CN104162142A - Application of N-acetyl aspartoyl glutamic acid dipeptide preparation in treatment of heroin addiction - Google Patents
Application of N-acetyl aspartoyl glutamic acid dipeptide preparation in treatment of heroin addiction Download PDFInfo
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- CN104162142A CN104162142A CN201410437809.0A CN201410437809A CN104162142A CN 104162142 A CN104162142 A CN 104162142A CN 201410437809 A CN201410437809 A CN 201410437809A CN 104162142 A CN104162142 A CN 104162142A
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Abstract
The invention relates to an application of N-acetyl aspartoyl glutamic acid dipeptide preparation in treatment of heroin addiction. The experiment shows that NAAG has a remarkable treatment effect on heroin addiction. The NAAG can remarkably reduce the heroin dosage of mice and the motivation of heroin dosage in the heroin addiction stage, the effect can be taken into play through a glutamic acid metabolism receptor 3 subtype, and the NAAG can also remarkably reduce the relapse rate of mice after heroin abstinence. The invention further provides a nasal delivery mode of the NAAG dipeptide preparation for treating heroin addiction. By adopting the delivery mode, the problems that a conventional NAAG oral medicine is low in bioavailability, and meanwhile the N-acetyl aspartoyl glutamic acid dipeptide preparation has the characteristics that use is simple, operation is convenient and carrying is convenient.
Description
Technical field
The invention belongs to biomedicine field, relate in particular to a kind of two peptide formulations and nasal-cavity administration mode thereof that is used for the treatment of heroin addiction.
Background technology
N-acetyl aspartoyl glutamic acid (N-acetylaspartylglutamate, NAAG) is find nineteen sixty-five very high and have brain district special allochoric two peptide molecules (Curatolo et al., 1965 at mammalian central nervous system content; Miyamoto et al., 1966), after the eighties, NAAG is accredited as a kind of neurotransmitter (Westbrook et al., 1986 of peptide class; Trombley et al., 1990).Endogenic NAAG is from synaptic vesicle is discharged into synaptic space, can be positioned at glutamate carboxypeptidase II and III (Glutamate carboxypeptidase II and III on astrocyte, GCPII and III) hydrolysis generates N-Acetyl Aspartate and glutamic acid (Robinson et al., 1987), and be considered to supplement in brain the deposit pond of glutamic acid.As neurotransmitter, NAAG is again the efficient agonist (Wroblewska et al., 1997) of metabotropic glutamate receptor 3 hypotypes (mGluR3).Research shows, suppress NAAG peptidase activity and can reduce its hydrolysis to NAAG, reduce synaptic space glutamic acid aggregate level on the one hand, the NAAG that synaptic space is accumulated on the other hand effectively activates the mGluR3 on presynaptic membrane, and the irritability that reduces presynaptic membrane glutamic acid discharges.Therefore, the inhibitor of NAAG peptidase or ectogenic NAAG have been used for studying the disease that the multiple glutamic acid for the treatment of is overexcited and is induced, and find that it has potential therapeutic effect in the animal models such as schizophrenia, amyotrophic lateral sclerosis, traumatic brain injury and carcinoma of prostate.
Drug dependence be a kind of take relapse the chronic encephalopathy as feature, the relapse rate under being in not becomes the Focal point and difficult point for the treatment of clinically addiction.The research of neurobiology shows: suck the medicines such as ***e, heroin and cause human or animal's brain ventral tegmental area to the increase of the dopaminergic projection of nucleus accumbens septi, and may be with other neurotransmitteies as interactions such as glutamic acid, acetylcholine, develop into subsequently addiction (Wise, 2004 to medicine; Calabresi et al., 2000).And prefrontal cortex is combined effect basis (McFarland et al., 2003 that the addictive drugs such as CH relapse to the Glutamatergic projection of nucleus accumbens septi inside brain; LaLumiere et al., 2008).Evidence show, (Tzschentke et al., 2003 of relapsing that in inhibition nucleus accumbens septi, the excitement of glutamic acid can reduce CH; Kalivas et al., 2009), but still lack a kind of little medicine of efficient, special side effect again relapsing for medicine at present.Before set forth, exogenous supplementary NAAG is by acting on the mGluR3 on presynaptic membrane, thereby reduces the too much release of glutamic acid.Research discovery, the peptidase inhibitors of exogenous supplementary NAAG or NAAG can reduce rat Relapse behavior (Xi et al., the 2010b that ***e ignites and induces; Peng et al., 2010), for not impact (Xi et al., 2010a) of rat ***e self administration behavior, pointed out NAAG to relapse middle possible therapeutical effect at ***e.The compare agonist LY379268 of similar mGluR2/3, NAAG craves for all less than impact for the foraging behavior of natural reward thing and sucrose, shows its specificity and relative few side effect (Xi et al., 2010b) to drug dependence treatment.
