CN104968351A - Topical vitamin D oral supplement compositions - Google Patents
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
- A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
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- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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Abstract
Topical, vitamin D, oral supplement compositions useful in treating oral inflammation comprising vitamin D in an aqueous-free emulsion containing a trans-oral mucosal absorption facilitator, where said emulsion forms a mucoadhesive coating in the presence of saliva; wherein saliva dissolution of the mucoadhesive gel releases vitamin D and the trans-oral mucosal, absorption facilitator; effecting: vitamin D passive diffusion; regulating in vivo availability and immune response of vitamin D; and maintaining adequate levels of circulating vitamin D while minimizing the risk of hypercalcemia.
Description
Technical field
The theme of the application relates to (topical) vitamin D oral cavity supplement composition of the local used in treatment oral inflammation.
Background technology
Nearest research shows, the peptide that human dental gingival epithelial cells (GEC) produces, and as alexin (defensins) and tubulin (cathelicidin) LL-37, both is all antibacterial and modulates innate immune response.See: Diamond, the people such as G, 2008, " in oral cavity and lung, keep Buchner's bodies: similarity and diversity " (" Hold defense peptides in the oral cavity and the lung:similarities and differences; "), dentistry research magazine (
j. Dent. Res.), the 87th volume: 915-927 page.Research also shows that these antibacterial peptides are most important in the prevention and corntrol of bacillary periodontal.Specifically, at periodontal pathogen bacterium actinomycetem comitans (Aggregaitbacter
actinomycetemcomitans) when existing, these peptides have been proved to be to cause to be increased immunne response and show antibacterial activity.Also confirm; when auxiliary therapy exists as Vitamin D supplements and vitamin D3 [1; 25(OH) 2D3] and its precursor and derivant, the gene being responsible for producing these antibacterial peptides can be raised (up-regulated) or induction produces protectant expression raising.See: McMahone, the people such as L, in June, 2011, the inherent immunity of vitamin D modulation-induced " in the human gingival epithelial cells " (" Vitamin D-mediated induction of innate immunity in gingival epithelial cells; "), infect with immune magazine (
infect. Immun.), the 79th volume 6 phase: 2250-7 page.
Summary of the invention
The invention provides vitamin D oral cavity, the local supplement composition being used for the treatment of oral inflammation.The vitamin D meeting the object of the invention suitable comprises:
Vitamin D,
1,3, and No. 25 carbon locations have the vitamin D compounds of hydroxyl,
1 α, 25-dihydroxyvitamin D
3esters,
1,25-dihydroxyvitamin D
3esters,
1,25 (OH)
2d
3, 1,25 (OH)
2d
3analog,
Calcitriol, 25 (OH) D
3with 25 (OH) D
3analog and their combination.
Vitamin D supplements and oral mucosa penetrate together with absorption enhancer and are comprised in anhydrous Emulsion.
The local vitamin D supplement composition being used for the treatment of oral inflammation provided by the invention comprises:
Dissolve in the anhydrous lactitol agent carrier of saliva;
Reach the Vitamin D supplements of effect level; With
Transbu ccal mucosa absorption enhancer; Wherein:
When being applied to oral mucosa, described compositions forms the mucoadhesive gel dissolving in saliva be attached on described oral mucosa;
When the described mucoadhesive gel dissolving in saliva is routinely exposed to saliva fluid, described mucoadhesive gel dissolves gradually, to control described Vitamin D supplements and described transbu ccal mucosa absorption enhancer is discharged into described oral mucosa; With
When contacting with described oral mucosa, described Vitamin D supplements and transbu ccal mucosa absorption enhancer Passive diffusion are through described oral mucosa:
(a) modulation vitamin D availability in vivo and immunne response;
B () maintains the level of vitamin D in abundance of circulation; With
C () minimizes the risk of hypercalcemia.
Vitamin D supplement composition of the present invention, when being applied on oral mucosa partly with the form of anhydrous emulsion composition, forms the gel be attached on oral mucosa.These gels dissolve gradually under saliva exists, release vitamin D and transbu ccal mucosa absorption enhancer, both compositions make vitamin D effectively Passive diffusion through mucosa.
The periodontal disease at initial stage, gingivitis are considered to the inflammatory reaction caused by the endotoxin of the lower release of bacterial biof iotalm existence at the conventional position of tooth structure.If do not treated, this situation often develops into more serious pathological condition and is called as periodontitis.Research is thought, the frequent vitamin D local of the present invention supplement composition that uses provides protection by the mucoadhesive gel formed, and mucoadhesive gel routinely discharges vitamin d compositions in inflamed sites; Induce the Passive diffusion of vitamin D in mucosa thus, this process correspondingly improves the output of antibacterial peptide and excites generally acknowledged treatment immunomodulation response.
The diffusion of Vitamin D supplements maintains the level of vitamin D in abundance of body-internal-circulation, and modulates vitamin D availability in vivo and immunne response, minimizes the risk of hypercalcemia simultaneously.
vitamin D in compositions of the present invention is safeguarding the effect in periodontal health
Periodontal is caused by oral cavity bacterium population, and these antibacterials cause local inflammation reaction, cause spy to be examined hemorrhage, the damage of the appendicular loss of periodontal and skeleton and tooth.They are relevant to the system status of human body, comprise heart disease, diabetes, obesity and metabolism syndrome.Contacting between periodontal and these system status seemingly connects because slight inflammation load makes them pass through common pathophysiological mechanism.It is contemplated that, merocrine cytokine and Periodontal Pathogens can enter blood, and then cause the infringement at other position of health, and have occurred the evidence of some this inflammation loads.
Tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) are the key cytokines causing and maintain Systemic inflammation, and development and the seriousness of itself and periodontitis are closely related.In addition, patients with periodontitis is compared to the individuality of periodontal health, and the serum levels observing these cytokines is higher.
The Adipocyte Factor that leptin, adiponectin and phylaxin are mainly secreted by fatty tissue, but also produced by mononuclear cell and macrophage, and directly can affect inflammation.
See: the people such as Teles, Periodontology (
journal of Periodontology),2011.
Vitamin D is in the growth of bone and have important function in safeguarding, this may to safeguarding that periodontal health is useful.Recently, have research to think, it is not by the impact of bone metabolism but by anti-inflammatory mechanisms, and to periodontal, dentine runs off and gingivitis applies positive influences.Therefore, maintained the blood serum values of sufficient vitamin D by local, complementary vitamin D supplement composition, this may be extremely important in the prevention and therapy of periodontal.
Vitamin D has important effect in calcium homeostasis, osteogenesis and maintenance.Prove the generation of the suppression that antigen induced T-cell is bred and cytokine, can as immunomodulator.
Recently, someone proposes vitamin D and also has antiinflammatory performance.By analyze 6700 samples (see people such as Dietrich, U.S. clinical threpsology magazine (
am. J. Clin. Nutr.), 2005,82nd volume: 575-580 page), find Serum Vitamin D the highest 1/5th individuality in show the loss of hemorrhage less, lower average depth of pocket and clinical attachment significantly, less absence of tooth quantity and BMI numerical value.Also propose, vitamin D (and calcium) supplement may produce active influence to periodontal health, particularly examine hemorrhage, gingival index and PD to spy.
