigating cutaneous penetration under laser assisted or injection, improve comfort level.

Imported in the suitable cicatricial tissue of the present invention and (refer mainly to the cutaneous penetration of laser assisted and use in syringe scar note The method penetrated).

Using laser assisted transdermal leading-in technique when, after the routine disinfection of scar surface, first use CO₂Dot matrix laser (also may be used To be ion beam etc.) micropore is established on cicatrix of skin surface, compound preparation solution of the present invention is then applied to CO₂Dot matrix laser Scar tissue surface after punching, using Fei Dun laser companies impact cutaneous penetrations hand have, using ultrasound push-and-pull action, Drug solution is promoted to enter inside cicatricial tissue.Described CO₂Dot matrix laser refers to Fei Dun laser companies (Alma Lasers) Spike carbon dioxide (Pixel CO₂) Super pulse laser；Described ultrasound refer to the said firm exploitation Impact it is transdermal to Medicine technology, in CO₂After dot matrix laser pre-treated, the frequency mixing ultrasonic wave energy of Impact hands tool produces in micro- strip off in passage to medicine Life " push-and-pull " effect, it is quick to promote medicine to be permeated downwards along microchannel, make medicine (peptides for including stability difference) can efficient, target To importing.Laser and ultrasound can also replace with the product of same performance respectively, for example laser can be replaced Fei Dun laser companies Glitter ion beam scar treatment instrument or the CO of other companies₂(such as section doctor people, section's English, strange cause is external and the country is public for dot matrix laser Department).

Using during injection technique, scar surface routine disinfection is molten directly by compound preparation of the present invention with syringe in scar Liquid is expelled to inside cicatricial tissue.

The present invention has advantages below：1) because ACE classes medicine clinically had certain application, especially ACEI and ARB application is very extensive, and its security is self-evident, and its pharmacology, pharmacokinetics, toxicological study are fairly perfect.Though 2) So reduce local T GF- β expression and can improve cicatrization and known together, but the improvement scar medicine clinically applied at present with Suppress inflammation (glucocorticoids, trade name " triamcinolone acetonide acetate urea cream " etc.), anti-inflammatory and softening scar (trade name For " Contractubex " etc.), wound healing (trade name " asiaticoside frost " etc.), silica gel piece it is (trade name " U.S. skin shield ", " celestial Card " etc.) and pressure therapy (Silica hydrogel pad pasting, trade name " easypro trace ", " easypro trace again ", " Shi Kefu " etc.) based on；Grind in laboratory Study carefully have transfected using gene, antibody etc. reduces TGF-β, but temporarily has no matured product；Literature query and our research are demonstrate,proved Real ACE related activities peptide/inhibitor can influence the expression of TGF-β in vitro, partly play the role of to reduce TGF-β well, this Invention is expected to fill up the market vacancy.3) " other " medicine (glucocorticoid, 5 FU 5 fluorouracil, bleomycin and bleomycin A5 Deng) effect is definite in terms of scar is suppressed, clinical practice is extensive, but has limitation in terms of side effect and curative effect, compound Its deficiency is can overcome the disadvantages that after " ACE classes " medicine.4) " compound ACE classes " medicine is formed by " ACE classes " medicine and " other " drug regimen, Worked in the different aspect for suppressing cicatrization, there is collaboration and complementation.5) " compound ACE classes " medicine with individually " ACE classes " or individually " other " medicine is compared, and advantage is：Effect is more comprehensively, better；After being matched using multi-medicament, Side effect can be reduced by reducing each component dosage.6) compound ACE class medicines are injected in the cutaneous penetration under laser assisted and scar Technology can greatly increase concentration of the active drug composition in local scar tissue, and can import unstable peptides.7) it is different The formulation soln of component and concentration is applicable to different type or the scar of different patients, passes through grinding for the proportioning to solution component Study carefully and screen the target that individualized treatment can be achieved.

Brief description of the drawings

Fig. 1 is the metabolism of the fibrosis related activity peptide of ACE regulation and control.

Fig. 2 is the making of mouse back incisional scar model.

Fig. 3 is Angiotensin II immunohistochemical experiment result, and K is ACE gene knockout groups, and R is Ramipril group, and H is Hydralazine low blood pressure control group, B are blank control group.

Fig. 4 is Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 immunohistochemical experiment result, and K is ACE gene knockout groups, and R is Ramipril group, and H is hydralazine Low blood pressure control group, B are blank control group.

Fig. 5 is the immunohistochemical experiment result of hypertensin 1-7, and K is ACE gene knockout groups, and R is Ramipril group, and H is Hydralazine low blood pressure control group, B are blank control group.

Fig. 6 is Angiotensin II, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2, the average ash of hypertensin 1-7 that each group measures under ImageJ softwares Spend (optical density) value.

Fig. 7 is concentration of the AcSDKP in cicatricial tissue, is from left to right ACE gene knockouts group, Ramipril group, hydrazine benzene Pyridazine low blood pressure control group and blank control group.

Fig. 8 is NIH3T3 cells cell proliferative conditions under ACE related activities peptide or inhibitor effect.

Fig. 9 is that NIH3T3 cells collagen under ACE related activities peptide or inhibitor effect generates situation.

Embodiment

The present invention is further described in conjunction with the accompanying drawings and embodiments.

The 0.1%ACEI of embodiment 1 and 0.1% Triamcinolone acetonide solution (suspension) and pulvis preparation

By taking Ramipril as an example, 0.01g Ramiprils and 0.01g Triamcinolone acetonides are gradually added in 10ml physiological saline, Stir while adding, until being completely dissolved.(4 DEG C) preservations of normal temperature or refrigeration after encapsulation.Above method obtains 0.1% Ramipril With the normal saline solution (suspension) of 0.1% Triamcinolone acetonide.Mixing powder can also be configured to by mentioned component and quality, sealed After dress normal temperature or refrigeration (4 DEG C) preservation, now the finished product of the anti-scar preparation of compound ACE classes is provided in the form of pulvis, preserve with Transport would be much more convenient；The normal saline solution of above-mentioned concentration will be produced before use, add 10ml physiological saline by user (suspension).

Compound ACE class drug solutions need aseptic process, preferred sterile bulk drug, and are kept in solution process for preparation It is sterile；If bulk drug is non-sterile, bulk drug is first sterilized using Co 60 irradiation etc. before solution is prepared, or after solution preparation Filtration sterilization (at utmost to ensure the stability of medicine).Similarly hereinafter.

