CN112043724B

CN112043724B - Application of arsenic-containing compound

Info

Publication number: CN112043724B
Application number: CN201910485372.0A
Authority: CN
Inventors: 谢和兵; 顾书华; 吕伟红; 李庆宜
Original assignee: Changzhou Hi Tech District Multiple Dimension Industry Technology Institute Co ltd
Current assignee: Changzhou Hi Tech District Multiple Dimension Industry Technology Institute Co ltd
Priority date: 2019-06-05
Filing date: 2019-06-05
Publication date: 2022-05-20
Anticipated expiration: 2039-06-05
Also published as: CN112043724A

Abstract

The invention discloses an application of an arsenic-containing compound with a structure shown as a general formula (I) in preparation of drugs treating AIDS.

Description

Application of arsenic-containing compound

Technical Field

The invention relates to the field of drug therapy, in particular to application of an arsenic compound in preparing a drug for treating AIDS.

Background

Arsenicum, Realgar, Orpimentum, etc. Arsenic is used for treating certain skin diseases (such as syphilis) in traditional Chinese medicine for a long time. Currently, clinically, arsenic trioxide (As)₂O₃) Is suitable for treating acute promyelocytic leukemia and advanced primary liver cancer.

The existing research discovers As₂O₃Can be used for treating AIDS (Qing Yang, Fengling Feng, Pingchao Li, et al. sensing trioxide images viral latency and delay viral recovered after determination of ART in chromatographic SIV-fed maps. Advanced Science,2019,1900319.). However, As is the main component of arsenic₂O₃The injection has strong toxicity, carcinogenesis, teratogenesis, and mutagenicity, and can cause nausea, emesis, leukopenia, bone marrow depression, and As₂O₃Slightly soluble in water, poor water solubility and low bioavailability. Therefore, further research on new compounds is needed to effectively reduce the toxic and side effects of arsenic, increase the solubility, increase the bioavailability and improve the curative effect of treating AIDS.

Disclosure of Invention

One of the features of the present invention is to provide a medicine for effectively treating AIDS, which is prepared with one kind of arsenic compound as the only active matter and medicinal carrier.

The arsenic-containing compounds of the present invention have the following structure (I):

(I)

wherein R is₁Independently selected from hydrogen, straight or branched chain alkanoyl having 2-20 carbon atoms or phenylalkanoyl having 7-12 carbon atoms; r₂Independently selected from hydrogen, straight or branched chain alkyl having 2 to 8 carbon atoms or phenylalkyl having 7 to 12 carbon atoms; wherein X is selected from X and H₂AsO₄ ^-、HLiAsO₄ ^-、 HKAsO₄ ^-、HNaAsO₄ ^-、Li₂AsO₄ ^-、K₂AsO₄ ^-、Na₂AsO₄ ^-、CaAsO₄ ^-、MgAsO₄ ^-、AsO₂ ^-、(NH4)₂AsO₄ ^-、 (NH₄)HAsO₄ ^-。

Preferred according to the invention are the salts of arsenic acid with carnitine derivatives of formula (II):

(II)

wherein R is₁Selected from acetyl, propionyl, butyryl, valeryl, isovaleryl, lauroyl, myristoyl, palmitoyl, stearoyl, benzoyl, phenylacetyl, phenylpropionyl, phenylbutyryl, phenylacetyl or isovaleryl; r₂Selected from ethyl, propyl, butyl, pentyl, isopentyl, benzyl, phenethyl, phenylpropyl, phenylbutyl, phenylpentyl or phenylpentyl.

The compound shown in the formula (II) comprises levorotatory compounds, dextrorotatory compounds and mixed isomer compounds, wherein the levorotatory compounds are particularly preferred.

The arsenic compound or the composition thereof can be prepared into various pharmaceutical preparations, and the preparations are oral administration preparations, injection administration preparations or local administration preparations, wherein:

(1) the oral administration preparation comprises common tablet, sustained release tablet, granule, hard or soft capsule, syrup, solution, and emulsion; the carrier of the oral administration preparation comprises filler, disintegrant, binder, lubricant, colorant, flavoring agent or other conventional additives, specifically including starch, lactose, microcrystalline cellulose, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone, hypromellose, magnesium stearate, silicon dioxide and polysorbate-80, sodium lauryl sulfate;

(2) the injection preparation comprises sterile injection water solution, sterile injection oil-in-water microemulsion and sterile powder for injection; the vehicle of injection comprises injection solvent and injection additive, wherein the injection solvent comprises injection water, injection oil such as soybean oil, injection solubilizer such as ethanol, propylene glycol, polyethylene glycol, and glycerol, and isotonic substance such as sodium chloride and glucose;

(3) the topical preparation is patch, suppository, cream, ointment, gel, solution, targeting preparation or suspension, wherein the targeting preparation comprises liposome, microsphere, nanoparticle, inclusion compound, and monoclonal antibody coupling compound; the carrier of the topical formulation includes conventional carriers for pharmaceutical use for topical administration.

Detailed Description

The following examples are intended to illustrate the invention, but not to limit it.

EXAMPLE 1 in vitro pharmacodynamic assay of arsenic-containing Compounds

Collecting peripheral blood of HIV infected patients, performing density gradient separation of lymphocyte stratified liquid, collecting peripheral blood lymphocyte, adding RPMI1640 culture medium, adding 10% fetal calf serum and 1% penicillin, and subculturing. Taking cells in logarithmic growth phase at 1 × 10⁵The cell count per ml was inoculated in a 96-well round bottom plateAdding test drugs with different concentrations into 100 μ l, each group having 4 wells, and introducing into CO₂The incubator was allowed to incubate for 72 hours. A blank control group containing no drug was also provided. Flow cytometry detected CD4+, CD8+, and CD4+/CD8+ after incubation. RT-PCR measures HIV RNA load.

