CN107320735A - A kind of TAM composition and its preparation - Google Patents
A kind of TAM composition and its preparation Download PDFInfo
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- CN107320735A CN107320735A CN201710551985.0A CN201710551985A CN107320735A CN 107320735 A CN107320735 A CN 107320735A CN 201710551985 A CN201710551985 A CN 201710551985A CN 107320735 A CN107320735 A CN 107320735A
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- tam
- water
- aromatic hydrocarbons
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
Abstract
The invention discloses a kind of TAM composition, containing water-soluble post [6] aromatic hydrocarbons of TAM solubility in water can be increased.Water-soluble post [6] aromatic hydrocarbons preparation method is easy, and environmental protection, cytotoxicity is low, while improving dissolubility of the indissoluble cancer therapy drug TAM in water by host-guest interaction；The TAM composition has good water-soluble and efficient anti-cancer effectiveness, is conducive to the dissolution and absorption of TAM, is greatly improved the bioavilability of TAM, can be used as the new supermolecule cancer therapy drug of a class.
Description
Technical field
The invention belongs to biomedical science field, and in particular to a kind of TAM composition and its preparation.
Background technology
Cancer, turns into the maximum killer of whole world human health at present.Scientists from all over the world pay arduous to capture cancer
Unsurpassed effort, but still this disease can not be restrained completely, make it turn into biggest threat and fear that human health faces.
By unremitting research and exploration, diversified cancer therapy drug is exploited for the drug therapy of cancer.The whole world
About 130~150 kinds of the cancer therapy drug of various countries' approved listing.The various anti-cancer drug preparations being configured to these medicines are big
It there are about 1300~1500 kinds.In addition, also substantial amounts of new cancer therapy drug constantly researches and develops release.And work as in these medicines
In, there are many medicines because water solubility is too poor and be difficult to further development and application.
The use of solubilizer and drug molecule composition supermolecule medicine is that a kind of promotion drug molecule dissolves and then increased in water
The easy and effective method of strong drug effect.But the solubilizer used in this method must is fulfilled for several conditions：Increase first
Solvent is nontoxic in itself, next to that the addition of solubilizer can improve or not influence the drug effect of drug molecule in itself, realizes simultaneously
Drug molecule preferable dissolubility in water solution system.
TAM is a kind of artificial synthesized nonsteroidal estrogen antagonism medicine, selecting property estrogenic agents,
For treating advanced breast cancer and oophoroma.But the solubility in water is extremely low, therefore the inefficiency in clinical practice.
Tamoxifen citrate mainly has the formulations such as tablet, capsule, injection to supply Clinical practice at present, and these formulations are in stomach
Enteron aisle dissolution rate is poor, and bioavilability is not high.CN1389199A discloses a kind of slow-releasing Tamoxifen citrate tablet,
CN1654037A discloses a kind of tamoxifen citrate dispersible tablet.But this preparation cost is high, bioavilability is low, it is impossible to
It is advantageously applied to clinic.
In summary, prior art can be utilized, suitable new solubilizers is selected, passes through supermolecule host-guest interaction shape
Into supermolecule medicine, the dissolubility of simple and effective raising anti-tumor drug molecule TAM is to realize that cancer therapy drug drug effect is carried
High key.
The content of the invention
There is provided a kind of containing water-soluble for the problem of purpose of the present invention is deficiency water-soluble for TAM in the prior art
The TAM composition of post [6] aromatic hydrocarbons, water-soluble post [6] aromatic hydrocarbons has good solubility in water, and toxicity is low, and energy
Solubility of the TAM in water is enough efficiently improved by host-guest interaction, while improving the anticarcinogen of the medicine
Effect.
A kind of TAM composition, containing water-soluble post [6] aromatic hydrocarbons of TAM solubility in water, institute can be increased
Water-soluble post [6] aromatic hydrocarbons is stated for formula (I)~at least one of compound shown in (III),
Preferably, described TAM composition by TAM and water-soluble post [6] aromatic hydrocarbons using mol ratio as 0.1~
1:1 composition.
