JPH03501253A - Liposome-based nucleoside analogs for the treatment of AIDS - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] The present invention generally relates to the treatment of viral infections using nucleoside analogues. related. More specifically, the present invention provides modified antiviral nucleoside analogs. Drugs of the above-mentioned similar substances when the substances are encapsulated in liposomes and administered to mammals. Concerning increasing efficacy.

The present invention was developed by the U.S. National Institutes of Health (National Institutes of Health). Health) from the University of California and the U.S. Government Department of Veterans Affairs (Vete. U.S. government grant provided to RANS Administration) This was done using the younger brother GM-24979. Therefore, the U.S. government and have certain rights.

Conventional technology Reference is made herein to describe the background of the invention and further details thereof with respect to the practice thereof. Publications and other references providing information are hereby incorporated by reference into this invention. shall be provided. For convenience, references are referred to herein by number and are referred to herein by number. This will be listed as a bibliography at the end.

In recent years, there has been much research into the use of nucleoside analogues for the treatment of viral infections. There is a lot of interest. Antiviral nucleoside analogues are effective against viral replication. By preventing the synthesis of new DNA by the viral reverse transcriptase during production, It is set to inhibit the function of the virus. Nucleosides are DNA or R It is a precursor of NA. One nucleoside is a pyrimidine attached to one pentose sugar. Or it consists of one pudding.

During DNA synthesis, free nucleoside triphosphates (nucleosides with three phosphate groups attached) are rheoside) reacts with the ends of the growing DNA strand. This reaction involves the formation of Free nucleosomes for the hydroxyl group at the 3° position of the sugar ring at the end of a certain DNA chain. Attachment of the phosphate group at the 5° position of the side triphosphate is required. remaining two phosphate groups is liberated during this reaction, resulting in the addition of one nucleoside to the DNA strand.

Nucleoside analogues are very similar to naturally occurring nucleosides. , a compound that can participate in the synthesis of viral DNA. However, anti-coronavirus Viral nucleosides have deliberate chemical structural differences that may inhibit the viral reverse transcriptase, or if similar substances are present in the growing DNA strand. When bound, it hinders the subsequent progress of DNA synthesis. Azidothymine ( AZT), dideoxycytidine, dideoxyadenosine, acyclovir, Riba Viran, and vidarabine disrupt the synthesis of viral DNA or RNA Examples of nucleoside-like substances that are currently under development or have been found to have medicinal efficacy. Yes (1).

Acquired immunodeficiency syndrome (AIDS) was the first major global pandemic in the second half of the 20th century. It is said that it is a disease (2). AIDS is caused by the human immunodeficiency virus (HIV). caused by At present, there are no effective treatments for AIDS.

Dideoxynucleoside analogues, such as AZT, are currently the most potent drugs known. However, recent human studies have shown that anemia (24%) and Strong toxicity was noted (37.38) consisting of granulocytopenia (16%).

HIV targets cells that have the CD4 (T4) surface antigen, such as CD4 helperin. Not only CD4 monocytes and macrophages are infected, but also CD4 monocytes and macrophages. CD4 lymph Infection of the bulb results in a cytolytic infection (3-5), and infection with HIV It also contributes to progressive immunodeficiency (6.7). Recently, CD4 monocytes or macro Phages have been shown to infect both in vitro (8,9) and in vivo (10-15). It is made clear. Infection of monocytes or macrophages also occurs in immunodeficiency, H. It may also contribute to IV-induced brain disease. Additionally, monocytes or maklov HIV replication in phages lasts longer and more rapidly than in lymphocytes. Because of their low cytolytic properties, these cells may serve as reservoir sites for the virus. There is a possibility (8, 9.13). AZT and other dideoxynucleosides provided a means to administer these drugs in such a way that their harmful side effects are diluted. It is desirable. In addition, dideoxy to monocytes or macrophages selectively targeting nucleosides to It is also desirable to provide enhanced efficacy of these agents against viral infections of bacterial populations. There will be.

In 1965, Alex Bangham and co. The researchers found that a dry thin film of phosphatidylcholine forms a closed bimolecular structure upon hydration. Bimolecular leaf vesicles spontaneously discovered that it forms. They used such a dispersed phase to capture cations. and its diffusion (18). As a result, such structures are commonly known as liposomes. It became knowledge. Subsequently, many possible applications have been suggested for liposomes, 19 By 1976, more than 60 substances will be encapsulated in liposomes. was reported. Liposomes in medicine include liposome-based insulin. oral administration of drugs, selective targeted administration of liposomes to organs, A wide range of applications have been suggested, including replenishment of missing enzymes and genetic material using the body. (19).

