WO2004069261A1

WO2004069261A1 - Process for producing antiherpesvirus preparation for external use

Info

Publication number: WO2004069261A1
Application number: PCT/JP2003/001047
Authority: WO
Inventors: Masaichi Yamamoto; Haruhiko Machida
Original assignee: Arigen, Inc.
Priority date: 2003-02-03
Filing date: 2003-02-03
Publication date: 2004-08-19
Also published as: JPWO2004069261A1

Abstract

A process for producing an antiherpesvirus preparation for external use which contains as an active ingredient a 5-[(E)-2-halogenovinyl]arabinofuranosyluracil represented by the following general formula (I), characterized in that in any one or more of steps for incorporating the active ingredient into a base, heating is conducted at a reduced pressure. In the formula (I), X represents halogeno. This process yields an external-use preparation which is an antiherpesvirus preparation having high antiherpesvirus activity and, despite this, is excellent in safety and stability.

Description

Description Method for producing anti-herpesvirus external preparation

The present invention relates to a method for producing an external preparation for anti-herpes virus which exhibits strong anti-herpes virus action and is excellent in safety and stability. Background art

Herpes virus is a DNA virus that has a double-stranded DNA genome, an icosahedral capsid, and an envelope derived from the host cell nuclear envelope. There are six typical herpesviruses that are pathogenic to humans: ① simple herpesvirus 1 (HSV-1) ② simple herpesvirus 2 (HSV-2) ③ varicella Herpes zoster virus (VZV) ③ Ebstein-Barr virus (EBV) ④ Cytomegalovirus (CMV) ⑤ Human virus 6 type. Herpesviridae virus infects the human body first, then latently infects. When the host person becomes immunocompromised, it is reactivated and becomes morbid (relapse). In other words, the primary infection is an exogenous infection from the host that has the virus and the environment (ice-infection-vertical infection), and the recurrent disease is an endogenous infection from within itself. In particular, the varicella-zoster virus hides in ganglia and is reactivated when the host's immune system is compromised, causing painful rashes and herpes (shingles) along the ganglia. Herpes infections tend to increase with aging, stress, and an increase in the number of AIDS patients, and are a major social problem.

Few drugs have been put into practical use as anti-herpes virus drugs, and at present, acyclovir, vidarabine, ganciclovir, etc. are used as anti-herpes virus drugs.

Japanese Patent Publication No. 57-48160 describes that 5-[(E) -2-halogenovinyl) arabinofuranosylperacyl has antiviral activity, and among them, 1--D-arabinofuranosyl- 5-[(E) -2-bromovul] peracyl (generic name: soribudine) has excellent antiviral activity, especially against HSV-1, EBV and VZV. This Was launched in Japan in 1993 under the brand name Youthville Tablets, but since it was developed as an oral drug, patients who co-administered with a fluorouracil-based anticancer drug died due to side effects due to the interaction. It was a big problem. Subsequent studies indicate that the mechanism of this interaction is that bromobulperacyl (BV D), a metabolite of sorivudine, inhibits the metabolism of fluorouracil-based anticancer drugs, resulting in abnormally elevated blood levels of fluorouracil-based anticancer drugs. However, it was found that severe bone marrow suppression such as leukopenia and thrombocytopenia, which are side effects of this anticancer drug, was caused.

Sorivudine is known to show a very strong anti-herpesvirus effect in the in Vro test compared to other anti-herpesvirus agents. In addition, it has been reported that application to the skin suppressed the skin symptoms caused by inoculation of herpes virus type I (Antiviral Research, 21, 47-57, 1993). However, 5-[(E) -2-halogenovinyl] arabinofuranosylperacyl, which contains soribudine, is hardly soluble. Therefore, ointment is applied in a usual manner using a conventional base used in external preparations. It has been difficult to produce stable external preparations such as olive oil and juru. Therefore, no consideration has been given as to whether these compounds can be used as effective and safe external preparations, and their interaction with fluorouracil drugs. Disclosure of the invention

Although sorivudine is known to have a very strong anti-herbal effect in in vitro studies, it is not used at present because oral administration causes the serious side effects described above. An object of the present invention is to provide 5-[(E) -2-halogenovinyl) arapinofuranosyl-dilacil containing sorivudine, while maintaining a strong anti-herpesvirus effect, and interacting with a fluorouracil-based anticancer agent. An object of the present invention is to provide a method for producing a topical virus virus preparation that is highly safe and does not exhibit side effects.