The 0.1%ARB of embodiment 2 and 0.3% betamethasone solution (suspension) preparation

By taking Losartan Potassium as an example, 0.01g Losartan Potassiums and 0.03g betamethasones are gradually added in 10ml physiological saline, Stir while adding, until being completely dissolved.(4 DEG C) preservations of normal temperature or refrigeration after encapsulation.Above method obtains 0.1% Losartan Potassium With the normal saline solution (suspension) of 0.3% betamethasone.Mixing powder can also be configured to by mentioned component and quality, sealed After dress normal temperature or refrigeration (4 DEG C) preservation, now the finished product of the anti-scar preparation of compound ACE classes is provided in the form of pulvis, preserve with Transport would be much more convenient；The normal saline solution of above-mentioned concentration will be produced before use, add 10ml physiological saline by user (suspension).

The 3%ARB of embodiment 3 and 1% dexamethasone solution (suspension) preparation

By taking Losartan Potassium as an example, 0.3g Losartan Potassiums and 0.1g dexamethasone are gradually added in 10ml physiological saline, side Side stirring is added, until being completely dissolved.(4 DEG C) preservations of normal temperature or refrigeration after encapsulation.Above method obtain 3% Losartan Potassium and The normal saline solution (suspension) of 1% dexamethasone.Mixing powder can also be configured to by mentioned component and quality, after encapsulation (4 DEG C) preservations of normal temperature or refrigeration, now the finished product of the anti-scar preparation of compound ACE classes is provided in the form of pulvis, storage and transport It would be much more convenient；Will be before use, adding 10ml physiological saline by user, the normal saline solution for producing above-mentioned concentration is (mixed Suspension).

The preparation of the 1%ACEI and 0.33%5-FU solution (suspension) of embodiment 4 and pulvis

By taking captopril as an example, 0.1g captoprils and 0.033g 5-FU are gradually added in 10ml physiological saline, Bian Jia Enter side stirring, until being completely dissolved.(4 DEG C) preservations of normal temperature or refrigeration after encapsulation.Above method obtain 1% captopril and 0.33%5-FU normal saline solution (suspension).Mixing powder can also be configured to by mentioned component and quality, after encapsulation (4 DEG C) preservations of normal temperature or refrigeration, now the finished product of the anti-scar preparation of compound ACE classes is provided in the form of pulvis, storage and transport It would be much more convenient；Will be before use, adding 10ml physiological saline by user, the normal saline solution for producing above-mentioned concentration is (mixed Suspension).

The 1%ARB of embodiment 5 and 2% bleomycin A5 solution (suspension) and pulvis preparation

By taking Irbesartan as an example, 0.1g Irbesartans and 0.2g bleomycin A5s are gradually added in 10ml physiological saline, side Side stirring is added, until being completely dissolved.(4 DEG C) preservations of normal temperature or refrigeration after encapsulation.Above method obtain 1% Irbesartan and The normal saline solution (suspension) of 2% bleomycin A5.Mixing powder can also be configured to by mentioned component and quality, after encapsulation (4 DEG C) preservations of normal temperature or refrigeration, now the finished product of the anti-scar preparation of compound ACE classes is provided in the form of pulvis, storage and transport It would be much more convenient；Will be before use, adding 10ml physiological saline by user, the normal saline solution for producing above-mentioned concentration is (mixed Suspension).

The 10%ACEI of embodiment 6,10% Triamcinolone acetonide and 5%5-FU solution (suspension) and pulvis preparation

By taking enalapril as an example, 1g enalaprils, 1g Triamcinolone acetonides and 0.5g 5-FU are gradually added to 10ml physiological saline In, stir while adding, until being completely dissolved.(4 DEG C) preservations of normal temperature or refrigeration after encapsulation.Above method obtains 10% Yi Napu The normal saline solution (suspension) of profit, 10% Triamcinolone acetonide and 5%5-FU.It can also be configured to mix by mentioned component and quality Pulvis is closed, (4 DEG C) preservations of normal temperature or refrigeration after encapsulation, now the finished product of the anti-scar preparation of compound ACE classes is carried in the form of pulvis For storage and transport would be much more convenient；The life of above-mentioned concentration will be produced before use, by user's addition 10ml physiological saline Manage saline solution (suspension).

The 10%ARB of embodiment 7,3.3% betamethasone and 10% bleomycin A5 solution (suspension) and pulvis preparation

By taking Valsartan as an example, 1g Valsartans, 0.33g betamethasones and 1g bleomycin A5s are gradually added to 10ml physiological saline In, stir while adding, until being completely dissolved.(4 DEG C) preservations of normal temperature or refrigeration after encapsulation.Above method obtains 10% figured silk fabrics sand The normal saline solution (suspension) of smooth, 3.3% betamethasone and 10% bleomycin A5.It can also match somebody with somebody by mentioned component and quality Mixing powder is made, (4 DEG C) preservations of normal temperature or refrigeration after encapsulation, now the finished product of the anti-scar preparation of compound ACE classes is with pulvis Form provides, and storage and transport would be much more convenient；It will be produced above-mentioned dense before use, by user's addition 10ml physiological saline The normal saline solution (suspension) of degree.

The 10%ACEI of embodiment 8,5% Triamcinolone acetonide, 5%5-FU and 5% bleomycin solution (suspension) and pulvis Prepare

It is by taking lisinopril as an example, 1g lisinoprils, 0.5g Triamcinolone acetonides, 0.5g 5-FU and 0.5g bleomycins is gradual Add in 10ml physiological saline, stir while adding, until being completely dissolved.(4 DEG C) preservations of normal temperature or refrigeration after encapsulation.With top Method obtains the normal saline solution (suspension) of 10% lisinopril, 5% Triamcinolone acetonide, 5%5-FU and 5% bleomycin. Mixing powder can be configured to by mentioned component and quality, (4 DEG C) preservations of normal temperature or refrigeration after encapsulation, now compound ACE classes resist The finished product of scar preparation is provided in the form of pulvis, and storage and transport would be much more convenient；Will be before use, being added by user 10ml physiological saline, produce the normal saline solution (suspension) of above-mentioned concentration.

