CN1089582C

CN1089582C - Agent for slow releasing medicine

Info

Publication number: CN1089582C
Application number: CN96115937A
Authority: CN
Inventors: 孔庆忠
Original assignee: Individual
Current assignee: Individual
Priority date: 1996-08-28
Filing date: 1996-08-28
Publication date: 2002-08-28
Anticipated expiration: 2016-08-28
Also published as: CN1174702A

Abstract

The present invention relates to an agent for a slow releasing medicine, which is prepared from macromolecular supporters with biologic capacitability and degradableabsorption, acidifying agents and chemotherapeutic medicines which are coated in the macromolecular supporters. After the agent is placed into bodies, the coated medicines can gradually and slowly release. Accordingly, when the partial medicine concentration is increased, the systemic toxicity reaction caused by the conventional chemotherapy is reduced. The released acidifying agents can block or break the protective regulation mechanism of tumor cells; when the growth of the tumors is suppressed, cytotoxicity reaction of the chemotherapy medicine can be reinforced, and the sensitivity of the tumor cells on other kinds of therapy can be reinforced. Accordingly, the present invention has very high clinical application value.

Description

Agent for slow releasing medicine

The present invention relates to agent for slow releasing medicine and preparation method thereof.

The pH value of discovering entity tumor in a large number is organized as low more normally, but the pH value in the tumor cell maintains physiological level usually.Its main cause is to be in the mechanism that tumor cell in the sour environment derives hydrogen ion concentration in many adjusting cells for a long time.The latter is relevant with medicine removing and chemical sproof generation.External and zooscopy has been found that the growth that acidify not only can suppress tumor cell also can strengthen the sensitivity of tumor to chemotherapy and other treatment, does not still have effective measures yet optionally reduce the partial pH value of human tumor.In addition, the principal element of decision chemotherapy effect is the drug level of tumor by local and the tumor cell sensitivity to chemotherapeutics.Thereby in a single day chemotherapeutics enters blood circulation and just may combine with the biotic component in the blood to make and can enter partial active drug concentration and reduce.The blood supply of entity tumor is widely different, has medicine to arrive in the poor position difficulty of blood fortune.Moreover the interstitial fluid pressure ratio normal structure height of tumor so not only influences the extroversion running of blood Chinese medicine, forms with interior to the opposite export-oriented convection current of diffusion in the tumor periphery simultaneously.Therefore conventional chemotherapy is that vein, abdominal cavity or artery administration even the injection of tumor drug disposition all are difficult to tumor by local and keep long-time active drug concentration.Because chemotherapeutics is not only toxic to tumor cell, and is also toxic to normal cell, therefore simple raising dosage can be subjected to the restriction of general reaction.

The objective of the invention is to design a kind of agent for slow releasing medicine, with chemotherapeutics and (or) acidulant is packaged in the holder that bio-capacitivity, degradable absorb.The pastille holder is a bio-capacitivity, so do not cause foreign body reaction.Place the back degradable in the body and absorb, medicine is slowly discharged at tumor by local, therefore optionally improve and prolong local drug concentration, reduce the general toxic reaction that causes by conventional chemotherapy simultaneously.Therefore the capable of blocking or tumoricidal protectiveness regulatory mechanism of the acidulant of being released also can strengthen the cytotoxic reaction of chemotherapeutics and tumor cell (the particularly chronic hypoxia cell) sensitivity to other therapies when suppressing tumor growth.

