JPH07109221A - Remedial combination - Google Patents

Abstract

PURPOSE: To obtain a mutation inducing HIV-RT inhibitor useful for improving or maintaining antiviral receptivity to zidovudine of HIV population. CONSTITUTION: This mutation inducing inhibitor of a human immunodeficiency virus reverse transcriptase(HIV-RT) induces mutation of a methionine residue at the position 184 to be substituted with a valine residue or an isoleucine residue in a sequence encoding a reverse transcriptase(RT). An antiviral oxathiolane nucleoside, preferably (-)-2',3'-dideoxy-3'-thiacytidine, (-)-2',3'- dideoxy-5-fluoro-3'-thiacytidine may be cited as the inhibitor. In order to treat or prevent HIV infection, especially zidovudine-resistant HIV infection, a therapeutic combination of zidovudine or its physiologically mobile derivative and a mutation inducting HIV-RT inhibitor is used so as to improve or maintain the antiviral receptivity of HIV population against zidovudine by the inhibitor.

Description

Detailed Description of the Invention

[0001]

This invention relates to zidovudine (zido).
vudine) and a drug having the effect of increasing the antiviral activity of zidovudine against the human immunodeficiency virus (HIV) population resistant to attack by zidovudine.

[0002]

2. Description of the Related Art Zidovudine has a chemical name of 3'-azido-
3'-Deoxythymidine, a treatment or prevention of HIV infection including related clinical conditions such as acquired immunodeficiency syndrome (AIDS), AIDS-related complex (ARC), asymptomatic HIV-infected patients or anti-HIV. It is now established as an important and useful chemotherapeutic drug for the treatment of antibody-positive patients.

With widespread clinical use of zidovudine in the treatment of such infections and conditions, after prolonged treatment, the virus develops a certain level of resistance to zidovudine and thus a loss of sensitivity to this drug. It has been recognized that there are some cases in which it occurs.

Other anti-HIV chemotherapeutic agents have been proposed and investigated, but most of these agents do not have the efficacy and safety of zidovudine. Among these agents are non-nucleoside inhibitors of various HIV reverse transcriptases that have been found to have useful anti-HIV activity in vitro. In contrast to nucleoside inhibitors, these compounds need not be phosphorylated in vivo in order to exert their inhibitory effect, but by their use they are resistant to the virus, that is to say that the virus is resistant to this compound. It has been found to rapidly induce a loss of viral susceptibility. Other agents include, for example, the nucleosides described in European Patent Specification No. 382526, especially (-)-2 ', 3'-dideoxy-3', also known as 3TC or lamivudine.
-Thiacitidine, and PCT patent specification WO 92/14
743, particularly having an oxathiolane residue in place of the sugar residue, such as (-)-2 ', 3'-dideoxy-5-fluoro-3'-thiacytidine, also known as FTC. Antiviral nucleoside analogs are included. These compounds can be prepared as described in the above patent specifications.

[0005]

DISCLOSURE OF THE INVENTION The present invention provides an anti-HI which is the development of resistance to zidovudine by HIV virus.
The challenge is to solve the problems faced by V-treatment.

[0006]

In particular, the present inventors have found that a sequence encoding reverse transcriptase (RT) (RT coding).
resistance to the HIV population by treating the virus population with an inhibitor of HIV reverse transcriptase (HIV-RT), which induces a mutation in which the methionine residue at position 184 is replaced by a valine or isoleucine residue. It has been found that the expression and persistence of H. pylori can be reduced or prevented, that is, the sensitivity of the HIV virus population to zidovudine can be increased. Hereinafter, such an inhibitor will be referred to as a "mutagenic HIV-RT inhibitor".

HIV inducing mutations of the type described above
Examples of -RT inhibitors include oxathiolane nucleosides of the type described above.

