CN1761452A - Subcutaneous delivery system, process for the preparation of the same and use of the same for the treatment of cholinergic deficient disorders - Google Patents
Subcutaneous delivery system, process for the preparation of the same and use of the same for the treatment of cholinergic deficient disorders Download PDFInfo
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- CN1761452A CN1761452A CN200480006944.4A CN200480006944A CN1761452A CN 1761452 A CN1761452 A CN 1761452A CN 200480006944 A CN200480006944 A CN 200480006944A CN 1761452 A CN1761452 A CN 1761452A
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Abstract
The present invention relates to a subcutaneous delivery system comprising a biodegradable polymeric matrix and at least one of the pharmacologically active substances of general formula (I): wherein A represents an amino group -NH2 or an ammonium group -NH3<+> or a residue of general formula (II): wherein each of X1 to X5 represents, independently, an hydrogen atom, a linear or branched C1 to C6 alkyl group, a linear or branched C1 to C6 alkyloxy group, a hydroxyl group -OH, an amino group -NH2, a primary or secondary C1 to C6 alkylamino group, a halogen atom, a nitro group -NO2; said substance being embedded into said matrix. It relates also to a process for its preparation and to its use for the preparation of a medicament.
Description
The present invention relates to comprise the subcutaneous delivery system of acetylcholinesteraseinhibitors inhibitors.It also relates to the method and this subcutaneous delivery system that prepare described subcutaneous delivery system and is used for the treatment of neuron dysfunction, more particularly, is used for the treatment of cholinergic deficient disorders and/or is used to improve the purposes of choline dependency function.
Neuron dysfunction comprises cognitive decline, it is characterized by and concentrates forfeiture, remembers and obtain forfeiture and information storage or recover forfeiture.Neuron dysfunction also may be caused by central nervous system injury such as apoplexy, spinal cord injury and peripheral nerve damage.Cognitive decline is the symptom of neuron obstacle, as with the aging cognitive decline relevant, and serious neural degeneration obstacle such as Alzheimer with minimum cognitive impairment.Neuron dysfunction is also relevant with amyotrophic lateral sclerosis with the obstacle such as the parkinson that cause the acrobatics and tumblings forfeiture.Think that the decline of central cholinergic system is the reason that causes cognitive decline.Alzheimer is the most prevalent form of dementia that influences the old people, and the average duration from the outbreak of clinical symptoms to death is about 8.5 years.Verified in the Alzheimer, the CAT of neopallium lacks, and this kind of enzyme is responsible for the synthetic of acetylcholine (ACh), and the minimizing that choline absorbs and ACh discharges and cholinergic neuron lose.
At present, also do not have the medicable treatment of Alzheimer, symptom treatment concentrates on to be increased on cholinergic neurotransmission.Several acetylcholinesteraseinhibitors inhibitors have been started selling the treatment that is used for Alzheimer.These comprise reversible inhibitor, as tacrine, donepezil, galantamine with intend reversible inhibitor, and bright as Li Fansi.
All these activating agents need through port administration every day.This route of administration is not suitable for suffering from the patient's of the loss of memory conventional therapy.
Huperzine A (CAS RN:102518-79-6), a kind of lycopodium alkaloid of from Chinese herbal medicine Herba Lycopodii serrati (Huperzia Serrata), separating, since people such as Wang at " Acta Pharmacologica Sinica " 1986,
7, become a kind of medicament likely since its anticholinesterase activity of the last reported first of 110-3.Think that now it is a kind of acetylcholinesteraseinhibitors inhibitors of reversible, high selectivity, and the gerontal patient with suffer from and demonstrate hypermnesic effect among the Alzheimer patient.In addition, the interior digital proof of external and body, huperzine A also has the performance of neuroprotective.After the pharmacological property of report huperzine A, a large amount of huperzine A derivatives have been synthesized so that identify more effective product.People such as Zhu have described huperzine A derivative very likely in patent application EP0806416, especially be considered to those of schiff base.Such chemical compound proof has than better therapeutic effect of huperzine A and lower toxicity.Especially, formula (III)
With huperzine A derivative, prove with butyrylcholine esterase and compare that acetylcholinesterase is had the high selectivity activity with CAS number of registration 180694-97-7.One of shortcoming of those huperzine A derivatives is their sensitivity to water, hindered any operation of the not controlled condition that use contacts with water.
A kind of route of administration of huperzine A treatment of proposal is an oral route.Yet one of inconvenient aspect of this class treatment is its frequent administration, every day two to four times or even more, this patient's strictness that may be suffered from Alzheimer is hardly followed scrupulously.One of inconvenient aspect of other of this treatment is when research all kinds brain injury, causes the transmutability of the exposure of more inapparent neuroprotective.Especially, this transmutability depends on or is subjected to the influence of food absorption and the fluctuation of huperzine A blood plasma level.
Except oral administration, also studied other different route of administration.