The 5%ARB of embodiment 9,5% betamethasone, 5%5-FU and 5% bleomycin A5 solution (suspension) and pulvis are matched somebody with somebody System

By taking Telmisartan as an example, by 0.5g Telmisartans, 0.5g betamethasones, 0.5g 5-FU and 0.5g bleomycin A5 by Gradually add in 10ml physiological saline, stir while adding, until being completely dissolved.(4 DEG C) preservations of normal temperature or refrigeration after encapsulation.More than Method obtains the normal saline solution (suspension) of 5% Telmisartan, 5% betamethasone, 5%5-FU and 5% bleomycin A5. Mixing powder can be configured to by mentioned component and quality, (4 DEG C) preservations of normal temperature or refrigeration after encapsulation, now compound ACE classes resist The finished product of scar preparation is provided in the form of pulvis, and storage and transport would be much more convenient；Will be before use, being added by user 10ml physiological saline, produce the normal saline solution (suspension) of above-mentioned concentration.

Embodiment 10 contains 0.1%ACEI, 0.1%ARB, 0.3% Triamcinolone acetonide, 0.2%5-FU and 0.1% bleomycin Solution (suspension) and pulvis preparation

ACEI by taking Ramipril as an example, ARB by taking Losartan Potassium as an example, by 0.01g Ramiprils, 0.01g Losartan Potassiums, 0.03g Triamcinolone acetonides, 0.02g 5-FU and 0.01g bleomycins are gradually added in 10ml physiological saline, are stirred while adding, directly To being completely dissolved.(4 DEG C) preservations of normal temperature or refrigeration after encapsulation.Above method is obtained containing 0.1%ACEI, 0.1%ARB, 0.3% song An Naide, 0.2%5-FU and 0.1% bleomycin physiological saline mixed solution (suspension).Can also by mentioned component and Quality is configured to mixing powder, after encapsulation normal temperature or refrigeration (4 DEG C) preservation, now the finished product of the anti-scar preparation of compound ACE classes with The form of pulvis provides, and storage and transport would be much more convenient；It will be produced before use, by user's addition 10ml physiological saline The normal saline solution (suspension) of above-mentioned concentration.

Embodiment 11 is containing 1%ACEI, 3%ARB, 3% betamethasone, 3%5-FU solution (suspension) and matching somebody with somebody for pulvis System

ACEI by taking enalapril as an example, ARB by taking Valsartan as an example, by 0.1g enalaprils, 0.3g Valsartans, 0.3g times he Meter Song, 0.3g 5-FU are gradually added in 10ml physiological saline, are stirred while adding, until being completely dissolved.Normal temperature or cold after encapsulation Hide (4 DEG C) preservations.It is molten that above method obtains the physiological saline mixing containing 1%ACEI, 3%ARB, 3% betamethasone and 3%5-FU Liquid (suspension).Mixing powder can also be configured to by mentioned component and quality, (4 DEG C) preservations of normal temperature or refrigeration after encapsulation, this The finished product of the anti-scar preparation of Shi Fufang ACE classes is provided in the form of pulvis, and storage and transport would be much more convenient；Will before use, 10ml physiological saline is added by user, produces the normal saline solution (suspension) of above-mentioned concentration.

Solution (suspension) of the embodiment 12 containing 5%ACEI, 10%ARB, 5% Triamcinolone acetonide and 5% bleomycin A5 solution With the preparation of pulvis

For ACEI by taking captopril as an example, ARB is bent by 0.5g captoprils, 1g Irbesartans, 0.5g by taking Irbesartan as an example An Naide and 0.5g bleomycin A5s are gradually added in 10ml physiological saline, are stirred while adding, until being completely dissolved.After encapsulation often (4 DEG C) preservations of temperature or refrigeration.Above method obtains the life containing 5%ACEI, 10%ARB, 5% Triamcinolone acetonide and 5% bleomycin A5 Manage salt water mixed solution (suspension).Mixing powder, normal temperature or refrigeration after encapsulation can also be configured to by mentioned component and quality (4 DEG C) preservations, now the finished product of the anti-scar preparation of compound ACE classes is provided in the form of pulvis, and storage and transport would be much more convenient； The normal saline solution (suspension) of above-mentioned concentration will be produced before use, add 10ml physiological saline by user.

Solution (suspension) of the embodiment 13 containing 5%ACEI, 10%ARB, 5% Triamcinolone acetonide and 5% bleomycin solution With the preparation of pulvis

For ACEI by taking captopril as an example, ARB is bent by 0.5g captoprils, 1g Irbesartans, 0.5g by taking Irbesartan as an example An Naide and 0.5g bleomycins are gradually added in 10ml physiological saline, are stirred while adding, until being completely dissolved.After encapsulation often (4 DEG C) preservations of temperature or refrigeration.Above method obtains the life containing 5%ACEI, 10%ARB, 5% Triamcinolone acetonide and 5% bleomycin Manage salt water mixed solution (suspension).Mixing powder, normal temperature or refrigeration after encapsulation can also be configured to by mentioned component and quality (4 DEG C) preservations, now the finished product of the anti-scar preparation of compound ACE classes is provided in the form of pulvis, and storage and transport would be much more convenient； The normal saline solution (suspension) of above-mentioned concentration will be produced before use, add 10ml physiological saline by user.

The preparation of solution (suspension) and pulvis of the embodiment 14 containing 10%ACEI, 6.7%ARB and 6.7% Triamcinolone acetonide

ACEI by taking lisinopril as an example, ARB by taking Telmisartan as an example, by 1g lisinoprils, 0.67g Telmisartans and 0.67g Triamcinolone acetonides are gradually added in 10ml physiological saline, are stirred while adding, until being completely dissolved.Normal temperature or cold after encapsulation Hide (4 DEG C) preservations.Above method obtains the physiological saline mixed solution containing 10%ACEI, 6.7%ARB and 6.7% Triamcinolone acetonide (suspension).Mixing powder can also be configured to by mentioned component and quality, (4 DEG C) preservations of normal temperature or refrigeration after encapsulation, now The finished product of the anti-scar preparation of compound ACE classes is provided in the form of pulvis, and storage and transport would be much more convenient；Will before use, by User adds 10ml physiological saline, produces the normal saline solution (suspension) of above-mentioned concentration.