That is, according to the present invention, (a) a mutagenic HIV-RT inhibitor or a physiologically functional derivative thereof used for improving or maintaining antiviral susceptibility of HIV population to zidovudine; (B) A therapeutic combination for the treatment or prevention of HIV infection, in particular zidovudine resistant HIV infection, which comprises zidovudine or a physiologically functional derivative thereof, and mutagenic H.
A therapeutic combination comprising an IV-RT inhibitor, which enhances or maintains the antiviral susceptibility of the HIV population to zidovudine by said inhibitor; (c) an antiviral HIV population to zidovudine or a physiologically functional derivative thereof. A method of increasing or maintaining susceptibility, comprising contacting the population with an effective amount of a mutagenic HIV-RT inhibitor; (d) a HIV infection resistant to zidovudine. A method of treating a subject (e.g., a human) having the method, comprising administering to the subject a combination of zidovudine or a physiologically functional derivative thereof and a mutagenic HIV-RT inhibitor; (E) Mutagenesis for use in HIV treatment for HIV infections resistant to zidovudine HIV-
RT inhibitor; (f) A method for increasing the susceptibility of a HIV population resistant to zidovudine or a physiologically functional derivative thereof, wherein the virus is a mutagenic HIV-
Methods are provided that include treating with an RT inhibitor.

Improving or maintaining the susceptibility of the HIV population to zidovudine in a patient may be accomplished, for example, by observing the relative clinical efficacy of the drug and / or in a sample of the patient's appropriate biological material (eg plasma). It will be appreciated that conventional methods can be readily used, such as analytically measuring the level of the virus or its marker and / or determining in vitro antiviral susceptibility of the virus obtained from the patient in cell culture.

[0010] By the passage test in vitro,
It was found that HIV rapidly acquired resistance to oxathiolane nucleosides such as FTC and 3TC. Therefore, among the zidovudine resistant HIV strains,
4 mutation to V (M184 to V mutat
Ion) (HIVRTMC), F
Increased resistance to TC was obtained (IC ₅₀ value 0.6
(Increased from 4 μM to> 500 μM), whereas the virus became less resistant to zidovudine (IC ₅₀
The value was reduced from 1.26 μM to 0.17 μM). Y1
The 81-to-C (Y181 to C) mutation results in M1
When introduced into this zidovudine resistant virus with a 84 to V mutation, there was a more pronounced effect on the increased zidovudine sensitivity. Such mutant virus strains, which were now co-resistant to oxathiolane nucleosides and non-phosphorylated HIV-RT inhibitors, became completely sensitive to zidovudine (zidovudine). IC ₅₀ value for 1.26 to 0.0
4).

According to the invention, mutagenic HIV-
RT inhibitors are zidovudine resistant HI to zidovudine
It can be used to increase the antiviral susceptibility of the V population, or it can be used to maintain the antiviral susceptibility of HIV populations in which zidovudine resistance has not been induced.

Mutagenic HIV-RT inhibitors include 1
Inhibitors of HIV-RT that induce mutations in the RT-encoding sequence in which the tyrosine residue at position 81 is replaced by a cysteine, eg, non-phosphorylated HIV-RT inhibitors, ie, inhibition of HIV-RT, may occur For in
It may be used with inhibitors that do not need to be phosphorylated in vivo.

Specific examples of non-phosphorylated HIV-RT inhibitors which may be used with the present invention include:

A) For example, Pauwels
s) et al. Nature, 343, 4
70-474 (1990) and European Patent Specification No. 3
84522, tetrahydro-imidazo [4,5,1-jk] [1,4] -benzodiazepin-2 (1H) -ones and tetrahydro-imidazo [4,5,1-jk] [1. , 4] -Benzodiazepine-
2 (1H) -thiones (so-called "TIBO" derivatives).

Particularly preferred TIBO for use in the present invention
The derivative is "chloro-TIBO" cited above.
(R-82913).

B) For example, Merluzzi
i) et al., Science, 250,
Dipyridodiazepinones described in 1411-1413 (1990) and European Patent Specification No. 429987.