However, it has also become clear that many of the above goals are difficult to achieve.

It is considered qualitatively unfeasible to have a sinusoidal structure or a fenestrated endothelium. It appears that only those organs that can be targeted can be targeted (20.21). Deficient enzymes and genes Replenishment of messenger substances also occurs because liposomes are relatively rapidly cleared from the vascular compartment and This does not seem to be easy to achieve because it fuses with the membrane on the surface of the vesicle (20).

As pointed out in a recent review by Marc Ostro, There are also many promising applications for liposomes, which are about to be translated into clinical settings. (22) For example, liposomal antimony drugs are (Black) and Watson (23), and Irvy As independently revealed by Alving et al. It is several hundred times more effective than the free drug in treating Niasis. encapsulated in liposomes Amphotericin B is recommended for the treatment of patients with weakened immune systems due to systemic fungal diseases. Therefore, it appears to be more medicinal than the free drug (25,26). to liposomes Other uses of encapsulation include suppression of doquinrubicin toxicity (27); and alleviation of aminoglycoside toxicity (22).

As previously mentioned, macrophages are a major reservoir site for HIV infection (28,2 9゜30), and macrophages are also the initial site of liposome uptake. It is currently thought to be (20°21). Therefore, by utilizing liposomes, It is desirable to enhance the efficacy of antiviral nucleoside analogues in the treatment of viral infections. It seems likely that

Use of nucleoside analogues, such as iodine, for the treatment of diseases other than AIDS. Oxyuridine (IUDR), acyclovir (ACV), and ribaviran Attempts have been made to incorporate into liposomes (16.17). But long These efforts have shown that such relatively small nucleoside analogues cannot be used in liposomes. (16,17) resulting in decreased efficacy of targeted administration. As a result, I have not reached the point where I am fully satisfied.

Kwang Tsui summary In accordance with the present invention, the virus is prevented in a manner that prevents or significantly reduces leakage. A novel anti-AIDS drug that encapsulates a substance similar to a nucleoside in liposomes. A treatment is disclosed. This reduction in leakage results in reduced toxicity. , and also the use of liposomes to deliver higher amounts of antiviral nucleoside analogues. The substance reaches macrophages and fights the HIV infection present in such cells. This makes it possible to reliably enhance the effects of these drugs. encapsulated in liposomes Analogues of the phosphorylated nucleosides convert this into a pre-phosphorylated antiviral nucleoside. As a CID, we believe that drugs that would otherwise greatly limit the antiviral activity of the drug itself. , by bypassing enzymologically defective steps in macrophages. This can further enhance the antiviral efficacy of the formulation (43).

The present invention provides 1. phosphorylation of nucleoside analogs before encapsulation into liposomes. If converted into a conductor, the leakage of said similar substances from liposomes would be significantly reduced. Based on the discovery that Conversion of nucleoside analogs to their respective phosphate derivatives This not only prevents the leakage of similar substances from liposomes, but also prevents HIV It is thought that it also increases the efficacy of similar substances against macrophage cells infected with available. As mentioned above, nucleosides are used to attach to a growing DNA or RNA strand. Prior to conjugation, it is phosphorylated to the triphosphate form. Macrophages are Oxynucleoside kinase activity is decreased and phosphorylates nucleosides It is known that the ability to Therefore, free nucleosides Analogs (i.e. non-phosphorylated analogs), e.g. AZT, dideoxycytidine , or dideoxyadenine is effective against HIV present in macrophage cells. However, it does not have any particular medicinal value (43). However, the link of the present invention Oxidized analogues can be administered using liposomal delivery systems. caused by the absence of deoxynucleoside kinase activity in clophages. It is more effective because it bypasses metabolic barriers.

For the features of the invention discussed above, and its attendant advantages, please refer to the detailed description below. I believe that by looking at it, you will understand it more deeply.