See: the people such as Garcia, Periodontology (
j. Periodontol.), the 82nd volume: 25-32 page; Withthe people such as Miley, Periodontology (
j. Periodontol.), 2009, the 80th volume: 1433-1439 page.
What is interesting is, the polymorphism of vitamin D receptor and popularity aggressive periodontitis (GAGP) (see: the people such as Park, clinical periodontology magazine (
j. Clin. Periodontol.)2006, the 33rd volume: 524-528 page) relevant with severe chronic periodontitis (see: the people such as Wang, Periodontology (
j. Periodontol.), 2009, the 80th volume: 603 to 608 pages).Examine in hemorrhage less, individuality compared with harmonic(-)mean PD value, CAL and absence of tooth quantity and reduced levels pathogenic bacterium showing to visit, detect that the level of the vitamin D of circulation is the highest.In addition, the antiinflammatory action of the vitamin D of original imagination, by itself and fat join albumen positive correlation and with the negative correlation of IL-6 and leptin and being proved.
The activity form of vitamin D, namely 1-25-(OH)2-D3 [1,25(OH) 2D3], is the secosteroid hormone of a kind of modulating intracellular calcium and bone metabolism, controls cell proliferation and differentiation and plays immunomodulatory activity.Function within the scope of these is developed clinically, is used for the treatment of various situation, and from secondary hyperparathyroidism to osteoporosis, autoimmune disease is as psoriasis.Recently, in understanding 1,25(OH) new development of 2D3 function and the neodoxy in the mechanism of immunomodulation performance show, this hormone has application widely in the treatment of oral inflammation.
The biologically active form of the dihydroxy of vitamin D3 is also referred to as calcitriol, it is a kind of core hormone in calcium homeostasis and bone metabolism, but also have some other function and significant powerful immunomodulation performance, this is attractive for supplement that are complementary, local.
U.S. Patent number 5952317 discusses calcitriol derivant and use thereof.By changing or modifying hydrolyzable group, through realizing vitamin D in vivo along with the Co ntrolled release of time variations to the modulation of calcitriol.Structurally, the key feature with the vitamin D compounds of the improvement of desirable biological nature is: they are derivants of 25-dihydroxy vitamin d3, or the analog of 25-dihydroxyvitamin D derivant, wherein hydrolyzable groups be connected to No. 25 carbon hydroxyl on and be optionally connected to other the hydroxyl any existed in molecule.Depend on various structural factor, the type of such as additive group, size, structural complexity, these derivants are considered to be hydrolyzed into 25-dihydroxy vitamin d3 with different speed in vivo or form 25-dihydroxy vitamin d3 analog, thus provide bioactive vitamin D compound (as 1-25-(OH)2-D3 or its analog) " slow releasing " in vivo.These compounds " slow releasing " activity curve in vivo can by using the mixture of derivant (as 1, the different derivant of 25-dihydroxy vitamin d3 or 1, the mixture of the different derivants of 25-dihydroxyvitamin analog) or use one or more vitamin D-derivatives together with 1,25(OH) the molecular mixture of chemical modification that derives of 2D3 and regulating further.For obtaining the analog of desired performance, whole molecule is modified.The novel vitamin D analogues different more than 1000 kinds is worldwide synthesized.All these analog fall into the present invention discuss and claimed vitamin D.
Vitamin D receptor (VDR) is a member of the nuclear receptor superfamily for steroid hormone and elliptic function-like solution.VDR is used as 1,25(OH) 2D3 activate transcription factor, its finally affect RNA polymerase mediation the speed of transcribing.VDRs not only exists in the cell being usually directed to calcium and bone metabolism, but also is present in the cell of other type, as immune cell.See: Chantal Mathieu and Luciano Adorini, " 1; 25-dihydroxy vitamin d3 analog is as the arrival in immunomodulator epoch " (" The coming age of 1; 25-dihydroxyvitamin D3 analogs as immunomodulatory agents "), molecular medicine trend magazine (TRENDS in Molecular Medicine), 8th volume, the 4th phase, in April, 2002.
Before 25 years, based on the observed result that two show, propose the immunomodulation effect of vitamin D first.First result: research show to derive from suffer from granulomatosis, the monocyte/macrophage of sarcoid patient structurally synthesized the activity form of vitamin D, namely synthesize from precursor 25-hydroxy-vitamin D (25OHD) 1,25-dihydroxyvitamin D (1,25 (OH)
2d).Second result: for 1,25(OH)
2d(vitamin D receptor, VDR) receptor be detectable in the lymphocyte of the propagation of activity.These observations indicate a mechanism, namely produced by mononuclear cell 1,25(OH)
2d can work to adjacent T cell or B cell, but the impact of this system is uncertain to normal immune control.In fact, just in recent years, vitamin D just shows image more clearly as the effect of the determiner of immunne response.Two new concepts have promoted this change.The first, the research of inherent immunity shows, the emiocytosis induction of the antibacterial activity of vitamin D is that monocyte/macrophage is to the key components infecting response.The second, be clear that now that the vitamin D state of suboptimum is a common feature of a lot of population in world wide, this may damage the monocyte/macrophage metabolism and follow-up 1,25(OH of 25OHD)
2the effect of D.Some nearer viewpoints have enriched these new progresses, the dependency that the inherent immunity specifically proposing metabolism and signal transduction mechanism and vitamin D controls and affects human diseases.See Martin Hewison, " summary: the intracrinology of vitamin D and inherent immunity " (" Review:Vitamin D and the intracrinology of innate immunity "), molecule and cellular endocrinology magazine (
molecular and Cellular Endocrinology), 2010, the 321st volume: 103-111 page.
In nearest this section of article 2007, Holick, New England Journal of Medicine (
n. Engl. J. Med.), the 357th volume: in the comment of 266-281 page, shows that the deficiency of vitamin D can be defined by the level of 25OHD of circulation, this level is higher than vitamin D deficiency (50 nM or 20ng/ ml) but be less than 75 nM(30 ng/ml).See: Holick, 2009, epidemiology magazine (
ann. Epidemiol.), the 19th volume: 73-7.
Therefore, since former sarcoidosis research, first a kind of mechanism has likely been proposed, the benefit of the innate immune response that the emiocytosis metabolism that this mechanism describes 25OHD in detail is infected relative to monocyte/macrophage.When facing immune problem, during as infected M.tb. pathogen induction receptor as TLRs trigger body, the expression of 1 α hydroxylase and VDR can be strengthened.There is provided abundant available 25OHD, this will improve 1,25(OH)
2the local horizontal of D, stimulate transcribing of HCAP gene, the antibacterial protein produced is introduced in lysosome, to impel killing bacteria.Initial period, HCAP is considered to mainly be worked by the cell membrane destroying antibacterial.See: Nizet and Gallo, lemology magazine (
scan. J. Infect. Dis.), 2003, the 35th volume: 670-676 page.