Agent for slow releasing medicine of the present invention is by chemotherapeutics, acidulant, holder and an amount of solvent composition, and wherein chemotherapeutics is meant the various chemicalses with antitumor action, has as commonly used clinically at present: (a) platinum class complex and analog thereof; (b) dichloromethylation medicine, (as chlormethine Min Erfalan etc.); (C) have the medicine of biological reducing effect, (as 4-hydrogen peroxide cyclophosphamide etc.) (d), other is as (Chlorambucil etc.).Acidulant comprises the various materials of interior pH value regulatory mechanism capable of inhibiting cell and the various materials that can directly or indirectly reduce the inside and outside pH value of cell.The former as: (a) hydrogen sodium ion exchange preparation (as 3,5-dihydro base-6-chloro-N diamino methylene pyrazine carbon oxamides and analog thereof etc.; (b) carbonate/chloride ion exchanger inhibitor, (as acetazolamide, 4,4-two different sulfo-polyurethane cyanato-stilbenes-2,2 ,-disulfonic acid and analog thereof etc.); (c) hydrion and the lactic acid pump inhibitor and the analog thereof etc. of the dependence of energy synzyme; (d) the mitochondrial respiratory chain inhibitor (as-iodobenzene guanidine and analog thereof etc.).The latter comprises that (a) reduces the extracellular Na ion concentration; (b) hydrogen/potassium ion exchange promoter, (as nigericin and phosphinylidyne cyanogen-3-chlorobenzene hydrazone etc.); (c) other can reduce the various materials of the inside and outside pH value of cell, (as lactate or glucose etc.) indirectly.This agent for slow releasing medicine is a holder with the macromolecule polymer (as high molecular lactic) that bio-capacitivity, degradable absorb, and also available on-macromolecular polymer is as holder, and the chemotherapeutics of packaging can activate or act on enhancing under sour environment.It is solvent that solvent adopts organic solvent (as dichloromethane or dimethyl formamide etc.).Each components in proportions is owing to select the different and difference to some extent of raw material for use.The ratio of general chemotherapeutics (cisplatin) and acidulant (3,5-diaminourea-6-chloro-N-diamino methylene pyrazine carbon oxamides) is 2: 1 to 1: 2, and the ratio of macromolecule polymer (lactic acid) and drug weight is by 6: 4 to be advisable at 9: 1.The consumption of organic solvent fully dissolves with solid polymer and medicine and is as the criterion.

Agent for slow releasing medicine preparation method of the present invention and step are as follows:

1. the solid polymer of weighing is put into container, add certain amount of organic solvent dissolving mixing.

2. adding the chemotherapeutics and the acidulant of weighing shakes up again.Chemotherapeutics and acidulant also can dissolve (fully mixing about 30 minutes) simultaneously with polymer.

3. with mixture vacuum drying or cold drying, remove organic solvent.But (vacuum suction 1-2 hour, or low temperature spends the night).

4. dried solid polymer is shaped immediately.Can make different shape according to different needs, as block, granular, garden column and membranaceous etc.

5. sterilize with r ray or other method after the packing.

6. the solid polymer made from this method is yellow or silvery white (its color is relevant with the drug level and the medicament categories of packaging).

The present invention makes the technological process of agent for slow releasing medicine and sees accompanying drawing.

The effect and the repeatability of the agent for slow releasing medicine treatment entity tumor made from this method can further be illustrated by following " embodiment ".

Embodiment 1

Be that 50000 lactic acid dissolution is in the container that fills 80 milliliters of dichloromethane with 4 mole, equivalent is assigned in four polytetrafluoroethylene beakers behind the dissolving mixing, burn to three respectively then and add 100 milligrams of cisplatin [beaker 1] in the ring, 50 milligram 3,5-diaminourea-6-chloro-N-diamino methylene pyrazine carbon oxamides (a kind of acidulant) (beaker 2), and 100 milligrams of cisplatin and 50 milligrams of 3-5-diaminourea-6-chloro-N-diamino methylene pyrazine carbon oxamides (beaker 3).The 4th beaker in contrast.Dry about 2 hours of dissolving mixing final vacuum.The weight of dried product exhibited is respectively 1: 1090 milligram in beaker; 2: 1035 milligrams in beaker; 3: 1125 milligrams in beaker; 4: 995 milligrams in beaker.Dried solid polymer is made little bulk, take by weighing 2 milligrams and make little garden column.In the right front leaf length of brain there is with 35 glioma sarcomatosum (1 week, about 4 millimeters of diameter) rat is divided into 5 groups, the solid polymer is put into tumor by local by 2 milligrams of fixedly intubate through being placed on the right front leaf of brain of every animal, found that all contrasts (n=7) and accept animal (n=7) death in two to three weeks after treatment of the treatment of pastille polymer not: contained 3, the average life of 5-diaminourea-6-chloro-N-diamino methylene pyrazine carbon oxamides polymer treatment animal (n=7) is 35 days, but none example radical cure (is standard with the pathologic finding 60 days time the behind the tumor planting); The average life that is contained cisplatin (N=7) polymer treatment animal is 50 days, and cure rate is 57% (4/7); Accepting both to have contained 3,5-diaminourea-6-chloro-N-diamino methylene pyrazine carbon oxamides contains again in the animal of cisplatin polymer treatment (N=7), and 71% (5/7) animal is effected a radical cure, and average life is 55 days.