Detailed rope friend explanation The present invention basically relates to phosphoric acid, which is intended for use in the treatment of viral infections. Encapsulation of antiviral nucleoside analogues into liposomes It's bad. The present invention provides a wide range of treatments that can be used to treat various viral infections. Although the application of nucleoside analogues is open, the explanation below is limited to acquired Immunodeficiency syndrome (AIDS) and related retroviral infections, e.g. related syndrome (ARC), asymptomatic infection due to HIV-1, HIV-2, and and HTLV-1 or HTLV-2 malignant (lymphoma) or neurological (tropical spasms) This shall be done regarding the treatment of patients suffering from the complications of paralysis (sexual paralysis).

Human immunodeficiency virus (HIV: formerly called HTLV-II [/LAV)] is the epidemiological agent of AIDS. According to estimates from serological surveys, 197 More than a million Americans have died since the virus was introduced to the United States in the late 2000s. It is believed that he was infected. To date, as many as 2 million people in the United States have been infected. It is assumed that there may be. The majority of these seropositive individuals are asymptomatic Although most, if not all, are persistently infected, Therefore, they constitute a reserve army of potential transmitters of infection. I wonder if these individuals lymphadenopathy and other symptoms are observed in the area of the body, and a small number (several percent per year) The disease progresses to AIDS, which has a long prognosis. Currently, this minority number is 35 in the United States alone. ,000 Å or more, and the number is doubling almost every year.

At the cellular level, HIV infects CD4 (T4) helper lymphocytes. , leading to the death of these cells. host by a decrease in CD4 helper lymphocytes. are vulnerable to well-known and endemic opportunistic infections and malignancies. HIV is 1 10 between the viral surface glycoprotein (gpHO) and the CD4 antigen of lymphocytes. binds to its CD4 receptor by forming a species complex (32.32 ). The virus was then removed by pretreatment of cells with NH, CI and amantadine. As suggested by the finding that productive infection is blocked by It is thought to enter cells by cis. With the assumed endosomal membrane After acid-mediated fusion, the viral reverse transcriptase and RNA reach the cytoplasm. The genetic material of the virus eventually reaches the genome of the cell. Ya by Yarcho-an and Broder. As described in a recent review (33), HIV replication has potential targets for therapeutic intervention. There are at least nine stages.

At present, inhibition of viral reverse transcriptase is the most promising antiretroviral therapy. showing the way.

Recently, it has been demonstrated that cells other than CD4 helper lymphocytes can be infected with HIV. There is (28, 29.30). The virus is present in B cells, promyelocytes, and monocytes. It has become clear that it can be replicated. Also, mononuclear phagocytes isolated from brain and lung HIV is latent in the human body, and normal peripheral blood macrophages are present in large numbers. It has also been shown that they produce viruses. Furthermore, human alveolar macrophages HIV is latent in brain macrophages as well, and the virus is present in these cells. The cytopathic effect of RUs is similar to that observed in HIV-infected helper 14928 bulbs. lower than that. HIV-infected macrophages and monocytes are virus reservoirs. This is the mechanism by which the virus persists and spreads in infected hosts. It has been proposed that this is possible (29.30).

The present invention utilizes the affinity of macrophages for liposomes as a means of transport. antiviral nucleoside analogues encapsulated in liposomes are For phages, monocytes, and any other infected cells that can take up liposomes. It is what we are trying to reach. Additionally, nucleoside analogues prior to encapsulation Phosphorylation of proteins provides the following benefits: That is, 1) nucleoside 2) The leakage of similar substances from liposomes is prevented, and 2) macrophages are released. The metabolic barrier associated with the inability to phosphorylate nucleosides is overcome. Ru. Finally, encapsulation of phosphorylated nucleosides into liposomes can enzymes such as alkaline phosphatase, phosphogesterase, or Essential for preventing hydrolysis of phosphate esters by 5°-nucleotidases. There are many things that can be mentioned.

The nucleoside analog is 3°-azido-3′-deoxythymidine (azidothymidine). 2°, 3°-dideoxycytidine (i.e. AZT), 2°, 3°-dideoxycytidine (dideoxycytidine) sine, i.e. ddC), 2°, 3°-dideoxyadenosine (dideoxyadenosine denosine (i.e. ddA), rivaviran, or any other suitable Any class of drugs known to be used in the treatment of AIDS, including oxynucleoside analogues. Similar substances are also possible. AZT is a preferred analog.

Similar substances can be prepared using conventional methods, such as Toorchen and Topal. (T.