For example, among the patent application CN1383824, people such as Wang propose, as alzheimer disease and dysmnesia or improve the treatment of memory function, nasal spray, nasal drop, ointment, gel, powder and microsphere come the administration huperzine A via nasal cavity by for example using.They mention each administration and 80 to 500 microgram huperzines can be conveyed in the body.Zhang has proposed similar nasal drug delivery system in patent application CN1279065.This route of administration allows directly to be penetrated in the blood and quick brain targeting through mucosa.Yet, be difficult to the monitoring dosage, and need repeat administration all day.For with above-mentioned closely similar reason, this route of administration is not suitable for suffering to be concentrated and the patient's of the loss of memory conventional therapy.
Patent US 6,352, and in 715, people such as Kou propose the patient who suffers from Alzheimer is used the transdermal delivery device of design in the following manner, its provide huperzine A in 7 days time period to be not less than 0.833 to 146 μ g/cm
2The sustained release of treatment effective speed .h.Think and under the technical ability of occupying them fully, provide the treatment benefit by this weekly sustained release skin patch of using that is designed to the patient.Yet, because their local irritation effects and suffer from memory and lose the fact that the patient with behavior problem may tear them, thereby negatively hindered treatment.
In the International Patent Application WO 03/04024, people such as Liu propose to be stated from sustained-release microsphere by per two weeks injection bag, and (comprise as biodegradable polymer, the huperzine A in poly-(lactide-co-glycolide) is treated the patient who suffers from Alzheimer.Obtain those microspheres according to two kinds of traditional methods, first method is called as " emulsion evaporation " method, use as solvent, and dichloromethane and water, second method is called as " spray drying " method.In view of the medicine release characteristic that these microspheres obtain, seemingly huperzine A discharged at least 17 days time period, but according to two stages of separating.Almost the huperzine A that is stated from the microsphere of bag of 40% amount discharged in the 1st day and the 2nd day, the mainly release in the 8th day to the 15th day of surplus medicine.The feature that such two stages discharge has the medicine outburst that discharges at once after the significant injection, may cause significant harmful side effect and since in the very short time over-exposure in acetylcholine ester inhibitor with in view of the narrow therapeutic index of this medicine.
From the review of prior art state, seemingly still there is the demand that Galenicals is provided to the clinician, this Green's logical sequence preparation allow huperzine A and/or some its pharmacological active substance analog in the time period of several weeks to several months gradually and sustained release, under sanitarian's minimum control and do not need any contribution of patient and avoided self-medication.
Surprisingly, those targets have successfully been reached with drug-supplying system of the present invention.
Therefore, one of purpose of the present invention relates to the subcutaneous administration device, and it comprises the pharmacological active substance of biodegradable polymer substrate and at least a general formula (I):
Wherein, residue A is represented amino-NH
2Or ammonium-NH
3 +Or the residue of general formula (II):
Wherein, X
1To X
5In each represent hydrogen atom, straight or branched C independently
1To C
6Alkyl, straight or branched C
1To C
6Alkoxyl, hydroxyl-OH, amino-NH
2, uncle or secondary C
1To C
6Alkyl amino, halogen atom, nitro-NO
2Described material is embedded in the described substrate.
Because the pharmacological active substance of general formula (I) definition has unsymmetry, present definition has comprised any possible optically pure isomer and the mixture of any described optically pure isomer.Preferably, the asymmetric carbon atom that has a residue A has absolute configuration R substantially (with reference to A is amino-NH
2).
Residue A is represented ammonium-NH in general formula (I)
3 +The time, respective substance and suitable acceptable counter ion of pharmacology such as the preferred cl anion of halogenide are present in the drug-supplying system together.
Residue A is represented amino-NH in general formula (I)
2The time, Ding Yi pharmacological active substance is a huperzine A like this, is preferably (-)-huperzine A.(-)-huperzine A can be by extracting from plant such as Herba Lycopodii serrati or by complete synthesis or semi-synthetic and indifference strange land acquisition.Two kinds of methods are all known from document.
When residue A is represented general formula (II) residue in the general formula (I), like this Ding Yi pharmacological active substance can by use described in patent application EP0806416 method or by with the similar method of this method, or, cause corresponding schiff base to obtain by condensation huperzine A and have the functional suitable part of aldehyde.
Preferably, residue A is represented amino-NH
2Or ammonium-NH
3 +Or the residue of general formula (II):
Wherein, X
1To X
5In each represent hydrogen atom, methyl or ethyl, methoxyl group, hydroxyl-OH, amino-NH independently
2, methylamino or dimethylamino, chlorine or bromine atom, nitro-NO
2
More preferably, this pharmacological active substance has following formula (III):
The pharmacological active substance of the above-mentioned qualification particularly main pharmacological effect of the material of formula (III) suppresses the ability of acetylcholine esterase for them.In addition, the material of formula (III) appears as the potent and selective depressant of acetylcholinesterase (AChE) in the different plant species (rat, cattle and people).On the contrary, it shows much more weak inhibition activity to butyrylcholine esterase (BuChE).These enzymes are the reasons that cause neurotransmitter acetylcholine (ACh) degraded.Therefore, the inhibition of acetylcholine esterase causes ACh along with the raising of cholinergic activity and increasing in periphery target organ (for example, muscle, conduction autonomic nervous system, gastronintestinal system) in the brain and on littler degree.