Further preferably, the mol ratio of TAM and water-soluble post [6] aromatic hydrocarbons is 0.3~0.6：1, TAM is in water
In dissolubility it is poor, solubility only has 5.90 × 10–3Mg/mL, in the proportion, described TAM composition can be
It is completely dissolved in water.
Preferably, water-soluble post [6] aromatic hydrocarbons (is abbreviated as full carboxylic acid ammonium's salt plug [6] aromatic hydrocarbons shown in formula (I)
WP6), the alkalescence of full carboxylic acid ammonium's salt plug [6] aromatic hydrocarbons is weaker, and the influence to the infiltration of cell is smaller, and its solubility in water is
92.4 ± 1.5mg/mL, TAM can form host-guest complex WP6-T with full carboxylic acid ammonium's salt plug [6] aromatic hydrocarbons, so as to increase
Strong dissolubility and anticancer drug effect of the TAM in water.
Present invention also offers the preparation containing above-mentioned TAM composition, said preparation is by TAM composition and pharmacy
Upper acceptable carrier or other medicinal active ingredients composition.
Preferably, the preparation is solid pharmaceutical preparation, semisolid preparation or liquid preparation.
Wherein, the preparation is the common dosage forms for oral use such as tablet, capsule, granule, powder, oral liquid；The medicine
Acceptable carrier refers to the conventional pharmaceutical carrier of pharmaceutical field on, by selected from filler, adhesive, disintegrant, lubricant,
One or more of groups in cosolvent, suspending agent, wetting agent, pigment, essence, solvent, stabilizer, surfactant or flavouring
Into.
The preparation is the common injection common dosage forms such as transfusion, liquid drugs injection, powder pin；The pharmaceutically acceptable carrier is
Refer to the conventional pharmaceutical carrier of pharmaceutical field, by selected from osmotic pressure regulator, pH adjusting agent, solubilizer, cosolvent, frozen-dried protective
One or more of compositions in agent, antioxidant and stabilizer.
Water-soluble post [6] aromatic hydrocarbons itself cytotoxicity used in the present invention is relatively low, and TAM composition for
Two kinds of cancer cells of breast cancer cell MCF-7 and HeLa cell Hela are shown compared to free TAM medicine more
Strong lethal efficiency.Illustrate that the TAM composition not only has water-soluble well, and with higher compared with TAM
Kill cancer cell efficiency.
Compared with prior art, the invention has the advantages that：
(1) water-soluble post [6] aromatic hydrocarbons preparation method is easy, and environmental protection, cytotoxicity is low, while mutual by Subjective and Objective
Effect improves dissolubility of the indissoluble cancer therapy drug TAM in water；
(2) TAM composition of the present invention, substantially increases solubility of the TAM in water, oral system is made
Agent, is conducive to the dissolution and absorption of TAM, is greatly improved the bioavilability of TAM；
(3) TAM composition of the present invention, which is dissolved in the host-guest complex formed after water, has the cause of very high cancer cell
Dead efficiency, can be used as a class new anticancer drug.
Brief description of the drawings
Fig. 1 is that WP6 improves the deliquescent experimental data figure of TAM；
Fig. 2 is WP6, WP6-T and TAM for two kinds of cancer cells of breast cancer cell MCF-7 and HeLa cell Hela
Toxicity test result figure.
Embodiment
Embodiment 1
Full carboxylic acid ammonium salt plug [6] aromatic hydrocarbons WP6 synthetic route：
Full hydroxyl post [6] aromatic hydrocarbons c 0.730g are weighed in 100mL round-bottomed flasks, 2.59g monoxone second is sequentially added
Ester, 6.62g Anhydrous potassium carbonate, 50mL acetonitrile, argon gas is protected, stirring reaction 48~50 hours at 85~90 DEG C.Reaction knot
Shu Hou, filtering, is spin-dried for solvent, gained solid is dissolved in 100~120mL dichloromethane, with 100~150mL water washing
Three times, 30~35min of anhydrous sodium sulfate drying, filtering is separated with silica gel column chromatography, and eluant, eluent is used：Petroleum ether：Ethyl acetate=
3：1, white solid is concentrated to give, as full ester group post [6] aromatic hydrocarbons b (0.74g, yield 46%).