This is phosphorylated according to the phosphorus oxychloride method of Pal) (34). preferred modification A similar substance is 5°--phosphate. AZT and other dideoxynucleotides Since only 5゛-hydroxyl group exists in osside, during phosphorylation, 5°--only phosphate is formed. Alternatively, 5°--phosphate nucleoside Dothioesters are also effective. Antiviral nucleosides diphosphate and triphosphate Phosphate analogs are also effective, but these di- or triphosphate analogs - They tend to be more unstable than phosphates and are gradually hydrolyzed in aqueous solutions to form − There is a possibility of reversion to phosphate derivatives.

After phosphorylation, the nucleoside analog is encapsulated in liposomes. capsule The process can be performed using well-known liposome encapsulation methods such as sonication and extrusion. You can do this according to: Suitable conventional capsule formation methods include pan Gum et al. (18), Olson et al. (39), Szoka and Papahadjapoulos (40), Mayhew et al. (41) Kim et al. (42), Mayhew et al. Mayer et al. (36) and Fukunaga et al. (35). There are methods that have been announced, but the method is not limited to these.

Liposomes are made from natural sources, such as phospholipids produced from eggs or animals or plants. For example, phosphatidylcholine, phosphatidylethanolamine, phosphatidyl ruglycerol, sphingomyelin, phosphatidylserine, or phosph Any conventional synthetic or natural phospholipid liposomes, such as atidylinositol It can also be manufactured using aluminum materials. Furthermore, as synthetic phospholipids, For example, simyristoylphosphatidylcholine, dioleoylphosphatidylcholine Dipalmitoylphosphatidylcholine, Distearoylphosphatidylcholine dilauroyl phosphatidylethanolamine, dimyristoyl phosphatide Dipalmitoylphosphatidylethanolamine, Dipalmitoylphosphatidylethanolamine, Geo Leoylphosphatidylethanolamine, and distearoylphosphatidyl ethanolamine can also be used. Other additives, e.g. Terols, or other sterols, glycolipids, cerebrosides, gangliosides, Fingolipids, glucopsychosine or psychosine, are also commonly known as can be added. If desired, the phospholipids used in the liposomes and the relative amounts of additives can be varied. The preferred range is phospholipid about 80-99 mol% and 1-20 mol% psychosine or other additives. Ru. Cholesterol can be used in a range of 0 to 50 mol%. Li The relative amount of antiviral nucleoside analogs encapsulated in the posomes The concentration of anti-anthropoietic substances in the aqueous compartment of the soma ranges from about 0.001 to about 300 mmol. You can vary this within a range.

To administer phosphorylated nucleoside analogs encapsulated in liposomes to patients, Any known method utilized for administering posomes may be used. buffered aqueous solution and Liposomes can be administered intravenously, intraperitoneally, or intramuscularly. . without disrupting the liposome structure or encapsulating phosphorylated nucleosides. Any pharmaceutically acceptable buffered aqueous solution may be used as long as it does not impair the activity of the compound. can also be used. An example of a suitable buffered aqueous solution is one with a pH of about 7.4. , there are 150 mmol NaCl containing 5 mmol of the sodium salt of phosphoric acid. However, other physiologically buffered saline solutions can also be used.

The dosage may vary according to the extent of the infection and its severity. can. Regarding the administered concentration of encapsulated phosphorylated nucleoside analogues: , so that approximately 0.001 to 1,000 μg/kg body weight is administered to the patient daily. must be done.

Below is an example demonstrating the reduction in leakage of phosphorylated nucleoside analogues from liposomes. Shown below.

[”Initial investigation using H1 thymidine and [14C]thymidine-5°--phosphoric acid was carried out. of 28.6 x 106 DPM dissolved in 2.0 ml of RPMI buffer. [8H cothymidine, and 2,5x106 DPM [! 4C] Thymidine-5°- - Phosphoric acid ([”C]TMP) of egg phosphatidylcholine and cholesterol Add to thin film (2:1 molar ratio). After swelling by vortexing for 10 minutes, the suspension were subjected to ultrasonication for 20 minutes, and then treated with cephalic acid as described in the paper by Fukunaga et al. (35). Pass through a column of wallose 4B. multilamellar vesicles (MLV) and small unilamellar vesicles ( Table 1 shows the DPM (and %) of each compound encapsulated in the SUV. M.L.V. In ["CITMP, 11% was retained, whereas in ["H] Only 0.1% of the amount is retained. In SUv, 5% of [”C]TMP is sealed. whereas only 0.4% of [lH]thymidine is encapsulated.