This inhibition feature has given formula (III) material especially and has lacked useful potential in the obstacle (as Alzheimer, myasthenia gravis, other source dementia as blood vessel) at choline, or to improve the cognition in the choline dependency function (as attention, memory, concentrate, consciousness, study) and therefore given in premorbid state (as minimum cognitive impairment) or continued to improve in cognition be useful potential in the useful situation (for example, pilot etc.).In addition, the reversible preventative selection of the acetylcholine esterase of preferred maincenter inhibition suppresses to protect to be subjected to for example people of organophosphate poisoning.
The interior digital proof of external and body, huperzine A also has the neuroprotective performance.This dual pharmacotoxicological effect mechanism gives the potential of pharmacological active substance neuroprotective in multiple cerebral disorders of general formula (I).These effects may be by regulating N-methyl-D-aspartate (NMDA) receptor and the mediation of other mechanism.Nmda receptor extensively is distributed in the brain, and plays an important role in brain development, memory form and learn.In addition, the nmda receptor activity may contribute to the nosetiology of many neurodegenerative diseases by the mechanism that is described to excitatory toxicity.Excitatory toxicity is present in the overacfivity that causes excitatory neurotransmitter to increase the uncontrolled synapse that discharges.Glutamic acid is excitatory neurotransmitter main in cortex and the hippocampal neuron.It comes the triggering signal cascade by activating postsynaptic nmda receptor.In case activate, the opening of their relevant ions access openings causes Ca
2+Flow in the cell.Ca in the excessive then born of the same parents
2+The ion-activated Ca that causes neuronal cell death
2+-Dependent pathway.
Many studies show that, different neuro pathology's situations can improve by the blocking-up nmda receptor.The glutamic acid level that increases in the Alzheimer brain causes the partial depolarization of nmda receptor, causes the Ca that increases
2+Interior stream.This Ca
2+In the lasting and constant prevention of stream in AD and other relate to the disease of excitatory toxicity, can bring better clinical effectiveness.The useful neuroprotective of huperzine A rescue treatment is shown in cerebral anoxia-ischemic rat model in addition.The minimizing of neuronal cell death is relevant with the cognitive impairment that reduces significantly.
In drug-supplying system of the present invention, substrate is made by the biodegradable polymer material, and this material is selected from: polyacetals and poly-(hydroxycarboxylic acid esters), poe, polyanhydride, polylactone or its mixture.Preferably, poly-(hydroxyl-carboxylate) is selected from the homopolymer and the copolymer of D-lactic acid and/or L-lactic acid and/or hydroxyacetic acid; And have its block polymer of Polyethylene Glycol; And polylactone is selected from polycaprolactone, poly-(3-hydroxyl-butyrolactone), and hydroxybutyrolactone-hydroxyl valerolactone copolymer.
More preferably, the biodegradable polymer material is selected from polylactic acid and D-lactic acid and/or L-lactic acid, and/or D, L-lactic acid, and/or the copolymer of hydroxyacetic acid.More preferably, the biodegradable polymer material is selected from poly-(D, L-lactide-co-glycolide) and polyactide.Constitute the D of biodegradable polymer material, the ratio between L-lactide and the Acetic acid, hydroxy-, bimol. cyclic ester is included in 25: 75 to 100: 0mol%, preferred 50: 50 to 75: in the scope of 25mol%.Biodegradable polymer properties of materials viscosity is comprised in 0.10 to 0.9dL/g, in preferred 0.15 to 0.6dL/g the scope.Provide ratio according in question polymer NMR spectrum record, the value that provides must be considered in the normal limit of error.25 ℃ of intrinsic viscosity, polymer is that 0.5g/dL is present in the chloroformic solution with concentration, and the value that provides must be considered in the normal limit of error.In above-mentioned scope, be poly-(D on the one hand, the L-lactide-co-glycolide) D in the polymer, the ratio of L-lactide and Acetic acid, hydroxy-, bimol. cyclic ester, be the suitable compromise between the intrinsic viscosity on the other hand, those skilled in the art can easily select suitable poly-(D, the L-lactide-co-glycolide) polymer as drug-supplying system substrate of the present invention, and this polymer allow general formula (I) pharmacological active substance in the time period of at least one month gradually and sustained release.Usually, selected polymer can commercial acquisition.For example, the BoehringerIngelheim of Germany provides the poly-(D of commodity Resomer by name, the L-lactide-co-glycolide) polymer, its D, the mol ratio of L-lactide/glycolides is 75: 25, intrinsic viscosity is 0.14 to 0.22dL/g, poly-(D, L-lactide-co-glycolide) polymer of commodity PLGA 5-50 by name, its D are provided with the Mitsui Chemicals of Japan, the mol ratio of L-lactide/glycolides is 50: 50, and intrinsic viscosity is 0.47 to 0.53dL/g.
Preferably, drug-supplying system of the present invention has the solid implant form.Can imagine the Any shape of this solid implant.Preferably, this solid implant is cylindrical.
One of other purpose of the present invention is the method for preparing drug-supplying system of the present invention.This method may further comprise the steps:
A) uniform homogeneous blend of the dry powder of an amount of described at least a general formula (I) pharmacological active substance of preparation and an amount of described biodegradable polymer material dry powder;
B) mixture that obtains in a) with the speed pressing steps of control passes and is positioned over 60 ℃ to the 120 ℃ punch dies with suitable annular cross section under the temperature;
C) pass basically the cross section of described extrudate and with suitable length cutting step b) in the extrudate that obtains, thereby obtain solid implant; With
D) with the implant sterilization that obtains in the step c).