Between vitamin D and human immunity, an interactional neodoxy shows, emiocytosis mechanism is the core of its immunomodulatory activity.Importantly, now known that the cell of the various tissues of these mechanism outside classical immune system is also very common, particularly " barrier " site is as skin, lung, intestinal, Placenta Hominis and oral mucosa.No matter whether cell type participates in reconciling reply the emiocytosis of vitamin D, these researchs have highlighted the potential problems coming from vitamin d insufficiency state and produce.Show as a kind of prevalent condition in the population of the latter all over the world, thus emphasize further to need new clinical research be intended to assess the physiology of vitamin d insufficiency and disease consequence and the present invention describe and the topical of claimed Vitamin D supplements to the potential of local inflammation disease.
Vitamin D deficiency is relevant to the increase of infection rate.From the 19th beginning of the century, the food source (i.e. cod-liver oil) of environment (i.e. sunlight) and vitamin D has been identified as can treat tuberculosis (TB).Nearest discovery, the expression of the antibacterial peptide gene of vitamin D induction partly explains " antibacterial " effect of vitamin D, and greatly have updated the immunologic function of understanding people improve to(for) vitamin D.For the response of the inherent immunity system that wound produces with the infection comprising oral cavity infection, follow-up research shows that this modulation is extremely important in a physiologically; Also show that deficiency disease may cause the suboptimization response for antibacterial and viral infection.The most promising to the potential of the supplement of the local vitamin D of oral cavity inflammatory response.
The 25(OH circulated in blood) D is attached in vitamin D binding protein, and this is a reliable index of vitamin D state.25(OH) D changes into 1,25-dihydroxyvitamin D (1,25(OH) 2D by mitochondrion 1 α hydroxylase (CYP2781)) and complete and activate fully.Human body most 1,25(OH) 2D synthesizes in the elementary renal tubules of kidney, but synthesis also occurs in many outside sites until cellular expression CYP2781.
1,25(OH) gene function of 2D is transcription factor by belonging to steroid/hormone receptor receptor family, namely vitamin D receptor (VDR) is modulated.
Vitamin D deficiency is relevant to the multiple health status in cancer context to bone health, but along with the discovery of the antibacterial peptide gene modulated by vitamin D approach, it is determined re-recognizing of immune system impact.It is specifically intended that recognized and may alleviate the many chronic persistent ailment of facing when we are old below in the enough levels of whole life-span mesopodium.Within a whole day, by the repeatedly topical of Vitamin D supplements, the level of " locally " vitamin D may be affected.
Many epithelial tissue such as oral mucosa, intestinal, skin, urinary tract and genitals are often exposed in this environment; there is provided in the protection of enantiopathy substance in these tissues, the importance of vitamin D-tubulin (cathelicidin) approach has been a focus.This comprises the local Vitamin D supplements coming from the present invention's announcement and claimed compositions and is applied to oral mucosa, and it effectively penetrates oral mucosa continuously and absorbs.
Have vitamin D level not enough in view of most people and have nearly 1,000,000,000 people to lack in the world, the research of rational mankind vitamin D will be extremely important, raises the benefit brought for determining by the serum levels of vitamin D.See: vitamin D antibacterial peptide approach and its effect (The Vitamin D-antimicrobial peptide pathway and its role in protection against infection) in infection, following microorganism magazine (
future Microbial.), 2009, the 4th volume 9 phase: 1151-1166 page.
Vitamin D is considered to can modulating intracellular calcium stable state, and has effect in the modulation of electrolyte and blood pressure.The evidence of more and more quantity is had now to show, 1,25(OH)
2d
3for the metabolite of most active vitamin D, modulate immunne response and there is anti-inflammatory activity.See: gastroenterology current visual angle (
current Opinion in Gastroentarology), 2010, the 26th volume: 591-595 page.
Vitamin D and vitamin D receptor (VDR) characteristic in immunologic function describes and achieves marked improvement.In the research to the intracellular signaling path of infecting and relate in inflammatory response, make by the understanding of VDR to the cell response of vitamin D more detailed.The present invention is based on nearest progress: how understand vitamin D to oral mucosa topical, how to contribute to mucosal immunity function, particularly relates to the molecular mechanism of the mucosal immunity of vitamin D and VDR impact, bacteriological infection and inflammation.
Recently, research shows that vitamin D has modulated T cell antigen receptor, thus further demonstrate that vitamin D has non-classical effect in immunomodulation.The antiinflammatory of vitamin D and infection function are new discovery and have very significant active, rely on local of the present invention vitamin D supplement composition to realize.Vitamin D/VDR stablizes at modulation intestinal environment, the invasion of compact siro spinning technology, pathogen, symbiotic bacteria field planting, the secretion of antibacterial peptide and the defence of mucosa response in there is multiple important function.What is interesting is, VDR intracellular signaling path has been modulated in microorganism.
Vitamin D is considered to a pivotal player in calcium homeostasis and electrolyte and blood pressure modulation.Recently, how to affect the pathogenesis of human diseases in the non-standard sexual activity understanding vitamin D and achieve impressive progress in preventing.Vitamin D and VDR have participated in the conduction of T cell antigen receptor signal directly.Vitamin D/the VDR participated in antiinflammatory and infection represents the new characteristic of a kind of VDR and has very significant active.Research has shown that the imbalance of VDR can cause excessive inflammatory response, and then improves the probability of vitamin D deficiency, and VDR intracellular signaling may be relevant with the chronic inflammatory disease comprising periodontitis to bacteriological infection.
In general, 1,25(OH)
2d
3immune impact is comprised: modulation φt cell receptor (TCR), reduce Th1/Th17 CD4+ T cell and cytokine, increase regulatory T cells, lower output that T cell drives and suppress the differentiation of dendritic cell.
In various cell type, 1,25(OH) 2D3 lowers the expression of many proinflammatory cytokines as IL-1, IL-6, IL-8 and TNF-α, and this and its antiinflammatory action meets.Comprise the immunocyte of T cell of macrophage, dendritic cell and activation, the VDR in express cell to 1,25(OH) 2D3 response.
Vitamin D deficiency is associated with the incidence rate increase of infection.In addition, 1,25(OH) 2D3 is induction of the expression of antibacterial peptide (such as carthelicidin).Therefore, nearest research has re-recognized 1,25(OH of use local of the present invention supplement composition widely) anti-infection activity of 2D3.See: Gombert A.F., following microorganism magazine (
future Microbial), 2009, the 4th volume: 1151 to 1165 pages.
Rely on local of the present invention supplement composition, manipulation 1,25(OH) 2D3 level in vivo supplement the function of course recovery VDR by local, this represent a kind of method for the treatment of periodontitis newly.1,25 (OH)
2d
3there is strong immunomodulation performance, facilitate its potential in the prevention and therapy of infectious disease comprising periodontitis.See: Newsson M, molecular cell magazine (
mol. Cell Endocrinol), 2010, the 321st volume: 103-111 page.
Vitamin D deficiency is when periodontal surgery, and the negative effect caused can continue 1 year.The analysis of data shows, the state of vitamin D is vital to operating postoperation recovery.Clinical research official scheme number is CT00277065.
The main source of vitamin D is that diet is taken in and the form of vitamin D2 and D3 is metabolised to 25-hydroxy-vitamin D [25(OH) D] under sunlight irradiates in liver.In kidney, further metabolism produces the activity form of vitamin D, i.e. 1,25-dihydroxyvitamin D.
