CN1270725C - Inorganic nitrite and organic acid in combination as topical antiviral composition - Google Patents
Inorganic nitrite and organic acid in combination as topical antiviral composition Download PDFInfo
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- CN1270725C CN1270725C CNB998035866A CN99803586A CN1270725C CN 1270725 C CN1270725 C CN 1270725C CN B998035866 A CNB998035866 A CN B998035866A CN 99803586 A CN99803586 A CN 99803586A CN 1270725 C CN1270725 C CN 1270725C
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- acidulant
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- acid
- nitric oxide
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- 230000001196 vasorelaxation Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention provides a dosage form for the treatment of bacterial, viral or fungal conditions which comprises, a pharmaceutically acceptable acidifying agent in an amount sufficient to reduce the pH at an environment of use to below pH4, and a pharmaceutically acceptable source of nitrite ions or a nitrate precursor therefor; wherein said acidifying agent and said source of nitrite ions or nitrate precursor are separately disposed in respective pharmaceutically acceptable carriers for admixture at the intended environment of use to release NO or NO2 ions. The invention also provides delivery systems for the topical medicament.
Description
The present invention relates to nitrite and the nitrogen oxide complex that acid reacts to each other and forms, be used as the local antiviral composition that uses with the treatment viral dermatosis.Described nitrogen oxide especially refers to NO, is even more important during by acidify.
In WO95/22335, we disclose a kind of pharmaceutical composition, and the acidulant that contains the nitrous acid Yanyuan of pharmaceutically approval and pharmaceutically approve especially is fit to the local directly treatment disease of using.These chemical compounds have direct effect to associated biomolecule, but definite model of action it be unclear that.
US-A-4595591 has disclosed a kind of compositions, contains nitric acid and nitrous aqueous acid, and pH is lower than 1, preferably also contains a kind of organic acid and copper, calcium ion, is used for the treatment of the skin superficial damage, for example tumprigenicity growth.
US-A-5648101 provides a kind of vasoactive compositions, contains the suitable NO that sends to health a part, especially passes through the mode of emulsifiable paste or ointment.Described NO mixes generation by ferrous sulfate, organic acid and inorganic nitrite, and the activity that become in the presence of near the moisture site of delivery or the position.Wherein do not speak of acidify.
WO96/02268 nitrogen oxide (NO
2) suppress virus, but wherein do not speak of the advantage that reduces environment for use PH.
WO93/25213 discloses a kind of skin composition that contains nitrogen oxide, and the main component of said composition comprises fatty acid or its lower alkyl ester, but does not wherein mention the pH of pH, especially environment for use.
The NO chemical compound discloses (63 by J.B.Mannick in the effect of vitro inhibition virus replication
RdForum inImmunology and papers in Intervirology 1995; 38:206-213, Trends in Microbiology1995; 3:81-82, Science, 1993:261; 1445-1448 and J.Clin.Investigation, 1993; 91:2446-2452).Above paper has disclosed the effect of NO to multiple virus, for example herpes simplex virus, vaccinia virus and vesicular stomatitis virus.External, use the exogenous NO gas donor, for example plain amine (SNAP) of S-nitroso-group-N-acetamido penicillanate or SIN-1 measure the effect of NO as antiviral compound.Use exogenous NO gas to suppress duplicating of DNA to experimental virus infected cell.As if suppress mechanism due to illness malicious and different.For example, be example with the vaccinia virus, it is believed that it may be by in conjunction with nonheme iron or sulfydryl that NO suppresses to duplicate, enzymatic activity was most important during the latter duplicated cowpox.In this external model, the antivirus action of NO does not need the immunity identification of infected cell, and therefore the early stage strick precaution to virus causing disease was provided before producing specific immune response.
Virus will be survived and duplicate, and just must escape the recognition reaction of host immune response.Though it is also not fully aware of to hide mechanism, efficient immune can be eliminated infection.Virus is cause of disease in the obligate born of the same parents.They utilize host's metabolic mechanism to duplicate.
At present, the Drug therapy to virosis depends on the chemical compound that minority suppresses virus replication.For example, to the effective acyclovir of herpesvirus, it is a kind of deoxyguanosine analog, with deoxyguanosine triphosphate be the competitive substrate of virus thymidine kinase, when it by phosphorylation and when entering viral DNA, cause the DNA chain to synthesize premature termination.
Unfortunately, antiviral drugs is only effective to the minority viral infection, and virus can make drug failure by sudden change.With contact molluscum 1 and 2 is example, and they are relevant with alastrim virus with positive smallpox virus, with vaccinia virus homeologous are arranged, but the other forms of treatment of essential use.Present therapy comprises that physical damage is carried out in extruding by hand, liquid nitrogen treatment or curettage, and they are all very painful but very ineffective, and can scab.The pain of these therapies is even more important, because most of patients is below 10 years old.
In the intractable wart, adopt for example liquid nitrogen of destructive therapy in the time of can not making wart disappear in the salicylic acid coating of routine.A problem of wart is that virus accumulates in the stem cell of epidermis bottom.Virion is generally removed in above-mentioned treatment, thereby eliminates the infection on epidermis top layer, but they can not be fully deep with the removal stem cell, thereby eliminates the source of infection.Therefore, wart can recur.