About the pharmacological active substance of formula (III) with when polymeric material during for poly-(D, L-lactide-co-glycolide) polymer, active substance is 20 to 60% with respect to the relative weight percentage ratio of the implant gross weight that is obtained, and is preferably 25 to 35%.The technical staff can easily select the suitable size of powder separately.Preferably, in the step b) of this method, temperature is 60 ℃ to 100 ℃, more preferably 60 ℃ to 90 ℃.Preferably, the internal diameter of punch die is less than 1.6mm, and the extrudate that is obtained passes its cross section and cuts with 2 to 6mm length.
This method is convenient especially according to drug-supplying system of the present invention for preparation, drug-supplying system of the present invention comprises the pharmacological active substance of general formula (I), the residue of A expression (II) wherein, because this method avoids in any step using or existing water, therefore got rid of in processing procedure or in case any or almost any degraded of described material when obtaining this doser.The drug-supplying system that obtains looks and meets the pharmacopeia stability criterion, can preserve the several months in room temperature (about 25 ℃).
One of other purpose of the present invention is the purposes of the drug-supplying system of above-mentioned qualification, be used to prepare treatment suffer from cholinergic deficient disorders the people's and/or improve the medicine of people's cholinergic dependency function.Those obstacles comprise the dementia of Alzheimer disease, mild cognitive impairment, myasthenia gravis, dementia, blood vessel origin; And those cognitive functions relate to people's class process, and this process is selected from consciousness, attention, study, memory, thinking, notion and forms, reads, deals with problems and language.
In the purposes of the present invention, medicine also is used for preventing and/or treating and suffers and/or by having the people that the active material of cholinesterase inhibitor is poisoned.The great majority of those materials are selected from organophosphorus ester.
Drug-supplying system of the present invention is just to be used as subcutaneous injection the at the position (as arm, thigh) of medicine subcutaneous administration usually at abdominal part or other.Fitness guru is with folded abdomen skin and insert a needle into subcutaneous and the injection implant.Before injection, can use local anesthetic to reduce possible discomfort.
Expect drug-supplying system of the present invention with the injection of the regular intervals of time of several weeks to several months, preferred interval be at least one month, be if possible three months or even longer, and for formula (III) material, the dosage range of covering 3mg to 50mg.Dosage can be according to reaction, and suitable injection device is regulated as the needs of any trocar device that can obtain on the market.This device will by and pass an injection site and provide several implants to allow simple, the adjustable injection of individuation dosage.
Hypodermic another advantage is the following fact: its common ratio as with prior art in the used intramuscular injection approach of those similar microspheres have better drug resistance.In addition, if treatment needs to interrupt, the effect of pharmacological active substance may be reverse.Passing the location of the implant of skin can finish according to the microsphere of intramuscular injection.This subcutaneous route also allows local chemical sproof easy monitoring.Under the situation that part or whole body do not tolerate, can be by simple and minimize the invasive surgical method and take out implant.
Drug-supplying system of the present invention, their preparation and their performance are described among the following embodiment.
In an embodiment,
After Fig. 1 represents the single subcutaneous administration of slow releasing preparation among the embodiment 1, the pharmacokinetic characteristic figure of formula (III) material in rat;
After Fig. 2 represents the single subcutaneous administration of slow releasing preparation among the embodiment 2, the pharmacokinetic characteristic figure of the derivant of formula (III) in rat.
Embodiment 1:
Be called as the implant of the method production of drying-squeezing and pressing method below the use by poly-(D, L-lactide-co-glycolide) polymer and formula (III) derivant composition.
At first, by mix in the ball mill (400rpm, 4 minutes) 14.0g ground (500 μ m) poly-(D, L-lactide-co-glycolide) (D, the mol ratio of L-lactide/glycolides is 54/51 to 46/49 mole of %; At 25 ℃ of chloroform (0.5g/dl CHCl
3In) in intrinsic viscosity be 0.47-0.53dL/g; Known to Mitsui Chemicals Inc. PLGA5-50 by name) and the derivant of 6.0g formula (III) prepare mixture.Then, use the screw-type extruding machine to extrude in the mixture that obtains, pass the punch die that diameter is 1.3mm through the continuum of 70,80,90,90 ℃ of temperature.The resulting extrudate that will contain formula (III) derivant (theoretical core loading is 30%w/w) cuts into implant (average diameter 1.5mm) and uses gamma-radiation (25kGy) sterilization.
According to following method in rat body build-in test implant.Hexad 10-11 week, big Sprague-Dawley male rat used trocar to give single subcutaneous administration implant (dosage: about 15mg/kg i.e. formula (III) derivant of 37 μ mol/kg) under skin of neck.
Administration the previous day, gather with reference to plasma sample.Then the 2h after the administration, 6h, 8h, 10h and thereafter from after the administration the 2nd day to the 35th day weekly twice collection be used for the plasma sample that medicine is measured.