The feature of periodontitis is the injury of alveolar bone that host immune response is induced when bacterial invasion.Because vitamin D serves vital effect in the maintenance and immunity of skeleton, so have reason to suspect that vitamin D deficiency can have a negative impact to periodontal biologically.The diagnosis of vitamin D deficiency is by analyzing 25(OH) serum levels of D detects.Serum 25(OH) normal range of D level is 20-74 ng/mL.Although do not have the absolute threshold of received deficiency disease state, most of mechanism thinks and at least constitutes slight shortage lower than 20-30 ng/mL, is then severe vitamin D deficiency from the level of 12 ng/mL.See: the people such as Bashutski, dentistry research magazine (
j. Dent. Res), the 90th volume 8 phase, 1007-1012 page.Vitamin D local in compositions of the present invention supplements, and have impact on " locally " vitamin D level of cell in the problem of being in.
In cross-sectional study, low vitamin D level is with the damage of gingivitis, injury of teeth, clinical attachment and be associated in the increase of the important periodontal of phenolics.Every day estimates the level that will increase " locally " vitamin D by the administration of local of the present invention supplement composition.
What is interesting is, in operation process, vitamin D can not prevent the negative clinical result relevant to basic deficiency disease.Patient supplements with vitamin D and continues only six time-of-weeks, but, need consumption to reach within 3 months, to make serum 25(OH after the intake increase of vitamin D) horizontal stable of D.See: the people such as Veith R, U.S. clinical threpsology magazine (
am. J. Clin. Nutr), February calendar year 2001, the 73rd volume 2 phase: 288-94 page.In view of in the patient taking placebo serum 25(OH) D level returns to baseline values after six months, the vitamin D of six weeks supplements and does not produce long-range effects individually.
The analysis of data shows, if individuality is vitamin D deficiency, so can obtain very little benefit from periodontal surgery.In addition, when performing the operation, vitamin D can not prevent this impact.In view of vitamin D deficiency is very general, can advise before periodontal surgery, guarantee there is sufficient vitamin D level, to obtain best result.Oral Vitamin D supplements combines with the supplement composition of local of the present invention vitamin D, advises administration every day in the longer-term before periodontal surgery.
Epidemiological study shows, low vitamin D level may increase risk or the seriousness of respiratory virus infection.The research and inquirement impact of vitamin D on the human airway epithelium cell that respiratory syncytial virus (RSV) infects.The epithelial portion of respiratory tract is by 25-hydroxy-vitamin D
3(file layout) is converted to 1,25 dihydroxyvitamin Ds
3(activity form).Produce the activated vitamin D of local in the tissue, this comprises it to the impact of immunne response to the non-skeleton effect of vitamin D is very important.Research finds, vitamin D induces the inhibitor of IkB α and NF-kB in the epithelial cell of respiratory tract, and the NF-kB reducing RSV induction drives gene as IFN-β and CXCL10.
Research finds, can reduce the induction of IFN-stimulatory protein(SP) under airway epithelial cell being exposed to vitamin D, and IFN-stimulatory protein(SP) has important antiviral activity (such as, the albumen of the IFN-stimulation of myxovirus opposing A and 15 kDa).Compared to the gene expression of RSV-induction, vitamin D does not affect IFN intracellular signaling, and independent INF can inducible gene expression.Give expression to the IKBA of non-degradable form and the adenovirus vector of simulating the effect of vitamin D can suppress NF-kB.When vitamin D receptor is reticent under siRNA effect, the effect of vitamin D disappears.Most important discovery is, although induction of IKBa and moistening chemotactic factor and IFN-β, virus mRNA or protein or virus replication all do not increase.
Can reach a conclusion thus, vitamin D reduces the inflammatory response at airway epithelial portion viral infection, and can not hinder the removing of virus.This shows that sufficient vitamin D level is by the seriousness reducing inflammation in the individuality contributing to infecting at RSV-and reduce disease.
Vitamin D is day by day considered to one and has multi-functional hormone, its function extended beyond its function of classics in calcium homeostasis.The evidence increased fast from the research that epidemiology and basis are explored discloses vitamin D and can modulate immunne response.Vitamin D deficiency is very general, and both relevant to the risk increasing serious inflammatory disease, also relevant to increasing the susceptibility comprising the infection of periodontitis.Local organization produces the key components that activated vitamin D is considered to non-classical vitamin D function specifically, and this depends on supplement composition of the present invention and can realize.The data delivered in the past show, normal lung epithelial portion is structurally 25-hydroxy-vitamin D
3(vitamin D storage form) is converted into 1,25-dihydroxyvitamin D
3(1,25D) (activity form of vitamin D), and the generation of activated vitamin D can increase under the existence of viral infection.
Inflammation is the necessary ingredient of body defenses; But opposing microorganism or the too violent response of inflammation may be harmful to body, cause the impaired of organ dysfunction.At the inflammation disease of animal model as in multiple sclerosis and type 1 diabetes, vitamin D has demonstrated the generation suppressing inflammatory chemokine.
The family that NF-kB transcribes modulation factor has central role in the expression of the various genes of cooperation control immunne response.NF-kB albumen is present in the Cytoplasm that same 1kBs is associated.IkBs is phosphorylation by IKB kinases, and carry out cytositimulation, then they are destroyed to being targeted property by Ubiquitin-Proteasome-Dependent degradation pathway thereupon.The degraded of IkB makes NF-KB protein translocation in nucleus, is combined and then activates a variety of gene with their DNA binding site.See: the people such as Sif Hansdottir, Journal of Immunology (
the Journal of Immunology),2010, the 184th volume: 965-974 page.
Vitamin D hormones form raises (up-regulates) antibacterial peptide (antimicrobial peptides), i.e. tubulin (cathelicidin), to strengthen the cleaning of antibacterial in each barrier position and immunocyte.Vitamin D by the activation of T cell and to antigen-presenting cell (ACPs) particularly the phenotype of DCs and function directly exert one's influence, thus modulate immune adaptability.
Along with in the past decade, the discovery of the crucial vitamin D metabolic enzyme of cellular expression in vitamin D receptor (VDR) and immune system, vitamin D has obtained more accreditation to the importance of cell modulation in immune system.In zooscopy, early stage epidemiology and clinical research think that vitamin D has potential supporting role in maintenance immune system balance.
Think at present, by raising antibacterial peptide in infection response, as tubulin (cathelicidin), vitamin D can strengthen inherent immunity.The rise of this antibacterial peptide relies on local of the present invention supplement composition to realize.
Therefore, antibacterial peptide (as tubulin) constitutes an ingredient of inherent immunity, to reply various infection, especially in barrier site, as oral mucosa.
These results of study comprehensive show, 1,25 (OH)
2d
3in various different cell, raise the output of antibacterial peptide, wherein mainly tubulin (cathelicidin), and vitamin D supplement composition of the present invention can be relied on to realize.