The another kind of Therapeutic Method of wart is to use dinitrochlorobenzene.The purpose of this treatment is to make the patient to dinitrochlorobenzene allergy, so patient's immune system produces immunoreation at position, wart place to dinitrochlorobenzene, sometimes, wart may disappear because of immunologic facilitation.Immunologic facilitation may be a kind of effective Therapeutic Method, still, and the atopic reaction danger that makes the patient that dinitrochlorobenzene take place to cause, uncertain and be difficult to control.
One of the object of the invention is to providing effectively such as viral cutaneous infections such as tumor, wart and contact molluscums but does not resemble Therapeutic Method painful the traditional remedies.
Another purpose of the present invention provides the system of a cover treatment viral dermatosis, and it is not subject to the influence of viral DNA sudden change.
Before this, we have proposed to treat by the skin of viral infection with the nitrogen oxide of some form, and for example, following reaction takes place for nitrite and acidulant:
Now, we find, so long as virus rather than antibacterial comprise for example NO and/or NO
2Though the nitrogen oxide mixture may affect to a certain extent and duplicate, the more important thing is the cell that has changed by viral infection, make its immune system can discern virion.Particularly following true this viewpoint of supporting: the effect of above mixture in immunosuppressed host is obviously lower.Usually, NO percentage ratio is high more, and immunostimulant is good more.If possible, can use 100% NO.
Though also need further research, it is believed that micromolecule, for example NO and NO
2, by direct diffusion or pass the sweat gland of epidermis or hair follicle sees through skin and enters sweat gland cells.Though have been found that healthy keratinocyte meet with nitrogen oxide toxicity can be dead because they have strong resistance to it.But unexpected clinical effectiveness is believed us among we embodiment, and virus infected cell is more responsive to above effect, thereby because of the toxicity that causes apoptosis with that virus immunity is replied enhanced comprehensive effect is destroyed.
Therefore, content according to first aspect present invention, the invention provides the purposes of a kind of topical formulations in making topica, this topical formulations comprises the nitric oxide source and the acidulant of approval pharmaceutically, is used for the viral enhance immunity system in the body of duplicating in epidermis when causing viral cutaneous infection.
According to the viral infection type, the component of nitric oxide source can produce synergism or onset separately.Nitrogen oxide, for example NO and NO
2, especially can spread by epidermis.With the wart is example, and this makes nitrogen oxide to arrive to be positioned at the ripe viral accumulative stem cell of having of epidermis base portion.In case arrival infection cell, nitrogen oxide just can be therein accelerated procedure cell death optionally, then, dead cell is absorbed by phagocyte and antigen-presenting cell, causes the immunity identification to original hidden virus antigen.In case be identified, specific immunity will be by cellular immunization and the infected cell of the common destruction of humoral immunization.
Be preferably, in epidermis, duplicate and cause that the virus of viral cutaneous infection is selected from: contact molluscum, 1 type and 2 type herpes simplex viruss, varicella zoster virus and human papillomavirus.Verified, effective especially with the treatment that the acidify nitric oxide source carries out to the viral cutaneous infection that above-mentioned virus causes.
Nitric oxide source generally contains nitric oxide, also may contain NO
-Or NO
+Ion or its precursor generally produce when the acidulant of pharmaceutically approving is in contact with one another at the biological agent position with the nitric oxide donor of pharmaceutically approving or its precursor.
If pharmaceutically Ren Ke acidulant contacted before arriving the biological agent position with nitric oxide donor or its precursor of pharmaceutically approval, therapeutic effect can because of nitrogen oxide in time inactivation reduce.
In a preferred embodiment, pharmaceutically in the nitric oxide donor of the acidulant of approval and the pharmaceutically approval of living or its precursor carrier that is included in pharmaceutically approval or the suitable diluent.
Be preferably, pharmaceutically Ren Ke acidulant is an organic acid, is that ascorbic acid, Palmic acid are disturbed in bad hematic acid ester, salicylic acid, lactic acid, citric acid, formic acid, benzoic acid and the tartaric acid at least a.
Type and the infected zone reaction to treating of viral cutaneous infection is depended in the selection of acidulant.Can generate a large amount of NO and NO rapidly with reductive acids such as ascorbic acid
2, and NO is obviously more than NO
2Other organic acid, for example salicylic acid can keep NO and NO in a period of time
2Concentration, but NO and NO
2Lower.As the nitric oxide donor of pharmaceutically approval or the inorganic nitrite of its precursor concentration of sodium nitrite (or otheralkali metal nitrite) for example, depend on used acid and concentration thereof.The reproducibility ascorbic acid is very active, so only need nitric oxide donor or its precursor (for example nitrite of sodium or otheralkali metal) reaction of the pharmaceutically approval of 1-10% and stoichiometric concentration.Ascorbic palmitate is more stable, but desired concn is higher than ascorbic acid, because the molecular weight of cetylate is bigger.Therefore, need the 3-25% ascorbic palmitate.If use salicylic acid, concentration is advisable with 0.5-30%, and the concentration of citric acid is higher, reaches 45% (all % are percentage by weights).
The sodium nitrite concentration required with the organic acid reaction of above concentration is 0.5-30%, and 5-20% is better.The nitric oxide source that other are pharmaceutically approved or its precursor need different concentration ranges.
Be preferably, pharmaceutically nitric oxide donor or its precursor of Ren Ke acidulant and pharmaceutically approval adopt its stoichiometric concentration.
If pharmaceutically nitric oxide donor or its precursor of Ren Ke acidulant and pharmaceutically approval adopt its stoichiometric concentration, incite somebody to action the not chemical compound of remained unreacted after reacting completely.So any chemical compound that remains in infected position all can not cause active medicine that anything that the position touches controlled in the pollution or the pollution of healthy skin, for example utensil and clothes.
