JPS6251617A - Vidarabin gel ointment - Google Patents

Abstract

PURPOSE:The titled gel ointment, obtained by incorporating a vidarabin with a local anesthesia, carboxyvinyl polymer which is a viscosity increasing agent, lower alcohol, neutralizing agent and water in a specific proprtion, readily handleable and having improved feeling of use, drug effect on herpes zoster, etc. CONSTITUTION:A vidarabin gel ointment obtained by incorporating 0.05-1wt% (expressed in terms of vidarabin) vidarabin expressed by the formula with 0-10wt% local anethesia, 0.1-5wt% carboxyvinyl polymer, 5-30wt% wetting agent, e.g. PEG, 5-50wt% 1-3C lower alcohol, neutralizing agent for adjusting pH and water in an adequate amount. The ointment is characterized in that the carboxyvinyl polymer is used as the gelling and viscosity increasing agent. The oingment has more improved feeling of use and percutaneous absorbability than the conventional oily ointment, and can be effectively used for local diseases, e.g. herpes zoster, labial herpes, etc., with good storage stability.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a topical aqueous gel ointment containing Vidarabine, which is effective in treating, for example, herpes zoster, herpes labialis, and the like.

[Background of the invention]

Vidarabine is an antiviral agent that has a strong growth-inhibiting effect on DNA viruses such as herpes simplex virus, varicella zoster virus, cytomegalovirus, vaccine virus, and adenovirus, and has the following chemical structure.

H Vidarabine undergoes phosphorylation within cells, and Ara-A
After passing through MP and Ara-ADP, it becomes Ara-ATP.

It is speculated that this Ara-ATP exerts its antiviral effect by strongly inhibiting DNA-dependent DNA polymerase, which is a replication enzyme for viral genes.

Vidarabine is used to treat various diseases caused by the aforementioned DNA viruses, such as chickenpox, herpes zoster (herpes zoster), herpes labialis,
It is known that it can be effectively used to treat genital herpes, stomatitis, tonsillitis, corneal herpes, etc.

Vidarabine is usually administered internally as an injectable preparation such as a single intravenous drip, and as an external preparation, the oil-based ointment previously published by the present inventors (Yakuji Shinpo No.

1305, 11.1984) is known.

[Purpose of the invention]

An object of the present invention is to provide a vidarabine external aqueous gel ointment that is easy to handle and has excellent usability and medicinal efficacy.

[Summary of the invention]

The present invention comprises 0.05-1% by weight of Vidarabine or its pharmaceutically acceptable salt (as Vidarabine), 0-10% by weight of a local anesthetic, 0.1-5% by weight of a carboxyvinyl polymer, and a humectant. 5-30% by weight,
5 to 50% by weight of lower alcohol having 3 or less carbon atoms, and p
i (invention of a vidarabine gel ointment consisting of a neutralizing agent for conditioning and an appropriate amount of water).

Vidarabine used in the present invention is usually used by dissolving its free form in various acids, or by using its pharmaceutically acceptable water-soluble salts, such as salts of mineral acids such as hydrochloric acid, sulfuric acid, and nitric acid. Or acetic acid, citric acid.

It is used as a salt of organic acids such as methanesulfonic acid and fumaric acid. The amount used is usually 0.05 to 1% by weight, preferably 0.1 to 0.5% by weight as free vidarabine; more than 1% causes problems in terms of solubility; If the amount is less than .05%, sufficient medicinal efficacy will not be exhibited.

In the present invention, examples of local anesthetics used for the purpose of pain relief and analgesic effect through antihistamine action, if necessary, include lidocaine, chloropropylene, tetracaine, mebipacaine, propitocaine, and pubivacaine. Typical examples include hydrochloric acid and other water-soluble salts such as dibucaine, and lidocaine, tetracaine, mebivacaine, and dibucaine are particularly preferably used. The blending amount is usually 0 to 10% by weight.

If necessary, in addition, antihistamines such as diphenhydramine, chlorpheniramine, antipruritic agents such as crotamiton, or preservatives such as alkylparabens, benzalkonium chloride, cetylpyridinium chloride, chlorhexidine, etc.) There is no problem even if an effective amount is mixed.

The most important role in the aqueous gel ointment of the present invention is the carboxyvinyl polymer used as a gelling thickener; However, the same effect as the present invention cannot be obtained. That is,
When using other thickeners instead of carboxyvinyl polymer, such as polyvinyl alcohol, polyvinylpyrrolidone, non-crosslinked sodium polyacrylate, methylcellulose, sodium alginate, etc., these agents have strong woody stickiness. However, since the thickening effect is low, it is necessary to add a relatively large amount of the solid base material, and the solid base material remains in the form of a solid residue on the skin surface after use. This may cause inconvenience such as

The reason why carboxyvinyl polymer is particularly effective as a gelatinizing thickener in the aqueous gel ointment of the present invention is that it does not have excessive stickiness and has strong thixotropic properties.
It is easy to apply and develop on the skin, has a smooth and non-sticky feel, and also has good retention of the drug on the skin. Furthermore, although the reason for the good transdermal absorption of drugs has not yet been fully elucidated, it is thought that the film-forming ability of carboxyvinyl polymers may have some effect.