An example of this type of compound is nevirapine (ne
Virapine) (BI-RG-587), a compound known as 11-cyclopropyl-
5,11-Dihydro-4-methyl-6H-dipyrido [3,2-6: 2 ', 3'-e] [1,4] diazepin-6-one.

C) For example, Goldman
n) et al., Proc. Nat. Acad. Sci, 8
8, 6863-6867 (1991) and European Patent Specification No. 462800 (the so-called "L-drugs").

Examples of compounds of this type are L-697,63
9, ie 3-[[(4,7-dimethyl-2-benzoxazolyl) methyl] amino] -6-ethyl-6-methyl-2 (1H) pyridinone.

D) See, for example, Romero et al., Proc. Nat. Acad. Sci. , 8806-
8810 (1991) and International Patent Specification No. WO91 /
Bis (heteroaryl) described in 09849
Piperazines (so-called "BHAPS").

An example of this type of compound is U-87201, ie 1- [3- (ethylamino) -2-pyridinyl].
-4-[(5-Methoxy-1H-indol-2-yl) carbonyl] -piperazine.

E) Pr according to, for example, Baba et al.
oc. Nat. Acad. Sci. , 88, 2356-
2360 (1991) and European Patent Specification No. 42
5-Ethyl-6- (phenylthio) uracil derivatives described in 0763 (so-called "HEPT" compounds).

F) For example, European Patent Specification No. 5
The quinazoline derivatives described in 30994.

G) For example, Proc. Natl. Aca
d. Sci. 90, 1711-15, (1993), anilinophenylacetamide derivatives.

[0025] The HIV-RT inhibitor at position 184 is described, for example, in European Patent Specification No. 38252
6, nucleosides, especially (−)-2 ′, 3′-dideoxy-3′-thiacytidine, also known as 3TC or lamivudine, and PCT patent specification N.
o. The nucleosides described in WO92 / 14743, in particular known as FTC (-)-2 ', 3'-.
Included are antiviral nucleoside analogs having oxathiolane residues in place of sugar residues, such as dideoxy-5-fluoro-3'-thiacytidine. These compounds can be prepared as described in the above patent specifications.

A particularly preferred embodiment of the invention involves the use of a non-phosphorylated HIV-RT inhibitor and a position 184 mutagenic HIV-RT inhibitor such as lamivudine or FTC with zidovudine. These two types of H
By using a combination of IV-RT inhibitors, HIV
The population has a very significant effect in reducing or preventing the development and maintenance of resistance to zidovudine.

The term "physiologically functional derivative" of zidovudine means a pharmaceutically acceptable salt, ester or ester salt of zidovudine, or (directly or indirectly) zidovudine or a salt thereof when administered to a therapeutic object. By other compounds is meant an active metabolite or residue.

Preferred esters according to the present invention include straight or branched chain alkyls where the non-carbonyl portion of the ester group is, for example n-propyl, t-butyl, n-butyl, alkoxyalkyl (eg methoxymethyl), aralkyl (eg Benzyl), aryloxyalkyl (eg phenoxymethyl) and aryl (eg phenyl)
A carboxylic acid ester selected from: a sulfonate ester such as an alkyl or aralkylsulfonyl (eg methanesulfonyl); an amino acid ester (eg L-valyl ester or L-isoleucyl ester); a dicarboxylic acid ester (eg hemisuccinate) and a mono-, di- Alternatively, triphosphate ester and the like are included. Phosphate esters can also be used, for example, with C _1-20 alcohols or their reactive derivatives or with 2,3-di (C
_6-24 ) It may be esterified with acyl glycerol.

Advantageously, any alkyl moiety present in such an ester will have from 1 to 18 carbon atoms, especially from 1 to 4 carbon atoms. Advantageously any aryl moiety present in such an ester comprises a phenyl group optionally substituted by eg halogen, C _1-4 alkyl, C _1-4 alkoxy or nitro.