In a word, 1,25 (OH)
2d include reducing Th1/Th17 CD4+ T cell and cytokine to immune impact, adds regulatory T cells, has lowered the output of the IgG of T cell-driving and has inhibit the differentiation of dendritic cell.While enhancing protectiveness innate immune response, 1,25 (OH)
2d contributes to the toleration maintaining self by suppressing excessive adaptive immune response.See: Diane L. Kamen and Via Taagpricha, vitamin D and molecule are to immune effect: congenital and autoimmune modulation (Vitamin D and molecular actions on the immune system:modulation of innate and autoimmunity), molecular medicine magazine (
j. Mol. Med), 2010, the 88th volume: 441-450 page.
Vitamin D carries out administration by local of the present invention supplement composition, may be useful for the treatment of periodontal, inflammatory conditions includes the activation being discharged the host defense cells that inflammatory mediator produces by antibacterial, which results in periodontal and support disorganization, comprise the destruction of connective tissue and alveolar bone.
Third National health and nutritional survey research (NHANES III), it comprises 12000 adults, finds periodontal health and has significant association between vitamin D and the intake of calcium.Therefore, the data obtained from the sample that this is huge will support this hypothesis, and the intake namely reducing vitamin D and calcium in diet may promote the not optimum of periodontal health, and relevant to concrete dosage.
The no matter supplementary information of calcium or vitamin D in its meals, the patient's periodontal health participating in regular periodontal care regimen improves.Even now, the supplement taking calcium and vitamin D, relative to not taking for this supplement, obtain better periodontal health.Show in report before, vitamin D reduces the susceptibility of gingivitis by antiinflammatory action effect, and another one research confirmation, 25(OH) be the linear correlation of inverse correlation between D and BOP.Report with this section, in supplement user, observe the minimizing of BOP and inflammation, after experimenter carries out Peridontal maintenance, datum line has obvious difference and significance can retain and reaches 1 year consistent.It should be pointed out that owing to relate to different covariants, the result of baseline analysis report is here slightly different previously in those reports in same population.See: the people such as M. Nathalia Garcia, vitamin D and calcium supplement the impact (One-Year Effects of Vitamin D and Calcium Supplementation on Chronic Periodontitis) within chronic periodontitis 1 year, Periodontology (
j. Periodontol), 2011, the 82nd volume: 25-32 page.
The optimum level of vitamin D should have immunosuppressive effect to periodontal.See: the people such as D. Dixon, the use (Calcium and vitamin D use among adults in periodontal disease maintenance programmes) of the calcium in human adult periodontal disease maintenance scheme and vitamin D, Britain's dentistry magazine (
british Dental Journal), 2009, the 208th volume: 827-831 page.
Except it is to the stable state effect of skeleton, by the inflammatory cytokine that the stimulation secretion of the antibacterial action peptide of the cell of immunocyte and monocytes/macrophages pedigree produces, vitamin D is its hormonal activity form 1 α particularly, and 25-dihydroxyvitamin D has antiinflammatory and antibacterial effect.These performances make them form local supplement composition, to treat " locally " oral cavity infection.
All clinical and eikonometry displays, it is better to have carried out experimenter's periodontal health that vitamin D and calcium supplements.In addition, because all experimenters take part in periodontal maintenance scheme, so these data are consistent with this viewpoint, the beneficial effect namely taking vitamin D and calcium to supplement more than or the effect of nursing beyond the periodontal of those standards.
Result shows, vitamin D and calcium complement agent can advocate the part as periodontal management.See: the people such as D. Douglas, Periodontology (
j. Periodontol), in JIUYUE, 2009, the 80th volume: 1433-1439 page.
Produced suggestion alter a great deal.But vitamin D also may have various useful effect to produce, as in muscle strength, colon cancer and inflammation disease except bone health.In this research, do not find that evidence is as 25(OH) threshold value of D serum-concentration, decline with the relatedness of gingivitis higher than after this threshold value.Therefore, the antiinflammatory action of vitamin D can increase serum-concentration to 90-100 nmol/L.These results are consistent with the antiphlogistic effects of vitamin D to gingivitis, and this as a kind of alternative approach, can may be conducive to the prevention of periodontal by means of this approach vitamin D.
Vitamin D can reduce the susceptibility of gingivitis by its antiinflammatory action.Gingivitis can as a useful clinical pattern, to assess the antiphlogistic effects of vitamin D, see: the people such as Thomas Dietrich, U.S. clinical threpsology magazine (
am. J. Clin. Nutr), 2005,82-575 page.
Detailed description of the invention
In the supplement composition of vitamin D oral cavity, a preferred local of the present invention, Vitamin D supplements strengthens inherent immunity by raising antibacterial peptide (tubulin).
In a preferred embodiment of the invention, vitamin D oral cavity, local supplement composition is its hormonal activity form, i.e. 1 α, 25-dihydroxyvitamin D, relying on modulation inflammatory cytokine output, by stimulating the secretion of anti-microbial property, showing antiinflammatory and antibacterial effect.Local vitamin D oral cavity supplement composition and described hormone activated form 1 α, 25-dihydroxyvitamin D, calcitriol all show immunomodulation performance.
The vitamin D oral cavity supplement composition of local in a preferred embodiment of the invention, the antiinflammatory of 1 α, 25-dihydroxyvitamin D and antibacterial effect are modulated by vitamin D receptor (VDR).
The vitamin D oral cavity supplement composition of local in a preferred embodiment of the invention, 1 α, 25-dihydroxyvitamin D comprises immune effect:
Modulation φt cell receptor (TCR);
Reduce TH1/TH17 CD4+ T cell and cytokine;
Increase regulatory T cells;
Lower the output that T cell drives; With
Suppress dendritic cell differentiation.
The present invention includes the method for the treatment of oral inflammation:
The method comprises by vitamin D supplement composition topical to oral mucosa, and described vitamin D supplement composition comprises:
Dissolve in the anhydrous lactitol agent carrier of saliva;
The vitamin D supplement of effect level; With
Transbu ccal mucosa absorption enhancer, wherein:
When being applied to oral mucosa, described compositions forms the mucoadhesive gel dissolving in saliva be attached on described oral mucosa;
When the mucoadhesive gel dissolving in saliva described in persistence release is in saliva fluid, described mucoadhesive gel dissolves gradually, to control described Vitamin D supplements and described transbu ccal mucosa absorption enhancer is released into described oral mucosa;
Wherein for vitamin D oral cavity, described local supplement composition application means be selected from the group be made up of following means: equipment (interproximal devices), buccal cavity gel, oral cavity ointment, pastes, oral cavity paint agent, mouth cavity liquid and their combination between the neighbour being coated with described compositions;
Wherein, the oral inflammation treatment comprising the topical of vitamin D supplement composition comprises and being combined by the daily topical of Vitamin D supplements gel with the dental instrument of coated described compositions, within a whole day, repeatedly apply described compositions.
Be suitable for topical to comprise to the vitamin d compositions of oral mucosa: for the anhydrous lactitol agent carrier of vitamin D, it also comprises oral mucosa and penetrates absorption enhancer, wherein said anhydrous Emulsion, when being exposed in saliva, forms the mucoadhesive gel be attached on oral mucosa.When this mucoadhesive gel is through saliva dissolves, the mixture of vitamin D/transbu ccal mucosa absorption enhancer gradually from the release of mucoadhesive gel Passive diffusion through oral mucosa, thus the system serum levels of vitamin D.