In one preferred embodiment, the form of medicine is smears, ointment, wax, ointment or emulsifiable paste.Above embodiment makes nitric oxide donor or its precursor of the acidulant of pharmaceutically approval and pharmaceutically approval can directly use infected position.The treatment of local each component of use the present invention preferably continues at least 1 month, and 2 months better.
The present invention also provides a kind of two-part delivery system that has, and is used for topical with the interior therapeutic dermatosis, and described system comprises:
First waxy component comprises the pharmaceutically acidulant of approval;
Second waxy component comprises pharmaceutically the nitric oxide source of approval, if simultaneously or and then be used for environment for use, active oxidation nitrogen will therefrom discharge.
Among another embodiment, first and second waxy components all contain paraffin.Acidulant is reproducibility organic acid or its salt preferably, for example ascorbic acid or ascorbic palmitate.Nitric oxide source can be alkali metal nitrites salts, for example sodium nitrite.
Use reductive acid or its salt using the position to produce the NO that has remarkable treatment and immunization in a large number.
Therefore, the invention provides nitric oxide source pharmacy and the prevention in purposes, at be the viral cutaneous infection that 1 type and 2 type herpes simplex viruss, varicella zoster virus, cowpox or human papillomavirus, particularly molluscum contagiosum virus cause.
The present invention also provides a kind of topica interior therapeutic dermopathic delivery system, comprise adhesive layer and the impregnated supporting layer of at least a drug component, it is characterized in that, drug component is acidulant of pharmaceutically approving and nitric oxide donor or its precursor of pharmaceutically approving, the method for the acidulant of pharmaceutically approval with the nitric oxide source combination of pharmaceutically approval also is provided.For example, described delivery system comprises two-layer, and original position discharges and comprises nitric oxide production nitrogen oxide.Can perspire by pressurization or skin and activate this system.
Be preferably, during virus replication caused viral cutaneous infection, in the suitable enhance immunity system of this delivery system of desired location, therefore described system class was easy to the outside of Gypsum Fibrosum is applied physical pressure like the viscosity Gypsum Fibrosum.
More convenient is, pharmaceutically Ren Ke nitric oxide donor be aqueous solution and be included in microsphere or liposome in, be dispersed in the support, be the form of film or gauze.Film or gauze can improve the pharmaceutically concentration of the acidulant of approval.If use salicylic acid solution, working concentration is 20-26wt% only, if but salicylic acid is immersed in film or the gauze, working concentration can reach 26-44wt%.
What stick with glue layer is also advantageous in that it can seal infected zone during treating, thereby improves the nitric oxide concentration that absorbs by epidermis.
With above delivery system rather than two kinds of emulsifiable pastes or ointment be also advantageous in that drug component will only be coated in infected zone, promptly not have excessive.And concerning the old people of possibility hand tremor, stick with glue layer than convenient with the smears.Just treat the contact molluscum that is mainly in 10 following patients, adhesive layer can have ornamental decorative pattern to attract the child.
As previously mentioned, be preferably,, destroy the integrity of carrier by pressurization adhesive layer and film or gauze being affixed on the skin behind the viral infection zone.If pharmaceutically nitric oxide donor or its precursor of Ren Ke acidulant and pharmaceutically approval are in contact with one another before being used for the biological agent position, they will react to each other, thereby reduce the effectiveness of medicine.So in this embodiment, the essential nitric oxide donor of the acidulant of pharmaceutically approval and pharmaceutically approval or its precursor of making isolated in film or gauze layer mutually.The pressure that is attached to the biological agent position acts on adhesive layer, be delivered to film or gauze layer then, can cause carrier, for example microsphere or liposome break, thereby are reacted and treated infection site by the acidulant of pharmaceutically approval and the nitric oxide donor of pharmaceutically approving or its precursor.
This delivery system can also with the topica coupling.Described topica is acidulant of pharmaceutically approving and nitric oxide donor or its precursor of pharmaceutically approving.
Therefore, can only provide acidulant that is immersed in the pharmaceutically approval in film or the gauze layer and the nitric oxide donor of pharmaceutically approving or its precursor one of them.Another chemical compound is not immersed in film or the gauze, can use infection site in the part.Such advantage is that film or the comparable infected zone of gauze layer are long, but pharmaceutically the acidulant of approval and the nitric oxide donor of pharmaceutically approval or the reaction between its precursor only occur in the infection site that medicine has been used in the part.
The chemical compound that can also not change in the delivery system by changing the local medicine that uses changes treatment.For example, if the nitric oxide donor that will pharmaceutically approve or its precursor are immersed in film or the gauze, then can change the local pharmaceutically acidulant of approval that uses, but used adhesive layer and film or gauze are constant.
Above delivery system is the ideal form of the sufficient wart of treatment, because this delivery system is hidden.
Below with reference to embodiment and accompanying drawing the present invention is described.
The comparison of wart extinction time, wherein n=32 after Fig. 1 shows the Verrucosis journey and uses embodiment 1 preparation;
Fig. 2 shows wart patient treatment result and time relation, wherein n=32.
The Kaplan Meier figure that Fig. 3 shows contact molluscum patient treatment result and concerns between the time.