Solution of the embodiment 15 containing 1%ARB, 1%SP antagonist, 3% betamethasone, 3%5-FU and 3% bleomycin A5 The preparation of (suspension) and pulvis

ARB is by taking Losartan Potassium as an example, and SP antagonist is by taking L-733060 as an example, by 0.1g Losartan Potassiums, 0.1g L- 733060th, 0.3g betamethasones, 0.3g 5-FU and 0.3g bleomycin A5s are gradually added in 10ml physiological saline, are stirred when adding Mix, until being completely dissolved.Normal temperature after encapsulation (being used in the short time), refrigeration (4 DEG C, use in a short time) or freezing (- 20 DEG C, compared with Used after long-time；Need to thaw before use) preserve.Above method is obtained containing 1%ARB, 1%SP antagonist, 3% times of his rice The physiological saline mixed solution (suspension) of pine, 3%5-FU and 3% bleomycin A5.It can also be prepared by mentioned component and quality Into mixing powder, (4 DEG C) preservations of normal temperature or refrigeration after encapsulation, now the finished product of the anti-scar preparation of compound ACE classes is with the shape of pulvis Formula provides, and storage and transport would be much more convenient；Above-mentioned concentration will be produced before use, by user's addition 10ml physiological saline Normal saline solution (suspension).

Solution of the embodiment 16 containing 10%ARB, 3.3%SP antagonist, 3.3% dexamethasone and 5% bleomycin is (mixed Suspension) and pulvis preparation

ARB is by taking Irbesartan as an example, and SP antagonist is by taking L-733060 as an example, by 1g Irbesartans, 0.33g L- 733060th, 0.33g dexamethasone and 0.5g bleomycins are gradually added in 10ml physiological saline, are stirred while adding, until complete Fully dissolved.Normal temperature or normal temperature (being used in the short time) after encapsulation, refrigeration (4 DEG C, use in a short time) or freezing (- 20 DEG C, when longer Between after use；Need to thaw before use) preserve.Above method is obtained containing 10%ARB, 3.3%SP antagonist, 3.3% ground plug rice Pine and the physiological saline mixed solution (suspension) of 5% bleomycin.Mixed powder can also be configured to by mentioned component and quality Agent, (4 DEG C) preservations of normal temperature or refrigeration after encapsulation, now the finished product of the anti-scar preparation of compound ACE classes is provided in the form of pulvis, is protected Deposit and transport would be much more convenient；The physiological saline of above-mentioned concentration will be produced before use, add 10ml physiological saline by user Solution (suspension).

Embodiment 17 containing 0.1%ACEI, 0.3%SP antagonist, 0.1% brad ykinin antagonists, 0.1% Triamcinolone acetonide, The preparation of the solution of 0.2%5-FU and 0.1% bleomycin A5 (suspension) and pulvis

ACEI by taking benazepil as an example, SP antagonist by taking L-733060 as an example, the antagonist of bradykinin using DALBK as Example；By 0.01g benazepils, 0.03g L-73306,0.01g DALBK, 0.01g Triamcinolone acetonides, 0.02g 5-FU and 0.01g Bleomycin A5 is gradually added in 10ml physiological saline, is stirred while adding, until being completely dissolved.Normal temperature is (in the short time after encapsulation Using), (- 20 DEG C, used after the long period for refrigeration (4 DEG C, use in a short time) or freezing；Need to thaw before use) preserve.With Upper method obtains containing 0.1%ACEI, 0.3%SP antagonist and the Triamcinolone acetonide of 0.1% brad ykinin antagonists 0.1%, 0.2%5-FU With the physiological saline mixed solution (suspension) of 0.1% bleomycin A5.Mixed powder can also be configured to by mentioned component and quality Agent, (4 DEG C) preservations of normal temperature or refrigeration after encapsulation, now the finished product of the anti-scar preparation of compound ACE classes is provided in the form of pulvis, is protected Deposit and transport would be much more convenient；The physiological saline of above-mentioned concentration will be produced before use, add 10ml physiological saline by user Solution (suspension).

Embodiment 18 containing 10%ACEI, 5%SP antagonist and, 3.3% brad ykinin antagonists and 3.3% dexamethasone The preparation of solution (suspension) and pulvis

ACEI by taking Ramipril as an example, SP antagonist by taking L-733060 as an example, the antagonist of bradykinin using DALBK as Example；1g Ramiprils, 0.5g L-733060,0.33g DALBK and 0.33g dexamethasone are gradually added to 10ml physiological saline In, stir while adding, until being completely dissolved.Normal temperature after encapsulation (being used in the short time), refrigeration (4 DEG C, use in a short time) or (- 20 DEG C, used after the long period for freezing；Need to thaw before use) preserve.Above method obtains short of money containing 10%ACEI, 5%SP The physiological saline mixed solution (suspension) of anti-agent and 3.3% brad ykinin antagonists and 3.3% dexamethasone.Can also be by above-mentioned Composition and quality are configured to mixing powder, (4 DEG C) preservations of normal temperature or refrigeration after encapsulation, now compound ACE classes anti-scar preparations Finished product is provided in the form of pulvis, and storage and transport would be much more convenient；Will be before use, adding 10ml physiology salts by user Water, produce the normal saline solution (suspension) of above-mentioned concentration.

Solution of the embodiment 19 containing 10%ACEI, 5%SP antagonist, 5% brad ykinin antagonists and 5% bleomycin A5 is (mixed Suspension) and pulvis preparation

ACEI by taking lisinopril as an example, SP antagonist by taking L-733060 as an example, the antagonist of bradykinin using HOE-140 as Example；1g lisinoprils, 0.5g L-733060,0.5g HOE-140 and 0.5g bleomycin A5s are gradually added to 10ml physiological saline In, stir while adding, until being completely dissolved.Normal temperature after encapsulation (being used in the short time), refrigeration (4 DEG C, use in a short time) or (- 20 DEG C, used after the long period for freezing；Need to thaw before use) preserve.Above method obtains short of money containing 10%ACEI, 5%SP The physiological saline mixed solution (suspension) of anti-agent, 5% brad ykinin antagonists and 5% bleomycin A5.Can also be by mentioned component Mixing powder is configured to quality, (4 DEG C) preservations of normal temperature or refrigeration, the now finished product of the anti-scar preparation of compound ACE classes after encapsulation There is provided in the form of pulvis, storage and transport would be much more convenient；Will be before use, adding 10ml physiological saline by user, i.e., Obtain the normal saline solution (suspension) of above-mentioned concentration.