Blood plasma level by the huperzine A of generation in formula (III) derivant in the simultaneously quantitative rat plasma sample of LC/MS/MS method and the body uses Reducing agent such as NaBH
4Inhibitor as the schiff base hydrolysis.For every rat Time Created-concentration curve, be recorded among Fig. 1.Calculate average pharmacokinetics curve chart (± SEM, n=6).Simultaneously, in the whole research process, observe the clinical sign of animal.When research finishes, sacrifice animal and pick up implant site, be used for estimating the degraded of local inflammation and implant.
Can draw following conclusion.Observed the progressive release of huperzine A in the blood plasma (hydrolyzing type in the body (III) derivant produces) at the 7th day to the 35th day, the 0th day is the administration same day.In one month time period, obtain the blood plasma level of lasting huperzine A, and the level of formula (III) derivant can be ignored.Variability between the individuality is low.In whole research process, do not observe clinical sign, do not report the local sign that does not tolerate yet.Implant almost completely has been degraded within 35 days after the administration.
Embodiment 2:
Use the similar methods production implant described in following and the embodiment 1, but be to use different poly-(D, L-lactide-co-glycolide) polymer.
At first, by mix in the ball mill (400rpm, 4 minutes) 14.0g ground poly-(D, L-lactide-co-glycolide) (D, L-lactide/glycolides mol ratio is 76/74 to 24/26; Intrinsic viscosity is 0.16-0.20dL/g (25 ℃, in 0.1% chloroform), and known to Boehringer Ingelheim Resomer RG 75 by name: 25H) derivant with 6.0g formula (III) makes mixture.Then, use the screw-type extruding machine to extrude in the mixture that obtains, pass the punch die that diameter is 1.3mm through the continuum of 60,70,80,75 ℃ of temperature.The resulting extrudate that will contain formula (III) derivant (theoretical core loading is 30%w/w) cuts into implant (average diameter 1.5mm) and uses gamma-radiation (25kGy) sterilization.
According to the method described in the embodiment 1,,, be recorded among Fig. 2 for every mouse foundation time-concentration curve separately in rat build-in test implant.Can draw the conclusion closely similar with embodiment 1.
It seems according to the slow releasing preparation of following method preparation and can realize all purposes of the present invention.
Embodiment 3
Produced the implant of forming by the derivant of poly-(D, L-lactide-co-glycolide) polymer and formula (III) by film extrusion according to following method.
At first, by anhydrous magnesium sulfate being suspended in the solvent subsequently, from ethyl acetate, remove and anhydrate by removing by filter this desiccant.The derivant of 600mg formula (III) is dissolved in the 10.0g ethyl acetate.By poly-(D, L-lactide-co-glycolide) 50: 50 polymer suspensions of 1.40g are made the polymer suspension in the 80.0g ethyl acetate.This suspension was accepted supersound process 15 minutes.The solution and the polymer suspension of formula (III) derivant are positioned in the round flask.This round flask is heated to 37 ℃ and with 75rpm rotation, therefore removes about 90% solvent by evaporation.Viscous suspension is come down in torrents on the polytetrafluoroethylene thin plate, dry under fume hood, dry under the room temperature vacuum in drying oven then to form thin film.The weight of resultant thin film is 1.64g.
Thin film is cut into slices, and the working pressure extruder extrudes in 54 ℃ of punch dies that pass 0.8mm.Resulting extrudate is cut into implant and sterilize with gamma-radiation.The implant average diameter is 1.30mm, comprises the derivant of the formula (III) of 24.80wt.%.The active component that mixes be 95.06% pure.
Embodiment 4
Use is called as the implant of the method production of drying-squeezing and pressing method by the derivant composition of poly-(D, L-lactide-co-glycolide) polymer and formula (III).
At first, will gather (D, L-lactide-co-glycolide) 50: 50 polymer grinds and obtains microgranule.Then, make physical mixture by the derivant of using mortar and ground polymer of pestle mixing 1400mg and 600mg formula (III).The punch die that uses the pressure type extruder to pass 0.8mm under 71-77 ℃ temperature this physical mixture extrudes.The weight of resulting extrudate is 1.3g.
Extrudate is cut into implant and sterilize with gamma-radiation.The implant average diameter is the derivant of 1.3mm and the formula (III) that comprises 30 (w/w).The active component that mixes be 97.56% pure.With this implant subcutaneous administration to the rat body.
Embodiment 5
Use is called as the implant of the method production of drying-squeezing and pressing method by the derivant composition of poly-(D, L-lactide-co-glycolide) polymer and formula (III).
At first, by using poly-(D, L-lactide-co-glycolide) 50: 50 polymer of mortar and pestle mixing 1400mg, be called as Resomer RG 503H (D, L-lactide: 48-52mol%; Acetic acid, hydroxy-, bimol. cyclic ester: 48-52mol%; Intrinsic viscosity: 25 ℃ of 0.1% CHCl
3In: 0.32-0.44dL/g)) and the derivant of 600mg formula (III) to make physical mixture.The punch die that uses the pressure type extruder to pass 0.8mm under 74 ℃ temperature this physical mixture extrudes.The weight of resulting extrudate is 1.320g.Extrudate is cut into implant and sterilize with gamma-radiation.The implant average diameter is 1.40mm and formula (III) derivant that comprises 27.65wt.%.The active component that mixes be 97.37% pure.With this implant subcutaneous administration to the rat body.