Fig. 4 shows that 0.083g 10%Ap wax and 0.014g 10% sodium nitrite wax discharge NO and NO
2, get 21 μ moleNaNO
2With 25 μ mole ascorbic palmitate.Among Fig. 4, square curve representation NO value, circle point curve is represented NO
2Value.
Embodiment 1
32 intractable viral wart patients accept with the acidifying different sodium nitrite preparation for treating of specific acid.Definite preparation sees Table 1.32 patients do not have effect through the wart topical therapeutic and at least twice liquid nitrogen therapy of routine.21 routine sole warts, 12 routine hands warts, 5 examples are suffered under the first or periungual wart, 1 routine hands plane wart, 1 routine perianal wart and 1 routine lip wart.
Average 24 months of Verrucosis journey illustrates that the chance of patient's spontaneous remission is lower (Fig. 1).
Table 1
| Acid | Nitrite | Controlled patient's number |
| 5% salicylic acid emulsifiable paste | 5% sodium nitrite emulsifiable paste | 5 |
| 5% ascorbic acid emulsifiable paste | 5% sodium nitrite emulsifiable paste | 7 |
| 10% ascorbic acid emulsifiable paste | 10% sodium nitrite emulsifiable paste | 2 |
| 23% salicylic alcohol radical wart smears | 10% sodium nitrite+0.5% copper acetate | 9 |
| 23% salicylic alcohol radical wart smears | 10% sodium nitrite emulsifiable paste | 3 |
| 23% salicylic alcohol radical wart smears | 15% sodium nitrite emulsifiable paste | 6 |
Wart is carried out pretreatment, and dead bark is removed in friction, is coated with the preparation that contains sodium nitrite then earlier, the acidulant that repaste is specific.Every night wart is handled, every 3 days, wart again rubbed.
No matter use what preparation, after average 2 months, wart begins disappear (seeing Fig. 1 and 2).Glutathion and protein that institute's cupric is used for the catalysis nitrosylation discharge nitrogen oxide, to prolong the release of nitrogen oxide.
4 example treatment failures are arranged, and wherein the patient of 3 examples accepts immunosuppressant treatment because of lupus erythematosus, renal transplantation and dermatomyositis.So all patient's cure rate is 88%, if the deduction immunosuppressed patient then is 96%.Existing treatment, for example the wart clearance rate with liquid nitrogen or salicylic acid smears is 50-80%.
Embodiment 2
30 contact molluscum patients have participated in a double-blind trial.They accept 5% sodium nitrite and the treatment of 5% salicylic acid or the treatment of not acidifying 5% sodium nitrite of lesion sealing randomly.Experimenter's mean age is 7 years old (one 47 years old exception is not calculated in meansigma methods).Infection time on average existing 8.23 ± 3.959 months.Just individual damage number or treatment number of times do not have marked difference between two groups.
In the coupling example, with cotton balls sodium nitrite is coated onto on the skin, change a cotton balls then and coat salicylic acid.In the single use-case of sodium nitrite, sodium nitrite is coated onto on the skin with cotton balls.Under two kinds of situations, if possible, cover the lesion with " adhesive film " or Sellotape .
As shown in table 2, in the active treatment group, 70% patient recovery from illness has 28% recovery from illness in the matched group.Average cure time is 1.83 ± 0.91 months.
Table 2
| Therapeutic Method | The recovery from illness number | The number of not fully recovering |
| Acid and nitrite | 12 | 4 |
| Contrast | 4 | 10 |
Draw the Kaplan Maier figure (Fig. 3) of active treatment and control patients, and analyze with the Logrank check, the result shows, has significant difference between viral survival curve, the cure rate of active treatment group higher (p=0.0183).
Embodiment 3
12 volunteers are current or do not have the skin medical history also not take any medicine recently, are coated with the nitrogen oxide mixture with low dosage (0.5% nitrite) and high dose (5% nitrite) randomly on their skin.
The experimenter is coated in contrast position and site of action with the aqueous cream of 2%w/w ascorbic acid.Site of action also is coated with the nitrite emulsifiable paste with low dosage or high dose.Emulsifiable paste is coated with 3 times every day, and 8 hours at interval, then, with polyene/plastic bandage wrapping sealing contrast position and site of action.
The assaying reaction that is coated with behind the emulsifiable paste 5 hours for the last time again allowing the instant vasorelaxation action of nitrogen oxide go down, thereby is only measured residual inflammation.
Measure the thickness that contrasts position and site of action with " Mitotoyu " spring thickness gauge, measure rubescent degree with reflection erythema measuring instrument.Drill through 2 parts of 4mm living tissue samples from effect or contrast position; Portion is used for histology's test and appraisal, cell dyeing, neutrophil elastase and original position breach end labelling through formalin fixed, and another part implanted to carry out immunohistochemical staining through quick freezing and OCT.
With Streptavidin-biotin method, carry out DAB with antibody in the table 3 and detect, and carry out immunohistochemistry research, the cell of evaluation program death with ApopTag Plus original position breach end labelling detection kit.
Quantitatively dye with computer image analysis,, the difference of many parts of uncorrelated samples is carried out the nonparametric analysis, determine the influence of the dosage and the course of treatment with the Kruskal-Wallis check with the data of Wilcoxon check analysis pairing sample.(seeing Fig. 4,5 and 6).