Oral administration of drugs requires large doses to reach the target site of the drug, and oral administration of sorivudine is also used in large doses. Therefore, most of the drug once absorbed from the intestine is excreted via the kidneys into the urine, but a part is excreted via the liver into the intestine, where it is treated by intestinal bacteria with bromovinylperacyl (BVD). Is metabolized and reabsorbed. BVD reabsorbed is a metabolic enzyme of fluorouracils Inhibits certain dihydropyrimidine dehydrogenase (DPD), which inhibits the metabolism of fluorouracils and increases toxicity.

The inventor of the present invention has found a method for producing an external preparation for using sorivudine or the like as an external preparation as a result of intensive studies, and the external preparation obtained in this way is used for herpes virus, particularly varicella-zoster virus (VZV). The present inventors have found that the present invention can effectively suppress the growth of BVD, prevent the production and reabsorption of BVD in the intestinal tract, and avoid the interaction with a fluorouracil-based anticancer agent.

The present invention relates to a method for producing a preparation for external use of anti-herpesvirus comprising 5-[(E) -2-halogenovinyl) arabinofuranosylperacyl represented by the following general formula (I) as an active ingredient. The present invention relates to the above-mentioned production method, characterized by comprising heating under reduced pressure in any one or more of the steps for blending into the base.

In the above formula, X represents a halogen atom.

In the above formula (I), X is preferably a bromine atom or a chlorine atom.

The present invention also relates to an external preparation for anti-herpes virus containing 5-[(E) -2-halogenovinyl) arabinofuranosylperacyl obtained by the above-mentioned production method as an active ingredient.

Hereinafter, the present invention will be described in detail.

The 5-[(E) -2-halogenovinyl) arabinofuranosylperacyl represented by the general formula (I) used in the method of the present invention for producing an external preparation for anti-herpes virus, The compound described in Japanese Patent Publication No. 57-48160 (US Pat. No. 4,386,076) has a potent anti-herpesvirus action, particularly a selective inhibitory action against VZV. In addition, the growth inhibitory effect on cells not infected with the virus is extremely low. This compound can be synthesized by a known method, for example, the method described in the above publication, or a method analogous thereto. As an example of the synthesis method, there is a method in which a halogen is reacted with 5-bularabinofuranosylperacil. The synthesis of 5-vinylarabinofuranosylperacil used is described in, for example, The Pharmaceutical Society of Japan, 1999 Abstracts of the meeting, p. 213, 30C10-2.

—R in the general formula (I) represents a halogen atom such as chlorine, bromine, iodine, or fluorine, and a compound in which R is a bromine atom. 1- / S-D-arabinofuranosyl-5- [(E) -2-buguchi mobul) Peracyl (generic name: sorivudine), and compounds where R is a chlorine atom, 1-^-D-arabinofuranosyl-5-[(E) -2 -Black mouth bur) Peracil (hereinafter referred to as 5-chloroara U) is preferably used.

Next, the compound of the above general formula (I) is made into an external preparation together with a suitable pharmaceutically acceptable base. As the base, any base commonly used in the manufacture of external preparations can be used.However, a base with less irritation or pain during application is selected for use in patients with abnormal skin such as shingles. I do. The form of the preparation may be any form such as an ointment, cream, jule, cataplasm, plaster, patch and the like. In the production method of the present invention, the active ingredient 5-[(E) -2-octogenobul) arabinofuranosyl peracyl may be added to one or more of the steps for blending in the base. And heating under reduced pressure.