Specific examples of the carboxyvinyl polymer used in the present invention include Hibisfuco-103 and Hibisfuco-104 manufactured by Wako Pure Chemical Industries, Ltd. Same 105° Same 106. Same 20
4. Product name: Carpo Ball 807, manufactured by Gutsudoritsu. Same a
tO, 334. 940. 941° Trade name: Shunron PW 110, manufactured by Nikki Junyaku ■. Same PW 111. Same F
Cross-linked polyacrylic acid such as W 150 is a typical example, but it goes without saying that it is not limited to these, and its blending amount is usually 0.1 to 5%.
Preferably it is 1 to 5%; if the concentration is too low, there will be no effect, and if the concentration is too high, the gel will become too hard, which is not preferred.

The humectant used in the present invention may be any one that imparts moisturizing properties to the stratum corneum of the skin and facilitates the permeation and absorption of herbal medicines, such as propylene glycol, diethylene glycol, glycerin, 1. Typical examples thereof include harmless polyols such as 3-butylene glycol and nrubitol, among which propylene glycol is particularly preferably used. The blending amount is usually 5 to 30%, preferably 10 to 20%, and if it is too small, it will be difficult to achieve the purpose, and if it is too large, it will be meaningless and cause a sticky feeling, so it is not preferable.

In the present invention, the lower alcohol having 3 or less carbon atoms used for the purpose of providing a refreshing feeling and mild anesthetic to the skin and alleviating patient pain and promoting transdermal absorption of herbal medicines is ethanol. , n-propatol, 1so-propatol, and other harmless lower alcohols, among which ethanol is particularly preferably used. Its blending amount is usually 5 to 50%, preferably 10 to 40%, and 5 to 50%.
If it is less than 50%, it will be difficult to achieve the objective, and if it exceeds 50%, the degreasing and dehydrating effects will be strong, causing problems such as rough skin, which is not preferable.

As a neutralizing agent for pH adjustment, ammonia water is usually preferably used, but it is not limited to this, and for example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. Harmless organic amines such as triethanolamine, diisopropanolamine, and triethylamine, as well as bases such as basic amino acids, can be used similarly. The amount to be used is appropriately increased or decreased depending on the concentration of the carboxyvinyl polymer, the vidarabine salt, or the acid used to dissolve the vidarabine, and the desired pH.

The water used in the present invention is preferably distilled water from the viewpoint of pharmaceuticals, and the amount used is determined appropriately depending on the amount of other ingredients, and it is extremely fluid.

The pH of the aqueous gel preparation of the present invention may range from pH 3 to 12 without any particular problem in its medicinal efficacy or as an aqueous gel ointment. Or its salts have good solubility at pH 4~
A range of 7 is preferably used.

The method for preparing the aqueous gel ointment of the present invention is roughly as follows.

That is, for example, when using water-soluble salts of vidarabine, dissolve it as is in an appropriate amount of distilled water (when using the free form of vidarabine, first dissolve it in an appropriate acid such as dilute hydrochloric acid or dilute sulfuric acid). (After that, add distilled water to adjust the liquid volume.) Next, add a certain amount (part of the predetermined amount) of carboxyvinyl polymer little by little while stirring, and if necessary, leave it for a day and night and then stir further. Disperse and dissolve thoroughly. Separately, the remaining carboxyvinyl polymer is added little by little to a predetermined amount of wetting agent under stirring, and in the same manner, if necessary, it is left to stand overnight and further stirred to prepare a solution in which it is sufficiently dispersed and dissolved. To the latter, add a solution in which a predetermined amount of local anesthetic is dissolved in a predetermined amount (a portion of the predetermined amount) of lower alcohol and mix. After stirring, mix the former uniformly, and then add the remaining lower alcohol to make a sufficient solution. Stir 0 Then, when neutralizing by gradually adding a neutralizing agent to this, the viscosity increases rapidly,
The appearance of the gel becomes colorless and transparent. Finally, add distilled water to adjust the liquid volume.

The thus obtained aqueous gel ointment of the present invention is extremely stable, and even after one year of storage at room temperature, there is no change at all from the time of preparation, no phase separation occurs, and there is no decrease in medicinal efficacy due to decomposition of the crude drug. do not have.

The aqueous gel ointment of the present invention is effective in treating various diseases caused by DNA viruses as described above, such as chickenpox, herpes zoster (herpes zoster), herpes labialis, genital herpes, stomatitis, tonsillitis, and corneal herpes. It can be expected that it can be used for

Since the aqueous gel ointment of the present invention is an external preparation, its therapeutic effect is more direct than that of an injection, and unlike injections, great care must be taken to prevent contamination with pyrogenic substances. It is very easy to handle and you don't have to pay anything.

The aqueous gel ointment of the present invention is easy to handle because there is less risk of spillage or scattering than other external preparations such as liquid preparations, and when applied to affected areas, it retains well on the skin surface, and , a film is formed by solvent evaporation, and the herbal medicine is immobilized on the trunk wound surface. In addition, it has a superior feel (feels smooth) compared to oil-based ointments, and is therefore more suitable for its purpose.