Full ester group post [6] aromatic hydrocarbons b 0.74g are weighed in 100mL round-bottomed flasks, 1.60g NaOH solids are sequentially added,
40mL ethanol, 20~22mL water, above-mentioned system is reacted 12~13 hours at 90~95 DEG C, is cooled to room temperature, adds salt
Acid acidifying, has a large amount of solids to separate out, suction filtration, and filter cake is with water washing is distilled 3~4 times, and vacuum drying obtains white solid, is complete
Carboxyl post [6] aromatic hydrocarbons a (0.61g, yield 93%).
Full carboxyl post [6] aromatic hydrocarbons a 0.56 is taken in 50mL round-bottomed flasks, 40~45mL ammoniacal liquor is added, stirs anti-at room temperature
Answer 4~5 hours.Decompression is spin-dried for, and obtains white solid, and (99%) 0.62g, yield is to as full carboxyl ammonium salt post [6] aromatic hydrocarbons WP6.
Product characterize data manufactured in the present embodiment is as follows：
Full ester group post [6] aromatic hydrocarbons b：
1H NMR(400MHz,CDCl3,298K,ppm):δ7.04(s,12H),4.56(s,24H,),3.87(s,12H),
3.60(m,36H)；13C NMR(400MHz,CDCl3,298K,ppm):δ169.8,148.9,128.5,114.4,65.5,51.8,
29.7,29.3。
Full carboxyl post [6] aromatic hydrocarbons a：
1H NMR(400MHz,DMSO-d6,298K,ppm):δ12.96(s,12H),7.11(s,12H),4.71(s,12H),
4.42(s,12H),3.74(s,12H)；13C NMR(400MHz,DMSO-d6,298K,ppm):δ170.5,148.4,128.0,
114.2,65.0,28.6。
Full carboxyl ammonium salt post [6] aromatic hydrocarbons WP6:
1H NMR(400MHz,D2O,298K,ppm):δ6.71(s,12H),4.20(s,24H),3.87(2,12H)；13C
NMR(400MHz,D2O,298K,ppm):176.8,150.1,128.4,115.9,67.9,30.1。
WP6 influences to test on TAM solubility：
Using solubility of the WP6 in water as scope, WP6 is dissolved in the water, set its concentration gradient for 1.63~
81.68mg/mL.Excessive cancer therapy drug TAM powder is added to the WP6 aqueous solution prepared, 24 are sufficiently stirred at 25 DEG C
After~25 hours, excessive undissolved TAM solid, TAM and WP6 formation host and guests are filtered out with 22 μm of aqueous phase filter membranes
Body complex compound WP6-T, obtains the solution containing WP6-T.TAM content assaying method is as follows, in D2In O solvents, by adding
After a certain amount of internal standard compound trimesic acid sodium,1Corresponding proton signal is shown on H-NMR nucleus magnetic hydrogen spectrums.Pass through phase
The integral area ratio at the proton signal peak answered can calculate with the addition of internal standard compound and obtain being dissolved in sample solution
TAM content.
Experimental result is as shown in Figure 1.
From analysis of experimental results：
WP6 can resist effectively by host-guest interaction formation host-guest complex WP6-T so as to improve slightly solubility
Solubility of the cancer drug TAM in water, in test scope, highest can put forward solubility of the TAM in water
Up to 4.64mg/mL, the solubility 5.90 × 10 with TAM itself–3Mg/mL is compared, and is significantly improved.
Detect WP6, host-guest complex WP6-T and TAM for two kinds of cancer cell breast cancer cell MCF-7 and
HeLa cell Hela lethal efficiency.
In 96 orifice plates, 5%CO2, breast cancer cell MCF-7 and HeLa cell Hela is incubated under 36 to 37 degrees Celsius of environment
23 to 24 hours standby.