TABLE 1 Effect of Levocarnitine arsenate on peripheral blood T lymphocyte subpopulations

TABLE 2 Effect of Acetyllevocarnitine arsenate on peripheral blood T-lymphocyte subpopulations

The results show that: the level of CD4+ T cells is in a recovery trend, while the level of CD8+ T cells is not obviously changed, and the ratio of CD4+/CD8+ is obviously increased. The HIV viral load (HIV rna load) decreases dose-dependently. The arsenic compound of the invention is suggested to have the function of treating AIDS.

Example 2

The injection containing the active compound of the present invention was prepared as follows (all contents are in weight percent):

0.3 percent of active compound,

0.88 percent of sodium chloride

Adding water to 100%

Adding active compound and sodium chloride into water, stirring to dissolve, adding 0.2% active carbon, and decolorizing to obtain injection.

Example 3

Tablets or capsules containing the active compounds according to the invention are prepared in the following manner (the contents are in each case in% by weight):

active compound 1.5%

Lactose 48%

45 percent of microcrystalline cellulose

2 percent of cross-linked polyvidone

Hydroxypropyl methylcellulose 2%

Magnesium stearate 1.5%

The process comprises the following steps: dissolving hypromellose in ethanol to obtain granulating solution, mixing other active compounds except magnesium stearate and adjuvants, adding granulating solution, making into soft material, sieving to obtain wet granule, air drying at 60 deg.C, sieving, grading, adding magnesium stearate, mixing, and press-molding with tablet press or filling into hard capsule.

Example 4

The patch containing the active compound of the invention was prepared as follows (all contents are in weight percent):

active compound 5%

Polyacrylate 95%

Dispersing active compound in polyacrylate glue solution, degassing, coating the medicated glue solution on the lining film, drying, laminating with protective film, cutting, and packaging.

Example 5

Ointments containing the active compounds according to the invention are prepared in the following manner (the amounts used are in each case in% by weight)

Active substance 5%

Lanolin 25%

35 percent of vaseline

20 percent of glycerin

0.2% aqueous solution of sodium lauryl sulfate 15%

Dissolving the active compound in sodium dodecyl sulfate water solution, mixing with glycerol, and mixing with lanolin and vaseline.

Example 6

The sustained-release implant of poly (hydroxyethyl methacrylate) (P- (HEMA)) -collagen containing arsenate L-botulinum base salt is prepared by the following method

1.4g of arsenic acid L-botulinum basic salt

Collagen solution (20g/L) 15ml

6ml of hydroxyethyl methacrylate (HEMA)

Ammonium persulfate solution (60g/L) 1.0ml

Sodium metabisulfite solution (12g/L) 1.0ml

Ethylene glycol 10ml

Taking the prescription amount of the arsenate L-botulinum salt and mixing with the above solutions, taking 1ml of the mixed solution and placing in a 1.5ml plastic centrifuge tube, placing at 37 ℃ and keeping the temperature for 3h, taking out the milky white semitransparent smooth elastic gel, namely the drug-containing poly (hydroxyethyl methacrylate) (P- (HEMA)) -collagen arsenate L-botulinum salt implant.

Example 7

Liposomes containing arsenic acid L-botulinum base salt were prepared as follows

The preparation is carried out by adopting a reverse phase evaporation method, and prescription dose of lecithin and cholesterol are dissolved in 10ml of diethyl ether; dissolving L-botulinum salt arsenate in 4ml of normal saline, mixing the two solutions in a solanaceous bottle, and ultrasonically oscillating for 2 min; performing rotary evaporation at 40 deg.C under reduced pressure to remove ether, adding 6ml physiological saline, and performing ultrasonic oscillation for 2 min; and continuously carrying out rotary evaporation for 1h under normal pressure to obtain the arsenic acid L-botulinum alkali salt liposome suspension emulsion.

Claims

1. The use of levorotatory body of arsenic-containing compound with the structure of the following formula (I) in the preparation of drugs for treating AIDS:

wherein R is₁Independently selected from hydrogen, acetyl; r₂Independently selected from hydrogen;

wherein X is selected from H₂AsO₄ ^-、HLiAsO₄ ^-、HKAsO₄ ^-、HNaAsO₄ ^-、Li₂AsO₄ ^-、K₂AsO₄ ^-、Na₂AsO₄ ^-、CaAsO₄ ^-、MgAsO₄ ^-、AsO₂ ^-、(NH4)₂AsO₄ ^-、(NH₄)HAsO₄ ^-。

2. The use of claim 1, wherein the arsenic-containing compound is the levorotatory form of an arsenic-containing compound having the following formula (II):

wherein R is₁Selected from acetyl; the structure is selected from levorotatory body.

3. The use of claim 1 or 2, wherein the levorotatory form of the arsenic-containing compound is a white crystalline or amorphous powder.

4. Use according to claim 3, wherein the white crystalline arsenic-containing compound is: arsenate L-acetyl-botulinum salt, arsenate L-botulinum salt.

5. The use according to any one of claims 1, 2, 4, wherein said medicament is in an oral dosage form, a needle for injection.

6. The use of claim 5, wherein the oral dosage form is selected from the group consisting of a solution, a suspension, a syrup, a tablet and a capsule, and the injectable needle is selected from the group consisting of a lyophilized powder.