Table 3
| Epi-position | Tire | Staining cell |
| CD1a | 0.0451388889 | Langerhans' cells |
| CD3 | 0.0555555556 | General-the T cell |
| CD4 | 1∶150 | T helper cell |
| CD8 | 0.0555555556 | T cell inhibition/cytotoxicity |
| CD54 | 1∶100 | ICAM-1 |
| CD6 | 0.0846111111 | Macrophage |
| CD106 | 1∶100 | VCAM-1 |
| p53 | 0.0763888889 | Wild type p53 albumen |
| Nitroso-group tyrosine * | 1∶100 | The cheese nitronic acid of nitrosylation |
| Neutrophil elastase | 1∶100 | Neutrophilic leukocyte |
| ApopTaq ** | Manufacturer's explanation | Dead cell |
*Polyclonal antibody, other all are monoclonal antibodies
*According to the shearing DNA in situ detection of developing with peroxidase
The reflection erythema testing result of nitrogen oxide mixture therapentic part is 32.25 ± 5.46, and (meansigma methods ± sd) is apparently higher than 18.08 ± 5.81 (p=0.0022, the Wilcoxon checks) at contrast position.The skinfold of nitrogen oxide mixture treatment sheet is 5.04 ± 0.75mm, apparently higher than 3.25 ± 0.54 (p=0.0022, Wilcoxon tests) of contrast skin.Dosage or time of contact are to the not obviously influence of above measurement result, but the skinfold of high dose group tends to thicker (5.4mm ± 0.21 contrast 4.7mm ± 0.32).(p＝0.075)。
All the histologic analysis at positive treatment positions show all that keratinocyte edema, endothelium are swollen, muddy bullate obvious aggravation and blended lymphocyte and neutrophilic infiltration.More than changing is the 0-4 level quantitatively, and, all similar in low dosage, high dose, short term contact and long-term contact test.That sees in the skin that mastocyte quantity of seeing in the Azure A stained and contrast and nitrogen oxide are handled is close.
All found cytotoxicity in all keratinocytes, shown as muddy swollen.Form bubble on the epidermis upper strata during muddy swollen expansion, wherein be full of inflammatory cell and change and nuclear takes place shrink, clarify the muddy bullate cell of kytoplasm on every side through cell toxicant.Judge to have only minority experience programmed death in these degenerated cells through ApopTag dyeing.In the epidermis of living, the cell of programmed death also increases.This shows, can not tolerated known nitric oxide production programmed cell death effect by the normal keratinocyte comparison of viral infection.Corium has also detected dead cell near the especially structure.Nitroso-group tyrosine stained positive prompting nitrogen oxide around the elaeodochon mainly absorbs by hair follicle.
Skin with the nitrogen oxide mixture process obviously increases the immunologically competent cell of expressing CD3, CD8, CD68 and neutrophil elastase, and the adhesion molecule ICAM-1 and the VCAM-1 that attract these cells to move to infection site.These intracellular nitroso-group tyrosine dyeing explanations have formed peroxidating nitrile (ONOO
-) and p53, the part effect that mixture is described is by the cytotoxicity mediation of pair cell DNA.In healthy skin, nitrogen oxide causes the part cell death really, and still, at used dosage, this effect is unexpected for a short time, and we estimate that this effect may be present in the infected cell.We find that the tree-shaped characteristic of the antigen processing cell (the CD1a positive) of skin is lost, and is from exfoliation, therefore, obviously less in processed skin.Because as if after these cells are activated above performance is arranged, and have the antigenic function of the new identification of processing, this has further proved the immunologic facilitation effect of nitrogen oxide mixture.The somatoblast Ki-67 dyeing of contrast and site of action does not have difference.This explanation, in (for example) wart, drug effect is not to reduce cell proliferation.
Measure the influence that nitrogen oxide treatment time replys clinical and immunohistochemistry with Kruskal-Wallis check.Dosage sees Table 5 to the influence of dermoreaction.The CD4 positive cell of high dose group is less than low dose group, and the CD68 cell too.Though the Ki-67 positive cell at contrast position and nitrogen oxide mixture process position does not have notable difference, compares with low dose group, high dose group has tangible increase.
Measure the cell death degree after contacting 24 hours and 48 hours with the nitrogen oxide mixture, see Table 6.Mortality rate after 48 hours is after 24 hours.With 12 hours after compare, the CD4 positive cell number after 24 hours obviously increases.The difference of p53 is not fairly obvious on statistical significance.As if similarly, the course of treatment is long more, and is muddy swollen severe more, but not obvious statistically.
Table 4
| The nitrogen oxide mixture | Contrast | Explicitly Wilcoxon check | |||
| Meansigma methods | SD | Meansigma methods | SD | ||
| ApopTag | 12.5 | 10.1 | 0.41 | 1.16 | 0.0033 |
| Ki67 | 6.82 | 3.88 | 6.62 | 2.854 | 0.67 |
| CD1a * | 0.86 | 0.69 | 3.43 | 0.53 | 0.022 |
| CD3 | 574.7 | 396.3 | 216.1 | 122.1 | 0.0186 |
| CD4 | 608.2 | 458.2 | 176.3 | 149.9 | 0.0125 |
| CD8 | 275.7 | 193.1 | 122.1 | 106.1 | 0.0284 |
| CD68 | 673.1 | 542.4 | 301.4 | 361.3 | 0.0044 |
| Nitroso-group tyrosine | 3.4 | 0.7 | 0.9 | 1.1 | 0.043 |
| p53 | 214.4 | 266.4 | 22.08 | 53.8 | 0.0029 |
| Neutrophilic leukocyte | 569.4 | 385.9 | 71 | 113.1 | 0.043 |
| ICAM-1 | 705.9 | 704.5 | 201.9 | 160.9 | 0.0209 |
| VCAM-1 | 1.5 | 1.17 | 0.5 | 0.9 | 0.0357 |
*Cell is difficult to counting, for example, more diffusion dyeing/arborescent cell, the subjectivity that will dye is divided into the 0-4 level.