The above MLV and SUV were placed in an Amicon ultrafiltration cell. When concentrated to a small volume, 86-87% of CITMP is retained in liposomes. In contrast, only 18-21% of [”H]thymidine is retained. . In the end, only 0.02-0.09% of the total [”H]thymidine is retained. On the other hand, [1'C]TMP is maintained at 0.9 to 4.3%. Eventually [1 The fact that 50 times more TMP is retained in liposomes than [”H ] Thymidine is probably encapsulated because it diffuses rapidly across the lipid bilayer. It shows that it is impossible.

Labeled A according to the phosphorus oxychloride method (34) of Tolchen and Topal. ZT-5°--phosphoric acid ([”H]AZT-MP) was prepared. 20 nmoles of A ZT (260 microcuries) is dried in the presence of nitrogen. Phosphate trime Add 20 μm of chill and 4 μm of triethylamine, and cool the mixture to -10°C. do. 4 μm of phosphorus oxychloride is added and the mixture is allowed to react at -10° C. for 30 minutes.

The reaction is stopped by adding an equal volume of 0.5 molar aqueous triethylamine solution.

Altex product number tube C18 Ultrosphere O. D-nis (Ultrosphere-High performance liquid using OD4゜column) According to the determination using chromatography (HPLC), AZT has more than 90% The yield was converted to AZT-MP.

The obtained ['H]AZT-MP was treated in the same manner as in the case of [14C cothymidine phosphate. and encapsulated in liposomes, then labeled free AZT ([”H]A Leakage was tested against ZT). The test results are shown in Table 2. [”H]AZT is Only 0.2% was encapsulated in liposomes, whereas [”H]AZT-M 3.8% of P was encapsulated. This is similar to [”H]thymidine (Table 1). , [”H]AZT is extracted from liposomes when isolated on a Sepharose 4B column. It shows that it spreads to In contrast, [2H]AZT-MP is easily sealed. entered. That is, 3.8% of the total amount was recovered in the liposome fraction; [''This is a 19x increase over the encapsulation percentage of HIAZT.

In cultured MT-2 and U937 cells and human macrophages, The effect of liposomal d-phosphate on HIV replication was tested as follows. Ta.

27 mg of cholesterol and egg phosphatidyl by rotary evaporation in vacuo A thin film consisting of 110 mg of choline was prepared, and 60 f nomoles of AZT-MP and 6 mmoles of choline were prepared. Add 1 liter of RPMI medium containing [''H]AZT-period of Ikrokiyuri. , the mixture was heated for 20 min at 20°C and then vortexed at 10 psi [ "H] AZT-MP-containing ML and V are produced.

Lipex Extruder: Canadian yellowtail Lipex Biomembranes, Vancouver, Columbia, Tisch Extrusion molding manufactured by Lipex Biomembranes, Inc. using a machine with a diameter of 100 mm using the method of Mayer et al. (36). Prepare small unilamellar vesicles (EVloo). This method uses two layers of polycarbonate. Natefilter [Nucleopore, Pleasanton, California, USA] Based on the extrusion molding of large multilamellar vesicles by passing through Ku.

The resulting liposome formulation was passed through a 1 x 15 cm column of Sepharose 4B, and R Elute using PMI buffer. EVloo containing [”H]AZT-MP The liposomes elute into the void volume and the free [3H] drug returns to the salt volume of the column. will be collected. Under these conditions, 14.3% of [”H]AZT-MP was encapsulated. It was. Using more phospholipids per unit volume of buffer and freezing and thawing It is possible to achieve even higher encapsulation efficiency by repeating (36).

MT-2 and U937 cells growing in the plate used for ELISA , adding EV100 liposomes containing [”H]AZT-MP at various concentrations, AZT-MP and AZT were added to the other recesses of the plate. After 3 days, fine Regarding the cell degeneration effect (CPE), the number of cells per well is 6x105. ). The results of the CPH evaluation are shown in Table 3.

Table 3 Experiment No. 8725 Effect of liposomal AZT-MP on HIV replication in MT-2 cells. 7th day rear.

P.E. Drug amount/concavity Free Liposome A Liposome B 2 o; o o; o o :.

O, 2o; o, o; o o;.

0.02 4+4+ 3+; 0 0; 00.002 4+; 4+ 4+; 4 + o;.