Vitamin d compositions of the present invention preferably uses the dental instrument of buccal cavity gel or coated vitamin d compositions to carry out for the topical of oral mucosa.Particularly preferably, by topical gels multiple dosing in a day of Vitamin D supplements, carry out once daily or twice the process of cleaning one's teeth with the dental instrument of the coated vitamin d compositions of the present invention of employing to combine simultaneously, effectively can realize the topical of vitamin D to oral mucosa.
In order to realize object of the present invention, the anhydrous Emulsion dissolving in saliva is included in those Emulsions of the polydimethylsiloxane composition in nonionic surfactant, as described by following U.S. Patent number 5032387,5098711,5538667 and 5651959, all these patents because of with reference to and to include in herein.
Preferred nonionic surfactant of the present invention can form mucoadhesive gel under the existence of saliva.It is selected from the group be made up of following material: poloxamer 237, Pluronic/Lutrol F 108, poloxamer188 and their combination.
In order to realize object of the present invention, oral mucosa penetrates absorption enhancer and is selected from the group be made up of following material: D-panthenol, (R)-4-isopropenyl-1-methyl-1-cyclohexene, poloxamer, Polyethylene Glycol (PEG), benzyl alcohol, carbopol (carbopol), chitosan (chitosan), N-N-trimethyl chitosan TMC, menthol and their combination.
As the anhydrous Emulsion dissolving in saliva that the carrier of vitamin D supplement composition of the present invention uses, preferably comprise the Emulsion of the polydimethylsiloxane (PDMS) of range of viscosities between about 1500cs to about 2,500,000 cs.Particularly preferably be, anhydrous Emulsion comprises the nonionic surfactant as continuous phase described in detail in the PDMS as discontinuous phase of viscosity between 10500cs and 2,500,000 cs and United States Patent (USP) 5651959.
Preferred polydimethylsiloxane is selected from the group be made up of the polydimethylsiloxane of following viscosity: 1500cs, 12500cs, 100000cs, 250000 cs, 500000cs, 750000cs, 1,500,000 cs, 2,200,000 cs, 2,500,000 cs and their combination.
The application means of vitamin D oral cavity, local of the present invention supplement composition are selected from the group be made up of following means: equipment between the neighbour of buccal cavity gel, oral cavity ointment, pastes, oral cavity paint agent, mouth cavity liquid agent and vitamin D oral cavity, various coated described local supplement composition.
Realize the preferred buccal cavity gel of the object of the invention and be included in those gels disclosed in U.S. Patent number 5009881,5032387,5057306,5057307,5057309,5538667 and 5651959, all these patents are included in herein because of reference.
Preferably, to be suitable between neighbour (interproximally) discharge vitamin D oral cavity supplement composition with coating neighbour between equipment, be included in equipment between those neighbours of disclosing in following U.S. Patent number 4911927,4942034,5098711,5165913,5665374,5711935,6545077,6575176,7017591,7025986 and 7152611, all these patents because of with reference to and include in herein.
The use of dental instrument is a kind of supplementary means of extremely important conventional dental health care.Dental instrument cleaning for a long time effectively for region between tooth and gingival edge bottom.When used correctly, dental instrument has found effectively to suppress decayed tooth and gum disease.Dentist advises that these equipment are for regular oral health routine.
In order to increase the effectiveness of dental instrument, some equipment have contained some medicinal ingredient or dentifrice ingredient, avoid acid attack to help prevent enamel.Antibacterial also connects use with dental floss, to suppress periodontal.
Vitamin D supplement composition in dental instrument of the present invention also can use simultaneously with the salt containing the ion mineralization again exciting hydroxyapatite in tooth structure and is coated on dental instrument.Such compound comprises: calcium, phosphorus and villiaumite, such as, with the form of dentifrice.The example of this kind of salt comprises: fluoride or fluorochemical as sodium fluoride, potassium fluoride, ammonium fluoride, sodium bifluoride, bifluoride potassium, difluoro ammonium, prodan, zinc fluoride and stannous fluoride, but are not limited to these.For example, other dentifrice comprises urase, acid phosphate, calcium carbonate and magnesium carbonate.For example, the example of operable acid phosphate comprises orthophosphoric acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, dikalium phosphate, Ammonium biphosphate, phosphoric acid half sodium salt and sodium hexameta phosphate.Dentifrice is preferably included within dental instrument, and provides effective local concentration with the dosage of abundance at dental surface.
Other active component that can be impregnated between neighbour in equipment comprises the composition of hydrogen peroxide or other generation peroxide as polyvinylpyrrolidone/hydrogen peroxide (PVP/H
2o
2) or urea peroxide, fluoride, tooth acidulant is as buffering or acidulated phosphate fluoride, sodium monofluorophosphate, antiplaque agents, tartar control agents, the antibiotic for the treatment of pyorrhea and gingivitis, tooth whitening and bleach, pH buffer agent, antifungal, mineral nitrogen agent again, hemorrhage, immunizing agent and nonionic and cationic antiseptic are as benzethonium chloride, acetyl trimethylammonium bromide, Sanguinaria canadensis, triclosan (nonionic), tetracycline, cetylpyridinium chloride and Benzethonium Chloride (benzythonium chloride).
Other active component that can be incorporated in dental instrument of the present invention comprises vitamin A, surfactant and pharmaceutical agent as anticarcinogen, analeptic, bone growth agent, antigen, hormone, steroid, antiinflammatory and analgesic.
In other embodiments, dental instrument comprises coagulating agent to suppress to use issuable any bleeding problems in dental floss process.Preferably, coagulating agent is blended in the coating of this equipment, directly to contact gingiva tissue.Coagulating agent can comprise vitamin K, the calcium ion of water-soluble calcium salt form and the blood factor of initiation coagulation cascade.As an alternative, coagulating agent can be dissolved in innoxious solvent, as ethanol, polyethylene terephthalate or ether.
Flavorant can join on dental instrument of the present invention by the known technology in this area, such as after equipment extrusion molding, directly add flavorant, or by flavorant is coated on the surface of equipment, or by fragrance memory, volatile fragrant is sent on equipment.The known flavorant being suitable for using in dental instrument of the present invention is such as Herba Menthae, Cortex Cinnamomi, bubble gum, by comprise International Flavors & Fragrances Inc. of the U.S. (IFF company), Dayton (Dayton), NJ a lot of suppliers can buy them.Other flavorant also can pass through pressed coated (compression coating) technique that describes in quoted document and add.
In order to provide a kind of visual impact to consumer, coloring agent can join in dental instrument of the present invention so that dental instrument is painted.Before extruded, coloring agent can join for the formation of in the nylon of wire rod or other granule.Can being used with the coloring agent of nylon resin use in conjunction of commercially available any one FDA approval.Color can be mutually corresponding with the flavouring agent of dental instrument, such as red corresponding Cortex Cinnamomi, or green corresponding Herba Menthae.In addition, multiple color can be extruded simultaneously, such as make wire rod be red and other is local for green.This equipment can also mix coloring agent or fluorescent dye, to identify residual plaque deposits, and such as red No. three and red No. four.
Illustrative embodiment
By use topical gels and dental strip vitamin d compositions of the present invention to be applied between oral mucosa and neighbour on surface appended by illustrative embodiment, set forth the present invention further.
embodiment 1-there is the topical oral gel of calcitriol.