Embodiment 20 containing 1%ARB, 1%SP antagonist and the Triamcinolone acetonide of 1% brad ykinin antagonists 3%, 3%5-FU and The solution (suspension) of 3% bleomycin A5 and the preparation of pulvis

ARB is by taking Losartan Potassium as an example, and SP antagonist is by taking L-733060 as an example, and the antagonist of bradykinin is by taking DALBK as an example； By 0.1g Losartan Potassiums, 0.1g L-733060,0.1g DALBK, 0.3g Triamcinolone acetonides, 0.3g 5-FU and 0.3g bleomycin A5s It is gradually added in 10ml physiological saline, stirs while adding, until is completely dissolved.It is normal temperature after encapsulation (being used in the short time), cold Hiding (4 DEG C, use in a short time) or freezing, (- 20 DEG C, used after the long period；Need to thaw before use) preserve.Above method obtains To the life containing 1%ACEI, 1%SP antagonist, 1% brad ykinin antagonists, 3% Triamcinolone acetonide, 3%5-FU and 3% bleomycin A5 Manage salt water mixed solution (suspension).Mixing powder, normal temperature or refrigeration after encapsulation can also be configured to by mentioned component and quality (4 DEG C) preservations, now the finished product of the anti-scar preparation of compound ACE classes is provided in the form of pulvis, and storage and transport would be much more convenient； The normal saline solution (suspension) of above-mentioned concentration will be produced before use, add 10ml physiological saline by user.

Embodiment 21 contains 10%ARB, 3.3%SP antagonist, 5% brad ykinin antagonists, 3.3%5-FU and 3.3% Pingyang The solution (suspension) of mycin and the preparation of pulvis

ARB by taking Candesartan as an example, SP antagonist by taking L-733060 as an example, the antagonist of bradykinin using HOE-140 as Example；1g Candesartans, 0.33g L-733060,0.5g HOE-140,0.33g 5-FU and 0.33 bleomycin A5 are gradually added to In 10ml physiological saline, stir while adding, until being completely dissolved；Then add, stirring is to being completely dissolved.Normal temperature after encapsulation (- 20 DEG C, used after the long period for (short time in use), refrigeration (4 DEG C, use in a short time) or freezing；Need to solve before use Freeze) preserve.Above method is obtained containing 10%ACEI, 3.3%SP antagonist, 5% brad ykinin antagonists, 3.3%5-FU and 3.3% The physiological saline mixed solution (suspension) of bleomycin A5.Mixing powder can also be configured to by mentioned component and quality, encapsulated (4 DEG C) preservations of normal temperature or refrigeration afterwards, now the finished product of the anti-scar preparation of compound ACE classes is provided in the form of pulvis, is preserved and is transported It is defeated to would be much more convenient；The normal saline solution of above-mentioned concentration will be produced before use, add 10ml physiological saline by user (suspension).

Embodiment 22 containing 1%ARB, 1%SP antagonist, 1% brad ykinin antagonists, 1%AcSDKP and 1%Ang 1-7, The solution (suspension) of 3% Triamcinolone acetonide, 1%5-FU and 1% bleomycin and the preparation of pulvis

ARB is by taking Losartan Potassium as an example, and SP antagonist is by taking L-733060 as an example, and the antagonist of bradykinin is by taking DALBK as an example； By 0.1g Losartan Potassiums, 0.1g L-733060,0.1g DALBK, 0.1g AcSDKP, 0.1g Ang 1-7, the bent peaces of 0.3g how Moral, 0.1g 5-FU and 0.1g bleomycins are gradually added in 10ml physiological saline, are stirred while adding, until being completely dissolved.Envelope (- 20 DEG C, used after the long period for normal temperature after dress (being used in the short time), refrigeration (4 DEG C, use in a short time) or freezing；Before use Need to thaw) preserve.Above method is obtained containing 1%ARB, 1%SP antagonist, 1% brad ykinin antagonists, 1%AcSDKP and 1% Ang 1-7,3% Triamcinolone acetonide, the physiological saline mixed solution (suspension) of 1%5-FU and 1% bleomycin.Can also be by upper State composition and quality is configured to mixing powder, (4 DEG C) preservations of normal temperature or refrigeration, the now anti-scar preparation of compound ACE classes after encapsulation Finished product provided in the form of pulvis, storage and transport would be much more convenient；Will be before use, adding 10ml physiology salts by user Water, produce the normal saline solution (suspension) of above-mentioned concentration.

Embodiment 23 containing 1%ARB, 1%SP antagonist, 1% brad ykinin antagonists, 1%AcSDKP and 1%Ang 1-7, The solution (suspension) of 3% Triamcinolone acetonide, 1%5-FU and 1% bleomycin A5 and the preparation of pulvis

ARB is by taking Losartan Potassium as an example, and SP antagonist is by taking L-733060 as an example, and the antagonist of bradykinin is by taking DALBK as an example； By 0.1g Losartan Potassiums, 0.1g L-733060,0.1g DALBK, 0.1g AcSDKP, 0.1g Ang 1-7, the bent peaces of 0.3g how Moral, 0.1g 5-FU and 0.1g bleomycin A5s are gradually added in 10ml physiological saline, are stirred while adding, until being completely dissolved.Envelope (- 20 DEG C, used after the long period for normal temperature after dress (being used in the short time), refrigeration (4 DEG C, use in a short time) or freezing；Before use Need to thaw) preserve.Above method is obtained containing 1%ARB, 1%SP antagonist, 1% brad ykinin antagonists, 1%AcSDKP and 1% Ang 1-7,3% Triamcinolone acetonide, the physiological saline mixed solution (suspension) of 1%5-FU and 1% bleomycin A5.Can also be by upper State composition and quality is configured to mixing powder, (4 DEG C) preservations of normal temperature or refrigeration, the now anti-scar preparation of compound ACE classes after encapsulation Finished product provided in the form of pulvis, storage and transport would be much more convenient；Will be before use, adding 10ml physiology salts by user Water, produce the normal saline solution (suspension) of above-mentioned concentration.