Pharmaceutically acceptable salts include, for example, alkali metal (eg sodium) salts, alkaline earth metal (eg magnesium) salts, ammonium and NX _4.
Salts of bases derived from suitable bases such as ⁺ (X is C _1-4 alkyl) are included. Pharmaceutically acceptable acid addition salts include acetic acid, lactic acid, tartaric acid, malic acid, isothionic acid, lactobionic acid.
id) and salts of organic carboxylic acids such as succinic acid; salts of organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid and hydrochloric acid, sulfuric acid, phosphoric acid and sulfamic acid. Such salts of inorganic acids are included.

Examples of viral infections and associated clinical conditions which can be treated or prevented according to the present invention include human retroviral infections such as HIV, eg HIV-1 or HIV-2 infections, eg HTLV. −
Human T cell lymphovirus (HTLV) such as I or HTLV-II infections. The combination of the present invention provides AIDS and AIDS-related complex (ARC), progressive systemic lymphadenopathy.
generalized lymphadenopath
y) (PGL), multiple sclerosis (multiples)
Clerosis) or local paresis (topica)
AIDS-related neurological conditions, such as thrombocytopenic purpura (thrombocy)
It is particularly useful for the treatment of AIDS-related clinical conditions such as anti-HIV antibody-positive and HIV-positive conditions such as topenic purpura). The combinations according to the invention can also be used for the treatment of psoriasis. It has been found that the combinations according to the invention have particular application in the treatment of HIV-related or HIV-induced diseases or subclinical infections.

According to the invention, the components of the combination according to the invention can be administered simultaneously or sequentially. However, in the latter case each component should be administered at short enough intervals to ensure an improved anti-virus sensitivity of the HIV population to zidovudine.

One of the advantages of the combination of the present invention is that it can treat subjects with zidovudine resistant HIV infection which would otherwise be excluded from such treatment with drugs.

Zidovudine and / or mutagenic HI
V-RT inhibitors may also be used in accordance with the present invention with other therapeutic agents for the treatment of the above infections or conditions. Examples of such additional therapeutic agents include 2 ', 3' such as, for example, 2 ', 3'-dideoxycytidine, 2', 3'-dideoxyadenosine and 2 ', 3'-dideoxyinosine.
-Dideoxynucleosides, carbo beer (carbo
vir), 2 ', 3'-didehydrothymidine, acyclic nucleosides (e.g., acyclovir)
ir), protease inhibitors such as RO 31-8959, cis-1- (2-hydroxymethyl) -1,3
-Oxathiolane-5-yl) cytosine (3TC) -like oxathiolane nucleoside analogues, interferons such as a-interferon, renal excretion inhibitors such as probenecid, nucleoside translocation inhibitors such as dipyridamole, and even interferons. Immunomodulators such as leukin II, granular macrophage colony promoting factor and erythropoietin (immummom
agents, phosphonoformic acid, soluble CD ₄ and their genetically engineered derivatives, which are effective in the treatment of HIV infection or related medical conditions. Each of the component compounds of such combination therapy may be administered simultaneously in separate or combined preparations, or may be administered at different time points such that the combined effects are achieved, such as sequential administration. Good.

The compounds used according to the invention can be administered to mammals in a conventional manner. As mentioned above, the components of the above combination may be administered simultaneously (eg in one unit pharmaceutical formulation) or separately (eg in separate pharmaceutical formulations). Generally, the combination can be administered topically, orally, rectally or parenterally (eg intravenously, subcutaneously or intramuscularly). It will be appreciated that these routes of administration may vary depending on, for example, the degree of condition being treated and the individuality of the recipient.

Accordingly, the mutagenic H of zidovudine (or a physiologically functional derivative thereof) used according to the invention.
The optimal molar ratio for the IV-RT inhibitor is 10: 1 to 1:10, preferably 1: 1 to 1: 5, most preferably 1: 3.

Hereinafter, each component of the combination of the present invention may be referred to as "active ingredient".