Count intraepidermal Ki67, the ApopTag positive cell/standard section of counting 3mm living tissue sample.Other countings carry out on fixed standard test frame by computer image analysis, are expressed as cell/mm
2
Table 5
| High dose (cell number/mm 2) | Low dosage (cell number/mm 2) | The Kruskal-Wallis check | |||
| Meansigma methods | SD | Meansigma methods | SD | ||
| Ki67 | 152 | 35.2 | 73.6 | 8 | 0.01 |
| CD4 | 280 | 78.4 | 936 | 185.6 | 0.02 |
| CD68 | 379.2 | 65.6 | 916.8 | 262.4 | 0.04 |
Table 6
| 12/24 hour | 48 hours | The Kruskal-Wallis check | |||
| Meansigma methods | SD | Meansigma methods | SD | ||
| ApopTag | 3.5 | 1.82 | 14.16 | 2.56 | ＜0.005 |
| CD4 | 285.9 | 193.6 | 824 | 193.6 | 0.05 |
| Muddy swollen ** | 1.7 | 0.33 | 2.5 | 0.224 | 0.07 |
| p53 | 70.1 | 47.04 | 335.2 | 125.7 | 0.07 |
Count intraepidermal Ki67, the ApopTag positive cell/standard section of counting 3mm living tissue sample.Other countings carry out on fixed standard test frame by computer image analysis, are expressed as cell/mm
2
*Be difficult to counting cells, for example, more diffusion dyeing/arborescent cell, the subjectivity that will dye is divided into the 0-4 level.
Nitrogen oxide mixture of the present invention can form by mixing ascorbic acid and nitrite on skin, and described mixing discharges nitrogen oxide, especially nitric oxide, nitrous oxide, nitrogen dioxide and nitrogen trioxide.Low dosage experimenter's t helper cell and the macrophage increase bright nitrogen oxide of more speaking more may have the inflammatory of causing when low dosage, and become immunologically competent cell is had cytotoxicity when high dose, and begin to bring into play depression effect.The nitrogen oxide mixture obviously induces ICAM-1 to express, and moderate increase VCAM-1 and express.The inflammation mode is different from generally, shows, only after 24 hours tangible macrophages infiltration is just arranged, and illustrates that activatory macrophage attracts more macrophages to kill cause of disease with nitrogen oxide.
The preparation that uses nitrite or its nitrogen oxide precursor and acidulant to combine will promote the death and the renewal of all immunologically competent cells, and it is necessary that this is that host immune system is effectively discerned cause of disease.So, more than find to support nitrite or other NO or NO
2Potential immunologic facilitation effect Deng nitrogen oxide precursor and acidulant combination.
Embodiment 4
Prepare a kind of two component delivery systems.The form of each component all is a rod wax, and can following the doctor's advice at interval, certain hour is coated onto on the site of action.
Be prepared as follows two components:
10% ascorbic palmitate
Component
Ascorbic palmitate 10%
White soft paraffin 25
Light liquid paraffin 20
Hard paraffin 20
Arlacel 165 15
Cetostearyl alcohol 10
Method
1. the container of packing into after the whole components of weighing.
2. heating container and stirring the mixture, up to all components fusion, it is even that mixture becomes.
3. molten wax is poured in the bottle, be cooled to room temperature.
10% sodium nitrite wax
Component
The A phase
Light liquid paraffin 7.5%
White soft paraffin 20
Arlacel 582 10
Cetostearyl alcohol 10
Phenyl phenol 1
The B phase
Sodium nitrite 10
Pure water 20
Method
1. weighing A phase component adds container, is heated to 70 ℃, is stirred to evenly.
2. weighing B phase component adds another container, is heated to 70 ℃, stirs, and guarantees all sodium nitrite dissolvings.
3. when reaching 70 ℃, A is added to the B phase, homogenize 5 minutes when biphase.
4. molten wax is poured in the bottle, be cooled to room temperature.
As shown in Figure 4, as if can discharge excessive N O greatly with above mixed method by two-part delivery system.This may be because NO is a micromolecule, and the treatment viral dermatosis is more effective.
Claims (27)
1. two parts delivery system that is used for local application with the interior therapeutic viral cutaneous infection, this system comprises respectively:
(a) the first wax component comprises the pharmaceutically acidulant of approval; With
(b) the second wax component comprises pharmaceutically the nitric oxide source of approval, when simultaneously or when and then the part is used for site of action, will discharge active oxidation nitrogen;
Wherein, the concentration of acidulant is 1-10wt%, and the concentration of described nitric oxide source is 0.5-30wt%.
2. delivery system according to claim 1, the first and second wax components wherein comprise paraffin.
3. dermopathic delivery system of topica interior therapeutic, comprise adhesive layer and the supporting layer that has flooded medicine, it is characterized in that, the nitric oxide source that described pharmaceutical pack contains the acidulant of pharmaceutically approval and pharmaceutically approves, and the acidulant that will pharmaceutically approve and the blended accessory of nitric oxide source, wherein, the concentration of acidulant is 1-10wt%, and the concentration of described nitric oxide source is 0.5-30wt%.