Heroin and ***e have some common mechanism of action on addiction and the neural loop that relapses, but both exist many difference (Kreek MJ., 2011) at aspects such as addiction and the epigenetics relapsing, mRNA level, neuropeptide level and protein levels.For example: ***e passes through to suppress the reuptake of nucleus accumbens septi DAT, thereby causes the release of nucleus accumbens septi dopamine to increase (Budygin EA., 2002); Heroin is the μ-opiate receptor acting on nucleus accumbens septi dopamine neuron, indirectly promotes the release of nucleus accumbens septi dopamine.In clinical treatment, the medicine disulfiram for the treatment of ***e addiction is not used for the treatment of heroin addiction; And can treat the alternative medicine methadone of Heroin readdiction, can not treat ***e and relapse (Kreek MJ., 2011).At present, the addicts of our country still be take heroin patient as main, and can NAAG also do not have report for heroin addiction and the research that relapses treatment, and have the low inferior actual application problem of the oral utilization rate of NAAG.
Summary of the invention
A technical problem to be solved by this invention is to provide a kind of side effect little two peptide formulations that are used for the treatment of heroin addiction for prior art present situation.
Above-mentioned new application is the treating narcotic addiction purposes of N-acetyl aspartoyl glutamic acid two peptide formulations, the specifically application of N-acetyl aspartoyl glutamic acid two peptide formulations in treatment heroin addiction.
Another technical problem to be solved by this invention is the nasal-cavity administration mode of two peptide formulations of the treatment heroin addiction that a kind of utilization rate is high that provides for prior art present situation.
The present invention solves the problems of the technologies described above adopted technical scheme: the application of these N-acetyl aspartoyl glutamic acid two peptide formulations in heroin addiction treatment.
Further, the application of described N-acetyl aspartoyl glutamic acid two peptide formulations in the treatment of heroin addiction stage.
Further, the application of described N-acetyl aspartoyl glutamic acid two peptide formulations in the treatment of Heroin readdiction stage.This relapses after the stage specifically refers to that heroin patient carries out detoxification and gives up, and in the past took drugs relevant environment, drugs itself or poison friend of contact instigates under induction again, tends to the impulsion that heroin is sucked in generation, and finally causes heroin addiction again.
The present invention also provides a kind of nasal-cavity administration mode for the treatment of N-acetyl aspartoyl glutamic acid two peptide formulations of heroin addiction.
As preferably, described N-acetyl aspartoyl glutamic acid is prepared into various nasal cavity medicines and carries out administration, and described dosage form comprises nasal drop, spray, powder spray, gel, microspheres agent, Emulsion and liposome nasal cavity medicine.
To further illustrate the beneficial effect of N-acetyl aspartoyl glutamic acid (NAAG) in heroin addiction treatment application by zoopery below.
1, the inhibitory action of NAAG to heroin-addicted rats self administration
(1) set up stable rat heroin self administration model
Classical rat heroin self administration model can well be simulated the heroin of drug addict clinically and be sucked behavior, rat can produce the automedication to heroin through training, and that in training process, constantly rises can reflect that to the behavior reaction rate of heroin and dosage drug addict contacts heroin from the beginning to such process of sucking in a large number heroin addiction simultaneously.