Embodiment 24 is containing 3.3%ARB, 3.3%SP antagonist, 3.3% brad ykinin antagonists, 3.3%AcSDKP, 3.3% The preparation of the solution of Ang 1-7 and 5% bleomycin A5 (suspension) and pulvis

ARB is by taking Olmesartan as an example, and SP antagonist is by taking L-733060 as an example, and the antagonist of bradykinin is by taking DALBK as an example； 0.33g Olmesartans, 0.33g L-733060,0.33g DALBK, 0.33g AcSDKP, 0.33g Ang 1-7 and 0.5g are put down Positive mycin is gradually added in 10ml physiological saline, is stirred while adding, until being completely dissolved.Normal temperature (makes in the short time after encapsulation With), (- 20 DEG C, used after the long period for refrigeration (4 DEG C, use in a short time) or freezing；Need to thaw before use) preserve.More than Method obtain containing 3.3%ARB, 3.3%SP antagonist, 3.3% brad ykinin antagonists, 3.3%AcSDKP, 3.3%Ang1-7 and The physiological saline mixed solution (suspension) of 5% bleomycin A5.Mixing powder can also be configured to by mentioned component and quality, sealed After dress normal temperature or refrigeration (4 DEG C) preservation, now the finished product of the anti-scar preparation of compound ACE classes is provided in the form of pulvis, preserve with Transport would be much more convenient；The normal saline solution of above-mentioned concentration will be produced before use, add 10ml physiological saline by user (suspension).

Embodiment 25 is containing 5%ARB, 2.5%SP antagonist, 5% brad ykinin antagonists, 2.5%AcSDKP, 5%Ang1-7 With 2.5%5-FU solution (suspension) and the preparation of pulvis

ARB is by taking Valsartan as an example, and SP antagonist is by taking L-733060 as an example, and the antagonist of bradykinin is by taking HOE-140 as an example； By 0.5g Valsartans, 0.25g L-733060,0.5g HOE-140,0.25g AcSDKP, 0.5g Ang 1-7 and 0.25g 5- FU is gradually added in 10ml physiological saline, is stirred while adding, until being completely dissolved.Normal temperature after encapsulation (being used in the short time), Refrigerating (4 DEG C, use in a short time) or freezing, (- 20 DEG C, used after the long period；Need to thaw before use) preserve.Above method Obtain containing 5%ARB, 2.5%SP antagonist, 5% brad ykinin antagonists, 2.5%AcSDKP, 5%Ang 1-7 and 2.5%5-FU Physiological saline mixed solution (suspension).Mixing powder can also be configured to by mentioned component and quality, after encapsulation normal temperature or (4 DEG C) preservations of refrigeration, now the finished product of the anti-scar preparation of compound ACE classes is provided in the form of pulvis, and storage and transport will more It is convenient；The normal saline solution (suspension) of above-mentioned concentration will be produced before use, add 10ml physiological saline by user.

The detection of each ACE related activities peptide in the mouse scar of embodiment 26

1. experimental method：

(1) experimental subjects：Select C57BL/6 mouse, be divided into 4 groups, respectively K groups be ACE gene knockouts group, R groups be thunder Meter Pu Li groups, H groups are hydralazine group, B groups are blank control group.Wherein K groups use ACE knock out mice, remaining each group It is the wild type with the compatriot's birth of ACE knock out mice.

(2) factor is handled：

After mouse conventinal breeding 3d, in the chloraldurate normal saline solution 0.1ml/10g of intraperitoneal injection 4%, anaesthetize into The hair of dorsal area is cut off after work(with scissors, depilatory cream further removes the hair of mouse back.Using mouse backbone as center line, side is opened Surgically left and right respectively cuts off 1 to 4mm (two defects of skin have some tension, can mutually pull, be advantageous to scar proliferation) Block 2mm × 15mm stringer rectangular slits (Fig. 2).Divide cage to feed mouse after otch foundation, add respectively in mouse drinking water Add different medicines, wherein B groups feed common drinking water；R groups feed the drinking water containing Ramipril (10mg/kg/ days)；H groups are fed Drinking water containing hydralazine (40mg/kg/ days)；K groups feed common drinking water.Treat that all mouse back operations in postoperative 14 days are cut Discharge surface scab puts to death mouse after coming off.Cut cicatricial tissue, FFPE, Ang II in row SABC detection tissue, SP and Ang 1-7 expression quantity；Take part cicatricial tissue ELISA method detection AcSDKP expression quantity.

2. experimental result：

(1) Ang II ImmunohistochemistryResults Results

Each group ImmunohistochemistryResults Results are shown in Fig. 3, as seen from the figure, the Ang II expression of ACE gene knockouts group and Ramipril group Amount is significantly lower than hydralazine group and blank control group (p<0.05)；But ACE gene knockouts group and Ramipril group difference are without system Meter learns meaning (p>0.05), hydralazine group and blank control group no significant difference (p>0.05).

(2) SP ImmunohistochemistryResults Results

Each group ImmunohistochemistryResults Results are shown in Fig. 4, and as seen from the figure, the SP expression quantity of ACE gene knockouts group and Ramipril group is bright It is aobvious to be higher than hydralazine group and blank control group (p<0.05)；But ACE gene knockouts group and Ramipril group no statistical difference Meaning (p>0.05), hydralazine group and blank control group no significant difference (p>0.05).

(3) Ang 1-7 ImmunohistochemistryResults Results

Each group ImmunohistochemistryResults Results are shown in Fig. 5, as seen from the figure, the Ang 1-7 expression of ACE gene knockouts group and Ramipril group Measure apparently higher than hydralazine group and blank control group (p<0.05)；But ACE gene knockouts group and Ramipril group difference are without system Meter learns meaning (p>0.05), hydralazine group and blank control group no significant difference (p>0.05).

(4) ImmunohistochemistryResults Results

Average gray (average optical density) result using ImageJ software quantitative analyses Ang II, SP and Ang 1-7 is shown in Fig. 6.Ang II expression quantity in ACE gene knockouts group, Ramipril group cicatricial tissue is significantly lower than blank control group and hydrazine benzene Pyridazine group (p<0.05), and SP and Ang 1-7 expression quantity is apparently higher than blank control group and hydralazine group (p<0.05).

(4) AcSDKP ELISA experimental results

Each group ELISA experimental results are shown in Fig. 7.The AcSDKP expression quantity of ACE gene knockouts group and Ramipril group is substantially high In hydralazine group and blank control group (p<0.05)；But ACE gene knockouts group and Ramipril group no significant difference (p>0.05), hydralazine group and blank control group no significant difference (p>0.05).