4. delivery system according to claim 3, delivery system wherein comprises the microsphere that contains drug component.
5. delivery system according to claim 3, delivery system wherein comprises the liposome that contains drug component.
6. the dermopathic delivery system of topica interior therapeutic comprises
Adhesive layer and flooded the supporting layer and second topica of first component;
Described first component is the acidulant of pharmaceutically approving, described second topica is the nitric oxide source of pharmaceutically approving, perhaps, described first medicine is the nitric oxide source of pharmaceutically approving, described second topica is the acidulant of pharmaceutically approving;
Described system also comprises acidulant and the blended accessory of nitric oxide source with pharmaceutically approval;
Wherein, the concentration of acidulant is 1-10wt%, and the concentration of described nitric oxide source is 0.5-30wt%.
7. delivery system according to claim 6, wherein the form of topica is ointment, emulsifiable paste, varnish, wax, plaster or smears.
8. delivery system according to claim 7, wherein the form of topica is a plaster.
9. according to the described delivery system of claim 1,3 or 6, wherein be that acidulant is reproducibility organic acid or salt.
10. delivery system according to claim 9, wherein pharmaceutically the acidulant of approval is an organic acid.
11. according to the described delivery system of aforementioned claim 9, wherein pharmaceutically the acidulant of approval is selected from ascorbic acid, ascorbic palmitate, salicylic acid, lactic acid, citric acid, formic acid, benzoic acid and tartaric acid.
12. according to claim 1 or 3 described delivery systems, wherein pharmaceutically the nitrogen oxide mixture donor of approval is an inorganic nitrite.
13. delivery system according to claim 12, wherein pharmaceutically the nitrogen oxide mixture donor of approval is an alkali metal nitrites salts.
14. according to claim 1 or 3 described delivery systems, wherein pharmaceutically the nitric oxide source of the acidulant of approval and pharmaceutically approval all adopts its chemical dose concentration.
15. delivery system according to claim 14, wherein said acidulant is an ascorbic acid.
16. delivery system according to claim 14, wherein said acidulant is a salicylic acid.
17. delivery system according to claim 14, wherein said acidulant is a citric acid.
18. delivery system according to claim 14, wherein said acidulant is an ascorbic palmitate.
19. delivery system according to claim 14, wherein said acidulant is a lactic acid.
20. delivery system according to claim 14, wherein said acidulant is a formic acid.
21. delivery system according to claim 14, wherein said acidulant is a benzoic acid.
22. delivery system according to claim 14, wherein said acidulant is a tartaric acid.
23. claim 1 or 3 described delivery systems are used for the treatment of or prevent purposes in the topical drug of viral cutaneous infection in preparation, described virus is selected from contact molluscum, 1 type and 2 type herpes simplex viruss, varicella zoster virus and human papillomavirus.
24. purposes according to claim 23, viral infection wherein is a parillomarvirus infections.
25. purposes according to claim 24, described viral infection is a wart.
26. purposes according to claim 23, viral infection wherein are the contact molluscums.
27. according to each described purposes among the claim 23-26, wherein the nitrogen oxide in the described delivery system of claim 1 mainly is a nitric oxide.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9804469.6 | 1998-03-02 | ||
| GBGB9804469.6A GB9804469D0 (en) | 1998-03-02 | 1998-03-02 | Antiviral composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1291897A CN1291897A (en) | 2001-04-18 |
| CN1270725C true CN1270725C (en) | 2006-08-23 |
Family
ID=10827886
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB998035866A Expired - Fee Related CN1270725C (en) | 1998-03-02 | 1999-03-01 | Inorganic nitrite and organic acid in combination as topical antiviral composition |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP1059928A1 (en) |
| JP (1) | JP2002505295A (en) |
| KR (1) | KR20010041527A (en) |
| CN (1) | CN1270725C (en) |
| AU (1) | AU758264B2 (en) |
| BR (1) | BR9908617A (en) |
| CA (1) | CA2322199A1 (en) |
| GB (1) | GB9804469D0 (en) |
| HU (1) | HUP0101374A3 (en) |
| MX (1) | MXPA00008583A (en) |
| NO (1) | NO20004302L (en) |
| NZ (1) | NZ506678A (en) |
| PL (1) | PL342755A1 (en) |
| WO (1) | WO1999044622A1 (en) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0021317D0 (en) | 2000-08-30 | 2000-10-18 | Queen Mary & Westfield College | Transdermal pharmaceutical delivery composition |
| GB0119011D0 (en) * | 2001-08-03 | 2001-09-26 | Univ Aberdeen | Treatment of nail infections |