The dosage of each compound will depend on the condition being treated, other clinical factors such as the weight and condition of the subject and the route of administration of the components of the combination of the invention. Examples of dosage ranges and component ratios are as follows.

Generally, a suitable dose of zidovudine (or a physiologically functional derivative thereof) is in the range of 3 to 120 milligrams per kilogram of recipient weight per day, preferably the weight of recipients per day. 6 to 90 milligrams per kilogram, most preferably 10 to 30 milligrams per kilogram body weight of the recipient per day. The desired dose is preferably divided into 2, 3, 4, 5, 6 or more doses and administered at appropriate intervals during the day. These divided doses are, for example, in a total amount of 10 to 1500 mg, preferably 20 to 1000 mg, most preferably 50 to 700.
It may be administered in a unit dosage form, such as containing milligrams of active ingredient in a unit dosage form.

For non-phosphorylated HIV-RT inhibitors, the dose will depend on the particular inhibitor used, in addition to the factors mentioned above. However, in general, a daily dose of 0.1 to 100 mg / kg, for example 1 to 50 mg / kg, will be used. Preferred daily doses of the above compounds or compounds are 0.01 to 20, preferably 0.1 to 5 milligrams / kilogram for chloro-TIBO and 0.5 milligrams to 1 gram / gram for nevirapine. 1 to 20 mg / kg for L-697,639, U-8720
0.1 to 500 mg / kg, H
The EPT compound has a dose of 1 to 100, preferably 5 to 50 mg / kilogram.

With respect to the 184-mutated HIV-RT inhibitors such as the above-mentioned antiviral oxathiolane nucleosides, the daily dose for the compound described in European Patent Specification No. 382526 is 1 to 750 mg / kg. , Preferably 3 to 120 mg / kg, particularly preferably 6 to 90 mg / kg. PCT Patent Specification No. WO92 /
The daily dose of the compound described in 14743 is 0.1 to 100 mg / kg, preferably 1 to 50 mg / kg,
Particularly preferably, it contains 1 to 20 mg / kg.

While it is possible for the active ingredients to be administered alone, it is preferable to present them as a pharmaceutical formulation. The pharmaceutical formulation according to the invention comprises a combination according to the invention 1
Included with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. When each component of the combination of the invention is administered separately, they are generally provided as a single pharmaceutical formulation. Hereinafter, unless otherwise specified, the term “preparation” refers to a preparation containing the combination of the present invention or its constituent components. Formulations include oral, rectal, intranasal, topical (including transdermal, buccal and sublingual), vaginal,
Or suitable for parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such a method is
The step of combining the active ingredient with the carrier which constitutes one or more additional ingredients.

In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping. Formulations of the invention suitable for oral administration may be prepared as separate units, such as capsules, cachets or tablets, each containing a predetermined amount of active ingredient; water or non-aqueous liquid solutions as powders or granules or As a suspension
It can be provided as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or pasta.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets contain the active ingredient in a free-flowing form such as a powder or granules in a suitable device, optionally with a binder (eg povidone (pov)).
idone), gelatin, hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (eg sodium starch glycolate, crosslinked povidone, crosslinked sodium carboxymethylcellulose),
It can be prepared by mixing with a surfactant or dispersant and compressing. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be coated or grooved,
The active ingredients therein may also be formulated for slow or controlled release, for example using different proportions of hydroxypropylmethylcellulose to provide the desired release profile. The tablets may be enteric coated to allow release in parts of the gastrointestinal tract other than the stomach.

Formulations suitable for topical administration in the mouth usually include a lozenge containing the active ingredient in a flavored base such as sucrose, acacia or tragacanth; gelatin and glycerin, or Pastilles containing the active ingredient in an inert base such as sucrose and acacia; including mouthwashes containing the active ingredient in a suitable liquid carrier. Formulations for rectal administration may be presented as a suppository with a suitable base including, for example, cocoa butter or salicylate.

Topical administration may be performed using a transdermal iontophoresis device.

Formulations suitable for vaginal administration are pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known to those skilled in the art.