In the rustless steel beaker of 500 mL, an overhead type stirrer is installed.The water of 135.834g adds the rear stirring starting appropriateness.Other composition is also added in container, in stirring appropriate under room temperature, the saccharin sodium of the potassium sorbate of the glycerol of the Sorbitol of 70% concentration of 102g, 15g, 0.45g, 0.225g, the sucralose of 0.6 g, the flavorant of 0.9525g are joined in container.
The beaker of a 100ml, the anhydrous Emulsion [poloxamer188/polydimethylsiloxane (2,500,000 cs)] (90:10) containing 9.54g, is heated to 95 DEG C under magnetic stirring.Under nitrogen blanket, the calcitriol of 0.15g joins in beaker.
Along with magnetic agitation and heating, in 50 mL beakers, add the propylene glycol of 30g and the methyl parahydroxybenzoate of 0.45 g.When temperature reaches 50 DEG C, in 3 minutes, slowly add the carboxymethyl cellulose 9H4XF of 4.65g.After stirring for 5 minutes, these compositions slowly join in the 100mL beaker containing anhydrous Emulsion.During Keep agitation borehole cooling to 40 DEG C, these compositions slowly joined in rustless steel beaker in 3 minutes.After 20 minutes, under nitrogen blanket, topical oral gel is packaged in pipe, can be carried out local application by extruding from pipe.
embodiment 2-vitamin D dental tape (PROPHY TAPE
?)
At the rustless steel containers of 2 gallons, an overhead type stirrer be installed and place on hot plate.The anhydrous Emulsion [poloxamer188/polydimethylsiloxane (12500 cs)] (90:10) of 1964g, is placed in a reservoir and under agitation melts.Temperature adds following ingredients after being elevated to 90 DEG C: the stearyl alcohol of Pluracare L-1220,600g of 120g, Witcodur 272 (microwax) ML445 and PEG 8000 join in the anhydrous Emulsion of thawing.Be placed with homogenizer in a reservoir, after the effect of 10 minutes, produce emulsifying.Under agitation following ingredients is added: the saccharin sodium of the dentifrice of dicalcium phosphate dihydrate, 240g, the propyl gallate of 4g, 72g, the ethylenediaminetetraacetic acid (EDTA) of 8g.Finally, the calcitriol of 2g is added in the coated composition of emulsifying.The band coating paste of emulsifying is assigned in band coating tank subsequently.The coating of compacting ultra-high molecular weight polyethylene dental strip, uses SOFT ABRASIVES subsequently
?bio-vitric carries out coated and completes, create a kind of dissolve in saliva, the dental strip of pressed coated and have vitamin D and SOFT ABRASIVES outer coating on coating.The mode that this dental strip is wound around with paper is packed, and be the form of single-layer sheet, length is 20 inches.The single-layer sheet of PROPHY TAPE dental tape is packaged in and is packaged with in the packaging of spice, is provided with the fragrance reservoir of the volatile spice adding about 20 in packaging.
Claims (19)
1. the vitamin D oral cavity supplement composition of local, is used for the treatment of oral inflammation, comprises:
Dissolve in the anhydrous emulsion carrier of saliva;
The Vitamin D supplements of effect level; With
Transbu ccal mucosa absorption enhancer, wherein:
When being applied to oral mucosa, described compositions forms the mucoadhesive gel dissolving in saliva be attached on described oral mucosa;
When constantly the described mucoadhesive gel dissolving in saliva being exposed in saliva fluid, described mucoadhesive gel little by little dissolves, and makes described Vitamin D supplements and described transbu ccal mucosa absorption enhancer Co ntrolled release to described oral mucosa; With
When contacting described oral mucosa, described Vitamin D supplements and transbu ccal mucosa absorption enhancer Passive diffusion are through described oral mucosa:
(a) modulation vitamin D availability in vivo and immunne response;
B () maintains the level of circulation vitamin D in abundance; With
C () minimizes the risk of hypercalcemia.
2. compositions according to claim 1, the wherein said anhydrous Emulsion dissolving in saliva is formed by polydimethylsiloxane emulsifying in nonionic surfactant, and described non-ionic surface active agent can form mucoadhesive gel when saliva exists.
3. compositions according to claim 1, wherein said Vitamin D supplements is selected from the group be made up of following material:
Vitamin D,
The vitamin D compounds of hydroxyl is equipped with at 1,3 and No. 25 carbon potential,
1 α, 25-dihydroxyvitamin D
3esters,
1,25-dihydroxyvitamin D
3esters,
1,25 (OH)
2d
3, 1,25 (OH)
2d
3analog, and
Calcitriol, 25 (OH) D
3, 25 (OH) D
3analog and their combination.
4. compositions according to claim 1, wherein said transbu ccal mucosa absorption enhancer is selected from the group be made up of following material: D-panthenol, (R)-4-isopropenyl-1-methyl-1-cyclohexene, poloxamer, Polyethylene Glycol, benzyl alcohol, carbopol, chitosan, N-N-trimethyl chitosan TMC, menthol and their combination.
5. compositions according to claim 1, the application means of the vitamin D oral cavity supplement composition of wherein said local are selected from the group be made up of following means: equipment, buccal cavity gel, oral cavity ointment, pastes, oral cavity paint agent, mouth cavity liquid agent and their combination between the neighbour of coated described compositions.
6. compositions according to claim 5, between wherein said neighbour, the application means of equipment are selected from the group be made up of following means: the dental strip of pressed coated, the dental floss of multifilament or monofilament, that one side has a coating or equipment between neighbour, dental instrument, dental pick, dentistry stimulator and their combination.
7. compositions according to claim 2, wherein said polydimethylsiloxane is selected from the group be made up of the polydimethylsiloxane of following viscosity: 1500 cs, 12500 cs, 100000 cs, 250000 cs, 500000 cs, 750000 cs, 1500000 cs, 2,200,000 cs, 2,500,000 cs and their combination.
8. compositions according to claim 2, the described nonionic surfactant that wherein can form mucoadhesive gel when saliva exists is selected from the group be made up of following material: poloxamer 237, Pluronic/Lutrol F 108, poloxamer188 and their combination.
9. the vitamin D oral cavity supplement composition of local according to claim 1, wherein said Vitamin D supplements strengthens inherent immunity by raising tubulin antibacterial peptide.
10. the vitamin D oral cavity supplement composition of local according to claim 1, wherein said Vitamin D supplements is its hormonal activity form 1 α, 25-dihydroxyvitamin D, rely on the output of modulation inflammatory cytokine, by stimulating the secretion of anti-microbial property, demonstrate antiinflammatory and antibacterial effect.
The vitamin D oral cavity supplement composition of 11. local according to claim 11,1 α of wherein said hormonal activity form, 25-dihydroxyvitamin D is calcitriol, demonstrates immunomodulation performance.
The microorganism D oral cavity supplement composition of 12. local according to claim 11, antiinflammatory and the antibacterial effect of wherein said 1 α, 25-dihydroxyvitamin D are modulated by vitamin D receptor.