0.002 4+; 4+ 4: 4+ 4+; 4+ control group without drug, 4+4+; Displays such as CPE, i.e., cytopathic effects. In RPMI medium, Mayer et al. [”H]AZT-phosphate-containing liposomes were prepared using method (36), and the pooled The AZT- MP was quantified. HIV-infected MT- in RPMI medium containing 10% fetal bovine serum. Add [”H]AZT-MP-containing liposomes to 2 cells to make a final volume of 0.200. It was set as m1. Liposome A contains 67 mol% egg phosphatidylcholine and 33 mol% % cholesterol, Liposome B contains 6.6 mol% psychosine, 60 mol% egg phosphatidylcholine and 33.3 mol% cholesterol Created using. The evaluation of CPH is based on the paper by Haertle et al. This was done as described in (44). In this system, 1+ means 1 per recess. Corresponds to ~3 syncytia (giant cells). 2+ is 3 to 10 per recess 2 syncytia, also corresponding to up to 20% cell death. 3+ means 1 recess This corresponds to 10-30 syncytia per day and a 20-70% decrease in cell viability. Accordingly, 4+ means 30 or more syncytia per recess and at least 70 syncytia. % reduction in the number of viable cells (44).

Similarly, 6x105 U937 cells growing on an ELISA plate were infected with HIV. Inoculated. As described above, A by AZT, AZT-MP, and liposomes ZT-MP was added to the culture solution.

After 4 days of growth, the cell supernatant was removed and diluted 1:100. dupont ELISA The device (Dupont ELISA System) (product number No. HIV gp24 was assayed using EK-041). The results are shown in Table 4. .

Table 4 Effect of liposomal AZT-MP on HIV replication in U937 cells gp24 antigen, pg/ml Lipid amount/recess Drug amount/recess Free Liposome A Liposome B 2.72 2 ．． 0 1,050 30 300.86 0,63 1.200 30 300 ．． 27 0.20 3.450 30 300.086 0.063 2,85 0 30 300.027 0.020 3,500 850 300.008 6 1-- ] AZT-MP-containing liposomes were prepared as in Table 1, and 10% HIV-infected U937 cells in 0.200 ml of RPMI medium containing fetal serum. Added this. Liposome A contains 67 mol% egg phosphatidylcholine and 33 mol% egg phosphatidylcholine. Liposome B contains 6.6 mol% of cholesterol. 60 mol% egg phosphatidylcholine, and 33 mol% cholesterol. is included. Results are the average of duplicate tests.

Cultured human cells according to the method used for IT-2 cells and 0937 cells. The effect of liposomal AZT--phosphate on clophages was also determined. Results first It is shown in Table 5.

Table 5 Effect of liposomal AZT-MP on HIV replication in cultured human macrophages effect gp24 antigen, pg/mi Lipid amount/concave area Drug amount/concave area Free Liposome A Liposome B micromol Nanomol AZT AZT-MP AZT-MP20.0 2,016 n, d, n, d.

6.3 1,844 n, d, n, d.

2.72 2.0 2,524 30 300.86 0.63 2.480 30 300.27 0.20 2.116 30 1600.086 0.0 63 2.172 30 300.027 0.02 On, d, 30 220 n, d, = not measured. Egg phospha containing [”H]AZT-MP at the stated concentration Liposomes of tidylcholine were prepared as in Table 1 and I added this to the phage. After 3 days of culture, supernatants were assayed for gp24. Li Posome A contains 67 mol% egg phosphatidylcholine and 33 mol% cholesterol. Liposome B contains 66 mol% psychosine and 60 mol% egg. Contains phosphatidylcholine, and 33 mole% cholesterol.

The following examples have been added.

[” Egg phosphatidylcholine and cholesterol containing HIAZT-MP (2:1) liposomes (100 nanometers in diameter) were extruded by Mayer et al. It was prepared in RPMI culture medium using the molding method (36), and using Sepharose 4B. 3H in the void volume peak obtained by gel permeation chromatography The amount of encapsulated [”H]AZT-MP was measured using the count number of . Varying amounts of AZT-MP were added to determine the effect on HIV-infected cells using Dupot. Quantify the production of the HIV antigen gp24 using a complete set of ELISA assay tools. It was judged by this. Create two types of liposomes and combine them into liposomes. A1 and liposome B.