Formulations suitable for parenteral administration include isotonic sterilization which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended treatment. Aqueous and non-aqueous solutions of injections; sterile suspensions of water and non-aqueous which may include suspending agents and thickening agents; and designed to direct the compound to blood components or one or more tissues Liposomes or other microparticulate systems. The formulations may be presented in unit-dose or multi-dose form in a hermetically sealed container such as an ampoule or vial, immediately before using a sterile liquid carrier, such as water for injection. It can be stored in a lyophilized form so that it only needs to be added. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Preferred unit dosage formulations are those containing a daily dose or daily sub-dose, as herein above recited, or an appropriate fraction thereof.

The formulations of the present invention may contain further additives in addition to the ingredients particularly mentioned above, such as sweetening amounts, thickeners and flavoring agents in formulations suitable for oral administration. Thus, it should be understood that other ingredients conventional in the art can be included in view of the type of formulation desired.

Each compound of the combinations of the invention can be obtained by conventional methods. Zidovudine can be prepared, for example, as described in US Pat. No. 4,724,232. This US patent forms part of the present disclosure. Zidovudine is also commercially available from Aldrich Chemical Company of WI53233, Milwaukee, USA.
chemical Co. ).

The mutagenic HIV-RT inhibitor can be prepared according to the methods described in the references cited above relating to such inhibitors.

[0053]

The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way. By "active ingredient" is meant zidovudine and / or a non-sulphonylated HIV-RT inhibitor.

Example 1: Tablets The following formulations A, B and C were prepared by moistening the ingredients with a solution of povidone, followed by compression with magnesium stearate.

Formulation A mg / tablet Active ingredient 250 Lactose (British Pharmacopoeia (BP)) 210 Povidone (BP) 15 Sodium starch glycolate 20 Magnesium stearate 5 500 Formulation B mg / tablet Active ingredient 250 Lactose (BP) 150 avicel PH101 60 Povidone (BP) 15 Sodium starch glycolate 20 Magnesium stearate 5 500 Formulation C mg / tablet Active ingredient 250 Lactose (BP) 200 Starch 50 Povidone 5 Magnesium Stearate 4 359 The following Formulations D and E were prepared by direct compression of the mixed ingredients.

Formulation D mg / tablet Active ingredient 250 Pregelatinized starch NF15 150 400 formulation E mg / tablet Active ingredient 250 Lactose (BP) 150 Avicel 100 500 formulation F (controlled release formulation) This formulation is a component Was prepared by moistening it with a solution of povidone, adding magnesium stearate, and then compressing.

Mg / tablet Active ingredient 500 Hydroxypropylmethylcellulose 112 (Methocel K2M premium) Lactose (BP) 53 Povidone (BP) 28 Magnesium stearate 7 700 Drug release about 6 to 8 It occurs in time and is complete after 12 hours.

Example 2: Capsule Formulation Formulation A A capsule formulation was prepared by mixing the ingredients of Formulation D from Example 1 above and filling a hard gelatin capsule in two parts. Formulation B (below) was prepared in a similar manner.

Formulation B mg / capsule Active ingredient 250 Lactose (BP) 143 Sodium starch glycolate 25 Magnesium stearate 2 420 Formulation C mg / capsule Active ingredient 250 Macrogel 400 (BP) 350 600 Preparation of formulation C The capsule is Macrogel 4000 (BP).
Was prepared by melting, dispersing the active ingredient in the melt, and filling the melt in a two-part hard gelatin capsule.

Formulation D mg / capsule Active ingredient 250 Lecithin 100 100 Peanut oil 100 450 Formulation D capsules are prepared by dispersing the active ingredient in lecithin and peanut oil and filling the dispersion into soft elastic gelatin capsules. did.