Embodiment 6
The implant of forming by the derivant of poly-(D, L-lactide-co-glycolide) polymer and formula (III) by film extrusion production according to following method.
At first, anhydrous magnesium sulfate is suspended in the solvent, by removing by filter this desiccant, from ethyl acetate, removes and anhydrate subsequently.The derivant of 900mg formula (III) is dissolved in the 20.0g ethyl acetate.By poly-(D, L-lactide-co-glycolide) 50: the 50 Lauryl Ester terminated polymers of 2.10g are dissolved in the 20.0g ethyl acetate and make polymer solution.These two kinds of solution are positioned in the round flask of 75rpm rotation.Solution is heated to 37 ℃.By the weight saving 33g of evaporating solvent with solution.Viscosity solution is come down in torrents on the polytetrafluoroethylene thin plate.Viscosity solution is carried out drying under fume hood, then the dry thin film that forms of vacuum chamber relaxing the bowels with purgatives of warm nature in drying oven.The weight of resulting thin film is 2.77g.
Thin film is cut into slices, and the working pressure extruder passes the punch die extrusion of 0.8mm under 38-49 ℃ temperature.The weight of resulting extrudate is 1.18g.Extrudate is cut into implant and sterilize with gamma-radiation.The average diameter of implant is 1.2mm, comprises the derivant of the formula (III) of 26.50% (w/w).The active component that mixes be 94.74% pure.With the implant subcutaneous administration to the rat body.
Embodiment 7
Use is called as the implant of the method production of drying-extruding by the derivant composition of poly-(D, L-lactide-co-glycolide) polymer and formula (III).
At first, will gather (D, L-lactide-co-glycolide) 50: 50 Lauryl Ester terminated polymers grinds to obtain microgranule.By using mortar and pestle that the derivant of 1.400g ground polymers and 600mg formula (III) is mixed to make physical mixture.Use the pressure type extruder that this physical mixture passes 0.8mm under 65 ℃ temperature punch die is extruded.The heavy 1.170g of resulting extrudate.
Extrudate is cut into implant and sterilize with gamma-radiation.The implant average diameter is 1.3mm and formula (III) derivant that comprises 27.59wt.%.The active component that mixes be 97.43% pure.With this implant subcutaneous administration to the rat body.
Embodiment 8
The implant of forming by the derivant of poly-(D, L-lactide-co-glycolide) polymer and formula (III) by film extrusion production according to following method.
At first, anhydrous magnesium sulfate is suspended in the solvent, by removing by filter this desiccant, from ethyl acetate, removes and anhydrate subsequently.Then, the derivant with 600mg formula (III) is dissolved in the 14.8g ethyl acetate.Then, by poly-(D, L-lactide-co-glycolide) 75: 25 polymer of 1.4g (are called as Resomer RG 75: 25H; D, L-lactide/glycolides mol ratio is 76/74 to 24/26; Intrinsic viscosity is 0.16-0.20dL/g (in 25 ℃ of 0.1% chloroform)) be dissolved in the 15.2g ethyl acetate and make polymer solution.Formula (III) derivative solution and polymer solution are positioned in the round flask.This round flask is heated to 37 ℃ and with 75rpm rotation, removes about 90% solvent whereby by evaporation.Viscous suspension is come down in torrents on the polytetrafluoroethylene thin plate, under fume hood, carries out drying, then in drying oven vacuum chamber relaxing the bowels with purgatives of warm nature drying to form thin film.The weight of resultant thin film is 1.56g.
Thin film is cut into slices, and the working pressure extruder passes the punch die extrusion of 0.8mm under 59 ℃ temperature.Resulting extrudate is cut into implant and sterilize with gamma-radiation.The implant diameter is approximately 1.3mm.This implant comprises formula (III) derivant of 24.8wt.%.The active component that mixes be 92.59% pure.With the implant subcutaneous administration to the rat body.
Embodiment 9
Use is called as the implant of the method production of drying-squeezing and pressing method by the derivant composition of poly-(D, L-lactide-co-glycolide) polymer and formula (III).
At first, by using mortar and pestle that poly-(D, L-lactide-co-glycolide) 75: 25 polymer of 1400mg (are called as Resomer RG 75: 25H; D, L-lactide/glycolides mol ratio is 76/74 to 24/26; Intrinsic viscosity is 0.16-0.20dL/g (25 ℃, in 0.1% chloroform)) and the derivant of 600mg formula (III) mix to make physical mixture.Use the pressure type extruder that this physical mixture passes 0.8mm under 65 ℃ temperature punch die is extruded.The heavy 1.283g of resultant extrudate.
Resulting extrudate is cut into implant and sterilize with gamma-radiation.The average diameter of implant is 1.5mm and formula (III) derivant that comprises 27.2wt.%.The active component that mixes be 97.3% pure.
Embodiment 10
By microsphere extruding production implant.