3. experiment conclusion：

(1) ACE is blocked to reduce cicatricial tissue Ang II expression by way of medicine or gene knockout.

(2) ACE is blocked to increase cicatricial tissue SP, Ang 1-7 and AcSDKP by way of medicine or gene knockout Expression.

The optium concentration of the ACE related activities peptide of embodiment 27/inhibitor (ACE classes medicine) stimulated in vitro

1. experimental method：

Using the DMEM cell culture fluid culture NIH 3T3 l cells containing 10%FBS, (fibroblast is The ultimate effector cell of cicatrization, other cells and factor are all finally by influenceing wound to fibroblastic effect Healing), but FBS was reduced to 1% to reduce the influence of various albumen in serum as far as possible in 24 hours before detection.Will NIH 3T3 fibroblasts (DMEM containing 1%FBS) are transferred to 96 orifice plates, and adding 1ng/ml TGF-βs 1 stimulates (TGF-β 1 It is the strong rush fibrosis factor, adding the restructuring TGF-β 1 of external source stimulates cell to simulate wound stimulation) pierced with simulating wound Swash；While the Ang II of at least 3 various concentrations (10 times are incremented by) are separately added into, SP, AcSDKP, Ang 1-7 and bradykinin, with And respective inhibitor (or antagonist) and ACE inhibitor.48 hours, using CCK-8 methods (Cell Counting Kit-8, Dojindo, Japan) detection cell proliferative conditions.

According to the action principle of each medicine, if selected medicine plays a driving role in NIH3T3 cells propagation, more No cytotoxicity is selected in individual concentration, promotes the optimal least concentration of cell cultivation effect as optium concentration；If selected medicine Inhibitory action is played in NIH3T3 cells propagation, then no cytotoxicity is selected in multiple concentration, suppresses cell cultivation effect most Good least concentration is as optium concentration.

2. experimental result

Experimental result is shown in Table 1.

The optium concentration of the ACE related activities peptide of table 1 and inhibitor stimulated in vitro

Biologically active peptide	Optium concentration	Inhibitor	Optium concentration
				AngII	10nM	Losartan	100μM
SP	100nM	L-733060	1μM
				Ang1-7	10nM	A779	10μM
AcSDKP	1×10-4mg/ml	S-17092	1×10-2mg/ml
				Bradykinin	1nM	DALBK	10nM
		HOE-140	100nM
						Lisinopril	10μM

The ACE class drug influence NIH 3T3 cells of embodiment 28 are bred and the experimental study of collagen

The final result of cicatrization shows hyperblastosis and collagen deposition in vivo, then finally shows thin in vitro Born of the same parents breed and collagen production.

1. experimental method：

Using the DMEM cell culture fluid culture NIH 3T3 l cells containing 10%FBS, but before detection FBS was reduced to 1% influence for having reduced various albumen in serum as far as possible in 24 hours.1ng/ml TGF-βs 1 are added to simulate Wound stimulates；While Ang II are separately added into, SP, AcSDKP, Ang 1-7 and bradykinin, and respective inhibitor (or antagonism Agent) and ACE inhibitor, the concentration of each active peptide and inhibitor (or antagonist) is all optimal dense in above-described embodiment Degree；After culture 48 hours, using CCK-8 methods (Cell Counting Kit-8, Dojindo, Japan) detection cell propagation feelings Condition, the collagen egg in nutrient solution is detected with Sirius Red Collagen Detection Kit (Chondres Inc.USA) White concentration.Above-mentioned every kind of ACE classes medicine does 6 repetitions, and the data of acquisition carry out single factor test using the SPSS19.0 of IBM Corporation Variance analysis, compare two-by-two using LSD methods, p<0.05 thinks statistically significant.

2. experimental result：

Cell proliferative conditions are shown in Fig. 4.Because cell proliferative conditions repeated detection, condition slightly has difference, but detects every time Contain blank control group (containing 1ng/ml TGF-βs 1), therefore be standardized with the group, i.e., by blank control group Absorbance values are all standardized as 1.Ang II, SP, A799, S-17902 and bradykinin play the role of to promote cell propagation；Its In, Ang II promote the best results (p of NIH3T3 propagation<0.05), SP, A799, S-17902 and bradykinin compare no system two-by-two Meter learns meaning (p>0.05).Losartan, L-733060, Ang 1-7, AcSDKP, 2 kinds of brad ykinin antagonists (DALBK and HOE- 140) and Lisinopril can suppress cell propagation, wherein Losartan, L-733060 and Lisinopril inhibition compared with Ang 1-7, AcSDKP and 2 kinds of brad ykinin antagonists more preferably (p<0.01), but the difference between former three between rear four Not statistically significant (p>0.05).

Collagen generation situation is shown in Fig. 5.Ang II, SP, A799, S-17902 and bradykinin can promote collagen to generate；Its In, Ang II promote the collagenogenic best results (p of NIH3T3<0.05), SP, A799, S-17902 and bradykinin compare two-by-two Not statistically significant (p>0.05).Losartan, L-733060, Ang 1-7, AcSDKP, 2 kinds of brad ykinin antagonists and Lisinopril can suppress collagen generation, and wherein Losartan, L-733060 and Lisinopril inhibition are compared with Ang 1- 7th, AcSDKP and 2 kinds of brad ykinin antagonists more preferably (p<0.01), but the difference between former three between rear four is without system Meter learns meaning (p>0.05).

3. experiment conclusion：

This experimental study ACE classes medicine promotion to cicatrization or inhibitory action in vitro.Wherein, Losartan, L-733060, Ang 1-7, AcSDKP, 2 kinds of brad ykinin antagonists (DALBK and HOE-140) and Lisinopril can suppress into fibre Cytoactive is tieed up, Losartan, L-733060 and Lisinopril inhibition are compared with Ang 1-7, AcSDKP and 2 kinds of bradykinins Antagonist is more preferably.

The CO of embodiment 29₂Dot matrix laser mediation compound ACE classes drug targeting suppresses the method that cicatrix of skin is formed

1) anaesthetize：General anesthesia mode (such as chloraldurate normal saline solution of intraperitoneal injection 4% may be selected in mouse, rat 0.1ml/10g)；Human injection can not anaesthetize, and surface anesthesia mode also may be selected and (apply " compound lidocaine emulsifiable paste " outside 1 hour After start to inject).