We adopt the self administration model of setting up with the following method rat: first, 32 SD rats carry out the operation of jugular vein intubate, at right jugular vein, insert one section of PE pipe, and through back, pass external, antibacterial and recover more than one week after operation.Subsequently, rat is trained respectively in 32 self administration operation cages, is communicated with the PE pipe and the heroin injecting systems operating in cage of rat back before each training; In operation cage, establish two the nose tentaculums in left and right, one of them is effective nose tentaculum, and the tactile nose of rat once effective nose tentaculum will obtain a pin heroin injection, and the cage lamp simultaneously operating in cage lights (as a kind of clue of accompanying medicine), computer recording; Another one is invalid nose tentaculum, and the tactile nose of rat once invalid nose tentaculum is injected and light, only computer recording without any heroin.Between the injection of twice heroin, have the refractory stage of 20 seconds, during touch the effective nose tentaculum of nose and will not have heroin injection and light, computer recording only, the heroin entry needle number of every day is restricted to 50 pins (preventing excessive injection death).32 operation cages adopt the computers of large servers to control simultaneously, the OBSM v5.0 of self administration training software for independently writing, the FR1 that training program is fixed ratio, rat touch nose once effectively nose tentaculum obtain a pin heroin injection.32 rats, through 10 days, after the training of 4 hours every days, effectively touch rhinoreaction rate and injection volume and all obviously rise, and within the end several days, tend towards stability, thereby have formed stable heroin addiction state (seeing Fig. 1).
(2) inhibitory action of NAAG to rat heroin self administration behavior
Rat is after 10 days train the heroin addiction state that reaches stable, within the 11st day, all rats are divided into 4 groups at random, every group 8, be respectively matched group, NAAG 50 μ g groups, NAAG 100 μ g groups and NAAG 100 μ g+LY341495 groups (LY341495 is the antagonist of mGluR2/3 receptor).1. matched group: before test, 2h nasal cavity gives 10 μ l normal saline, and every one-sided nasal cavity gives 5 μ l; 2. NAAG 50 μ g groups: before test, 2h nasal cavity gives the NAAG of 50 μ g/10 μ l; 3. NAAG 100 μ g groups: before test, 2h nasal cavity gives the NAAG of 100 μ g/10ul; 4. NAAG 100 μ g+LY341495 groups: before 2h nasal cavity gives the NAAG joint test of 100 μ g/10ul before test, 30min abdominal cavity gives LY341495, and LY341495 dosage is 1mg/kg, and concentration is 1mg/ml.All rats carry out the heroin self administration test of 4 hours subsequently, and method is the same with previous training, and program is also the FR1 of fixed ratio.At the 12nd day, the 13rd day, proceed heroin self administration and measure (after the 24h after being administration, 48h, and no longer administration before test).Evaluate NAAG for the therapeutical effect (seeing Fig. 2 a, 2b) of heroin addiction.
From Fig. 2 a, observe: NAAG 50 μ g groups, NAAG 100 μ g groups and matched group comparison, effectively touch rhinoreaction and slightly declined at the 11st day, but there is no statistical significance (p value >0.05); And effectively touch all obviously decline of rhinoreaction in the 12nd day NAAG 50 μ g groups and NAAG100 μ g group, more all there are statistical significance (* and matched group comparison in figure with matched group, p value <0.05, effective percentage reaches more than 95%), result has shown NAAG, and for the inhibitory action of heroin self administration, the 24h after giving NAAG is the most remarkable, show NAAG enter may need the long period just can reach the most potent of medicine after nasal cavity should.
From Fig. 2 b, observe: with matched group comparison, the heroin injection volume of NAAG 50 μ g groups and NAAG 100 μ g groups is also at the 12nd day, to have obvious inhibitory action (* and matched group comparison in figure, p value <0.05, effective percentage reaches more than 95%), corresponding with the tactile rhinoreaction of Fig. 2 a.