WP6, host-guest complex WP6-T, 0.5 μM of the standard liquid of the various concentrations gradient of TAM, 1 are prepared respectively
μM, 2 μM, 5 μM, 10 μM, 15 μM, 20 μM it is standby.Wherein, host-guest complex WP6-T compound method is：5mM is prepared first
The WP6 aqueous solution, then excessive TAM powder add the solution, be sufficiently stirred for 24~25 hours, filter out at 25 DEG C
Undissolved unnecessary TAM, solution is diluted to required concentration；Because TAM own solubility is too low, its solution
Compound method be：TAM powder is first dissolved in DMSO in large quantities, the concentrated solution of TAM is configured to, is then diluted to
Required concentration, while making the content of DMSO in cell culture system be no more than 5%, it is ensured that cell survival is not by solvent effect.
In the culture medium that above-mentioned solution is added to breast cancer cell MCF-7 and HeLa cell Hela, at 36~37 DEG C
Continue to hatch 4~5 hours.The survival rate of above two cell is determined with mtt assay, WP6, WP6-T, TAM are determined with this
Cytotoxicity
Experimental result is as shown in Fig. 2 wherein figure (a) is WP6, WP6-T, TAM to breast cancer cell MCF-7 phase
To cytoactive；Scheme (b) active to HeLa cell Hela versus cell for WP6, WP6-T, TAM.
As a result show, WP6 has relatively low cytotoxicity in the concentration range of test, and TAM is due to processing
Time is shorter, and obvious cytotoxicity is not shown in the brooding time of 4~5 hours yet, and WP6-T is for two kinds of tests
Cancer cell, all shows the obvious elevated stronger cytotoxicity with concentration increase, shows with good anticancer effect,
The anticancer drug effect of TAM can be strengthened.
Embodiment 2
The synthesis of full carboxylic acid sodium salt plug [6] aromatic hydrocarbons：
Full carboxyl post [6] aromatic hydrocarbons a prepared by Example 1
Full carboxyl post [6] 0.67~0.68g of aromatic hydrocarbons a are taken in 50mL round-bottomed flasks, 0.2~0.3g NaOH is added and consolidates
Body, 30mL water, at room temperature 12~13h of stirring reaction.PH to 6.5 or so, decompression rotation are adjusted with 1.0M~1.5M hydrochloric acid solution
Water in dry system, obtains white solid, and as (0.79~0.80g, yield is 97~100%) for full carboxyl sodium salt post [6] aromatic hydrocarbons.
The characterize data of full carboxyl sodium salt post [5] aromatic hydrocarbons of product manufactured in the present embodiment is as follows：
1H NMR(400MHz,D2O,298K,ppm):6.58(s,12H),4.08(s,24H),3.75(s,12H)；13C
NMR(400MHz,D2O,298K,ppm):179.76,152.64,130.86,117.64,70.65,32.62。
Embodiment 3
The synthesis of full carboxylic acid potassium salt post [6] aromatic hydrocarbons：
Full carboxyl post [6] aromatic hydrocarbons a prepared by Example 1
Full carboxyl post [6] 0.67~0.68g of aromatic hydrocarbons a are taken in 50mL round-bottomed flasks, 0.2~0.3g NaOH is added and consolidates
Body, 30mL water, at room temperature 12~13h of stirring reaction.PH to 6.5 or so, decompression rotation are adjusted with 1.0M~1.5M hydrochloric acid solution
Water in dry system, obtains white solid, and as (0.88~0.89g, yield is 97~100%) for full carboxyl sodium salt post [6] aromatic hydrocarbons.
The characterize data of full carboxyl sodium salt post [5] aromatic hydrocarbons of product manufactured in the present embodiment is as follows：
1H NMR(400MHz,D2O,298K,ppm):6.58(s,12H),4.08(s,24H),3.75(s,12H)；13C
NMR(400MHz,D2O,298K,ppm):179.76,152.64,130.86,117.64,70.65,32.62。
Embodiment 4
By full carboxylic acid ammonium's salt plug [6] aromatic hydrocarbons and TAM using mol ratio as 0.3:1 mixing, obtains TAM combination
Thing, gained TAM composition is can dissolve in water as clear transparent solutions, obtains the water-soluble of the WP6-T containing host-guest complex
Liquid.
Embodiment 5
By full carboxylic acid ammonium's salt plug [6] aromatic hydrocarbons and TAM using mol ratio as 0.5:1 mixing, obtains TAM combination
Thing, gained TAM composition is can dissolve in water as clear transparent solutions, obtains the water-soluble of the WP6-T containing host-guest complex
Liquid.