2) delivery time：14 days mouse back operative incision scabs come off after mouse, rat operation, expose the scar under scab Started medication after trace tissue；Human body scar is started medication taking out stitches 1 week.

3) medication：Scar and surrounding skin routine disinfection；Utilize the CO of Fei Dun laser companies₂Dot matrix laser, use Lite Scan hands have, energy density 20-25mj/pixel, pulsewidth 0.8,1 grade of spot diameter, 5 grades of coverage rate, on scar surface Scan several unduplicated rectangular areas and covering scar is completely covered；Then corresponding medicine is quantitatively extracted with 1ml syringes Solution, left and right sides scar surface is respectively overlay in, per side 0.05-0.2ml/ square centimeters；With Fei Dun laser companies Impact cutaneous penetrations hand tool (frequency 30-50 hertz, dutycycle 50%) is close to scar tissue surface slip, and solution is pushed into scar In trace.

The method of injection compound ACE class medicines in the scar of embodiment 30

1) anaesthetize：General anesthesia mode may be selected in mouse, rat, rabbit；Human injection can not anaesthetize, and surface anesthesia also may be selected Mode (applies " compound lidocaine emulsifiable paste " to start to inject after 1 hour) outside.2) when starting to inject in scar, a hand finger is placed in Local skin is tightened around scar；Another hand syringes (25-30G syringe needles), it is ensured that pinpoint inclined plane is upward；Acupuncture people's scar It may need slightly to exert oneself when interior；Enter shallow-layer in pin to scar, the withdraw of the needle injects medicine simultaneously；When scar swelling becomes big, and show It can terminate to inject when white or yellow-white；When pulling out pin due to pinpoint inclined plane upward, when syringe needle exits scar surface, medicine may Meeting four dissipates splashes, now pays attention to protection (usable safety goggles).3) repeated multiple times if necessary, multi-point injection keloid until Its color and luster bleaches.4) usual 3 times are a course for the treatment of, every minor tick -2 months 2 weeks, specifically depending on curative effect；After one course for the treatment of terminates Visual scar situation stops injection or continues to inject.

Claims (9)

1. a kind of anti-scar preparation of compound Angiotensin-Converting class, it is characterised in that by one or more of ACE classes medicines The active ingredient of active component and other one or more anti-scarring drugs composition, dosage form are pulvis or solution, wherein Other anti-scarring drugs select glucocorticoid, 5-FU, bleomycin or bleomycin A5.

2. the anti-scar preparation of a kind of compound Angiotensin-Converting class according to claim 1, it is characterised in that described Angiotensin-Converting class medicine is ARB, N- acetyl group-seryl-aspartoyl-lysyls- Proline, hypertensin 1-7, Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 antagonist L-733060, brad ykinin antagonists DALBK and HOE-140 and blood vessel are tight Plain converting enzyme inhibitor, wherein, ARB be selected from Losartan, Irbesartan, Valsartan, for meter Sha Smooth, Olmesartan, Candesartan；Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 antagonist is selected from L-733060；Brad ykinin antagonists are selected from DALBK and HOE-140； Angiotensin converting enzyme inhibitor is selected from lisinopril, Ramipril, captopril, Cilazapril, enalapril, Bei Napu Profit.

3. the anti-scar preparation of a kind of compound Angiotensin-Converting class according to claim 1, it is characterised in that described Glucocorticoid is selected from Triamcinolone acetonide, betamethasone, dexamethasone.

4. the anti-scar preparation of a kind of compound Angiotensin-Converting class according to claim 1, it is characterised in that described The mode of a variety of Angiotensin-Converting class effective ingredients combination is：ARB and vasotonia Plain converting enzyme inhibitor combination, quality proportioning 0.33-3:0.33-3；The antagonism of ARB and Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 Agent is combined, quality proportioning 0.33-3:0.33-3；The antagonist of angiotensin converting enzyme inhibitor and Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2, bradykinin Antagonist-combination, quality proportioning 0.33-3:0.33-3:0.33-3；The antagonism of ARB and Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 Agent, the antagonist-combination of bradykinin, quality proportioning 0.33-3:0.33-3:0.33-3；ARB and P The antagonist of material, the antagonist of bradykinin, and N- acetyl group-seryl-aspartoyl-lysyl-proline, blood vessel are tight Open plain 1-7 combinations, quality proportioning 0.33-3:0.33-3:0.33-3:0.33-3:0.33-3；Other combinations are according to blood vessel Converting Enzyme suppresses fibrosis and the selection of scar situation.

5. the anti-scar preparation of a kind of compound Angiotensin-Converting class according to claim 1, it is characterised in that described The mode of various other anti-scarring drug combination of active principles is：Glucocorticoid combines with 5 FU 5 fluorouracil, and quality proportioning is 0.33-3:0.33-3；Glucocorticoid combines with bleomycin, quality proportioning 0.33-3:0.33-3；Glucocorticoid is with putting down Positive mycin combination, quality proportioning 0.33-3:0.33-3；5 FU 5 fluorouracil combines with bleomycin, quality proportioning 0.33-3: 0.33-3；5 FU 5 fluorouracil combines with bleomycin A5, quality proportioning 0.33-3:0.33-3；Glucocorticoid is urinated phonetic with 5- fluorine Pyridine and bleomycin combination, quality proportioning 0.33-3:0.33-3:0.33-3；Glucocorticoid and 5 FU 5 fluorouracil and Pingyang Mycin combines, quality proportioning 0.33-3:0.33-3:0.33-3.

6. the anti-scar preparation of a kind of compound Angiotensin-Converting class according to claim 1, it is characterised in that described The total mass concentration of preparation of traditional Chinese medicine is 0.1%-25%, when by several drugses combination of active principles, the quality such as each composition is Mixing, or 3 times of highest when the quality such as being transferred in the quality of any of which composition or minimum 1/3 times when the quality such as being adjusted downward to.

7. the anti-scar preparation of a kind of compound Angiotensin-Converting class according to claim 1, it is characterised in that described Solution is suspension.

A kind of 8. anti-scar preparation of Angiotensin-Converting class according to claim 1, it is characterised in that the preparation In can add liquor capacity 20%-100% 2% lidocaine.

A kind of 9. anti-scar preparation of Angiotensin-Converting class according to claim 1, it is characterised in that the preparation Need aseptic process.