With 50 milligrams of cisplatin and 50 milligram 3,5-diaminourea-6-chloro-N-diamino methylene pyrazine carbon oxamides (1: 1) repeats embodiment 1 method therefor and step, still both to contain 3, the therapeutic effect that 5-diaminourea-6-chloro-N-diamino methylene pyrazine carbon oxamides contains the polymer of cisplatin again is best to the result.

Embodiment 2

Molecular weight is 50000 lactic acid 2 grams

100 milligrams of dichloromethane

1000 milligrams of cisplatin

3,150 milligrams of 5-diaminourea-6-chloro-N-diamino methylene pyrazine carbon oxamides

It is made agent for slow releasing medicine by flow process shown in the accompanying drawing.Take by weighing 1.5 milligrams and make little garden column.10000 glioma sarcomatosum cells are planted cerebral cortex in rat through the fixedly intubate that is placed on the right front leaf of brain, after 1 week the solid polymer is put into tumor by local by 1.5 milligrams of every animals through same approach, found that all contrasts (n=5) and accept animal (n=5) death in two to three weeks after treatment of not pastille polymer treatment; The average life that is contained acidulant polymer treatment animal (n=5) is 33 days, but none example radical cure (is standard with the pathologic finding 60 days time the behind the tumor planting); Contained the average life 44 days of cisplatin (N=5) polymer treatment animal, its cure rate is 40% (2/5); Accepting not only to contain acidulant but also containing in the animal of cisplatin polymer treatment (N=5), 60% (3/5) animal is effected a radical cure, and average life is 53 days.

Embodiment 3

Molecular weight is 50000 lactic acid 1 gram

150 milliliters of dichloromethane

100 milligrams of cisplatin

3,200 milligrams of 5-diaminourea-6-chloro-N-diamino methylene pyrazine carbon oxamides

It is made agent for slow releasing medicine by flow process shown in the accompanying drawing.Dried solid polymer is made little bulk, take by weighing 1 milligram and make little garden column.10000 glioma sarcomatosum cells are planted cerebral cortex in rat through the fixedly intubate that is placed on the right front leaf of brain, after 1 week pastille solid polymer is put into tumor by local for 1 milligram by every animal, found that and contain 3, the polymer of 5-diaminourea-6-chloro-N-diamino methylene pyrazine carbon oxamides or cisplatin all has certain therapeutic effect when using separately, and the polymer therapeutic effect that the both contains is best.

Agent for slow releasing medicine of the present invention is a bio-capacitivity because of its holder, so do not cause foreign body reaction.Place the back degradable in the body and absorb, so the taking-up of need not performing the operation again.In the process of degraded and absorbed with the chemotherapeutics of institute's bag and (or) acidulant slowly discharges, thereby optionally improve and prolong the local drug concentration of tumor.Local place be surrounded by chemotherapeutics and (or) polymer of acidulant not only improved therapeutic effect, and reduced the general toxic reaction that is caused by conventional chemotherapy.Therefore have unique advantage and very high clinical value.For example:

(1) be used for various former and shift the treatment of entity tumor:

Entity tumor is based on operative treatment, yet operation can not be removed residual cell, therefore is easy to recurrence.The latter often is the main cause of patient death.Operation back is local place be surrounded by chemotherapeutics and (or) polymer of acidulant has unique effect to the radical cure tumor.Some tumor growth can not exenterate at the key position (locating as brain stem etc.) of human body, and the slow release of topical remedy can replace excision.Some malignant tumor operation operation may promote the tumor diffusion, and the slow release of topical remedy may be the more selection of science.