When manufacturing ointments, creams and joules, an oil base or emulsion base may be used as a base. In the production of an ointment, for example, the above-mentioned active ingredient or active ingredient is mixed with a base such as propylene glycol and the like under a reduced pressure by heating, stirring and mixing with an oily base. As an example of the preparation of a cream, the above active ingredient dissolved in a base such as propylene glycol under heating under reduced pressure is heated under reduced pressure in a previously prepared emulsion base. Added. For example, a joule agent is prepared by dissolving a joule base in water, adding a hydrophilic organic solvent, and gradually dissolving the active ingredient in a base such as dipropylene glycol under heating under reduced pressure. It can be manufactured by adding. For plasters, patches, and cataplasms, plasters containing active ingredients obtained by a method similar to the above method are spread on a support such as a nonwoven fabric or woven fabric, and cut into appropriate sizes. Can be manufactured.

Examples of the oily base that can be used in the present invention include oils and fats, waxes, hydrocarbons, fatty acids, alcohols, alkyl glyceryl ethers, esters, silicone oils, fluorine oils, and polyhydric alcohols.

As fats and oils, vegetable and animal fats and oils can be widely used. Vegetable oils include olive oil, safflower oil, persic oil, cucumber oil, wheat germ oil, rice bran oil, rice germ oil, evening primrose oil, high oleic sunflower oil, macadamia nut oil, meadow home oil, and the like. Animal oils include tallow, hardened oil, and egg yolk fatty oil.

Waxes are mainly composed of esters of higher fatty acids and higher alcohols (wax esters). The carbon number of the ester is widely used as C12-C34. Animal systems include lanolin, whale wax, beeswax, shellac wax, and liquid orange roughy oils, and plant systems include carnaupa wax, candelillaro 'ゥ, and liquid jojoba oil.

Examples of the hydrocarbon include chain hydrocarbons, and liquid paraffins, which are mixtures of various hydrocarbons, branched paraffins, solid paraffins, and serine. Fatty acids include natural and synthetic fatty acids, and include, for example, raperic acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, isostearic acid, 12-hydroxystearic acid, pendecylic acid, and the like.

Alcohols include, for example, higher alcohols of about C8 to C32, i.e., cabrilyl alcohol, capryl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, peryl alcohol, behyl alcohol, seryl alcohol, Laxeryl alcohol and the like. Animal and plant sterols can also be used.

Examples of the alkyl glyceryl ether include batyl alcohol, chimyl alcohol, seraky alcohol, and isostearyl glyceryl ether.

Esters are compounds obtained by the dehydration reaction of fatty acids and alcohols. Esters of linear fatty acids with lower alcohols include ethyl oleate, isopropyl myristate, butyl stearate, etc. Esters of linear fatty acids with linear higher alcohols are cetyl palmitate and myristin. Acid myristyl and the like. Esters of linear fatty acids and higher branched alcohols include octyldodecyl myristate and octyldodecyl oleate. Esters of linear fatty acids and polyhydric alcohols include triglycerides of medium chain fatty acids. Examples of the ester of a branched fatty acid and a lower alcohol include isopropyl isostearate and butyl isostearate. Examples of the ester of a branched fatty acid and a higher linear alcohol include cetyl 2-ethylhexanoate and 2-ethylhexanoic acid. Stearyl is mentioned. Examples of the ester of a branched fatty acid and a straight-chain higher alcohol, and the ester of a branched fatty acid and a branched higher alcohol include isosetyl isostearate and octyldodecyl dimethyloctanoate. In addition, examples of the ester of hydroxycarboxylic acid and alcohol include myristyl lactate, trioctyldodecyl citrate, diisostearyl phosphate, and the like.

Examples of silicone oil include dimethyl silicone oil, methylphenyl silicone oil, cyclic dimethyl silicone oil, methyl hydridone silicone oil and modified silicone oil, and examples of fluorine oil include perfluoropolyether .