| AU2004255268B2 (en) | 2003-07-09 | 2010-04-01 | Loma Linda University | Use of nitrite salts for the treatment of cardiovascular conditions |
| US8557300B2 (en) | 2005-05-19 | 2013-10-15 | University Of Cincinnati | Methods for treating bacterial respiratory tract infections in an individual using acidified nitrite |
| WO2008104028A1 (en) | 2007-02-28 | 2008-09-04 | Invasive Animals Crc Ltd | Nitrite salts as poisons in baits for omnivores |
| US8932650B2 (en) * | 2011-01-11 | 2015-01-13 | Kantian Skincare LLC | Multifunctional topical formulation for the treatment of acne vulgaris and other skin conditions |
| CN103127504A (en) * | 2011-12-05 | 2013-06-05 | 尼奥克斯(文莱)控股有限公司 | Compositions and methods for topical nitric oxide generation |
| US11077194B2 (en) | 2012-03-14 | 2021-08-03 | Novan, Inc. | Nitric oxide releasing pharmaceutical compositions |
| CN103622917B (en) * | 2012-08-23 | 2017-12-29 | 尼奥克斯(文莱)控股有限公司 | Delay based on microencapsulation nitrite and acidifying hydrogel produces nitric oxide production system and method |
| US9855211B2 (en) | 2013-02-28 | 2018-01-02 | Novan, Inc. | Topical compositions and methods of using the same |
| US11813284B2 (en) | 2013-08-08 | 2023-11-14 | Novan, Inc. | Topical compositions and methods of using the same |
| WO2016007834A1 (en) * | 2014-07-11 | 2016-01-14 | Novan, Inc. | Topical antiviral compositions and methods of using the same |
| US10322082B2 (en) | 2014-07-11 | 2019-06-18 | Novan, Inc. | Topical antiviral compositions and methods of using the same |
| ITUB20154719A1 (en) | 2015-10-21 | 2017-04-21 | Glano Tech Ltd | FORMULATION FOR THE RELEASE OF NITRIC OXIDE |
| EP3758679A4 (en) | 2018-03-01 | 2021-12-15 | Novan, Inc. | Nitric oxide releasing suppositories and methods of use thereof |
| US10716805B2 (en) | 2018-03-19 | 2020-07-21 | Glanotech Limited | Formulation for release of nitric oxide |
| CN109437134A (en) * | 2018-10-26 | 2019-03-08 | 中国核电工程有限公司 | The preparation method and device of nitrogen oxides |
| WO2020245574A1 (en) | 2019-06-04 | 2020-12-10 | Thirty Respiratory Limited | Methods and compositions for generating nitric oxide and uses thereof to deliver nitric oxide via the respiratory tract |
| JP2023510661A (en) | 2019-06-04 | 2023-03-15 | サーティー ホールディングス リミテッド | Methods and compositions for producing nitrogen oxides and their use |
| GB2610722A (en) | 2020-04-23 | 2023-03-15 | Thirty Respiratory Ltd | Nitric oxide or nitric oxide releasing compositions for use in treating SARS-COV and SARS-COV-2 |
| GB2610721A (en) | 2020-04-23 | 2023-03-15 | Thirty Respiratory Ltd | Methods and compositions for treating and combatting tuberculosis |
| CN116617254A (en) * | 2022-09-26 | 2023-08-22 | 杭州泽德医药科技有限公司 | Anti-pathogenic microorganism composition containing boric acid and nitrite and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4923899A (en) * | 1987-12-22 | 1990-05-08 | Cetylite Industries, Inc. | Sterilant composition |
| MY128187A (en) * | 1993-06-23 | 2007-01-31 | Icn Switzerland Ag | Preparation for skin and mucous membrane |
| CZ286286B6 (en) * | 1994-02-21 | 2000-03-15 | Aberdeen University | Antimicrobial preparation and application thereof |
-
1998
- 1998-03-02 GB GBGB9804469.6A patent/GB9804469D0/en not_active Ceased
-
1999
- 1999-03-01 JP JP2000534223A patent/JP2002505295A/en not_active Withdrawn
- 1999-03-01 WO PCT/GB1999/000605 patent/WO1999044622A1/en not_active Application Discontinuation
- 1999-03-01 AU AU32617/99A patent/AU758264B2/en not_active Ceased
- 1999-03-01 MX MXPA00008583A patent/MXPA00008583A/en not_active Application Discontinuation
- 1999-03-01 BR BR9908617-4A patent/BR9908617A/en not_active Application Discontinuation
- 1999-03-01 EP EP99937878A patent/EP1059928A1/en not_active Ceased
- 1999-03-01 HU HU0101374A patent/HUP0101374A3/en unknown
- 1999-03-01 PL PL99342755A patent/PL342755A1/en not_active Application Discontinuation
- 1999-03-01 KR KR1020007009698A patent/KR20010041527A/en not_active Application Discontinuation
- 1999-03-01 CA CA002322199A patent/CA2322199A1/en not_active Abandoned
- 1999-03-01 CN CNB998035866A patent/CN1270725C/en not_active Expired - Fee Related
- 1999-03-01 NZ NZ506678A patent/NZ506678A/en unknown
-
2000
- 2000-08-29 NO NO20004302A patent/NO20004302L/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA00008583A (en) | 2003-07-14 |
| KR20010041527A (en) | 2001-05-25 |
| CN1291897A (en) | 2001-04-18 |
| JP2002505295A (en) | 2002-02-19 |
| NO20004302L (en) | 2000-10-30 |
| EP1059928A1 (en) | 2000-12-20 |
| HUP0101374A2 (en) | 2001-08-28 |
| AU758264B2 (en) | 2003-03-20 |
| GB9804469D0 (en) | 1998-04-29 |
| HUP0101374A3 (en) | 2003-07-28 |
| NO20004302D0 (en) | 2000-08-29 |
| PL342755A1 (en) | 2001-07-02 |
| AU3261799A (en) | 1999-09-20 |
| CA2322199A1 (en) | 1999-09-10 |
| NZ506678A (en) | 2003-04-29 |
| WO1999044622A1 (en) | 1999-09-10 |
| BR9908617A (en) | 2000-12-05 |
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