Compared to the oil-based ointment previously disclosed by the present inventor, the aqueous gel ointment of the present invention shows good results even at a low vidarabine concentration of 0.15 to 0.3%, and has a higher transdermal absorption rate. It has been proven in terms of clinical efficacy that it is clearly superior to oil-based ointments. Because vidarabine is completely dissolved in the gel in the form of water-soluble salts such as hydrochloric acid and sulfuric acid, it is more easily absorbed into the skin than conventional formulations in which the crystalline form is dispersed and mixed in an ointment base. One of the reasons for this is thought to be that alcohols promote skin permeation of drugs, and local concentration of herbal medicines due to solvent evaporation are also thought to be contributing factors.

Examples are given below, but the present invention is not limited in any way by these Examples.

〔Example〕

Example 1 300 mg of vidarabine was added to 0. After completely dissolving in 8 g (equimol) of IN hydrochloric acid, add distilled Honduri 75- (or dissolve the said equivalent amount of solid soluble salts of pre-synthesized vidarabine in distilled water of 8B-), While stirring, Hibiswako-104 (carboxyvinyl polymer:
Add 3 g of Wako Pure Chemical Industries (trade name) little by little and leave it for day and night (solution ■). Separately, 30 g of propylene glycol
Add 1g of Hibiswako 104 little by little while stirring.
Similarly, it was left overnight (solution ■), and to solution ■, a solution of 8 g of lidocaine (local anesthetic) dissolved in 3 fligs of ethanol was added, and solution ■ was evenly mixed with this, and then 20 g of ethanol was added and stirred thoroughly. Next, 12 g of 5% aqueous ammonia was gradually added to neutralize the gel. At this time, the viscosity rapidly increased and the appearance of the gel became colorless and transparent. Finally, distilled water was added to bring the total amount to 200 g.

The aqueous gel ointment obtained here has excellent stability, can be stored at room temperature, and does not undergo phase separation even after being stored at room temperature for one year.
In addition, there were no oral changes such as decomposition of the herbal medicine, and there was no problem in using it as an external gel ointment. In addition, when the aqueous gel ointment obtained here was applied to the affected area of a herpes zoster patient, the feeling of use and the appearance after application were both good. It has been shown that its transdermal absorption rate is clearly better than that of oil-based ointments from the point of view of clinical efficacy.

Example 2 Clinical Examples Using Vidarabine Gel Ointment Three clinical examples using the vidarabine gel ointment obtained by the preparation method of Example 1 are shown below.

1 bed fLll Patients: 46 females Disease name or symptoms: Facial herpes zoster with erythema in the trigeminal nerve region Small vesicles after using Vidarabine gel ointment:

(11th to 14th, complete recovery in 1 ward) Patient 2, male, 58 years old Disease name or symptoms: Herpes labialis After using Vidarabine gel ointment Patient 2, female, 60 years old Disease name or symptoms: Right chest herpes zoster in the intercostal nerve area Vidarabine gel ointment After use: [Effects of the invention] As described above, the present invention provides a method for effectively using vidarabine, an antiviral agent that has been used only as an injection, as an external preparation for local diseases caused by herpes. The range of indications is expanded, and by using the vidarabine gel ointment of the present invention, the following effects can be obtained.

(1) Since it is applied directly to the affected area, the action is more direct and faster.

(2) For example, for patients with extensive lesions seen in herpes zoster, the usability of external preparations is an important issue.
By using the gel ointment of the present invention, ease of application to the affected area is improved, and an excellent feeling of use is obtained, such as the cooling sensation provided by the alcohol.

(3) Depending on the degree of pain, the amount of local anesthetic can be adjusted to increase the effectiveness of Bain Clinic.

(4) Compared to oil-based ointment, vidarabine concentration is 0.15 to 0.
A good effect was observed even at a low concentration of 3%, and the patent applicant: Wako Pure Chemical Industries, Ltd. Procedural Amendments November 2, 1985 Commissioner of the Patent Office Mr.'-゛1, Indication of Case 1985 Patent Application No. 191160 No. 2, Name of the invention Vidarabine Gel Ointment 3, Relationship with the person making the amendment Patent applicant: 541 Address: 3-10 Domine-cho, Higashi-ku, Osaka-shi, Osaka Contact information: Patent Division (Tokyo) 03-270- 8571 Spontaneity 5, column for detailed description of the invention in the specification subject to amendment.

6. Contents of the amendment (1) "Not necessarily" written on page 5, line 5 of the specification is amended to "necessarily".

(2) "It is more purposeful." written on page 11, line 3 of the specification is amended to "It is more purposeful."

that's all

Claims (1)

[Claims] Vidarabine or a pharmaceutically acceptable salt thereof 0.05-1% by weight (as vidarabine),
Local anesthetic 0-10% by weight, carboxyvinyl polymer 0.1-5% by weight, wetting agent 5-30% by weight, lower alcohol having 3 or less carbon atoms 5-50% by weight, and neutralizing agent for pH adjustment. , as well as a suitable amount of water.