Examples of polyhydric alcohols include ethylene glycol, diethylene glycol, triethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, glycerin, diglycerin, polyglycerin, 3-methyl-1,3-butanediol. , 1,3-butylene glycol and the like.

Emulsifiable bases that can be used in the present invention include 0 / W bases, W / 0 bases and suspending bases. As the 0 / W base, components such as lanolin, propylene glycol, stearyl alcohol, petrolatum, silicone oil, liquid paraffin, glyceryl monostearate, etc. in the aqueous phase in the presence or absence of a surfactant The W / 0 base is prepared by emulsifying and dispersing components such as serine, higher fatty acid alcohol, and liquid paraffin with water in the presence of a nonionic surfactant. Is mentioned. In the above formulation, fatty acid monoglyceride, Polyoxyethylene nonionic surfactants such as polyhydric alcohol esters such as rubitan fatty acid esters, sucrose and polyglycerin fatty acid esters, polyoxyethylene derivatives of aliphatic alcohols, and polyoxyethylene derivatives of fatty acids; Can be used. Examples of the suspendable base include an aqueous base formed by adding glycerin, carboxymethylcellulose, carboxylic acid polymer, water and the like to form a gel. For the production of plasters and patches, support for nonwoven fabrics and other materials, natural rubber, polyisobutylene, butyl rubber, polyvinyl alkyl ether, polyacrylate, polyurethane, polyamide, acrylate, acrylate copolymer, An elastic material such as polybutylene rubber or the like, a tackifier such as polyterpene resin, rosin or an ester thereof, or the like may be used, and various fillers, release agents, softeners and the like may also be blended.

For the preparation of cataplasms, a support such as nonwoven fabric, pectin, polyacrylic acid or a salt thereof, polybutyl alcohol, polybutylpyrrolidone-butyl acetate copolymer ', polyethylene oxide, carboxymethylcellulose, hydroxypropyl Bases such as cellulose, methylcellulose, alginate, xanthan gum, tragacanth gum, methylbutyl ether, and maleic anhydride copolymer can be used. Examples of the adhesive include synthetic polymer compounds such as carboxyvinyl polymer and the like and natural polymer compounds such as gum arabic and xanthan rubber. Examples of the surfactant include polysorbate 80 and sorbitan sesquioleate. As the pH adjuster, citric acid, tartaric acid or the like can be used, and as the curing agent, a polyvalent metal compound such as zinc oxide or aluminum hydroxide can be used.

In addition, various antioxidants can be used to enhance the stability in the formulation. Specifically, vitamin E, nordihydroguaiarenic acid, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), propyl gallate, erythorbic acid, sodium erisorbate, ascorbyl palmitate, and ascorbyl stearate And the like. Further, preservatives such as paraoxybenzoic acid, methylparaben, ethylparaben, and propylparaben, and perfumes may be added.

Since this product is used for patients infected with herpes simplex virus herpes zoster virus, etc., it is possible to prevent the skin from drying out, especially by adding a moisturizer. Polyhydric alcohol for moisturizer , Sugars, biopolymers, etc. can be used. Examples of polyhydric alcohols include glycerin propylene glycol, 1,3-butylene glycol, polyethylene glycol, sorbitol, isoprene glycol, P0E methyl glucoside, and the like. Examples of the saccharide include trehalose, pullulan, and maltose.Examples of the biopolymer include sodium hyaluronate, sodium chondroitin sulfate, collagen, and elastin.Others include amino acids, sodium lactate, and sodium pyrrolidone carbonate. Examples include lium and urea. Further, as an anti-inflammatory agent, aminocarboxylic acid, glycyrrhizic acid, monoglycyrrhetinic acid, lysozyme chloride, hydrocortisone and the like may be blended.