With poly-(D, L-lactide-co-glycolide) 50: 50 polymer of 3.5g, be called as ResomerRG 503H (D, L-lactide: 48-52mol%; Acetic acid, hydroxy-, bimol. cyclic ester: 48-52mol%; Intrinsic viscosity: 25 ℃, 0.1%CHCl
3In: 0.32-0.44dL/g), be dissolved in the 60g dichloromethane.The derivant of 1.5g formula (III) is dissolved in the 35g dichloromethane, pours in the polymer solution then.Use small-sized spray drying device that the mixture that is obtained is sprayed under 45 ℃ temperature, cause microsphere to form.
By pass diameter under the temperature between 60-95 ℃ is that 1.0 to 2.0mm punch die pushes the implant that these microspheres form different-diameter.
Resulting extrudate is cut into implant and uses the sterilization of gamma-radiation line.These implants of subcutaneous administration.
Embodiment 11
By microsphere extruding production implant.
Poly-(D, L-lactide) the ester terminated polymer of 3.0g (is obtained the CHCl of 30 ℃ of 0.5g/dL from Absorbable PolymerTechnologies
3Middle intrinsic viscosity of measuring is 0.09-0.10dL/g) be dissolved in the 60g dichloromethane.The derivant of 2.0g formula (III) is dissolved in the 35g dichloromethane, pours in the polymer solution then.Use small-sized spray drying device that the mixture that is obtained is sprayed at 40 ℃, cause microsphere to form.
By pass diameter under the temperature between 60-95 ℃ is that 1.0 to 2.0mm punch die pushes the implant that these microspheres form different-diameter.
Resulting extrudate is cut into implant and sterilize with gamma-radiation.These implants of subcutaneous administration.
Embodiment 12
By microsphere extruding production implant.
(free carboxy obtains the CHCl of 30 ℃ of 0.5g/dL from Absorbable PolymerTechnologies with poly-(D, the L-lactide) polymer of 3.0g
3Middle intrinsic viscosity of measuring is 0.09-0.10dL/g) be dissolved in the 60g dichloromethane.The derivant of 2.0g formula (III) is dissolved in the 35g dichloromethane, pours in the polymer solution then.Use small-sized spray drying device that the mixture that is obtained is sprayed under 40 ℃ temperature, cause microsphere to form.
By pass diameter under the temperature between 60-95 ℃ is that 1.0 to 2.0mm punch die pushes the implant that these microspheres form different-diameter.
Resulting extrudate is cut into implant and sterilize with gamma-radiation.
Embodiment 13
Use is called as the method production of drying-squeezing and pressing method by poly-D, the implant that the derivant of L-(lactide) polymer and formula (III) is formed.
At first by using mortar and pestle that ground poly-(D, L-lactide) the ester terminated polymer of 2.1g (is obtained the CHCl of 30 ℃ of 0.5g/dL from Absorbable Polymer Technologies
3In the intrinsic viscosity of measuring be 0.09-0.10dL/g) and the derivant mixing of 900mg formula (III) to make physical mixture.Use the pressure type extruder that this physical mixture passes 1.0-2.0mm under 30-50 ℃ temperature punch die is extruded.
Resulting extrudate is cut into implant and sterilize with gamma-radiation.These implants of subcutaneous administration.
Embodiment 14
Use is called as the method production of drying-squeezing and pressing method by poly-D, the implant that the derivant of L-(lactide) polymer and formula (III) is formed.
At first, (free carboxy obtains the CHCl of 30 ℃ of 0.5g/dL from Absorbable Polymer Technologies with ground poly-(D, the L-lactide) polymer of 2.1g by using mortar and pestle
3In the intrinsic viscosity of measuring be 0.09-0.10dL/g) and the derivant mixing of 900mg formula (III) to make physical mixture.Use the pressure type extruder that this physical mixture passes 1.0-2.0mm under 30-50 ℃ temperature punch die is extruded.
Resulting extrudate is cut into implant and sterilize with gamma-radiation.These implants of subcutaneous administration.
Claims (15)
1, subcutaneous delivery system, it comprises the pharmacological active substance of biodegradable polymer substrate and at least a general formula (I):
Wherein, residue A is represented amino-NH
2Or ammonium-NH
3 +Or the residue of general formula (II):
Wherein, X
1To X
5In each represent hydrogen atom, straight or branched C independently
1To C
6Alkyl, straight or branched C
1To C
6Alkoxyl, hydroxyl-OH, amino-NH
2, uncle or secondary C
1To C
6Alkyl amino, halogen atom, nitro-NO
2Described material is embedded in the described substrate.
According to the drug-supplying system of claim 1, it is characterized in that 2, in the described pharmacological active substance that general formula (I) limits, residue A is represented amino-NH
2Or ammonium-NH
3 +Or the residue of general formula (II):
Wherein, X
1To X
5In each represent hydrogen atom, methyl or ethyl, methoxyl group, hydroxyl-OH, amino-NH independently
2, methylamino or dimethylamino, chlorine or bromine atom, nitro-NO
2
3,, it is characterized in that described pharmacological active substance has following formula (III) according to the drug-supplying system of claim 1:
4,, it is characterized in that the biodegradable polymer material of described substrate is selected from polyacetals and poly-(hydroxycarboxylic acid esters), poe, polyanhydride, polylactone or its mixture according to the drug-supplying system of claim 1.