(3) NAAG is to the relation between rat heroin self administration Behavior inhibition effect and mGluR2/3 receptor
Because the drug metabolism half-life of LY341495 is shorter, after 24 hours, the inhibitory action of NAAG is not affected.From Fig. 2 a and 2b, do not observe NAAG for the inhibition of heroin self administration and the relation between LY341495 injection.For further clear and definite, whether this NAAG works by mGluR2/3 receptor to the depression effect of heroin addiction, we train 32 rats to set up stable heroin self administration addiction model again, and in grouping, done following change in the 11st day: 1. matched group: before test, 2h nasal cavity gives 10 μ l normal saline, ditto; 2. NAAG 50 μ g groups: before test, 2h nasal cavity gives the NAAG of 50 μ g/10 μ l, the same; 3. NAAG 100 μ g groups; Before test, 2h nasal cavity gives the NAAG of 100 μ g/10ul, the same; 4. NAAG 100 μ g+LY341495 groups: from front once different, before training 2h nasal cavity give the NAAG of 100 μ g/10ul and respectively before test before the test of 30min and the 2nd day 30min abdominal cavity give LY341495, dosage is 1mg/kg, and concentration is 1mg/ml.After administration, all rats carry out the heroin self administration test of 4 hours, and at the 12nd day, the 13rd day, proceed heroin self administration test (Fig. 3 a and Fig. 3 b).
From Fig. 3 a, observe with Fig. 3 b: compare with matched group, effectively touch rhinoreaction and the heroin dosage of NAAG 50 μ g groups and NAAG 100 μ g groups obviously reduced (* and matched group comparison in figure at the 12nd day, p value <0.05, effective percentage reaches more than 95%); And NAAG 100 μ g+LY341495 groups are compared with NAAG 100 μ g groups, and all obviously risings of effectively tactile rhinoreaction and heroin dosage (in figure, # and NAAG 100 μ g groups compare, p value <0.05, effective percentage reaches more than 95%).Show again to inject LY341495 and can obviously overturn NAAG for the inhibitory action of heroin self administration before training in the 12nd day, results suggest NAAG may mediate by mGluR2/3 receptor the therapeutical effect of rat heroin addiction.
2, the inhibitory action of NAAG to rat heroin award motivation:
Adopt progression ratio PR
3-4program is measured the Break-Point (breakpoint) of rat, trains fixed ratio program used, PR before being different from
3-4under program determination, rat obtains the desired nose number of times that effectively touches of each heroin injection and is progression ascendant trend, and the meaning of Break-Point is to evaluate the subjective initiative that rat sucks heroin, is equivalent to the motivation that clinical patients is sucked heroin.At progression ratio PR
3-4under program, rat needs the more rhinoreaction of effectively touching could obtain heroin injection next time, and specifically numerical value is referring to following formula (Roberts et al., 1993): tactile rhinoreaction number=(5x e (
0.2xinfusion number))-5, for instance, the heroin of 28 times injection altogether, effectively touching nose number needs 1,2,4,6,9,12,15,20,25,32,40,50,62,77,95,118,145,178,219,268,328,402,603,737,901,1102 and 1347 times, successfully obtain heroin for the last time and inject Break-Point (Duvauchelle et al., 1998 that the effectively tactile nose number of paying is considered to this training period; Wang et al., 2009).
We prove that by following experiment NAAG is for the impact of rat heroin award motivation.First, the heroin self administration training of training 32 rats to carry out 10 days, and reach stable heroin addiction state (that train former right employing is fixed ratio program FR1), and be divided into 4 groups, 8 every group at the 11st day.1. matched group: before test, 2h nasal cavity gives 10ul normal saline; 2. NAAG 50 μ g groups: before test, 2h nasal cavity gives the NAAG of 50 μ g/10 μ l; 3. NAAG 100 μ g groups: before test, 2h nasal cavity gives the NAAG of 100 μ g/10 μ l; 4. NAAG 100 μ g+LY341495 groups: before training 2h nasal cavity give the NAAG of 100 μ g/10 μ l and before test 30min abdominal cavity give LY341495 (dosage is 1mg/kg, concentration 1mg/ml).Adopt subsequently progression ratio PR
3-4program is measured the Break-Point of rat, thereby evaluates NAAG for the impact (seeing Fig. 4) of heroin self administration motivation.
From Fig. 4, observe: compare with matched group, the Break-Point value of NAAG 50 μ g groups and NAAG 100 μ g groups obviously reduces (effective percentage reaches more than 95% for * and matched group comparison in figure, p value <0.05); Compare with NAAG 100 μ g groups, and the obviously rising of Break-Point value of NAAG 100 μ g+LY341495 groups (in figure, # and NAAG 100 μ g groups compare, p value <0.05, effective percentage reaches more than 95%).Show to inject the LY341495 inhibitory action of NAAG to heroin self administration motivation of can obviously overturning, dimension NAAG may mediate by mGluR2/3 receptor the inhibitory action of rat heroin administration motivation.