According to the production method of the present invention, the compound of the above-mentioned general formula (I) having a strong anti-Herwirs virus action, which is also proved by Δη vitro, is used as an active ingredient, and as shown in the following examples, in V 1 vo kinetics "Experiment 1" can also provide an anti-herpesvirus external preparation that can exert an anti-virus virus action. It is possible to avoid the interaction with fluorouracil-based drugs, which is a problem in the above, and there is no skin toxicity, therefore, it can be used as a safe and effective therapeutic agent for herpes virus infection, especially Its strong selective inhibitory effect on varicella-zoster virus allows effective treatment of herpes zoster.

The dose of the external preparation obtained according to the present invention varies depending on age, disease state, sex, days after onset, etc., but preferably 1 to 100 mg / _kg per day as the compound of the general formula (I) as an active ingredient. Weight. As a method of administration, a composition containing 0.1 to 10%, particularly 0.5 to 5%, of the compound of the formula (I) is applied to a lesion on the skin of a patient once to several times a day. Is preferred. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a diagram showing the results of tests on the antiviral effect of the external preparation obtained by the present invention using a mouse skin infection model. BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited thereto.

[Example 1]

500 g of glyceryl monostearate (5) glycer, 30 g of methylpolysiloxane, 150 g of cetanol, 50'0 g of paraffin, 900 g of petrolatum, 50 g of glyceryl monostearate, and 5 g of BHT5, and heated to 75 ° C under reduced pressure, Stir to obtain a homogeneous solution. A solution obtained by mixing and dissolving 5.565 L of purified water and 300 g of propylene glycol is added thereto, and the mixture is emulsified by heating and stirring under reduced pressure. To this, 500 g, 300 g, and 100 g of sorivudine and propylene glycol, 1.5 g, 1.7 g, and 1.9 kg, respectively, are heated at 75 ° C under reduced pressure, and the dissolved solution is gradually added. The solution was cooled to room temperature with stirring to obtain 10 kg of cream preparations of 5% (formulation No. 1), 3% (formulation No. 2), and 1% (formulation No. 3) of soribidine.

A solution prepared by dissolving 300 g of 5-chlorovinylara U and 1.7 kg of propylene glycol in a preliminarily prepared emulsion as described above in place of sorivudine as the main component while heating at 75 ° C under reduced pressure at 75 ° C. Was gradually added in the same manner as above to obtain 10 kg of a 5-chlorovinylara U 3% cream preparation (Formulation No. 4).

[Example 2]

2 kg of white petrolatum and 6 kg of liquid paraffin were dissolved with stirring at 75 ° C. To this solution, 300 g of sorivudine and 1.7 kg of propylene glycol were heated at 75 ° C under reduced pressure, stirred and mixed to obtain 10 kg of a 3% sorivudine ointment preparation (Formulation N0.5).

[Example 3]

Dissolve uniformly 200g of carboxyvinyl polymer and 20g of methylcellulose in purified water. Further, 4 kg of PEG 1500, 25 g of titanium dioxide and 25 g of EDTA are added. To 300 g of sorivudine, 3.5 kg of dipropylene glycol and 500 g of P0E oleyl alcohol ether are added under reduced pressure and dissolved by heating at 50 to 55 ° C, and then 250 g of preservative paraben is added. This is gradually added while stirring the previously prepared aqueous phase. Finally, add 10 ml of an aqueous solution of potassium hydroxide for neutralization and mix well,

(Formulation N0.6) 10 kg was obtained.

[Example 4] Propylene glycol lkg 100 g of sorivudine and 50 g of polysorbate 80 are mixed by stirring under reduced pressure so as to be uniform. Separately, 1.5 g of glycerin, 500 g of titanium dioxide, and 500 g of sodium polyacrylate are mixed, and 6.15 kg of purified water and 200 g of citric acid are added to this solution, and the mixture is heated and dissolved at 50 to 55 ° C under reduced pressure to obtain a uniform solution. Solution. The solution prepared above is gradually added to this solution, and the solution is heated and dissolved at 50 to 55 ° C. under reduced pressure to obtain a sorivudine-containing plaster having a pH of 5. Next, this was spread on a piece of cloth, and the plaster surface was covered with a storage film and cut into a predetermined size to obtain a poultice containing 1% sorivudine (formulation No. 7).