Liposome A contains 67 mol% egg phosphatidylcholine and 33 mol% cholesterol. Liposome B contains 6.6 mol% psychosine, 60 mol% Contains egg phosphatidylcholine (P), and 33 mol% cholesterol. Ru.

The test results are shown in Table 6.

Table 6 Effect of liposomal AZT-MP on HIV replication in U937 cells gp24 antigen, ng/ml PC amount/recess area Drug amount/recess area Free Liposome A Liposome B 4.6 2. 0 2,740 60 600.46 0.2 3.120 78 600.0 46 0.02 5,060 2,140 1.3530.0046 0.00 2 4,460 2,120 13.2900.00046 0.0002 1 0,910 13,100 13.9800 0 (15,420) - Liposome AZT-M prepared for testing against U937 as described in Table 6 P was also used against HIV-infected human macrophages. As mentioned above regarding Table 6 The test was carried out in the same manner as above and the results shown in Table 7 were obtained.

Table 7 Effect of liposomal AZT-MP on HIV replication in human macrophages PC amount/recess area Drug amount/recess area Free Liposome A Liposome B 4.6 2. 0 2,016 30 300.46 0.2 1.872 30 300.0 46 0.02 2,268 30 490.0046 0.002 2J32 2,084 1,6320.00046 0.0002 2,248 1,7 32 1.3160.000046 0.00002 2,800 1,448 1.7440 0 2.276 Having described the preferred embodiments of the present invention, those skilled in the art will appreciate the If so, only examples are disclosed here, and within the scope of the present invention, It must be noted that various other alternatives, adaptations and modifications may be made. stomach. Accordingly, the present invention is not limited to the specific embodiments described herein, but is is limited only to the scope of the claims.

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international search report ””””””””””1111I” PCT/LIS88103210

Claims (29)