The vitamin D oral cavity supplement composition of 13. local according to claim 11, wherein said 1 α, 25-dihydroxyvitamin D comprises immune effect:
Modulation φt cell receptor,
Reduce TH1/TH17 CD4+ T cell and cytokine,
Increase regulatory T cells,
Lower the output that T cell drives, and
Suppress the differentiation of dendritic cell.
The method of 14. treatment oral inflammations, comprise by vitamin D supplement composition topical to oral mucosa, described vitamin D supplement composition comprises:
Dissolve in the anhydrous emulsion carrier of saliva;
The Vitamin D supplements of effect level; With
Saturating buccal absorption promoter, wherein:
When being applied to oral mucosa, described compositions forms the mucoadhesive gel dissolving in saliva be attached on described oral mucosa,
When constantly the described mucoadhesive gel dissolving in saliva being exposed in saliva fluid, described mucoadhesive gel little by little dissolves, to control described Vitamin D supplements and described transbu ccal mucosa absorption enhancer is discharged into described oral mucosa; With
When contacting described oral mucosa, described Vitamin D supplements and transbu ccal mucosa absorption enhancer Passive diffusion are through described oral mucosa:
(a) modulation vitamin D availability in vivo and immunne response;
B () maintains the level of vitamin D in abundance of circulation; With
C () minimizes the risk of hypercalcemia.
15. methods according to claim 15, the wherein said anhydrous Emulsion dissolving in saliva is formed by polydimethylsiloxane emulsifying in nonionic surfactant, can form mucoadhesive gel when it exists in saliva.
16. methods according to claim 15, wherein said Vitamin D supplements is selected from the group be made up of following material:
Vitamin D,
The vitamin D compounds of hydroxyl is equipped with at 1,3 and No. 25 carbon potential,
1 α, 25-dihydroxyvitamin D
3esters,
1,25-dihydroxyvitamin D
3esters,
1,25 (OH)
2d
3, 1,25 (OH)
2d
3analog,
Calcitriol, 25 (OH) D
3, 25 (OH) D
3analog and their combination.
17. methods according to claim 15, wherein said transbu ccal mucosa absorption enhancer is selected from the group be made up of following material: D-panthenol, (R)-4-isopropenyl-1-methyl-1-cyclohexene, poloxamer, Polyethylene Glycol, benzyl alcohol, carbopol, chitosan, N-N-trimethyl chitosan TMC, menthol and their combination.
18. methods according to claim 15, the application means of the vitamin D oral cavity supplement composition of wherein said local are selected from the group be made up of following means: equipment, buccal cavity gel, oral cavity mastic, pastes, oral cavity paint agent, oral cavity sealer, mouth rinse, mouth cavity liquid agent and their combination between the neighbour of coated described compositions.
19. according to claim 15ly to comprise vitamin D supplement composition topical to oral mucosa to treat the method for oral inflammation, wherein, by the daily topical of Vitamin D supplements gel with the dental instrument adopting coated described compositions is combined, compositions described in whole day repeated application.
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|---|---|---|---|
| CN201910163471.7A CN109908157A (en) | 2012-10-12 | 2013-10-10 | Vitamin D oral cavity supplement composition locally |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13/650,963 US9149528B2 (en) | 2011-10-13 | 2012-10-12 | Topical vitamin D oral supplement compositions |
| US13/650,963 | 2012-10-12 | ||
| PCT/US2013/064358 WO2014059157A1 (en) | 2012-10-12 | 2013-10-10 | Topical vitamin d oral supplement compositions |
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| CN201380053186.0A Pending CN104968351A (en) | 2012-10-12 | 2013-10-10 | Topical vitamin D oral supplement compositions |
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| EP (1) | EP2887945A4 (en) |
| JP (1) | JP6420766B2 (en) |
| CN (2) | CN109908157A (en) |
| AU (1) | AU2013329170B2 (en) |
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| WO (1) | WO2014059157A1 (en) |
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| CN114746072A (en) * | 2019-11-15 | 2022-07-12 | 高露洁-棕榄公司 | Oral care compositions |
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|---|---|---|---|---|
| CN1190342A (en) * | 1995-06-05 | 1998-08-12 | 白山口腔技术有限公司 | Oral care ultramulsion based product |
| US20080039434A1 (en) * | 2004-03-01 | 2008-02-14 | Bioxell S. P.A. | Treatment of Interstitial Cystitis with Vitamin D Compounds |
Family Cites Families (4)
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|---|---|---|---|---|
| US5665374A (en) * | 1995-06-05 | 1997-09-09 | Whitehill Oral Technologies, Inc. | Ultramulsion containing interdental delivery devices |
| WO2006105615A1 (en) * | 2005-04-08 | 2006-10-12 | Ozpharma Pty Ltd | Buccal delivery system |
| US20070166244A1 (en) * | 2006-01-19 | 2007-07-19 | The Procter & Gamble Company | Compositions comprising silicone pressure sensitive adhesives for delivering oral care substances |
| WO2009153634A1 (en) * | 2008-06-19 | 2009-12-23 | University Of Witwatersrand, Johannesburg | A transmucosal delivery system |
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2013
- 2013-10-10 JP JP2015536896A patent/JP6420766B2/en not_active Expired - Fee Related
- 2013-10-10 CA CA2886067A patent/CA2886067C/en active Active
- 2013-10-10 EP EP13844920.2A patent/EP2887945A4/en not_active Withdrawn
- 2013-10-10 CN CN201910163471.7A patent/CN109908157A/en active Pending
- 2013-10-10 CN CN201380053186.0A patent/CN104968351A/en active Pending
- 2013-10-10 AU AU2013329170A patent/AU2013329170B2/en not_active Ceased
- 2013-10-10 WO PCT/US2013/064358 patent/WO2014059157A1/en active Application Filing
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1190342A (en) * | 1995-06-05 | 1998-08-12 | 白山口腔技术有限公司 | Oral care ultramulsion based product |
| US20080039434A1 (en) * | 2004-03-01 | 2008-02-14 | Bioxell S. P.A. | Treatment of Interstitial Cystitis with Vitamin D Compounds |
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| LAURA MCMAHON等: "Vitamin D-Mediated Induction of Innate Immunity in Gingival Epithelial Cells", 《INFECTION AND IMMUNITY》 * |
| SARAH DIMELOE等: "Regulatory T cells, inflammation and the allergic response—The role of glucocorticoids and Vitamin D", 《JOURNAL OF STEROID BIOCHEMISTRY & MOLECULAR BIOLOGY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114746072A (en) * | 2019-11-15 | 2022-07-12 | 高露洁-棕榄公司 | Oral care compositions |
Also Published As
| Publication number | Publication date |
|---|---|
| JP6420766B2 (en) | 2018-11-07 |
| CA2886067A1 (en) | 2014-04-17 |
| AU2013329170B2 (en) | 2018-03-29 |
| CN109908157A (en) | 2019-06-21 |
| WO2014059157A1 (en) | 2014-04-17 |
| AU2013329170A1 (en) | 2015-04-09 |
| EP2887945A1 (en) | 2015-07-01 |
| JP2015533167A (en) | 2015-11-19 |
| CA2886067C (en) | 2021-04-06 |
| EP2887945A4 (en) | 2016-03-23 |
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