[Test Example 1]

Using the cream obtained in Example 1 in a mouse skin infection model of HSV-1 (Uichi et al., Antiviral Research, 21, 47, 1993), the appropriate efficacious concentration of this formulation was determined as follows. Was observed.

At 6 weeks of age, male Balb / c mice were tested.The right half of the body was shaved under Nembutal anesthesia. did. HSV-1 WT-51 strain was applied to the abraded area. The drug was applied four times a day for 7 days using a cotton swab 16 hours after virus inoculation, including the site of virus inoculation, to the area where a band-like lesion might appear. The mice were observed for life and death for 20 days. As a positive control, Zovirax (trade name of acyclovir) 5% ointment was used (NO. 8). For placebo, a formulation (NO. 9) was prepared from the formulation of Example 1 except for sorivudine. As a result of the test, the effect of 3% or more of sorivudine was confirmed to be equal to or better than that of the commonly used zovirax 5% ointment (Figure 1 and Table 1). In addition, no dermal toxicity was observed in any of the preparations, which proved to be safe. Table 1 Formulation name Number of onset / total number of survivors / total number of average surviving days

No. 1 (Soribudine 5%) 2/10 10/10 ―

No. 2 (Soribudine 3%) 3/10 10/10 ―

No. 3 (Soribudine 1%) 6/10 5/10 10.3

No. 8 (Zovirax 5%) 3/10 10/10 ―

No. 9 (Placebo) 10/10 0/10 7.5 [Test Example 2]

Sorivudine 3% cream formulation (NO. 2) obtained in Example 1 and 5-Chlorovinylara U 3% cream formulation (NO. 4), sorivudine 3% ointment (NO. 5), and the sorivudine 3% gel agent (NO. 6) obtained in Example 3 and the poultice agent (NO. 7) obtained in Example 4 as a fluorouracil-based drug, 5-FU. The presence or absence of interaction with was observed. For external preparations, female rats of the Wsitter series were preliminarily reared for one week, then shaved from the scapula to the lumbar region under anesthesia, and the preparations were applied to the portions three times a day for 7 days.

As a result of the test, in the positive control group in which sorivudine was orally administered and 5-FU was used, significant body weight loss and side effects of bone marrow suppression due to the interaction occurred, but the topical formulation of the present invention (soribudine or 5- The combined use of Chlorovinylara U topical formulation) and 5-FU was one or ^four ! (Table 2).

Table 2

*: 5-FU was administered at 60 mg / kg (p.o.) in both the single dose group and the drug combination group.

Administered for 7 days.

**: Pre / 7d; before study / 7 days after administration

The red blood cell count and white blood cell count indicate the measured values 7 days after administration. Industrial applicability

ADVANTAGE OF THE INVENTION According to the manufacturing method of the anti-herpes virus external preparation of the present invention, it is possible to obtain an external preparation having a high anti-herpes virus activity, and being safe and excellent in stability. This topical formulation, while maintaining excellent anti-herpes' virus activity, can avoid the interaction of sorivudine with fluorouracils, which was a problem with oral drugs, especially in the form of varicella. Effective for the treatment of herpes.

Claims

The scope of the claims

1. This is a method for producing an external preparation for anti-herpes virus comprising 5-[(E) -2-halogenovinyl) -arabinofuranosyl-racil represented by the following general formula (I). The method according to any one of the preceding claims, comprising heating under reduced pressure in one or more of the steps for blending the active ingredient into the base.

X represents a halogen atom.

2. The method according to claim 1, wherein in the general formula (I), X is a bromine atom or a chlorine atom.

3. An active ingredient comprising 5-[(E) -2-halogenovinyl) -arapinofuranosylperacyl, which is obtained by the production method according to claim 1 or 2.