3, the inhibitory action that NAAG relapses for heroin withdrawal rat:
Relapsing is the difficult point for the treatment of clinically heroin addiction, after heroin patient carries out detoxification and gives up, contact was taken drugs under relevant environment, drugs itself or poison friend instigation induction in the past again, tended to produce the impulsion of sucking heroin, and finally caused heroin addiction again.Relapsing model and can reflecting that patient in the heroin withdrawal phase contacts again and sucked environment that heroin is relevant or heroin originally after one's death in the past of rat, causes the behavior of Heroin readdiction (addiction again).In order to evaluate NAAG, whether for the Relapse behavior of heroin-addicted rats, have impact, the rat that we have set up respectively Conditioned cues or heroin priming induction relapses model.First, train 48 rats through the heroin self administration of 14 days, to train in self administration operation cage, all rats natural withdrawal 14 days in rearging cage subsequently, the finally rat Heroin readdiction behavior of condition determination clue or heroin priming induction respectively in operation cage.
(1) the rat Heroin readdiction behavior determination of Conditioned cues induction:
From all rats, choose 24 rats heroin withdrawal within the 14th day, carry out Heroin readdiction mensuration, be divided into 3 groups, 8 every group.1. matched group: before test, 2h nasal cavity gives 10 μ l normal saline, and every one-sided nasal cavity gives 5 μ l; 2. NAAG50 μ g group: before test, 2h nasal cavity gives the NAAG of 50 μ g/10 μ l; 3. NAAG 100 μ g groups; Before test, 2h nasal cavity gives the NAAG of 100 μ g/10ul.The operation cage that all rats are treated when correspondence is positioned over the training of self administration before respectively subsequently, utilize Conditioned cues (the cage lamp lighting when training gives heroin injection before rat, the sound of syringe pump) to induce rat to produce the behavior relapsing, program is also the FR1 of fixed ratio.When program starts, the cage lamp in operation cage lights, and now rat touches the effective nose tentaculum of nose, and syringe pump can send sound, but there is no heroin injection, and the testing time is 2h.Thereby evaluate NAAG whether the rat Heroin readdiction behavior of Conditioned cues induction is had to impact (seeing Fig. 5).
From Fig. 5, observe: compare with matched group, the rhinoreaction of effectively touching of NAAG 50 μ g groups and NAAG 100 μ g groups obviously reduces (* and matched group comparison in figure, p value <0.05, effective percentage reaches more than 95%), show that NAAG nasal-cavity administration has obvious inhibitory action for the rat Relapse behavior of environmental induction.
(2) the rat Heroin readdiction behavior determination of heroin priming induction
From all rats, choose other 24 rats heroin withdrawal within the 14th day, carry out Heroin readdiction mensuration, be divided into 3 groups, 8 every group.1. matched group: before test, 2h nasal cavity gives 10 μ l normal saline, and every one-sided nasal cavity gives 5 μ l; 2. NAAG 50 μ g groups: before test, 2h nasal cavity gives the NAAG of 50 μ g/10 μ l; 3. NAAG 100 μ g groups; Before test, 2h nasal cavity gives the NAAG of 100 μ g/10ul.The subcutaneous pin heroin (0.25mg/kg) of all injecting of all rats 15min before test, the operation cage for the treatment of when corresponding placement self administration is before trained respectively subsequently, when heroin priming induction rat relapses mensuration, cage lamp and syringe pump sound no longer occur, rat touches only computer recording of the effective nose tentaculum of nose, there is no too heroin injection, the testing time is 2h.Thereby evaluate NAAG on heroin self ignite induction the behavior of rat Heroin readdiction whether have impact (seeing Fig. 6).