5,, it is characterized in that described poly-(hydroxycarboxylic acid esters) is selected from the homopolymer and the copolymer of D-lactic acid and/or L-lactic acid and/or hydroxyacetic acid according to the drug-supplying system of claim 4; With its block polymer that has Polyethylene Glycol; And described polylactone is selected from polycaprolactone, poly-(3-hydroxyl-butyrolactone) and hydroxybutyrolactone-hydroxyl valerolactone copolymer.
6,, it is characterized in that described biodegradable polymer material is selected from polylactic acid and D-lactic acid and/or L-lactic acid and/or D, the copolymer of L-lactic acid and/or hydroxyacetic acid according to the drug-supplying system of claim 4.
7, according to the drug-supplying system of claim 6, it is characterized in that described biodegradable polymer material is selected from poly-(D, the L-lactide-co-glycolide) and polyactide, and constitute the D of this biodegradable polymer material, ratio between L-lactide and the Acetic acid, hydroxy-, bimol. cyclic ester is comprised in 25: 7 to 100: 0mol%, and preferred 50: 50 to 75: in the scope of 25mol%; Described biodegradable polymer properties of materials viscosity is comprised in 0.10 to 0.9dL/g, in preferred 0.15 to 0.6dL/g the scope.
8,, it is characterized in that it has the form of solid implant, is preferably cylindrical according to the drug-supplying system of claim 1.
9, preparation is as the method for the drug-supplying system defined in the claim 4, and it may further comprise the steps:
A) uniform homogeneous blend of the dry powder of an amount of described at least a general formula (I) pharmacological active substance of preparation and an amount of described biodegradable polymer material dry powder;
B) mixture that obtains in a) with the speed pressing steps of control passes and is positioned over 70 ℃ to the 100 ℃ punch dies with suitable annular cross section under the temperature;
C) pass basically described extrudate the cross section and with suitable length the extrudate that obtains in the step b) is cut and
D) with the implant sterilization that obtains in the step c).
10, be used for the treatment of the people who suffers from cholinergic deficient disorders and/or be used for improving the purposes of the medicine of people's cholinergic dependency function in preparation as drug-supplying system that claim 1 limited.
11,, it is characterized in that described obstacle comprises the dementia of Alzheimer, mild cognitive impairment, myasthenia gravis, dementia, blood vessel origin according to the purposes of claim 10; And described cognitive function relates to people's class process, and this process is selected from consciousness, attention, study, memory, thinking, notion and forms, reads, deals with problems and language.
12,, it is characterized in that described medicine is used to prevent and/or be used for the treatment of the people who suffers and/or caused poisoning by the material with acetylcholine esterase inhibition affinity according to the purposes of claim 10.
13,, it is characterized in that described material is selected from organophosphorus compounds according to the purposes of claim 12.
14,, it is characterized in that the pharmacological active substance of the general formula (I) that comprises in the described system discharges continuously in the time of at least one month according to the purposes of claim 10.
15, according to the purposes of claim 14, it is characterized in that with regular intervals of time described patient's drug administration, continue at least one month.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IBPCT/IB03/00942 | 2003-03-14 | ||
| IB0300942 | 2003-03-14 | ||
| IBPCT/IB03/04945 | 2003-11-05 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1761452A true CN1761452A (en) | 2006-04-19 |
| CN100398093C CN100398093C (en) | 2008-07-02 |
Family
ID=34957220
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004800069444A Expired - Fee Related CN100398093C (en) | 2003-03-14 | 2004-03-15 | Subcutaneous delivery system, process for the preparation of the same and use of the same for the treatment of cholinergic deficient disorders |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN100398093C (en) |
| ZA (1) | ZA200507367B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101244026B (en) * | 2007-02-14 | 2011-03-16 | 中国科学院上海药物研究所 | Huperzine and its derivant or its salt implantation agent, its preparation method and application |
| CN102178680A (en) * | 2011-04-24 | 2011-09-14 | 浙江现代中药与天然药物研究院有限公司 | Long-acting and high-content Huperzine paster and preparation method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1125725A (en) * | 1994-12-28 | 1996-07-03 | 中国科学院上海药物研究所 | First-kind "Haikelin" alkali derivant and its usage |
| CN1194688C (en) * | 2001-07-03 | 2005-03-30 | 山东绿叶制药股份有限公司 | Slow releasing microspheres of transcutaneous huperzine A and its derivative or salt for injection and its preparing process |
-
2004
- 2004-03-15 CN CNB2004800069444A patent/CN100398093C/en not_active Expired - Fee Related
-
2005
- 2005-09-13 ZA ZA200507367A patent/ZA200507367B/en unknown
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101244026B (en) * | 2007-02-14 | 2011-03-16 | 中国科学院上海药物研究所 | Huperzine and its derivant or its salt implantation agent, its preparation method and application |
| CN102178680A (en) * | 2011-04-24 | 2011-09-14 | 浙江现代中药与天然药物研究院有限公司 | Long-acting and high-content Huperzine paster and preparation method thereof |
| CN102178680B (en) * | 2011-04-24 | 2012-09-05 | 浙江现代中药与天然药物研究院有限公司 | Long-acting and high-content Huperzine plaster and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200507367B (en) | 2007-01-31 |
| CN100398093C (en) | 2008-07-02 |
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