Embodiment 6
By full carboxylic acid ammonium's salt plug [6] aromatic hydrocarbons and TAM using mol ratio as 0.7:1 mixing, obtains TAM combination
Thing, gained TAM composition is can dissolve in water as clear transparent solutions, obtains the water-soluble of the WP6-T containing host-guest complex
Liquid.
Embodiment 7
By full carboxylic acid ammonium's salt plug [6] aromatic hydrocarbons and TAM using mol ratio as 1:1 mixing, obtains TAM composition,
Gained TAM composition is can dissolve in water as clear transparent solutions, obtains the aqueous solution of the WP6-T containing host-guest complex.
Embodiment 8
By full carboxylic acid sodium salt plug [6] aromatic hydrocarbons and TAM using mol ratio as 0.5:1 mixing, obtains TAM combination
Thing, gained TAM composition is can dissolve in water as clear transparent solutions.
Embodiment 9
By full carboxylic acid potassium salt's post [6] aromatic hydrocarbons and TAM using mol ratio as 0.5:1 mixing, obtains TAM combination
Thing, gained TAM composition is can dissolve in water as clear transparent solutions.
Embodiment 10
By full carboxylic acid ammonium's salt plug [6] aromatic hydrocarbons and TAM using mol ratio as 0.5:1 mixing, obtains TAM combination
Thing, was crushed after 100 mesh sieves, filling capsule.TAM composition capsule is made in the irradiated sterilizing of capsule.
Embodiment 11
By full carboxylic acid ammonium's salt plug [6] aromatic hydrocarbons and TAM using mol ratio as 0.5:1 mixing, obtains TAM combination
Thing, was crushed after 100 mesh sieves, then by the pharmaceutical composition powder and microcrystalline cellulose using mass ratio as 1：1 mixing is abundant, pressure
Piece, is coated, and tablet is made, and TAM composition piece is made in the irradiated sterilizing of tablet.
Claims (7)
1. a kind of TAM composition, it is characterised in that containing the water-soluble post of TAM solubility in water can be increased
[6] aromatic hydrocarbons, water-soluble post [6] aromatic hydrocarbons is formula (I)~at least one of compound shown in (III),
2. TAM composition according to claim 1, it is characterised in that described TAM composition by him not
Former times, fragrant and water-soluble post [6] aromatic hydrocarbons was using mol ratio as 0.1~1:1 composition.
3. TAM composition according to claim 2, it is characterised in that TAM and water-soluble post [6] aromatic hydrocarbons
Mol ratio be 0.3~0.6：1.
4. TAM composition according to claim 1, it is characterised in that water-soluble post [6] aromatic hydrocarbons is formula (I)
Shown full carboxylic acid ammonium's salt plug [6] aromatic hydrocarbons.
5. the preparation containing the TAM composition described in any one of Claims 1 to 44, it is characterised in that by TAM group
Compound and pharmaceutically acceptable carrier or other medicinal active ingredients composition.
6. preparation according to claim 5, it is characterised in that the preparation is solid pharmaceutical preparation, semisolid preparation or liquid
Preparation.
7. preparation according to claim 6, it is characterised in that the preparation is tablet, capsule, granule, powder, defeated
Liquid, liquid drugs injection, powder pin or oral liquid.
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Cited By (2)
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| CN112608245A (en) * | 2020-12-11 | 2021-04-06 | 华南理工大学 | Cationic water-soluble inclined column [6] arene and synthetic method thereof |
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| CN102911071A (en) * | 2012-09-29 | 2013-02-06 | 上海大学 | Super-molecule complex containing amino acid and water-solubility pillar [5] arene and preparation method for complex |
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Cited By (2)
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| CN109232614A (en) * | 2018-10-26 | 2019-01-18 | 四川理工学院 | A kind of column [5] aromatic hydrocarbons-bis- cups [4] pyrroles's chirality supermolecule, preparation method and its application |
| CN112608245A (en) * | 2020-12-11 | 2021-04-06 | 华南理工大学 | Cationic water-soluble inclined column [6] arene and synthetic method thereof |
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Application publication date: 20171107 |