[Claims] 1. For use in the treatment of acquired immunodeficiency syndrome and related retroviral infections A composition intended for the purpose of A composition comprising a cid-like substance and a pharmaceutically acceptable carrier thereof. . 2. Nucleoside analogues include azidothymidine, dideoxycytidine, and dideoxycytidine. The composition of claim 1 selected from the group consisting of cyadenosine and ribaviran. thing. 3. The phosphorylated nucleoside analog is a 5'-phosphate derivative of azidothymidine. The composition according to claim 2. 4. A phosphorylated nucleoside analogue is the 5′-phosphate of dideoxyadenosine. The composition according to claim 2, which is a derivative. 5. Phosphorylated nucleoside analogs induce the 5′-phosphate of dideoxycytidine. The composition according to claim 2, which is a conductor. 6. The phosphorylated nucleoside analog is the 5'-phosphate derivative of ribaviran. The composition according to claim 2. 7. Liposomes contain phosphatidylcholine, phosphatidylethanolamine, Phosphatidylglycerol, sphingomyelin, phosphatidylserine, Sphatidylinositol, dilauroyl phosphatidylcholine, dimyristoy Ruphosphatidylcholine, dioleoylphosphatidylcholine, dibalmitoyl Phosphatidylcholine, distearoylphosphatidylcholine, dilauroylpholine Sphatidylethanolamine, dimyristoylphosphatidylethanolamine dibalmitoylphosphatidylethanolamine, dioleoylphosphatide dilethanolamine, and distearoylphosphatidylethanolamine Produced using at least one phospholipid selected from the group consisting of A composition according to claim 1. 8. Liposomes contain cholesterol, glycolipids, cerebroside, gandarioside, selected from the group consisting of sphingolipids, glucopsychosine, and psychosine; 8. The composition according to claim 7, further comprising an additive. 9. The liposome contains about 80-99 mol% egg phosphatidylcholine and about 1-99 mol% egg phosphatidylcholine. 9. The composition of claim 8, consisting essentially of 20 mol% psychosine. 10. Phosphorylated nucleoside analogs induce 5′-phosphate of azidothymidine. The composition according to claim 9, which is a body. 11. The composition of claim 1, wherein the pharmaceutically acceptable carrier is a buffered aqueous solution. 12. Acquired Immune Deficiency Syndrome and Associated Retroviral Infections in Mammals A method for treating phosphorylated nucleotides encapsulated in liposomes, the method comprising: a pharmaceutically acceptable amount of a combination of a cid analogue and a pharmaceutically acceptable carrier thereof; A method of treatment comprising the step of administering a composition to said mammal. 13. Nucleoside analogues such as azidothymidine, dideoxycytidine, dideoxycytidine, The treatment according to claim 12, selected from the group consisting of oxyadenosine and ribaviran. Treatment method. 14. Phosphorylated nucleoside analogs are derived from the 5′-phosphate of azidothymidine. 14. The method of treatment according to claim 13, wherein the method is applied to the body. 15. A phosphorylated nucleoside analogue is added to the 5'-phosphorus of dideoxyadenosine. 4. The method of treatment according to claim 3, wherein the method is an acid derivative. 16. The phosphorylated nucleoside analogue is converted into 5′-phosphate of dideoxycytidine. 14. The therapeutic method according to claim 13, wherein the method is a derivative. 17. A phosphorylated nucleoside analogue is used as a 5′-phosphate derivative of ribaviran. The treatment method according to claim 13. 18. Liposomes, phosphatidylcholine, phosphatidylethanolamine , phosphatidylglycerol, sphingomyelin, phosphatidylserine, Phosphatidylinositol, dilauroyl phosphatidylcholine, dimyrist Ilphosphatidylcholine, dioleoylphosphatidylcholine, dibalmitoy Ruphosphatidylcholine, distearoylphosphatidylcholine, dilauroyl Phosphatidylethanolamine, dimyristoylphosphatidylethanolamine dibalmitoylphosphatidylethanolamine, dioleoylphospha Tidylethanolamine, and distearoylphosphatidylethanolamine The therapeutic method according to claim 12, wherein the method is produced using a phospholipid selected from the group consisting of Law. 19. Liposomes contain cholesterol, glycolipids, cerebrosides, and gandariosides. , sphingolipids, glucopsychosine, and psychosine. 19. The therapeutic method according to claim 18, further comprising an additive. 20. The liposome contains about 80-99 mol% egg phosphatidylcholine and about 1-99 mol% egg phosphatidylcholine. 20. The treatment according to claim 19, consisting essentially of up to 20 mol% psychosine. Method. 21. Phosphorylated nucleoside analogs are derived from the 5′-phosphate of azidothymidine. 21. The method of claim 20, wherein the treatment method is to treat the body. 22. 13. The method of treatment according to claim 12, wherein the pharmaceutically acceptable carrier is a buffered aqueous solution. . 23. 13. The method of treatment according to claim 12, wherein the composition is administered intravenously to the mammal. 24. The concentration of phosphorylated nucleoside analogs encapsulated in liposomes is approximately 0. ．． 8. The composition of claim 7, wherein the amount is between 0.001 mmol and 300 mmol. 25. Encapsulation of phosphorylated nucleoside analogs into liposomes forming a phosphorylated nucleoside analog containing the encapsulated nucleoside; combining a phosphorylated nucleoside analog with a pharmaceutically acceptable carrier thereof; A method for producing a drug, comprising: 26. Phosphorylated nucleoside analogs, azidothymidine, dideoxycytidine 25. selected from the group consisting of , dideoxyadenosine, and ribaviran. Manufacturing method described. 27. Phosphorylated nucleoside analogs include trimethyl phosphate and triethyl phosphate. using a step in which a nucleoside analog is reacted with phosphorus oxychloride in the presence of 26. The manufacturing method according to claim 25, wherein the method is prepared by: 28. Phosphorylated nucleoside analogs are derived from the 5′-phosphate of azidothymidine. 27. The manufacturing method according to claim 26, wherein the method is a body. 29. Liposomes contain phosphatidylcholine and phosphatidylethanolamine. , phosphatidylglycerol, sphingomyelin, phosphatidylserine, Phosphatidylinositol, dilauroyl phosphatidylcholine, dimyrist Ilphosphatidylcholine, dioleoylphosphatidylcholine, dibalmitoy Ruphosphatidylcholine, distearoylphosphatidylcholine, dilauroyl Phosphatidylethanolamine, dimyristoylphosphatidylethanolamine dibalmitoylphosphatidylethanolamine, dioleoylphospha Tidylethanolamine, and distearoylphosphatidylethanolamine 26. The product according to claim 25, which is produced using a phospholipid selected from the group consisting of Construction method. The composition according to claim 1, wherein the nucleoside analog is a diphosphate derivative. The composition according to claim 1, wherein the nucleoside analog is a triphosphate derivative.