From Fig. 6, observe: compare with matched group, the rhinoreaction of effectively touching of NAAG 50 μ g groups and NAAG 100 μ g groups obviously reduces (* and matched group comparison in figure, p value <0.05, effective percentage reaches more than 95%), show that NAAG nasal-cavity administration has obvious inhibitory action for the rat Relapse behavior of heroin priming induction.
Accompanying drawing explanation
Fig. 1 rat heroin self administration illustraton of model: in figure, Active poke effectively touches nose number, and Inactive poke is invalid tactile nose number, and Infusion is heroin entry needle number;
Fig. 2 a NAAG nasal-cavity administration touches the impact of rhinoreaction on heroin-addicted rats heroin: in figure, Active effectively touches nose number, and Inactive is invalid tactile nose number;
The impact of Fig. 2 b NAAG nasal-cavity administration on heroin-addicted rats heroin injection volume: in figure, Infusion is heroin entry needle number;
Fig. 3 a NAAG nasal-cavity administration touches the II that affects of rhinoreaction on heroin-addicted rats heroin;
The affect II of Fig. 3 b NAAG nasal-cavity administration on heroin-addicted rats heroin injection volume;
The impact of Fig. 4 NAAG nasal-cavity administration on heroin-addicted rats self administration motivation: in figure, Break-Point is rat heroin self administration motivation value;
The impact of Fig. 5 NAAG nasal-cavity administration on the rat Heroin readdiction behavior of Conditioned cues induction: in figure, Active poke effectively touches nose number, and Inactive poke is invalid tactile nose number;
The impact of Fig. 6 NAAG nasal-cavity administration on the rat Heroin readdiction behavior of heroin priming induction: in figure, Active poke effectively touches nose number, and Inactive poke is invalid tactile nose number;
Fig. 7 is nasal atomizer schematic diagram in the present embodiment 1.
The specific embodiment
Below in conjunction with the drawings and embodiment NAAG nasal-cavity administration mode in the present invention is described further.
Embodiment 1:
Nasal-cavity administration is current a kind of newer and extremely potential administering mode, after medicine via intranasal application enters, by its mucosa absorption, brings into play systemic treatment effect.This method convenient drug administration, absorbs rapidly, and bioavailability is high.In recent years, along with to medicament carrier system as the development of fat trace, nanoparticle and bioadhesive material etc., nasal-cavity administration technology also constantly obtains development.On people's nasal mucosa, have very abundant microvillus, total surface area increases therefore and greatly, is rich in the aquaporin of micro-aperture simultaneously, and the aperture of these passages is generally about 0.4-0.8nm, so the absorption that nasal-cavity administration is beneficial to small-molecule substance is passed through.Many medicines are particularly useful for nasal-cavity administration comprising biologics such as protein/polypeptide class, hormones and vaccines.Nasal-cavity administration also has another advantage to be that it can form central administration, the nervi olfactory that distributing above the nose olfactory region of nasal cavity, and connect brain olfactory bulb through nervi olfactory.Experiment showed, the medicine per nasal such as cefalexin, fluorine piperazine pyrimidine to after, the drug level in cerebrospinal fluid can be higher than the concentration of drug administration by injection, therefore can be using nasal-cavity administration as a kind of succinct approach to brain delivering medicament.
During NAAG nasal-cavity administration, first be dissolved in various medicament carrier systems, be stored in subsequently in nasal atomizer, this type of nasal atomizer can dosed administration, heroin addiction patient is when administration, aim at nasal cavity, press nasal atomizer and to nasal cavity, give the NAAG of doses, thus the object that reaches treatment heroin addiction and relapse.The advantage of this administering mode is: nasal cavity gives NAAG can avoid gastrointestinal to the Digestion of peptide class and the first pass effect of avoiding liver, improve bioavailability, and see through brain barrier by nasal mucosa, and just as directly administration in brain, the effect of performance treatment heroin addiction.This administering mode is easy to operate simultaneously, and medicine is beneficial to be carried, and is convenient to patient and directly uses.
The dosage form of NAAG nasal-cavity administration:
NAAG with dimethyl sulfoxide hydrotropy after, can combine with pharmaceutical carrier, make various form of administration.Concrete dosage form is as follows:
(1) nasal drop: NAAG solution is directly stored in nasal atomizer, directly splashes into nasal-cavity administration.