(2) with high thermal therapeutical use in conjunction:

Studies show that much hyperpyrexia can reduce the pH value of tumor, and the existence of acidulant can strengthen the sensitivity of tumor cell to high thermal therapeutical.As high thermal therapeutical sensitizer, many medicines have demonstrated the acidization to tumor.Acidulant not only can be strengthened the tumor growth inhibitory action that hyperpyrexia causes, and can suppress the generation of human tumor heat tolerance phenomenon, and the latter is the principal element of the high thermal therapeutical of restriction.In addition, the effect of the pH value decision heat emission treatment before the treatment, under low PH environment, hyperpyrexia can strengthen tumor cell, and particularly the hypoxic cell group is to radiocurable sensitivity.The acidulant local slow is discharged the effect enhancing that may make high thermal therapeutical and has more selectivity.

(3) with the radiotherapy use in conjunction:

The PH of most entity tumors is on the low side, and the existence of its inner tumour cell depends on the regulatory mechanism of cell itself.Suppress or block this regulatory mechanism and reduced tumor cell radiocurable tolerance.Use acidulant to make its effect addition after discovering the tumor by local radiotherapy.When the extracellular pH value reduced to 6.0, cell obviously reduced the repair ability of radiation injury.At PH is 6.0 o'clock, and the bifilar connection again of dna breakage significantly reduces, and is 7.6 o'clock at PH, and this effect is not obvious.Radiate and check to find in PH is 6.0 environment, to have 51 percent dna breakage not connect in back 2 hours, and in PH is 6.7 and 7.6 environment, have only 1 15.At human tumor, the height of PH affects the action effect of heat emission treatment equally.The release of acidulant local slow may be made radiocurable effect enhancing and has more selectivity.

(4) with the immunization therapy use in conjunction:

Someone finds that weakly acidic condition can lure that lymphocyte moves in extracellular matrix, and can promote the release with the link coupled medicine of monoclonal antibody.Also the someone finds that the performance of the cytotoxicity of tumor necrosis factor is influenced by the PH of environment, and effect strengthens under acid situation.

(5) acidify is to the influence of chemotherapy:

Chemotherapeutics must enter a series of cytotoxicity of cell competence exertion.Through active transport still is the influence that passive diffusion all is subjected to the environment pH value.Low pH value can strengthen the effect of many medicines, as: the prodrug of platinum class complex, alkylating agent, acid-sensitive sense and some dichloromethylation medicine.Be under 6.2 the situation at PH, the inhibitory action that 4-hydrogen peroxide ring phosphinylidyne ammonia pair cell clone forms is strong 200 times under 7.4 the situation at PH.Medicine such as chlormethine and Min Erfalan also has same purpose.The enhanced medicine of external cytotoxicity is many in addition under acid condition.When the tumor pH value when 7.3 reduce to 6.9, the tissue of 5-FU is removed the half-life increases by 2.5 times.External, cisplatin is directly proportional with time of contact to the effect of tumor cell.Therefore, if chemotherapeutics is packaged in the holder of degradable absorption, when particularly having acidulant to exist, high local concentrations can further be maintained, and general reaction also can be controlled.Acidify itself can suppress the growth of tumor cell, also can strengthen the sensitivity of tumor cell to other treatment simultaneously.The local chemotherapeutics that discharges all has synergism with radiotherapy and high thermal therapeutical, therefore except that independent application, also can with acidulant and radiotherapy and (or) high thermal therapeutical unites.

Claims

1, a kind of agent for slow releasing medicine, it is characterized in that this agent for slow releasing medicine is a holder with the macromolecule polymer lactic acid that bio-soluble, degradable absorb, be coated on and activate or act on enhanced chemotherapeutics and acidulant under the sour environment, described chemotherapeutics is that cisplatin, acidulant are 3,5-diaminourea-6-chloro-N-diamino methylene pyrazine carbon oxamides; Cisplatin is 2 with the ratio of acidulant: 1-1: 2, and macromolecule polymer lactic acid is 9 with the ratio of drug weight: 1-6: 4.