Formulation E (Controlled Release Capsule) The following controlled release capsule was prepared by molding components a, b and c using an extruder, spheroidizing the extrudate and drying. The dried pellets were coated with a controlled release membrane (d) and filled into two-part hard gelatin capsules. mg / capsule (a) Active ingredient 250 (b) Microcrystalline cellulose 125 (c) Lactose (BP) 125 (d) Ethylcellulose 13 513 Example 3: Injection preparation Formulation A mg Active ingredient 200 0.1M hydrochloric acid solution Or, with 0.1 M sodium hydroxide solution, pH 4.0 to 7.0, sterilized water was added, and 10 ml of the active ingredient was dissolved in most of water (35 to 40 ° C.).
Is adjusted to 4.0-7.0 with hydrochloric acid or sodium hydroxide. The batch is made up to 10 ml with water and then placed in a 10 ml amber glass vial (type 1) through a sterile micropore filter and sealed with a sterile lid and overseal.

Formulation B Active Ingredient 125 mg Sterilized, Pyrogen Free, pH 7 with 25 ml of Phosphate Buffer Example 4: Intramuscular Injection Active Ingredient 200 mg Benzyl Alcohol 0.10 g Glycofurol 75 1.45 g Add Water for Injection 3.00 ml The active ingredient is dissolved in glycoflor. To this, benzyl alcohol is added and dissolved, and water is added to make 3.0 ml. The mixture is passed through a sterile microporous filter and then sealed in a sterile 3 ml amber glass vial (type 1).

Example 5: Syrup Active ingredient 250 mg Sorbitol solution 1.50 g Glycerol 2.00 g Sodium benzoate 0.005 g Flavor, peach 17.42.3169 0.0125 ml Purified water added 5.00 ml Active ingredient glycerol And dissolve in a mixture of most purified water. An aqueous solution of sodium benzoate is added to this aqueous solution, followed by the sorbitol solution and finally the flavor. Adjust the volume with purified water and stir well.

Example 6: Suppository mg / Capsule Suppository Active Ingredient 250 Hard fat (Witepsol H15-Dynamit Nobel) 1770 5/20 520 Witepsol H15 is melted in a steam jacketed pan at a maximum of 45 ° C. The active ingredients are passed through a 2001M sieve and mixed on the molten substrate using a Silverson equipped with a cutting head,
A smooth dispersion is obtained. The mixture is kept at 45 ° C. and the remaining Witepsol H15 is added to the suspension and stirred to make a homogenous mixture. 2501m for all suspensions
Pass through a stainless steel screen and continue to stir 40
Cool to ℃. At a temperature of 38 ° C to 40 ° C, 2.02 grams of this mixture is filled into a suitable 2 milliliter plastic mold. Allow the suppository to cool to room temperature.

Example 7: Pessary mg / Pessary Active ingredient 250 Anhydrous dextrose 380 Potato starch 363 Magnesium stearate 7 1000 A pessary is prepared by directly mixing the above ingredients and compressing the mixture directly.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical indication (C07D 411/04 239: 47 327: 04) (72) Inventor Brendan Alexander Ladder United Kingdom, B3, 3BES, Kent, Beckenham, South Eden Park Road, Langley Court (no address), The Welcome Foundation Limited (72) Inventor Sharon Down Kemp United Kingdom, Beer 3/3 Bees, Kent, Beckenham, South Eden Park Road, Langley Court (no house number), in The Welcome Foundation Limited

Claims (3)

[Claims] 1. A human immunodeficiency virus reverse transcriptase (HI)
V-RT), which induces a mutation in which a methionine residue at position 184 is replaced by a valine or isoleucine residue in a sequence encoding reverse transcriptase (RT). An inhibitor used to enhance or maintain the antiviral susceptibility of the human immunodeficiency virus (HIV) population zidovudine or a physiologically functional derivative thereof. 2. The inhibitor according to claim 1, which is an antiviral oxathiolane nucleoside. 3. The inhibitor according to claim 2, which is selected from (−)-2 ′, 3′-dideoxythiacytidine and (−)-2 ′, 3′-dideoxy-5-fluoro-3′-thiacytidine.