(2) spray: NAAG solution is stored in after nasal atomizer, the power producing by compressed air by atomising device makes a kind of dosage form of medical liquid atomizing ejection.
(3) powder spray: NAAG and adjuvant are mixed into uniformly, prepare after the satisfactory powder in powder footpath, are stored in a kind of dosage form of nasal atomizer posterula administration.
(4) gel: add high molecular weight water soluble polymer (as poly-the third ethylene, polyvinyl alcohol, carbomer etc.) to increase medicine viscosity in NAAG solution, increase medicine in the retention time of nasal cavity, a kind of dosage form of raising bioavailability thereby reach.
(5) microspheres agent: NAAG is embedded in microsphere or absorption, be coupled at microsphere surface, thereby delays a kind of dosage form of drug release.
(6) Emulsion: be emulsion liquid medicament, NAAG makes O/W and w/o type Emulsion, thereby a kind of dosage form of improving the water solublity of medicine and medicament being extended in the holdup time on nasal mucosa surface.
(7) liposome nasal cavity medicine: NAAG combines with liposome vectors, and then forms a kind of dosage form of nasal-cavity administration.This dosage form has good bioadhesive and the compatibility, is not easy to be removed by nose cilium, can directly enter blood, and liposome is decomposed gradually by the effect of various enzymes and discharges medicine, and nasal membrane is damaged gently to even not damaged.This pharmaceutical preparation is applicable to long term administration.
The nasal atomizer pattern of NAAG and concrete administration operation:
Fig. 7 is a kind of nasal atomizer front decomposing schematic representation of NAAG administration, and wherein 1 is this aerosol apparatus head, and 3 is sprayer body, 2 be can be flexible between aerosol apparatus head and body part.NAAG is stored in nasal atomizer body 3 after making above-mentioned any one nasal cavity medicine, and by pressing head 1 to nasal atomizer body 3 directions, NAAG from the head 1 top quantitatively sprays, thereby reaches patient's nasal mucosa, is further absorbed into brain.
Claims (5)
1. the N-acetyl aspartoyl glutamic acid two peptide formulations application in heroin addiction treatment.
2. the application of N-acetyl aspartoyl glutamic acid according to claim 1 two peptide formulations in heroin addiction treatment, is characterized in that: the application of described N-acetyl aspartoyl glutamic acid two peptide formulations in the treatment of heroin addiction stage.
3. the application of N-acetyl aspartoyl glutamic acid according to claim 1 two peptide formulations in heroin addiction treatment, is characterized in that: the application of described N-acetyl aspartoyl glutamic acid two peptide formulations in the treatment of Heroin readdiction stage.
4. a nasal-cavity administration mode for the treatment of N-acetyl aspartoyl glutamic acid two peptide formulations of heroin addiction.
5. the N-acetyl aspartoyl glutamic acid two peptide formulations nasal-cavity administration modes for the treatment of heroin addiction according to claim 4, it is characterized in that: described N-acetyl aspartoyl glutamic acid is prepared into various nasal cavity medicines and carries out administration, and described dosage form comprises nasal drop, spray, powder spray, gel, microspheres agent, Emulsion and liposome nasal cavity medicine.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1440298A (en) * | 2000-01-25 | 2003-09-03 | 气体药品技术公司 | Medical aerosol formulation |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1440298A (en) * | 2000-01-25 | 2003-09-03 | 气体药品技术公司 | Medical aerosol formulation |
Non-Patent Citations (3)
| Title |
|---|
| ZHENG-XIONG XI 等: "Inhibition of NAALADase by 2-PMPA attenuates ***e-induced relapse in rats: a NAAG-mGluR2/3-mediated mechanism.", 《JOURNAL OF NEUROCHEMISTRY》 * |
| ZHENG-XIONG XI 等: "N-acetylaspartylglutamate (NAAG) inhibits intravenous ***e self-administration and ***e-enhanced brain-stimulation reward in rats", 《NEUROPHARMACOLOGY》 * |
| 楼忠泽 等: "N-乙酰天门冬氨酰谷氨酸及其肽酶抑制剂在药物成瘾治疗中的作用", 《中国药物依赖性杂志》 * |
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